Drug News

Drug Safety Updates 2005

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Deaths reported with use of drug, Palatin asked to stop sales of Neutrospec

December 20, 2005

ST. LOUIS (MD Consult) - On December 19, 2005, the US Food and Drug Administration (FDA) issued a public health advisory to alert health care providers that the agency has requested the market withdrawal of the diagnostic imaging agent NeutroSpec (technetium-99m fanolesomab) pending review of reported deaths and serious and life-threatening adverse events associated with use of the product. The manufacturer, Palatin Technologies Inc, and marketing partner, Mallinckrodt, have agreed to implement an immediate voluntary market suspension, making the product unavailable for approved or investigational uses.

The adverse event reports submitted to the FDA as part of the agency's routine postmarket surveillance of all medical products revealed cases in which NeutroSpec caused hypersensitivity reactions within minutes of administration. These reactions led to the death of 2 patients and to cardiopulmonary failure, central nervous system reactions, and infusion reactions in other patients. Mallinckrodt, Palatin Technologies, and the FDA notified health care professionals of serious and life-threatening cardiopulmonary events related to Neutospec in correspondence dated November 30, 2005.

In premarket studies submitted to the agency as part of the drug's application for approval, NeutroSpec was administered to 523 patients. These studies revealed relatively few safety concerns. Most of the adverse events occurred in patients who were given the drug after approval on an off-label basis. All of the reactions occurred immediately after NeutroSpec was administered. There is no evidence that patients who already safely received the drug face any long-term risk.

NeutroSpec, a radiodiagnostic agent consisting of a murine immunoglobulin M monoclonal antibody formulated to be labeled with technetium, was approved for marketing in July 2004. The diagnostic imaging agent is administered intravenously to help diagnose appendicitis in patients 5 years of age and older with possible appendicitis who lack its conventional signs and symptoms. The FDA said the decision to suspend marketing was based on the life-threatening nature of the associated adverse events, the unpredictability of the reaction, and the availability of other means of diagnosing appendicitis that do not carry these risks.

The FDA urges health care providers to discontinue use of existing stocks of NeutroSpec and to contact Palatin Technologies regarding their return. The FDA is conducting further investigation into the deaths and adverse events associated with NeutroSpec. The agency is working closely with the manufacturers of the product to evaluate the risks and benefits associated with its use.

The FDA also plans to convene an advisory committee meeting in early 2006 to discuss the existing data about the risks and benefits of NeutroSpec, what additional safety measures can be taken with its use, and what indications may exist where benefits of the product are outweighed by the known risks. The FDA will notify health care providers and patients in a timely manner after further scientific investigation of adverse event reports.

For more information, including a link to the FDA's public health advisory, visit fda.gov/cder/drug/infopage/technetium99/default.htm.

To request more information or to report serious adverse events suspected to be associated with the use of NeutroSpec, call 1-888-744-1414. Alternatively, adverse event information may be reported directly to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Bedford recalls one lot of methotrexate for injection

December 14, 2005

ST. LOUIS (MD Consult) - On December 8, 2005, Bedford Laboratories announced that it is voluntarily recalling one lot of methotrexate for injection (preservative free), USP 1 g/vial (NDC 55390-143-01), Lot #859142, with an expiration date of 09/07. The recall has been instituted because the active drug substance used to manufacture Lot #859142 contained low levels of ethylene glycol.

Preservative-free methotrexate is the only formulation that is acceptable for intrathecal administration; human use of preservative-free methotrexate formulations for intrathecal administration containing ethylene glycol is not permissible.

Bedford Laboratories is working with the US Food and Drug Administration on this recall. No serious health or safety reports attributed to this situation have been received.

The prescription product was distributed throughout the United States in October and November 2005 to wholesalers and distributors, who further distributed the product to hospitals. Customers who have any vials of this 1 lot of methotrexate for injection have been instructed to discontinue distribution and use of this lot immediately and contact Bedford Laboratories Customer Service Department (1-800-562-4797) for a returned goods authorization. Consumers who have questions regarding this recall should also contact the Bedford Customer Service Department at 1-800-562-4797, between the hours of 8 AM and 5 PM (EST).

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Congenital abnormalities warrant category D designation for paroxetine

December 9, 2005

ST. LOUIS (MD Consult) - On December 8, 2005, the US Food and Drug Administration (FDA) announced that it has determined that exposure to paroxetine in the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiac malformations. At the FDA's request, the manufacturer has changed paroxetine's pregnancy category from C to D and added new data and recommendations to the Warnings section of paroxetine's prescribing information. Paroxetine is available as Paxil, Paxil CR, Pexeva, and generic paroxetine hydrochloride.

The FDA's conclusions and changes in paroxetine's prescribing information are based on preliminary analyses of 2 recent unpublished epidemiology studies.

• In a study using Swedish national registry data, women who received paroxetine in early pregnancy had an approximately 2-fold increased risk for giving birth to an infant with a cardiac defect compared with the entire national registry population (the risk of a cardiac defect was about 2% in paroxetine-exposed infants vs 1% among all registry infants).
• In a separate study using a United States insurance claims database, infants of women who received paroxetine in the first trimester had a 1.5-fold increased risk for cardiac malformations and a 1.8-fold increased risk for congenital malformations overall compared with infants of women who received other antidepressants in the first trimester. The risk of a cardiac defect was about 1.5% in paroxetine-exposed infants versus 1% among infants exposed to other antidepressants.
• Most of the cardiac defects observed in these studies were atrial or ventricular septal defects. In general, septal defects are one of the most common types of congenital malformations. They range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve on their own. It is of note that the data in these studies was limited to first-trimester exposures only, and currently no data exists to address whether this or any other risk extends to later periods of pregnancy.

The FDA is awaiting the final results of the recent studies and accruing additional data related to the use of paroxetine in pregnancy to better characterize the risk for congenital malformations associated with paroxetine. In the interim, the FDA makes the following recommendations.

Physicians who are caring for women receiving paroxetine should alert them to the potential risk to the fetus if they plan to become pregnant or are currently in their first trimester of pregnancy. Discontinuing paroxetine therapy should be considered for these patients. In individual cases, the benefits of continuing paroxetine may outweigh the potential risk to the fetus. If the decision is made to discontinue paroxetine and switch to another antidepressant or cease antidepressant therapy altogether, paroxetine discontinuation should be undertaken only as directed in the prescribing information. Paroxetine should generally not be initiated in women who are in their first trimester of pregnancy or in women who plan to become pregnant in the near future.

Women who are pregnant, or planning a pregnancy, and currently taking paroxetine should consult with their physicians about whether to continue taking it. Women should not stop taking the drug without discussing the best way to do that with their physicians.

For more information on paroxetine, including patient and health care professional information sheets, visit fda.gov/cder/drug/infopage/paroxetine/default.htm.

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Miracle II Neutralizer products unapproved and contaminated, FDA warns

December 8, 2005

ST. LOUIS (MD Consult) - On December 6, 2005, the US Food and Drug Administration (FDA) issued a statement advising consumers not to use Miracle II Neutralizer and Miracle II Neutralizer Gel products manufactured by Tedco, Inc, because the products are bacterially contaminated and have not been proved to be safe and effective. Use of these products could pose a risk of serious adverse events such as infections, particularly in children, the elderly, and persons with weakened immune systems who are particularly susceptible to illness.

"We will not tolerate the marketing of products that use deceptive and untruthful claims to lure consumers into potentially dangerous situations," said Margaret O'K. Glavin, the FDA's Associate Commissioner for Regulatory Affairs. "We consider it a significant public health hazard when consumers are deliberately deceived into using potentially dangerous products that promise health benefits but deliver only risk of harm."

Tedco, Inc, based in West Monroe, La, promotes Miracle II Neutralizer for ophthalmic use, including treatment of cataracts and pink eye, and as an eyewash. The FDA requires that all ophthalmic products be sterile. Due to the substantial risk posed by nonsterility, Miracle II Neutralizer should never be applied to the eyes.

The company also markets Miracle II Neutralizer for other unapproved uses, including treatment of AIDS, cancer, Crohn's disease, dermatitis, diaper rash, diabetes, earache, hemorrhoids, hives, gout, herpes, mouth ulcers, psoriasis, skin cancer, and yeast infection. The firm sells Miracle II Neutralizer Gel for many of the same unapproved uses, including diaper rash, diabetes, gout, psoriasis, and skin cancer.

Tedco, Inc, promotes its Miracle II products with claims such as, "Supreme technology has made possible for a perfect soap cleaner, deodorizer, natural insecticide and antibacterial product to be put on the market. This is the only product that is made in the world that can wash a newborn baby or clean up an oil spill and everything in between." Contrary to such claims, recent FDA testing of Miracle II Neutralizer and Miracle II Neutralizer Gel revealed bacterial contamination and poor manufacturing conditions.

Although Tedco, Inc, has been advised by the FDA of the contamination found in its Miracle II Neutralizer and Miracle II Neutralizer Gel products, the firm has declined to voluntarily remove the products from the market.

A number of stores sell Miracle II Neutralizer and Miracle II Neutralizer Gel, and the products are distributed and sold worldwide and sold via the Internet. The products are packaged in 8-oz, 22-oz, and 1-gallon containers.

The FDA urges consumers, health care providers, and caregivers to cease using and dispose of these products and report any adverse events related to these products to MedWatch, the FDA's voluntary reporting program, by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Reports of fatal and life-threatening cardiopulmonary events associated with NeutroSpec

December 5, 2005

ST. LOUIS (MD Consult) - On November 30, 2005, Mallinckrodt, Palatin Technologies, and the US Food and Drug Administration (FDA) notified health care professionals of postmarketing reports of serious and life-threatening cardiopulmonary events that occurred after the administration of NeutroSpec (technetium [99m Tc] fanolesomab), a radiodiagnostic agent consisting of a murine immunoglobulin M (IgM) monoclonal antibody formulated to be labeled with technetium. The drug is indicated for scintigraphic imaging of patients aged 5 years or older with equivocal signs and symptoms of appendicitis.

According to a letter issued by Mallinckrodt and Palatin, the companies have been informed of 2 deaths attributed to cardiopulmonary failure within 30 minutes of injection and additional cases of serious cardiopulmonary events including cardiac arrest, hypoxia, dyspnea, and hypotension.

Onset of these events generally occurred within minutes of injection and required resuscitation with intravenous fluids, vasopressors, and oxygen. The majority of these reports described patients with underlying cardiopulmonary disease who received NeutroSpec for unapproved indications. However, any patient who receives NeutroSpec should be closely monitored for at least 1 hour after product administration. Resuscitation equipment and appropriately trained personnel must be readily available during this time. Patients with underlying cardiopulmonary conditions may be at higher risk for serious complication. NeutroSpec should only be administered to these patients after careful consideration of the known and potential risks and benefits, including the possibly higher risks.

Mallinckrodt and Palatin are working with the FDA to review these cases and revise the NeutroSpec US package insert to provide additional warnings and safety information. Updated information will be distributed to health care professionals once the review is complete.

As a reminder, the companies note that a single patient dose of NeutroSpec for imaging contains 75 to 125 mcg of fanolesomab labeled with 10 to 20 mCi (370 to 740 MBq) Sodium Pertechnetate Tc 99m Injection, USP. They also ask that physicians refer to the Warnings section of the full prescribing information for NeutroSpec (fda.gov/medwatch/safety/2005/NeutroSpec_PI_R1-2005.pdf) for information about the risk of anaphylaxis and other types of hypersensitivity reactions.

For any questions, to request more information, or to report serious adverse events suspected to be associated with the use of NeutroSpec, call 888-744-1414. Alternatively, adverse event information may be reported directly to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Pure red cell aplasia and severe anemia reported with use of Aranesp, Epogen, and Procrit

December 2, 2005

ST. LOUIS (MD Consult) - On December 1, 2005, Amgen, Ortho Biotech, and the US Food and Drug Administration notified health care professionals of revision to the Warnings, Precautions, Adverse Reactions, and Dosage and Administration sections of the prescribing information for Epogen (epoetin alfa), Procrit (epoetin alfa), and Aranesp (darbepoetin alfa).

The revised labeling provides updated safety information regarding reports of pure red cell aplasia and severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin in patients treated with these products. This has been reported predominantly in patients with chronic renal failure receiving these products by subcutaneous administration. It is now recommended that the intravenous route of administration be used in patients receiving hemodialysis. Recommendations for evaluation and treatment are provided in the new prescribing information.

Amgen, manufacturer of Aranesp and Epogen, stated that when these medications are used in accordance with the approved prescribing information, the benefit/risk profile continues to be favorable. Ortho Biotech has made the same statement regarding use of Procrit.

Because the potential for pure red cell aplasia and anti-erythropoietin antibody-associated severe anemia applies to all marketed erythropoietic proteins, product labeling for all drugs in this class have been updated in a consistent manner to state the following:

1. If a patient develops a sudden loss of response, accompanied by severe anemia and low reticulocyte count, an evaluation for causative factors should be undertaken. If anti-erythropoietin antibody-associated anemia is suspected, physicians should withhold Aranesp/Epogen/Procrit and contact Amgen/Ortho Biotech to perform assays for binding and neutralizing antibodies.
2. Aranesp/Epogen/Procrit should be permanently discontinued in patients with antibody-mediated anemia.
3. Patients should not be switched to other erythropoietic proteins, as there is a potential for the antibodies to cross-react.

Full text of the revised sections of the labels for Aranesp, Epogen, and Procrit are available at fda.gov/medwatch/SAFETY/2005/safety05.htm#aranesp2.

Procrit, Epogen, and Aranesp are all indicated for the treatment of anemia associated with chronic renal failure, including patients receiving dialysis and patients not receiving dialysis. Procrit and Epogen are indicated to elevate or maintain the red blood cell level and to decrease the need for transfusions in these patients.

Procrit and Epogen are also indicated for the treatment of anemia related to therapy with zidovudine in HIV-infected patients, and to elevate or maintain the red blood cell level and to decrease the need for transfusions in these patients.

Procrit, Epogen, and Aranesp are indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. Procrit and Epogen are indicated to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy for a minimum of 2 months.

Procrit and Epogen are indicated for the treatment of anemic patients scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogenic blood transfusions. Procrit and Epogen are also indicated for patients at high risk for perioperative transfusions with significant, anticipated blood loss.

Amgen requests that health care professionals to report any adverse patient experiences associated with its products (eg, Aranesp and Epogen) to the company at 1-800-77-AMGEN or online at amgenmedinfo.com. Likewise, Ortho Biotech encourages anyone with knowledge of adverse events associated with Procrit to contact the company at 1-800-325-7504, prompt #2.

Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Thromboembolic adverse events possible with NovoSeven, drugmaker says

December 2, 2005

ST. LOUIS (MD Consult) - On November 23, 2005, Novo Nordisk notified health care professionals of revisions to the Warnings and Adverse Reactions sections of the prescribing information for NovoSeven coagulation factor VIIa (recombinant). The changes were instituted to provide updated safety information on thrombotic and thromboembolic adverse events, based on the results of clinical studies in patients without hemophilia and postmarketing safety surveillance.

A clinical study in elderly, nonhemophiliac, intracerebral hemorrhage patients indicated a potential increased risk of arterial thromboembolic adverse events with use of NovoSeven, including myocardial ischemia, myocardial infarction, cerebral ischemia, and infarction.

The new information contains the following text:

Warnings The extent of the risk of thrombotic adverse events after treatment with NovoSeven in patients with hemophilia and inhibitors is not known but is considered to be low. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates) may have an increased risk of developing thrombotic events due to circulating TF or predisposing coagulopathy. (See Adverse Reactions and Drug Interactions.) The extent of the risk of arterial and venous thromboembolic adverse events after treatment with NovoSeven in patients without hemophilia is also not known. A clinical study in elderly nonhemophilia intracerebral hemorrhage patients indicated a potential increased risk of arterial thromboembolic adverse events with use of NovoSeven, including myocardial ischemia, myocardial infarction, cerebral ischemia, and/or infarction.

Revisions to the Adverse Reactions section of the NovoSeven prescribing information are as follows:

Adverse Reactions Postmarketing Experience The following postmarketing adverse events are reported voluntarily from a population of uncertain size; hence, it is not possible to estimate their frequency or establish a causal relationship to exposure. The following additional adverse events were reported following the use of NovoSeven in both labeled indications and unlabeled indications that included individuals with situational coagulopathy, and without known coagulopathy: high D-dimer levels and consumptive coagulopathy, thromboembolic events including myocardial infarction, myocardial ischemia, cerebral infarction and/or ischemia, thrombophlebitis, arterial thrombosis, deep vein thrombosis and related pulmonary embolism, and isolated cases of hypersensitivity reactions including anaphylactic reactions. (See Warnings and Precautions.) Evaluation and interpretation of these postmarketing events is confounded by underlying diagnoses, concomitant medications, preexisting conditions, and inherent limitations of passive surveillance. A causal relationship has not been established for the above events.

NovoSeven is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX. This medication should be administered to patients only under the direct supervision of a physician experienced in the treatment of hemophilia.

NovoSeven should not be administered to patients with known hypersensitivity to any of the components of the drug. Its use is contraindicated in patients with known hypersensitivity to mouse, hamster, or bovine proteins.

For more details, including complete prescribing information for NovoSeven, visit fda.gov/medwatch/safety/2005/novose_pi_fa.pdf or contact Novo Nordisk at 1-877-NOVO-777.

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Maker of OTC eyedrops agrees to cease manufacture and distribution

November 30, 2005

ST. LOUIS (MD Consult) - The US Food and Drug Administration (FDA) announced on November 29, 2005, that MBI Distributing, Inc, also known as Molecular Biologics, a manufacturer of over-the-counter (OTC) eyedrops and other products, has signed a consent decree that requires it to cease manufacturing and distributing drugs until it corrects manufacturing deficiencies and other violations at its Benicia, Calif, facility. The consent decree was submitted to the US District Court for the Eastern District of California by the Department of Justice on behalf of the FDA and is subject to approval by the court.

MBI's product line includes eyedrops sold under the brand names Oxydrops, Bright Eyes, Bright Eyes II, Clarity Vision for Life, Visitein, and Can-C, as well as several OTC pain-relieving drugs. These products are sold by retailers nationwide.

This action is a result of the FDA's determination that the firm has been manufacturing eyedrops in a manner that does not conform to the FDA's current good manufacturing practice requirements. The firm has not corrected violations noted during inspections, despite agency efforts to have the company achieve compliance. Among other things, at the FDA's most recent inspection, the firm lacked manufacturing controls to ensure that its eyedrops were sterile.

The FDA has also determined that 2 of the firm's eyedrop brands, Visitein and Clarity Vision for Life, are unapproved drugs. In addition, 3 of the firm's OTC pain-relieving drugs, Biogesic, Bio-Ice, and Bio-Heat, do not provide adequate warnings for their safe use.

Under the terms of the consent decree, MBI is enjoined from producing and distributing drugs until the firm corrects the manufacturing violations for its eyedrops and its violations of the marketing approval and labeling requirements of the Federal Food, Drug, and Cosmetic Act.

The firm's poor manufacturing conditions have called into question the safety of its eyedrops, and the lack of necessary warnings could undermine the ability of a consumer to safely use the firm's pain-relieving drugs listed above. The FDA therefore recommends that consumers, health care providers, and caregivers dispose of the Oxydrops, Bright Eyes, Bright Eyes II, Clarity Vision for Life, Visitein, and Can-C brands of eyedrops and the Biogesic, Bio-Ice, and Bio-Heat pain-relieving drugs. The agency requests that any adverse events related to these products be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Sterility question prompts recall of GenTeal eyedrops

November 23, 2005

ST. LOUIS (MD Consult) - On November 22, 2005, Novartis Ophthalmics and the US Food and Drug Administration (FDA) notified health care professionals and patients of a voluntary recall due to a lack of sterility assurance of 7 lots of 2 products, GenTeal Gel and GenTeal GelDrops (hydroxypropyl methylcellulose), intended for use to relieve dryness of the eye. Although the risk of potential contamination is believed to be very low, contaminated product could cause infections in susceptible persons.

The 5 lots of GenTeal Gel include about 142,500 tubes that were distributed nationwide from March to November 2004. The five lots of GenTeal Gel being recalled are as follows:

• Lot #Z12468, 10 mL, expiration date 01/2006
• Lot #Z12912, 3.5 mL, expiration date 03/2006
• Lot #Z12900, 10 mL, expiration date 04/2006
• Lot #Z13161, 10 mL, expiration date 05/2006
• Lot #Z13314, 3.5 mL, expiration date 06/2006

The 2 lots of GenTeal GelDrops include about 12,000 dropper bottles that were distributed nationwide in October 2005. The two lots are as follows:

• Lot #51139, 15 mL, expiration date 07/2007
• Lot #51283, 25 ml, expiration date 07/2007

The GenTeal Gel recall is being conducted in response to concerns regarding sterility of the product made for Novartis by a contract manufacturer. Additional sterility tests were conducted on several lots of GenTeal Gel. Test results for GenTeal Gel indicated the presence of mold in a small number of samples, leading Novartis to initiate a recall of the 5 lots. The species of mold that is suspected is generally not harmful but has the potential to cause an eye infection in susceptible persons, especially in those with compromised immune systems.

The GenTeal GelDrops lots are being recalled due to a lack of sterility assurance. Although the risk of potential contamination is believed to be very low, the risk for infection in susceptible persons initiated the recall as a precautionary measure. The sterility assurance issues have been corrected. Only the 2 distributed GenTeal GelDrops lots named above are affected, Novartis stated.

The distributing company advises consumers who have purchased GenTeal Gel or GenTeal GelDrops with any of these lot numbers to contact Novartis Ophthalmics at 1-866-393-6336 or novartisophthalmics.com for further instructions.

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Revisions to Flomax label include warning for surgical problems

November 23, 2005

ST. LOUIS (MD Consult) - On November 22, 2005, Boehringer Ingelheim and the US Food and Drug Administration notified health care professionals of revisions to Precautions and Adverse Reactions sections of the prescribing information for Flomax (tamsulosin hydrocholoride), indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. A surgical condition termed intraoperative floppy iris syndrome (IFIS) has been observed during phacoemulsification cataract surgery in some patients treated with alpha-1 blockers, including Flomax.

Most of these reports were in patients taking the alpha-1 blocker when IFIS occurred, but in some cases alpha-1 blocker had been stopped before surgery. It is recommended that male patients being considered for cataract surgery, as part of their medical history, be specifically questioned whether they have taken Flomax or other alpha-1 blockers. If so, the patient's ophthalmologist should be prepared for possible modifications to their surgical technique that may be warranted should IFIS be observed during the procedure.

IFIS is a variant of small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. Measures such as the use of iris hooks, iris dilator rings, or the use of viscoelastic devices such as Healon 5 can minimize the consequences of this syndrome.

More details are available in the full prescribing information for Flomax at fda.gov/medwatch/safety/2005/Flomax_final_%20PI.pdf.

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FDA issues health advisory for bronchodilators

November 21, 2005

ST. LOUIS (MD Consult) - On November 18, 2005, the US Food and Drug Administration (FDA) requested that the manufacturers of Advair Diskus (fluticasone propionate and salmeterol inhalation powder), Foradil Aerolizer (formoterol fumarate inhalation powder), and Serevent Diskus (salmeterol xinafoate inhalation powder) update their existing product labels with new warnings and a medication guide for patients. The new information is being added to alert health care professionals and patients that these medicines may increase the chance of severe asthma episodes and death when those episodes occur.

All of these products contain medicines belonging to the class known as long-acting beta 2-adrenergic agonists (LABAs), which are long-acting bronchodilator medicines. Bronchodilator medicines help to relax the muscles around the airways in the lungs. Bronchspasm happens when the muscles around the airways tighten. The information in the FDA's proposed changes to the product labels explains that, even though LABAs decrease the number of asthma episodes, these medicines may increase the chances of a severe asthma episode when they do occur.

In one asthma medicine study, an increased number of people taking an LABA in addition to their usual asthma care died from their asthma compared with people taking a placebo in addition to their usual asthma care, although the number of asthma deaths in the study was small.

The FDA is issuing this public health advisory to highlight the following recommendations about the use of a LABA medicine for asthma:

• LABAs should not be the first medicine used to treat asthma. LABAs should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low- or medium-dose corticosteroids.
• Patients should not stop using their LABA or other asthma medicines that their health care professionals have prescribed unless they have discussed with their health care providers whether or not to continue treatment.
• Patients should not use their LABA to treat wheezing that is getting worse. They should contact their health care professionals right away if wheezing worsens while using a LABA.
• LABAs do not relieve sudden wheezing. Patients should always have a short-acting bronchodilator medicine on hand to treat sudden wheezing.

The medication guide contains information about these risks for patients and caregivers in language approved by the FDA and will be given to patients when a prescription for a LABA is filled or refilled.

LABAs are used for long-term control and prevention of asthma symptoms, for preventing bronchospasm caused by exercise in adults and children, and for long-term control of bronchospasm in adults with chronic obstructive pulmonary disease. The new warnings are about LABA use for asthma. Information is not available regarding whether there are similar concerns when LABAs are used for exercise-induced bronchospasm or chronic obstructive pulmonary disease.

Additional information, including patient and health care professional information sheets, are available at fda.gov/cder/drug/infopage/LABA/default.htm.

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Amevive not safe for HIV-positive patients, says FDA

November 11, 2005

ST. LOUIS (MD Consult) - Ligand Pharmaceuticals Inc and the US Food and Drug Administration (FDA) notified health care professionals on November 3, 2005, of revisions to Boxed Warning, Warnings, Precautions, Clinical Pharmacology, and Dosage and Administration sections of the prescribing information of Avinza (morphine sulfate extended-release capsules).

Amevive reduces CD4+ T lymphocyte counts, which might accelerate disease progression or increase complications of disease in these patients. In addition, other sections of the product labeling have been revised to reflect additional safety information.

The new contraindication of Amevive for patients who are HIV positive is based on the pathophysiology of HIV and the effect of Amevive on T lymphocytes. This contraindication is consistent with the company decision not to study Amevive in HIV-positive psoriatic patients due to the theoretical safety concern in this patient population. The new contraindication states:

Amevive should not be administered to patients infected with HIV. Amevive reduces CD4+ T lymphocyte counts, which might accelerate disease progression or increase complications of disease in these patients (see Warnings: Lymphopenia and Warnings: Serious Infections).

Biogen Idec is requesting that health care professionals report any serious adverse events suspected to be associated with the use of Amevive to the company at 1-866-263-8483. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

For more information on this medication, visit amevive.com or contact Biogen Idec at biogen.com.

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Estrogen levels in contraceptive patch higher, label revised

November 11, 2005

ST. LOUIS (MD Consult) - On November 10, 2005, the US Food and Drug Administration (FDA) approved updated labeling for the Ortho Evra (ethinyl estradiol/norelgestromin) contraceptive patch to warn health care providers and patients that this product exposes women to higher levels of estrogen than most birth control pills.

Ortho Evra, a weekly prescription, was the first skin patch approved for birth control. It releases ethinyl estradiol (an estrogen hormone) and norelgestromin (a progestin hormone) through the skin into the bloodstream. The FDA advises women to talk with their health care providers about whether the patch is the right method of birth control for them.

Furthermore, women taking or considering using this product should work with their health care providers to balance the potential risks related to increased estrogen exposure against the risk of pregnancy if they do not follow the daily regimen associated with typical birth control pills. Because Ortho Evra is a patch that is changed once a week, it decreases the chance associated with typical birth control pills that a woman might miss one or more daily doses.

The addition of this new warning is a result of the FDA's and the manufacturer's analysis directly comparing the levels for estrogen and progestin hormones in users of Ortho Evra with those in a typical birth control pill. In general, increased estrogen exposure may increase the risk of blood clots. However, it is not known whether women using Ortho Evra are at a greater risk of experiencing these serious adverse events.

The new bolded warning includes the following text:

The pharmacokinetic (PK) profile for the Ortho Evra patch is different from the PK profile for oral contraceptives in that it has higher steady state concentrations and lower peak concentrations. AUC [area under the curve] and average concentration at steady state for ethinyl estradiol (EE) are approximately 60% higher in women using Ortho Evra compared with women using an oral contraceptive containing EE 35 mcg. In contrast, peak concentrations for EE are approximately 25% lower in women using Ortho Evra.

The FDA is continuing to monitor safety reports for the Ortho Evra patch. The manufacturer, Ortho McNeil Pharmaceuticals, is conducting additional studies to compare the risk of serious blood clots occurring in women using Ortho Evra to the risk in women using typical birth control pills that contain 35 mcg of estrogen.

The new Ortha Evra labeling information, along with additional information for health care providers and consumers, is available at fda.gov/cder/drug/infopage/orthoevra/default.htm.

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Glucose readings may be inaccurate, FDA warns

November 11, 2005

ST. LOUIS (MD Consult) - On November 10, 2005, the US Food and Drug Administration (FDA) notified health care professionals of the potential for life-threatening falsely elevated glucose readings in patients who have received parenteral products containing maltose or galactose, or oral xylose, and are subsequently tested using glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ)-based glucose-monitoring systems. The GDH-PQQ method of glucose determination is non-specific for glucose and, in the presence of maltose, xylose, or galactose, may yield falsely elevated glucose readings.

Self-monitoring glucose devices used by persons with diabetes at home and in point-of-care settings, and laboratory glucose assays all use one of the following test methods: GDH-PQQ, glucose dehydrogenase nicotinamide adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase. The test method is clearly marked in the device labeling/operator's manual. Glucose monitoring systems that use GDH-NAD, glucose oxidase, or glucose hexokinase methods are not affected by the presence of maltose, galactose, or xylose.

There have been reports of the inappropriate administration of insulin and consequent life-threatening/fatal hypoglycemia in response to erroneous test results obtained from patients receiving parenteral products containing maltose. Cases of true hypoglycemia can go untreated if the hypoglycemic state is masked by false elevation of glucose readings.

A preliminary listing of US products that may cause interference is available at fda.gov/cber/safety/maltose110405.htm.

The following precautions should be taken when patients are receiving products containing the sugars maltose (or sugars that are metabolized to maltose, such as peritoneal dialysis solutions containing icodextrin [eg, Extraneal]), xylose, or galactose:

1. Review the labeling for both the glucose meter and the test strips to be used to monitor glucose levels to determine what type of method is used for glucose determination.
2. Use only test methods not affected by the presence of maltose, galactose, or d-xylose, such as GDH-NAD–, glucose oxidase–, or glucose hexokinase–based test methods.
3. If in doubt, contact the manufacturer of the glucose-monitoring system to determine the specific type of testing that is used in the system.

The FDA advises health care providers who prescribe a GDH-PQQ method of glucose determination to persons for whom blood sugar measurements are routinely performed on an outpatient basis to notify patients who may be receiving a parenteral product containing maltose, galactose, or oral xylose that they should use only those glucose-testing methodologies for blood sugar monitoring that are not subject to interference.

For additional information on the subject, see the FDA Reminders For Falsely Elevated Glucose Readings available at fda.gov/cdrh/oivd/news.html#110905.

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FDA warns against unapproved alternative hormone therapies

November 11, 2005

ST. LOUIS (MD Consult) - The US Food and Drug Administration (FDA) announced on November 10, 2005, that the agency has taken action against a number of firms marketing unapproved "Alternative Hormone Therapies" because the products these firms are selling are unapproved new drugs that have not been found safe and effective to treat or prevent certain serious or life-threatening diseases or conditions.

The FDA issued warning letters to 16 dietary supplement and hormone cream marketers who are making unproven claims that tout the benefits of their "alternative hormone therapy" products in treating or preventing serious diseases (including cancer, heart disease, and osteoporosis) and in affecting the structure or function of the body. These alternative therapies are often promoted as "natural" or "safer" treatments that can be used in place of approved hormone treatments. Marketers have 15 days to respond to the FDA.

"[The] FDA takes seriously its responsibility to protect consumers from products promoted with unproven claims. It's particularly troublesome when these claims provide false hope to patients with serious or life-threatening conditions," said Margaret O'K. Glavin, the FDA's Associate Commissioner for Regulatory Affairs.

In the warning letters, the FDA advises the firms that, under the federal Food, Drug, and Cosmetic Act, a product is considered to be a drug if it claims to diagnose, cure, mitigate, treat, or prevent disease or, for products other than foods and dietary supplements, if it claims to affect the structure or function of the body. The letters further state that the FDA considers these products to be "new drugs" that require FDA approval before marketing.

Examples of the unproven claims cited in the Warning Letters include:

• reversing osteoporosis-related bone loss and increasing bone density
• reducing, arresting, or inhibiting the growth of cancer cells
• protecting against fibroids, ovarian, and endometrial cancers
• treating various forms of arthritis

The FDA letters also advise the marketers that advertising claims are governed by the Federal Trade Commission (FTC) Act and other laws enforced by the FTC.

As part of the joint effort, the FTC is also issuing letters notifying 34 Web sites that are promoting "alternative hormone therapy" products with similar claims pointing out that the FTC is unaware of any competent and reliable scientific evidence to support the claims. As stated in these letters, the FTC Act prohibits unfair or deceptive acts and practices, including false and unsubstantiated advertising claims.

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Ligand warns against mixing Avinza with alcohol consumption

November 7, 2005

ST. LOUIS (MD Consult) - Ligand Pharmaceuticals Inc and the US Food and Drug Administration (FDA) notified health care professionals on November 3, 2005, of revisions to Boxed Warning, Warnings, Precautions, Clinical Pharmacology, and Dosage and Administration sections of the prescribing information of Avinza (morphine sulfate extended-release capsules).

The changes were introduced to highlight and strengthen the warning that patients should not consume alcohol while taking Avinza. Additionally, patients must not use prescription or nonprescription medications containing alcohol while being treated with Avinza therapy.

The Black Box Warning, Warnings, and Dosage and Administration sections of the package insert for Avinza now contain the following words:

Patients must not consume alcoholic beverages while on Avinza therapy. Additionally, patients must not use prescription or nonprescription medications containing alcohol while on Avinza therapy. Consumption of alcohol while taking Avinza may result in the rapid release and absorption of a potentially fatal dose of morphine.

The following new or additional text is now included in the Precautions: Information for Patients section:

Patients should be informed that they must not consume alcoholic beverages while on Avinza therapy. Additionally, patients should be informed that they must not use prescription or nonprescription medications containing alcohol while on Avinza therapy. Consumption of alcohol while taking Avinza may result in the rapid release and absorption of a potentially fatal dose of morphine.

In the Clinical Pharmacology and Warnings sections of the prescribing information, the following text now appears:

In vitro studies performed by the FDA demonstrated that when Avinza 30 mg was mixed with 900 mL of buffer solutions containing ethanol (20% and 40%), the dose of morphine that was released was alcohol concentration–dependent, leading to a more rapid release of morphine. While the relevance of in vitro lab tests regarding Avinza to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine.

Full prescribing information for Avinza is available at ligand.com/pdf/AVINZAPI.pdf.

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Cutaneous reactions associated with Zevalin, drugmaker says

October 31, 2005

ST. LOUIS (MD Consult) - On October 28, 2005, Biogen Idec and the US Food and Drug Administration (FDA) notified health care professionals of new safety information that is being added to the prescribing information for Zevalin (ibritumomab tiuxetan). The medication, as part of a therapeutic regimen, is indicated for the treatment of non-Hodgkin's lymphoma.

Severe cutaneous or mucocutaneous reactions, some with fatal outcome, have been reported in association with the Zevalin therapeutic regimen in the postmarketing experience. Similar events have been associated with Rituxan (rituximab), a component of the Zevalin therapeutic regimen. The potential risk of these reactions should be considered when using the Zevalin therapeutic regimen. Patients experiencing a severe cutaneous or mucocutaneous reaction should not receive any further components of the Zevalin therapeutic regimen and should seek prompt medical evaluation.

In September 2005, the Boxed Warnings, Warnings, and Adverse Reactions sections of the Zevalin prescribing information were updated to include this important new safety information.

The following information has been added to the Boxed Warnings section:

Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some with fatal outcome, have been reported in association with the Zevalin therapeutic regimen. Patients experiencing a severe cutaneous or mucocutaneous reaction should not receive any further component of the Zevalin therapeutic regimen and should seek prompt medical evaluation (see Warnings and Adverse Reactions).

The Warnings section has been revised to include the following information:

Severe Cutaneous and Mucocutaneous Reactions (see Boxed Warnings and Adverse Reactions): There have been postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis in patients who received the Zevalin therapeutic regimen. Some of these events were fatal. The onset of the reactions was variable; in some cases, acute (days), and in others, delayed (3-4 months). Patients experiencing a severe cutaneous or mucocutaneous reaction should not receive any further components of the Zevalin therapeutic regimen and should seek prompt medical evaluation.

Recommended storage: Store Kaletra film-coated tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Dispense in original container. For patient use: exposure of this product to high humidity outside the original container for longer than 2 weeks is not recommended.

The Adverse Reactions section has been revised to include the following information:

The most serious adverse reactions caused by the Zevalin therapeutic regimen include prolonged and severe cytopenias, infections (predominantly bacterial in origin), hemorrhage while thrombocytopenic (resulting in deaths), and allergic reactions (bronchospasm and angioedema). In addition, patients who have received the Zevalin therapeutic regimen have developed myeloid malignancies and dysplasias. Fatal infusion reactions have occurred following the infusion of rituximab. In postmarketing reports, cutaneous and mucocutaneous reactions have been associated with the Zevalin therapeutic regimen. Please refer to the Boxed Warnings and Warnings sections for detailed descriptions of these reactions.

This new labeling will be included in Zevalin kits manufactured after September 2005.

To view full prescribing information for Zevalin and rituximab, including all boxed warnings, visit zevalin.com.

Biogen Idec is requesting that health care professionals report any serious adverse events in patients treated with Zevalin to the company at 1-877-866-4332. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Liver toxicity warrants removal from market for pemoline

October 25, 2005

ST. LOUIS (MD Consult) - On October 24, 2005, the US Food and Drug Administration (FDA) announced it has concluded that the overall risk of liver toxicity from Cylert (pemoline) and generic pemoline products outweighs the benefits of this drug. In May 2005, Abbott chose to stop sales and marketing of Cylert in the United States. All companies manufacturing generic forms have also agreed to stop sales and marketing of this product.

Cylert, a central nervous system stimulant indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD), is considered second-line therapy for ADHD because of its association with life-threatening hepatic failure. Health care professionals who prescribe Cylert or any of its generic formulations should transition their patients to an alternative therapy. Cylert will remain available through pharmacies and wholesale merchants until supplies are exhausted. No additional product will be available.

The FDA is aware of 13 reports of liver failure resulting in liver transplant or death, usually occurring within 4 weeks of the onset of signs and symptoms of liver failure. Although the absolute number of reported cases of liver failure with pemoline is not large, the reporting rate for liver failure with pemoline is 10 to 25 times greater than the background rate of liver failure in the general population.

Despite diminished use of Cylert and generic pemoline products since the addition of a boxed warning in 1999 (about one fifth the number of prescriptions now compared with before the inclusion of the boxed warning) and restrictive labeling (eg, boxed warning, second-line therapy, medication guide), a risk of liver failure remains; the FDA is aware of 1 new case of pemoline-associated liver failure since the introduction of the boxed warning in 1999. Given the availability of multiple other pharmaceutical treatments for ADHD, including one that is not scheduled and several products that can be given once a day, the FDA has concluded that the risk of liver failure with pemoline outweighs the potential benefits.

The FDA requests that any serious adverse events associated with the use of pemoline be reported to the agency's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

Full Cylert labeling information, including the boxed warning and patient package insert, is available at fda.gov/cder/foi/label/2003/016832s022_017703s018lbl.pdf.

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Cymbalta may increase risk for liver damage, Lilly cautions

October 18, 2005

ST. LOUIS (MD Consult) - On October 17, 2005, Eli Lilly and the US Food and Drug Administration (FDA) notified health care professionals of a revision to the Precautions/Hepatotoxicity section of the prescribing information for Cymbalta (duloxetine hydrochloride), indicated for treatment of major depressive disorder and diabetic peripheral neuropathic pain.

Postmarketing reports of hepatic injury (including hepatitis and cholestatic jaundice) suggest that patients with preexisting liver disease who take duloxetine may have an increased risk for further liver damage. The new labeling extends the precaution against prescribing Cymbalta for patients with substantial alcohol use to include those patients with chronic liver disease. It is recommended that Cymbalta not be administered to patients with any hepatic insufficiency.

Before approval, and as described in the Precautions section of the previous package insert, it was known that use of duloxetine was associated with mild to moderate and usually transient elevation of hepatic enzymes that infrequently led to Cymbalta discontinuation. In addition, some cases of severe hepatic injury in patients consuming large quantities of alcohol were observed during duloxetine clinical trials, as is described in the original package insert.

Since approval on August 3, 2004, approximately 1 million patients have taken duloxetine. Among these, several cases of hepatic injury have been spontaneously reported. Some of these patients had underlying liver disease. Review of these cases suggests that patients with underlying chronic liver disease may be at increased risk of hepatotoxicity with duloxetine. In addition to hepatocellular and mixed liver injury, cases of cholestatic jaundice have been reported.

Patients and prescribers should be aware of the signs and symptoms of liver damage (eg, pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained flu-like symptoms), and health care professionals are encouraged to investigate such symptoms and signs promptly.

Questions or concerns can be directed to the Lilly medical department at 1-800-Lilly-Rx. Likewise, serious adverse events can be reported to the company. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

Complete prescribing information is available at insidecymbalta.com.

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Dryvax smallpox vaccine linked to cardiac events, says FDA

October 13, 2005

ST. LOUIS (MD Consult) - A new black box warning for cardiac events and other safety information has been added to the prescribing information for Wyeth Pharmaceuticals' Dryvax smallpox vaccine (dried, calf lymph type), the US Food and Drug Administration announced on October 11, 2005. The new warning states that cases of myopericarditis have occurred after vaccination with Dryvax in healthy adults. The problem was reported in some patients in 2003.

Full text of the new warning is as follows:

Acute myopericarditis has been observed following the administration of Dryvax to healthy adults (see Warnings and Adverse Reactions). Encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia, severe vaccinial skin infections, and bullous erythema multiforma resulting in permanent sequelae or death have occurred following either primary vaccination or revaccination with Dryvax (see Adverse Reactions). Dryvax is contraindicated in nonemergency situations in the following individuals: Immunocompromised individuals, including those taking immunosuppressive medications Persons with cardiac disease, or a history of cardiac disease Persons with eczema and persons with a history of eczema or other acute or chronic exfoliative skin conditions Women who are pregnant, breast feeding, or suspect they may be pregnant Infants less than 12 months of age (See Contraindications, Contraindications for Non-Emergency Vaccine Use for additional information.)

For more information about the new warning for Dryvax and access to the revised drug labeling for the vaccine, visit fda.gov/cber/products/smalwye101105.htm.

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FDA and CDC issue alert on Menactra meningococcal vaccine and Guillain Barré syndrome

October 4, 2005

ST. LOUIS (MD Consult) - On September 30, 2005, the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) alerted consumers and health care providers to 5 reports of Guillain Barré syndrome (GBS) following the administration of meningococcal conjugate vaccine A, C, Y, and W135 (Menactra), manufactured by Sanofi Pasteur.

It is not known yet whether these cases were caused by the vaccine or are coincidental. The FDA and the CDC are sharing this information with the public now and are actively investigating the situation because of its potentially serious nature.

GBS is a serious neurologic disorder that can occur, often in healthy persons, either spontaneously or after certain infections. GBS typically causes increasing weakness in the legs and arms that can be severe and require hospitalization.

Meningococcal infection, which Menactra prevents, is a major cause of bacterial meningitis, affecting approximately 1 in 100,000 persons annually. The infection can be life threatening: 10% to 14% of cases are fatal, and 11% to 19% of survivors may have permanent disability.

According to Dr Jesse Goodman, director of the FDA's Center for Biologics Evaluation and Research, no changes in recommendations for vaccination are needed at present; persons should continue to follow their physicians' recommendations. The FDA and the CDC are not able to determine whether any or all of the cases were caused by vaccination. The current information is very preliminary, and the two agencies are continuing to evaluate the situation.

Because of the potentially serious nature of this matter, the FDA and the CDC are asking any persons with knowledge of any possible cases of GBS occurring after Menactra administration to report them to the Vaccine Adverse Event Reporting System (VAERS) to help the agencies further evaluate the situation. Persons can report to VAERS by phone at 1-800-822-7967 or via the Internet (vaers.hhs.gov.)

The 5 cases of GBS that reportedly occurred after administration of Menactra were in persons living in New York, Ohio, Pennsylvania, and New Jersey. All 5 patients were aged 17 or 18 years and developed weakness or abnormal sensations in the arms or legs 2 to 4 weeks after vaccination. All persons are reported to be recovering or to have recovered.

More than 2.5 million doses of Menactra vaccine have been distributed to date. The rate of GBS based on the number of cases reported following administration of Menactra is similar to what might have been expected to occur by coincidence, that is, even without vaccination. However, the timing of the events is of concern. Also, vaccine adverse events are not always reported to the FDA, so there may be additional cases of which the agency is unaware at this time.

Prelicensure studies conducted by Sanofi Pasteur of more than 7,000 recipients of Menactra showed no GBS cases. The CDC conducted a rapid study using available health care organization databases and found that no cases of GBS have been reported to date among 110,000 Menactra recipients.

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FDA issues public health advisory on Strattera for attention-deficit disorder

September 30, 2005

ST. LOUIS (MD Consult) - On September 29, 2005, the US Food and Drug Administration (FDA) issued a Public Health Advisory to alert physicians of reports of suicidal thinking in children and adolescents associated with Strattera (atomoxetine), a medication approved to treat attention-deficit/hyperactivity disorder (ADHD) in pediatric and adult patients.

The FDA directed Eli Lilly and Company (Lilly), the manufacturer of Strattera, to revise the labeling for this product to include a boxed warning and additional warning statements that alert health care providers to an increased risk of suicidal thinking in children and adolescents being treated with this drug. The FDA also informed Lilly that it has determined that a Patient Medication Guide (MedGuide), which will advise patients of the risks associated with Strattera and precautions that can be taken, should be distributed to patients when Strattera is dispensed.

The increased risk of suicidal thinking for this drug was identified in a combined analysis of 12 short-term (6-18 weeks) placebo-controlled trials (11 in ADHD and 1 in enuresis). These 12 trials involved approximately 2,200 patients, including 1,357 children who received Strattera and 851 children who received placebo. The analysis showed a greater risk of suicidal thinking during the first few months of treatment in those receiving Strattera. The average risk of suicidal thinking was about 4 per 1,000 patients treated with Strattera compared with no events in placebo-treated patients. One suicide attempt occurred in a patient treated with Strattera. On the basis of these data, the FDA has determined the following points are appropriate for inclusion in the boxed warning:

• Strattera increases the risk of suicidal thinking in children and adolescents with ADHD.
• Anyone considering the use of Strattera in a child or adolescent for ADHD must balance the increased risk of suicidal thinking with the clinical need for the drug.
• Patients who are started on therapy should be observed closely for clinical worsening, suicidal thinking or behaviors, or unusual changes in behavior.
• Families and caregivers should be advised to closely observe the patient and to communicate changes or concerning behaviors with the prescriber.

Pediatric patients being treated with Strattera should be closely observed for clinical worsening as well as agitation, irritability, suicidal thinking or behaviors, and unusual changes in behavior, especially during the initial few months of a course of drug therapy or at times of dose changes, either increases or decreases. This monitoring should include daily observation by families and caregivers and frequent contact with the physician.

In addition, a MedGuide is being prepared for Strattera to provide information directly to patients and their families and caregivers about the increased risk of suicidal thinking in children and adolescents prescribed the drug. The MedGuide is intended to be distributed by the pharmacist with each prescription or refill of a medication.

A similar analysis in adult patients treated with Strattera for either ADHD or major depressive disorder found no increased risk of suicidal ideation or behavior with use of Strattera.

The FDA plans to work closely with Lilly to optimize the safe use of this drug and to implement the proposed labeling changes and other safety communications in a timely manner.

Health care professionals are encouraged to report any unexpected adverse events associated with Strattera directly to Eli Lilly at 1-800-LillyRx. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet ( fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Congenital malformations linked with paroxetine use, study says

September 29, 2005

ST. LOUIS (MD Consult) - On September 27, 2005, GlaxoSmithKline and the US Food and Drug Administration (FDA) notified health care professionals of changes to the Pregnancy/Precautions section of the prescribing information for Paxil (paroxetine) and Paxil CR tablets. The added text describes the results of a GlaxoSmithKline retrospective epidemiologic study of major congenital malformations in infants born to women taking antidepressants during the first trimester of pregnancy.

Paroxetine currently carries a category C pregnancy precaution, indicating that there are no adequate and well-controlled studies in humans to determine the effect of paroxetine on the fetus. Labeling states that the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The label also currently includes information related to possible nonteratogenic effects, including symptoms and complications observed in neonates exposed to paroxetine in the third trimester of pregnancy.

Preliminary results of GlaxoSmithKline's retrospective study suggest an increase in the risk of overall major congenital malformations associated with the use of paroxetine compared with other antidepressants (odds ratio, 2.2; 95% confidence interval, 1.34-3.63). The types of congenital malformations, which were most commonly cardiovascular, were reflective of those seen in the general population. The most common cardiovascular malformations observed in the study were ventricular septal defects.

The preliminary results of this study and recently published abstracts differ from previous epidemiologic studies, making it difficult to conclude whether a causal relationship exists. For example, data from the Swedish Medical Birth Registry, one of the largest available birth registries, have not provided evidence for an increased risk of major malformations with selective serotonin reuptake inhibitors, including paroxetine. However, the results of the GlaxoSmithKline study were deemed significant enough to warrant adding this information to the Paxil labeling.

Paxil is indicated for the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, and posttraumatic stress disorder. Paxil CR is indicated for the treatment of major depressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder.

Health care professionals are advised to carefully weigh the potential risks and benefits of using paroxetine therapy in women during pregnancy and to discuss these findings as well as treatment alternatives with their patients.

If it is decided to discontinue treatment with paroxetine, the instructions outlined in the Discontinuation of Treatment with Paxil/Paxil CR subsection of the Precautions section in the labeling should be followed.

The complete FDA MedWatch 2005 Safety summary, including links to GlaxoSmithKline's letter to health care professionals and revised labeling, are available at fda.gov/medwatch/safety/2005/safety05.htm#Paxil2.

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Fluorouracil injection may contain glass particles, recall instituted

September 29, 2005

ST. LOUIS (MD Consult) - On September 19, 2005, American Pharmaceutical Partners, Inc, (APP) notified health care professionals about a voluntary nationwide recall of its product, fluorouracil injection 50 mg/mL (500 mg/10 mL single-dose vial), because of the potential for invisible glass particles containing silica and aluminum in vials of the product. The company states that only product code 101710 is susceptible to this type of glass breakdown. APP's other fluorouracil product codes are manufactured in a different type of glass vial.

APP has announced that 10-mL doses of fluorouracil are still available; however, a filter must be used in the preparation of a dose of fluorouracil injection 50 mg/mL (500 mg/10 mL single-dose vial), code 101710. The company says its studies have demonstrated this filtering can effectively remove glass particles from the injection. APP will temporarily supply 5-micron filter needles with their 10-mL fluorouracil vials.

As soon as alternate product is available, APP will discontinue distribution of these kits.

Pharmacy bulk packs are available for facilities able to use them; these packs are not affected by the glass particle problem. The packs are available at the same concentration of 50 mg/mL in either 50- or 100-mL sizes (codes 101751 and 101761, respectively). The 20-mL single-dose vial (code 101720) is not currently available.

For more information on the recall, for full instructions on how to inspect vials of fluorouracil for precipitate, or for more information on the medication/filter kits available from APP, contact the company's Quality Assurance Department at 1-847-939-8138. For clinical or technical information, contact APP Medical Information at 1-800-551-7176.

A complete safety summary from MedWatch, the US Food and Drug Administration (FDA)'s safety information reporting program, including links to the recall notice from the FDA and APP, and APP's letter to health care professionals, is available at fda.gov/medwatch/safety/2005/safety05.htm#Fluorouracil.

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Similar drug names leading to drug administration errors, says FDA

September 27, 2005

ST. LOUIS (MD Consult) - On September 26, 2005, the US Food and Drug Administration (FDA) and AstraZeneca notified pharmacists and other health care professionals about reports of medication dispensing or prescribing errors between Toprol-XL (metoprolol succinate) extended-release tablets and Topamax (topiramate), a product of Ortho-McNeil Neurologics, Inc. Toprol-XL is indicated for the treatment of hypertension, long-term treatment of angina pectoris, and heart failure New York Heart Association Class II or III, and Topamax is approved for the treatment of epilepsy and for migraine prophylaxis. There have also been reports of medication errors involving confusion between Toprol-XL and Tegretol or Tegretol-XR (carbamazepine), products of Novartis Pharmaceuticals Corporation, indicated for the treatment of complex partial seizures, generalized tonic-clonic seizures, and trigeminal neuralgia. These reports include instances in which Toprol-XL was incorrectly administered to patients instead of Topamax, Tegretol, or Tegretol-XR, and vice versa, sometimes leading to adverse events.

Adverse events have been reported to occur as a result of nonadministration of the intended medication and/or exposure to the wrong medication. In some cases, hospitalization was required. Examples of serious events reported that might represent relapses or worsening of the underlying conditions under treatment include recurrence of seizures, return of hallucinations, suicide attempt, and recurrence of hypertension. Bradycardia occurring in a patient erroneously receiving Toprol-XL is one example of serious events reported that are consistent with the pharmacologic activity of the administered agent.

According to the medication error reports, verbal and written prescriptions were incorrectly interpreted and/or filled due to the similarity in names between Toprol-XL, Topamax, Tegretol, and Tegretol-XR. Furthermore, overlapping strengths between Toprol-XL and Topamax (25, 50, 100, and 200 mg) and between Toprol-XL, Tegretol, and Tegretol-XR (100 and 200 mg), and the fact that these 3 products were stocked close together in most pharmacies, may also have contributed to causing these errors.

The prescribing information for Toprol-XL includes a boxed warning against abrupt cessation of therapy in patients with ischemic heart disease because it may precipitate angina or myocardial infarction. The labeling for Tegretol has a boxed warning regarding aplastic anemia and agranulocytosis. And Topamax, Tegretol-XR, and Tegretol labeling includes a warning stating that, as with all antiepileptic drugs, they should only be withdrawn gradually to minimize the potential of increased seizure frequency.

The products involved in medication errors are indicated for the treatment of serious medical conditions. Erroneous administration or delay in administration of the prescribed medications of Toprol-XL, Topamax, Tegretol, and Tegretol-XR may cause serious health consequences.

Pharmacists and other health care professionals are asked to be sure to clearly communicate oral and written prescriptions for these products to help avoid future dispensing errors. Steps to decrease the potential for medication errors include printing legible prescriptions that include the brand and generic names with indication and discussing indications and proper use of medications with patients.

Persons who become aware of any name confusion or dispensing errors are requested to report them immediately to the appropriate manufacturer (AstraZeneca, 1-800-236-9933; Ortho-McNeil Neurologics, Inc, 1-800-682-6532; Novartis Pharmaceuticals Corporation, 1-888-669-6682). Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

For full prescribing information for Toprol-XL, visit Toprol-XL.com.

To view AstraZeneca's letter to health care professionals, which includes color images of the involved medications, visit fda.gov/medwatch/safety/2005/toprol_dhcp.pdf.

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Injectable products recalled due to sterility concerns

September 20, 2005

ST. LOUIS (MD Consult) - On September 16, 2005, Central Admixture Pharmacy Services, Inc, of Lanham, Md, (CAPS) and the US Food and Drug Administration notified health care professionals and hospitals about a product recall involving all injectable products manufactured by CAPS. The recall was prompted by concerns regarding the sterility of these injectable products. CAPS distributed the affected injectable products to hospitals in Maryland, Delaware, Washington, DC, and Virginia.

Gram-negative rods have been identified in 2 lots of Cardioplegia solution manufactured by CAPS. Nonsterility of injectable products could represent a serious hazard to health that could lead to life-threatening injuries and death.

The following products distributed up to September 16, 2005, are affected by this action:

• Cardioplegia solutions, including Cardioplegia, Cold Cardioplegia, Warm Cardioplegia, Blood Cardioplegia 1, Blood Cardioplegia 2, Cardioplegia Base 1, Cardioplegia Base 2, Cardioplegia Base, Cardioplegia Reperfusion, Cardioplegia High Potassium, Cardioplegia Low Potassium, Cardioplegia #1, Cardioplegia #2 Cardioplegia #3; Maintenance Cardioplegia, Enriched Cardioplegia, Cardioplegia Hot Shot, and Cardioplegia Base Enriched
• Oxytocin injectable products, including Oxytocin Infusion, Oxytocin 20 units, Oxytocin 30 units, Oxytocin D5 ½ NS, and Oxytocin in lactated Ringer's solution
• Promethazine
• Magnesium-containing injectable products, including Magnesium 1 GM, Magnesium 2 GM, Magnesium Sulfate 2 GM, Magnesium 4 GM, Hydration-Magnesium in D5W, Magnesium Infusion, and Magnesium in lactated Ringer's solution
• Heparin Replacement
• Antibiotic Irrigation Bag and Bottle
• Bupivicaine 0.25 % and 0.5%, Pain Bags (Bupivicaine 0.25 %)
• Dialysate solutions, including Citrate Dialysate, Heparin Dialysate, Pediatric Dialysate, Hydration Dialysate #1, Hydration Dialysate #2, CRRT Dialysate, CVVHD (Dialysate) 300, CVVHD (Dialysate) 342, CVVHD Pediatric Formula (Normocarb), CVVHD Formalin #1, CVVHD Formalin #2, CVVHD Formalin #3, CVVHD Non-Standard, CVVHD D5W, CVVHD ½ NS, and CVVHD NS
• Total Parenteral Nutrition (TPN) products, including TPN-Day and TPN-Day 1 Neonatal Stock Solution
• Diltiazem (Cardizem)
• Norepinephrine (Levophed)
• Cefazolin

Although CAPS has directly notified known hospital customers of the recall, all hospital personnel, physicians, and health care workers are urged to examine their supplies for any injectable products from CAPS of Lanham, Md, and immediately discontinue their use and quarantine the products.

The manufacturer has announced that instructions as to what to do with the quarantined products will be forthcoming. CAPS can be contacted by telephone at 1-301-459-9301 or 1-877-416-5376.

Any problems associated with any of these products can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Campath trial interim results reveal treatment efficacy but dangerous effects

September 19, 2005

ST. LOUIS (MD Consult) - On September 16, 2005, Genzyme Corporation and Schering AG Germany announced interim results from a phase 2 trial comparing Campath (alemtuzumab) with Rebif (interferon beta-1a) for the treatment of multiple sclerosis. The announced results derive from a prespecified efficacy and safety interim analysis conducted after 1 year of treatment for all patients in the planned 3-year trial. This review was conducted in conjunction with an independent data safety monitoring board.

Analysis of the primary end points after 1 year of treatment showed a large treatment effect in favor of alemtuzumab. Review of the data also showed that 3 confirmed cases of severe idiopathic thrombocytopenic purpura (ITP) occurred in the trial. On the basis of these results, and after consultation with the US Food and Drug Administration (FDA), the companies will continue to collect both efficacy and safety data from this trial while preparing to initiate a phase 3 trial. Dosing with alemtuzumab in this trial has been suspended while the companies work closely with regulatory authorities and clinical investigators to ensure that a comprehensive approach is in place to manage patient safety. Campath continues to be available in its current labeled indication for the treatment of B-cell chronic lymphocytic leukemia.

The phase 2 trial involved 334 randomly assigned patients with active relapsing-remitting multiple sclerosis at 49 medical centers in Europe and the United States. Patients were treated with alemtuzumab at 1 of 2 doses administered in once-a-year intravenous infusion regimens, or interferon beta-1a administered 3 times per week as indicated in its product label. The randomized, open-label trial compared the safety and efficacy of alemtuzumab with interferon beta-1a, examining 2 primary end points: the rate of relapse of multiple sclerosis symptoms and the time to progression of clinically significant disability (time to sustained accumulated disability at 6 months as measured by Expanded Disability Status Score [EDSS]). EDSS assessments were blinded and treatment groups were comparable at baseline for all key demographic and clinical parameters.

Analysis of the first co-primary end point showed that patients taking alemtuzumab at high and low doses experienced at least a 75% reduction in the risk for relapse after at least 1 year of follow-up when compared with patients treated with interferon beta-1a. This difference was statistically significant in favor of the alemtuzumab patients at both the high and low doses according to the P value assigned for the 1-year interim analysis (P = .00267).

In the other co-primary endpoint, patients treated with the high and low doses of alemtuzumab experienced at least a 60% reduction in the risk for progression of clinically significant disability (P < .05) when compared with patients treated with interferon beta-1a. This result did not achieve statistical significance according to the P value assigned for the 1-year interim analysis (P = .00015).

In the trial, serious adverse events related to treatment occurred in 2 patients receiving interferon beta-1a, 4 patients receiving the low-dose of alemtuzumab, and 5 patients receiving the high-dose of alemtuzumab. ITP is a condition in which patients experience a low platelet count that can result in abnormal bleeding. Of the 3 documented cases of ITP, 2 occurred in the high-dose-alemtuzumab group and 1 in the low-dose group. One case of ITP in the trial resulted in a fatality. In the 2 remaining cases, patients have responded to treatment and their conditions are being appropriately managed by their physicians using accepted treatment regimens.

As expected, common nonserious adverse events included infusion reactions in the patients receiving alemtuzumab patients and flulike symptoms in those receiving interferon beta-1a.

Genzyme and Schering's risk management plan for ITP has included notification of regulatory authorities, trial sites, and patients and consultation with a panel of hematologists with expertise in ITP to advise on risk management. The companies have moved forward to implement a series of provisions in the study, including more frequent hematologic monitoring and patient education about the signs and symptoms of ITP. Genzyme and Schering are also working to update informed consent forms, to conduct a thorough review of patient laboratory data, and to seek indicators that might help identify those at risk for developing these types of problems. The companies are currently in discussions with the FDA about what additional steps might be needed to protect patient safety.

Nearly all patients taking alemtuzumab in the trial have received their second year's dose. In the coming months, Genzyme and Schering will evaluate the necessity and timing of the third planned dose. Because the high dose appears to offer no efficacy advantage compared with that achieved by the low-dose group, the companies will no longer use the higher dose.

Multiple sclerosis is a chronic, debilitating disease in which a person's immune system attacks his or her brain and spinal cord. The disease causes a wide range of symptoms including fatigue, difficulty walking, numbness, and vision problems, and it can progress to cause severe disability. Relapsing-remitting multiple sclerosis is the most common form of this disease.

Campath is indicated in the United States for the treatment of B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and whose conditions have failed to respond fludarabine therapy. Determination of the effectiveness of Campath is based on overall response rates. Comparative, randomized trials demonstrating increased survival or clinical benefits such as improvement in disease-related symptoms have not yet been conducted. Campath is a humanized monoclonal antibody that binds to a specific target, CD52, on cell surfaces directing the body's immune system to destroy malignant cells. It is the first monoclonal antibody to be approved by the FDA for the treatment of B-cell chronic lymphocytic leukemia.

Genzyme and Schering are codeveloping alemtuzumab in oncology and other indications. Campath was launched in the United States in June 2001.

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Potential for dispensing errors prompts change in labeling for Novolog insulins

September 15, 2005

ST. LOUIS (MD Consult) - On August 26, 2005, Novo Nordisk Incorporated and the US Food and Drug Administration notified pharmacists of an initiative implemented to help prevent dispensing errors. Until recently, the product packaging for NovoLog Mix 70/30, a premixed insulin analog, and NovoLog, a rapid-acting insulin analog, were very similar.

To facilitate the dispensing of the correct product, color-branded labeling has been introduced for NovoLog Mix 70/30 and NovoLog. The previous box for NovoLog Mix 70/30 was white with a blue band. The current packaging for NovoLog Mix 70/30 is very similar and remains white with a blue band. The packaging for NovoLog previously was also white with a blue band; the current packaging is now white with an orange band.

It is important that all pharmacists carefully distinguish insulin formulations by name and NDC number when dispensing. Patients receiving the incorrect insulin could be subject to the risk of adverse events, such as hyperglycemia or hypoglycemia. The use of color-branded labeling will aid in facilitating dispensing of the correct product.

NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection, [rDNA origin]) is available in 10-mL vials, 1 package of 5 NovoLog Mix 70/30 FlexPen prefilled syringes as well as 1 package of 5 PenFill cartridges. NovoLog Mix 70/30 is a white suspension that becomes cloudy when mixed. The previous box for this product was white with a blue band. The current packaging is very similar and remains white with a blue band.

NovoLog Mix 70/30 is indicated for the treatment of patients with diabetes mellitus for the control of hyperglycemia. Because NovoLog Mix 70/30 has peak pharmacodynamic activity 1 hour after injection, it should be administered with meals. Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog Mix 70/30. Use of this product is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog Mix 70/30 or one of its excipients. Potential side effects associated with the use of all insulins include hypoglycemia, hypokalemia, lipodystrophy, and allergic reactions. Because of differences in the action of NovoLog Mix 70/30 and other insulins, care should be taken in patients in whom these conditions may be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, are using potassium-lowering drugs, or are taking drugs sensitive to serum potassium level). Do not mix NovoLog Mix 70/30 with any other insulin product.

NovoLog (insulin apart [rDNA origin] injection) is available in 10-mL vials, 1 package of 5 NovoLog FlexPen prefilled syringes as well as 1 package of 5 PenFill cartridges. NovoLog is a clear and colorless solution. The previous box for this product was white with a blue band; the current packaging is white with an orange band.

NovoLog is indicated for the treatment of diabetes mellitus in adult patients for the control of hyperglycemia. NovoLog has a more rapid onset and shorter duration of action than regular human insulin. Because of the fast onset of action, the injection of this product should be immediately followed by a meal. Because of the short duration of action of NovoLog, patients with diabetes also may require a longer-acting insulin to maintain adequate glucose control. NovoLog is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog or one of its excipients.

Any change in insulin should be made cautiously and only under medical supervision.

Novo Nordisk offers the following recommendations to help reduce the potential for dispensing errors:

• Confirm that the product name on the prescription and store printed pharmacy label match the name on the product dispensed.
• If you remove the insulin from the box for any reason, be sure to put it back in the exact same box.
• Separate medications with similar names from one another where they are stored.
• Ensure that the patient is knowledgeable about the insulin name and type that was prescribed by his or her health care professional.
• Have the patient check the insulin name and type when picking up his or her prescription.
• Instruct the patient to speak with a pharmacist immediately regarding any problems, questions, or concerns he or she may have about their medication.
• Provide counseling on how to use the medication properly.

The manufacturer requests that prescription dispensing errors involving NovoLog Mix 70/30 or NovoLog be reported to Novo Nordisk at 1-800-727-6500. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (www.fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Monitoring recommended after infusion with Erbitux, drugmaker says

September 15, 2005

ST. LOUIS (MD Consult) - On September 13, 2005, ImClone Systems Incorporated, Bristol-Myers Squibb Company, and the US Food and Drug Administration notified health care professionals of changes to the Warnings, Precautions, Adverse Reactions, and Dosage and Administration sections of the prescribing information for Erbitux (cetuximab), indicated for the treatment of epidermal growth factor receptor (EGFR) expressing metastatic colorectal carcinoma.

The Warnings and Dosage and Administration sections have been revised to include specific recommendations on observation periods after an Erbitux infusion. The following text was added to the Infusion Reactions subsection of the Warnings section of the Erbitux prescribing information:

A 1-hour observation period is recommended following the Erbitux infusion. Longer observation periods may be required in patients who experience infusion reactions.

The following sentence was added to the Preparation for Administration subsection of the Dosage and Administration section:

Longer observation periods may be required in those who experience infusion reactions.

In addition, the Precautions and Adverse Reactions sections have been revised to discuss results seen in Erbitux clinical trials regarding an increased incidence of hypomagnesemia and recommendations for electrolyte monitoring. A new subsection, titled "Laboratory Tests: Electrolyte Monitoring," has been added to the Precautions section and contains the following text:

Patients should be periodically monitored for hypomagnesemia, and accompanying hypocalcemia and hypokalemia, during and following the completion of Erbitux therapy. Monitoring should continue for a period of time commensurate with the half-life and persistence of the product; ie, 8 weeks.

A new Electrolyte Depletion subsection has been added under the Adverse Reactions section and contains the following text:

In 224 patients evaluated in ongoing, controlled clinical trials, the incidence of hypomagnesemia, both overall and severe (NCI-CTC Grades 3 and 4), was increased in patients receiving Erbitux alone or in combination with chemotherapy as compared to those receiving best supportive care or chemotherapy alone. Approximately one half of these patients receiving Erbitux experienced hypomagnesemia and 10% to 15% experienced severe hypomagnesemia. The onset of electrolyte abnormalities has been reported to occur from days to months after initiation of Erbitux. Electrolyte repletion was necessary in some patients, and in severe cases intravenous replacement was required. The time to resolution of electrolyte abnormalities is not well known, hence monitoring after Erbitux treatment is recommended.

For more details regarding Erbitux, including full prescribing information, visit erbitux.com.

To report serious adverse events related to the use of Erbitux, contact the manufacturer at 1-888-ERBITUX (1-888-372-4889). Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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New cardiotoxicity info available for cancer treatment

September 8, 2005

ST. LOUIS (MD Consult) - On August 31, 2005, Genentech and the US Food and Drug Administration (FDA) notified health care professionals of updated cardiotoxicity information related to the use of Herceptin (trastuzumab), obtained from the National Surgical Adjuvant Breast and Bowel Project (NSABP) study (B-31). This randomized, phase III trial was conducted in 2,043 women with operable, HER2-overexpressing breast cancer (IHC 3+ or FISH+). The study demonstrated a significant increase in cardiotoxicity in patients who were randomly assigned to the Herceptin-containing arm versus patients who received chemotherapy alone.

A preliminary analysis of the safety data from Study NSABP B-31 was presented at the annual meeting of the American Society of Clinical Oncology in May 2005, during the presentation of a joint analysis of Study NSABP B-31 and the North Central Cancer Treatment Group (NCCTG) study (N9831). Study NSABP B-31 was intended, in part, to characterize cardiotoxicity associated with Herceptin use and to assess the value of serial cardiac monitoring during Herceptin therapy as a predictor of cardiotoxicity and as an aid to early identification of cardiac toxicity.

Study NSABP B-31 evaluated the addition of Herceptin to standard adjuvant chemotherapy. The chemotherapy regimen consisted of 4 cycles of doxorubicin and cyclophosphamide (AC) followed by 4 cycles of paclitaxel every 3 weeks; patients were randomly assigned to receive Herceptin for 1 year, at the approved dose and schedule, during and after paclitaxel (arm 2) or to receive paclitaxel alone (arm 1). Patients in this study were required to have a baseline assessment of cardiac function with either multigated acquisition scan or echocardiogram and to have follow-up assessments at the completion of AC and at 6, 9, and 18 months after the initiation of paclitaxel with or without Herceptin. Eligible patients had a left ventricular ejection fraction (LVEF) measurement at baseline (before any therapy) that was within normal limits and no history of or active cardiac disease, including cardiomyopathy, congestive heart failure, prior myocardial infarction, or arrhythmia.

Before initiation of Herceptin (arm 2), LVEF measurements were required to be at or above the radiology facility's lower limit of normal and be no more than 15 points below baseline measurements.

Herceptin was permanently discontinued in patients with symptomatic cardiac toxicity. In the event that Herceptin administration was withheld or discontinued because of cardiotoxicity, paclitaxel was administered at the investigator's discretion.

A total of 1,019 patients were randomly assigned to arm 2. Based on preliminary data and analyses through April 2005, 6.8% of patients were unable to initiate Herceptin per the protocol because of decreased LVEF or symptoms of cardiac toxicity experienced during the AC portion of therapy. Among the evaluable patients who had adequate cardiac function and initiated Herceptin therapy, 30.5% required at least 1 dose delay because of asymptomatic decrease in LVEF or cardiac symptoms. In 18.6% of patients, Herceptin was discontinued before the completion of 1 year of therapy because of asymptomatic decrease in LVEF (14.3%) and symptomatic cardiac dysfunction/other cardiac toxicity (4.3%). In addition, a statistically significant increase in the 3-year cumulative incidence of New York Heart Association class III and IV congestive heart failure and cardiac death was observed in patients who received the Herceptin-containing regimen (4.1%) compared with control (0.8%). There were no cardiac deaths observed in patients who received the Herceptin-containing regimen and 1 cardiac death was observed in the control arm.

Final analysis of the cardiac safety data collected in studies NSABP B-31 and NCCTG N9831 is ongoing.

Risk factors for cardiac dysfunction will be analyzed with data from both the NSABP B-31 and NCCTG N9831 trials, when available. A preliminary exploratory analysis performed by NSABP investigators suggests that age and LVEF after AC chemotherapy may identify patients at greatest risk for symptomatic cardiac dysfunction.

Herceptin as a single agent is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received 1 or more chemotherapy regimens for their metastatic disease. Herceptin in combination with paclitaxel is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease. Herceptin should be used in patients whose tumors have been evaluated with an assay validated to predict HER2 protein overexpression. It should be noted that Herceptin is not indicated for any other patients, including those with newly diagnosed, operable breast cancer.

Genentech has requested that health care professionals report any serious adverse events suspected to be associated with the use of Herceptin to the company at 1-888-835-2555. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Trypan Blue 0.06% ophthalmic solution recalled nationwide

August 30, 2005

ST. LOUIS (MD Consult) - On August 26, 2005, Custom RX Compounding Pharmacy of Richfield, Minn, announced it is initiating a nationwide recall of Trypan Blue 0.06% Ophthalmic Solution because it may be contaminated with Pseudomonas aeruginosa. If applied to the eyes, P aeruginosa might lead to serious injury, including possible blindness. Use of the recalled Trypan Blue lots should stop immediately.

Trypan Blue was distributed to hospitals and clinics in Maryland, Minnesota, Illinois, Nebraska, North Dakota, Michigan, Washington, DC, and Pennsylvania. This product is intended for ophthalmic use during cataract surgery. The US Food and Drug Administration (FDA) requires that all ophthalmic products be sterile.

The solution is dark blue in appearance and is packaged in 1-cc sterile tuberculin syringes. Custom Rx Pharmacy is asking that all unexpired syringes be collected and returned to the pharmacy. The recall includes, but may not be limited to, the following lot numbers: 05042005:86@17, 05252005:36@13, 06282005:91@27, 08012005:63@24, and 08182005:43@17.

The pharmacy has voluntarily recalled the products based on 2 reports of loss of vision possibly associated with use of the product as reported by Centers for Disease Control and Prevention (CDC) and a positive bacterial culture obtained at an outside hospital. Custom RX has verified the processes and technicians involved in the preparation of this medication. The pharmacy has been apprising the FDA of the recall efforts and is working with the agency on its investigation into the cause of the contamination.

The pharmacy immediately began notifying customers and distributors and working with the CDC has called each individual hospital and clinic to arrange for the return of , destruction of , and reimbursement for all recalled product.

For more information on the recall, please contact Verne Betlach with Custom RX Pharmacy at 612-866-2211 or 612-810-1363 (mobile) for information.

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FDA announces program to promote safe use of isotretinoin

August 15, 2005

ST. LOUIS (MD Consult) - On August 12, 2005, the US Food and Drug Administration (FDA) announced approval of a strengthened distribution program for isotretinoin, called iPLEDGE, aimed at preventing use of the drug during pregnancy. Women who are pregnant or who might become pregnant should not take the drug. Isotretinoin (including generic formulations and brand name drugs such as Accutane) is a highly effective treatment for severe recalcitrant nodular acne, but it carries a significant risk of birth defects if taken during pregnancy.

The manufacturers are implementing a program that requires registration in iPLEDGE by doctors and patients who agree to accept specific responsibilities before receiving authorization to prescribe or use the drug. These measures are designed to guard against pregnancies while the drug is being used. Wholesalers and pharmacies must also comply with the manufacturers' program requirements in order to distribute and dispense the product. The FDA is approving this program under its regulations, known as Subpart H, that require restrictions on the distribution of a drug to ensure safe use.

"This stronger program is a major step in protecting against inadvertent pregnancy exposure by tightly linking negative pregnancy testing with dispensing of isotretinoin," said Dr Steven Galson, Director, FDA's Center for Evaluation and Research. "iPLEDGE, using a computer-based and telephone system, will provide health care professionals with the real-time information necessary to effectively manage the risks of isotretinoin."

In February 2004, at a joint meeting, the FDA's Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee reviewed the existing isotretinoin risk management programs in effect at that time. Based on its review, the joint committee called for major improvements in the restricted distribution program, including mandatory registration to ensure that patients who could become pregnant have negative pregnancy test results and birth control counseling before receiving the drug.

To inform health care providers about iPLEDGE, the FDA has issued a public health advisory and revised the patient and health care provider information sheets that detail the tightened restrictions and increased responsibilities under iPLEDGE for prescribing, dispensing, distributing, and obtaining isotretinoin.

To obtain the drug, in addition to registering with iPLEDGE, patients must comply with a number of key requirements that include completing an informed consent form, obtaining counseling about the risks and requirements for safe use of the drug, and, for women of childbearing age, complying with required pregnancy testing.

A reporting and collection system for serious adverse events associated with the use of isotretinoin has also been implemented. All pregnancy exposures to isotretinoin must be reported immediately to the FDA via MedWatch (1-800-FDA-1088) and to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the iPLEDGE Web site. Doctors, patients, and pharmacies can obtain program information and register with iPLEDGE via the Internet, beginning August 22, 2005, at ipledgeprogram.com or telephone 1-866-495-0654.

In addition to approving the iPLEDGE program, the FDA has approved changes to the existing warnings, patient information, and informed consent document so that patients and prescribers can better identify and manage the risks of psychiatric symptoms and depression before and after prescribing isotretinoin.

Under the program, after October 31, 2005, wholesalers and pharmacies will have to register with iPLEDGE to obtain isotretinoin from a manufacturer. Starting December 31, 2005, all patients and prescribers must register and comply with requirements for office visits, counseling, birth control, and other responsibilities.

The manufacturers participating in the iPLEDGE program include the following:

• Hoffman-LaRoche, manufacturer of Accutane;
• Genpharm, manufacturer of Amnesteem, which is distributed by Mylan/Bertek;
• Ranbaxy Pharmaceuticals, manufacturer of Sotret;
• and Barr Laboratories, manufacturer of Claravis.

For additional consumer information, visit the following Web site sponsored by the FDA: fda.gov/cder/drug/infopage/accutane/default.htm.

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FDA alerts US residents to recall of counterfeit Lipitor sold in the United Kingdom

August 5, 2005

ST. LOUIS (MD Consult) - On July 29, 2005, the US Food and Drug Administration (FDA) alerted US residents to the recent recall of a batch of counterfeit Lipitor (atorvastatin) sold in the United Kingdom (UK). Lipitor is used to treat high cholesterol.

The counterfeit Lipitor 20-mg tablets were recalled in the United Kingdom on July 28, 2005. Health authorities in the United Kingdom stated that initial results of tests performed on the counterfeit drugs do not indicate this product poses an immediate risk to patients; however, they advise patients to stop taking the drug and to return it to the pharmacy where they obtained it. UK pharmacies are being advised to return all remaining stock of this batch to Pfizer Ltd, the manufacturer of Lipitor.

Consumers who purchased FDA-approved Lipitor products through legitimate US pharmacies should not have received any of these counterfeit tablets and are not subject to this recall. But some US residents may have obtained prescription drugs from the United Kingdom through on-line or storefront operations that do not supply legitimate, FDA-approved products or through state-run drug importation programs that facilitate the purchase of unapproved foreign drugs. Consumers who purchase drugs through these arrangements may have received these counterfeit products.

"Americans need to be very careful when buying drugs outside of the US drug distribution system," said FDA Commissioner Lester M. Crawford. "The American drug supply system is in fact a very safe one that consumers can count on."

The affected product is 20-mg Lipitor and is sold in packages of 28 tablets. The drug packages are marked with batch number 004405K1 and an expiration date of "11 2007." The batch number can be found on the end of the box next to the expiration date and on the foil backing of the drug's blister pack. Legitimate UK Lipitor also has this same batch number.

Because the recalled Lipitor is fake, there is no guarantee of its quality or effectiveness. US patients who have the identified UK drugs should stop using them and should consult their physician or pharmacist if they have any questions or concerns. Patients should resume treatment as soon as they can obtain from their physicians or pharmacists a legitimate supply of Lipitor or an equivalent medicine. When patients resume taking the drug, they should take only the daily dose prescribed and not try to make up for missed doses.

Information on Pfizer's recall of the one batch of Lipitor can be accessed from the following links: mhra.gov.uk/news/press_Lipitor_280705.pdf.

medicines.mhra.gov.uk/ourwork/monitorsafequalmed/defmedsrepcen/Lipitor_EL_05_A11Final.pdf.

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FDA issues safety alert on infants' oral drops containing enclosed syringe

August 3, 2005

ST. LOUIS (MD Consult) - The US Food and Drug Administration (FDA) announced on August 2, 2005, that the Perrigo Company has initiated a voluntary nationwide recall of all lots of concentrated infants' oral drops that are packaged with a dosing syringe bearing only a "1.6 mL" mark containing acetaminophen; acetaminophen, dextromethorphan hydrobromide, and pseudoephedrine hydrochloride; or dextromethorphan hydrobromide and pseudoephedrine hydrochloride.

The dosing syringe may be confusing in determining the proper dose for infants younger than 2 years as directed by a physician and could lead to improper dosing, including overdosing. The following products are being recalled to the retail level:

• Cherry Flavor Infant Pain Reliever 160 mg Acetaminophen (0.5 oz and 1.0 oz);
• Grape Flavor Infant Pain Reliever 160 mg Acetaminophen (0.5 oz and 1.0 oz);
• Cherry Flavor Cough and Cold Infant Drops (0.5 oz); and
• Cherry Flavor Decongestant and Cough Infant Drops (0.5 oz).

The directions on the bottle and carton labeling for infants aged 2 to 3 years and weighing 24 to 35 pounds allow safe and effective dosing for this age and weight group. However, these products are also intended for use by children younger than 2 years and weighing less than 24 pounds. The labeling directs consumers to ask a physician for dosing directions for this age and weight group.

The oral dosing syringe enclosed with these products is not marked so as to accurately measure doses less than 1.6 mL when prescribed by physicians for infants younger than 2 years and weighing less than 24 pounds. Until recently these products were provided with a dropper, not the oral dosing syringe, and the dropper had two markings on it: "0.4 mL" and "0.8 mL."

The single mark on the current syringe along with the changeover from the dropper to this syringe has caused some confusion among consumers and health care professionals and may lead to improper dosing. Taking more than the recommended dose of acetaminophen may cause liver damage. Consumers who have questions should discuss this with their physician to accurately determine proper dosage.

In using an alternative over-the-counter product, parents and physicians should thoroughly discuss the specifics about the product and the dosing device, particularly the labeling and marking, so the proper dose can be measured and administered correctly.

The confusion of the dosing syringe was noted after a physician filed a complaint with the American Academy of Pediatrics.

The recalled products were sold nationally at retail chains under the following store-brand labels: American Fare, Best Choice, Brooks, Berkley & Jensen, CVS, Dollar General, Eckerd, Equaline, Equate, Family Dollar, Food Lion, Good Neighbor, GoodSense, Healthy Generations, Health Pride, Hy-Vee, Kroger, Leader, Longs, Major, Medicine Shoppe, Meijer, Parklane, Publix, Rite Aid, Safeway, Shop Rite, Sunmark, Target, Today's Health, Top Care, Walgreens, Western Family, and Winn Dixie.

Perrigo is cooperating with the FDA in this recall and in the effort to alert consumers and retailers about this issue. Questions or concerns about a product described in this recall should be directed to Perrigo's Consumer Affairs Department, toll free, at 800-321-0105.

Any adverse reactions experienced with the use of these products should also be reported to the FDA's MedWatch Program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-1078, by mail at MedWatch, HF-410, FDA, 5600 Fishers Lane , Rockville, MD 20852-9787, or via the MedWatch Web site at accessdata.fda.gov/scripts/medwatch/.

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Labeling revised for psoriasis treatment

July 20, 2005

ST. LOUIS (MD Consult) - On July 20, 2005, the US Food and Drug Administration (FDA) announced revisions to the Warnings and Adverse Reactions sections and the patient information sheet for Raptiva (efalizumab), indicated for the treatment of adult patients (18 years and older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Genentech informed health care providers of a new warning regarding events of immune-mediated hemolytic anemia and updated warnings regarding postmarketing reports of serious infections and thrombocytopenia.

Two cases of hemolytic anemia were observed in Raptiva clinical trials. Two additional cases were reported in the postmarketing setting. In 2 severe cases, the hemoglobin decreased to 6 and 7 g/dL. A causal relationship between Raptiva and these events has not been established but cannot be excluded.

Based on this data, the following Warning has been added to the Raptiva prescribing information:

Immune-Mediated Hemolytic Anemia Reports of hemolytic anemia, some serious, diagnosed 4 to 6 months after the start of Raptiva treatment have been received. Raptiva should be discontinued if hemolytic anemia occurs.

This information has also been included in the Adverse Reactions section and the patient information sheet.

The Warnings section concerning serious infections has been updated to include rare postmarketing reports of necrotizing fasciitis, tuberculous pneumonia, bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia, and worsening of infection (eg, cellulitis, pneumonia) despite antimicrobial treatment.

The Warnings section concerning thrombocytopenia has been relabeled "Immune-Mediated Thrombocytopenia" and has been updated to include postmarketing reports.

Genentech is committed to ensuring that Raptiva is used safety and effectively. Any questions regarding the use of Raptiva can be directed to Genentech's Medical Communications department at 1-800-821-8590. The company's Web site is available at www.gene.com.

Health care professionals are requested to report any serious adverse events suspected to be associated with the use of Raptiva to Genentech at 1-888-835-2555. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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FDA investigates link between RU-486 and sepsis deaths

July 20, 2005

ST. LOUIS (MD Consult) - The US Food and Drug Administration (FDA) announced on July 19, 2005, that it is researching recently reported serious adverse events associated with Mifeprex (mifepristone, also known as RU-486). Related to this investigation, the agency issued a public health advisory highlighting the risk of sepsis or blood infection when undergoing medical abortion using Mifeprex and misoprostol in a manner that is not consistent with the approved labeling. Four deaths from infection between September 2003 and June 2005 occurring after medical abortion with these drugs have now been been reported.

"The FDA is committed to sharing emerging drug information with the public, and we believe it is important to share with health care providers and patients the latest serious reports of infection associated with this drug that we have received," said Dr Steven Galson, Acting Director of the FDA's Center for Drug Evaluation and Research.

The bacteria thought to have caused the fatal infection (Clostridium sordellii) have been identified in 2 of the cases, and the other 2 cases are under investigation by the FDA along with the Centers for Disease Control and Prevention, state and local health departments, and the manufacturer of Mifeprex, Danco Laboratories.

Sepsis is a known risk related to any type of abortion. The symptoms in these cases were not the usual symptoms of sepsis. At this time, the FDA does not claim to know whether using Mifeprex or misoprostol caused these reported deaths. Patients should contact a health care professional right away if they have taken these medicines and develop stomach pain or discomfort, or if they have weakness, nausea, vomiting, or diarrhea with or without fever, more than 24 hours after taking misoprostol. These symptoms, even without a fever, may indicate sepsis. Patients should make sure their health care practitioners know they are undergoing a medical abortion. Doctors are urged to have a higher level of suspicion for sepsis if their patients are taking Mifeprex.

In November 2004, the FDA received reports of serious bacterial infection, bleeding, ectopic pregnancies that have ruptured, and death related to use of Mifeprex. Those reports led to the revision of the black box labeling packaged with this medication.

Mifeprex was approved by the FDA in September 2000 for the termination of early pregnancy, defined as 49 days or less, counting from the beginning of the last menstrual period. For more information, visit fda.gov/cder/drug/infopage/mifepristone/default.htm.

The FDA's new public health advisory, which contains more detailed instructions for health care workers and approved regimens of Mifeprex, is available at fda.gov/cder/drug/advisory/mifeprex.htm.

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Panel clarifies warnings for CHF medication

July 19, 2005

ST. LOUIS (MD Consult) - Scios and the US Food and Drug Administration notified health care professionals on July 13, 2005, about the recommendations of an expert panel of cardiology and heart failure clinicians with regard to Natrecor (nesiritide). Recent questions raised about worsened renal function and mortality prompted the formation of the panel, which provided a consensus statement on each issue, provided advice on the ongoing and planned clinical development program, made recommendations about the appropriate use of the drug, and recommended an educational campaign to ensure that clinicians understand when the use of Natrecor is appropriate and when it is not.

In a letter addressed to health care professionals, California-based biopharmaceutical company Scios noted that the panel, led by Dr Eugene Braunwald, Distinguished Hersey Professor of Medicine, Harvard Medical School, reviewed the available data, including review of the original 2001 Natrecor product labeling that has described these risks. They endorsed the company's plan to conduct several clinical trials, including a large trial of clinical outcomes to further assess the benefits and risks of Natrecor. The panel also strongly encouraged Scios and investigators to continue enrollment of patients in current Natrecor trials (eg, Follow-up Serial Infusion of Nesiritide [FUSION] II) and in the planned Natrecor trials.

The panel also made recommendations about the appropriate use of Natrecor and encouraged the manufacturer to engage in a campaign to further educate clinicians about the drug. The panel made the following specific recommendations:

1. The use of Natrecor should be strictly limited to patients presenting to the hospital with acutely decompensated congestive heart failure (CHF) who have dyspnea at rest, as were the patients in the largest trial that led to approval of the drug (VMAC). Physicians considering the use of nesiritide should consider its efficacy in reducing dyspnea, the possible risks of the drug, and the availability of alternate therapies to relieve the symptoms of CHF.
2. Nesiritide should not be used to replace diuretics. Furthermore, because sufficient evidence is not currently available to demonstrate benefit for the applications listed below, nesiritide should not be used:
   • For intermittent outpatient infusion
   • For scheduled repetitive use
   • To improve renal function
   • To enhance diuresis
3. Scios should immediately undertake a proactive educational program to inform physicians regarding the conditions and circumstances in which nesiritide should and should not be used, as described above. Sponsor-supported communications, including review articles of nesiritide, should reflect the above recommendations. Scios should ensure that current and future marketing and sales activities related to nesiritide are consistent with this educational program.

Natrecor is indicated for the intravenous treatment of patients with acutely decompensated CHF who have dyspnea at rest or with minimal activity. In this population, the use of Natrecor reduced pulmonary capillary wedge pressure and improved dyspnea. The recommended dose of Natrecor is an intravenous bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Consistent with the clinical trials supporting its approval, the commercial use of Natrecor in clinical practice (noninvestigational) should be strictly limited to patients with acutely decompensated heart failure with a clinical presentation severe enough to warrant hospitalization. Natrecor should be administered in a clinical setting where blood pressure can be closely monitored. The drug should not be initiated at a dose higher than the recommended dose.

The prescribing information for Natrecor reflects data from 10 clinical trials including 941 patients with CHF (NYHA class II-III, 61%; class IV, 36%; mean age, 60 years; women, 28%). There were 5 randomized, multicenter, placebo- or active-controlled studies in which 772 patients with decompensated CHF received continuous infusions of Natrecor at doses ranging from 0.01 to 0.03 mcg/kg/min. Of these patients, the majority (70%) received the Natrecor infusion for at least 24 hours; 48% received Natrecor for 24 to 48 hours, and 22% received Natrecor for greater than 48 hours.

All of the patients participating in each of these trials required hospitalization for acutely decompensated heart failure. The study trials permitted entry at any point during the treatment course of acutely decompensated CHF, demonstrating that the use of Natrecor is safe and effective in a broad range of hospitalized patients. For example, the studies included patients in whom the study drug (either Natrecor or control) was started as the first intravenous vasoactive therapy before or after intravenous diuretics, as replacement therapy for patients not sufficiently responsive to another intravenous vasoactive therapy, or as add-on therapy in patients refractory to dobutamine or dopamine.

The VMAC trial, the largest relied on for the approval of the drug, was a randomized, double-blind study of 489 patients who required hospitalization for management of shortness of breath at rest or with minimal activity (eg, talking, eating, or bathing) due to acutely decompensated CHF. Patients with acute coronary syndrome, preserved systolic function, arrhythmia, and renal insufficiency were not excluded. The study compared the effects of Natrecor, placebo, and intravenous nitroglycerin when added to background therapy (intravenous and oral diuretics, nonintravenous cardiac medications, dobutamine, and dopamine). VMAC was designed to show primary efficacy comparisons between Natrecor and placebo. The nitroglycerin arm was included to show the relative safety and tolerability of Natrecor in comparison with a commonly used intravenous vasodilator.

The primary end points of VMAC were the change from baseline in patients' dyspnea and the change from baseline in pulmonary capillary wedge pressure (PCWP), evaluated after 3 hours. Patients receiving Natrecor reported greater improvement in dyspnea at 3 hours than patients receiving placebo plus standard care (P = .034). Natrecor led to a significant reduction in PCWP compared with placebo at 3 hours, when added to standard care (P < .001). There was a significant reduction in mean PCWP, relative to placebo, within 15 minutes of starting the Natrecor infusion, with most of the effect observed at 3 hours being achieved within the first 60 minutes of the infusion.

In its letter to health care professionals, Scios acknowledged that Natrecor is sometimes administered via intermittent and scheduled infusions to treat severely ill patients with CHF, particularly in the outpatient setting. Although a clinical development program is currently underway in this setting (FUSION II trial), Scios does not recommend Natrecor for this use at this time.

According to Scios, the only controlled clinical trial to assess the use of Natrecor for serial infusions in the outpatient setting is FUSION I. FUSION I was a pilot study (n = 210) and was not powered to adequately assess the effectiveness or safety of serial infusions of Natrecor. The size of the study, its design, and its findings provide an inadequate basis to recommend the routine use of intermittent, serial, or scheduled repetitive infusions of Natrecor.

In certain instances, Natrecor is also being used to replace diuretics, to improve renal function, or to enhance diuresis. To date, adequate clinical data that demonstrate clinically relevant diuretic properties or positive renal effects of Natrecor do not exist. The manufacturer does not recommend such use. Moreover, it is important to understand that clinical trial data show that the use of Natrecor was associated with a dose-dependent increase in serum creatinine. In VMAC, the serum creatinine level rose by more than 0.5 mg/dL above baseline in at least 1 blood draw in 7% of patients in the control groups and 8% in the nesiritide groups by 5 days, and by 21% and 28% respectively, by 30 days. Most of these increases occurred days after discontinuation of the drug.

Natrecor may cause hypotension. If hypotension occurs during the administration of Natrecor, the dose should be reduced or discontinued, and blood pressure should be monitored closely. At the recommended dose of Natrecor, the incidence of symptomatic hypotension (4%) was similar to that of intravenous nitroglycerin (5%). Asymptomatic hypotension occurred in 8% of patients treated with either drug. The mean duration of symptomatic hypotension was longer with Natrecor than intravenous nitroglycerin (2.2 vs 0.7 hours, respectively). Higher doses of Natrecor increased the risk of hypotension and elevated creatinine. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with Natrecor may be associated with azotemia.

Other adverse events reported at a rate of at least 5% during the first 24 hours of infusion with either Natrecor plus standard care or intravenous nitroglycerin plus standard care therapy, respectively, included the following: ventricular tachycardia (3%, 5%), nonsustained ventricular tachycardia (3%, 5%), headache (8%, 20%), abdominal pain (1%, 5%), and nausea (4%, 6%). Natrecor should not be used in patients with systolic blood pressure <90 mm Hg or as primary therapy in patients with cardiogenic shock. Natrecor is not recommended for patients for whom vasodilating agents are not appropriate and should be avoided in patients with low cardiac filling pressures. In the 7 Natrecor clinical trials that collected mortality data through 30 days, 5.3% in the Natrecor treatment group died, compared with 4.3% in the group treated with other standard medications. In the 4 clinical trials in which mortality was collected through 180 days, 21.7% in the Natrecor treatment group died compared with 21.5% in the group treated with other standard medications. There are insufficient numbers of deaths to identify or exclude, with confidence, a moderate excess of risk to survival after treatment with Natrecor.

For more information about the use of Natrecor, call the Scios Medical Information department at 1-877-4-NATRECOR (1-877-462-8732) or visit natrecor.com.

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Additional safety warnings issued for fentanyl transdermal patches

July 15, 2005

ST. LOUIS (MD Consult) - On July 15, 2005, the US Food and Drug Administration (FDA) issued a public health advisory to alert health care professionals, patients, and their caregivers of reports of death and other serious adverse effects from overdoses of fentanyl in patients using fentanyl transdermal patches for pain control.

Deaths and overdoses have occurred in patients using both the brand name product Duragesic and the generic product. The directions for using the fentanyl skin patch must be followed exactly to prevent death or other serious side effects from overdosing with fentanyl. Some patients and health care providers may not be fully aware of the dangers of this very strong narcotic painkiller. Therefore, the FDA is issuing this advisory to alert patients and their caregivers and health care professionals by highlighting the following important safety information:

• Fentanyl skin patches are very strong opioid painkillers that may cause death from overdose. The fentanyl skin patch should always be prescribed at the lowest dose needed for pain relief.
• Fentanyl skin patches should not be used to treat short-term pain, pain that is not constant, or for pain that occurs after an operation. Fentanyl skin patches should only be used by patients who are already opioid tolerant, and who have chronic pain that is not well controlled with shorter-acting painkillers.
• Patients who are using the fentanyl skin patch and their caregivers should be told about the directions for safe use of the patch and should follow the directions exactly. These directions are provided in the patient package insert.
• Patients who are using the fentanyl skin patch and their caregivers should be told about safe methods for storage and disposal of used, unneeded, or defective fentanyl skin patches. Fentanyl skin patches should be stored in a safe place and kept out of the reach of children. Safely dispose of used, unneeded, or defective fentanyl skin patches by folding the sticky side of the patch over on itself (until it sticks to itself) and flushing it down the toilet.
• Health care professionals who prescribe the fentanyl skin patch and patients who use the fentanyl skin patch and their caregivers should be aware of the signs of fentanyl overdose. Signs of fentanyl overdose include trouble breathing or shallow breathing; tiredness, extreme sleepiness, or sedation; inability to think, talk, or walk normally; and feeling faint, dizzy, or confused. If these signs occur, medical attention should be sought immediately.
• Patients using the fentanyl skin patch may experience a sudden and possibly dangerous rise in their body level of fentanyl or experience a stronger effect from fentanyl if they use other medicines that affect brain function, drink alcohol (beer, wine, or distilled spirits), have an increase in body temperature or are exposed to heat, or use other medicines that affect how fentanyl is broken down in the body. These factors are described further in the product label.

In June 2005, the Duragesic product label was updated to add new safety information in several areas of labeling, and a "Dear Healthcare Professional" letter about these changes was issued by the manufacturer and is available at this link fda.gov/medwatch/SAFETY/2005/duragesic_ddl.pdf.

The FDA continues to work with the manufacturers of these products to identify and manage factors that contribute to fentanyl overdose from use of the fentanyl skin patch. Updates will be provided as new information is available.

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Fatal reactions can occur when Palladone taken with alcohol, drug withdrawn from market

July 14, 2005

ST. LOUIS (MD Consult) - According to an announcement made July 13, 2005, the US Food and Drug Administration (FDA) has asked Purdue Pharma, the makers of Palladone (hydromorphone hydrochloride) extended-release capsules, to withdraw the drug from the market. This action was taken after the FDA acquired new information that serious and potentially fatal adverse reactions can occur when Palladone is taken together with alcohol.

Palladone is a once-a-day pain management drug containing a very potent narcotic. New data gathered from a company-sponsored study testing the potential effects of alcohol use shows that when Palladone is taken with alcohol the extended-release mechanism is harmed, which can lead to dose dumping. Dose dumping is a term that describes the rapid release of the active ingredient from an extended-release product into the bloodstream. The consequences of dose dumping at the lowest marketed dose (12 mg) of Palladone could lead to serious or even fatal adverse events in some patients, and the risk is even greater for the higher strengths of the product. As a result of this potential serious safety risk, the FDA has asked Purdue Pharma, and they have agreed, to suspend all sales and marketing of Palladone in the United States pending further discussions with the agency.

"All powerful pain management drugs have serious risks if used incorrectly, but the current formulation of Palladone presents an unacceptably high level of patient risk," said Dr Steven Galson, FDA Acting Director of the Center for Drug Evaluation and Research. "Although we have not received reports of serious problems, this product has so far been used in a relatively small number of patients. We are concerned that as more patients take this drug, safety problems will arise since even having one alcoholic drink could have fatal implications."

The current labeling for Palladone, approved in September 2004, already includes the standard opioid warning against the use of alcohol and Palladone. However, the FDA does not believe that the risk of serious and potentially fatal adverse events can be effectively managed by label warnings and a risk management plan.

Patients currently taking Palladone should consult their physicians for alternative treatments. Patients who, on the advice of their physician, continue to take their current supply of Palladone should not drink alcohol—including beer, wine, or distilled spirits—or take other prescription or over-the-counter-medicines that contain alcohol on days they take Palladone. In addition, the FDA instructed that any unused Palladone capsules should be disposed of safely by flushing them down the toilet.

The FDA's public health advisory on this topic is available at fda.gov/cder/drug/advisory/palladone.htm. For additional information on Palladone, please visit fda.gov/cder/drug/infopage/palladone/default.htm.

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New labeling for pain patch warns of interactions with alcohol and CNS depressants

July 12, 2005

ST. LOUIS (MD Consult) - On July 8, 2005, Janssen and the US Food and Drug Administration (FDA) notified health care professionals of changes to the boxed warning and Warnings, Contraindications, Precautions, and Dosage and Administration sections of the prescribing information for Duragesic (fentanyl transdermal system). The changes reflect the FDA's efforts to harmonize labeling for controlled-release CII products as well as a heightened awareness of safety issues associated with opioids in general, such as abuse, misuse, and diversion.

The changes include important safety information in the following areas of the labeling: Use Only in Opioid-Tolerant Patients; Misuse, Abuse, and Diversion; Hypoventilation (Respiratory Depression); Interactions with CYP3A4 Inhibitors; Damaged or Cut Patches; Accidental Exposure to Fentanyl; Chronic Pulmonary Disease; Head Injuries and Intracranial Pressure; Interactions with Other CNS Depressants; and Interactions with Alcohol and Drugs of Abuse.

Duragesic contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances (which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone) have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (Duragesic) may be a particular target for abuse and diversion.

Duragesic is indicated for management of persistent, moderate to severe chronic pain that:

• requires continuous, around-the-clock opioid administration for an extended period of time, and
• cannot be managed by other means such as nonsteroidal analgesics, opioid combination products, or immediate-release opioids.

Duragesic should only be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to Duragesic 25 mcg/h. Patients who are considered opioid tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could occur, Duragesic (fentanyl transdermal system) is contraindicated in the following situations:

• when a patient is not opioid tolerant;
• in the management of acute pain or when a patient requires opioid analgesia for a short period of time;
• in the management of postoperative pain, including use after outpatient or day surgeries (eg, tonsillectomies);
• in the management of mild pain;
• in the management of intermittent pain (eg, use on an as-needed basis [PRN]).

Full prescribing information for Duragesic is available at janssen.com/html/jan/pd_our_products.xml?article=prescribinginfo_duragesic.jspf.

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FDA reports eye problems related to erectile dysfunction meds, labeling updated

July 12, 2005

ST. LOUIS (MD Consult) - On July 8, 2005, the US Food and Drug Administration (FDA) approved updated labeling for the erectile dysfunction treatments Cialis (tadalafil), Levitra (vardenafil hydrochloride), and Viagra (sildenafil citrate) to reflect a small number of postmarketing reports of sudden vision loss attributed to nonarteritic ischemic optic neuropathy (NAION), a condition in which blood flow is blocked to the optic nerve.

The FDA advises patients to stop taking these medicines and to call a doctor or health care provider right away if they experience sudden or decreased vision loss in 1 or both eyes. Furthermore, patients taking or considering taking these products should inform their health care professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Such patients are at an increased risk of experiencing NAION again.

At this time, it is not possible to determine whether these oral medicines for erectile dysfunction were the cause of the loss of eyesight or whether the problem is related to other factors such as high blood pressure, diabetes, or a combination of these problems. The new labeling information is available along with additional information for health care providers and consumers on the FDA Web site at the following addresses:

Viagra (fda.gov/cder/consumerinfo/viagra/vIAGRA.htm)

Levitra (fda.gov/cder/drug/infopage/vardenafil/default.htm)

Cialis (fda.gov/cder/drug/infopage/cialis/default.htm)

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FDA warns consumers, dietary supplement Liqiang 4 could be dangerous

July 6, 2005

ST. LOUIS (MD Consult) - On July 1, 2005, the US Food and Drug Administration (FDA) issued a nationwide warning to consumers not to take Liqiang 4 Dietary Supplement Capsules because they contain glyburide, a drug that could have serious, life-threatening consequences in some persons.

Glyburide is a drug used to lower blood sugar and is safe and effective when used as labeled in FDA-approved medications. Persons who have low blood sugar or those with diabetes can receive dangerously high amounts of glyburide by consuming Liqiang 4. Consumers should immediately stop using these products and seek medical attention, especially if they are currently being treated with diabetes drugs or if they have symptoms of fatigue, excessive hunger, profuse sweating, or numbness of the extremities. Consumers who have this product should dispose of it immediately.

This product is sold as part of a shrink-wrapped two-bottle set. One of the 90-capsule bottles is labeled Liqiang 4 Dietary Supplement Capsules, the other bottle is promoted as a "bonus pack" of Liqiang 1. At this time, the FDA is evaluating Liquang 1 and other versions of this line of products to determine their composition and safety. The product is manufactured by Liqiang Research Institute, China, and marketed throughout the United States in herbal stores and through mail-order by Bugle International of Northridge, Calif.

The FDA learned of the potential problem through an anonymous consumer complaint and followed up with testing that revealed the presence of glyburide in this product.

The product has also been termed "Liqiang Xiao Ke Ling" (Liqiang Thirst Quenching Efficacious) in ads in Chinese-language publications that promote it as useful for the control of diabetes and derived only from natural ingredients.

The FDA encourages consumers, health care providers, and caregivers to report any adverse events related to this product to MedWatch, the FDA's voluntary reporting program, by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, Rockville, MD 20852-9787).

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Lidoderm sales materials are misleading, says FDA

June 30, 2005

ST. LOUIS (MD Consult) - On June 28, 2005, the US Food and Drug Administration (FDA) sent a letter to Endo Pharmaceuticals instructing the company to immediately stop distributing two direct mail pieces that contain false or misleading information about Lidoderm (lidocaine patch 5%). The FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) determined that the pieces contain unsubstantiated effectiveness claims for Lidoderm, and they omit and minimize serious risk information associated with Lidoderm. In addition, they fail to communicate an important limitation in the drug's FDA-approved indication. Thus, the agency stated, the direct mailing pieces misbrand the drug within the meaning of the Federal Food, Drug, and Cosmetic Act and are a public health concern because they may encourage use of Lidoderm in circumstances other than those in which the drug has been shown to be safe and effective.

Lidoderm is a topical anesthetic patch composed of an adhesive material containing 5% lidocaine. According to its FDA-approved product labeling, "Lidoderm is indicated for relief of pain associated with postherpetic neuralgia [PHN]. It should be applied only to intact skin" (emphasis in original).

The prescribing information also states that Lidoderm is associated with numerous important risks, including the following:

Contraindications Lidoderm is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product. Warnings Accidental Exposure in Children Even a used Lidoderm patch contains a large amount of lidocaine (at least 665 mg). The potential exists for a small child or a pet to suffer serious adverse effects from chewing or ingesting a new or used Lidoderm patch, although the risk with this formulation has not been evaluated. It is important for patients to store and dispose of Lidoderm out of the reach of children and pets. Excessive Dosing Excessive dosing by applying Lidoderm to larger areas or for longer than the recommended wearing time could result in increased absorption of lidocaine and high blood concentrations, leading to serious adverse effects (see Adverse Reactions, Systemic Reactions). Precautions General Hepatic Disease. Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of lidocaine because of their inability to metabolize lidocaine normally. Drug Interactions Antiarrhythmic Drugs. Lidoderm should be used with caution in patients receiving class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic. Adverse Reactions Application Site Reactions During or immediately after treatment with Lidoderm, the skin at the site of application may develop erythema, edema, bruising, papules, vesicles, discoloration, depigmentation, burning sensation, pruritus, dermatitis, petechia, blisters, exfoliation, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours.

As the FDA stated in its letter, both of the promotional pieces make effectiveness claims for Lidoderm that, as far as the agency knows, have not been demonstrated by substantial evidence or substantial clinical experience. For example, the first piece (LD-1204F) presents the following claims:

• 66% of patients (n = 310) reported improvement in pain intensity at week 1
• 78% of patients (n = 310) reported improvement in quality of life at week 1

The second piece (LD-1316B) presents the following claims:

• 2 out of 3 patients (n = 310) achieved reduction in pain intensity at week 1
  • No serious systemic adverse events were seen in this predominantly elderly population (mean age, 71 years)
• Continue with Lidoderm and more of your patients may respond
• 4 out of 5 patients (n = 310) achieved reduction in pain intensity at week 2, with efficacy sustained for the duration of the trial

These claims are misleading because they are not supported by substantial evidence or substantial clinical experience. The study cited for support of these claims was an open-label, single-arm study with no concurrent control group, rather than a well-controlled study. Without a control group and blinding to reduce the possibility of bias, subjective end points such as "pain intensity" and "quality of life" cannot be properly assessed. It is therefore not possible to tell from the study whether patient outcomes on Lidoderm were better than what would be expected in the absence of treatment. Furthermore, in its letter, the FDA stated that it was not aware of any other evidence or clinical experience that substantiate claims detailed in the mailings.

Both of the direct mailing pieces present numerous effectiveness claims for Lidoderm, including the following: "improvement in pain intensity," "improvement in quality of life," "relief of the neuropathic pain of PHN," "Pain relief is within reach!", "for localized pain relief," and "With Lidoderm...it all adds up to relief." Under the Federal Food, Drug, and Cosmetic Act, whether a drug's labeling is misleading depends not only on the representations made or suggested in it, but also on the extent to which the labeling fails to reveal facts material in light of those representations. In this instance, both pieces fail to include such information. Specifically, they fail to reveal important risks associated with use of Lidoderm as presented in the prescribing information. For example, both pieces omit the serious warnings set forth above regarding accidental exposure in children and excessive dosing. According to the FDA, in addition to omitting important risk information, the direct mailing pieces also misleadingly minimize the risks they do mention. First, the agency stated, one of the marketing pieces (LD-1204F) minimizes Lidoderm's risks by virtue of its physical configuration. In this piece, all of the risk information is only accessible after pulling a tab on the front of the piece and then turning the page over and reading the back of the tab. If the tab is reinserted before turning the page, the information is no longer visible. There are also no signals within the piece to alert readers to the presence of this important risk information inside the tab.

Second, the information relating to risk that is presented in the pieces does not adequately describe the risks associated with Lidoderm. Specifically, the pieces claim: "Most commonly reported adverse event in this study was localized rash, which was considered to be related to study treatment in majority of cases" (LD-1204F) and "Most commonly reported adverse event was localized rash (12%)" (LD-1316B). The FDA pointed out that these statements are insufficient to describe the myriad of application site reactions associated with Lidoderm use, as presented in the prescribing information.

Both direct mailing pieces claim that Lidoderm is for "the neuropathic pain of postherpetic neuralgia (PHN)." This presentation is misleading, said the FDA, because it fails to communicate an important limitation in Lidoderm's approved indication as reflected in the prescribing information; specifically, that Lidoderm "...should be applied only to intact skin" (emphasis in original). By failing to adequately communicate Lidoderm's approved indication, the direct mailing pieces fail to appropriately caution against unsafe use of Lidoderm, including application to broken or inflamed skin, which, according to the Precautions section of the prescribing information, "...may result in higher blood concentrations of lidocaine from increased absorption."

In addition to requesting that Endo immediately cease the distribution of these promotional materials for Lidoderm, the DDMAC requested that the company explain its plan for discontinuing use of the materials and a comprehensive plan to disseminate "truthful, non-misleading, and complete corrective messages about the issues discussed" to those who may have received the direct mail pieces. Failure to correct the violations could result in FDA regulatory action, including seizure or injunction.

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Distribution of Iressa limited, lack of survival benefit cited

June 20, 2005

ST. LOUIS (MD Consult) - On June 17, 2005, the US Food and Drug Administration (FDA) announced newly approved labeling for Iressa (gefitinib) that limits the indication to cancer patients who, in the opinion of their treating physicians, are currently benefiting or have previously benefited from gefitinib treatment. The FDA has agreed to AstraZeneca's proposal of a risk management plan called the Iressa Access Program, which would limit distribution of this drug to the following patient populations:

• patients currently receiving and benefiting from Iressa;
• patients who have previously received and benefited from Iressa; and
• previously enrolled patients or new patients in non–Investigational New Drug (IND) clinical trials approved by an institutional review board before June 17, 2005.

New patients may also be able to obtain Iressa if AstraZeneca decides to make it available under the IND and the patients meet the criteria for enrollment under the IND.

Gefitinib, an orally administered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was approved for marketing in May 2003 for patients with non–small cell lung cancer (NSCLC) under Subpart H accelerated approval regulations that allow products to be approved on the basis of a surrogate end point for clinical efficacy. For gefitinib, the surrogate end point was tumor response rate. The response rate in patients taking the drug was approximately 10%. The approved indication was for the treatment of patients who were refractory to established cancer treatments (both a platinum drug and docetaxel). However, since the initial approval of Iressa, Tarceva (erlotinib) has been approved for treatment of this same group. Tarceva was approved based on improved overall survival.

The FDA has carefully reviewed data from 2 failed clinical studies of Iressa, 1 of which was required by the agency as part of the drug's accelerated approval. This trial enrolled patients with regionally advanced or metastatic NSCLC who had failed 1 or 2 prior treatment regimens. In this large study, 1,692 patients were given either gefitinib or placebo. There was no significant survival benefit in the overall study population nor in patients who had high levels of the surface marker EGFR. In contrast, the presence of EGFR at high levels appears to predict a good response to Tarceva.

In the second trial in patients with stage III NSCLC, after completion of induction and consolidation chemotherapy and radiation therapy, patients were given either gefitinib or placebo maintenance therapy. No gefitinib survival benefit could be demonstrated.

The FDA is not considering market withdrawal of gefitinib at this time. New clinical trials are being developed, other ongoing trials are being completed, and there will be further analysis of the completed trials described above. These will determine the future role of gefitinib treatment.

More information on Iressa is available from the FDA at fda.gov/cder/drug/infopage/gefitinib/default.htm.

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Quality Care Products furthers Able Labs recall

June 16, 2005

ST. LOUIS (MD Consult) - On June 15, 2005, Quality Care Products, LLC, a federally licensed drug repackager, announced a nationwide recall of any and all products it repackaged from drugs that were manufactured by Able Laboratories Inc. This recall is due to Able Laboratories' voluntary recall of all of their drug products because of the US Food and Drug Administration (FDA)'s serious concerns that they were not produced according to sufficient quality assurance standards.

The agency recommends that people who have been taking drugs produced by Able Laboratories speak with their health care providers or pharmacists to obtain a replacement drug product. Consumers should continue taking the medication until they have spoken with their health care providers. In many cases, the risk of suddenly stopping administration of needed medication before getting replacement drugs may outweigh the risk of continuing to use the recalled products.

A full list available on the FDA Web site at fda.gov/oc/po/firmrecalls/qualitycare06_05.html provides the names of the recalled drugs and their imprint codes. Imprints are marks (usually letters and numbers) found on the surface of a capsule and or tablet. Liquid products that are being recalled can be identified by the lot numbers printed on their packaging.

It is important to note that this recall only applies to the drugs produced by Able Laboratories, and not to the same drugs produced by other manufacturers.

The FDA has been apprised of this action on the part of Quality Care Products. No injuries from this recall have been reported to date. These products were distributed to physician office dispensaries in more than 12 states.

Quality Care Products has already notified all of its physician dispensaries via letter and has arranged for a replacement of all full or partially filled bottles. Questions can be directed to the company via e-mail at consumer@qcpmeds.com or via phone at 800-337-8603 (8 AM to 5 PM EST).

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Sustiva not safe during first trimester, FDA says

June 13, 2005

ST. LOUIS (MD Consult) - On June 10, 2005, the US Food and Drug Administration announced a notification to health care professionals of revisions to the prescribing information for Sustiva (efavirenz), indicated in the treatment of HIV-1 infection. The revisions, made to the Warnings, Precautions: Pregnancy and Information for Patients, and Patient Information sections of the drug labeling, are a result of 4 retrospective reports of neural tube defects in infants born to women with first trimester exposure to Sustiva. Because this drug may cause fetal harm when administered during the first trimester to a pregnant woman, pregnancy should be avoided in women receiving Sustiva.

The pregnancy category for Sustiva has been changed from Category C (risk of fetal harm cannot be ruled out) to Category D (positive evidence of fetal risk). The 4 neural tube defects reported included 3 cases of meningomyelocele and 1 Dandy Walker syndrome.

Women of childbearing potential should undergo pregnancy testing before initiation of treatment with Sustiva. If this medication is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be notified of the potential harm to the fetus. Although there are no adequate, well-controlled studies in pregnant women, Sustiva should be used during the first trimester of pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. Barrier contraception should always be used in combination with other contraceptive methods.

During the development of Sustiva, which is manufactured by New York–based Bristol-Myers Squibb, animal studies were performed to assess the potential for birth defects. Malformations were observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (vs 0 of 20 concomitant control subjects) in a developmental toxicity study. Throughout pregnancy (postcoital days 20-150), the monkeys were given 60 mg/kg of efavirenz daily, a dose resulting in plasma drug concentrations similar to those in humans given 600 mg/d of Sustiva. Anencephaly and unilateral anophthalmia were observed in 1 monkey fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations. An increase in fetal resorptions was observed in rats given efavirenz doses that produced peak plasma concentrations and area under the curve (AUC) values in female rats equivalent to or lower than those achieved in humans given 600 mg of Sustiva once daily. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg of Sustiva once daily.

Limited data are available regarding birth defects occurring after intrauterine exposure to Sustiva. The outcomes of pregnancy have been reviewed for 206 women (207 fetuses) after being exposed to efavirenz-containing regimens, most of which were first-trimester exposures. Birth defects occurred in 5 of 188 live births with first-trimester exposure and in 0 of 13 live births with second- or third-trimester exposure. None of these prospectively reported defects were neural tube defects. However, there have been 4 retrospective reports (ie, after the results of the pregnancy were known) of findings consistent with neural tube defects, as noted above. All 4 mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of Sustiva has not been established, similar defects have been observed in preclinical studies of efavirenz.

Sustiva, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection. This indication is based on 2 clinical trials of at least 1-year duration that demonstrated prolonged suppression of HIV RNA.

Coadministration of Sustiva with astemizole, cisapride, midazolam, triazolam, ergot derivatives, or voriconazole is contraindicated. Concomitant use of Sustiva and St John's wort (Hypericum perforatum) or St John's wort–containing products is not recommended. (This list of medications is not complete.)

Serious psychiatric adverse experiences, including severe depression (2.4%), have been reported in patients treated with Sustiva. In addition to Sustiva, factors identified in a clinical study that were associated with an increase in psychiatric symptoms included history of injection drug use, psychiatric history, and use of psychiatric medication. There have been occasional reports of suicide, delusions, and psychosis-like behavior, but it could not be determined whether Sustiva was the cause. Patients with serious psychiatric adverse experiences should be evaluated immediately to determine whether the risks of continued therapy outweigh the benefits.

Fifty-three percent of patients reported nervous system symptoms when taking Sustiva compared with 25% of patients receiving control regimens. These symptoms usually begin during days 1 or 2 of therapy and generally resolve after the first 2 to 4 weeks of therapy. Nervous system symptoms are not predictive of less frequent serious psychiatric symptoms.

Mild to moderate rash is a common side effect of Sustiva. In controlled clinical trials, 26% of patients treated with Sustiva experienced new-onset skin rash compared with 17% of patients treated in control groups. Sustiva should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Rash is more common and often more severe in pediatric patients.

Liver enzymes should be monitored in patients with known or suspected hepatitis B or C and when Sustiva is administered with ritonavir. In addition, Sustiva should be used with caution in patients with a history of seizures.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Sustiva. Furthermore, redistribution and/or accumulation of body fat have been seen in patients receiving antiretroviral therapy. A causal relationship has not been established.

It is recommended that Sustiva be taken on an empty stomach, preferably at bedtime. The increased concentrations after administration of Sustiva with food may lead to an increase in frequency of adverse events. Dosing at bedtime may improve the tolerability of nervous system symptoms.

To monitor fetal outcomes of pregnant women exposed to Sustiva, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 800-258-4263.

Questions regarding these changes to the prescribing information are referred to the Virology Medical Services Department at Bristol-Myers Squibb Company at 1-800-426-7644 (select Option 3). More information on Sustiva is also available at sustiva.com.

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Labeling confusion prompts McNeil to recall some Tylenol products

June 6, 2005

ST. LOUIS (MD Consult) - On June 3, 2005, McNeil Consumer & Specialty Pharmaceuticals announced it is voluntarily recalling all lots and all flavors of Children's Tylenol Meltaways 80 mg packaged in bottles and blisters, Children's Tylenol SoftChews 80 mg packaged in blisters, and Junior Tylenol Meltaways 160 mg packaged in blisters. The blister package design, as well as the information on the blister package and on the blister and bottle cartons may be confusing and could lead to improper dosing, including overdosing.

The blister packaging, designed to be convenient for parents who need dosing flexibility depending on the age or weight of the child, includes some blister cavities that contain 1 tablet and others that contain 2 tablets. Concerns have been raised that labeling on the carton and on the back of the 2-tablet cavities may erroneously suggest to the consumer that 2 tablets provide a total of 80 mg of the active ingredient, acetaminophen; however, 2 tablets would actually provide 160 mg of acetaminophen. Consumers should know that each tablet of Children's Tylenol Meltaways and Children's Tylenol SoftChews contains 80 mg of this active ingredient. Each tablet is imprinted with the number "80" to reflect this amount. Caregivers should be guided by the dosage directions in the "Drug Facts" labeling on the carton for the correct number of individual tablets to be given based on the child's age and weight.

In addition, some Children's Tylenol Meltaways 80 mg are packaged in a bottle. The bottle is packaged in a carton. Concerns have been raised that the information on the front panel of the carton for Children's Tylenol Meltaways 80 mg may be confusing to some consumers in determining the proper dosage. The carton labeling says that each dose provides 80 mg of acetaminophen. Consumers should know that each tablet of Children's Tylenol Meltaways contains 80 mg of acetaminophen. Caregivers should be guided by the dosage directions on the bottle label for the correct number of individual tablets to be given based on the child's age and weight.

Concerns have also been raised that the carton labeling for Junior Tylenol Meltaways 160 mg may be confusing to some consumers in determining the proper dosage. This labeling says that each "dose" provides 160 mg of acetaminophen. Consumers should know that each tablet of Junior Tylenol Meltaways contains 160 mg of acetaminophen. Caregivers should be guided by the dosage directions in the "Drug Facts" labeling on the carton for the correct number of individual tablets to be given based on the child's age and weight.

Taking more than the recommended dose of acetaminophen may cause liver damage when taking the product for fever or pain relief over the course of the 3- or 5-day period specified by the labeling.

McNeil is working with the U.S. Food and Drug Administration (FDA) in this recall and in the effort to alert consumers and retailers nationwide about this issue. Consumers or retailers who have questions or concerns about a product described in this alert can contact McNeil's Consumer Relationship Center at 1-877-895-3665 (English) or 1-888-466-8746 (Spanish) or visit TYLENOL.com. The Web site contains written material and photos of the product and the packaging.

Any adverse reactions experienced with the use of these products should be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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All drugs manufactured by Able Labs recalled, FDA announces

June 2, 2005

ST. LOUIS (MD Consult) - On May 27, 2005, the US Food and Drug Administration (FDA) notified consumer and health care professionals of a nationwide recall of all manufactured drugs (mostly generic prescription drugs, including drugs containing acetaminophen) from Able Laboratories of Cranbury, NJ, because of serious concerns that they were not produced according to quality assurance standards. Able Laboratories has ceased all current production.

"The FDA continues to evaluate the situation at Able Laboratories to determine the safety and quality of their products and will update the public on our findings as necessary," said Margaret O'K. Glavin, the agency's Associate Commissioner for Regulatory Affairs. The FDA recommends that people who have been taking drugs produced by this firm speak with their health care providers or pharmacists to obtain a replacement drug product. Consumers should continue taking the medications until they have spoken with their health care providers.

Visit the FDA Web site (fda.gov/bbs/topics/NEWS/2005/NEW01182.html) for a complete list of recalled Able drugs and their imprint codes.

Liquid products that are being recalled can be identified by the lot numbers printed on their packaging.

It is important to note that this recall only applies to the drugs produced by Able Laboratories, and not to the same drugs produced by other manufacturers. An investigation is underway to identify all the repackers and wholesalers who distribute these drugs from Able Laboratories. In the meantime, the best way for consumers to know whether they have a product produced by Able Laboratories is to check the online list and either contact their pharmacists or compare the imprint numbers on their individual tablets with the imprint numbers listed on the FDA Web site.

Consumers with questions can contact Able Laboratories at 1-800-982-2253.

Persons wanting to report any adverse events to the FDA may contact the FDA's MedWatch office by phone (1-800-FDA-1088), fax (1-800-FDA-0178),Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Risks of cardiotoxicity and secondary AML added to Novantrone label

May 26, 2005

ST. LOUIS (MD Consult) - On May 24, 2005, the US Food and Drug Administration (FDA)'s MedWatch safety information program announced revisions to the prescribing information for Novantrone (mitoxantrone for injection concentrate), indicated for treatment of multiple sclerosis (MS). The medication's manufacturer, Serono, circulated a letter in April 2005 addressed to health care professionals with the aim to supplement previously provided information concerning the risks of cardiotoxicity associated with Novantrone treatment for MS and also provides supplemental information regarding secondary acute myelogenous leukemia (AML) reported in patients with MS taking Novantrone.

Reports received through postmarketing surveillance have shown that diminished cardiac function may occur early in the treatment course with Novantrone. Therefore, the product labeling for Novantrone was updated in March 2005 to state that cardiac monitoring of MS patients should be performed at baseline and before administration of every dose of Novantrone. Refer to product labeling for full prescribing information, especially the sections on Boxed Warnings, Warnings, and Dosage and Administration.

Novantrone is indicated for reducing neurologic disability and the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS (ie, patients whose neurologic status is significantly abnormal between relapses). Novantrone is not indicated in the treatment of patients with primary progressive MS.

Cardiotoxicity

The revised Boxed Warning section of Novantrone's prescribing information reads as follows:

Use of Novantrone has been associated with cardiotoxicity. Cardiotoxicity can occur at any time during Novantrone therapy, and the risk increases with cumulative dose. Congestive heart failure (CHF), potentially fatal, may occur either during therapy with Novantrone or months to years after termination of therapy. All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of Novantrone therapy. Baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multigated radionuclide angiography (MUGA) should be performed. Multiple sclerosis patients with a baseline LVEF <50% should not be treated with Novantrone. LVEF should be reevaluated by echocardiogram or MUGA prior to each dose administered to patients with multiple sclerosis. Additional doses of Novantrone should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below 50% or a clinically significant reduction in LVEF during Novantrone therapy. Patients with multiple sclerosis should not receive a cumulative dose greater than 140 mg/m2. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2. Presence or history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with Novantrone may occur whether or not cardiac risk factors are present. For additional information, see Warnings: Cardiac Effects and Dosage and Administration.

The Warnings section of the drug labeling for Novantrone was changed as follows:

LVEF should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of Novantrone. Multiple sclerosis patients with a baseline LVEF of <50% should not be treated with Novantrone. Subsequent LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop, and prior to all doses administered to multiple sclerosis patients. Novantrone should not be administered to multiple sclerosis patients with an LVEF of <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥140 mg/m2.

Secondary Leukemia

Revisions to the boxed warning within the prescribing information for Novantrone include the following text:

Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone. In a cohort of mitoxantrone-treated MS patients followed for varying periods of time, an elevated leukemia risk of 0.25% (2/802) has been observed. Postmarketing cases of secondary AML have also been reported. In 1,774 patients with breast cancer who received Novantrone concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related AML was estimated as 1.1% and 1.6% at 5 and 10 years, respectively (see Warnings section). Secondary AML has been reported in cancer patients treated with anthracyclines. Novantrone is an anthracenedione, a related drug. The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.

Cases of secondary AML in MS patients treated with Novantrone have been reported in peer-reviewed literature, through the collection of spontaneous reports, and in a prospective observational study. Because the number of MS patients exposed to Novantrone in postmarketing is unknown and because spontaneous reporting of adverse events can be subject to underreporting, it is not possible to determine incidence—or relative risks to a patient with MS—of developing secondary AML.

The Registry to Evaluate Novantrone Effects in Worsening MS (RENEW) is an ongoing 5-year, postmarketing, observational study involving a cohort of 505 patients with worsening relapsing-remitting, secondary progressive, or progressive-relapsing MS. Since initiation of patient enrollment in April 2001, there has been 1 case of secondary AML reported, involving a 52-year-old female with secondary progressive MS. She had received a cumulative total of 72 mg/m² of Novantrone, in 6 infusions given from August 2001 to December 2002, when she was noted to be neutropenic; at that time her treatment with Novantrone was stopped. In May 2004, she was noted to have peripheral blasts, and bone marrow biopsy confirmed AML. This patient had no other known risk factors for leukemia and no concomitant potentially cytotoxic drugs were listed. Her AML was considered probably related to Novantrone. Since treatment with idarubicin and ara-C, she has been in remission. Based on this case, the incidence rate in this study is increased compared with a nonexposed matched population.

Because of the risk of secondary AML, strict adherence to existing blood cell count monitoring recommendations for patients being treated with Novantrone for MS should be followed up with complete blood counts, including platelets before each course of Novantrone and in the event that signs or symptoms of infection develop. Novantrone generally should not be administered to patients with MS with neutrophil counts less than 1,500 cells/mm³. Also, regular blood cell counts should be monitored after discontinuation of Novantrone therapy.

Full prescribing information for Novantrone is available at fda.gov/medwatch/SAFETY/2005/Novantrone_PI_may24.pdf, with revised portions of the drug labeling highlighted.

Prescribers are advised to adhere to the monitoring recommendations made in the prescribing information and to make a careful risk-benefit assessment of the use of Novantrone in their patients with MS or cancer.

Serono invites those with questions to contact the company at 1-888-ASK-SERO (1-888-275-7376). In addition, health care professionals are requested to report any serious adverse events suspected to be related to Novantrone to Serono by phone at 1-800-283-8088 or fax at 1-781-681-2961.

Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch Office, 5600 Fishers Lane, HFD-410, Rockville, MD 20852-9787).

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Mortality warnings added to drug labeling for Natrecor

May 23, 2005

ST. LOUIS (MD Consult) - On May 19, 2005, a US Food and Drug Administration (FDA) MedWatch alert announced that drugmaker Scios has notified health care professionals of revisions to the Adverse Reactions/Effect on Mortality section of the prescribing information for Natrecor (nesiritide). This medication is indicated for the treatment of acutely decompensated congestive heart failure (ADHF).

The letter from Scios addressed to health care professionals pointed out that recent reports have suggested Natrecor may have adverse effects on survival and kidney function compared with control agents (generally nitroglycerin and diuretics). Risks of mortality have also been exposed in recent studies.

Heart failure affects about 5 million Americans, the drugmaker said, and ADHF is a life-threatening condition for which there are limited treatment options. Patients with advanced ADHF have a 30% risk of mortality within 1 year. Natrecor was approved for the treatment of advanced ADHF on the basis of its ability to improve dyspnea and reduce pulmonary capillary wedge pressure. In these studies, the mortality was somewhat greater in the Natrecor group than in the comparator groups, and this has been noted in labeling since Natrecor was first marketed. It was not clear that the small increase was drug related.

Updated labeling for Natrecor was recently approved based on ongoing discussions with the FDA. The revised label language is based on the analyses of survival data from 7 controlled studies, including 3 studies used in the meta-analysis that appeared in the April 20, 2005, issue of The Journal of the American Medical Association. The label now includes 30-day mortality data in addition to the 180-day data that previously appeared in the label. The analyses show a nominal increase in mortality, but the increases are not statistically significant and thus remain of uncertain clinical significance.

In 7 Natrecor clinical trials (1,700 patients), the 30-day mortality rate was 5.3% in the Natrecor treatment group compared with 4.3% in the group treated with other standard medications. In 4 of these 7 clinical trials where it was measured, the 180-day mortality rate was 21.7% in the Natrecor treatment compared with 21.5% in the group treated with other standard medications. None of these mortality differences reached statistical significance.

Full prescribing information for Natrecor is available at natrecor.com.

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Data on treatment-naive patients added to Viread label

May 18, 2005

ST. LOUIS (MD Consult) - On May 12, 2005, the US Food and Drug Administration approved new labeling for Viread (tenofovir disoproxil fumarate). The label was updated to include results from Study 903, specifically, the 144-week efficacy and safety data in treatment-naive patients. Study 903 fulfills part of the requirement for traditional approval by confirming long-term efficacy in treatment-naive patients and by providing long-term safety information with respect to bone effects.

The changes made to the package insert are listed below.

The 144-week efficacy data from Study 903 was added:

Description of Clinical Studies Sixty-eight percent of patients who received Viread in combination with Epivir (lamivudine) and Sustiva (efavirenz) achieved and maintained confirmed HIV RNA < 400 copies/mL at week 144 compared with 62% of patients who received Zerit (stavudine) in combination with Epivir (lamivudine) and Sustiva (efavirenz).

New text describing the genotypic analysis performed during Study 903 was added as follows:

Genotypic analyses of patients with virologic failure showed development of efavirenz-associated and lamivudine-associated mutations to occur most frequently and with no difference between the treatment arms. The K65R mutation occurred in 8 patients in the Viread arm and in 2 patients in the stavudine arm. Of the 8 patients who developed K65R in the Viread arm through 144 weeks, 7 of these experienced the occurrence in the first 48 weeks of treatment and 1 at week 96. Other mutations resulting in resistance to Viread were not identified in this study.

Within the Precautions section, the Bone Effects subsection was updated with Study 903 data through 144 weeks of dosing as follows:

Precautions In Study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving Viread + lamivudine + efavirenz (-2.2% ± 3.9) compared with patients receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the 2 treatment groups (-2.8% ± 3.5 in the Viread group vs -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the study and was sustained through week 144. Twenty-eight percent of Viread-treated patients versus 21% of the stavudine-treated patients lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients in the Viread group and 8 patients in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the Viread group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 vitamin D levels were also higher in the Viread group. Except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of Viread-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Bone monitoring should be considered for HIV-infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

A new paragraph, "Immune Reconstitution Syndrome," was added. This paragraph is being incorporated into the labels of all antiretroviral drugs:

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Viread. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

In the Adverse Reactions section, text and tables displaying Selected Treatment-Emergent Adverse Events (Grades 2-4) and Grade 3/4 Laboratory Abnormalities in Study 903 was updated with data through 144 weeks of dosing. In the Postmarketing Experience subsection, increased amylase, increased liver enzymes, hepatitis, and nephrogenic diabetes insipidis were added to the list of reported disorders.

For more information, visit viread.com.

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Counterfeit drugs purchased in Mexico unsafe, FDA warns

May 11, 2005

ST. LOUIS (MD Consult) - The US Food and Drug Administration (FDA) issued an alert on May 10, 2005, warning the public about the sale of counterfeit versions of Lipitor (atorvastatin calcium), Viagra (sildenafil citrate), and an unapproved product promoted as "generic Evista" (raloxifene hydrochloride) to US consumers at pharmacies in Mexican border towns.

According to the FDA, consumers who have any of these counterfeit products should not use them and should contact their health care providers immediately. The agency warned consumers that prescription drugs purchased in foreign countries are not regulated by the FDA and do not carry the same assurances of safety, effectiveness, and manufacturing quality as drugs purchased within the United States.

Counterfeit versions of Lipitor (a cholesterol-lowering drug), Viagra (a treatment for erectile dysfunction), and Evista (a treatment and prevention medication for osteoporosis in postmenopausal women) can pose significant risks to consumers, the FDA said. Counterfeit Lipitor that contains no active ingredient or not enough active ingredient could present a long-term risk for the various complications of high cholesterol, such as heart disease. The counterfeit product purchased in Mexico was associated with several reports of high cholesterol in consumers who had used the product. Counterfeit Viagra that contains little or no active ingredient would be less effective than a legitimate product or altogether ineffective. Women who take the substandard generic Evista product that contains no active ingredient may be at risk for developing osteoporosis or for having their osteoporosis progress.

The "generic Evista" was analyzed by the FDA in coordination with the National Association of Boards of Pharmacy and was found to contain no active ingredient. The counterfeit Lipitor and Viagra were analyzed by Pfizer, Inc, and were also found to contain no active ingredient.

The "generic Evista" product was purchased from Agua Prieta, Sonora, Mexico, and is labeled as "Raloxifeno, fenilox, 50 tabletas, 60 mg." It is made or distributed by Litio and labeled as manufactured in Monterrey, Nuevo Leon, Mexico. The label has red triangles across the top and bottom. (Photographs of the products are available on the FDA Website at fda.gov/bbs/topics/news/photos/border.html).

Counterfeit Lipitor and Viagra were purchased in the Mexican border towns of Juarez, Los Algodones, Nogales, and Tijuana. The counterfeit Lipitor and Viagra products were labeled only in English, whereas legitimate Mexican pharmaceuticals are usually labeled in Spanish. In addition, the counterfeit Lipitor was provided in round white plastic bottles; however, authentic Lipitor in Mexico is sold only in boxes of blister packs.

FDA and Mexican federal health officials are continuing to work together to address the issue of counterfeit human drug products, especially along their common border. Recently, federal health officials in Mexico's Federal Commission for the Protection from Sanitary Risks (COFEPRIS) have undertaken several specific operations to target illegal drugs, including counterfeit drugs, in Mexican drug stores. These operations throughout Mexico, including the areas that border the United States, have resulted in the suspension of 19 pharmacies and the confiscation and recall of over 105 tons of medicines.

The FDA requests that reports of suspected counterfeit drugs be submitted to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

For additional consumer information on counterfeit drugs, visit fda.gov/cder/consumerinfo/counterfeit_text.htm.

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Concern over sterility initiates recall by Bedford Labs

May 2, 2005

ST. LOUIS (MD Consult) - Bedford Laboratories announced on April 28, 2005, that it is voluntarily recalling 1 lot of Famotidine Injection, 20 mg/2 mL (NDC 55390-029-10), lot #609336, due to a lack of sterility assurance. The lot carries an expiration date of 04/06.

This prescription product was distributed in August 2004 throughout the United States to wholesalers and distributors, who further distributed the product to hospitals. Customers who have any vials of this lot of Famotidine Injection should discontinue distribution and use of the lot immediately and contact Bedford Laboratories Customer Service Department (1-800-562-4797) for a returned goods authorization.

Bedford Laboratories is working with the US Food and Drug Administration on this recall. No serious health or safety reports have been received that are attributed to this situation.

Headquartered in Bedford, Ohio, Bedford Laboratories is a division of Ben Venue Laboratories, Inc, a subsidiary of Boehringer Ingelheim Corporation based in Ridgefield, Conn, and a member of the Boehringer Ingelheim group of companies. For more information on Bedford's injectable famotidine, including full prescribing information, visit www.bedfordlabs.com/products/029-10.html.

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Xigris still not indicated for children, says Lilly

April 29, 2005

ST. LOUIS (MD Consult) - On April 21, 2005, Eli Lilly announced the discontinuation of study F1K-MC-EVBP, an investigation of the efficacy and safety of Xigris (drotrecogin alfa [activated]) in pediatric severe sepsis, after an analysis showed that Xigris was "highly unlikely to show an improvement over placebo." Xigris is not indicated for use in pediatric severe sepsis.

The external, independent data monitoring committee of the randomized, double-blind, placebo-controlled trial recommended that the trial be stopped for futility. The planned interim analysis showed that Xigris was highly unlikely to show an improvement over placebo in the primary end point of "composite time to complete organ failure resolution" over 14 days.

The data monitoring committee also noted a numerical increase in the rate of central nervous system (CNS) bleeding in those taking Xigris versus the placebo group. Over the infusion period (study days 0-6), the number of patients experiencing an intracranial hemorrhage event was 4 versus 1 for the overall population (Xigris vs placebo), with 3 of the 4 events in the Xigris group occurring in patients aged 60 days or younger. Mortality, the rate of serious adverse events, overall serious bleeding events, and major amputations appeared to be similar in the Xigris and placebo groups.

Data collection in study EVBP is ongoing. All patients enrolled will be followed up for the complete 28-day study period. Lilly reports that full results of the data will be available in the latter part of 2005 and publicly presented as soon as possible.

The company requests that adverse events associated with Xigris be reported to the Lilly Answer Center at 1-800-LILLYRx (1-800-545-5979). Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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One lot of epilepsy medicine recalled, Pfizer reminds public

April 26, 2005

ST. LOUIS (MD Consult) - On April 22, 2005, pharmaceutical company Pfizer issued a statement declaring its voluntarily recall of one lot (#15224V) of 100-mg capsules of its epilepsy medication, Neurontin (gabapentin). Pfizer said only 100-mg-strength capsules from the one lot, which consisted of 40,000 bottles distributed in October and November 2004, are included in the recall. The company said it is possible that patients taking Neurontin to control epilepsy could experience seizures from a missed dose of the product.

The recall was first announced on February 23, 2005, after a manufacturing mechanical failure resulted in some bottles containing empty or partially filled capsules. The production lot was distributed only in the United States, and no other Neurontin lots were affected. The company said the statement, issued 2 months after the recall, was intended to ensure that all potentially affected patients have been fully notified, even though pharmacists and Pfizer distributors were notified in February 2005 of the recall and pharmacists were instructed to immediately contact any of their customers using Neurontin.

Patients should not stop taking Neurontin before consulting with their physicians. If they filled a prescription for the product in 100-mg dose between October 1, 2004, and March 15, 2005, and are concerned that any unused capsules may be part of the recalled lot, they should contact their pharmacists.

More information is available from the drugmaker by calling Pfizer Medical Information at 1-800-438-1985.

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Berlex says its MS treatment may be related to hepatic toxicity

April 25, 2005

ST. LOUIS (MD Consult) - On April 22, 2005, the U.S. Food and Drug Administration issued a reminder regarding the prescribing information for Betaseron (interferon beta-1b) as it pertains to hepatic toxicity. Betaseron is approved for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations.

Hepatotoxicity has been a reported adverse reaction to all beta-interferons. There have been rare reports of serious hepatic injury including autoimmune hepatitis and severe liver damage leading to hepatic failure and transplant. These events were reported during postmarketing safety surveillance. In some cases, these hepatotoxic events reported for patients taking beta-interferons have occurred in the presence of other drugs or comorbid medical illnesses associated with hepatic injury.

The drug's manufacturer, Berlex, Inc, reminded health care professionals of the information in a letter dated April 15, 2005. Since market introduction in 1993, the company pointed out, the Betaseron prescribing information has recommended liver function testing at regular intervals (1, 3, and 6 months) after introduction to Betaseron therapy, and periodically thereafter in the absence of clinical symptoms.

More than 300,000 patient years of experience have been accumulated since Betaseron was released on the U.S. market. The most commonly reported adverse reactions are lymphopenia, injection-site reaction, asthenia, flu-like symptom complex, headache, and pain. Betaseron should be used with caution in patients with depression. Injection-site necrosis has been reported in 5% of patients in controlled trials. Patients should be advised of the importance of rotating injection sites. Female patients should be warned about the potential risks involved in taking Betaseron while pregnant. Cases of anaphylaxis have been reported rarely.

Product information for Betaseron is available at berlex.com/html/products/condition8.html.

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Epilepsy treatment may cause dermatologic problems, drugmaker says

April 20, 2005

ST. LOUIS (MD Consult) - On April 19, 2005, Novartis Pharmaceuticals and the U.S. Food and Drug Administration (FDA) notified health care professionals about revisions to the Warnings and Precautions sections of the prescribing information for Trileptal (oxcarbazepine) tablets and oral suspension. The drug is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children aged 4 to 16 years with epilepsy. The updated Warnings section describes serious dermatologic reactions that have been reported in both children and adults in association with Trileptal use. The Precautions section has been updated to include language regarding multiorgan hypersensitivity reactions that have been reported in association with use of the medication.

The following information regarding serious dermatologic reactions has been added to the Warnings section of Trileptal's prescribing information:

Warnings Serious Dermatologic Reactions Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with Trileptal use. The median time of onset for reported cases was 19 days. Such serious skin reactions may be life-threatening, and some patients have required hospitalization with very rare reoprts of fatal outcome. Recurrence of the serious skin reactions following re-challenge with Trileptal has also been reported. The reporting rate of TEN and SJS associated with Trileptal use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 and 6 cases per million person years. Therefore, if a patient develops a skin reaction while taking Trileptal, consideration should be given to discontinuing Trileptal use and prescribing another antiepileptic medication.

The following information regarding multiorgan hypersensitivity reactions has been inserted to the Precautions section of the Trileptal prescribing information:

Precautions Multiorgan hypersensitivity Multiorgan hypersensitivity reactions have occurred in close temporal association (median time to detection, 13 days; range, 4-60) to the initiation of Trileptal therapy in adult and pediatric patients. Although there have been a limited number of reports, many of these cases resulted in hospitalization and some were considered life-threatening. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included lymphadenopathy, hepatitis, liver function test abnormalities, hematologic abnormalities (eg, eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, Trileptal should be discontinued and an alternative treatment started. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with multiorgan hypersensitivity would indicate this to be a possibility (see Warnings, Patients with a Past History of Hypersitivity Reaction to Carbamazepine subsection).

Additional language regarding serious dermatologic reaction and multiorgan hypersensitivity have been inserted under the Information for Patients heading of the Precautions section of the prescribing information and are related to these important changes to the Warnings and Precautions sections of the prescribing information.

Novartis requests that any adverse events in patients treated with Trileptal, such as those listed above, be reported to the company. Novaris can be contacted by phone at 1-800-882-6577 or by fax at 1-888-299-4565. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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FDA expands PharMEDium solution alert, all lots recalled

April 13, 2005

ST. LOUIS (MD Consult) - On April 12, 2005, the U.S. Food and Drug Administration (FDA)'s MedWatch Safety Information and Adverse Event Reporting Program announced that PharMEDium Services is recalling all strengths of 50-mL admixtures of Magnesium Sulfate in 5% Dextrose solution because of a potential lack of sterility assurance for these products. In addition, the company is voluntarily ceasing production and distribution of this product until it can determine and correct the source of this problem.

Two previously distributed lots of this product have been associated with outbreaks of Serratia marcescens infection, which can potentially cause serious or life-threatening conditions in patients, particularly those with compromised immune systems.

The products subject to recall are those labeled under the following Service Codes:

• 2K2410
• 2K2411
• 2K2412
• 2K2413
• 2K2419

These products were manufactured by PharMEDium Services of Houston, Tex, and were distributed to several hospitals around the country. On March 18, 2005, the FDA issued a nationwide alert regarding PharMEDium Services' Magnesium Sulfate 1 g in 50 mL D₅W (piggyback) IV solution, lot number 100504900049 and expiration date 4/4/05, after it was associated with 5 cases of S marcescens infection in a hospital in New Jersey.

Health care practitioners with questions can contact the manufacturer at 1-847-457-2300.

Persons wanting to report anything to the FDA regarding this product can contact the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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Antipsychotic drugs may not be safe for elderly dementia patients, FDA warns

April 13, 2005

ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) issued a public health advisory on April 11, 2005, to alert health care providers, patients, and patient caregivers to new safety information concerning an unapproved (ie, "off-label") use of certain drugs called atypical antipsychotic drugs. These drugs are approved for the treatment of schizophrenia and mania, but clinical studies of these drugs to treat behavioral disorders in elderly patients with dementia have shown a higher death rate associated with their use compared with patients receiving a placebo (sugar pill).

This advisory applies to such antipsychotic drugs as Abilify (aripiprazole), Zyprexa (olanzapine), Seroquel (quetiapine), Risperdal (risperidone), Clozaril (clozapine), and Geodon (ziprasidone). Symbyax (olanzapine and fluoxetine hydrochloride), which is approved for treatment of depressive episodes associated with bipolar disorder, is also included in the agency's advisory.

The FDA is requesting that the manufacturers of all of these kinds of drugs add a boxed warning to their drug labeling describing this risk and noting that these drugs are not approved for the treatment of behavioral symptoms in elderly patients with dementia. Patients receiving these drugs for treatment of behavioral disorders associated with dementia should have their treatment reviewed by their health care providers.

In analyses of 17 placebo-controlled studies of 4 drugs in this class, the rate of death for those elderly patients with dementia was about 1.6 to 1.7 times that of placebo. Although the causes of death were varied, most seemed to be either heart-related (such as heart failure or sudden death) or from infections (pneumonia).

The atypical antipsychotics fall into 3 drug classes based on their chemical structure. Because the increase in mortality was seen with atypical antipsychotic medications in all 3 chemical classes, the agency has concluded that the effect is probably related to the common pharmacologic effects of all atypical antipsychotic medications, including those that have not been studied in the dementia population.

The agency is considering adding a warning to the labeling of older antipsychotic medications because limited data also suggest a similar increase in mortality for these drugs. The review of the data on these older drugs, however, is still ongoing.

Full text of the FDA's public health advisory is available on the agency's Web site at www.fda.gov/cder/drug/advisory/antipsychotics.htm.

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Pfizer voluntarily recalls Bextra, labeling for other NSAIDs to change

April 8, 2005

ST. LOUIS (MD Consult) - On April 7, 2005, the U.S. Food and Drug Administration (FDA) announced that it has asked Pfizer, Inc, to voluntarily withdraw Bextra (valdecoxib) from the market. Pfizer has agreed to suspend sales and marketing of Bextra in the United States, pending further discussions with the agency. The FDA is also asking manufacturers of all marketed prescription nonsteroidal anti-inflammatory drugs (NSAIDs), including Celebrex (celecoxib), a cyclo-oxygenase 2 (COX-2) selective NSAID, to revise the labeling for their products to include a boxed warning and a medication guide. The boxed warning will highlight the potential for increased risk of cardiovascular events with these drugs and the well-described, serious, and potentially life-threatening gastrointestinal bleeding associated with their use. The medication guide will accompany every prescription NSAID at the time it is dispensed to better inform patients about the cardiovascular and gastrointestinal risks.

In addition, the FDA is asking manufacturers of nonprescription (over-the-counter; OTC) NSAIDs to revise their labeling to include more specific information about the potential gastrointestinal and cardiovascular risks, as well as information to assist consumers in the safe use of the drugs. This announcement does not apply to aspirin because it has clearly been shown to reduce the risk of serious adverse cardiovascular events in certain patient populations.

In reaching these decisions, the FDA has carefully considered the available data on all of the NSAIDs. The agency has also considered presentations, discussions, and votes from the joint public meeting of the FDA Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee held on February 16-18, 2005, to discuss the cardiovascular safety concerns for these drugs along with their overall risk-benefit.

This current reexamination of the cardiovascular risks of NSAIDs began after Merck conducted a voluntary worldwide withdrawal of its COX-2 selective NSAID, Vioxx (rofecoxib), in September 2004. The FDA will carefully review any proposal from Merck for resumption of marketing of Vioxx.

Specifically, the FDA is requesting the actions listed below and will work closely with the manufacturers to ensure their timely implementation.

Bextra (valdecoxib tablets)

The FDA has concluded that the overall risk-versus-benefit profile for Bextra is unfavorable and has requested that Pfizer, the drug's manufacturer, voluntarily withdraw Bextra from the market. This request is based on the following:

• There is a lack of adequate data on the cardiovascular safety of long-term use of Bextra, along with the increased risk of adverse cardiovascular events in short-term coronary artery bypass surgery trials that the FDA believes may be relevant to chronic use.
• Serious and potentially life-threatening skin reactions, including deaths, have been reported in patients using Bextra. The risk of these reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa allergy, and after both short- and long-term use.
• Demonstrated advantages for Bextra compared with other NSAIDs are lacking.

Pfizer has agreed to suspend sales and marketing of Bextra in the United States, pending further discussions with the agency.

Patients currently taking Bextra should contact their physicians to consider alternative treatments.

Celebrex (celecoxib tablets)

The FDA has concluded that the benefits of Celebrex outweigh the potential risks in properly selected and informed patients. Accordingly, the FDA will allow Celebrex to remain on the market and has asked Pfizer to take the actions listed below.

• Revise the Celebrex label to:
  • Include a boxed warning containing the class NSAID warnings and contraindication (see below) about cardiovascular and gastrointestinal risk, plus specific information on the controlled clinical trial data that demonstrate an increased risk of adverse cardiovascular events for celecoxib.
  • Encourage prescribers to discuss with patients the potential benefits and risks of Celebrex and other treatment options before a decision is made to use Celebrex.
• Encourage practitioners to use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
• Include a medication guide as part of the labeling. It will be required to be given at the time the drug is dispensed to inform patients of the potential for cardiovascular and gastrointestinal risk associated with NSAIDs in general, and Celebrex specifically. The medication guide will inform patients of the need to discuss with their doctors the risks and benefits of using NSAIDs and the importance of using the lowest effective dose for the shortest duration possible.
• Commit to conduct a long-term study to address the safety of Celebrex compared with naproxen and other appropriate drugs. The FDA will work with Pfizer to design this long-term study and ensure its timely initiation and completion.

Patients who are taking Celebrex should discuss questions or concerns about this new information with their physicians.

Nonselective NSAIDs

A number of nonselective NSAIDs (prescription and nonprescription) are approved for marketing in the United States. A list of these products is available at fda.gov/cder/drug/infopage/cox2/default.htm#list.

Long-term controlled clinical trials have not been conducted with most of these NSAIDs. However, the available data suggest that use of these drugs may increase cardiovascular risk. It is very difficult to draw conclusions about the relative cardiovascular risk among the COX-2 selective and nonselective NSAIDs with the data available.

The FDA will work closely with sponsors and other interested stakeholders (eg, the U.S. National Institutes of Health) to encourage additional long-term controlled clinical trials of nonselective NSAIDs to further evaluate the potential for increased cardiovascular risk.

In addition, the FDA is requesting labeling changes for both prescription and OTC nonselective NSAIDs. The use and labeling for the prescription products is different from those available without a prescription.

Prescription Nonselective NSAIDs

The FDA will request that manufacturers of all prescription products containing nonselective NSAIDs revise their product labeling to include:

• A boxed warning regarding the potential serious adverse cardiovascular events and the serious and potentially life-threatening gastrointestinal adverse events associated with the use of this class of drugs
• A contraindication for use in patients who have recently undergone coronary artery bypass surgery
• A medication guide for patients regarding the potential for cardiovascular and gastrointestinal adverse events associated with the use of this class of drugs; the medication guide will also inform patients of the need to discuss with their doctor the risks and benefits of using NSAIDs and the importance of using the lowest effective dose for the shortest duration possible if treatment with an NSAID is warranted for an individual patient

Patients who are taking a prescription nonselective NSAID should discuss questions or concerns about this new information with their physicians.

OTC Nonselective NSAIDs

The available data do not suggest an increased risk of serious cardiovascular events for the short-term, low-dose use of the NSAIDs available OTC. The FDA will allow these products to remain on the market but will request changes to the label to better inform consumers regarding the safe use of these products.

The FDA will ask manufacturers of all OTC products containing ibuprofen (eg, Motrin, Advil, Ibu-Tab 200, Medipren, Cap-Profen, Tab-Profen, Profen, Ibuprohm), naproxen (Aleve), and ketoprofen (Orudis, Actron) to revise their labeling to include:

• More specific information about the potential cardiovascular and gastrointestinal risks
• Instructions about which patients should seek the advice of a physician before using these drugs
• Stronger reminders about limiting the dose and duration of treatment in accordance with package instructions, unless otherwise advised by a physician
• A warning about potential skin reactions

Patients who are taking an OTC NSAID should carefully follow the labeled directions, particularly with regard to dose and duration of use, and should contact their physicians regarding any questions or concerns they may have about this new information.

The FDA expects that these actions will further encourage the safe and effective use of these products. The agency will continue to notify health care providers and patients in a timely fashion as new information becomes available.

Health care providers and patients are encouraged to report adverse event information to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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Alzheimer's treatment may be linked to sudden death, FDA warns

April 4, 2005

ST. LOUIS (MD Consult) - As the U.S. Food and Drug Administration (FDA) announced on April 1, 2005, the manufacturer of Reminyl (galantamine hydrobromide) has modified the Precautions section of the prescribing information for the drug. The changes provide new safety information regarding the results of two 2-year trials of subjects with mild cognitive impairment (MCI), in which a total of 13 subjects taking Reminyl and 1 subject receiving placebo died.

The new prescription information was communicated by Ortho-McNeil Neurologics in the form of a letter addressed to health care professionals on March 31, 2005. The updated details include the following information regarding the results of 2 investigational studies of Reminyl in persons with MCI. Reminyl is approved only for the treatment of mild to moderate Alzheimer's disease. No indication is being sought for the treatment of persons with mild cognitive impairment.

Precaution Deaths in Subjects with Mild Cognitive Impairment (MCI) In two randomized, placebo-controlled trials of 2 years' duration in subjects with mild cognitive impairment (MCI), a total of 13 subjects on Reminyl (n = 1,026) and 1 subject on placebo (n = 1,022) died. The deaths were due to various causes which could be expected in an elderly population; about half of the Reminyl deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death). Although the difference in mortality between Reminyl and placebo-treated groups in these two studies was significant, the results are highly discrepant with other studies of Reminyl. Specifically, in these two MCI studies, the mortality rate in the placebo-treated subjects was markedly lower than the rate in placebo-treated patients in trials of Reminyl in Alzheimer's disease or other dementias (0.7 per 1,000 person years compared with 22-61 per 1,000 person years, respectively). Although the mortality rate in the Reminyl-treated MCI subjects was also lower than that observed in Reminyl-treated patients in Alzheimer's disease and other dementia trials (10.2 per 1,000 person years compared with 23-31 per 1,000 person years, respectively), the relative difference was much less. When the Alzheimer's disease and other dementia studies were pooled (n = 6,000), the mortality rate in the placebo group numerically exceeded that in the Reminyl group. Furthermore, in the MCI studies, no subjects in the placebo group died after 6 months, a highly unexpected finding in this population. Individuals with MCI demonstrate isolated memory impairment greater than expected for their age and education, but do not meet current diagnostic criteria for Alzheimer's disease.

Ortho-McNeil requests that consumers and health care professionals report any serious adverse events related to Reminyl to the company at 1-800-526-7736. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

Ortho-McNeil (ortho-mcneil.com) is headquartered in Raritan, NJ, and is a member of the Johnson & Johnson family of companies.

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Antiretroviral drug not safe for pregnant women

April 5, 2005

ST. LOUIS (MD Consult) - On March 31, 2005, the U.S. Food and Drug Administration (FDA) issued an alert stating that Bristol-Myers Squibb Company has issued a Dear Health Care Provider Letter highlighting important information about Sustiva (efavirenz) and pregnancy. The manufacturer announced new information in the Sustiva package insert, including a change in the pregnancy category for Sustiva from Category C (Risk of Fetal Harm Cannot Be Ruled Out) to Category D (Positive Evidence of Fetal Risk).

This change is a result of 4 retrospective reports of neural tube defects in infants born to women with first-trimester exposure to Sustiva, including 3 cases of meningomyelocele and 1 case of Dandy Walker syndrome. Because Sustiva may cause fetal harm when administered during the first trimester to a pregnant woman, pregnancy should be avoided in women taking the medication.

Women of childbearing potential should undergo pregnancy testing before initiation of treatment with Sustiva. If Sustiva is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Although there are no adequate, well-controlled studies in pregnant women, Sustiva should be used during the first trimester of pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. Barrier contraception should always be used in combination with other contraceptive methods.

During the development of Sustiva, animal studies were performed to assess the potential for birth defects. Malformations were observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (vs 0 of 20 concomitant control subjects) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20-150) with efavirenz 60 mg/kg daily, a dose resulting in plasma drug concentrations similar to those in humans given 600 mg/d of Sustiva. Anencephaly and unilateral anophthalmia were observed in one monkey fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations. An increase in fetal resorptions was observed in rats given efavirenz doses that produced peak plasma concentrations and area under the curve (AUC) values in female rats equivalent to or lower than those achieved in humans given 600 mg of Sustiva once daily. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg of Sustiva once daily.

Limited data are available regarding birth defects occurring after intrauterine exposure to Sustiva. The outcomes of pregnancy have been reviewed for 206 women (207 fetuses) after being exposed to efavirenz-containing regimens, most of which were first-trimester exposures. Birth defects occurred in 5 of 188 live births with first-trimester exposure and in 0 of 13 live births with second- or third-trimester exposure. None of these prospectively reported defects were neural tube defects. However, there have been 4 retrospective reports (ie, after the results of the pregnancy were known) of findings consistent with neural tube defects, including 3 cases of meningomyelocele. All 4 mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of Sustiva has not been established, similar defects have been observed in preclinical studies of efavirenz.

Sustiva, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection. This indication is based on 2 clinical trials of at least 1 year's duration that demonstrated prolonged suppression of HIV RNA.

Important safety information regarding Sustiva issued by Bristol-Myers Squibb includes the following:

• Coadministration with astemizole, cisapride, midazolam, triazolam, ergot derivatives, or voriconazole is contraindicated. Concomitant use of Sustiva and St. John's wort (Hypericum perforatum) or St. John's wort–containing products is not recommended. This list of medications is not complete. Serious psychiatric adverse experiences, including severe depression (2.4%), have been reported in patients treated with Sustiva. In addition to Sustiva, factors identified in a clinical study that were associated with an increase in psychiatric symptoms included history of injection drug use, history of psychiatric disorder, and use of psychiatric medication. There have been occasional reports of suicide, delusions, and psychosis-like behavior, but it could not be determined if Sustiva was the cause. Patients with serious psychiatric adverse experiences should be evaluated immediately to determine whether the risks of continued therapy outweigh the benefits.
• Fifty-three percent of patients reported nervous system symptoms when taking Sustiva compared with 25% of patients receiving control regimens. These symptoms usually begin during the first 2 days of therapy and generally resolve after the first 2 to 4 weeks of therapy. Nervous system symptoms are not predictive of less frequent serious psychiatric symptoms.
• Sustiva may cause fetal harm when administered to a pregnant woman. Women should not become pregnant or breast-feed while taking Sustiva. Barrier contraception (eg, condom, diaphragm) must always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptive). If a woman becomes pregnant while taking Sustiva during the first trimester of pregnancy, she should be apprised of the potential harm to the fetus.
• Mild to moderate rash is a common adverse effect of Sustiva. In controlled clinical trials, 26% of patients treated with Sustiva experienced new-onset skin rash compared with 17% of patients treated in control groups. Treatment with Sustiva should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Rash is more common and often more severe in pediatric patients.
• Liver enzymes should be monitored in patients with known or suspected hepatitis B or C and when Sustiva is administered with ritonavir.
• Sustiva used be used with caution in patients with a history of seizures.
• Redistribution or accumulation of body fat have been seen in patients receiving antiretroviral therapy. A causal relationship has not been established.
• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Sustiva.
• It is recommended that Sustiva be taken on an empty stomach, preferably at bedtime. The increased concentrations after administration of Sustiva with food may lead to an increase in frequency of adverse events. Dosing at bedtime may improve the tolerability of nervous system symptoms.

In an effort to monitor fetal outcomes of pregnant women exposed to Sustiva and similar medications, an Antiretroviral Pregnancy Registry has been established. The Registry is a voluntary prospective, exposure-registration, observational study designed to collect and evaluate data on the outcomes of pregnancy exposures to antiretroviral products. Physicians are encouraged to register patients by calling 1-800-258-4263. More information is available at apregistry.com.

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FDA announces labeling changes to HIV treatments

April 5, 2005

ST. LOUIS (MD Consult) - On March 30, 2005, the U.S. Food and Drug Administration (FDA) announced the recent update of product labeling for two drugs used to treat HIV infection, Norvir (ritonavir) and Kaletra (lopinavir/ritonavir). The new information involves interactions with fluticasone (a synthetic corticosteroid) and trazodone (a nontricyclic antidepressant). In addition, alfuzosin—an alpha-blocker used to increase the flow of urine in people with benign prostatic hypertrophy—was added to the Contraindications section of the Norvir package insert.

Listed below are labeling revisions for the Norvir package insert. Results of the drug interaction studies with Norvir and fluticasone propionate aqueous nasal spray and trazodone were included:

NORVIR Clinical Pharmacology Norvir increased fluticasone AUC [area under the curve] and Cmax by approximately 350-fold and 25-fold, respectively. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC. Norvir increased trazodone AUC and Cmax by 2.4-fold and 34%, respectively.

In addition, the alpha1-adrenoreceptor antagonist drug, alfuzosin HCL, was added to the contraindicated list.

The following Warning regarding fluticasone was included in the Norvir packaging:

Warnings A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and Norvir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see Precautions: Drug Interactions).

In the Precautions section, the following clinical comment was included regarding interactions of both fluticasone and trazodone with Norvir:

Precautions Concomitant use of fluticasone propionate and Norvir increases plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and Norvir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see Warnings). Concomitant use of trazadone and Norvir increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and Norvir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

KALETRA Warnings A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of Kaletra and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and Kaletra is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see Precautions: Drug Interactions). Precautions Concomitant use of fluticasone propionate and Kaletra may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and Kaletra is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see Warnings). Concomitant use of trazodone and Kaletra may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

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Renal deterioration warning added to prescribing info for Zometa

April 1, 2005

ST. LOUIS (MD Consult) - On March 25, 2005, the U.S. Food and Drug Administration (FDA) announced revisions to the "Dosage and Administration" and "Warnings" sections of the prescribing information of Zometa (zoledronic acid) to reflect new safety information on the management of patients with advanced cancer and renal impairment, whose baseline creatinine clearance is 60 mL/min or lower. The recommended Zometa doses for patients with reduced renal function (mild and moderate renal impairment) were provided to health care professionals in a letter from Novartis, the drug's manufacturer. The company recommended that, during treatment, serum creatinine be measured before each dose of Zometa is administered, and treatment should be withheld in cases of renal deterioration.

Zoledronic acid for injection is indicated for the treatment of hypercalcemia of malignancy.

The prescribing information changes (noted in bold italic) that affect the clinical management of patients with renal impairment are listed below.

Dosage and Administration Multiple Myeloma and Metastatic Bone Lesions From Solid Tumors The recommended dose of Zometa in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance <60 mL/min, is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known. Upon treatment initiation, the recommended Zometa doses for patients with reduced renal function (mild and moderate renal impairment) are listed in the following table. These doses are calculated to achieve the same AUC [area under the curve] as that achieved in patients with creatinine clearance renal function of 75 mL/min. Creatinine clearance (CrCl) is calculated using Cockcroft-Gault formula. Baseline Creatinine Clearance (mL/min) Zometa Recommended Dose* <60 4.0 mg 50-60 3.5 mg 40-49 3.3 mg 30-39 3.0 mg *Doses calculated assuming target AUC of 0.66(mg·hr/L) (CrCl = 75 mL/min) During treatment, serum creatinine should be measured before each Zometa dose and treatment should be withheld for renal deterioration. In clinical studies, renal deterioration was defined as follows: For patients with normal baseline creatinine, increase of 0.5 mg/dL. For patients with abnormal baseline creatinine, increase of 1.0 mg/dL. In the clinical studies, Zometa treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zometa should be reinitiated at the same dose as that prior to treatment interruption. Preparation of Solution 4-mg dose Vials of Zometa concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% sodium chloride, USP, or 5% dextrose injection, USP. Do not store undiluted concentrate in a syringe, to avoid inadvertent injecton. The dose must be given as a single intravenous infusion over no less than 15 minutes. Reduced doses for patients with baseline CLcr ≤60 mL/min: Withdraw an appropriate volume of the 5-mL Zometa concentrate as needed: 4.4 mL for 3.5-mg dose 4.1 mL for 3.3-mg dose 3.8 mL for 3.0-mg dose The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% sodium chloride, USP, or 5% dextrose injection, USP. The dose must be given as a single intravenous infusion over no less than 15 minutes. Warnings Pre-existing renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs should be indentified and managed if possible.

The drug's manufacturer requests that health care professionals report all serious adverse events associated with the use of Zometa to Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936 or by phone (888-669-6682). The company can be reached via the Internet at us.zometa.com/utils/contact/hcp/emailh.jsp. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

Revised prescribing information for Zometa is available at fda.gov/medwatch/SAFETY/2005/Zometa_PI_nov2004.pdf.

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FDA issues alert on one lot of PharMEDium Services solution

March 23, 2005

ST. LOUIS (MD Consult) - On March 18, 2005, the U.S. Food and Drug Administration announced a nationwide alert against the use of PharMEDium Services Magnesium Sulfate 1 g in 50 mL D₅W (piggyback) IV solution, lot number 100504900049, with the expiration date of 4/4/05. This product is manufactured by PharMEDium Services of Houston, Tex, and may be contaminated with Serratia marcescens bacteria. This organism can cause serious, life-threatening illness in patients with compromised immune systems.

This product is frequently administered intravenously to patients undergoing cardiac surgery and was apparently distributed to several hospitals around the country. To date, it has been associated with at least 5 recent cases of S marcescens infection in a hospital in New Jersey. All patients have responded to treatment with antibiotics and are reportedly recovering well.

The firm has notified the FDA that it is in the process of withdrawing this lot from hospitals. The FDA, the U.S. Centers for Disease Control and Prevention, and other public health authorities are investigating this problem to determine whether other lots of this product may be affected. More information will be provided as the investigation develops.

Health care practitioners with questions can contact the manufacturer at 1-847-457-2300. Persons wanting to report anything to the FDA regarding this product can contact FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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Xigris may be related to risk of death after surgery, Lilly announces

March 18, 2005

ST. LOUIS (MD Consult) - On March 17, 2005, the U.S. Food and Drug Administration (FDA) notified health care professionals about revisions to the Warnings section of labeling for Xigris (drotrecogin alfa [activated]), a biological therapeutic product indicated for the treatment of adult patients with severe sepsis who are at high risk of death.

The warning is based on exploratory analyses of the ADDRESS clinical trial database and subsequent reanalysis of the PROWESS (Phase 3 registration) clinical trial database. Among patients with single organ dysfunction and recent surgery, all-cause mortality was numerically higher in the Xigris group compared with the placebo group. Patients with single organ dysfunction and recent surgery may not be at high risk of death and therefore may not be among the indicated population. Xigris should be used in these patients only after careful consideration of the risks and benefits.

This information was also communicated to health care professionals in a letter from the drug's manufacturer, Eli Lilly and Company.

The revised portion of the Xigris prescription information is as follows:

Warnings Mortality in Patients with Single Organ Dysfunction and Recent Surgery Among the small number of patients enrolled in PROWESS with single organ dysfunction and recent surgery (surgery within 30 days prior to study treatment) all-cause mortality was numerically higher in the Xigris group (28-day: 10/49; in-hospital: 14/48) compared with the placebo group (28-day: 8/49; in-hospital: 8/47). In a preliminary analysis of the subset of patients with single organ dysfunction and recent surgery from a separate, randomized, placebo-controlled study (ADDRESS) of septic patients at lower risk of death (APACHE II score <25 or single sepsis-induced organ failure at any APACHE II score) all-cause mortality was also higher in the Xigris group (28-day: 67/323; in-hospital: 76/325) compared with the placebo group (28-day: 44/313; in-hospital: 62/314). Patients with single organ dysfunction and recent surgery may not be at high risk of death irrespective of APACHE II score and therefore may not be among the indicated population. Xigris should be used in these patients only after careful consideration of the risks and benefits.

This observation underscores the importance of accurate severe sepsis diagnosis and assessment of risk of death when considering the administration of Xigris.

Lilly requests that any adverse events be reported to the company at 1-800-545-5979. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

Full prescribing information for Xigris is available at fda.gov/medwatch/SAFETY/2005/xigris_USPI_17Dec04.pdf.

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FDA announces risk of hepatic injury related to Avonex

March 17, 2005

ST. LOUIS (MD Consult) - On March 15, 2005, the U.S. Food and Drug Administration (FDA) announced an update to the prescribing information for Avonex (interferon beta-1a) based on reports of severe hepatic injury, including cases of hepatic failure, among patients taking the drug. Biogen Idec, manufacturer of Avonex, alerted health care professionals of revisions to the Warnings, Precautions: Drug Interactions and Adverse Reactions: Post-Marketing Experience sections and medication guide.

In addition to hepatic injury, asymptomatic elevation of hepatic transaminases has also been reported, and in some patients this has recurred upon rechallenge. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential risk of Avonex used in combination with known hepatotoxic drugs or other products (eg, alcohol) should be considered before Avonex is administered, or when new agents are added to the treatment regimen of patients already taking Avonex.

Avonex is indicated for the treatment of relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. Safety and efficacy in patients with chronic progressive multiple sclerosis have not been evaluated.

The Warnings section of the drug labeling for Avonex has been revised to include the following information:

Hepatic Injury

Severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients taking Avonex. Asymptomatic elevation of hepatic transaminases has also been reported, and in some patients has recurred upon rechallenge with Avonex. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential risk of Avonex used in combination with known hepatotoxic drugs or other products (eg, alcohol) should be considered prior to Avonex administration, or when adding new agents to the regimen of patients already on Avonex. Patients should be monitored for signs of hepatic injury (see Precautions: Laboratory Tests).

The Precautions section has been revised to include the following information:

Drug Interactions

...the potential for hepatic injury should be considered when Avonex is used in combination with other products associated with hepatic injury, or when new agents are added to the regimen of patients already on Avonex (see Warnings: Hepatic Injury).

The Adverse Reactions section has been revised to include the following statement:

Hepatic injury, including hepatic failure and elevated serum hepatic enzyme levels, has been reported in post-marketing experience (see Warnings: Hepatic Injury).

The Adverse Reactions: Post-Marketing Experience section has been revised to add hepatic failure. Additionally, the Precautions: Information to Patients and Pregnancy sections of the prescribing information and the medication guide were revised to include information regarding the Avonex Pregnancy Registry. The company requests that physicians whose patients become pregnant while taking Avonex consider enrolling them in the Avonex Pregnancy Registry.

The new labeling will be included in packaging for Avonex manufactured after April 18, 2005.

Full prescribing information for Avonex is available at fda.gov/medwatch/SAFETY/2005/Avonex_PI.pdf.

Biogen Idec requests that health care professionals report any serious adverse events related to Avonex to the company at 1-800-456-2255. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet ( fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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FDA warns of cancer risk related to eczema treatments

March 11, 2005

ST. LOUIS (MD Consult) - On March 10, 2005, the U.S. Food and Drug Administration (FDA) advised health care professionals to prescribe Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment only as directed and only after other eczema treatments have failed to work because of a potential cancer risk associated with their use. In addition, the FDA is adding a black box warning to the health professional label for the 2 products and developing a medication guide for patients.

The agency's actions follow the recommendations made by the FDA's Pediatric Advisory Committee during its February 15, 2005, meeting. At this meeting, findings of cancer in 3 different animal species were reviewed. The data showed that the risk of cancer increased as the amount of the drug given increased. The data also included a small number of reports of cancers in children and adults treated with Elidel or Protopic.

It may take human studies of 10 years or longer to determine whether use of Elidel or Protopic is linked to cancer. In the meantime, this risk is uncertain and the FDA advises that Elidel and Protopic should be used only as labeled, for patients who have failed treatment with other therapies. The manufacturers of the products have agreed to conduct research to determine whether there is an actual risk of cancer in humans, and, if so, its extent. Both products are applied to the skin to control eczema by suppressing the immune system.

The FDA's Public Health Advisory specifically advises physicians to weigh the risks and benefits of these drugs in adults and children and consider the following:

• Elidel and Protopic are approved for short-term and intermittent treatment of atopic dermatitis in patients unresponsive to or intolerant of other treatments.
• Elidel and Protopic are not approved for use in children younger than 2 years old. The long-term effect of Elidel and Protopic on the developing immune system in infants and children is not known. In clinical trials, infants and children younger than 2 years of age treated with Elidel had a higher rate of upper respiratory infections than those treated with placebo cream.
• Elidel and Protopic should be used only for short periods of time, not continuously. The long-term safety of these products is unknown.
• Children and adults with a weakened or compromised immune system should not use Elidel or Protopic.
• The minimum amount of Elidel and Protopic needed to control the patient's symptoms should be used. The animal data suggest that the risk of cancer increases with increased exposure to Elidel or Protopic.

In addition to an ointment, tacrolimus also comes as a pill or by injection, and this form is known as Prograf. Prograf is approved to prevent liver or kidney transplant rejection. It is known to cause both skin cancers and lymphoma in humans by suppressing the body's normal immune defenses against cancer. The cancer risk increases with higher doses and longer treatment courses of Prograf. Both Elidel and Protopic are sometimes absorbed through the skin, although usually at very low amounts. Occasionally, children who have been treated with Elidel or Protopic have had high blood levels of these drugs.

Protopic was approved in December 2000 and Elidel in December 2001. Since their approval, the FDA has received reports of lymphoma and skin cancer in children and adults treated with Elidel or Protopic; whether the reported cancers are associated with these products has not been clearly established.

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GlaxoSmithKline products seized due to violations of good manufacturing practice

March 10, 2005

ST. LOUIS (MD Consult) - In a response to ongoing concerns about manufacturing quality, on March 4, 2005, the U.S. Food and Drug Administration (FDA) and the Department of Justice initiated seizures of Paxil CR (paroxetine) and Avandamet (rosiglitazone maleate/metformin hydrochloride) tablets manufactured by GlaxoSmithKline, Inc. (GSK). Manufacturing practices for the two drugs, approved to treat depression and panic disorder (Paxil CR) and type II diabetes (Avandamet), failed to meet the standards laid out by the FDA that ensure product safety, strength, quality, and purity.

"[The] FDA and the Department of Justice will not allow drug manufacturers to ignore our high public health standards for drug manufacturing," said John M. Taylor, FDA Associate Commissioner for Regulatory Affairs. "Once we discover a company is not following the standards, which were created to ensure safety and quality, we expect them to correct the deficiencies in an expedited manner. American consumers deserve the best health care products on the market today, and companies that are not adhering to these standards cannot assure [the] FDA and American consumers of the quality of their products."

The FDA is not aware of any harm to consumers by the products subject to this seizure, and its members do not believe that these products pose a significant health hazard to consumers. Consequently, the FDA urges patients who use these two drugs to continue taking their tablets and to talk with their health care providers about possible alternative products for use until the manufacturing problems have been corrected. The FDA has determined that neither product is medically necessary and that alternative products are available for consumer use.

The agency is concerned that GSK's violation of manufacturing standards may have resulted in the production of poor-quality drug products that could potentially pose risks to consumers. Among the violations noted during the FDA's latest inspection was the finding that the Paxil CR tablets could split apart and patients could receive a portion of the tablets that lacks any active ingredient, or alternatively, they could receive a portion that contains active ingredient and does not have the intended controlled-release effect. Additionally, the FDA found that some Avandamet tablets did not have an accurate dose of rosiglitazone, an active ingredient in this product.

The seizures follow warrants issued by the U.S. District Courts for the District of Puerto Rico and the Eastern District of Tennessee. The seizures were executed today by the U.S. Marshals Service at GSK's Cidra, Puerto Rico, manufacturing facility, its Knoxville, Tenn, distribution facility, and a Puerto Rico distribution facility. GSK has voluntarily recalled some of the affected lots of Paxil CR and Avandamet; however, it has failed to recall all affected lots of these products. This failure on the part of GSK resulted in today's seizures by federal authorities.

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Statins may be linked to muscle damage, FDA warns

March 3, 2005

ST. LOUIS (MD Consult) - Rhabdomyolysis has been reported in patients taking Crestor (rosuvastatin calcium) as well as other statin drugs. On March 2, 2005, the U.S. Food and Drug Administration (FDA) issued a public health advisory, a patient information sheet, and a corresponding health care professional information sheet further explaining the identified risks and benefits of Crestor, a cholesterol-lowering drug. The labeling for Crestor is being revised to highlight important information on the safe use of Crestor to reduce the risk for serious muscle toxicity (myopathy/rhabdomyolysis), especially at the highest approved dose of 40 mg.

The FDA is providing up-to-date information about the risk of rhabdomyolysis in patients taking Crestor as well as other statin drugs. This is a well-known, rare adverse effect of all statins. Extensive review of the large amount of data available to date from controlled trials as well as the latest postmarketing safety information indicates that patients taking recommended doses of Crestor have a similar risk of rhabdomyolysis as patients receiving other statin cholesterol treatments.

Crestor's manufacturer Astra-Zeneca Pharmaceuticals has revised the package insert for Crestor, based on discussions with the FDA. These changes reemphasize recommendations made in the original label about the need for physicians to consider using lower starting doses of the drug in some persons as a means of reducing the risk of rhabdomyolysis.

The revised labeling notes that this may be particularly important for treating Asian American patients, reflecting the results of a large pharmacokinetic study. The study involved a diverse population of Asian patients compared with a white control group and found drug levels to be elevated approximately 2-fold, demonstrating that the former (along with patients on cyclosporine or patients with severe renal insufficiency) may have higher drug levels and may therefore be at greater risk than the general population for muscle injury due to Crestor.

Kidney failure of various types has also been reported in patients treated with Crestor as well as other statins. Patients who are candidates for statin therapy (eg, patients with diabetes, hypertension, atherosclerosis, and/or heart failure) may also be at higher risk for kidney failure even when they are not taking statins. At this time, the FDA cannot conclude that recommended doses of Crestor can cause or exacerbate renal failure, but is continuing to carefully evaluate the data.

The agency has stated its overall belief that the potential benefits of statin drugs (including Crestor) when used as labeled and indicated for the treatment of elevated cholesterol outweigh their potential risks and provide an important treatment option for millions of Americans at risk of heart disease.

The FDA's public health advisory on Crestor can be obtained at www.fda.gov/cder/drug/advisory/crestor_3_2005.htm. Full prescribing information for this medication is also available on the FDA Web site: www.fda.gov/cder/foi/label/2005/21366slr005lbl.pdf.

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Marketing of Tysabri suspended, possible link with progressive multifocal leukoencephalopathy

March 2, 2005

ST. LOUIS (MD Consult) - On February 28, 2005, the U.S. Food and Drug Administration (FDA) issued a public health advisory to inform patients and health care providers about the suspended marketing of Tysabri (natalizumab) due to 2 serious adverse events reported with its use. The FDA has received a report from Biogen Idec, the manufacturer of Tysabri, of 1 confirmed, fatal case and 1 possible case of progressive multifocal leukoencephalopathy (PML) in patients receiving Tysabri for the treatment of multiple sclerosis (MS). Both patients were enrolled in a long-term clinical trial and had been taking Tysabri for more than 2 years. There have been no previous cases of PML reported in patients taking Tysabri.

Although the relationship between Tysabri and PML is not known at this time, because of the rare, serious, and often fatal nature of PML, the FDA is announcing the following, effective immediately:

• Biogen Idec is voluntarily suspending marketing of Tysabri.
• Biogen Idec is suspending dosing of Tysabri in clinical trials and is notifying patients and investigators of the possible association between Tysabri and PML.

Patients being treated with Tysabri should contact their physicians to discuss appropriate alternative treatments. At this time, there are no specific diagnostic or therapeutic interventions recommended for patients who have been taking Tysabri, other than to discontinue its use. Physicians should evaluate all patients who have received Tysabri and who have signs or symptoms suggestive of PML. The FDA and Biogen Idec will provide further guidance should additional recommendations be deemed appropriate.

Discussions between the FDA, Biogen Idec, and scientific experts have begun in order to assess the potential association between Tysabri and PML and the methods for early diagnosis of PML, and to determine whether patients with MS who may be at particular risk can be identified. These discussions will be informed by the substantial amount of patient data from clinical trials expected to be obtained in the next few months, including specific assessments of patients who have received Tysabri for evidence of early-stage PML, and will be used to guide decisions regarding future marketing of Tysabri.

PML is a rare, serious, progressive neurologic disease, usually occurring in immunosuppressed patients and often resulting in irreversible neurologic deterioration and death. There is no known effective treatment for PML, although reversing immune system suppression may slow or arrest progression of the disease.

Based on information submitted to the FDA this week, neither patient described above has known risk factors for PML. Both patients received concomitant Avonex (interferon beta-1a). The use of interferons, including Avonex, has not been associated with PML. To further understand the association between Tysabri and the development of PML, Biogen Idec is reviewing all adverse events in the clinical trial database for Tysabri to determine whether any of these could possibly represent cases of PML.

Tysabri received accelerated FDA approval in November 2004 for reducing the frequency of exacerbations in patients with remitting-relapsing MS, the most common form of this disease, after 1 year of treatment. Tysabri, when added to Avonex, reduced the risk of exacerbations by 54% compared with Avonex alone. Tysabri by itself reduced the risk by 66% compared with placebo. These results represent an important and meaningful benefit for patients with MS. At the time of approval, approximately 1,100 patients with MS had received Tysabri for 1 year or more. Confirmatory studies were required to be carried out to show continued benefit of the drug after 2 years of treatment. The 2 cases reported here occurred in patients in the confirmatory studies. No cases of PML were observed during the clinical trials performed before approval of Tysabri.

The FDA will continue to notify health care providers and patients in a timely fashion as new information becomes available.

The FDA urges health care providers and patients to report adverse event information to the FDA via the MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (www.fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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Gabitril may cause seizures in patients without epilepsy, FDA warns

February 22, 2005

ST. LOUIS (MD Consult) - On February 18, 2005, the U.S. Food and Drug Administration (FDA) announced that a bolded warning will be added to the labeling for Gabitril (tiagabine) to warn prescribers of the risk of seizures in patients without epilepsy being treated with this drug. Gabitril has been approved since 1997 for patients 12 years of age and older as adjunctive therapy for partial seizures. Recently, the FDA has become aware of reports of the occurrence of seizures in more than 30 patients prescribed Gabitril for conditions other than epilepsy. Most of these uses were in patients with psychiatric illnesses. Such "off-label" prescribing is a common practice among physicians. Because of the risk of seizures, however, in addition to adding the bolded warning to product labeling, the drug's sponsor, Cephalon, has agreed to undertake an educational campaign targeted to health care professionals and patients in which such off-label use will be discouraged.

In addition to the occurrence of isolated seizures, the FDA has received several reports of status epilepticus in patients without epilepsy. Status epilepticus is a particularly dangerous event in which patients have continuous seizures without regaining consciousness between seizures. In some cases, prescribers have continued to treat with, or actually increased the dose of, Gabitril in patients without epilepsy in whom seizures occurred. Presumably, this was done because the prescribers were unaware of the possibility that Gabitril could cause seizures and they believed that, as a drug approved to treat epilepsy, Gabitril might be beneficial in this situation as well.

Typically, the seizures have occurred soon after the initiation of treatment with Gabitril or soon after an increase in dose, although some patients experienced seizures after several months of treatment. Some seizures have occurred at very low doses compared with the doses approved for use in patients with epilepsy. Although most of the patients in whom seizures occurred were also taking other medications that may infrequently cause seizures, the temporal relationship to the initiation of treatment with Gabitril or to dose increases in many cases, as well as the number of patients reporting seizures, strongly suggests that the seizures were caused by Gabitril.

Because the system for reporting adverse events is voluntary, the number of reports of adverse reactions that the FDA receives once a drug has been marketed is probably less than the actual number of reactions that have actually occurred. For this reason, it is expected that the number of patients who have experienced a seizure while taking Gabitril is likely to be greater than the number reported, although it is impossible to know what the difference might be.

Because seizures are a serious and potentially life-threatening event and because prescribers are unlikely to expect that a drug to treat epilepsy can cause seizures in other patients, the FDA has requested that this information be included in a bolded warning and announced to health care professionals via a letter from Cephalon. In addition, as noted above, the sponsor has agreed to undertake an educational campaign in which it will discourage the off-label use of Gabitril. The FDA will work closely with the company to expedite the adoption and dissemination of the revised label and educational materials.

Health care professionals should be aware that the use of Gabitril for any indication other than for partial seizures in patients with epilepsy who are at least 12 years old is an off-label use, meaning evidence to support the safety and effectiveness for those uses has not been approved by the FDA. For this reason, the labeling for Gabitril will not contain any needed precautions and warnings that might result from such a submission and review. Patients should be aware that the use of Gabitril for the treatment of any condition other than partial seizures is considered an off-label use, and that there is a risk that they may experience a seizure. The risks of seizures should be explained, and patients should report any adverse events promptly to their health care professionals.

The revised medication label is available on the FDA Web site at www.fda.gov/medwatch/SAFETY/2005/Gabitril_PI_feb2005.pdf.

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Phenergan unsafe for children younger than 2 years

February 18, 2005

ST. LOUIS (MD Consult) - On February 16, 2005, the U.S. Food and Drug Administration (FDA) Safety Information and Adverse Event Reporting Program, MedWatch, announced a change to the prescribing information for Phenergan (promethazine). In January 2005 the drug's manufacturer, Wyeth, notified health care professionals of revisions to the Contraindications, Warnings/Use in Pediatric Patients, and Dosage and Administration sections of the medication's labeling. Phenergan is contraindicated for use in pediatric patients younger than 2 years of age because of the potential for fatal respiratory depression.

Postmarketing cases of respiratory depression, including fatalities, have been reported with the use of Phenergan in pediatric patients younger than 2 years old. Caution should also be exercised when administering Phenergan to pediatric patients 2 years of age and older.

Based on a review of adverse events of Phenergan in pediatric patients, the FDA has requested the following changes be made to the product prescribing information:

Contraindications Phenergan Tablets and Suppositories are contraindicated for use in pediatric patients less than two years of age. Warnings Phenergan should not be used in pediatric patients less then 2 years of age because of the potential for fatal respiratory depression. Postmarketing cases of respiratory depression, including fatalities, have been reported with the use of Phenergan in pediatric patients less than 2 years of age. A wide range of weight-based doses of Phenergan have resulted in respiratory depression in these patients. Caution should be exercised when administering Phenergan to pediatric patients 2 years of age and older. It is recommended that the lowest effective dose of Phenergan be used in pediatric patients 2 years of age and older and concomitant administration of other drugs with respiratory depressant effects be avoided. Warnings: Use in Pediatric Patients Phenergan Tablets and Suppositories are contraindicated for use in pediatric patients less than two years of age. Caution should be exercised when administering Phenergan to pediatric patients 2 years of age and older because of the potential for fatal respiratory depression. Respiratory depresion and apnea, sometimes associated with death, are strongly associated with promethazine products and are not directly related to individualized weight-based dosing, which might otherwise permit safe administration. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. Antiemetics are not recommended for treatment of uncomplicated vomiting in pediatric patients, and their use should be limited to prolonged vomiting of known etiology. The extrapyramidal symptoms which can occur secondary to Phenergan Tablets and Suppositories administration may be confused with the CNS signs of undiagnosed primary disease, eg, encephalopathy or Reye's syndrome. The use of Phenergan Tablets and Suppositories should be avoided in pediatric patients whose signs and symptoms may suggest Reye's syndrome or other hepatic diseases. Dosage and Administration Phenergan Tablets and Phenergan Rectal Suppositories are contraindicated for children under 2 years of age (see Warnings-Black Box Warning and Use in Pediatric Patients).

The complete revised label is available on the FDA Web site at fda.gov/medwatch/SAFETY/2005/Phenergan_PI.pdf.

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Methylin CT recall expanded, Alliant announces

February 16, 2005

ST. LOUIS (MD Consult) - On February 9, 2005, Alliant Pharmaceuticals, Inc, announced it is expanding its voluntary recall of Methylin (methylphenidate hydrochloride) Chewable Tablets to include all lots of the product. The nationwide recall now includes all 2.5-, 5-, and 10-mg dosage strengths because some tablets may contain too much or too little active ingredient.

The company initially recalled 1 lot of the 5-mg product, lot #AMT50402A, from the market on January 14, 2005, because it was determined that some tablets may contain up to 3 times the required amount of active ingredient. After further investigation, the manufacturer, Mallinckrodt, Inc, of St. Louis, Mo, determined that there was potential for other lots to contain superpotent and subpotent tablets. On further investigation, Mallinckrodt found that the potential problem was the result of a manufacturing mixing issue and not due to the medication's active ingredient.

Methylin is indicated for the treatment of attention deficit hyperactivity disorder and narcolepsy. The drug is sold in 100-tablet bottles and dispensed to patients in amounts prescribed by a physician.

The company notified the U.S. Food and Drug Administration of its findings and is notifying wholesalers and pharmacists of the recall by letter. They are asking pharmacists to attempt to notify patients who were dispensed prescriptions from their pharmacy. Distributors and pharmacies should promptly quarantine any product with the following lot numbers:

• 2.5 mg (NDC 68188-132-01); lot numbers: AMT20401A, AMT20402A, AMT20403A, AMT20404A
• 5 mg (NDC 68188-135-01); lot numbers: AMT50401A, AMT50402A (previously recalled), AMT50403A, AMT50404A
• 10 mg (NDC 68188-137-01); lot numbers: AMT100401A, AMT100402A, AMT100403A, AMT100404A

Alliant's liquid form of the product, Methylin Oral Solution (5 mg/5 mL and 10 mg/5 mL strengths), is not affected by this recall. In addition, Mallinckrodt's Methylin ER and Methylin immediate release products are not affected by the recall.

Patients should call their pharmacists or physicians if they have questions about the recall. Health care providers or patients who have questions can contact Alliant Pharmaceuticals at 770-817-4500 or visit alliantpharma.com.

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Sudden deaths in children elicit suspension of Adderall XR sales in Canada

February 11, 2005

ST. LOUIS (MD Consult) - On February 9, 2005, the U.S. Food and Drug Administration (FDA) issued an alert announcing that Health Canada, the Canadian drug regulatory agency, has suspended the sale of Adderall XR (amphetamine) in the Canadian market. Adderall XR is a controlled-release amphetamine used to treat patients with attention deficit hyperactivity disorder (ADHD). The Canadian action was based on U.S. postmarketing reports of sudden deaths in pediatric patients.

Adderall XR is approved in the United States for the treatment of adults and pediatric patients 6 years of age and older with ADHD, and Adderall, the immediate-release formulation of the drug, is approved for pediatric patients with ADHD. The FDA has been aware of these postmarketing cases and evaluated the risk of sudden death with Adderall before approving the drug for treatment of ADHD in adults in 2004.

Of 12 total cases, 5 occurred in patients with underlying structural heart defects (eg, abnormal arteries or valves, abnormally thickened walls), all conditions that increase the risk for sudden death. Several of the remaining cases presented problems of interpretation, including a family history of ventricular tachycardia; association of death with heat exhaustion, dehydration, and near-drowning; very rigorous exercise; fatty liver; heart attack; and type 1 diabetes mellitus. One case was reported 3 to 4 years after the event, and another had above-toxic blood levels of amphetamine. The duration of treatment varied from 1 day to 8 years. The number of cases of sudden deaths reported for Adderall is only slightly greater, per million prescriptions, than the number reported for methylphenidate products, which are also commonly used to treat pediatric patients with ADHD.

The FDA announced that it is continuing to evaluate these and other postmarketing reports of serious adverse events in children, adolescents, and adults being treated with Adderall and related products. When one considers the rate of sudden death in pediatric patients treated with Adderall products based on the approximately 30 million prescriptions written between 1999 and 2003 (the period of time in which these deaths occurred), it does not appear that the number of deaths reported is greater than the number of sudden deaths that would be expected to occur in this population without treatment, the agency pointed out. For this reason, the FDA has not decided to take any further regulatory action at this time. However, because it appeared that patients with underlying heart defects might be at increased risk for sudden death, the labeling for Adderall XR was changed in August 2004 to include a warning that these patients might be at particular risk, and that these patients should ordinarily not be treated with Adderall products.

In a statement issued by the FDA on February 9, 2005, the agency recommended that patients using Adderall (or parents of children taking the drug) who have questions about this medication should consult their physicians before making any alterations to their therapy.

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Drugmaker warns Agrylin may not be safe for patients with hepatic impairment

February 10, 2005

ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration announced on February 9, 2005, that UK-based pharmaceutical company Shire has circulated a letter notifying health care professionals of changes to the Contraindications and Warnings sections of the prescribing information for Agrylin (anagrelide hydrochloride). Pharmacokinetic studies have revealed an 8-fold increase in total exposure (AUC) to anagrelide hydrochloride in patients with moderate hepatic impairment. Use of anagrelide hydrochloride has not been studied in patients with severe hepatic impairment.

Agrylin is approved for the treatment of thrombocythemia resulting from myeloproliferative disorders to reduce platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombohemorrhagic events.

Labeling changes include a contraindication to the use of Agrylin in patients with severe hepatic impairment. The Warnings section (which previously contained information regarding hepatically impaired patients) and the Clinical Pharmacology section have been updated to include this new information. The updated Warnings section also notes the need for dosage reduction in patients with moderate hepatic impairment and the necessity of monitoring these patients carefully for cardiovascular effects.

Additional information is available by contacting Shire's Medical Information Group at 1-800-828-2088. The company's Web site is shire.com.

Full prescribing information for Agrylin is available at fda.gov/medwatch/SAFETY/2005/Agrylin_PI_12_04.pdf. Modified portions are highlighted in yellow.

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Errors may result from similar medication names, Lilly warns

February 9, 2005

ST. LOUIS (MD Consult) - On January 26, 2005, Eli Lilly and Company issued a letter notifying health care professionals of reports of medication dispensing or prescribing errors between the atypical antipsychotic agent ZyPrexa (olanzapine) and the antihistamine Zyrtec (cetirizine hydrochloride), which is marketed by Pfizer. These reports include instances in which Zyprexa was incorrectly dispensed for Zyrtec and vice versa, leading to unnecessary adverse events or potential relapse in patients suffering from schizophrenia or bipolar disorder.

The U.S. Food and Drug Administration (FDA)-approved indications for each of these drugs differ considerably. ZyPrexa is indicated for the short-term and maintenance treatment of schizophrenia and is also indicated for the short-term treatment of acute mixed or manic episodes associated with bipolar I disorder and as a maintenance treatment in bipolar disorder (normal dose, 5-20 mg/d), whereas Zyrtec is indicated for the treatment of allergic rhinitis or chronic urticaria (normal dose, 5-10 mg/d). However, many similarities do exist that could contribute to medication errors, including names starting with the same 2 letters, the availability of same dose strengths (5- and 10-mg tablets), the same dosing interval (once daily), and the fact that these 2 products are generally stored near each other on pharmacy shelves. It is these similarities that likely contribute to errors in dispensing or prescribing.

The ZyPrexa 2.5-, 5-, 7.5-, and 10-mg tablets are white, round, and imprinted in blue ink with "LILLY" and tablet number. The 15-mg tablets are elliptical, blue, and embossed with "LILLY" and tablet number. The 20-mg tablets have the same embossment and are elliptical and pink

Zyrtec tablets are white, film-coated, and in the shape of a rounded-off rectangle. They contain 5 or 10 mg of cetirizine hydrochloride and are engraved with "ZYRTEC" on one side and dose strength on the other.

In its letter to health care professionals, Lilly named measures that have been or will be taken by the company to help reduce the potential for future errors. These included:

• Making changes to ZyPrexa's label on the 10-mg bottles from "ZYPREXA" to "ZyPREXA," for easier identification
• Launching awareness direct mail campaign to pharmacists
• Sponsoring a continuing education campaign on medication error prevention
• Distributing journal ads focusing on this dispensing error potential, with emphasis on good prescribing and good dispensing practices

The nonprofit organization Institute for Safe Medication Practices (ISMP) recommends that products with reports of medication errors, such as ZyPrexa and Zyrtec, be stored in different locations. The ISMP also recommends that prescribers print both the brand and generic names of medication on all prescriptions. Furthermore, the organization recommends that health care professionals remember to discuss medications, their indications, and their proper use when counseling patients.

Additional information on medication errors and good prescribing and dispensing practices in various health care settings can be found at the ISMP Web site, ismp.org.

Lilly requests that any prescription dispensing error involving these products be reported to the appropriate manufacturer (Eli Lilly and Company: 1-800-Lilly RX; Pfizer Inc: 1-800-438-1985). Alternatively, this information can be reported to the ISMP Medication Errors Reporting Program (1-800-FAILSAFE) or the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

Full prescribing information for Zyrtec can be found at www.zyrtec.com. Full prescribing information for ZyPrexa is available at pi.lilly.com/us/zyprexa-pi.pdf.

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Roche Labs warns of interaction between saquinavir/ritonavir and rifampin

February 9, 2005

ST. LOUIS (MD Consult) - On February 8, 2005, the U.S. Food and Drug Administration (FDA) announced that Roche Laboratories Inc. has issued a "Dear Health Care Provider" letter to communicate an important drug interaction warning for saquinavir/ritonavir, used as part of combination therapy for the treatment of HIV infection. The letter states that drug-induced hepatitis with marked transaminase elevations has been observed in healthy volunteers receiving rifampin 600 mg once daily in combination with ritonavir 100 mg/saquinavir 1,000 mg twice daily (ritonavir-boosted saquinavir).

In a phase I, randomized, open-label, multiple-dose clinical pharmacology study of healthy volunteers, 11 of 28 (39.3%) subjects developed significant hepatocellular toxicity during the 28-day study period. Among these subjects, transaminase elevations of up to more than 20 times the upper limit of normal values were noted, and 1 subject was admitted to the hospital with marked transaminase elevations. For all study participants, dosing of all study medications was immediately terminated and the study was discontinued. After drug discontinuation, liver function tests in all affected subjects returned to normal, clinical symptoms abated, and no deaths from this clinical study have been reported.

As a result of this high incidence of hepatotoxicity in a phase I, randomized, open-label, multiple-dose clinical pharmacology study in healthy volunteers, Roche now advises prescribers that rifampin should not be administered to patients also receiving saquinavir/ritonavir as part of combination antiretroviral therapy for HIV infection.

The current package inserts for both Invirase (saquinavir mesylate capsules and tablets) and Fortovase (saquinavir soft gelatin capsules) already contraindicate the use of rifampin together with saquinavir. This contraindication is based on a pharmacokinetic interaction between rifampin and saquinavir that results in reduced saquinavir plasma levels. The phase I study reported above was undertaken to determine whether boosting of saquinavir with ritonavir would overcome the interaction.

Roche is collaborating closely with the FDA on this issue, and appropriate changes to the package insert will be made as soon as possible.

Health care professionals are encouraged to report any unexpected events associated with the use of saquinavir/ritonavir directly to Roche Laboratories at 1-800-526-6367. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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Serious health risk elicits recall of Methylin CT

January 20, 2005

ST. LOUIS (MD Consult) - On January 14, 2005, the U.S. Food and Drug Administration (FDA) and Alliant Pharmaceuticals notified health care professionals and consumers of the voluntary recall of one lot of Methylphenidate HCl Chewable Tablets, 5 mg strength, indicated for attention deficit hyperactivity disorder and narcolepsy. After testing and evaluation, Alliant found that lot number #AMT50402A [expiration date April 2006] might contain up to 3 times the active ingredient and elected to recall the medication because it could pose a serious health risk for some patients.

Georgia-based Alliant is notifying doctors and pharmacists of the recall by letter. They will be asking pharmacists to notify patients who purchased the recalled product from their pharmacy. Distributors and pharmacies should check the lot numbers on the product label and promptly quarantine any product with the recalled lot number and expiration date.

Of the 2,820 bottles from this lot, the company estimates fewer than 500 bottles of the affected product are in distribution. To date, the company has not received any complaints or reports of adverse events associated with the affected lot. Patients should call their pharmacists or physicians if they have questions about the recall. Health care providers or patients who have questions or wish to report adverse events can also contact Alliant Pharmaceuticals at 770-817-4500.

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Danger of liver toxicity warrants new warnings for nevirapine, FDA says

January 20, 2005

ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) issued a public health advisory on January 19, 2005, to inform health care providers and patients about recent safety-related changes to the nevirapine (Viramune) label and about appropriate use of HIV triple combination therapy containing nevirapine, which is one treatment option available in the United States and which is increasingly being used globally.

The nevirapine label has been revised several times over the last 2 years to include more information on liver toxicity associated with long-term nevirapine use. The Indications and Usage sections of the Viramune label now recommends against prescribing nevirapine treatment for women with CD4+ cell counts greater than 250 cells/mm³ unless benefits clearly outweigh risks. This recommendation is based on a higher observed risk of serious liver toxicity in patients with higher CD4 cell counts before initiation of therapy. In addition, the revised label now includes a medication guide to inform patients about risks associated with nevirapine when used for the treatment of HIV.

Both clinically symptomatic and asymptomatic liver toxicity are observed with long-term use of nevirapine in combination with other HIV treatments, according to the FDA. Asymptomatic liver toxicity is defined as increases in liver enzymes without any associated clinical signs or symptoms and is similar to that seen with other antiretroviral drugs. Symptomatic liver toxicity is more common with nevirapine compared with other antiretroviral drugs. Important information regarding symptomatic nevirapine liver toxicity is summarized as follows:

• Symptomatic nevirapine liver toxicity consists of elevated liver enzymes plus at least 1 symptom, which is typically rash but may include flu-like symptoms or fever. The severity of symptomatic liver toxicity ranges from mild symptoms with liver enzyme abnormalities to rapidly occurring liver failure and death.
• Symptomatic nevirapine liver toxicity typically occurs after only a few weeks of dosing and may progress to liver failure despite monitoring of laboratory tests, which is not characteristic of other antiretrovirals.
• Women and patients with higher CD4+ cell counts are at increased risk of liver toxicity. Female patients have a 3-fold higher risk of symptomatic nevirapine liver toxicity than males, and women with CD4+ cell counts > 250 cells/mm³ have a 12-fold higher risk of symptomatic liver toxicity than women with CD4+ cell counts < 250 (11% vs 0.9%). Male patients with CD4+ cell counts > 400 cells/mm³ have a 3-fold higher risk of symptomatic liver toxicity than males with CD4+ cell counts < 400 (6.3% vs 2.3%).
• Nevirapine-related deaths due to symptomatic liver toxicity, including some in HIV-infected pregnant women, have been reported to the FDA's Medwatch program. Serious and fatal liver toxicity has not been reported after single doses of nevirapine.

In spite of the potential for serious and life-threatening liver toxicity and skin rashes with nevirapine, there are multiple reasons why nevirapine remains an important part of an HIV treatment regimen for many HIV-infected individuals worldwide. These reasons include the following:

• Triple antiretroviral regimens have been shown to have a large impact on the reduction of AIDS morbidity and mortality. Triple antiretroviral drug regimens containing a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as nevirapine, are standard of care for HIV treatment and are needed to adequately and durably suppress the virus.
• Many options are needed for HIV-infected patients because resistance to antiretroviral drugs or to an entire antiretroviral class can develop.
• Symptomatic liver toxicity has not been reported with the use of single doses of nevirapine to the mother and to the child for prevention of perinatal HIV infection.
• Alternatives to nevirapine are limited by other toxicities, potential drug interactions, and by the risk of drug-related birth defects if given to a woman in the first trimester of pregnancy.
• Nevirapine liver toxicity is less frequent (<2% for both men and women with CD4+ cell counts <250 cells/mm³) when given to patients with lower CD4 counts. Therefore, symptomatic liver toxicity in resource-poor countries is likely to be much lower if World Health Organization (WHO) standards are used for starting treatment. The WHO recommends the initiation of ART treatment in patients with advanced disease or with CD4 counts < 200 cells/mm³.
• Nevirapine is chemically stable in environmental conditions where other antiretrovirals are not.
• Symptomatic liver toxicity has not been reported in HIV-infected children, and nevirapine is available in a liquid formulation whereas many other antiretrovirals are not.

In conclusion, the FDA states, the seriousness of the underlying disease must be considered as part of the risk benefit analysis when treating HIV-infected patients. HIV infection will progress to AIDS and death if left untreated. Treatment with combination antiretroviral drugs, including nevirapine, can slow clinical progression and may delay the development of AIDS or death for years. The agency advises health care providers to weigh the benefits and risks associated with nevirapine use before prescribing nevirapine for the treatment of their HIV-infected patients.

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Safety warning issued for Amgen's Aranesp

January 14, 2005

ST. LOUIS (MD Consult) - On January 11, 2005, the U.S. Food and Drug Administration (FDA) and Amgen notified health care professionals of revisions to the Warnings and Precautions sections of the prescribing information for Aranesp (darbepoetin alfa). Aranesp is indicated for the treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies.

Amgen has updated the safety information in the Aranesp prescribing information to reflect results from 2 recent investigational studies with other erythropoietic products (i.e., epoetin alfa [Eprex] and epoetin beta [NeoRecormon]), conducted outside the United States, where patients with cancer were treated to hemoglobin target levels beyond those recommended for the correction of their anemia.

These studies permitted or required dosing to achieve hemoglobin levels of greater than 12 g/dL. An increased frequency of adverse outcomes, including increased mortality and thrombotic vascular events, were reported in these studies. Additional details of these studies are included in the Warnings and Precautions sections of the revised Aranesp prescribing information.

Although these studies were conducted with other erythropoietic products, Amgen has incorporated this information into the aforementioned sections of the Aranesp prescribing information. This new information does not change the Dosage and Administration section of the Aranesp prescribing information; Amgen continues to recommend that the target hemoglobin level should not exceed 12 g/dL in men or women as indicated in the Aranesp prescribing information.

Amgen requests that any serious adverse events associated with Aranesp be reported to the company's Medical Information Connection at 1-800-77-AMGEN. Alternatively, this information may be reported to the FDA's MedWatch reporting system by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet ( fda.gov/medwatch/report.htm), or mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787).

A copy of the revised prescribing information for Aranesp can be found at: fda.gov/medwatch/SAFETY/2005/Aranesp_PI.pdf.

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FDA mandates medication guide for Wyeth's arrhythmia treatment

January 11, 2005

ST. LOUIS (MD Consult) - On January 10, 2005, the U.S. Food and Drug Administration (FDA) announced that New Jersey–based Wyeth has notified pharmacists and physicians of a new medication guide for Cordarone (amiodarone hydrochloride tablets). The FDA regulation 21CFR 208 requires a medication guide to be provided with each prescription that is dispensed for products that the FDA determines pose a serious and significant public health concern.

In a letter dated December 30, 2004, Wyeth circulated the required medication guide as well as prescribing information for Cordarone tablets. The company noted that physicians and pharmacists should not use the medication guide as a substitute for talking to patients about the risks relative to benefits associated with taking the medication.

The following boxed warnings about Cordarone tablets are included in the prescribing information.

Cordarone (amiodarone HCl) is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Cordarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10% to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/d, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with Cordarone but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, for example, by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2% to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2% to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with Cordarone than with many other agents used in this population, the effects are prolonged when they occur. Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an acceptable risk, Cordarone poses major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone is given, and a response generally requires at least 1 week, usually 2 or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15% to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.

Full prescribing information for Cordarone is available on the Wyeth product information Web site: wyeth.com.

The medication guide for Cordarone is available on the FDA Web site. In addition, a list of all of the currently approved medication guides are available at fda.gov/cder/Offices/ODS/labeling.htm.

Wyeth requests that adverse events related to the use of Cordarone be communicated to Wyeth Global Safety Surveillance and Epidemiology via fax (1-610-989-5544) or by mail (GSSE, 500 Arcola Rd, Collegeville, PA 19426). Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

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Avastin may be dangerous for chemotherapy patients, manufacturer warns

January 7, 2005

ST. LOUIS (MD Consult) - On January 5, 2005, the U.S. Food and Drug Administration (FDA) and Genentech notified health care professionals of revisions to the Warnings, Precautions, Adverse Events, and Dosage and Administration sections of the Avastin (bevacizumab) labeling. Avastin, used in combination with intravenous 5-fluorouracil–based chemotherapy, is indicated for first-line treatment of metastatic carcinoma of the colon or rectum.

Arterial thromboembolic events, including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving Avastin in combination with chemotherapy compared with those receiving chemotherapy alone. These events were fatal in some instances.

In randomized, active-controlled studies, the overall incidence of arterial thromboembolic events was increased with the use of Avastin in combination with chemotherapy (4.4% vs 1.9%). The incidences of both cerebrovascular arterial events (1.9% vs 0.5%) and cardiovascular arterial events (2.1% vs 1.0%) were increased in patients receiving Avastin in combination with chemotherapy. In addition, there was a correlation between patient age (65 years and older) and the increase in risk of thromboembolic events. The letter issued by Genetech emphasized that the risk of these events should be viewed in the context of Avastin's ability to improve overall survival in patients with metastatic colorectal cancer (median survival, 20.3 vs 15.6 months).

Genetech requests that any serious adverse events associated with Avastin be reported to the company at 1-888-835-2555. Alternatively, this information can be reported to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch/report.htm), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).

A PDF of the Avastin label can be accessed on the FDA Web site.

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FDA issues NSAID health advisory pending further evaluation

December 28, 2004

ST. LOUIS (MD Consult) - On December 23, 2004, the U.S. Food and Drug Administration (FDA) issued a public health advisory summarizing the agency's recent recommendations concerning the use of nonsteroidal anti-inflammatory drug products (NSAIDs), including those known as cyclooxygenase 2 (COX-2) selective agents. The public health advisory is an interim measure, pending further review by the FDA of data that continue to be collected.

In addition, the FDA announced that it is requiring evaluation of all prevention studies that involve the COX-2 selective agents Celebrex (celecoxib) and Bextra (valdecoxib) to ensure that adequate precautions are implemented in the studies and that local institutional review boards reevaluate them in light of the new evidence that these drugs may increase the risk of heart attack and stroke.

The FDA is issuing an advisory because of recently released data from controlled clinical trials showing that the COX-2 selective agents (ie, Vioxx [rofecoxib], Celebrex, and Bextra) may be associated with an increased risk of serious cardiovascular events (eg, heart attack and stroke), especially when they are used for long periods of time or in very high risk settings (eg, immediately after heart surgery).

Also, as the FDA announced earlier this week, preliminary results from a long-term clinical trial (up to 3 years) suggest that long-term use of a nonselective NSAID, naproxen (sold as Aleve, Naprosyn, and other trade name and generic products), may be associated with an increased cardiovascular risk compared with placebo.

Although the results of these studies are preliminary and conflict with other data from studies of the same drugs, the FDA is making the following interim recommendations:

• Physicians prescribing Celebrex or Bextra should consider this emerging information when weighing the benefits against risks for individual patients. Patients who are at a high risk of gastrointestinal tract bleeding, have a history of intolerance to nonselective NSAIDs, or are not doing well taking nonselective NSAIDs may be appropriate candidates for COX-2 selective agents.
• Individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account for each prescribing situation.
• Consumers are advised that all over-the-counter pain medications, including NSAIDs, should be used in strict accordance with the label directions. If use of an over-the-counter NSAID is needed for longer than 10 days, a physician should be consulted.

Nonselective NSAIDs are widely used in both over-the-counter and prescription settings. As prescription drugs, many are approved for short-term use in the treatment of pain and primary dysmenorrhea and for longer-term use to treat the signs and symptoms of osteoarthritis and rheumatoid arthritis. The FDA has previously posted extensive NSAID medication information at www.fda.gov/cder/drug/analgesics/default.htm.

The FDA is collecting and will be analyzing all available information from the most recent studies of Vioxx, Celebrex, Bextra, and naproxen, as well as other data for COX-2 selective and nonselective NSAID products to determine whether additional regulatory action is needed. An advisory committee meeting is planned for February 2005, which will provide for a full public discussion of these issues.

The FDA urges health care providers and patients to report adverse event information to the agency via the MedWatch program by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or via the Internet at fda.gov/medwatch/index.html.

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Crixivan not recommended to treat HIV in pregnant women, FDA warns

December 28, 2004

ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration announced on December 27, 2004, that the Clinical Pharmacology section of the Crixivan (indinavir sulfate) label has been revised to include pharmacokinetic data from a study (PACTG 358) in HIV-infected pregnant women. Results from this study show substantially reduced indinavir concentrations in women at 30 to 32 weeks' gestation compared with postpartum concentrations. Based on these data, the Precautions section now states that indinavir is not recommended in HIV-infected pregnant patients.

The following text was added to the Clinical Pharmacology, Pharmacokinetics, Pregnant Patients section.

Pregnant Patients: The optimal dosing regimen for use of indinavir in pregnant patients has not been established. A Crixivan dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). The mean indinavir plasma AUC0-8hr at weeks 30 to 32 of gestation (n = 11) was 9,231 nM*hr, which is 74% (95% CI: 50%, 86%) lower than that observed 6 weeks postpartum. Six of these 11 (55%) patients had mean indinavir plasma concentrations 8 hours post-dose (Cmin) below assay threshold of reliable quantification. The pharmacokinetics of indinavir in these 11 patients at 6 weeks postpartum were generally similar to those observed in non-pregnant patients in another study (see Precautions, Pregnancy).

The following was added to the Precautions, Pregnancy, Pregnancy Category C section.

A Crixivan dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). Given the substantially lower antepartum exposures observed and the limited data in this patient population, indinavir use is not recommended in HIV-infected pregnant patients (see Clinical Pharmacology, Pregnant Patients).

Crixivan is indicated for the treatment of HIV infection, in combination with antiretroviral agents. Capsules are available for oral administration in strengths of 100, 200, 333, and 400 mg of indinavir (corresponding to 125, 250, 416.3, and 500 mg indinavir sulfate, respectively).

For more information, visit crixivan.com/indinavir_sulfate/crixivan/consumer/index.jsp.

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Hepatic reactions reported in conjunction with Centocor's Remicade

December 28, 2004

ST. LOUIS (MD Consult) - On December 22, 2004, the U.S. Food and Drug Administration (FDA) announced that the agency and Centocor have notified health care professionals of revisions to the Warnings and Adverse Reactions sections and the patient package insert of the prescribing information for Remicade (infliximab). Severe hepatic reactions have been reported in patients receiving Remicade. Though the reports were rare, some of these cases were fatal or necessitated liver transplantation.

This medication is indicated for the treatment of rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis.

According to the letter to health care professionals circulated by Centocor, the company has added a warning on hepatotoxicity to the product labeling as follows:

WARNINGS: Hepatotoxicity Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis, have been reported rarely in postmarketing data in patients receiving Remicade. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than a year after initiation of Remicade; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, Remicade should be discontinued, and a thorough investigation of the abnormality should be undertaken. As with other immunosuppressive drugs, use of Remicade has been associated with reactivation of hepatitis B in patients who are chronic carriers of this virus (ie, surface antigen positive). Chronic carriers of hepatitis B should be appropriately evaluated and monitored prior to the initiation of and during treatment with Remicade. In clinical trials, mild or moderate elevations of ALT [alanine aminotransferase] and AST [aspartate aminotransferase] have been observed in patients receiving Remicade without progression to severe hepatic injury (see Adverse Reactions, Hepatotoxicity).

The Adverse Reactions section and patient information sheet were also updated to include important information regarding hepatotoxicity.

In addition, Centocor has added a risk of pneumonia to the existing Warnings on Risk of Infections based on clinical trial data in patients with rheumatoid arthritis described in the Adverse Reactions section of the labeling.

Centocor requests that any adverse reactions associated with Remicade be reported to the company at 1-800-457-6399. Alternatively, this information can be reported to the FDA's MedWatch reporting system by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch, or mail (MedWatch, HF-2, 5600 Fishers Ln, Rockville, MD 20852-9787.

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