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