Atazanavir not to be coadministered with PPIs, says Bristol-Myers Squibb
Pfizer's COX-2 inhibitor may involve cardiovascular risk, NCI says
FDA announces new dosage recommendations for use of Procrit in cancer patients
Inadequate syphilis treatment may stem from similarity of medication names, says FDA
FDA initiates plan to protect children treated with antidepressants
HBV patients taking Rituxan at risk for serious complications, drugmakers say
Study connects Vioxx to heart attack and stroke, Merck issues voluntary withdrawal
FDA-mandated diabetes warning added to Pfizer's antipsychotic Geodon
Prescription drugs from Web site substandard and potentially dangerous
Wyeth adds warnings for neonatal effects and suicidality risk to antidepressant
Antidepressant labeling warns of worsening depression and suicidal behavior
Children's Motrin tablets may mistakenly contain Tylenol 8-hour extended release geltabs
Serious bleeding may result from interaction between Oxandrin and warfarin
New research shows OTC progesterone cream as potent as pills
New cautions from FDA guard those with sensitivities to ingredients in OTC drugs
FDA advises monitoring of adults and children taking antidepressants
Bristol-Myers Squibb corrects its claims regarding anticholesterol drug
FDA warns severe skin reactions and cardiovascular risk possible with Bextra
Unapproved Canadian product Carbolith might be substandard, says FDA
Serious risks may be involved with pregnancy termination drug
Dietary supplements Actra-Rx and Yilishen could be dangerous, FDA warns
Osteonecrosis of the jaw linked to usage of two Novartis drugs
Oral erythromycin combined with CYP3A inhibitors may increase the risk of sudden cardiac death
Cancer drug linked to arterial thromboembolic events, says FDA
FDA warns consumers about counterfeit drugs purchased in Mexico
Vaccine recommendation info contains dangerous errors, FDA warns
New Serzone labeling warns of hepatic failure and worsening depression
Bristol-Myers Squibb announces adverse drug interactions related to Desyrel
FDA changes labeling for Voriconazole (VFEND) when given with efavirenz or ritonavir
FDA prohibits sale of ephedrine alkaloids, courts do not object
Propharma issues recall of Major Twice-A-Day 12-Hour Nasal Spray–Nasal Decongestant
Zyprexa may increase risk of hyperglycemia and diabetes, says FDA
FDA uncovers potentially dangerous illegally imported drug shipments
December 21, 2004
ST. LOUIS (MD Consult) - On December 20, 2004, the U.S. National Institutes of Health (NIH) announced that research investigators suspended, until further notice, the use of 2 drugs, naproxen (Aleve) and celecoxib (Celebrex), in a large, 3-arm, national Alzheimer's disease prevention trial sponsored by the National Institute on Aging, a part of the NIH. The trial, called the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) was designed to assess the potential benefit of long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen (220 mg twice a day) and the COX-2 inhibitor celecoxib (200 mg twice a day) in decreasing the risk of developing Alzheimer's disease in people 70 years of age or older who were considered to be at increased risk because of family history but did not have symptoms of the disease.
Approximately 2,400 volunteer participants were randomly assigned to receive naproxen, celecoxib, or placebo for up to 3 years. Although no significant increase in risk for celecoxib was found in this trial, the use of these drugs in the study was suspended in part because of findings reported last week from a National Cancer Institute trial to test the effectiveness of celecoxib in preventing colon cancer. In addition, however, data from the ADAPT trial indicated an apparent increase in cardiovascular and cerebrovascular events among the participants taking naproxen when compared with those taking placebo.
"This step is being taken as a precautionary measure to ensure the safety of the study's participants," said NIH Director Elias A. Zerhouni, MD. "The investigators made their decision based on the risk/benefit analysis specific to this trial."
The ADAPT trial began in 2001 and was conducted at 6 sites across the United States: Tampa, Fla; Rochester, NY; Baltimore, Md; Sun City, Ariz; Seattle, Wash; and Boston, Mass. The principal investigator for the study is John Breitner, MD, of the Veterans Affairs Medical Center Puget Sound and the University of Washington.
In light of these findings, investigators and NIH scientists will continue to review this and other NSAIDs studies sponsored by the NIH. It should be pointed out that the cancer prevention trials and the ADAPT study are among the first long-term, clinical trials to test these classes of drugs. The studies are examining these compounds for uses very different from the uses for which these medications are currently approved. The NIH and the FDA will work together to provide the public with information they need to make informed health decisions.
An NIH press release stated that information for the public and health professionals will be posted on the agency's Web site (nih.gov) as additional data become available.
In the meantime, the FDA advises patients who are currently taking over-the-counter naproxen products to carefully follow the instructions on the label. Patients should not exceed the recommended doses for naproxen (220 mg twice daily) and should not take naproxen for longer than 10 days unless a physician directs otherwise. Patients with questions about naproxen should consult their physicians.
Naproxen was first sold as a prescription drug under the trade name Naprosyn in 1976. The FDA approved its use as an over-the-counter drug in 1994.
December 21, 2004
ST. LOUIS (MD Consult) - Bristol-Myers Squibb has issued a letter addressed to health care providers regarding important new pharmacokinetic data concerning the coadministration of Reyataz (atazanavir) and Norvir (ritonavir) with Prilosec (omeprazole), said the U.S. Food and Drug Administration in a December 20, 2004, announcement. Omeprazole is a proton-pump inhibitor (PPI) indicated for the treatment of acid-related diseases; it works by suppressing gastric acid secretion.
The observations in Bristol-Myers Squibb's letter were made from a randomized, open-label, multiple-dose drug interaction study.
A 76% reduction in atazanavir area under the concentration-time curve (AUC) and a 78% reduction in atazanavir trough plasma concentration (Cmin) were observed when Reyataz/ritonavir 300/100 mg was coadministered with omeprazole 40 mg.
Based on the study results:
Investigations are ongoing regarding the potential drug interaction between Reyataz (atazanavir sulfate) and H2-receptor antagonists (another type of gastric medication) when coadministered. Until data are available, clinicians should note the following statements from the Reyataz package insert:
| Reduced plasma concentrations of atazanavir are expected if H2-receptor antagonists are administered with Reyataz (atazanavir sulfate). This may result in loss of therapeutic effect and development of resistance. To lessen the effect of H2-receptor antagonists on atazanavir exposure, it is recommended that an H2-receptor antagonist and Reyataz be administered as far apart as possible, preferably 12 hours apart. |
Full prescribing information for Reyataz is available at reyataz.com/managehiv/reyataz/dtc/index.jsp?BV_UseBVCookie=Yes.
December 20, 2004
ST. LOUIS (MD Consult) - On December 17, 2004, the U.S. Food and Drug Administration (FDA) advised health care professionals about a new warning for Strattera (atomoxetine hydrochloride), a drug approved for attention deficit hyperactivity disorder in adults and children. The labeling is being updated with a bolded warning about the potential for severe liver injury following 2 reports (1 teenager and 1 adult) in patients who had been treated with Strattera for several months, both of whom recovered.
The labeling warns that severe liver injury may progress to liver failure, resulting in death or the need for a liver transplant in a small percentage of patients. The labeling also notes that the number of actual cases of severe liver injury is unknown because of underreporting of postmarketing adverse events.
The bolded warning indicates that the medication should be discontinued in patients who experience jaundice or exhibit laboratory evidence of liver injury.
Strattera has been on the market since 2002 and has been used in more than 2 million patients. In clinical trials of 6,000 patients, no signal for liver problems (hepatotoxicity) had emerged.
The FDA has asked the manufacturer to add a bolded warning about severe liver injury to the labeling. Eli Lilly has agreed to alert health care professionals about the new information in a letter. The company will also update the patient package insert with information about the signs and symptoms of liver problems, which include:
Health care professionals are encouraged to report any unexpected adverse events associated with Strattera directly to Indianapolis-based Eli Lilly at 1-800-LillyRx or to the FDA MedWatch program at 1-800-FDA-1088. The MedWatch form is available online at fda.gov/medwatch/safety/3500.pdf for download. The form can be submitted by fax to 1-800-FDA-0178 or by mail to MedWatch, HFD-410, FDA, 5600 Fishers Ln, Rockville, MD 20857.
December 20, 2004
ST. LOUIS (MD Consult) - On December 17, 2004, the U.S. Food and Drug Administration (FDA) released a statement announcing that the National Cancer Institute (NCI) has stopped drug administration in an ongoing clinical trial investigating a new use of of the cyclo-oxygenase 2 (COX-2) inhibitor Celebrex (celecoxib) to prevent colon polyps. The trial was halted because of an increased risk of cardiovascular events in patients taking Celebrex versus those taking a placebo.
Patients in the clinical trial taking 400 mg of Celebrex twice daily had a 3.4 times greater risk of cardiovascular events compared with placebo. For patients in the trial taking 200 mg of Celebrex twice daily, the risk was 2.5 times greater. The average duration of treatment in the trial was 33 months.
A similar ongoing study comparing Pfizer's Celebrex 400 mg once a day versus placebo, in patients followed up for a similar period of time, has not shown increased risk.
Although these are important findings, at this point the FDA has seen only the preliminary results of the studies. The FDA will obtain all available data on these and other ongoing Celebrex trials as soon as possible and will determine the appropriate regulatory action.
Although the FDA has not seen all of the available data on Celebrex, these findings are similar to recent results from a study of Vioxx (rofecoxib), another drug in the same class as Celebrex. Vioxx was recently voluntarily withdrawn by Merck. Another drug in this class, Bextra (valdecoxib), has shown an increased risk for cardiovascular events in patients after heart surgery. Bextra and Celebrex are the only 2 selective COX-2 agents currently on the U.S. market.
Physicians should consider this evolving information in evaluating the risks and benefits of Celebrex in individual patients. The FDA advises evaluating alternative therapy. At this time, if physicians determine that continued use is appropriate for individual patients, the FDA advises the use of the lowest effective dose of Celebrex.
Patients who are currently taking Celebrex and have questions or concerns about the drug should discuss them with their physicians.
Celebrex is approved for use in the United States for the treatment of arthritis and pain, at recommended doses of 100 to 200 mg daily for osteoarthritis and 200 to 400 mg/d for rheumatoid arthritis. It is also approved for a rare condition called familial adenomatous polyposis in doses up to 800 mg/d.
Previous large studies of Celebrex, including clinical trials and epidemiology studies, have not suggested the sort of cardiovascular risk found in the NCI polyp study. Because similar long-term studies of other products in the class of nonsteroidal anti-inflammatory drugs (NSAIDS) other than COX-2 inhibitors have not been done, it is not known whether other NSAIDS pose a similar risk.
The FDA has stated it will provide updates on Celebrex in particular and this class of drugs in general as more information becomes available.
December 10, 2004
ST. LOUIS (MD Consult) - On December 9, 2004, the U.S. Food and Drug Administration (FDA) announced important new information on adverse effects associated with the use of Bextra, a cyclo-oxygenase 2 (COX-2) selective nonsteroidal anti-inflammatory drug (NSAID) indicated for the treatment of osteoarthritis, rheumatoid arthritis, and dysmenorrhea. A boxed warning, strengthening previous warnings about the risk of life-threatening skin reactions, and a new bolded warning contraindicating the use of Bextra in patients undergoing coronary artery bypass graft (CABG) surgery will be added to the label.
In addition, the FDA will also seek input from the public and from outside experts on the appropriate uses for Bextra and other NSAIDs at a previously announced advisory committee meeting to be held early in 2005.
Boxed and bolded warnings provide health care professionals and patients with important information on drugs that may be associated with serious adverse effects in a way that maximizes the drug's benefits and minimizes its risks.
The new boxed warning on Bextra's label states that patients taking the medication have reported serious, potentially fatal skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These skin reactions are most likely to occur during the first 2 weeks of treatment but can occur any time during therapy. In a few cases, these reactions have resulted in death. The labeling advises doctors that Bextra should be discontinued at the first appearance of a skin rash, mucosal lesions (such as sores on the inside of the mouth), or any other sign of allergic reactions. The new boxed warning also states that Bextra contains sulfa, and patients with a history of allergic reactions to sulfa may be at a greater risk of skin reactions.
As of November 2004, the FDA had received reports of a total of 87 cases in the United States of severe skin reactions in association with Bextra. Twenty of the 87 cases involved patients with a known allergy to sulfa. Of these 87 cases, 36 hospitalizations were reported, including 4 deaths. Other COX-2 selective inhibitors and traditional NSAIDs such as naproxen and ibuprofen also have a risk for these rare, serious skin reactions, but the reported rate of these adverse effects appears to be greater for Bextra than for other COX-2 agents.
In addition to highlighting serious skin reactions, the strengthened label warnings also highlight new data about cardiovascular risks. A recently completed study conducted by Pfizer that included over 1,500 patients treated after CABG showed an increased cardiovascular risk in patients treated with Bextra compared with placebo. Observed cardiovascular events included thromboembolic events such as myocardial infarction, cerebrovascular accident, deep vein thrombosis, and pulmonary embolism.
Pfizer submitted the final report of the new CABG study to the FDA on November 5, 2004. The report confirms the risk of intravenous Bextra (about 2% of patients had such an adverse event) and also shows that the oral form is associated with a lower, but existing, risk (about 1% of patients) immediately after CABG surgery-a very specific medical setting. In the placebo group, about 0.5% of patients had an adverse cardiovascular event. Bextra is not approved for use in the treatment of postoperative pain of any type; however, the FDA believes that these new findings should be made available to health care professionals and patients, and the bolded warning specifically contraindicates Bextra for treatment of pain immediately after CABG.
The FDA urges health care providers and patients to report adverse event information to the FDA via the MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), or the Internet (fda.gov/medwatch/index.html).
December 10, 2004
ST. LOUIS (MD Consult) - On December 8, 2004, the U.S. Food and Drug Administration (FDA)'s MedWatch safety information program announced a letter addressed to oncologists, hematologists, and other health care professionals regarding the safety of Procrit (epoetin alfa). In the letter, Ortho Biotech Products notified these health care professionals of important changes to the safety information and dosing sections of the product labeling for Procrit. To ensure consistency with labeling for other products in this class, changes to hemoglobin rate of rise and target were made.
The new prescribing information recommends that the target hemoglobin level in patients with cancer should be individually determined for each patient, and this target should not exceed 12 g/dL in men and women. The dose should be withheld if the hemoglobin level is 13 g/dL or higher. Dosing interruption and modification are recommended if the rate of rise of hemoglobin exceeds 1 g/dL over a 2-week period. This guidance applies whether patients are treated with Procrit 3 times weekly or with the newly approved once-weekly dosing regimen.
The new recommendations result from recent investigational studies, some with erythropoietin products other than Procrit, and some conducted outside the United States, where patients with cancer were treated to high hemoglobin target levels, beyond the correction of anemia. These studies permitted or required dosing to achieve hemoglobin levels greater than 12 g/dL. An increased frequency of adverse patient outcomes, including increased mortality and thrombotic vascular events, was reported in these studies. Additional details of these studies are included in the following sections of the revised prescribing information, specifically in the sections titled, "Warnings - Thrombotic Events and Mortality" and "Precautions - Tumor Growth Factor Potential."
Since all erythropoietin products share similarities in mechanism of action, Ortho Biotech deems this information to be relevant for prescribers and patients to help ensure the safe and effective use of Procrit.
Previously, the only dosing regimen specified in Procrit labeling for the cancer chemotherapy indication was 150 IU/kg given subcutaneously (SC) 3 times/wk. Recently, another dosing regimen—40,000 IU SC weekly—has been approved for use in this patient population. The revised product labeling includes the following guidance regarding once-weekly dosing of Procrit:
Ortho Biotech requests that any adverse events related to Procrit be reported to the company at 1-800-325-7504, prompt #2. Alternatively, this information can be reported to the FDA's MedWatch system by phone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (fda.gov/medwatch), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).
Full prescribing information is available at fda.gov/medwatch/SAFETY/2004/Procrit_PI.pdf.
December 10, 2004
ST. LOUIS (MD Consult) - In an announcement made on December 8, 2004, the U.S. Food and Drug Administration (FDA) advised consumers about a Canadian recall of Carbolith (lithium carbonate) 150-mg capsules distributed in Canada by Valeant Canada Limited. Although Carbolith is not an FDA-approved product, the FDA is investigating several Web sites advertising Carbolith for sale to U.S. consumers. Carbolith 150-mg capsules are used in the treatment of manic-depressive illness. The company's recent testing led to the conclusion that the product may not deliver adequate amounts of the drug to ensure effective treatment.
As a precaution, Health Canada recently advised persons taking Carbolith 150-mg capsules to continue taking their medication but to consult their health care professionals as soon as possible. This product has been available to the Canadian public with a prescription from physicians.
U.S. consumers who have purchased this drug through the Internet and taken it for the treatment of manic-depressive illness could experience adverse events associated with lowered blood lithium levels. These events could include a worsening of manic-depressive illness, a serious psychiatric condition. A worsening of this condition could result in symptoms associated with mania (eg, motor hyperactivity, delusions of grandeur, poor judgment, and aggressiveness) and depression or suicidal thoughts that may require hospitalization.
Additionally, consumers who may have taken the Carbolith product for several weeks or more may experience toxic effects when they switch to a lithium carbonate product that delivers adequate amounts of the drug. Mild toxicity could result in tremors of the hands, thirst and more frequent urination, drowsiness, ringing in the ears, and blurred vision. More severe toxicity could result in confusion, muscle twitching, vomiting, diarrhea, seizures, coma, and death.
Because lithium carbonate requires careful, closely monitored dosing and periodic blood tests to measure the level of the drug in the blood, U.S. consumers who have taken Carbolith 150-mg capsules should continue to take the product and consult a health care provider as soon as possible so that an alternative medication can be prescribed.
Consumers and health care professionals are urged to report adverse reactions associated with Carbolith 150-mg capsules to the FDA's MedWatch program via the Internet (fda.gov/medwatch/report.htm), fax (800-332-0178), phone (800-332-1088), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787) and to Health Canada by toll-free telephone at 1-866-234-2345 or by toll-free fax at 1-866- 678-6789.
A public advisory issued by Health Canada about this recall can be found at hc-sc.gc.ca/english/protection/warnings/2004/2004-10-29.html. A Dear Health Care Professional Letter dated November 4, 2004, issued by Valeant Canada Limited can be found at hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/carbolith_hpc_e.html.
December 1, 2004
ST. LOUIS (MD Consult) - In November 2004, King Pharmaceuticals and the U.S. Food and Drug Administration (FDA) reminded health care professionals of important labeling changes regarding Bicillin C-R (penicillin G benzathine and penicillin G procaine injectable suspension) and Bicillin L-A (penicillin G benzathine injectable suspension). These labeling changes highlight existing precautionary and prescribing information.
Bicillin L-A is the only currently approved penicillin G benzathine product indicated for the treatment of syphilis, and Bicillin C-R should not be administered in place of Bicillin L-A. Administration of Bicillin C-R instead of Bicillin L-A in the treatment of syphilis may result in inadequate treatment.
The U.S. Centers for Disease Control and Prevention (CDC)'s 2002 Sexually Transmitted Diseases Treatment Guidelines recommend penicillin G benzathine for the treatment of syphilis infection, consistent with the labeled indications for Bicillin L-A. However, King Pharmaceuticals was made aware of postmarketing reports from clinics treating sexually transmitted diseases in the United States where Bicillin C-R has been inappropriately used to treat patients infected with syphilis; therefore, the FDA, the CDC, and King Pharmaceuticals have issued materials reiterating that Bicillin L-A is the only currently approved penicillin G benzathine product indicated for the treatment of syphilis.
To help health care professionals better distinguish between the two types of Bicillin and to better ensure the proper use of each of those products, Bicillin C-R cartons and syringe labels have been modified. The background colors for the C-R cartons have been changed from white to pale green (Bicillin C-R) and pale purple (Bicillin C-R 900/300). Bicillin L-A cartons will retain the white background. The reminder statement "Not for the Treatment of Syphilis" has been added in bold, capital letters to the front panel, the back panel, and 1 side panel of both the Bicillin C-R and Bicillin C-R 900/300 cartons. The statement "Not for the Treatment of Syphilis" has also been added in red text to both the Bicillin C-R and Bicillin C-R 900/300 syringe labels.
In addition, a black box warning has been added to the prescribing information of both Bicillin products to emphasize that these products should only be administered by deep intramuscular injection. The new warning appears below:
| Warnings
Warning: not for intravenous use. Do not inject intravenously or admix with other intravenous solutions. There have been reports of inadvertent intravenous administration of penicillin G benzathine which has been associated with cardiorespiratory arrest and death. Prior to administration of this drug, carefully read the Warnings, Adverse Reactions, and Dosage and Administration sections of the labeling. |
In addition, a new reminder "Warning: Not for Intravenous Use" has been added in red, bold, all capital letters to the Bicillin C-R and Bicillin L-A cartons and syringe labels.
King Pharmaceuticals requests that any adverse events associated with the use of Bicillin be reported to King Pharmaceuticals, Inc, at 800-546-4905. Alternatively, this information can be reported to the FDA's MedWatch program via phone (800-FDA-1088), fax (800-FDA-1078), Internet (fda.gov/medwatch), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).
November 18, 2004
ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) announced on November 17, 2004, that a "black box" warning, highlighting the premise that prolonged use may result in the loss of bone density, will be added to the labeling of Depo-Provera Contraceptive Injection (medroxyprogesterone acetate), an established injectable drug approved for use in women to prevent pregnancy.
Although Depo-Provera Contraceptive Injection has been used for decades as a means of birth control throughout the world and remains a safe and effective contraceptive, the FDA and Pfizer (the drug's manufacturer) are taking this action to ensure that physicians and patients have access to this important information
The black box warning for Depo-Provera points out that prolonged use of the drug may result in significant loss of bone density, and that the loss is greater the longer the drug is administered. This bone density loss may not be completely reversible after discontinuation of the drug. Thus, the warning states that a woman should only use Depo-Provera Contraceptive Injection as a long-term birth control method (eg, longer than 2 years) if other birth control methods are inadequate for her.
Black box warnings are designed to highlight special problems, particularly those that are serious, and to give health care professionals a clear understanding of a potential medical complication associated with a drug. Black box warnings provide physicians with important insights as to how to prescribe a drug that may be associated with serious adverse effects in a way that maximizes its benefits and minimizes its risks.
The addition of the black box warning came as a result of the drug manufacturer's and the FDA's analysis of data that clarified the drug's long-term effects on bone density.
In addition to the black box warning on the labeling, the drug's manufacturer will issue a letter addressed to health care practitioners regarding the effect of long-term treatment on bone mineral density. Pfizer will issue this letter to parties likely to prescribe the drug and will incorporate the new information in the patient information sheet distributed with the drug.
November 16, 2004
ST. LOUIS (MD Consult) - In November 2004, Bristol-Myers Squibb issued a letter addressed to health care providers regarding coadministration of Viread (tenofovir disoproxil fumarate [TDF]), Videx EC (didanosine delayed-release capsules, enteric-coated beadlets [ddI EC]), and either Sustiva (efavirenz [EFV]) or Viramune (nevirapine [NVP]). Results from two recently conducted, investigator-sponsored trials have demonstrated a potential for early virologic failure associated with this antiretroviral regimen in treatment-naive HIV patients with high baseline viral loads. The mechanism of early virologic failure in these patients is unclear.
Early virologic failure appears to be limited to the specific combination of TDF and ddI EC, plus either EFV or NVP, because there are data from registrational trials supporting the efficacy of EFV- and TDF-based regimens as well as EFV- and ddI EC–based regimens in treatment-naive HIV patients. Additionally, a recent post-hoc analysis performed in treatment-experienced HIV patients with high baseline viral loads receiving a boosted protease inhibitor with two nucleoside reverse transcriptase inhibitors demonstrated lower virologic failure rates in subjects receiving ddI EC and TDF than those receiving another nucleoside analog in combination with TDF, although significance testing could not be performed due to the small number of patients (n = 55).
Data for the EFV–TDF–ddI EC regimen are derived from an open-label randomized study (virologic failure in 6 of 14 patients) and a retrospective database analysis (virologic failure in 5 of 10 patients), and data for NVP–TDF–ddI EC combination are derived from a retrospective database analysis (virologic failure in 2 of 4 patients).
Based on this information, clinicians should use caution when coadministering TDF, ddl EC, and either EFV or NVP in treatment-naive HIV patients with high baseline viral loads. Further investigations are ongoing regarding the clinical implications of these results.
For full prescribing information, visit viread.com/pdf/pi.pdf.
November 16, 2004
ST. LOUIS (MD Consult) - On November 15, 2004, the U.S. Food and Drug Administration (FDA) announced important new safety changes to the Danco Laboratories’ labeling of Mifeprex (mifepristone; also known as RU-486). Mifeprex was approved in 2000 for the termination of early pregnancy, defined as occurring when the fetus has a gestational age of 49 days or less. The FDA and Danco Laboratories have received reports of serious bacterial infection, bleeding, ectopic pregnancies that have ruptured, and death, including another death from sepsis that was recently reported to the FDA. These reports have led to the revision of the black box labeling.
The new warnings to health care providers and consumers include changes to the existing black box on the product to add new information on the risk of serious bacterial infections, sepsis, bleeding, and death that may occur after any termination of pregnancy, including use of Mifeprex. Although these risks are rare, the new labeling and medication guide will provide the latest available information.
The new information reminds health care providers that serious bacterial infection and sepsis may occur without the usual signs of infection, such as fever and tenderness on examination. Health care providers should be aware that prolonged, heavy bleeding may warrant surgical interventions. The label also warns that health care providers should be vigilant for patients with undiagnosed ectopic pregnancies because this condition may be missed by physicial examination and ultrasound. Some of the symptoms of an ectopic pregnancy may mimic the expected symptoms of a medical termination of pregnancy. Mifepristone is not effective for termination of these pregnancies.
For consumers, the medication guide states they should contact their health care providers right away if they experience fever, abdominal pain, or heavy bleeding. Also, consumers are advised to take their medication guide to the emergency room or any health care provider they visit for treatment of these problems. This allows health care providers to understand that the patient is undergoing a termination of pregnancy and assess risks associated with that condition.
The revised labeling will provide physicians and patients with important information so that they can respond and possibly prevent rare but serious complications that can occur with any termination of pregnancy. The FDA will continue to monitor the usage of Mifeprex and may take further action.
November 10, 2004
ST. LOUIS (MD Consult) - In a letter dated November 5, 2004, the U.S. Food and Drug Administration (FDA) and Abbott Pharmaceuticals notified health care professionals of revisions to the Warnings section of the prescribing information of Humira (adalimumab), indicated for the treatment of rheumatoid arthritis. These warnings include risks of serious infections with the combined use of Humira and anakinra, hypersensitivity reactions, including anaphylaxis, and hematologic events, including pancytopenia and aplastic anemia.
The FDA received information regarding serious infections observed with the use of anakinra and another tumor necrosis factor (TNF)-blocking agent and has requested that all manufacturers of TNF-blocking agents add the following new information to the Warnings section of the prescribing information.
| Use with Anakinra
Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocking agent, with no added benefit. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from combination of anakinra and other TNF-blocking agents. Therefore, the combination of Humira and anakinra is not recommended (see Precautions, Drug Interactions). |
In addition, Abbott has received rare postmarketing reports of anaphylaxis associated with Humira. As a result, Abbott has included the following new information in the Warnings section of the prescribing information for the drug.
| Hypersensitivity Reactions
In postmarketing experience, anaphylaxis has been reported, rarely, following Humira administration. If an anaphylactic or other serious allergic reaction occurs, administration of Humira should be discontinued immediately and appropriate therapy instituted. In clinical trials of Humira, allergic reactions overall (eg, allergic rash, anaphylactoid reaction, fixed drug reaction, nonspecified drug reaction, urticaria) have been observed in approximately 1% of patients. |
Finally, Abbott has received infrequent reports of hematologic events associated with Humira, including medically significant cytopenia, and the FDA has received rare reports of pancytopenia, including aplastic anemia, with TNF-blocking agents. As a result, Abbott has included the following new information in the Warnings section of the drug's prescribing information:
| Hematologic Events
Rare reports of pancytopenia including aplastic anemia have been reported with TNF-blocking agents. Adverse events of the hematologic system, including medically significant cytopenia (eg, thrombocytopenia, leukopenia) have been infrequently reported with Humira (see Adverse Reactions, Other Adverse Reactions). The causal relationship of these reports to Humira remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (eg, persistent fever, bruising, bleeding, pallor) while on Humira. Discontinuation of Humira therapy should be considered in patients with confirmed significant hematologic abnormalities. |
Abbott requests that adverse events associated with Humira be reported to Abbott at 800-633-9110. Alternatively, this information can be reported to FDA's MedWatch system by phone (800-FDA-1088), fax (800-FDA-0178), Internet (fda.gov/medwatch), or mail (MedWatch, HF-5600 Fishers Lane, Rockville, MD 20852-9787).
November 4, 2004
ST. LOUIS (MD Consult) - On November 2, 2004, the U.S. Food and Drug Administration (FDA) warned consumers not to purchase or to consume Actra-Rx or Yilishen, two products promoted and offered for sale on Web sites as "dietary supplements" for treating erectile dysfunction and enhancing sexual performance for men. These products in fact contain an active prescription drug ingredient. The FDA has also issued an import alert instructing FDA field personnel to stop the importation of Actra-Rx and Yilishen.
A research letter published in the February 4, 2004, issue of The Journal of the American Medical Association described the results of a chemical analysis of Actra-Rx, finding that each capsule analyzed contained prescription-strength quantities of sildenafil. Sildenafil is the active drug ingredient in Viagra, a Pfizer prescription drug product approved in the United States for the treatment of erectile dysfunction. The FDA conducted its own tests of Actra-Rx and also found that the product contained prescription-strength sildenafil.
An interaction between sildenafil and certain prescription drugs containing nitrates (such as nitroglycerin) or nitrates found in illicit substances (such as amyl nitrate) may cause a significant lowering of blood pressure to an unsafe level. Consumers with diabetes, high blood pressure, high cholesterol, or heart disease often take nitrates.
Because erectile dysfunction can be a common problem in individuals with these conditions, these consumers may take Actra-Rx or Yilishen and risk experiencing serious adverse effects. Anyone experiencing erectile dysfunction should seek guidance from their health care provider before purchasing a product to treat that condition.
Consumers who have taken Actra-Rx or Yilishen should stop taking it and consult with their health care providers regarding erectile dysfunction treatment. Consumers who are seeking treatment for erectile dysfunction should not take Actra-Rx or Yilishen because either can be dangerous to their health and even life-threatening.
October 26, 2004
ST. LOUIS (MD Consult) - On October 15, 2004, the U.S. Food and Drug Administration (FDA), Janssen Pharmaceutica Products, and Johnson & Johnson Pharmaceutical Research & Development notified health care professionals of reports of medication errors involving confusion between Reminyl (galantamine hydrobromide), a drug approved for the treatment of mild to moderate dementia of the Alzheimer's type, and Amaryl (glimepiride), a product of Aventis Pharmaceuticals, indicated for the treatment of non–insulin-dependent (type 2) diabetes mellitus. These reports include instances in which Reminyl was prescribed but Amaryl was incorrectly dispensed and administered instead, leading to various adverse events including severe hypoglycemia and one death.
Janssen announced that, according to spontaneous reports submitted to the FDA and the United States Pharmacopoeia, prescriptions have been incorrectly written, interpreted, labeled, and/or filled due to the similarity in names between Reminyl and Amaryl. These products have an overlapping strength (4 mg) and an overlapping dosage form (tablets). In addition, the two products have generic names (galantamine versus glimepiride) that might lead to their storage in close proximity.
It is important to note that Reminyl has a starting dosage of 4 mg twice a day, whereas Amaryl is initially dosed at 1 to 2 mg once a day, with a maximum starting dosage of 2 mg.
Reminyl is supplied for oral administration as 4-mg (round, off-white), 8-mg (round, pink), and 12-mg (round, orange-brown) tablets. Reminyl tablets are imprinted with "JANSSEN" on one side, and "G" and the strength "4," "8," or "12" on the other side.
Amaryl is supplied for oral administration in flat-faced, oblong pills with notched sides at a double bisect and the imprint "AMARYL." The tablets are available in doses of 1 mg (pink), 2 mg (green) and 4 mg (blue).
In the letter the health care professionals, Janssen pointed out that the physician's role in avoiding such errors is pivotal. The company requested the assistance of health care workers in clearly communicating oral and written prescriptions for these 2 products to help avoid future medication errors. For phone prescriptions, the recommendation is to spell out the name of the medication. For written prescriptions, the name of the medication should be printed clearly.
Janssen requests that anyone aware of any medication errors involving Reminyl report them immediately at 1-800-JANSSEN or 1-800-526-7736, and if Amaryl is involved, to Aventis Pharmaceuticals at 1-800-633-1610. Medication errors should also be reported to the USP Medication Errors Reporting Program in cooperation with the Institute for Safe Medication Practices (1-800-23ERROR; 1-800-FAIL-SAF) or the FDA's MedWatch Adverse Event Reporting Program via phone (800-FDA-1088), fax (800-FDA-1078), Internet (fda.gov/medwatch), or mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).
October 18, 2004
ST. LOUIS (MD Consult) - On October 15, 2004, Pfizer addressed a letter to health care professionals reviewing information about the cardiovascular profile of its cyclo-oxygenase 2 (COX-2) product Bextra (valdecoxib). In 2 trials in the high-risk surgery coronary artery bypass graft, an increase in stroke and heart attack was observed in patients receiving Bextra alone or in combination with the investigational drug parecoxib (an intravenous formulation).
However, in studies in general surgery, Bextra in combination with parecoxib showed no increased risk of cardiovascular thromboembolic events. Pfizer emphasized that Bextra is not approved for use in any surgical setting in the United States.
The information is based on analyses of a comprehensive clinical trial database of nearly 8,000 patients treated with Bextra for 6 to 52 weeks. Available clinical information for Bextra suggests there is no increased risk of cardiovascular thromboembolic events in people treated for osteoarthritis and rheumatoid arthritis.
Since 2002, the Bextra product label has included information regarding the risk of a very rare but serious skin reaction. The risk of this skin reaction exists with many other medications. Based on additional spontaneous event reporting data, this risk exists with Bextra primarily within the first 2 weeks of therapy and, although very rare, at a reported rate greater than other COX-2 products, such as Celebrex (celecoxib). Pfizer is working with regulatory authorities around the world to update the Bextra product label.
Pfizer will be conducting further studies to confirm the long-term cardiovascular safety profile of Bextra in patients who require chronic treatment for arthritis with a COX-2-specific inhibitor.
Bextra is indicated for the relief of signs and symptoms of osteoarthritis and adult rheumatoid arthritis and for the treatment of primary dysmenorrhea. Bextra was approved and introduced in the U.S. market in 2001.
For more details, including full prescribing information, visit bextra.com.
October 15, 2004
ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) issued a public health advisory on October 15, 2004, announcing a multi-pronged strategy to warn the public about the increased risk of suicidality in children and adolescents being treated with antidepressant medications.
The agency is directing manufacturers of all antidepressant medications to add a "black box" warning that describes the increased risk of suicidality in children and adolescents given antidepressant medications and notes what uses the drugs have been approved or not approved for in these patients. The FDA's letters to the manufacturers also discuss other labeling changes designed to include additional information about pediatric studies of these drugs. These labeling changes are applicable to the entire category of antidepressant medications because the currently available data are not adequate to exclude any single medication from the increased risk of suicidality.
Prozac (fluoxetine hydrochloride) is currently the only medication approved to treat depression in children and adolescents. The analyses of the placebo-controlled trials in children and adolescents summarized in the revised labeling are based on studies of 5 selective serotonin reuptake inhibitors—Prozac, Celexa (citalopram hydrobromide), Luvox (fluvoxamine maleate), Paxil (paroxetine hydrochloride), and Zoloft (sertraline hydrochloride)—and 4 "atypical" antidepressants, namely Wellbutrin (bupropion hydrochloride), Remeron (mirtazapine), Serzone (nefazodone hydrochloride), and Effexor XR (venlafaxine hydrochloride). In these studies, there was no reported case of a suicide.
A black box warning is the most serious warning placed in the labeling of a prescription medication. Advertisements that serve to remind health care professionals of a product's availability are not allowed for products with black box warnings. Until now, only 10 drug products approved for children contained a black box warning about their use in children. The new warning language does not prohibit the use of antidepressants in children and adolescents. Rather, it warns of the risk of suicidality and encourages prescribers to balance this risk with clinical need.
The FDA recognizes that depression and other psychiatric disorders in pediatric patients can have significant consequences if not appropriately treated. The new warning language recognizes this need but advises close monitoring of patients as a way of managing the risk of suicidality.
The second element of the agency's strategy is a patient medication guide (MedGuide), FDA-approved user-friendly information for patients that advises them of the risk and precautions that can be taken. MedGuides are intended to be distributed by pharmacists with each prescription or refill of a medication. The FDA will work with the manufacturers of antidepressant medications to make the MedGuides available as soon as possible.
In addition, the FDA intends to work with manufacturers to implement "unit-of-use" packaging for all antidepressants as a means of ensuring that patients receive a MedGuide with every prescription or refill. Unit-of-use packaging is a method of preparing a medication in an original container, sealed and prelabeled by the manufacturer, and containing sufficient medication for one normal course of therapy.
These actions are consistent with the recommendations made at the September 2004 joint meeting of the FDA's Psychopharmacologic Drugs Advisory Committee and Pediatric Drugs Advisory Committee.
For more information, visit the FDA's Center for Drug Evaluation and Research Web site at fda.gov/cder/drug/antidepressants/default.htm.
October 13, 2004
ST. LOUIS (MD Consult) - On October 13, 2004, the U.S. Food and Drug Administration (FDA) announced revisions to the Warnings and Adverse Reactions sections of the prescribing information for Remicade (infliximab), a biological therapeutic product indicated for the treatment of rheumatoid arthritis and Crohn's disease. The drug's manufacturer, Centocor, instituted these changes in October 2004.
The FDA convened its Arthritis Advisory Committee in March 2003 to review and advise on safety data for marketed tumor necrosis factor (TNF) blockers, including Remicade. A particular focus was placed on the incidence of neoplasia and lymphoma in patients receiving these agents. Safety data from controlled clinical trials and postmarketing experience were examined. As a result of this evaluation, a warning concerning malignancy has been added to the labeling for all therapeutic agents that block TNF.
In consultation with the FDA, Centocor (affiliated with Johnson & Johnson) has added a warning to the labeling for Remicade, which appears as follows:
| Warnings
Malignancies In the controlled portions of clinical trials of all the TNFa-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. During the controlled portions of Remicade trials in patients with moderately to severely active rheumatoid arthritis and Crohn's disease, 1 patient developed lymphoma among 1,389 Remicade-treated patients versus 0 among 483 control patients (median duration of follow-up, 1.1 years). In the controlled and open-label portions of these clinical trials of Remicade, 3 patients developed lymphomas (1 patient with rheumatoid arthritis and 2 patients with Crohn's disease) among 2,410 patients (median duration of follow-up, 1.1 years). In rheumatoid arthritis patients, this is approximately 3-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis and Crohn's disease, this is approximately 6-fold higher than expected in the general population. Rates in clinical trials for Remicade cannot be compared to rates of clinical trials of other TNF blockers and may not predict rates observed in a broader patient population. Patients with Crohn's disease or rheumatoid arthritis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma. The potential role of TNFa-blocking therapy in the development of malignancies is not known (see ADVERSE REACTIONS, Malignancies). No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving Remicade; thus additional caution should be exercised in considering Remicade treatment of these patients. |
Also, the Adverse Reaction section of the Remicade prescribing information has been updated, with the following section on malignancies added.
| Adverse Reactions
Malignancies Among 2,410 patients with moderately to severely active rheumatoid arthritis and Crohn's disease treated with Remicade in clinical trials with a median of 1.1 years of follow-up, 3 patients developed lymphomas, for a rate of 0.07 cases per 100 patient-years of follow-up in patients with rheumatoid arthritis and 0.12 cases per 100 patient-years of follow up in the combined clinical trial data for rheumatoid arthritis and Crohn's disease patients. This is approximately 3-fold higher in the [rheumatoid arthritis] clinical trial population and 6-fold higher in the overall clinical trial population than expected in an age-, gender-, and race-matched general population based on the Surveilance, Epidemiology and End Results Database. Rates in clinical trials for Remicade cannot be compared to rates of clinical trials of other TNF blockers and may not predict rates observed in a broader patient population. An increased rate of lymphoma up to several fold has been reported in the Crohn's disease and rheumatoid arthritis patient populations and may be further increased in patients with more severe disease activity. Other than lymphoma, 13 patients developed malignancies, which was similar in number to what would be expected in the general population. Of these, the most common malignancies were breast, colorectal, and melanoma. (See WARNINGS, Malignancies.) Malignancies, including non-Hodgkin's lymphoma and Hodgkin's disease, have also been reported in patients receiving Remicade during post-approval use. |
Centocor requests that reports of adverse events related to Remicade be communicated to the company at 800-457-6399. Alternatively, this information can be reported to the FDA's MedWatch system by phone at 800-FDA-1088, by fax at 800-FDA-0178, via the Internet at fda.gov/medwatch, or via mail at MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787.
Remicade was approved for use in the United States in August 1998. Full prescribing information is available at centocor.com/pi/IN04560.pdf.
October 13, 2004
ST. LOUIS (MD Consult) - In a letter dated July 12, 2004, Biogen Idec and Genentech notified health care professionals of revisions to the Warnings section of the prescribing information of Rituxan (rituximab) due to reports of hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death in some patients with hematologic malignancies. The letter and the revised label were posted to the U.S. Food and Drug Administration (FDA) MedWatch site on October 8, 2004.
Rituxan is indicated for the treatment of patients with relapsed or refractory low-grade or follicular, CD-20–positive, B-cell non-Hodgkin's lymphoma.
Based on review of recent postmarketing and clinical safety reports, the following details were added to the Warnings section of the Rituxan prescribing information.
| Warnings
Hepatitis B Reactivation with Related Fulminant Hepatitis: Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignances treated with Rituxan. The majority of patients received Rituxan in combination with chemotherapy. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately 1 month after the last dose. Persons at high risk of HBV infection should be screened before initiation of Rituxan. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and for up to several months following Rituxan therapy. In patients who develop viral hepatitis, Rituxan and any concomitant chemotherapy should be discontinued and appropriate treatment including antiviral therapy intiated. There are insufficient data regarding the safety of resuming Rituxan therapy in patients who develop hepatitis subsequent to HBV reactivation. |
Rituxan is contraindicated in patients with known anaphylaxis of immunoglobulin E–mediated hypersensitivity to murine proteins or to any component of this product.
Health care professionals should report any serious adverse events possibly associated with the use of Rituxan to Genetech Drug Safety at 888-835-2555. Alternatively, this information can be reported to the FDA's MedWatch reporting system by phone (800-FDA-1088), by fax (800-FDA-1078), via the MedWatch Web site (fda.gov/medwatch), or by mail (MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).
October 1, 2004
ST. LOUIS (MD Consult) - On September 24, 2004, the U.S. Food and Drug Administration (FDA) and Novartis notified health care professionals of revisions to the prescription information of Aredia (pamidronate disodium) Injection and Zometa (zoledronic acid) Injection. These changes relate to spontaneous reports of osteonecrosis of the jaw (ONJ), mainly in cancer patients, who have received bisphosphonates as a component of their therapy.
In the U.S. package inserts for both Aredia and Zometa, the following information on ONJ has been added under the Precautions section.
| PRECAUTIONS Osteonecrosis of the jaw ONJ has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (eg, cancer, chemotherapy, corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. |
In addition, the U.S. package inserts for both Aredia and Zometa feature the following information on osteonecrosis, which had previously been added to the Adverse Reactions section under the "Post-Marketing Experience" heading.
| ADVERSE REACTIONS Post-Marketing Experience Cases of osteonecrosis (primarily involving the jaws) have been reported in patients treated with bisphosphonates. The majority of the reported cases are in cancer patients attendant to a dental procedure. Osteonecrosis of the jaw has multiple well-documented risk factors including a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy, corticosteroids) and comorbid conditions (eg, anemia, coagulopathies, infection, pre-existing oral disease). Although causality cannot be determined, it is prudent to avoid dental surgery as recovery may be prolonged. (See Precautions.) |
Novartis encourages health care professionals to report all serious adverse events suspected to be associated with the use of Aredia or Zometa to Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, by phone at 888-669-6682, or via the Internet at novartis.com.
Alternatively, this information may be reported to the FDA's MedWatch Reporting System by phone at 800-FDA-1088, by fax at 800-FDA-0178, or via the MedWatch Web site at fda.gov/medwatch/index.html.
September 30, 2004
ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) acknowledged on September 30, 2004, the voluntary withdrawal from the market of Vioxx (rofecoxib) by Merck & Co, manufacturer of the drug. The FDA immediately issued a public health advisory to inform patients of this action and to advise them to consult with a physician about alternative medications.
Merck is withdrawing Vioxx from the U.S. and worldwide market after the data safety monitoring board overseeing a long-term study of the drug (Adenomatous Polyp Prevention on Vioxx [APPROVe]) recommended that the study be halted because of an increased risk of serious cardiovascular events, including heart attacks and strokes, among study patients taking Vioxx compared with patients receiving placebo. The study involved patients at risk of developing recurrent colon polyps.
"Merck did the right thing by promptly reporting these findings to [the] FDA and voluntarily withdrawing the product from the market," said Acting FDA Commissioner Dr. Lester M. Crawford. "Although the risk that an individual patient would have a heart attack or stroke related to Vioxx is very small, the study that was halted suggests that, overall, patients taking the drug chronically face twice the risk of a heart attack compared to patients receiving a placebo."
Dr. Crawford added that the FDA will closely monitor other drugs in this class for similar adverse effects. "All of the NSAID drugs have risks when taken chronically, especially of gastrointestinal bleeding, but also liver and kidney toxicity. They should only be used continuously under the supervision of a physician."
Vioxx is a prescription nonsteroidal anti-inflammatory drug (NSAID) that was approved by the FDA in May 1999 for the reduction of pain and inflammation caused by osteoarthritis, as well as for acute pain in adults and for the treatment of menstrual pain. It was the second of a new kind of NSAID (cyclooxygenase 2 [COX-2] selective) approved by the FDA. Subsequently, the agency approved Vioxx to treat the signs and symptoms of rheumatoid arthritis in adults and children.
At the time that Vioxx and other COX-2 selective NSAIDs were approved, it was hoped that they would have a lower risk of gastrointestinal ulcers and bleeding than other NSAIDs (such as ibuprofen and naproxen). Vioxx is the only NSAID demonstrated to have a lower rate of these adverse effects.
Merck contacted the FDA on September 27, 2004, to request a meeting and to advise the agency that the long-term study of Vioxx in patients at increased risk of colon polyps had been halted. Merck and FDA officials met the next day, September 28, and during that meeting the company informed the FDA of its decision to remove Vioxx from the market voluntarily.
In June 2000, Merck submitted to the FDA a safety study called Vioxx Gastrointestinal Outcomes Research (VIGOR) that found an increased risk of serious cardiovascular events, including heart attacks and strokes, in patients taking Vioxx compared with patients taking naproxen. After reviewing the results of the VIGOR study and other available data from controlled clinical trials, the FDA consulted with its Arthritis Advisory Committee in February 2001 regarding the clinical interpretation of this new safety information. In April 2002, the FDA implemented labeling changes to reflect the findings from the VIGOR study. The labeling changes included information about the increase in risk of cardiovascular events, including heart attack and stroke.
Recently, other studies in patients taking Vioxx have also suggested an increased risk of cardiovascular events. The FDA was in the process of carefully reviewing these results to determine whether further labeling changes were warranted when Merck informed the agency of the results of the new trial and its decision to withdraw Vioxx from the market.
Additional information about this withdrawal of Vioxx, as well as questions and answers for patients, is available online at fda.gov/cder/drug/infopage/vioxx/default.htm. The FDA advises health care professionals with additional questions to contact Merck at 1-888-368-4699 or merck.com or the FDA’s Drug Information Office at 301-827-4573 or 1-888-463-6332.
September 13, 2004
ST. LOUIS (MD Consult) - Patients who took the antibiotic erythromycin with medications that inhibit CYP3A drug enzymes, such as certain calcium-channel blockers, certain anti-fungal drugs, and some anti-depressants, had a five-times greater risk of sudden death from cardiac causes than patients who did not take the drugs at the same time, according to a new study published in the September 9, 2004, issue of New England Journal of Medicine.
Erythromycin is a commonly used antibiotic because it is considered to be inexpensive and very safe. In the study, Wayne A. Ray, Ph.D., and colleagues at the Agency for Healthcare Research and Quality's (AHRQ) Center for Education and Research on Therapeutics (CERTs) at Vanderbilt University, did not find the same increased risk for patients who took CYP3A inhibitors with other antibiotics, such as amoxicillin, or for those who had taken erythromycin in the past. The CERTs program is a national initiative to increase the awareness of the benefits and risks of new, existing, or combined uses of therapeutics and devices.
"This study provides critical scientific evidence that can be used to improve health care quality and safety by preventing potentially dangerous drug interactions," said AHRQ Director Dr. Carolyn M. Clancy. "These findings will help clinicians to make more informed choices about which antibiotics should be used with patients who are taking multiple medications."
Researchers reviewed medical records for the Tennessee Medicaid program and identified patients who had experienced sudden death from cardiac causes during the period of January 1, 1988, to December 31, 1993. They reviewed prescriptions for erythromycin, amoxicillin, and other medications from computerized Medicaid pharmacy files that included the drug, dose, and total medication dispensed. Behavioral risk factors, such as smoking and a lack of physical activity, were not studied.
The researchers conclude that clinicians should avoid prescribing a combination of erythromycin and CYP3A inhibitors to patients at the same time because safer alternatives are available.
September 1, 2004
ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) and Pfizer notified health care professionals of a revision to the Warnings section of the labeling of Geodon (ziprasidone), a schizophrenia treatment recently approved to also treat acute bipolar mania.
The labeling changes describe the increased risk of hyperglycemia and diabetes in patients taking Geodon. The FDA has asked all manufacturers of atypical antipsychotic medications, including Pfizer, to add this Warning statement to its labeling.
Pfizer's letter, intended for neuropsychiatric health care professionals, was made available on the FDA's MedWatch Web site on August 31, 2004. The amended warning information reads as follows:
| WARNINGS Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with antipsychotics. There have been few reports of hyperglycemia or diabetes in patients treated with Geodon. Although fewer patients have been treated with Geodon, it is not known if this more limited experience is the sole reason for the paucity of such reports. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies, which did not include Geodon, suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because Geodon was not marketed at the time these studies were performed, it is not known if Geodon is associated wtih this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. |
Pfizer is conducting an investigation as to whether Geodon administration is linked to an increased incidence of diabetes. To date, there have been few reports of hyperglycemia or diabetes in patients taking this medication.
For more information, including full prescribing details, visit geodon.com or call 800-438-1985.
Health care professionals are requested to report any adverse events related to Geodone the FDA's MedWatch program by phone (800-FDA-1088), by fax (800-FDA-0178), via the program's Web site (fda.gov/medwatch), or by mail to MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787.
August 25, 2004
ST. LOUIS (MD Consult) - On August 11, 2004, Johnson & Johnson subsidiary Centocor issued a letter to health care professionals announcing that, together with the U.S. Food and Drug Administration (FDA), the company had revised the Warnings and Adverse Reactions sections of the labeling for Remicade (infliximab). Remicade is indicated for the treatment of rheumatoid arthritis and Crohn's disease.
The added warning regarding hematologic events reads as follows:
Hematologic Events
Cases of leukopenia, neutropenia, and pancytopenia, some with fatal outcome, have been reported in patients receiving Remicade. The causal relationship to Remicade therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with Remicade who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (eg, persistent fever) while on Remicade. Discontinuation of Remicade therapy should be considered in patients who develop significant hematologic abnormalities.
In addition, Centocor has updated the warning on neurologic events. The new text now includes a description of rare cases of central nervous system (CNS) manifestation of systemic vasculitis. Also, a warning has been added that discontinuation of Remicade should be considered in patients who develop significant CNS adverse reactions.
Lastly, the Adverse Reaction section of the Remicade prescribing information has been updated to add information regarding adverse events that have been reported during post-approval use of Remicade. Neutropenia, pericardial effusion, and systemic and cutaneous vasculitis have all occurred.
Remicade was approved for use in the United States in August 1998.
Health care professionals are requested to report any adverse events related to Remicade to Centocor at 800-457-6399 or to the FDA's MedWatch program by phone (800-FDA-1088), by fax (800-FDA-0178), via the program's Web site (fda.gov/medwatch), or by mail to MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787.
To read more, including full prescribing information, visit Remicade.com.
August 18, 2004
ST. LOUIS (MD Consult) - On August 17, 2004, the U.S. Food and Drug Administration and Aventis Pharmaceuticals announced revisions to the drug labeling for Lovenox (enoxaparin sodium injection). Changes were made to the Clinical Pharmacology, Precautions, and Dosage and Administration sections of labeling.
These labeling changes followed a March 2004 letter addressed to health care professionals, in which Aventis announced new prescribing information for Lovenox.
Clinical Pharmacology
Information in the Pharmacokinetics section has been revised as follows:
Precautions
Information in the Precautions section has been revised as follows:
Dosage and Administration
Information in the Dosage and Administration section has been revised as follows:
Lovenox injection is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight heparin. Lovenox is indicated for the inpatient treatment of acute deep vein thrombosis (DVT) with or without pulmonary embolism (PE), when administered in conjunction with warfarin sodium, and for the outpatient treatment of acute DVT without PE when administered in conjunction with warfarin sodium.
In addition, Lovenox is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing abdominal surgery who are at risk for thromboembolic complications; in patients undergoing hip replacement surgery, during and following hospitalization; in patients undergoing knee replacement surgery; and in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.
Lovenox is also indicated for the prophylaxis of ischemic complications of unstable angina and non–Q-wave myocardial infarction, when concurrently administered with aspirin.
The full prescribing information, including a boxed warning, can be found at lovenox.com.
August 16, 2004
ST. LOUIS (MD Consult) - On August 12, 2004, the U.S. Food and Drug Administration (FDA) and Genentech, Inc, issued an important drug warning to health care providers announcing that there is evidence of an increased risk of serious arterial thromboembolic events related to Avastin (bevacizumab). These events may include cerebrovascular accident, myocardial infarctions, transient ischemic attacks, and angina. Patients who experience an arterial thromboembolic event during treatment should permanently discontinue Avastin.
The risk of fatal arterial thrombotic events is also increased. In randomized, active-controlled studies conducted in patients with metastatic colorectal cancer, the risks of a serious arterial thrombotic event was approximately twice as high in patients receiving infusional 5-fluorouracil–based chemotherapy plus Avastin, with an estimated overall rate of up to 5%. Risk factors for the development of arterial thromboembolic events included a history of arterial thromboembolism prior to Avastin exposure, age 65 years and older, and Avastin therapy. These adverse events occur at a higher rate in these high-risk groups.
A revised Avastin package insert containing more detailed information on arterial thromboembolic events is in development.
Avastin is a first-line treatment of metastatic cancer of the colon and rectum. Gastrointestinal perforation and wound dehiscence, complicated by intra-abdominal abscesses, occurred at an increased incidence in patients receiving bevacizumab compared with control subjects. Bevacizumab has also been shown to impair wound healing in preclinical animal models. Bevacizumab therapy should be permanently discontinued in patients with gastrointestinal perforation or wound dehiscence requiring medical intervention. The appropriate interval between termination of bevacizumab and subsequent elective surgery required to avoid the risks of impaired wound healing/wound dehiscence has not been determined.
Health care professionals are requested to report any serious adverse events suspected to be associated with the use of Avastin to Genentech at 888-835-2555. Alternatively, this information can be reported to the FDA's MedWatch reporting system by phone (800-FDA-1088), by fax (800-FDA-0178), online (accessdata.fda.gov/scripts/medwatch), or via mail, using MedWatch form FDA 3500, sent to FDA Medical Products Reporting Program, 5600 Fishers Lane, Rockville, MD 20852-9787.
August 6, 2004
ST. LOUIS (MD Consult) - The Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) have been notified about the potential for the inadvertent administration of tetanus-toxoid–containing vaccines (TTCVs) instead of the tuberculin purified protein derivative (PPD) used for tuberculosis skin tests (TSTs), according to an article in the July 30, 2004, issue of Morbidity and Mortality Weekly Report.
The Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system jointly operated by the CDC and the FDA, detected clusters of medication errors in at least 2 states. These findings, along with another previously reported investigation involving the same error, suggest the need for health care providers to take additional steps to minimize the risk for inadvertent intradermal injections of TTCVs.
In April 2004, 5 reports of medication error involving tetanus toxoid (TT) from a health care provider were identified. Patients were vaccinated on 3 different dates; all experienced local reactions without complications. Another cluster reported to VAERS in June 2003 involved an undisclosed number of patients; a health care provider confused the tetanus and diphtheria toxoids (Td) vaccine for adult use (adsorbed) with PPD and administered Td intradermally. Patients with adverse reactions to these administrations had skin reactions that were interpreted as positive TSTs, which resulted in treatment with isoniazid. Review of the lot numbers on products thought to be PPD revealed that they were Td. Affected patients were identified and retested with PPD; all TSTs were negative. Isoniazid was discontinued, and no adverse reactions were observed.
As of March 2004, approximately 100 patients had been identified in reports of TTCV administration instead of PPD. A total of 21 states have reported both clusters and single cases. Vaccines substituted mistakenly for PPD include Td (13 reports), TT (12 reports), and diphtheria and tetanus toxoids adsorbed (5 reports).The reports of Td, TT, and diphtheria and tetanus toxoid products that were involved included those manufactured by Aventis-Pasteur and Wyeth and vaccines from other unspecified manufacturers. The CDC and the FDA have initiated a full review of adverse events caused by the inadvertent administration of vaccines and PPD products reported to VAERS and the FDA MedWatch Program. A preliminary review indicates that multiple vaccines other than TTCVs have been involved.
Similarities in the packaging of PPD and TTCVs might have contributed to the medication errors. Both products require refrigeration, and they are often stored side by side. The lack of availability of Td in single-dose syringes, which results in provider purchase of multiple-dose vials, was cited as a contributing factor to medication error in 1 cluster. Conversely, at least 8 reports of inadvertent substitution for vaccine products have been documented; these have resulted in the intramuscular administration of PPD.
Health care providers should consider ways to prevent vaccine misadministration. As more vaccines and combination products become available, the potential for medication errors may increase. Possible measures to prevent misadministration could include pharmacy dispensing of vaccines when feasible, physical separation of products, careful visual inspection and reading of labels, preparation of PPD for patient use only at the time of testing, and improved record keeping of lot numbers of vaccines and other injectable products.
Prevention of such errors through barcode scanning technology is the goal of a recent FDA rule requiring individual drug packages to have identifying barcodes. For health care facilities that possess such technology, package scanning could help prevent errors made during pharmacy dispensing of products or during vaccine or PPD administration. In addition, the Product Identification Guide for Routine Vaccines is a helpful resource for distinguishing commonly used vaccine products; the guide can be ordered from the California Department of Health Services by calling 619-594-5933.
Adverse events associated with inadvertent vaccine administration can be reported to VAERS at vaers.org or by telephone at 800-822-7967. Adverse events after PPD administration can be reported to the FDA MedWatch program at fda.gov/medwatch or by telephone at 800-332-1088.
August 2, 2004
ST. LOUIS (MD Consult) - On July 30, 2004, the US Food and Drug Administration (FDA) warned the public about counterfeit versions of the drugs Zocor (simvastatin) and carisoprodol that were recently imported from Mexico by individual Americans. Tests indicated that the counterfeit Zocor did not contain any active ingredient and that the counterfeit carisoprodol differed in potency as compared with the authentic product.
Carisoprodol is used for the treatment of painful musculoskeletal conditions, and Zocor is a cholesterol-lowering drug. The counterfeit versions were reportedly purchased at Mexican border town pharmacies and sold under the names Zocor, 40/mg (lot number K9784, expiration date November 2004), and Carisoprodol, 350/mg (lot number 68348A). Patients who rely on these counterfeit versions of these drugs could develop serious health risks (with the counterfeit Zocor) or have insufficient pain relief (with the counterfeit carisoprodol).
The FDA has repeatedly expressed its concern about the purchase of drugs from foreign countries by Americans. As demonstrated by this incident, purchasers cannot assume that the products meet the quality, efficacy, and safety standards of FDA-authorized products or that the FDA is ensuring the quality, safety, and efficacy of products purchased from outside of the United States.
Medications purchased within the US system for prescription drugs have undergone rigorous testing and review to verify their identity, potency, and purity and to ensure that they are safe and effective for their intended use. In addition, safeguards exist to help maintain the integrity of the products while they are in shipment to pharmacies and before they are dispensed to patients.
Anyone who may have recently purchased the above-described versions of Zocor 40/mg and Carisoprodol 350/mg from Mexican pharmacies should consult with their physician and notify their local FDA field office.
The FDA is investigating this matter and working with Mexican authorities to ensure that further sale and importation of these products is halted.
July 20, 2004
ST. LOUIS (MD Consult) - A U.S. Food and Drug Administration (FDA) analysis of 3 commonly prescribed drugs purchased from a Web site advertised as Canadian showed that so-called "Canadian Generics" bought from the Web site were fake, substandard, and potentially dangerous, according to an FDA announcement made on July 13, 2004. One of the drugs was a controlled substance. In light of these findings, the FDA reiterated its strong concerns about purchasing prescription drugs online from unknown sources.
FDA investigators recently purchased 3 commonly prescribed drugs from a Web site advertising "Canadian Generics," which had been sending "spam" e-mails promoting its products. The products purchased were "generic" versions of Viagra, Lipitor, and Ambien. None of the 3 products has a U.S.-approved generic version, and so all 3 drugs were unapproved.
"The test results of our analyses offer proof positive that buying prescription drugs online from unknown foreign sources can be a risky business. As was the case here, even where a Web site looks legitimate, [the] FDA has clear evidence that the Web site is dispensing misbranded drugs that are not the same quality as those approved by the FDA for sale in the United States. Consumers who believe they are getting equivalent products from reputable sources are being misled and putting their health at risk," said FDA Acting Commissioner Dr. Lester M. Crawford. "This firm shipped drugs that were the wrong strength, including some that were substantially super-potent and that pose real health risks as a result, drugs that didn't dissolve properly, drugs that contained contaminants, and drugs that should not have been given because of potentially dangerous drug interactions."
Ambien, a controlled substance (schedule IV), is approved for the short-term treatment of insomnia in the United States. The product the FDA obtained online contained too much active ingredient, including 1 tablet that was nearly double the labeled potency. Taking "superpotent" Ambien puts patients at risk for central nervous system depression, especially in elderly or debilitated patients.
The so-called generic Lipitor purchased by the FDA was subpotent and failed standard dissolution tests, providing on average only 57% of the active ingredient claimed on the label. It also failed the FDA's purity testing. Clinically, subpotent product could present a long-term risk for the various complications of high cholesterol, such as heart disease. In addition, the so-called "generic" Lipitor product was furnished to the FDA's online purchaser, even though the purchaser said that he was taking the antibiotic erythromycin. Lipitor's label warns against taking Lipitor and erythromycin at the same time.
Viagra is sold in the United States to treat impotence. The so-called generic version of this product purchased through the Web site also contained too little of the active ingredient, failed the dissolution test, and had an unacceptable level of impurities. Although subpotent "generic" Viagra may not place patients at additional risk, the purchaser informed the firm in its online questionnaire that he was taking erythromycin. Use of Viagra in patients taking erythromycin is contraindicated.
The FDA continues to advise patients and consumers that they must use great care when purchasing prescription drugs online. Their evidence indicates that although a Web site may appear to be hosted by a reputable source and may look similar to other retail pharmacy Web sites, many of these sites in fact operate from outside the United States and are providing unapproved drugs from unreliable sources. The National Association of Boards of Pharmacy has established a program called VIPPS designed to certify Web sites that meet industry standards. The Agency believes that consumers should look for participation in this type of certification program as one method to help minimize the risks of getting bad-quality drugs from disreputable sources.
The FDA's test results are summarized in a chart that can be accessed at fda.gov/importeddrugs/chart071304.html. Additional information about buying drugs online is available at the FDA's Web site, fda.gov/oc/buyonline/default.htm.
July 14, 2004
ST. LOUIS (MD Consult) - The U.S. Food Administration (FDA) released a warning letter on July 13, 2004, stating that product materials for several GlaxoSmithKline hepatitis vaccines contain false information about flu vaccines that could lead to public health problems.
The FDA noted that hepatitis vaccines Havrix, Twinrix, and Engerix-B all included the company's version of general U.S. government vaccine guidelines but listed incorrect or misleading statements regarding the live attenuated influenza vaccine and failed to reveal material facts regarding specific risks associated with the use of these medications.
The FDA's warning letter stated that GlaxoSmithKline's summary of product information creates a serious public health concern because it could lead to incorrect administration of the live attenuated influenza vaccine to individuals, including pregnant women with medical conditions and children aged 6 months to 5 years, for whom that product has not been demonstrated to be safe and effective. In addition, this summary was distributed during the height of the flu season with false and misleading information regarding the live attenuated influenza vaccine, making the misinformation more visible and hence more dangerous to the public at large.
According to the FDA-approved professional labeling, Engerix-B is a noninfectious recombinant DNA hepatitis B vaccine that is supplied as a sterile suspension for intramuscular administration and is indicated for immunization against infection caused by all known subtypes of hepatitis B virus. Engerix-B will not prevent hepatitis caused by other agents, such as hepatitis A, C, and E viruses, nor other pathogens known to infect the liver. Immunization is recommended in persons of all ages, especially those who are, or will be, at increased risk of exposure to hepatitis B virus.
Havrix is a noninfectious hepatitis A vaccine that contains a sterile suspension of inactivated virus for intramuscular administration. Havrix is indicated for active immunization of persons 2 years of age or older against disease caused by hepatitis A virus. Havrix will not prevent hepatitis caused by other agents such as hepatitis B, C, and E viruses, nor other pathogens known to infect the liver. Immunization with Havrix is indicated for people desiring protection against hepatitis A. Primary immunization should be completed at least 2 weeks before expected exposure to hepatitis A virus.
Twinrix is a sterile bivalent vaccine containing the antigenic components used in producing Havrix and Engerix-B. Twinrix is supplied as a sterile suspension for intramuscular administration. Twinrix is indicated for active immunization of persons 18 years of age or older against disease caused by hepatitis A virus and infection by all known subtypes of hepatitis B virus. Twinrix will not prevent hepatitis caused by other agents such as hepatitis C and E viruses, nor other pathogens known to infect the liver. Immunization is recommended for all susceptible persons 18 years of age or older who are, or will be, at risk of exposure to both hepatitis A and hepatitis B viruses.
According to the FDA, examples of important risk information found in the product labeling for these products include:
The FDA charged that the British drugmaker failed to list critical safety warnings, including adverse reactions and medical conditions that should prevent some patients from getting the vaccine. Failure to correct the violations could result in FDA regulatory action, according to the warning letter, including seizure or injunction.
A spokesperson for GlaxoSmithKline stated that distribution of the materials occurred in late 2003 and early 2004 but has been discontinued. She also announced that corrected information would be circulated, and that the company was reviewing all of its vaccine promotional materials to make sure they were FDA compliant.
The warning letter, which was dated July 6, 2004, was posted on the FDA Web site at fda.gov on July 13.
July 14, 2004
ST. LOUIS (MD Consult) - According to the U.S. Food and Drug Administration (FDA), on July 1, 2004, the product labeling information for Viread (tenofovir disoproxil fumerate) was updated to include a warning that the drug is not indicated for the treatment of chronic hepatitis B virus (HBV) infection. Furthermore, the new warnings on the packaging point out that the safety and efficacy of Viread have not been established in patients coinfected with HBV and human immunodeficiency virus (HIV).
The FDA's alert was spurred by the presence of severe acute exacerbations of hepatitis B reported in patients who are coinfected with HBV and HIV and have discontinued a regimen of Viread. It is recommended that all patients with HIV be tested for the presence of chronic HBV before initiating antiretroviral therapy. The agency also cautions that hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue taking Viread and are coinfected with HIV and HBV. If appropriate, initiation of anti–hepatitis B therapy might be warranted.
Additionally, the Clinical Pharmacology and Precaution sections of the labeling were updated to include information regarding drug-drug interactions with atazanavir, adefovir, and ribavirin. No such interaction was seen between tenofovir and adefovir nor between tenofovir and ribavirin.
The following text was added to the Precaution section:
The Carcinogenesis, Mutagenesis, Impairment of Fertility section was revised to include results of the long-term carcinogenicity studies in mice and rats. The new information notes that long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study had negative results for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
In the United States, Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of Viread in treatment-naive and treatment-experienced adults. There are no study results demonstrating the effect of Viread on the clinical progression of HIV. The use of Viread should be considered for treating adult patients with HIV strains that are expected to be susceptible to tenofovir as assessed by laboratory testing or treatment history.
The most common adverse events that occurred in patients receiving Viread with other antiretroviral agents in clinical trials were dizziness and mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Adverse events and laboratory abnormalities observed in clinical studies occurred with similar frequency in the Viread and placebo or control groups. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. Renal impairment has been associated with the use of Viread during post-approval surveillance. The majority of cases occurred in patients with underlying systemic or renal disease or in patients concomitantly taking nephrotoxic agents. Exacerbations of hepatitis B have been reported in patients coinfected with HIV and chronic hepatitis B after discontinuation of Viread.
Viread is manufactured by biopharmaceutical company Gilead Sciences, which is headquartered in Foster City, California. The drug was approved by the FDA for treatment of HIV infection in October 2001.
July 14, 2004
ST. LOUIS (MD Consult) - On July 6, 2004, the U.S. Food and Drug Administration (FDA) approved a new dosing regimen for Reyataz. In antiretroviral-experienced patients, the new recommended dose is 300 mg of Reyataz (atazanavir sulfate; two 150-mg capsules) once daily plus 100 mg of ritonavir once daily taken with food. For antiretroviral-naive patients, the recommended dose remains 400 mg of Reyataz (two 200-mg capsules) taken once daily with food.
The data to support the new dosing regimen came from study AI424-045, a study of patients who had failed at least 2 regimens containing medications from the 3 antiretroviral drug classes available at the time of enrollment. This 48-week trial evaluated the efficacy and safety of Reyataz 300 mg plus ritonavir 100 mg once daily or Reyataz 400 mg plus saquinavir 1,200 mg once daily compared with lopinavir/ritonavir 400/100 mg twice daily, each with tenofovir and a nucleocide reverse transcriptase inhibitor.
Reyataz/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. The HIV RNA change from baseline was –1.58 log10 copies/mL for Reyataz/ritonavir and –1.70 log10 copies/mL for lopinavir/ritonavir
Study AI424-045 was not large enough to reach a definitive conclusion that Reyataz/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measures of proportion below the HIV RNA lower limit of detection. The proportions of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at week 48 were 55% and 38% for Reyataz/ritonavir and 57% and 45% for lopinavir/ritonavir, respectively.
Major revisions to the Reyataz package insert read as follows:
| Indications and Usage This data pertains to Reyataz/ritonavir. The following points should be considered when initiating therapy with Reyataz:
Clinical Pharmacology Microbiology A table was included in the new insert to provide information regarding HIV RNA response at week 48 by number and type of baseline protease inhibitor mutations and baseline phenotype in treatment-experienced subjects (Study AI424-045). In summary, for HIV RNA the response rate (< 400 copies/mL) was 75% for both Reyataz/ritonavir (50/67) and lopinavir/ritonavir (50/67) in patients with 0 to 2 baseline primary protease inhibitor mutations. In patients with 3 to 4 baseline primary protease inhibitor mutations, the response rates were 41% (14/34) and 43% (12/28) for Reyataz/ritonavir and lopinavir/ritonavir, respectively. In patients with 5 or more baseline primary protease inhibitor mutations, the response rates were 0% (0/9) and 23% (5/18) for Reyataz/ritonavir and lopinavir/ritonavir, respectively. Warnings PR Interval Prolongation
Precautions A subsection regarding rash was included to state that the incidence of rash in controlled clinical trials (n = 1,597) was 21%. The median time to onset of rash was 8 weeks after initiation of Reyataz, and the median duration of rash was 1.3 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Dosing with Reyataz was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical studies was 0.4%. Reyataz should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving Reyataz. Drug Interactions A change to the clinical comment for the interaction between efavirenz and Reyataz was made to distinguish the dose adjustment of Reyataz/ritonavir/efavirenz 300/100/600 mg once daily that applies to treatment-naive subjects. Appropriate dosing recommendations for efavirenz and Reyataz in treatment-experienced subjects have not been established. |
Reyataz is manufactured by U.S. pharmaceutical company Bristol-Myers Squibb. Full prescribing information is available at bms.com/cgi-bin/anybin.pl?sql=select%20PPI%20from%20TB_PRODUCT_PPI%20where%20PPI_SEQ=103.
July 2, 2004
ST. LOUIS (MD Consult) - In an announcement made June 30, 2004, the U.S. Food and Drug Administration (FDA) alerted pharmacies and the public to a small number of confirmed reports involving counterfeit Viagra (sildenafil citrate) sold in 2 California pharmacies. Both the FDA and Connecticut-based Pfizer, Inc, the manufacturer of the legitimate anti-impotence drug Viagra, are analyzing the counterfeit product to determine its true composition and whether it poses any health risks.
No injuries have yet been reported in connection with this problem, and the counterfeit products have only been found in pharmacies in Glendale and Fresno, Calif.
It is important to note that the concern over these counterfeit drugs in no way applies to real Viagra tablets, which are formulated and manufactured in strict compliance with the FDA's standards.
Pfizer and the FDA are providing pharmacists and the public with information on how to identify counterfeit Viagra packaging and tablets. The counterfeit drugs bear the lot number 3023803 with an expiration date of 1 MAR 06 (this lot number and date were used on legitimate Viagra product distributed between July 1 and July 18, 2003) and resemble real Viagra tablets in terms of their general size, shape, color, and imprints. However, several significant deviations are evident between the counterfeit and real drugs; these differences can be seen in comparative photos included with Pfizer's Dear Pharmacist letter, posted on the company's Web site at pfizer.com/subsites/counterfeit_importation/mn_pharmacist_viagra.html. These differences include a different debossing font, more pronounced tablet edges, and the lighter blue film-coat.
Consumers who have Viagra at home and may have questions about its legitimacy can reference the above Web site or contact the dispensing pharmacist. Pharmacists and consumers who have counterfeit Viagra should contact their local FDA office.
According to Pfizer spokesman Byrant Haskins, there is no evidence to suggest this is a widespread counterfeiting operation. However, the FDA's Office of Criminal Investigations is actively investigating this case, and the agency will aggressively prosecute those found responsible for any counterfeiting operation.
June 28, 2004
ST. LOUIS (MD Consult) - On June 3, 2004, Wyeth Pharmaceuticals issued a letter addressed to health care professionals to notify them of revisions to the Warnings, Precautions, and Dosage and Administration sections of labeling for Effexor (venlafaxine hydrochloride). This alert to health care providers of two important safety issues was made in cooperation with the U.S. Food and Drug Administration (FDA).
Neonates exposed to Effexor, other serotonin and norepinephrine reuptake inhibitors (SNRIs), or selective serotonin reuptake inhibitors (SSRIs) late in the third trimester of gestation have been shown to experience complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery.
Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, drug discontinuation syndrome. According to the new drug labeling, it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
In addition, the FDA has recently communicated to manufacturers of antidepressants, including Wyeth, the recommendation that labeling changes are warranted to caution practitioners and patients about the need for close observation of patients being treated with antidepressants for clinical worsening of the symptoms of depression, the emergence of suicidality, and the emergence of a variety of other symptoms that may represent a worsening of the patient's condition. Patients with major depressive disorder, both adult and pediatric, may experience these adverse effects, and it is recommended that persons being treated with antidepressants be observed closely especially at the beginning of a course of drug therapy or at the time of dose changes (both increases and decreases). If such adverse effects are observed, this should be reported to the patient's physician immediately.
Other than Effexor, medications affected by the FDA's advisory regarding antidepressants include the following: paroxetine hydrochloride (Paxil), bupropion hydrochloride (Wellbutrin), fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), nefazodone hydrochloride (Serzone), and mirtazepine (Remeron). The revised labeling for these drugs carry the same warnings as those for Effexor regarding the emergence of suicidal ideation and worsening of depression.
Effexor is indicated for the treatment of major depressive disorder. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. Adverse reactions, some of which were serious, have been reported in patients who recently discontinued taking an MAOI and began taking Effexor, or who had recently discontinued taking Effexor before the initiation of an MAOI regimen. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. Based on the half-life of Effexor, at least 7 days should be allowed after stopping Effexor before starting administration of an MAOI.
The FDA requests that any adverse events be reported to the agency's MedWatch program by phone at 800-FDA-1088, by fax at 800-FDA-0178, via the Internet at www.fda.gov/medwatch, or by mail at MEDWATCH HF-2, FDA, 5600 Fisher's Lane, Rockville, MD 20857.
June 25, 2004
ST. LOUIS (MD Consult) - On June 18, 2004, Bristol-Myers Squibb notified health care professionals of revisions to the labeling for Serzone (nefazodone hydrochloride), an antidepressant approved for the treatment of major depressive disorder in adults. The new product information reinforces the importance of doing a thorough risk-benefit analysis when considering prescribing Serzone for the treatment of depression, including consideration of the risk of hepatic failure. In addition, the labeling has been revised to include a warning recommended by the U.S. Food and Drug Administration (FDA) for drugs in the antidepressant class concerning the emergence of suicidal ideation and attempts in patients taking antidepressants.
Revised sections of the Serzone product labeling read as follows:
| Indications and Usage Serzone (nefazodone hydrochloride) is indicated for the treatment of depression. When deciding among the alternative treatments available for this condition, the prescriber should consider the risk of hepatic failure associated with Serzone treatment (see Warnings). In many cases, this would lead to the conclusion that other drugs should be tried first. Dosage and Administration When deciding among the alternative treatments available for depression, the prescriber should consider the risk of hepatic failure associated with Serzone treatment (see Warnings). |
In addition, the FDA has recently communicated to manufacturers of antidepressants, including Bristol-Myers Squibb, the recommendation that labeling changes are warranted to caution practitioners and patients about the need for close observation of patients being treated with antidepressants for clinical worsening of the symptoms of depression, the emergence of suicidality, and the emergence of a variety of other symptoms that may represent a worsening of the patient's condition.
In accordance with these recommendations from the FDA, the Warnings section of the Serzone labeling information has also been revised. The new information includes the notice that patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, states the labeling, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy or at the time of dose changes, whether an increase or decrease. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.
Both adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications have reported anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania, especially early during antidepressant treatment. Consideration should be given to changing the therapeutic regimen, including discontinuing the medication, in patients for whom such symptoms are severe, are abrupt in onset, or were not among the presenting symptoms.
Serzone is not approved for use in treating any indications in the pediatric population.
Family members and other caregivers of any patient being treated with antidepressants for major depressive disorder or other indications should be alerted as to the need to monitor patients for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence of suicidality. Such symptoms should be reported to the patient's physician immediately.
Other than Serzone, medications affected by the FDA's advisory regarding antidepressants include the following: paroxetine hydrochloride (Paxil), bupropion hydrochloride (Wellbutrin), fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), venlafaxine (Effexor), and mirtazepine (Remeron). The revised labeling for these drugs carry the same warnings as those for Serzone regarding the emergence of suicidal ideation and worsening of depression.
June 24, 2004
ST. LOUIS (MD Consult) - On June 22, 2004, the U.S. Food and Drug Administration (FDA) and GlaxoSmithKline notified health care professionals of revisions to the Warnings and Precautions sections of labeling for certain medications to alert health care professionals that patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications. The warning recommends patients being treated with antidepressants be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases.
The revised labeling is a follow-up to a Public Health Advisory issued on March 22, 2004, in which the FDA cautioned physicians, patients, and their families about the need to closely monitor all patients being treated with antidepressants. This Advisory was a result of the FDA's ongoing review of potential safety issues involving antidepressants and pediatric patients. Additional information concerning this review is expected by the end of 2004.
Included in the new warning are revisions to the labeling for the following drug products: Paxil (paroxetine hydrochloride) Tablets, Paxil Controlled-Release Tablets, Wellbutrin (bupropion hydrochloride) Tablets, Wellbutrin Sustained-Release Tablets, and Wellbutrin Extended-Release Tablets. These products are not approved for use in the pediatric population. In addition, clinical trials of Paxil failed to demonstrate efficacy in pediatric depression.
The new labeling information states that consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.
In addition to the labeling changes for paroxetine and bupropion, the FDA announced that it was proposing changes for the following other antidepressants: fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), venlafaxine (Effexor), nefazodone (Serzone), and mirtazepine (Remeron). These labeling changes carry the same warnings as those for paroxetine and bupropion regarding the emergence of suicidal ideation and worsening of depression.
Patients taking these medications and their family members should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient's physician immediately.
GlaxoSmithKline requests that adverse events related to its medications be reported to the company at 888-825-5249. Alternatively, the FDA's MedWatch program encourages reporting of this information by phone at 800-FDA-1088, by fax at 800-FDA-0178, via the Internet at www.fda.gov/medwatch, or by mail at MEDWATCH HF-2, FDA, 5600 Fisher's Lane, Rockville, MD 20857.
June 10, 2004
ST. LOUIS (MD Consult) - The U.S. Food and Drug Administration (FDA) issued a Public Health Advisory notifying health care professionals of a revised package insert released on June 9, 2004, for use in the 22 member states of the European Union (EU). The changes to the European labeling are in response to adverse event reports in patients receiving Crestor (rosuvastatin) and highlight certain patient populations who may be at an increased risk for myopathy associated with Crestor use, especially at the highest approved dose of 40 mg. These risk factors and many of the recommendations for how to minimize the risk of myopathy are already captured in the FDA-approved labeling for Crestor in the United States. The FDA alerted physicians to carefully read the Crestor product label and follow the recommendations for starting doses, dose adjustments, and maximum daily doses to minimize the risk of myopathy in individual patients.
Crestor, a member of a class of cholesterol-lowering drugs commonly referred to as statins, was approved in the United States in August 2003, based on review of an extensive clinical database involving approximately 12,000 patients. At that time, the FDA identified in the Warnings section of the product label those patients whose increased baseline risk for myopathy warranted more careful monitoring when prescribed Crestor. The FDA-approved labeling included a specific section titled, "Myopathy/Rhabdomyolysis," which states that patients who are of advanced age (65 years or older), have hypothyroidism, and/or have renal insufficiency should be considered to have a greater risk for developing myopathy while receiving a statin. Physicians are warned to prescribe Crestor with caution in these patients, particularly at higher doses, because the risk of myopathy increases with higher drug levels.
In addition, the United States–approved labeling for Crestor states that increased rosuvastatin drug levels were observed in certain subpopulations of patients (eg, subgroups of Asians, patients concomitantly using cyclosporine and gemfibrozil), conferring increased risk of myopathy. Because of these findings, the FDA required AstraZeneca to make available in the United States a 5-mg dose that could be used in patients requiring less aggressive cholesterol-lowering or who were concurrently taking cyclosporine. The maximum recommended dose in the FDA-approved label is 10 mg daily in patients with severe renal impairment or who are also taking gemfibrozil.
The FDA has received reports of rhabdomyolysis in association with Crestor, as it has with other drugs in the statin class. In an ongoing fashion, the agency is evaluating these reports of adverse muscle effects with regard to clinical severity and apparent relationship to the drug. The FDA is comparing the frequency of reporting of muscle injury with Crestor to that with other statins, given differences in prescribing rates for the different drugs. Pending the evaluation of the recent Crestor safety experience, the FDA is not proposing to change the U.S. labeling for Crestor, but the agency does want to reemphasize to physicians the importance of carefully following the recommendations in the current product label. Analysis of accumulating safety data in the United States and worldwide will be considered in any future labeling changes for Crestor and in making recommendations on risk management plans for Crestor.
Health care professionals prescribing Crestor are reminded of the following key safety messages from the Crestor label: starting doses and maintenance doses of the drug should be based on individual cholesterol goals and apparent risks for adverse effects; all patients should be informed that statins can cause muscle injury, which in rare, severe cases, can cause kidney damage and other organ failure that are potentially life-threatening; and patients should be told to promptly report to their physicians signs or symptoms of muscle pain and weakness, malaise, fever, dark urine, nausea, or vomiting.
The current FDA-approved label can be obtained at fda.gov/cder/foi/label/2003/21366_crestor_lbl.pdf.
May 14, 2004
ST. LOUIS (MD Consult) - On May 12, 2004, the U.S. Food and Drug Administration (FDA) and McNeil Consumer and Specialty Pharmaceuticals alerted health care professionals and consumers that one manufacturing lot (Lot No. JAM108, exp. 1/06) of Children's Motrin (ibuprofen) Grape Chewable Tablets may mistakenly contain Tylenol 8-Hour extended-release (acetaminophen) Geltabs. Lot No. JAM108 was distributed nationwide to wholesale and retail customers between February 5, 2004, and April 1, 2004. The bottles are labeled as containing 24 tablets. The Tylenol 8-Hour product provides an adult dose of acetaminophen, and use of this adult product could provide more than the recommended dose (overdose) for children.
The mislabeled bottles appear to be the result of a packaging error for this one lot. To date, 2 mislabeled bottles have been identified, but no injuries have been reported as a result of this issue. In the interest of patient health and safety, McNeil, in consultation with the FDA, is taking the precaution of alerting consumers nationwide about this issue to help them identify the potentially affected product. McNeil also has alerted retailers nationwide.
The two medicines are visibly different. Children's Motrin Grape Chewable Tablets are round, purple-colored, scored tablets with the letters MO and the number 50 on the tablet surface. These tablets have a non-glossy finish and a grape smell. The Tylenol 8-Hour Geltabs are hard, round, gelatin coated, and shiny. The geltabs are white on one side, red on the other, with "8 Hour" printed in blue on either the red or the white side.
Consumers can identify the manufacturing lot number that is both embossed on the carton end flap and printed on the bottle label under McNeil's address as "Exp 1/06 JAM108." Anyone identifying one of the bottles included in this consumer alert should contact McNeil's Consumer Relationship Center at 1-800-962-5357. Parents who believe their children may have taken Tylenol 8-Hour Geltabs, believing them to be Children's Motrin Grape Chewable Tablets, should contact their health care provider or a poison control center immediately.
For more information on this consumer alert, or to report an adverse event, please call McNeil's Consumer Relationship Center at 1-800-962-5357.
May 13, 2004
ST. LOUIS (MD Consult) - On May 12, 2004, the U.S. Food and Drug Administration (FDA) announced Bristol-Myers Squibb's release of a letter alerting health care professionals to important package insert changes to Desyrel (trazodone hydrochloride) tablets, which are indicated for the treatment of depression. In compliance with the FDA, Bristol-Myers-Squibb Company adopted new labeling for Desyrel.
The following label changes include modifications to the "Clinical Pharmacology" section:
| Metabolism In vitro studies in human liver microsomes show that trazodone is metabolized to an active metabolite, m-chlorophenylpiperazine (mCPP) by cytochrome P450 3A4 (CYP3A4). Other metabolic pathways that may be involved in metabolism of trazodone have not been well characterized. Elimination In some patients, Desyrel may accumulate in the plasma. Drug Interactions See also PRECAUTIONS: Drug Interactions. In vitro drug metabolism studies reveal that trazodone is a substrate of the cytochrome P450 3A4 (CYP3A4) enzyme and trazodone metabolism can be inhibited by the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of trazadone increased by 34%, the area under the curve (AUC) increased by 2.4-fold, the half-life increased by 2.2-fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were coadministered. Carbamazepine induces CYP3A4. Following coadministration of carbamazepine 400 mg/d with trazodone 100 to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone (as well as mCPP) by 76% and 60%, respectively, compared to pre-carbamazepine values. |
Additionally, the "Drug Interactions" subsection within the PRECAUTIONS section has been updated with the following information:
| In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with CYP3A4 inhibitors. Ritonavir, a potent CYP3A4 inhibitor, increased the Cmax, AUC, and elimination half-life, and decreased clearance of trazodone after administration of ritonavir twice daily for 2 days. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were coadministered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole or nefazodone may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered. Carbamazepine reduced plasma concentrations of trazodone when coadministered. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs. |
Bristol-Myers Squibb stated that it strongly encourages health care professionals to report any serious adverse events that occur concurrently with the use of Desyrel. The company can be contacted at 800-321-1335.
Adverse events can be reported to the FDA's MedWatch program by phone at 800-FDA-1088, by fax at 800-FDA-0178, via the MedWatch Web site at FDA.gov/medwatch, or by mail at MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787. A postage-paid form is available on the MedWatch Web site.
Full prescribing information for Desyrel is available at bms.com/products.
May 12, 2004
ST. LOUIS (MD Consult) - On April 20, 2004, Savient Pharmaceuticals, Inc, issued a letter notifying health care professionals of an important drug interaction between Oxandrin (oxandrolone), a synthetic derivative of testosterone, and the oral anticoagulant warfarin administered for systemic anticoagulation. Concurrent dosing of Oxandrin and warfarin may result in unexpectedly large increases in the international normalized ratio (INR) or prothrombin time (PT). When Oxandrin is prescribed to patients being treated with warfarin, doses of warfarin may need to be decreased significantly to maintain a desirable INR level and to diminish the risk of potentially serious bleeding.
Physicians should instruct their patients to immediately report any use of warfarin and any bleeding.
Oxandrin is indicated as adjunctive therapy to promote weight gain after weight loss following extensive surgery, chronic infections, or severe trauma, and in some patients who without definite pathophysiologic reasons fail to gain or to maintain normal weight; to offset the protein catabolism associated with prolonged administration of corticosteroids; and for the relief of the bone pain frequently accompanying osteoporosis.
According to the letter circulated by Savient, anabolic androgenic steroids as a class may increase susceptibility specifically to oral anticoagulants, with reduction of the anticoagulant dosage necessary to maintain the desired PT. No specific directions have previously been available for any anabolic androgenic agents. A recent clinical study conducted by Savient demonstrated a significant decrease (80%-85%) in the warfarin dose needed to achieve therapeutic effect when subjects were also treated with Oxandrin. The study results were significant, and the U.S. Food and Drug Administration approved a change to the Oxandrin labeling as a result. The recommendations are specific to Oxandrin and cannot be presumed to be applicable for other anabolic androgenic steroids.
A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and area under the curve from 4.55 to 12.08 ng/hr/mL; similar increases in R-warfarin half-life were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 to 1.13 mg/day (approximately 80%-85% reduction of warfarin dose) was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or PT should be monitored closely and the dose of warfarin adjusted as necessary until a stable INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT and adjustment of the warfarin dosage, if indicated, are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding.
Oxandrin is available in 2.5- and 10-mg tablets. For full prescribing information, visit oxandrin.com.
May 11, 2004
ST. LOUIS (MD Consult) - According to a news release issued by the U.S. National Institutes of Health on May 4, 2004, the U.S. Food and Drug Administration has instituted labeling changes for Voriconazole (VFEND) triazole antifungal agent, to include drug interaction information when coadministered with efavirenz or ritonavir.
The following paragraph was added to "Drug Interactions, Effects of Other Drugs on Voriconazole":
| Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): Ritonavir (400 mg Q12h for 9 days) decreased the steady state Cmax and AUCt of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. The effect of ritonavir (100 mg Q12h as used to inhibit CYP3A and increase concentrations of other antiretroviral drugs) on voriconazole concentrations has not been studied. Repeat oral administration of voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) did not have a significant effect on steady state Cmax and AUCt of ritonavir following repeat dose administration (400 mg Q12h for 9 days) in healthy subjects. Coadministration of voriconazole and ritonavir (400 mg Q12h) is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions). |
The following paragraph was added to "Drug Interactions, Two-Way Interactions":
| Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate): Steady state efavirenz (400 mg PO QD) decreased the steady state Cmax and AUCt of voriconazole (400 mg PO Q12h for 1 day, then 200 mg PO Q12h for 8 days) by an average of 61% and 77%, respectively, in healthy subjects. Voriconazole at steady state (400 mg PO Q12h for 1 day, then 200 mg Q12h for 8 days) increased the steady state Cmax and AUCt of efavirenz (400 mg PO QD for 9 days) by an average of 38% and 44%, respectively, in healthy subjects. Coadministration of voriconazole and efavirenz is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions). |
The following paragraph was modified in "Drug Interactions, Two-Way Interactions":
| Other Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) (CYP3A4 substrates, inhibitors or CYP450 inducers): In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by an NNTRI (e.g., delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy volunteers suggest that the metabolism of voriconazole may be induced by a NNRTI. This in vivo study also showed that voriconazole may inhibit the metabolism of a NNRTI. Efavirenz and voriconazole coadministration is contraindicated (see CLINICAL PHARMACOLOGY - Drug Interactions, CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g. nevirapine and delavirdine) (see PRECAUTIONS - Drug Interactions). |
The following paragraphs were added to the "Contraindications" section:
| Coadministration of VFEND with ritonavir (400 mg Q12h) is contraindicated because ritonavir (400 mg Q12h) significantly decreases plasma voriconazole concentrations in healthy subjects. The effect of ritonavir (100 mg Q12h as used to inhibit CYP3A and increase concentrations of other antiretroviral drugs) on voriconazole concentrations has not been studied (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
Coadministration of VFEND with efavirenz is contraindicated because efavirenz significantly decreases voriconazole plasma concentrations while VFEND also significantly increases efavirenz plasma concentrations (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions). |
In addition, Tables 8 and 9 in the "Drug Interactions" section were revised to include information concerning ritonavir and efavirenz.
For more information, visit the U.S. Department of Health and Human Services AIDSinfo Web site at aidsinfo.nih.gov.
April 29, 2004
ST. LOUIS (MD Consult) - On April 28, 2004, the U.S. Food and Drug Administration (FDA) announced the addition of new risk information to the health professional labeling for Zelnorm (tegaserod maleate). Zelnorm is a prescription medication for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation. The labeling is being revised to ensure that health professionals and patients have the most current and complete information available when prescribing and taking Zelnorm.
The specific revisions include:
The new warning states, "Serious consequences of diarrhea, including hypovolemia, hypotension and syncope have been reported in the clinical studies and during marketed use of Zelnorm. In some cases, these complications have required hospitalization for rehydration. Zelnorm should be discontinued immediately in patients who develop hypotension or syncope. Zelnorm should not be initiated in patients who are currently experiencing or frequently experience diarrhea."
The new precaution on ischemic colitis states, "Ischemic colitis, and other forms of intestinal ischemia, have been reported in patients receiving Zelnorm during marketed use of the drug. A causal relationship between Zelnorm use and these events has not been established. Placebo-controlled clinical trials of 7,000 patients for 3-month duration showed no cases of these events, and would suggest the rate of these events is low. Zelnorm should be discontinued immediately in patients who develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrhea or new or worsening abdominal pain. Patients developing these symptoms should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with Zelnorm should not be resumed in patients who develop findings consistent with ischemic colitis."
Under the Postmarketing Experience heading in the adverse reactions section, the labeling now states, "Voluntary reports of adverse events occurring with the use of Zelnorm include the following: ischemic colitis, mesenteric ischemia, gangrenous bowel, rectal bleeding, syncope, suspected sphincter of Oddi spasm, bile duct stone, and cholecystitis with elevated transaminases. Because these cases are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. No causal relationship between these events and Zelnorm use has been established. Hypokalemia secondary to diarrhea has also been reported."
The new patient information advises patients who get new or increased stomach pain or blood in their stools to stop taking Zelnorm right away and to immediately contact their doctors to determine whether they may have a serious problem. In addition, the new labeling advises patients to stop taking Zelnorm and to call a doctor right away if they experience diarrhea that leads to lightheadedness, dizziness or fainting.
The FDA approved Zelnorm on July 24, 2002, following the recommendation for approval made by the FDA's Gastrointestinal Drugs Advisory Committee on June 26, 2000 (see fda.gov/bbs/topics/ANSWERS/2002/ANS01160.html.). Zelnorm is the only FDA-approved prescription drug for the short-term treatment of women with IBS whose primary bowel symptom is constipation.
Zelnorm increases the movement of stools through the bowels. Zelnorm does not cure IBS, nor does it treat diarrhea-predominant IBS. Zelnorm reduces pain and discomfort in the abdominal area and reduces bloating and constipation. The safety and effectiveness of Zelnorm in men have not been established.
In conjunction with this FDA announcement, the manufacturer of Zelnorm, New Jersey–based Novartis Pharmaceuticals Corporation, has issued a letter to health professionals to highlight the labeling changes.
April 19, 2004
ST. LOUIS (MD Consult) - On April 12, 2004, the U.S. Food and Drug Administration (FDA) announced its final rule on dietary supplements containing ephedrine alkaloids had become effective. The rule, which was published on February 11, 2004, in the Federal Register, declares dietary supplements containing ephedrine alkaloids (ephedra) adulterated because such supplements present an unreasonable risk of illness or injury.
Two manufacturers had asked the United States District Court in New Jersey to enter a temporary injunction to prohibit the FDA from enforcing the rule. However, on April 12 the court ruled it would not immediately stay the rule. The court ordered the parties to submit additional briefs so it could decide whether to permanently stay the rule.
According to the April 12, 2004, issue of the New York Times, before he could grant a restraining order against the FDA, the Judge Joel A. Pisano was required to find that the manufacturers would likely win their case, that the manufacturers would undergo irreparable harm if the FDA moved forward with their ban, and that the public interest would be served by the injunction against the FDA. "He ruled against the company on all three points," said the Times.
"We will take appropriate enforcement actions if needed to stop manufacturers from illegally selling and distributing dietary supplements containing ephedra alkaloids," said U.S. Department of Health and Human Services Secretary Tommy G. Thompson. "These products pose unacceptable health risks, and any consumers who are still using them should stop immediately."
On December 30, 2003, the FDA issued over 60 letters to manufacturers notifying them of the agency's intent to publish the rule as well as a consumer alert warning the public of the dangers of ephedra and asking that they stop taking these products immediately.
"Dietary supplements containing ephedrine alkaloids have been shown to pose a real risk to health," said Dr. Lester M. Crawford, Acting FDA Commissioner. "The court's decision today makes clear that these dietary supplements may not be lawfully marketed while the matter remains under review by the Court."
The FDA plans to step up Internet surveillance to determine whether anyone, including the original 60+ targeted firms, is continuing to actively promote and sell these products. The agency stated that it has already seen progress in its regulatory efforts, in that a majority of the manufacturers to whom letters were sent have stopped selling dietary supplements containing ephedrine alkaloids.
For more information, visit fda.gov/oc/initiatives/ephedra/february2004/.
April 13, 2004
ST. LOUIS (MD Consult) - On April 9, 2004, the U.S. Food and Drug Administration (FDA) warned consumers not to purchase or consume products that claim to provide "safe legal highs" or that are marketed as "street drug alternatives" by Cytotec Solutions, Inc, of Tampa, Fla. This warning expands on the February 2004 warning concerning a product called Green Hornet, also distributed by Cytotec Solutions. Products marketed by this company have been promoted and sold on the Internet and in stores as legal versions of illicit street drugs.
The FDA issued a warning in February 2004 about adverse events experienced by 4 teenagers after they consumed Green Hornet Liquid that contained high levels of the over-the-counter drugs diphenhydramine and dextromethorphan.
The FDA analyses of additional products manufactured or distributed by Cytotec Solutions, Inc, has not only found the drugs diphenhydramine hydrochloride and dextromethorphan, but ephedrine and the controlled substances gamma butyrolactone (GBL) and gamma hydroxybutyric acid (GHB) as well. Although this firm is no longer producing these products, they remain under investigation, and the FDA is working to identify and address additional distributors of the products. The agency is issuing this warning because consumers may still have these products in their possession or may be able to buy them commercially.
"[The] FDA has taken numerous actions against various products that are being manufactured, marketed, or distributed as street drug alternatives," said Lester M. Crawford, DVM, PhD, Acting FDA Commissioner. "There is no doubt that these products pose a potential public health concern, and [the] FDA is concerned that these products may be misused or abused by individuals, especially minors and young adults."
The products included in this warning, which consumers should not use, are Trip2Night, Invigorate II, Snuffadelic, Liquid Speed, Solar Water, Orange Butterfly, Schoomz, and Green Hornet Liquid. The labeling for these products lists a variety of herbal and other ingredients but provides neither the name of the manufacturer nor the presence of these drug ingredients.
The FDA considers any product that is promoted as a street drug alternative to be an unapproved new drug and a misbranded drug marketed in violation of the Federal Food, Drug, and Cosmetic Act. Also, any product containing undeclared active drug ingredients violates the law. Such violations may result in enforcement action, including seizure and injunction.
April 13, 2004
ST. LOUIS (MD Consult) - On March 25, 2004, Bristol-Myers Squibb announced a revision to the "Warnings" section of labeling for its drug Abilify (aripiprazole), describing the risk of hyperglycemia and diabetes in patients taking the medication. The change was made in response to a request from the U.S. Food and Drug Administration (FDA) that all manufacturers of atypical antipsychotic medications, including Bristol-Myers Squibb, add this warning statement to labeling.
The new warning provides the following information that is specific to Abilify, hyperglycemia, and related adverse events:
As noted above, there have been few reports of hyperglycemia in patients treated with Abilify, and an exhaustive review of the Abilify database revealed no increased signal for diabetes. Additional information is needed to confirm this. However, as noted in the new warning, it is prudent to monitor patients treated with atypical antipsychotic agents for signs and symptoms of diabetes. Patients with risk factors for diabetes mellitus (eg, obesity, family history) who are starting treatment with atypical antipsychotics should undergo baseline screening and routine monitoring throughout therapy to mitigate the risk of developing serious metabolic complications.
Abilify is indicated for the treatment of schizophrenia. Clinical data demonstrates that Abilify delivers proven efficacy with a mean weight change of only 1 kg over 1 year, and is comparable to placebo with respect to lipids.
As with other antipsychotic medications, a rare condition referred to as neuroleptic malignant syndrome has been reported with its use. And as with all antipsychotic medications, prescribing should be consistent with the need to minimize the risk of tardive dyskinesia.
Abilify may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions that would predispose them to hypotension. As with other antipsychotic drugs, Abilify should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Seizures occurred in 0.1% of patients treated with Abilify in placebo-controlled trials.
Patients should not drive or operate heavy machinery until they are certain Abilify does not affect them adversely.
Treatment-emergent adverse events reported with Abilify include headache, anxiety, insomnia, nausea, vomiting, somnolence, lightheadedness, akathisia, and constipation.
For additional information about Abilify, including full prescribing information, visit abilify.com or contact Bristol-Myers Squibb at 800-321-1335.
April 7, 2004
ST. LOUIS (MD Consult) - On April 2, 2004, the U.S. Centers for Disease Control and Prevention (CDC) announced a voluntary recall of the Imovax Rabies Vaccine by the manufacturer, Pennsylvania-based Aventis Pasteur. The CDC and the U.S. Food and Drug Administration (FDA) were notified that a recent quality-assurance test of Imovax identified the presence of noninactivated Pitman-Moore virus (the attenuated vaccine strain) in a single product lot. Imovax is an inactivated viral vaccine and should not contain live virus. The vaccine lot containing noninactivated virus was not distributed.
As a precautionary measure, Aventis Pasteur initiated a voluntary recall of lot numbers X0667-2, X0667-3, W1419-2, and W1419-3, which were produced during the same period as the lot that contained noninactivated Pitman-Moore virus. These four lots, which were distributed in the United States between September 23, 2003, and April 2, 2004, passed all FDA-approved release tests, including testing to confirm the absence of live virus. These test results suggest that any potential risk to those vaccinated with recalled vaccine is likely to be low. No unusual adverse events associated with the recalled vaccine have been reported.
The manufacturer has indicated that additional lots of recalled vaccine were distributed internationally. These lots also passed all release tests. The manufacturer is working with regulatory authorities to determine lot numbers of vaccine and countries that might have received recalled lots. In its April 2, 2004, Morbidity and Mortality Weekly Report Dispatch, the CDC stated that more information about these internationally distributed lots will be provided as it becomes available.
Aventis Pasteur is providing additional detailed information to all distributors and providers. Health care providers should contact persons who received recalled vaccine to implement the recommendations outlined by the CDC. In addition, persons who know they received rabies vaccine between September 23, 2003, and April 2, 2004, should contact their health care providers to determine whether they received vaccine from any of the 4 lots being recalled and, if so, whether they should be treated as outlined by the CDC. Vaccine distributors and health care providers who have any remaining doses of the recalled lots should not use them and should contact Aventis Pasteur regarding their disposal. Information about this recall is available from the Aventis Pasteur Medical Information Services Department at 800-835-3587 or vaccineshoppe.com.
All persons who have begun a rabies vaccination series (whether for preexposure or postexposure prophylaxis) must complete that vaccination series on time, using nonrecalled vaccine. Information about human rabies prevention based on current recommendations of the Advisory Committee on Immunization Practices is available at cdc.gov/mmwr/preview/mmwrhtml/00056176.htm.
Most persons receiving rabies vaccine do so because of exposure to a rabid animal, and treatment is needed to prevent fatal illness. Thus, persons who are receiving postexposure prophylaxis must not omit or delay receiving any remaining injections; injections needed to complete the series should use nonrecalled vaccine. Recalled vaccine is considered fully immunogenic, and previously administered doses can be considered a dose in a postexposure prophylaxis regimen.
Although unlikely, a theoretical possibility exists that persons who received vaccine from a recalled lot could have been exposed to the noninactivated Pitman-Moore vaccine strain of rabies virus. Even in the event of such an exposure, the timely administration of treatment, as described here, will help to ensure negligible risk to persons who have received vaccine from a recalled lot. Persons who received recalled vaccine should receive treatment equivalent to postexposure prophylaxis, similar to published guidelines, as follows:
All clinically significant adverse events following receipt of rabies vaccine should be reported to (1) Aventis Pasteur at 800-835-3587 and (2) the Vaccine Adverse Event Reporting System at vaers.org or 800-822-7967.
Additional information about rabies and its prevention is available from CDC at 404-639-1050 or cdc.gov/ncidod/dvrd/rabies.
April 12, 2004
ST. LOUIS (MD Consult) - On April 2, 2004, Janssen Pharmaceutica notified health care professionals of an expanded recall of Duragesic (fentanyl transdermal system) 75 mcg/h, originally recalled in February 2004. Four additional lots are subject to the present expanded recall. The manufacturing lots now included are 0327192, 0327193, 0327294, 0327295, and 0330362. Patches from all other 75-mcg/h and all 25-, 50-, and 100-mcg/h patches are not part of this recall.
The company recalled one lot of Duragesic 75-mcg/h patches (control number 0327192) in February 2004 after determining that some patches in this lot may leak medication due to improper sealing of one of their edges. Since then, a small number of patches with the same problem have been identified in one additional lot. As a precaution, the company is recalling four additional lots of patches of the same dosage that were produced on the same manufacturing line during the same period.
If medication leaks out of the patch, exposure to the medication could result in inadvertent ingestion or an increased transdermal absorption of the active opiate component fentanyl, leading to potentially life-threatening complications. In addition, leakage of medication could lead to inadequate dosing, resulting in treatment failure, opiate withdrawal, or both.
Health care professionals, caregivers, or anyone who comes in contact with medication that may leak from Duragesic 75-mcg/h patches from the affected lots may be at risk of potentially life-threatening complications. Drug exposure among these persons could be more clinically significant because such individuals may not be opiate tolerant. Anyone who comes in contact with the leaked medication is advised to rinse exposed skin thoroughly with water only; soap should not be used.
Patients or caregivers in possession of patches from the lots included in the recall should immediately contact their physicians or pharmacists for specific instructions about returning affected patches and obtaining a new supply of medication.
In a letter addressed to health care professionals, Janssen spokespersons stated that patients using Duragesic patches that are not included in the recall can continue to use them. Sudden discontinuation of Duragesic, according to the letter, can cause loss of efficacy and opioid withdrawal.
For more information regarding this product recall, including photos of the outer carton and foil pounch illustrating the location of the product's control numbers, visit duragesic.com or Janssen.com.
Janssen requests that adverse events and product defect relating to its products be reported to the company at 800-526-7736 or to the FDA MedWatch Program by phone at 800-FDA-1088; by fax at 800-FDA-0178; by mail at MedWatch, FDA, 5600 Fishers Lane, Rockville, MD 20852; or via accessdata.fda.gov/scripts/medwatch.
April 9, 2004
ST. LOUIS (MD Consult) - On April 1, 2004, Novartis Pharmaceuticals addressed a letter to health care professionals announcing the revision to the "Warnings" section of Clozaril (clozapine) labeling, describing the increased risk of hyperglycemia and diabetes in patients taking Clozaril. The U.S. Food and Drug Administration (FDA) has asked all manufacturers of atypical antipsychotic medications, including Novartis, to add this warning statement to labeling.
According to the letter, the FDA acknowledges that the relationship between atypical antipsychotic use and hyperglycemia is not completely understood and is confounded by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes in the general population.
Although similar information was previously provided in the "Precautions" section of the prescribing information for Clozaril, Novartis concurs with the FDA that the safe use of atypical antipsychotics can be enhanced by informing patients and prescribers about these adverse events with the "Warnings" section of the prescribing information. The text of this new warnings statement follows below. All patients being treated with Clozaril, as well as their caregivers, should be fully informed of this increased risk of hyperglycemia and diabetes.
| NEW WARNING LABEL: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents including Clozaril. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who begin taking atypical antipsychotic medications should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who begin receiving treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glycose testing. In some cases, hyperglycemia has resolved when the administration of atypical antipsychotic medication was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. |
Health care professionals are requested to report all serious adverse events suspected to be associated with use of Clozaril to the FDA's MedWatch Reporting System by phone at 800-FDA-0178; by mail (using Form 3500) at MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20857; or via the Internet at accessdata.FDA.gov/scripts/medwatch.
Alternatively, this information can be reported to Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936; by phone at 888-669-6682; or via the company's Web site at novartis.com/contact/en/index.shtml.
The 2004 MedWatch safety summary, including links to the "Dear Doctor" letter and revised label, are available at fda.gov/medwatch/SAFETY/2004/safety04.htm#clozaril.
March 31, 2004
ST. LOUIS (MD Consult) - A widely used, over-the-counter (OTC) cream containing natural progesterone (Pro-Gest) may expose women to higher levels of the hormone than previously thought, according to findings presented on March 25, 2004, by Dr. Anne Hermann at the annual meeting of the American Society for Clinical Pharmacology and Therapeutics in Miami Beach, Fla.
Pro-Gest, along with more than 2 dozen creams containing progesterone, is a popular alternative to synthetic hormone therapies. These creams, which are sold OTC, are generally considered less potent and, thus, less harmful than federally regulated progesterone pills. A recent study, however, has shown that women using Pro-Gest and women taking the U.S. Food and Drug Administration–approved progesterone capsule Prometrium later had the same levels of progesterone in their bloodstreams.
Dr. Hermann's paper, "The Bioequivalence of Over-The-Counter Progesterone Cream," is the result of 2 years of study conducted at the Clinical Pharmacology Research Center at Bassett Healthcare in Cooperstown, NY, in conjunction with Prevalere Life Sciences in Whiteboro, NY. The study was performed on post-menopausal women because progesterone levels are no longer detected in this population.
"Women should only use over-the-counter progesterone creams with medical supervision," Dr. Hermann said. "Bassett scientists are confident of the accuracy of this study for two reasons," she added. "First, whole blood was measured, and secondly, the steady state levels of whole blood were measured in a unique way."
The Bassett study measured whole blood with red blood cells and other cells in it. Many progesterone studies only measure serum. This can result in inaccurate results because progesterone circulates in the blood bound to cell membranes. When progesterone reaches receptors in the organs of influence—the breast, uterus, or placenta—it detaches from cell membranes and attaches to the receptors. Therefore, to be accurate, whole blood must be measured.
The study also measured the steady state levels of whole blood by using a very sensitive instrument to measure progesterone levels. Prior to 5 to 7 days, average progesterone levels in the blood are still building up. After about a week, a dose of progesterone will yield blood concentrations that are the same every day, whether on day 10 or day 100. Levels were measured on day 12 to ensure that the concentration was "steady" and no longer "building up." Many prior studies measured blood levels of progesterone after 1 dose, which will give much lower concentrations. In addition, older studies often used instruments that gave incorrect data on blood progesterone levels.
Multiple studies have shown that combined hormone replacement therapy—estrogen plus progestin—or progestin alone for 5 years or longer is associated with a 26% to 53% increase in breast cancer and other adverse effects.
With at least 30 companies in the United States producing progesterone creams, it is estimated that millions of tubes of the cream are sold every year without prescriptions, potentially putting women at risk for heart disease and other diseases from unregulated and unmonitored progesterone use.
Emerita, the company that makes Pro-Gest, has said no solid evidence that natural progesterone carries health risks exists.
March 30, 2004
WASHINGTON (Reuters) - On March 24, 2004, the U.S. Food and Drug Administration (FDA) published new rules requiring content labeling (amount present per dosage unit, eg, tablet) and warning labeling for over-the-counter (OTC) drugs that contain levels of calcium, magnesium, sodium, or potassium that might be harmful to people with certain underlying medical conditions. The FDA published these final rules in the Federal Register to enhance the safe use of these products by providing uniform content and warning labeling for oral OTC drug products containing levels of these substances that exceed specific thresholds. Mouth rinses, fluoride toothpastes, and mouth washes are not covered by this regulation.
In addition, the agency is proposing to extend sodium content labeling requirements to OTC rectal drug products containing sodium phosphates. The FDA is taking this action because people with certain medical conditions may be at risk for serious or life-threatening electrolyte imbalances when using these products.
Under the new rules, the labeling of oral OTC drugs containing sodium, calcium, magnesium, or potassium must state the amount of a particular ingredient in each dose if they contain any of the following:
The new rules also require new warnings on the label to alert people with kidney stones, decreased kidney function due to kidney disease, or people who are adhering to sodium-, calcium-, magnesium-, or potassium-restricted diets to consult their doctors before using products for oral ingestion that contain any of the following:
"These new warnings provide an extra level of safety for people who may be especially sensitive to these commonly used OTC ingredients," said Acting FDA Commissioner Lester M. Crawford, DVM, PhD. "Although these ingredients can generally be used safely and provide benefit to many consumers, people with conditions that put them at risk of side effects need to be aware of the presence of these ingredients."
Sodium may be related to high blood pressure and is a concern for individuals with congestive heart failure. In people with kidney disease, blood levels of calcium, magnesium, and potassium can reach potentially dangerous levels due to their decreased elimination. People with kidney stones need to carefully monitor their calcium intake.
The final rules become effective on April 23, 2004. Full compliance with the regulations is required by September 25, 2005.
March 29, 2004
WASHINGTON (Reuters) - On March 18, 2004, the U.S. Food and Drug Administration (FDA) announced a recall of Major Twice-A-Day 12 Hour Nasal Spray–Nasal Decongestant, ½-oz. bottle, lot #K4496, with an expiration date of 10/06. The recall was issued because the lot is contaminated with a type of bacteria called Burkholderia cepacia. Use of this contaminated product could cause serious or potentially life-threatening infections in patients with compromised immune systems, particularly individuals with cystic fibrosis.
This product is a nasal decongestant containing the active ingredient oxymetazoline hydrochloride 0.05%. The lot number and expiration date can be found on the bottom of the carton and on the back of the bottle label.
The entire lot has been distributed nationwide to wholesalers, pharmacies, hospitals, and retailers by Major Pharmaceuticals of Livonia, Michigan. Major Pharmaceuticals has initiated a recall down to the consumer level.
The drug's distributor, Miami-based Propharma, Inc, was alerted to this problem after reports of infections and findings of Burkholderia cepacia in the nasal spray by a hospital in Colorado. An FDA sample analysis confirmed the presence of the bacteria in unopened bottles from the affected lot.
Consumers and retailers who have the product should return it to their place of purchase for a full refund. Consumers with questions regarding the recall can contact Major Pharmaceuticals at 734-743-6181.
March 23, 2004
WASHINGTON (Reuters) - On March 22, 2004, the U.S. Food and Drug Administration (FDA) issued a Public Health Advisory that provides further cautions to physicians, their patients, and families and caregivers of patients about the need to closely monitor both adults and children with depression, especially at the beginning of treatment or when medication doses are changed with either an increase or decrease in the dose.
The FDA has been closely reviewing the results of antidepressant studies in children since June 2003, after an initial report on studies with paroxetine (Paxil) and subsequent reports on studies of other drugs appeared to suggest an increased risk of suicidal thoughts and actions in the children being given antidepressants. There were no suicides in any of the trials. On close examination of the initial reports, it was unclear whether certain behaviors reported in these studies represented actual suicide attempts or other self-injurious behavior that was not suicide related.
The FDA has initiated a full review of these reported behaviors by experts in such evaluation. However, it is not yet clear whether antidepressants contribute to the emergence of suicidal thinking and behavior. The agency is advising clinicians, patients, families, and caregivers of adults and children that they should closely monitor all patients being administered therapy with these drugs for worsening depression and suicidal thinking, which can occur during the early period of treatment. The agency is also advising that these patients be observed for certain behaviors that are known to be associated with these drugs, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania, and that physicians be particularly vigilant in patients who may have bipolar disorder.
The FDA is asking manufacturers to change the labels of 10 drugs to include stronger cautions and warnings about the need to monitor patients for the worsening of depression and the emergence of suicidal ideation, regardless of the cause of such worsening.
The drugs under review include bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, escitalopram, and venlafaxine. It should be noted that the only drug that has received approval for use in children with major depressive disorder is fluoxetine (Prozac). Several of these drugs are approved for the treatment of obsessive-compulsive disorder in pediatric patients; these are sertraline (Zoloft), fluoxetine (Prozac), and fluvoxamine (Luvox). Luvox is not approved as an antidepressant in the United States.
These interim actions follow recommendations made by the FDA's Psychopharmacologic Drugs and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committees, which met on February 2, 2004. The advisory committee members advised the FDA that the labeling should draw more attention to the need to monitor patients being treated with certain antidepressants.
The FDA has previously noted (in Public Health Advisory and a Talk Paper T03-70 published October 27, 2003) the possible finding of increased suicidal thinking or behavior, but it emphasized that it was not clear that the drugs caused such events and additional analyses were being done to allow the FDA to seek more definitive answers.
The Public Health Advisory containing the new label warnings and cautions is available online at fda.gov/cder/drug/antidepressants/default.htm.
Later this summer, the FDA plans to update the Advisory Committees on the results of the expert analyses and its own analyses of the pediatric suicidality data.
March 23, 2004
WASHINGTON (Reuters) - On March 1, 2004, the U.S. Food and Drug Administration (FDA) and Eli Lilly and Company notified health care professionals of a revision to the "Warnings" section of Zyprexa (olanzapine) labeling, describing the increased risk of hyperglycemia and diabetes in patients taking Zyprexa. The FDA has asked all manufacturers of atypical antipsychotic medications, including Lilly, to add this warning statement to their labeling.
The announcement from Lilly came in the form of a letter that detailed the complications found to be involved with the company's drug. According to Lilly, hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents including Zyprexa. An assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who begin taking atypical antipsychotic agents should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who start treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotic drugs should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when administration of the atypical antipsychotic agent was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
In addition to Zyprexa, the atypical antipsychotic class includes clozapine (Clozaril; manufactured by Novartis), risperidone (Risperdal; Janssen), quetiapine (Seroquel; AstraZeneca), ziprasidone (Geodon; Pfizer), and aripiprazole (Abilify; Bristol Myers Squibb and Otsuka American Pharmaceutical).
Questions or concerns regarding Zyprexa safety information can be directed to Eli Lilly and Company at 1-800-Lilly-Rx. For revised labeling for Zyprexa, including full prescribing information, visit fda.gov/medwatch/SAFETY/2004/zyprexa_PI.pdf.
Serious adverse events should be reported to Lilly at 1-800-Lilly-Rx or to the FDA MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, or by email at fda.gov/medwatch.
February 26, 2004
ST. LOUIS (MD Consult) - On February 25, 2004, the U.S. Food and Drug Administration (FDA) announced a warning issued to consumers against purchasing or consuming a liquid product called Green Hornet. This product is promoted on the Internet and sold in stores as a herbal version of the illegal street drug "ecstasy." The FDA considers this product to be an unapproved new drug because it contains, among other ingredients, the undeclared active ingredients diphenhydramine and dextromethorphan, found in over-the-counter (OTC) drugs.
The FDA recently became aware of reports of adverse events experienced by 4 teenagers after consuming Green Hornet. The teenagers were rushed to a hospital emergency room experiencing seizures, excessive heart rates, severe body rashes, and high blood pressure. The FDA is investigating whether Green Hornet alone or in combination with other substances caused the severe adverse reactions.
"We are investigating whether the product consumed by the 4 teenagers caused the seizures and other symptoms. Our advice about so-called 'safe' alternatives to street drugs remains the same: They are not safe. Do not buy them, and do not use them," said FDA Commissioner Mark B. McClellan, MD, PhD. "[The] FDA will pursue every available enforcement option to remove these products from the marketplace and will seek penalties against those responsible for offering them."
The Green Hornet product involved in this case was sold by Kekio, Inc, Colorado Springs, Colo, doing business as a store called Mind Excursions. The store, which also operates a Web site, has stopped selling the product.
The product comes in 4- and 16-oz bottles, and the label does not bear the name of the manufacturer. The product labeling lists a variety of herbal ingredients; however, an FDA analysis has identified 2 drug ingredients in this product: diphenhydramine and dextromethorphan, which are individually found in numerous OTC cough/cold products.
The FDA has taken numerous actions against various products that are being manufactured, marketed, or distributed as alternatives to illicit street drugs. The agency is concerned that these products are being abused, including abuse by minors, and that they pose a potential threat to the public health.
The FDA considers any product that is promoted as a street drug alternative to be an unapproved new drug and a misbranded drug marketed in violation of the Federal Food, Drug, and Cosmetic Act. Any product containing undeclared active drug ingredients violates the law. Such violations may result in enforcement action, including seizure and injunction.
February 20, 2004
ST. LOUIS (MD Consult) - On February 16, 2004, Janssen Pharmaceutica Products announced a recall of its 75-mcg/h Duragesic (fentanyl transdermal system CII) patches, which are used to treat moderate to severe chronic pain. A small percentage of these patches may leak medication along one edge. The affected patches were distributed only in the United States, and the manufacturer has consulted with the U.S. Food and Drug Administration.
The recall applies to one manufacturing lot with the control number 0327192. No other lots or dosage strengths appear to be affected.
If the medication leaks from the patch, patients can get either too much or too little medication. Exposure to too much medication can occur if the medicine leaks directly onto the skin and the body absorbs an amount that is higher than intended. This overexposure can cause nausea, sedation, drowsiness, or potentially life-threatening complications. In addition, if the medication leaks out, there might not be enough remaining to provide adequate pain control, and the patient may experience withdrawal symptoms. These include sweating, sleeplessness, and abdominal discomfort.
Health care professionals, caregivers, and anyone else who comes in contact with an affected patch from this lot might also be at risk. Anyone who comes in contact with the leaked medication should thoroughly rinse exposed skin with water only; soap should not be used.
Anyone who has 75-mcg/h Duragesic patches should check the outer carton or foil pouch for the control number 0327192. Patients who have patches from the affected lot should contact a physician or pharmacist immediately for specific instructions and to coordinate returning affected patches and obtaining a new supply. Patients wearing Duragesic patches that are not from the affected lot can continue to wear them. Sudden discontinuation of Duragesic can cause health problems.
Duragesic is a prescription transdermal opioid medication indicated for the treatment of moderate to severe chronic pain. Duragesic patches are available in 4 dosage strengths: 25, 50, 75, and 100 mcg/h. Only the 75-mcg/h strength is involved in this voluntary recall.
Janssen estimates that fewer than 19,000 patches, or less than 5% of this lot, are affected by this problem. This quantity represents less than 1% of the total number of Duragesic patches currently in distribution. The affected lot was shipped to distributors in the United States between mid December 2003 and early January 2004.
For information on this product recall, visit Duragesic.com or Janssen.com. These Web sites contain written material and photos of the Duragesic pouch illustrating the control number.
To report an adverse event, please call Janssen at 800-526-7736.
February 18, 2004
ST. LOUIS (MD Consult) - On February 12, 2004, Bristol-Myers Squibb issued a letter announcing an important correction of information regarding its drug Pravachol (pravastatin sodium) tablets, a cholesterol-lowering medication. The U.S. Food and Drug Administration (FDA) recently determined that previously released advertisements and statements made by Bristol-Myers Squibb were misleading.
The FDA determined that certain promotional materials for Pravachol, directed to health care professionals and consumers, were false or misleading because they suggested Pravachol is approved to: help prevent heart attacks and strokes in patients with diabetes; help prevent stroke in patients without coronary heart disease (CHD); help prevent heart attack and stroke in patients with borderline high cholesterol but without CHD; and reduce cholesterol in patients with borderline high cholesterol who are not drug eligible according to National Cholesterol Education Program (NCEP) guidelines.
In fact, Bristol-Myers Squibb's letter emphasizes, Pravachol has not been proved to help prevent heart attacks and strokes in patients with diabetes. Pravachol has not been proved to help prevent stroke in patients without CHD, nor has it been proved to help prevent heart attack or stroke in borderline high cholesterol patients without CHD. In addition, Pravachol is not appropriate for reducing cholesterol levels in borderline high cholesterol patients who are not drug eligible according to NCEP guidelines.
Furthermore, Pravachol is no longer the only cholesterol-lowering drug approved to help prevent first and second heart attack. In April 2003, Merck's drug Zocor (simvastatin) was approved to reduce the risk of heart attacks and stroke in patients with CHD, or without CHD but at high risk of coronary events because of diabetes, peripheral vessel disease, or history of stroke or other cerebrovascular disease.
On February 20, 2004, Bristol-Myers Squibb will begin running corrected advertisements in newspapers and magazines to clarify its statements.
When diet and exercise are not effective, Pravachol—with changes in diet—is approved to lower cholesterol in persons with high cholesterol, to help prevent heart attacks in persons with high cholesterol or heart disease, and to help prevent stroke in persons with heart disease.
Pravachol should not be used by patients with active liver disease or those who have repeated blood tests indicating possible liver problems.
Pregnant women should not take Pravachol because it may harm the fetus. Women of childbearing age should not take Pravachol unless it is highly unlikely they will become pregnant. If a woman becomes pregnant while taking Pravachol, she should immediately stop taking the drug and consult her physician. In addition, women who are breastfeeding should not take Pravachol.
Placebo-controlled trials revealed the presence of adverse effects, generally mild and short-lived, including chest pain, rash, nausea, vomiting, diarrhea, abdominal pain, constipation, gas, heartburn, fatigue, flu, muscle pain or weakness, headache, dizziness, sleep disturbance, runny nose, and vision disturbances.
Rare cases of rhabdomyolysis with acute renal failure caused by myoglobinuria have been reported with use of pravastatin and other drugs in this class. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, or marked elevation of creatine phosphokinase. Patients taking Pravachol should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
For more information about Pravachol, contact Bristol-Myers Squibb at 212-546-4000 or visit bms.com.
February 2, 2004
ST. LOUIS (MD Consult) - On January 30, 2004, the U.S. Food and Drug Administration (FDA) announced that Boehringer Ingelheim Pharmaceuticals had issued a "Dear Health Care Professional" letter regarding clarification of risk factors for severe, life-threatening, and fatal hepatotoxicity associated with nevirapine (Viramune).
The letter states that important labeling information has been added to the boxed warning for Viramune, a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. Specifically, the manufacturer pointed out the following:
This new information is the result of recent postmarketing surveillance data and further analysis of the Viramune clinical trial database.
Although this new information describes patients at increased risk, any patient taking the drug can experience hepatic events and should be monitored carefully. As is already described in the product labeling for Viramune, some experts recommend clinical and laboratory monitoring more often than once a month, and in particular would include monitoring of liver function tests at baseline, at the time of dose escalation, and 2 weeks after dose escalation. All patients developing a rash at any time during Viramune treatment, but particularly during the first 18 weeks, should have liver function tests performed at that time. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout Viramune treatment.
It is important to counsel all patients that if signs or symptoms of hepatitis, severe skin reactions, or hypersensitivity reactions occur, they should discontine Viramune treatment and seek medical evaluation immediately. Viramune should not be restarted in these patients.
Clinical practice has shown that the most serious adverse reactions associated with nevirapine are clinical hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Clinical hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity that may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction.
Severe and life-threatening hepatotoxicity and fatal fulminant hepatitis have been reported in patients treated with nevirapine. Hepatic adverse events have been reported to occur more frequently during the first 18 weeks of treatment, but such events can occur at any time during treatment.
The most common clinical toxicity of nevirapine is rash. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face, and extremities. Women tend to be at higher risk for development of nevirapine-associated rash.
The most frequently reported adverse events related to nevirapine in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children. Serious adverse events were assessed in ACTG 245, a double-blind, placebo-controlled trial of nevirapine (n = 305) in which pediatric patients received combination treatment with nevirapine. In this trial, 2 patients were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Cases of allergic reaction, including one case of anaphylaxis, were also reported.
Adverse reactions can be reported to the Drug Information Unit at Boehringer Ingelheim Pharmaceuticals, Inc. (the U.S. affiliate of Germany-based Boehringer Ingelheim), at 800-542-6257, option #4; by fax at 800-821-7119; or via e-mail at druginfo@rdg.boehringer-ingelheim.com.
Alternatively, those wishing to report a reaction can contact the FDA MedWatch program by telephone at 800-332-1088, by fax at 800-332-0178, via fda.gov/medwatch, or by mail at MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 30857.
A copy of the letter from Boehringer Ingelheim and revised labeling can be found at viramune.com.
January 28, 2004
ST. LOUIS (MD Consult) - On January 27, 2004, the U.S. Food and Drug Administration (FDA) and the U.S. Customs and Border Protection (CBP) agency announced that a second series of import blitz examinations found 1,728 unapproved drugs, including so-called "foreign versions" of FDA-approved drugs, recalled drugs, drugs requiring special storage conditions, drugs requiring close physician monitoring, and drugs containing addictive controlled substances.
The FDA has been examining trends in the illegal importation of unsafe drugs since 2001 when it undertook a blitz examination at a mail facility in California. The first joint FDA/CBP import blitz occurred in July and August 2003.
During the current blitz, the FDA and CBP inspectors examined a total of 1,982 parcels that appeared to contain drug products. The majority of the products found in the examined parcels were drugs. The parcels also contained other types of FDA-regulated products, such as dietary supplements and foods, as well as products not regulated by the FDA such as pens and notepads.
Parcels were examined irrespective of the country from which they were being exported. Canadian parcels appeared more frequently than parcels from any other country. Of the 1,006 parcels that entered through the mail facilities, the FDA determined that approximately 80% of the parcels were exported from Canada, approximately 16% from Mexico, and the remaining 4% were exported from Japan, the Netherlands, Taiwan, Thailand, and the United Kingdom.
The following examples are typical of the unapproved drug products found during the blitzes:
These findings provide additional evidence of the serious risks posed by the illegal importation of prescription drugs. Unapproved drugs lack assurances of safety, effectiveness, quality, and purity. Moreover, the FDA cannot assure the safety and efficacy of a drug product it has not reviewed and approved nor when the agency has not monitored the manufacturing and quality control processes of the facility in which the product was produced.
January 6, 2004
ST. LOUIS (MD Consult) - On January 2, 2004, the U.S. Food and Drug Administration (FDA) announced that, in conjunction with Roche Laboratories, it was notifying health care professionals of new preclinical safety data that may have implications for the use of Tamiflu (oseltamivir phosphate) in very young children.
According to the FDA's Safety Alert, "Preclinical findings in juvenile rats have raised concerns regarding the use of Tamiflu in infants less than 1 year of age." When a single dose of 1,000 mg/kg oseltamivir phosphate (about 250 times the recommended dose in children) was administered to 7-day-old rats, deaths associated with levels of oseltamivir phosphate in the brain occurred approximately 1,500 times more than those seen in adult animals. It is likely that these high exposures are related to an immature blood-brain barrier.
The clinical significance of these preclinical data to human infants is unclear. Given the uncertainty in predicting the exposures in infants with immature blood-brain barriers, it is recommended that Tamiflu not be administered to children younger than 1 year, the age at which the human blood-brain barrier is generally recognized to be fully developed.
According to a December 2003 letter from Roche Laboratories addressed to health care professionals, the Centers for Disease Control and Prevention (CDC) estimates that the serious complications of influenza, including pneumonia, commonly hospitalize approximately 114,000 people annually in the United States. Some health experts estimate the death toll from the 2003-2004 influenza outbreak will exceed the annual average of 36,000 people. "Of particular concern," says the Roche letter, "is that at least 42 children under age 18 have died so far this season from illness attributed to influenza and its complications."
The early start of the influenza season this year, coupled with early reports of increased hospitalizations and deaths in children, has raised concern among parents and physicians about influenza this winter. However, Roche and the FDA stress that caution should be exercised. "Given the possible desire to treat very young children with Tamiflu during this active season," said Dominick Iacuzio, PhD, Medical Director at Roche Laboratories, "we wish at this time to emphasize the importance of using Tamiflu only for labeled indications and only in patients 1 year and older."
Tamiflu is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days. The medication is also indicated for the prophylaxis of influenza in adult patients and adolescents 13 years and older.
Roche asserts that the data from these clinical studies do not affect the use of Tamiflu in older children or in adults. In clinical trials, patients 1 year and older who were treated with Tamiflu within 2 days of symptom onset experienced a reduction in the duration of flu of about 1.5 days. Tamiflu is also effective is preventing the spread of influenza among close contacts in adolescents aged 13 years and older and in adults.
For additional information regarding Tamiflu, contact the Roche Pharmaceuticals Service Center at 800-526-6367.
The manufacturer requests that any adverse reactions to Tamiflu be reported to Roche Laboratories at 800-526-6367. In addition, adverse reactions should be reported to the FDA MedWatch program via fda.gov/medwatch or by mail to MedWatch, HF-2, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
January 6, 2004
ST. LOUIS (MD Consult) - On December 30, 2003, Secretary of Health and Human Services Tommy G. Thompson announced the U.S. Food and Drug Administration (FDA) had issued a consumer alert regarding the safety of dietary supplements containing ephedra and has notified manufacturers of its intent to publish a final rule on dietary supplements containing ephedrine alkaloids. The rule will state that dietary supplements containing ephedrine alkaloids present an unreasonable risk of illness or injury. The rule would have the effect of banning the sale of dietary supplements containing ephedrine alkaloids when it becomes effective, 60 days following publication, although it was not specified when the rule would be published.
"[The] FDA will publish a final rule as soon as possible that will formalize its conclusions that dietary supplements containing ephedrine alkaloids present unreasonable risks to those who take them for any reason," Secretary Thompson said. "Today's action puts companies on notice of our intentions, and it tells consumers that the time to stop using ephedra products is now."
"We are taking action today to notify Americans about the unreasonable risk of ephedra as currently marketed in dietary supplements," said FDA Commissioner Mark B. McClellan, MD, PhD. "By issuing these letters today, we're sending a strong and unambiguous signal about the safety of dietary supplement products containing ephedrine alkaloids. Consumers should stop buying and using ephedra products right away, and [the] FDA will make sure consumers are protected by removing these products from the market as soon as the rule becomes effective."
According to the Federal Food, Drug, and Cosmetic Act, a dietary supplement product is adulterated if it or a dietary ingredient within it presents a significant or unreasonable risk of illness or injury under conditions of use suggested in the labeling or under ordinary conditions of use. Under the Dietary Supplement Health and Education Act of 1994, the FDA bears the burden of proof to show that a dietary supplement presents a significant or unreasonable risk to prevent it from being marketed; in contrast, for drugs that have similar pharmacologic properties to ephedra, manufacturers bear the burden of proof of showing that the drug is safe and effective before it can be marketed.
Ephedra, also called Ma huang, is a naturally occurring substance derived from plants. Its principal active ingredient is ephedrine, which, when chemically synthesized, is regulated as a drug. In recent years, ephedra products have been extensively promoted to aid weight loss, enhance sports performance, and increase energy.
The FDA's concerns about dietary supplements containing ephedra arise in part from ephedra's mechanism of action in the body. Ephedra is an adrenaline-like stimulant that can have potentially dangerous effects on the heart. The FDA's evaluation also reflects the available studies of the health effects of ephedra. This includes many studies reviewed by the RAND Corporation, which found little evidence for effectiveness other than for short-term weight loss, as well as evidence suggesting safety risks. Other recent studies have confirmed that ephedra use raises blood pressure and otherwise stresses the circulatory system, effects that have been conclusively linked to significant and substantial adverse health effects such as heart problems and strokes.
The FDA's notification reflects the agency's recent comprehensive evaluation of the science as well as a public comment period intended to cap years of debate about the risks and safety of ephedra in dietary supplements. In 1997, the FDA first proposed a rule on dietary supplements containing ephedra including requiring a warning statement on these products. The FDA modified this proposed rule in 2000, and in February 2003 the agency announced a series of comprehensive actions designed to protect Americans from the potentially serious risks of dietary supplements containing ephedra. To solicit comments on new evidence about ephedra as well as on a proposed warning statement, last February's actions included publishing a Federal Register notice outlining the FDA's concerns and reopening the comment period.
After publication of this notice, the FDA received and reviewed tens of thousands of comments. The agency has also reviewed a comprehensive RAND Corporation report on the data on ephedra and a series of adverse event reports it was unable to obtain more quickly because, under the Dietary Supplement Health and Education Act, such adverse event reports are not required to be submitted to the FDA.
"We are going to issue a rule that clarifies and applies a legal standard that that has never been used before. Using the challenging standard provided under the law, we have done all we can to make sure our regulatory action will succeed," said Dr. McClellan.
The FDA has sent 62 letters to firms marketing dietary supplements containing ephedra and ephedrine alkaloids alerting them of this future rule.
While working on the forthcoming rule, the FDA has been actively protecting the public health through a series of high-profile enforcement actions aimed at addressing the public health danger. Dietary supplement enforcement actions include inspections that resulted in voluntary compliance, voluntary recalls, warning letters, seizures and injunctions, criminal enforcement, and joint enforcement actions with the Federal Trade Commission and the Department of Justice. In conjunction with the FDA's actions to date, classes of ephedra products have already been removed from the market (for example, many products marketed for enhancing sports performance), the demand for ephedra products has declined significantly, and many companies have already ceased marketing. More detail on these actions can be found at fda.gov/ola/2003/dietarysupplements1028.html.
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