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.