Selected Significant Drug Safety Summaries: August 2000 to August 2001

Product

Safety Issue

Amiodarone (Cordarone)

March 2001: Wyeth Ayerst notified health professionals regarding revisions in the product labeling regarding the leaching out of plasticizers, such as DEHP (di-(2-ethylhexyl)phthalate) from intravenous tubing. Concerns surround the exposure to DEHP and possible adverse effects on the male reproductive tract development if exposed during fetal, infant and toddler stages. Thus, the use of this product is limited to lower doses in pediatric patients. In addition, clinicians were notified of possible effects of neonatal exposure to benzyl alcohol, a preservative found in intravenous amiodarone. (posted on FDA home page in June 2001)
Manufacturer Letter: http://www.fda.gov/medwatch/safety/2001/safety01.htm#cordar

Aresenic Trioxide (Trisenox)

March 2001: Cell Therapeutics notified health professionals regarding a recent publication in Blood (March 2001; 97:1514-16) regarding QT prolongation and torsade de pointes associated with the use of arsenic trioxide in the treatment of acute myeloid leukemia. These cases led to revisions in the package insert, including boxed warnings regarding the importance of ECG monitoring and electrolyte monitoring during arsenic trioxide therapy.
Manufacturer’s Letter: http://www.fda.gov/medwatch/safety/2001/safety01.htm#trisen

Aristolochic Acid Herbal Products

April 2001: FDA published a Consumer Advisory and updated industry and health professionals regarding dietary supplements and botanical products that may contain aristolochic acid. Aristolochic acid has been associated with nephropathy leading to end stage renal disease and with urological malignancies. Urothelial carcinomas have also been reported in patients with "Chinese herb nephropathy". A list of botanicals containing these products was provided.
FDA Consumer Advisory: http://www.cfsan.fda.gov/%7Edms/addsbot.html
FDA Letter to Health Professionals: http://www.cfsan.fda.gov/%7Edms/ds-botl3.html
Botanical List: http://www.cfsan.fda.gov/~dms/ds-bot2.html
FDA Letter to Industry: http://www.cfsan.fda.gov/%7Edms/ds-botl4.html
FDA Center for Food Safety and Applied Nutrition (CFSAN) Aristolochic Acid web page:http://www.cfsan.fda.gov/%7Edms/ds-bot.html

November 2000: Roche Laboratories informed helath professionals regarding safety related changes to the product information, specifically to contraindicate the use of this product in patients with severe renal impairment (CrCl < 30 mL/min). In addition, in patients with mild renal impairment (CrCl: 30 to 50 mL/min) the dose of capecitabine should be reduced to 75% of the recommended starting dose.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/2000/safety00.htm#xeloda

June 2001: Bayer Corporation notified health professionals regarding changes in the prescribing information of cerivastatin based on an increased incidence of reports of muscle weakness and rhabdomyolysis during post-marketing surveillance. The starting dose of 0.4 mg daily was emphasized with a notice that starting doses above this range increased the risk of myopathy and rhabdomyolysis. In addition, the combined use of cerivastatin and gemfibrozil has a contraindication was re-emphasized.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/2001/baycol.htm

August 2001: Bayer Corporation and the FDA notified health professionals regarding the withdrawal of cerivastatin from the United States market based on repeated reports of rhabdomyolysis when the drug was used alone and in combination with gemfibrozil. Fatal reports were received most frequently with higher doses, when used in elderly patients, and in combination with gemfibrozil.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/2001/Baycol2.htm
FDA Talk Paper: http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01095.html
Baycol Question & Answer Web Page: http://www.fda.gov/cder/drug/infopage/baycol/baycol-qa.htm

August 2000: The results of a recently completed clinical trial demonstrated that the 48-week virologic response of didanosine once daily was significantly lower than observed in the comparator arm. Therefore, the preferred dosing frequency of didanosine is twice-daily because there is more evidence to support the effectiveness of this dosing frequency.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2000/videx.htm

January 2001: Fatal lactic acidosis has been reported in pregnant women who received concurrent therapy with stavudine and didanosine during pregnancy. Both manufacturers of these products recommend caution when prescribing these agents during pregnancy and only if benefit clearly outweighs the risk.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/zerit&videx_letter.htm
FDA Talk Paper: http://www.fda.gov/bbs/topics/ANSWERS/ANS01063.html

(Enbrel)

October 2000: The FDA and Immunex notified health professional regarding recent postmarketing reports of CNS and hematological disorders in patients receiving etanercept. Specific events included multiple sclerosis, myelitis, optic neuritis, aplastic anemia, and pancytopenia. Hematological events have occurred as early as 2 weeks after therapy was initiated. Clinicians should use caution when prescribing this agent in patients with recent onset or pre-existing CNS demyelinating disorders. If symptoms of blood dyscrasias develop, patients are advised to seek immediate medical attention.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/2000/enbrel2.htm

Famotidine (Pepcid)

March 2001: Health professionals were notified that dosage adjustments are now recommended with famotidine use in patients with moderate to severe renal impairment (CrCl: < 50 mL/min). Previous recommendations were for severe renal failure only.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/pepcid_summary.htm

Filgrastim (Neupogen)

May 2001: Health professionals were alerted to possible counterfeit product labeled as Neupogen 300 mcg vials. These products were clear liquid but possessed no active ingredient. Lot numbers included P000948, P000954, P000992 or P000890. More information on other characteristics associated with counterfeit products can be found on the manufacturer's website.
Manufacturer's Letter: http://www.amgen.com/news/news01/release010510.html

January 2001: Roche laboratories announced the release of new medication guide for Accutane and an informed consent form for all Accutane patients. These documents were sent to all physicians and pharmacists to further communicate the risks associated with isotretinoin use. The medication guide summarizes all major adverse events associated with the drug in the package inset and is mandated for use with all patients receiving the drug.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/2001/accutane.htm
Medication Guide for Accutane:  http://www.fda.gov/cder/drug/infopage/accutane/medicationguide.htm
Accutane Informed Consent/Patient Agreement: http://www.fda.gov/cder/drug/infopage/accutane/consent.htm

Itraconazole (Sporanox)

May 2001: Janssen Pharmaceuticals notified health professionals of revised safety labeling for itraconazole. Specifically, the drug should not be administered to patients with active or prior ventricular dysfunction (i.e., CHF). If symptoms of CHF occur during therapy, the drug should be discontinued. Other revisions in the package labeling include a contraindication for use of itraconazole with dofetilide, a precaution for use with erythromycin, and modifications of the calcium channel blocker drug interaction statement. New labeling also recommends that healthcare providers obtain nail specimens for laboratory testing prior to prescribing the medications for onychomycosis to confirm the diagnosis.
Manufacturer’s Letter: http://www.fda.gov/medwatch/safety/2001/safety01.htm#sporan
FDA Talk Paper: http://www.fda.gov/bbs/topics/answers/2001/ans01083.html
FDA Question and Answer Paper: http://www.fda.gov/cder/drug/advisory/sporanox-lamisil/qa.htm
FDA Public Health Advisory: http://www.fda.gov/cder/drug/advisory/sporanox-lamisil/default.htm

Levomethadyl Acetate (ORLAAM)

April 2001: Roxanne Laboratories and the FDA strengthened warnings to physicians regarding serious cardiac events associated with levomethadyl. Specific changes have included the contraindicated use of the drug in patients with known or suspected QT prolongation. In addition, a 12 lead ECG is warranted prior to initiation of therapy. Concurrent therapy with drugs known to prolong the QT interval or induce/inhibit the cytochrome P450 system are not recommended. Patients who exhibit symptoms suggestive of an arrhythmia (i.e., palpitations, dizziness, syncope) should seek medical attention immediately.
Manufacturer’s Letter: http://www.fda.gov/medwatch/safety/2001/safety01.htm#orlaam
FDA Talk Paper: http://www.fda.gov/medwatch/safety/2001/safety01.htm#orlaam

(Lithobid)

August 2000: A temporary reduction in the expiration dating for Lithobid was announced based on a shortage of raw material, lithium carbonate. This change in expiration dating reflects the period needed to gather longer term stability data. Prescribers are advised to limit prescription to no more than 30 days, and to consider alternate medications and/or other formulations of the drug.
Manufacturer’s Letter: http://www.fda.gov/medwatch/safety/2000/lithob.htm

(Zyvox)

March 2001: Pharmacia notified health professionals regarding new additions to the warning section of the package insert. Specific warnings, based on postmarketing reports, included the risk of myelosuppression (i.e., anemia, leukopenia, pancytopenia). Weekly complete blood cell counts are recommended, particularly in patients receiving linezolid for greater than two weeks.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/safety01.htm#zyvox

Mesoridazine (Serentil)

September 2000: Novartis Pharmaceuticals advised health professionals of safety labeling changes including a new boxed warning about mesoridazine associated QT prolongation and contraindicated use with other drugs known to prolong the QT interval. Based on a recently published study, mesoridazine is now indicated only in schizophrenics unresponsive to other antipsychotics. Baseline ECG and serum potassium monitoring are recommended prior to the initiation of therapy.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2000/serent.htm

Miconazole (Intravaginal)

February 2001: The FDA recommended a new warning in the OTC labeling of vaginal miconazole products regarding a probable interaction with warfarin. This revision was based on two adverse reports in women who developed prolonged prothrombin times after concurrent therapy with intravaginal miconazole products and warfarin for two to three days. One patient also developed bruising, gingival bleeding and a nosebleed.
FDA Science Background Paper: http://www.fda.gov/cder/drug/infopage/miconazole/default.htm
FDA Talk Paper: http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01071.html

Nevirapine (Virammune)

November 2000: Based on postmarketing surveillance reports, the risk of serious and fatal hepatotoxicity was added to package labeling of nevirapine, Because most serious hepatic events occurred during the first 12 weeks, intensive clinical and laboratory monitoring , including liver function tests are recommended during this period. Periodic testing is also recommended thereafter.
Manufacturer’s Letter: http://www.fda.gov/medwatch/safety/2000/viramune.htm
Patient Information: http://www.fda.gov/medwatch/safety/2000/safety00.htm#viramu

Oprelvekin (Neumega)

August 2001: Data from a small safety and kinetic study in children identified papilledema as a dose limiting adverse reaction (100 mcg/kg/day). The manufacturer recommended that the use of oprelvekin in children, particularly those less than 12 yrs, should be restricted to controlled clinical trial settings with close safety monitoring.
Manufacturer’s Letter: http://www.fda.gov/medwatch/safety/2001/neumega.htm

Oxycodone (Oxycontin)

July 2001: Based on numerous reports of misuse and diversion in the United States, the manufacturer revised the warning section of package labeling to emphasize the potential for this problem and to reinforce information regarding appropriate dosing and patient population.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/oxycontin.htm
FDA Talk Paper: http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01091.html
FDA Question and Answers Page: http://www.fda.gov/cder/drug/infopage/oxycontin/oxycontin-qa.htm

Phenylpropanolamine (Various)

November 2000: The FDA encouraged the removal of phenylpropanolamine (PPA) from all drug products, particularly OTC cold/cough and weight loss formulations based on a study demonstrating an increased risk of hemorraghic stroke.
FDA Public Health Advisory: http://www.fda.gov/cder/drug/infopage/ppa/default.htm

Propofol (Diprivan)

March 2001: A recent controlled trial in pediatric ICU patients demonstrated an increase in mortality rate when the drug was used for sedation (initial dose: 5.5 mg/kg/hr). The manufacturer reminded health care professionals that propofol is not FDA approved for this indication in the united States.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/safety01.htm#dipriv

Rapacuronium (Raplon)

March 2001: Rapacuronium was withdrawn from the US market based on increased postmarketing surveillance reports of severe bronchospasm.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/raplon_DDL.htm
FDA Talk Paper: http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01072.html

Rivastigamine (Exelon)

January 2001: Clinicians were informed that in patients who have temporarily stopped rivastigamine, dosing should be restarted at the lowest daily dose and titrated back to maintenance dosing. This change in dosing recommendations is based on reports of severe vomiting with esophageal rupture after reinitiation of therapy at a high dose (4.5 mg) after an interruption of therapy for eight weeks.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/exelon.htm

Somatropin (Serostim)

January and May 2001: Counterfeit material made to resemble somatropin (rDNA origin) bears the lot number MNH605A. Patients or health care professionals obtaining such product should report it to the manufacturer (Serono).
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/serostim.htm
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/sero_faked.htm

(Zerit)

January 2001: Fatal lactic acidosis has been reported in pregnant women who received concurrent therapy with stavudine and didanosine during pregnancy. Both manufacturers of these products recommend caution when prescribing these agents during pregnancy and only if benefit clearly outweighs the risk.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/zerit&videx_letter.htm
FDA Talk Paper: http://www.fda.gov/bbs/topics/ANSWERS/ANS01063.html

Terbinafine (Lamisil)

May 2001: Health professionals were notified of new safety data regarding rare cases of severe and fatal hepatic failure associated with oral terbinafine use. This product should not be used in patients with chronic or active liver disease and baseline liver function tests should be performed prior to initiation of therapy. In addition, in vitro testing has demonstrated that terbinafine inhibits CYP 2D6 mediated metabolism. Prescribing and dispensing errors have also occurred with this agent and lamotrigine (Lamictal).
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2001/safety01.htm#sporan
FDA Talk Paper: http://www.fda.gov/bbs/topics/answers/2001/ans01083.html
FDA Question and Answer Paper: http://www.fda.gov/cder/drug/advisory/sporanox-lamisil/qa.htm
FDA Public Health Advisory: http://www.fda.gov/cder/drug/advisory/sporanox-lamisil/default.htm

(Triax Metabolic Accelerator)

November 2000: The FDA warned against consuming dietary supplements containing titraticol, also known as triiodothyroacetic acid. This product is a potent thyroid hormone and has been associated with serious adverse events, including heart attacks and stroke.
FDA Talk Paper: http://www.fda.gov/bbs/topics/ANSWERS/ANS01057.html

Zafirlukast (Accolate)

September 2000: Astra Zeneca notified health care professionals of more specific patient management instructions in the event of hepatic dysfunction in the package labeling of zafirlukast. Drug therapy should be discontinued and liver function testing started immediately. In addition, reports of arthralgia and myalgia were added to the adverse drug reactions section.
Manufacturer's Letter: http://www.fda.gov/medwatch/safety/2000/accola.htm