Withdrawal of Troglitazone and Cisapride

The FDA wishes to inform physicians of the removal from the market of troglitazone (Rezulin, Parke-Davis/Warner-Lambert Co, Morris Plains, NJ), a treatment for type 2 diabetes mellitus, and cisapride (Propulsid, Janssen Pharmaceutica Inc, Titusville, NJ), a treatment for severe heartburn.

Troglitazone has been associated with rare but severe liver toxicity since 1997, and close monitoring of liver function of patients using the drug was recommended. A year ago, when it was the only drug of an important class, an FDA advisory committee recommended that troglitazone continue to be available for patients whose disease was not well-controlled by other medications, on the grounds that its benefit to the great majority of patients far outweighed the risk.

The FDA concurred while awaiting postmarketing experience with two subsequently approved drugs for type 2 diabetes mellitus, rosiglitazone (Avandia, SmithKline Beecham Pharmaceuticals, Philadelphia) and pioglitazone (Actos, Takeda Pharmaceuticals America Inc and Eli Lilly, Indianapolis). When these drugs showed the same benefits to patients as troglitazone, apparently without the same level of toxicity, the FDA asked that troglitazone be removed from the market.

The FDA plans to discuss this decision on May 19, at the next meeting of the endocrine and metabolic drugs advisory committee. For the time and place, see the FDA Web site at http://www.fda.gov/po/upcoming.html or call Kathleen Reedy at (301) 827-7001.

Cisapride has been associated with at least 341 reports of heart rhythm abnormalities, including 80 deaths. Most of these events occurred in patients who were taking other medications or who had underlying conditions known to increase the risk of cardiac arrhythmia.

Therefore, the company will stop marketing cisapride in the United States as of July 14, 2000. It will continue to make the drug available to patients who meet specific eligibility criteria for a limited-access protocol. Physicians who believe their patients may qualify for access to cisapride under this protocol are encouraged to contact the manufacturer at (800) JANSSEN.

The FDA has licensed the first pneumococcal vaccine for use in infants and toddlers. The 7-valent, polysaccharide-protein conjugate vaccine (Prevnar, Wyeth Lederle Vaccines, Philadelphia) was approved for active immunization of infants and toddlers against invasive disease (meningitis and bacteremia) caused by Streptococcus pneumoniae. The capsular serotypes contained in the conjugate vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F) cause approximately 80% of invasive disease in children under age 6 years in the United States. The routine schedule is a four-dose series of 0.5 mL beginning at age 2 months.

The efficacy of Prevnar was assessed in a prospective, double-blind clinical trial with approximately 38,000 children who were randomized (1:1) to receive Prevnar or the control vaccine (an investigational meningococcal group C conjugate vaccine [MnCC]) at 2, 4, 6, and 12 through 15 months of age. Routinely recommended vaccines were also administered. Among fully vaccinated children, 17 cases of invasive disease were identified in the controls vs 0 cases in the Prevnar group.

The safety of Prevnar was evaluated in five clinical studies, in which 18,168 infants and children received 58,699 doses of vaccine at 2, 4, 6, and 12 through 15 months of age. In the large efficacy study, local and systemic reactions occurring within 48 hours of a vaccine dose were monitored for approximately 4500 children who received Prevnar. The entire study cohort was evaluated for 30 days postvaccination to determine the rates of relatively rare events requiring emergency department visits and for 60 days to determine events requiring hospitalization.

Although most local and systemic reactions were reported with similar frequency for both groups, the rates of fever (>38°C) among Prevnar recipients were 15% to 34% vs 9% to 24% for MnCC recipients, and the rates of irritability within 48 hours of a vaccine dose were 44% to 65% for the Prevnar group vs 43% to 60% for the MnCC group.

The FDA has announced that Clinipad Corp of Rocky Hill, Conn, is voluntarily recalling antiseptic sterile skin preparations because of confirmed bacterial contamination in some lots.

The recall of the Clinipad sterile products includes povidone iodine, tincture of iodine, benzoin tincture, acetone alcohol and alcohol antiseptic products, and Sterile Cliniguard Protective Dressing manufactured since January 1, 1997. The recalled products have been distributed under the names Cliniswab, Clinipad, Clinidine, Cliniguard, EZ Prep, Steri Wipe, Cooper Instrument Corp, Moore Medial Corp, and Rauscher. All products with lot numbers beginning with 7, 8, 9, or 0, and labeled as "sterile" should be destroyed.

The FDA has posted at http://www.fda.gov/cber/infosheets.htm information on methods and products that may be used for arm preparation prior to the collection of blood and blood components. Additional information is at http://www.fda.gov/medwatch/safety/2000/safety00.htm.

Questions regarding this alert may be e-mailed to phann@cdrh.fda.gov, faxed to Marian Zellner at (301) 594-2968, or mailed to her at FDA, CDRH, HFZ-510, Piccard Dr, Rockville, MD 20850.

Written inquiries may be directed to Jane E. Henney, MD, Commissioner of Food and Drugs, HF-1, Room 14-71, 5600 Fishers Ln, Rockville, MD 20857.