May 4, 2005 — The U.S. Food and Drug Administration approved in February revisions to safety labeling to advise that use of alosetron HCl has been associated rarely with serious gastrointestinal tract adverse events and concomitant administration of alosetron HCl and fluvoxamine is contraindicated; caspofungin acetate should be administered concomitantly with cyclosporine only in those patients for whom the potential benefit outweighs the potential risk of elevated liver enzyme levels; the atenolol component of atenolol-chlorthalidone tablets is associated with a risk of clinically significant bradycardia in neonates born to mothers receiving the fixed-dose combination drug at parturition or while breast-feeding.
On Feb. 18, the FDA approved revisions to the safety labeling for alosetron HCl tablets (Lotronex, made by GlaxoSmithKline) to advise of contraindications and warnings associated with its use.
Concomitant use of alosetron with fluvoxamine is contraindicated. Fluvoxamine is a known strong inhibitor of CYP1A2 that has been shown in clinical studies to increase mean alosetron plasma concentrations by approximately sixfold and prolong its half-life by approximately threefold.
The FDA warns that use of alosetron has been associated with infrequent reports of serious gastrointestinal tract adverse events such as ischemic colitis and complications of constipation. Some of these events have occurred without warning and have resulted in hospitalization, but rarely have resulted in blood transfusion, surgery, or death.
Serious complications of constipation, including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia, have been reported in alosetron clinical trials and during postapproval use. Intestinal surgery, including colectomy, has been required in some cases. Postmarketing reports have also included rare incidences of perforation and death.
In clinical trials, constipation-related adverse events resulted in a discontinuation rate of approximately 10% among alosetron recipients (overall incidence rate for patients is about 0.1%; 1 per 1,000 patients).
The FDA notes that the risk of serious complications of constipation may be increased in patients who are elderly, debilitated, or concurrently receiving medications that reduce gastrointestinal motility.
Alosetron therapy has also been associated with rare reports of ischemic colitis in clinical trials and during postapproval use.
In clinical trials, the cumulative incidence of ischemic colitis was 0.2% in women receiving alosetron for three months (2 per 1,000 patients; 95% confidence interval [CI], 1 - 3) and 0.3% after six months of therapy (3 per 1,000 patients; 95% CI, 1 - 4). According to the FDA, these data from controlled studies are insufficient to estimate the incidence of ischemic colitis in patients receiving alosetron therapy for longer than six months.
Alosetron is indicated for the treatment of chronic, severe, diarrhea-predominant irritable bowel syndrome in women who have not responded adequately to conventional therapy.
On Feb. 16, the FDA approved revisions to the safety labeling for caspofungin acetate injection (Cancidas, made by Merck & Company, Ltd.) to warn that caspofungin acetate should be administered concomitantly with cyclosporine only in those patients for whom the potential benefit outweighs the potential risk of elevated liver enzyme levels.
Transaminase elevations have been observed in clinical trials of caspofungin acetate plus cyclosporine therapy, in some cases resulting in patient withdrawal from the study.
Patients who develop abnormal liver enzyme levels during concomitant therapy should be monitored, and the risks and benefits of continuing therapy evaluated.
Caspofungin acetate infusion is indicated for the treatment of presumed fungal infection in neutropenic patients; candidemia and intra-abdominal abscesses, peritonitis, and pleural space infections caused by Candida; esophageal candidiasis; and invasive aspergillosis in patients who are refractory to or intolerant of other therapies.
On Feb. 9, the FDA approved revisions to the safety labeling for atenolol plus chlorthalidone tablets (Tenoretic, made by AstraZeneca Pharmaceuticals LP) to warn that the atenolol component is associated with a risk of clinically significant bradycardia in neonates born to mothers administered the combination drug at parturition or while breast-feeding.
The FDA notes that atenolol is secreted in human breast milk at a ratio of 1.5 to 6.8 relative to plasma concentration. Infants who are premature or have impaired renal function may be at increased risk of atenolol-related adverse events.
Atenolol plus chlorthalidone fixed-dose combination tablets are indicated for the treatment of hypertension.
Reviewed by Gary D. Vogin, MD
Medscape Medical News © 2005 Medscape
Cite this: Yael Waknine. FDA Safety Labeling Changes: Lotronex, Cancidas, Tenoretic - Medscape - May 04, 2005.