FDA Safety Changes: Ultram, Ultracet, Sustiva, Kayexalate

Yael Waknine

October 28, 2009

October 28, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn of the risk for serotonin syndrome in patients receiving treatment with tramadol HCl, efavirenz drug interactions with hormonal contraceptives and certain immunosuppressants, and the potential for serious gastrointestinal tract events in patients receiving sodium polystyrene sulfonate oral suspension.

Tramadol (Ultram and Ultracet) Linked to Risk for Serotonin Syndrome

On September 9, the FDA approved safety labeling revisions for tramadol HCl (marketed alone and with acetaminophen as Ultram and Ultracet tablets by Ortho McNeil Pharmaceuticals), to warn of the potential risk for potentially life-threatening serotonin syndrome.

Serotonin syndrome may occur with use of tramadol alone but particularly in combination with use of serotonergic drugs such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and triptans; drugs that inhibit serotonin metabolism, including MAOIs; and drugs that impair the metabolism of tramadol, such as cytochrome P 450 isoenzyme 2D6 (CYP 2D6) and CYP 3A4 inhibitors. Adverse events may occur at the recommended tramadol dose, the FDA said.

Symptoms of serotonin syndrome may include mental status changes (eg, agitation, hallucinations, and coma), autonomic instability (eg, tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (eg, hyperreflexia and incoordination), and/or gastrointestinal tract symptoms (eg, nausea, vomiting, and diarrhea).

Tramadol is indicated for the management of moderate to moderately severe pain in adults. Administered as a combination tablet with acetaminophen, tramadol is indicated for the short-term (≤ 5 days) management of acute pain.

Efavirenz (Sustiva) May Decrease Contraceptive Efficacy

On September 23, the FDA approved safety labeling revisions for efavirenz capsules and tablets (Sustiva; Bristol-Myers Squibb Co) to warn of drug interactions with progestins and certain immunosuppressants.

Postmarketing cases of contraceptive failure have been reported with use of etonogestrel implants in efavirenz-treated patients, the FDA warned, noting that drug interactions may lead to decreased plasma concentrations of etonogestrel and other progestins such as those found in oral contraceptives (norelgestromin and levonorgestrel).

Because efavirenz may cause fetal harm (pregnancy category D), hormonal contraceptive measures must always be accompanied by a reliable method of barrier contraception.

Treatment with efavirenz may also decrease exposure to immunosuppressants metabolized by the hepatic cytochrome P450 isoenzyme 3A4 (CYP 3A4), such as cyclosporine, sirolimus, and tacrolimus. Dose adjustments may be required, and immunosuppressant concentrations should be monitored closely for at least 2 weeks when starting or stopping treatment with efavirenz.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Sodium Polystyrene (Kayexalate) Linked to Risk for Serious Gastrointestinal Tract Events

On September 2, the FDA approved safety labeling revisions for sodium polystyrene sulfonate powder for oral suspension (Kayexalate; sanofi-aventis US, Inc) to warn of the potential for serious gastrointestinal tract events.

Cases of colonic necrosis and other serious gastrointestinal tract adverse events (bleeding, ischemic colitis, and perforation) have been reported in association with use of sodium polystyrene, the majority occurring with concomitant use of sorbitol.

Many of the affected patients also had risk factors for gastrointestinal tract adverse events, including prematurity, history of intestinal disease or surgery, hypovolemia, and renal insufficiency or renal failure. Coadministration of sorbitol with sodium polystyrene is not recommended, the FDA said.

Sodium polystyrene is indicated for the treatment of hyperkalemia.

Sustiva Prescribing Information

Ultram Prescribing Information

Ultracet Prescribing Information

Kayexalate Prescribing Information

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