Faster-Acting Film-Coated Trecator to Replace Sugar-Coated Formulation

Yael Waknine

Disclosures

March 25, 2005

March 25, 2005 — The U.S. Food and Drug Administration (FDA) and Wyeth Pharmaceuticals, Inc, have advised healthcare professionals via letter that the new film-coated formulation of ethionamide tablets (Trecator) has a pharmacokinetic profile differing from that of the sugar-coated tablets (Trecator-SC) it will be replacing, according to an alert sent yesterday from MedWatch, the FDA's safety information and adverse event reporting program.

The film-coated tablets were formulated for increased stability and are more rapidly absorbed, resulting in higher peak concentrations (C max) of ethionamide that may potentially lead to patient intolerance when therapy is initiated at doses used for the sugar-coated tablets.

A study of 40 healthy volunteers demonstrated that although administration of 250-mg tablets yielded similar mean ethionamide area under the curve (7.67 vs 6.59 µg · hour/mL), the mean C max was significantly increased (about 46%), and the median time to C max (T max) significantly decreased for the film-coated tablets compared with the sugar-coated formulation (2.16 vs 1.48 µg/mL and 1.02 vs 1.49 hours, respectively).

Due to this pharmacokinetic difference, the FDA recommends careful monitoring of patients and dose retitration when switching from the sugar-coated to the film-coated tablet formulation.

The recommended adult dose of ethionamide is 15 to 20 mg/kg per day to be administered in divided doses for patients with poor gastrointestinal tract tolerance. The initial 250-mg dose should be titrated upwards gradually and as tolerated to a patient's optimal dose, not exceeding a 1 g daily total.

The initial regimen suggested for the sugar-coated tablet (250 mg/day for one to two days, followed by 250 mg twice daily for one to two days, with subsequent increase to 1 g in three or four divided doses), has not been studied for use with the film-coated formulation.

The FDA notes that ethionamide is primarily indicated for use in combination with other drugs to treat isoniazid- or rifampin-resistant active tuberculosis infection; its use as monotherapy results in rapidly developed resistance to the drug.

The most common adverse events are gastrointestinal tract disturbances, including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, and weight loss. These events appear to be dose related, with approximately 50% of patients unable to tolerate 1 g as a single dose. To minimize their occurrence, dosage reduction, alteration of ethionamide administration times, or concurrent administration of an antiemetic agent are advised.

Nervous system adverse events reported with ethionamide therapy include psychotic disturbances (including mental depression), drowsiness, dizziness, restlessness, headache, and postural hypotension. Peripheral neuritis, optic neuritis, diplopia, blurred vision, and a pellagra-like syndrome also rarely have been reported. The FDA recommends concurrent administration of pyridoxine to prevent or relieve neurotoxic effects.

Hepatic adverse events include transient increases in serum bilirubin, aspartate aminotransferase, alanine aminotransferase, and hepatitis (with or without jaundice). Rare incidences of hypersensitivity reactions (including rash), photosensitivity, thrombocytopenia, and purpura have been reported; hypoglycemia, gynecomastia, impotence, and acne have also occurred.

Use of ethionamide is contraindicated in patients with severe hepatic impairment and in patients who are hypersensitive to the drug. The FDA notes that the treatment of patients with diabetes mellitus may become more difficult with ethionamide therapy due to the potential for hypoglycemic effects.

Further information regarding film-coated ethionamide tablets may be obtained by calling Wyeth Pharmaceuticals, Inc, Product Information at 1-800-934-5556.

Adverse events related to use of ethionamide tablets should be reported to the FDA's MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.

Reviewed by Gary D. Vogin, MD

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