FDA Safety Changes: Toprol XL, Revlimid, Fludara

Yael Waknine

April 16, 2009

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April 15, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to provide recommendations for extended-release metoprolol therapy in the setting of pheochromocytoma, lenalidomide dose adjustments for patients with renal impairment, and warnings regarding the risk for central nervous system toxicity with recommended doses of fludarabine.

Extended-Release Metoprolol ( Toprol-XL) Must Be Combined With Alpha-Blocker in Pheochromocytoma

On February 12, the FDA approved safety labeling revisions for metoprolol succinate (Toprol-XL extended-release tablets; AstraZeneca LP) to provide recommendations regarding its use in the setting of pheochromocytoma.

Patients diagnosed with pheochromocytoma should only receive extended-release metoprolol in combination with an alpha-blocker and only after alpha-blocker therapy has been initiated. Administration of beta-blockers alone in this setting has been linked to a paradoxic increase in blood pressure because of the attenuation of beta-mediated vasodilation in skeletal muscle.

Metoprolol is a beta 1-selective (cardioselective) adrenoceptor-blocking agent indicated for the treatment of hypertension; angina pectoris; and stable, symptomatic heart failure of ischemic, hypertensive, or cardiomyopathic origin.

A pheochromocytoma is a neuroendocrine tumor that usually grows within the adrenal glands and causes overproduction of catecholamines, resulting in sympathetic nervous system hyperactivity. Signs and symptoms include elevated blood pressure and heart rate, orthostatic hypotension, palpitations, anxiety, diaphoresis, headaches, pallor, and weight loss.

Lenalidomide ( Revlimid) Dose Adjustments Required for Renal Impairment

On February 23, the FDA approved safety labeling revisions for lenalidomide capsules (Revlimid; Celgene Corp) to provide strengthened recommendations regarding dose adjustments for patients with renal impairment.

Because lenalidomide is primarily excreted unchanged by the kidney, dose adjustments are recommended to provide appropriate drug exposure for patients with moderate or severe renal impairment and for those receiving dialysis. The following recommendations were derived from a pharmacokinetic study of patients with renal impairment from nonmalignant conditions.

The recommended starting dose of lenalidomide for myelodysplastic syndromes is 10 mg daily. Patients with moderate renal impairment (30 mL/minute ≤ creatinine clearance [CrCl] < 60 mL/minute) should receive a reduced dose of 5 mg every 24 hours, those with severe renal impairment (CrCl < 30 mL/minute) should receive 5 mg with an extended dosing interval of 48 hours, and patients with end-stage renal disease should be started on a 5-mg dose given 3 times weekly after dialysis.

For patients with multiple myeloma, the normal starting dose of lenalidomide is 25 mg/day on days 1 to 21 of repeated 28-day cycles. The dose should be adjusted downwards to 10 mg every 24 hours for patients with moderate renal impairment, 15 mg every 48 hours for those with severe renal impairment, and 5 mg daily for patients with end-stage renal disease (given after dialysis on dialysis days).

The FDA notes that nondialysis patients with a CrCl of less than 11 mL/minute and dialysis patients with a CrCl of less than 7 mL/minute have not been studied. For all patients, dose interruptions are warranted for treatment-emergent thrombocytopenia and neutropenia.

Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. It is indicated for the treatment of transfusion-dependent anemia from low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without other cytogenetic abnormalities and in combination with dexamethasone for the second-line treatment of multiple myeloma.

Fludarabine Phosphate Infusion ( Fludara) Linked to Risk for Neurotoxicity

On February 10, the FDA approved safety labeling revisions for fludarabine phosphate intravenous infusion (Fludara; Bayer HealthCare Pharmaceuticals, Inc) to warn of the risk for central nervous system (CNS) toxicity.

The FDA previously warned of the dose-dependent toxic effects associated with fludarabine therapy. Dose levels approximately 4 times that recommended for chronic lymphocytic leukemia (CLL; 96 mg/m2/day for 5 - 7 days vs 25 mg/m2/day for 5 days) were linked to the development of a syndrome characterized by delayed blindness, coma, and death that appeared from 21 to 60 days after the last dose in 13 (36%) of 36 clinical study patients.

The FDA now warns that similar severe CNS toxicity has been reported in patients with CLL receiving doses within the recommended range. Symptoms have included coma, seizures, agitation, and confusion.

The agency notes that the effects of long-term fludarabine therapy on the CNS remain unclear, and some patients have received the recommended dose for up to 15 weeks of therapy.

Fludarabine is a fluorinated nucleoside analogue of the antiviral agent vidarabine. It is indicated for the treatment of adult patients with refractory B-cell CLL whose disease has not responded to or has progressed during treatment with at least 1 standard alkylating-agent–containing regimen.

Toprol-XL Prescribing Information

Revlimid Prescribing Information

Fludara Prescribing Information

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