FDA Safety Changes: Sarafem, Mavik, Cordarone

Yael Waknine

June 17, 2009

This activity is part of an ongoing CME/CE initiative to provide information on labeling changes reported by the FDA. Activities of this nature will be posted on Medscape on a weekly basis.

June 17, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to provide updated information regarding drug interactions that raise the risk for serotonin syndrome in patients receiving treatment with fluoxetine HCl, drug interactions between angiotensin-converting enzyme inhibitors and injectable gold therapy, and drug interactions between amiodarone HCl and certain 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors.

Additional Agents Implicated in Fluoxetine HCl Risk for Serotonin Syndrome

The FDA approved class labeling safety labeling changes for fluoxetine HCl to provide updated information regarding drug interactions that increase the risk for serotonin-related adverse events in patients receiving treatment with selective serotonin-reuptake inhibitors (SSRIs) such as fluoxetine. This information also applies to selective serotonin-norepinephrine reuptake inhibitors (SNRIs). On April 22, the label for Sarafem tablets (Warner Chilcott Co, Inc) was updated.

The agency previously warned of the risk for potentially life-threatening serotonin syndrome in patients receiving 5-hydroxytryptamine receptor agonists (triptans) in conjunction with SSRIs or SNRIs.

An expanded section now warns that serotonin syndrome or neuroleptic malignant syndrome (NMS)–like reactions can occur with use of SSRIs alone but are more likely with concomitant use of serotonergic drugs (including triptans), agents that impair serotonin metabolism (including monoamine oxidase inhibitors [MAOIs]), or with antipsychotics and other dopamine antagonists.

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). Severe cases can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

Clinicians are reminded that concomitant treatment of depression with MAOIs and SSRIs is contraindicated. SSRI-treated patients receiving triptans should be observed closely, particularly during initiation of therapy, dose increases, or the addition of another serotonergic drug.

Concomitant use of SSRIs with serotonin precursors (eg, tryptophan) is not recommended. Treatment with SSRIs and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately in patients in whom symptoms of serotonin syndrome develop.

Fluoxetine tablets, when marketed as Sarafem, are indicated for the treatment of premenstrual dysphoric disorder.

ACE Inhibitor Drug Interaction With Injectable Gold Linked to Nitritoid Reactions

The FDA approved class safety labeling revisions for trandolapril and other angiotensin-converting enzyme (ACE) inhibitors to warn of drug interactions with injectable gold. On April 8, the label for Mavik tablets (Abbott Laboratories, Inc) was updated.

According to the FDA, nitritoid reactions have been reported rarely in patients receiving concomitant treatment with injectable gold (sodium aurothiomalate) and ACE inhibitors. Symptoms may include facial flushing, nausea, vomiting, and hypotension.

Intramuscular gold therapy is used to treat rheumatic diseases such as rheumatoid and psoriatic arthritis and is generally reserved for patients who show evidence of continued or additional disease activity despite conservative drug therapy with salicylates or other anti-inflammatory agents.

Trandolapril is indicated for the treatment of hypertension and to decrease the risk for cardiovascular death in stable patients with evidence of left ventricular systolic dysfunction or who are symptomatic from congestive heart failure within the first few days after sustaining a myocardial infarction.

Amiodarone HCl (Cordarone) Therapy May Necessitate Lower Doses of Certain Statins

On April 21, the FDA approved safety labeling revisions for amiodarone HCl (Cordarone tablets; Wyeth Pharmaceuticals, Inc) to advise of recommended dosing adjustments when administering certain 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, also known as "statins."

Statins are linked to an exposure-related risk for myopathy that presents as muscle pain, tenderness, or weakness, with elevated creatine kinase levels greater than 10 times the upper limit of normal. Myopathy may also take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, with a potential for fatal outcome.

The FDA warns that amiodarone is an inhibitor of the hepatic cytochrome P450 isoenzyme 3A4 (CYP 3A4), and coadministration of HMG-CoA reductase inhibitors that are CYP 3A4 substrates (eg, simvastatin and atorvastatin) may lead to elevated statin plasma levels and related toxicity. Because of the potential for myopathy/rhabdomyolysis, lower starting and maintenance doses for these agents should be considered.

Amiodarone is a class 3 antiarrhythmic agent indicated for the treatment of recurrent ventricular fibrillation or hemodynamically unstable ventricular tachycardia that has not responded to adequate doses of other available antiarrhythmics or when alternative agents are not tolerated.

HMG-CoA reductase inhibitors are indicated for the treatment of dyslipidemias in patients with or at risk for cardiovascular disease.

Sarafem Prescribing Information

Mavik Prescribing Information

Cordarone Prescribing Information


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