FDA Safety Changes: Zithromax, Frova, Lexiscan

Yael Waknine

May 13, 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.

May 13, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise that concomitant use of azithromycin may potentiate the effects of oral anticoagulants, frovatriptan succinate is linked to a risk for serotonin syndrome that is increased by coadministration of antidepressants, and regadenoson injection may cause heart block and hypotension in some patients.

Azithromycin May Potentiate the Effects of Oral Anticoagulants

The FDA approved class labeling changes for azithromycin tablets and oral suspension to advise of a potential drug interaction with warfarin. On February 27, the label for Zithromax (Pfizer, Inc) was updated.

Although data from a pharmacokinetic study of 22 healthy men taking a 5-day course of azithromycin did not support an interaction with subsequently administered warfarin, postmarketing reports suggest that azithromycin may potentiate the effects of oral anticoagulants.

The FDA advises careful monitoring of prothrombin time in warfarin-treated patients receiving a course of azithromycin.

Azithromycin is a macrolide antibiotic indicated for the treatment of nongonococcal urethritis and cervicitis as a result of Chlamydia trachomatis and for the prophylaxis and treatment of disseminated Mycobacterium avium complex disease.

Warfarin is an oral anticoagulant indicated for the prophylaxis and/or treatment of venous thromboembolism and pulmonary embolism; thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement; and to reduce the risk for death, recurrent myocardial infarction, and thromboembolic events after myocardial infarction.

Triptans Such as Frovatriptan Succinate (Frova) Linked to Risk for Serotonin Syndrome

The FDA approved class labeling changes for frovatriptan succinate tablets to provide updated information regarding the risk for potentially life-threatening serotonin syndrome in patients receiving treatment with 5-hydroxytryptamine receptor agonists (triptans). On March 3, the label for Frova (Endo Pharmaceuticals, Inc) was updated.

Although this reaction has occurred in patients receiving triptans alone, the risk for its occurrence is significantly increased by concomitant use of selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram) or serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine and duloxetine).

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).

The FDA advises close monitoring of SSRI- or SNRI-treated patients receiving triptans, particularly during initiation of therapy and dose increases.

Frovatriptan is indicated for the acute treatment of migraine with or without aura in adults.

Regadenoson (Lexiscan) Linked to Risks for Nodal Block and Hypotension in Some Patients

On March 17, the FDA approved safety labeling revisions for regadenoson injection (Lexiscan; Astellas Pharma US, Inc) to provide additional postmarketing information regarding the risks for sinoatrial (SA) and atrioventricular (AV) nodal block and hypotension.

Adenosine receptor agonists, including regadenoson, can depress SA and AV nodal function potentially leading to first-, second-, or third-degree AV block or sinus bradycardia requiring intervention, the FDA warned.

In clinical trials, the risk appeared to be low: 2015 patients (3%) had first-degree AV block (PR prolongation > 220 milliseconds) within 2 hours of regadenoson administration, and 1 patient (.05%) had transient second-degree AV block with 1 dropped beat. However, the FDA has since received postmarketing reports of third-degree heart block and asystole within minutes of regadenoson use.

Adenosine receptor agonists also induce arterial vasodilation and hypotension. In clinical trials of regadenoson, 7% and 4% of patients experienced decreased systolic (> 35 mm Hg) and diastolic (> 25 mm Hg) blood pressure, respectively, within 45 minutes of regadenoson administration.

The FDA notes that the risk for serious hypotension may be increased for patients with autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. In postmarketing experience, syncope and transient ischemic attacks have been observed.

Regadenoson is a pharmacologic stress agent indicated for radionucleotide myocardial perfusion imaging in patients unable to undergo an adequate exercise stress test.

Zithromax Prescribing Information

Frova Prescribing Information

Lexiscan Prescribing Information

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