Safety of EMBEDA® (morphine sulfate and naltrexone hydrochloride) extended-release capsules: Review of postmarketing adverse events during the first year

Background: EMBEDA® (morphine sulfate and naltrexone hydrochloride) extended-release capsules, indicated for management of chronic, moderate-tosevere pain, contain pellets of morphine sulfate with a core of sequestered naltrexone, an opioid antagonist.Objective: To review postmarketing adverse event (AE) reports received during first year following approval.Methods: All postmarketing AEs reported to the manufacturer were reviewed.Results: During the reporting period, ~97,000 prescriptions for EMBEDA were dispensed. One hundred eighty-two case reports containing 429 events were reviewed; 33 (18 percent) were reported as serious and 149 (82 percent), as nonserious. Of 429 AEs reported, the most common were drug ineffective (7 percent), headache (6 percent), drug withdrawal syndrome (6 percent), and nausea (4 percent). Seven cases involved oral overdose; of these, two suicide attempts resulted in fatalities. Product tampering was confirmed in six cases; suspected in five. No cases of confirmed tampering resulted in fatality; none resulted in symptoms typically associated with opioid overdose. Three were associated with opioid withdrawal symptoms, suggesting that naltrexone released during tampering potentially blocked the opioid effects. Twenty-five cases involving reported withdrawal or symptoms of withdrawal were reviewed; most were associated with dose interruption, capsule manipulation, history of drug abuse, or intolerance to a new opioid regimen.Conclusions: Results suggest that the safety profile of EMBEDA is consistent with that of an extended-release morphine formulation. Reports of exposure to tampered product yielded either withdrawal reactions or events not typical of opioid abuse. The clinical effects of EMBEDA in the context of misuse and abuse require further clinical and epidemiological exploration.