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

Vincent C. Badalamenti, PharmD; Jill W. Buckley, PharmD; Eric T. Smith, PharmD

doi:10.5055/jom.2012.0104

Authors

Vincent C. Badalamenti, PharmD
Jill W. Buckley, PharmD
Eric T. Smith, PharmD

DOI:

https://doi.org/10.5055/jom.2012.0104

Keywords:

abuse, adverse events, morphine, naltrexone, opioid, pain

Abstract

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.

Author Biographies

Vincent C. Badalamenti, PharmD

Director, Pharmacovigilance, Worldwide Safety and Regulatory Operations, Pfizer Inc, Cary, North Carolina.

Jill W. Buckley, PharmD

Senior Vice President, Drug Safety and Pharmacovigilance, Worldwide Safety Strategy, Pfizer Inc, Cary, North Carolina.

Eric T. Smith, PharmD

Senior Director, Risk Management and Safety Evaluation, Worldwide Safety Strategy, Pfizer Inc, Cary, North Carolina.

References

US Food and Drug Administration: EMBEDA, 2009. Drugs@FDA Web site. Available at www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search. DrugDetails. Accessed February 14, 2011.

King Pharmaceuticals®, Inc.: Embeda [package insert]. Bristol, TN: King Pharmaceuticals®, Inc., June 2009.

Katz N, Sun S, Johnson F, et al.: ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules in the treatment of chronic pain of osteoarthritis of the hip or knee: Pharmacokinetics, efficacy, and safety. J Pain. 2010; 11(4): 303-311.

Webster LR, Brewer R, Wang C, et al.: Long-term safety and efficacy of morphine sulfate and naltrexone hydrochloride extended release capsules, a novel formulation containing morphine and sequestered naltrexone, in patients with chronic, moderate to severe pain. J Pain Symptom Manage. 2010; 40(5): 734-746.

Johnson FK, Stark JG, Bieberdorf FA, et al.: Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: A single-dose, randomized-sequence, openlabel, three-way crossover trial in healthy volunteers. Clin Ther. 2010; 32(6): 1149-1164.

Stauffer J, Setnik B, Sokolowska M, et al.: Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: A randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009; 29(12): 777-790.

Compton WM, Volkow ND: Major increases in opioid analgesic abuse in the United States: Concerns and strategies. Drug Alcohol Depend. 2006; 81(2): 103-107.

US Food and Drug Administration: Background on opioid REMS, 2009. Available at www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm187975.htm. Accessed February 11, 2011.

US Food and Drug Administration: REMS and opioid analgesics webinar outline. Available at www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM163667.pdf. Accessed March 7, 2011.

Sloan P, Babul N: Extended-release opioids for the management of chronic non-malignant pain. Expert Opin Drug Deliv. 2006; 3(4): 489-497.

Kim D, Irwin KS, Khoshnood K: Expanded access to naloxone: Options for critical response to the epidemic of opioid overdose mortality. Am J Public Health. 2009; 99(3): 402-407.

US Food and Drug Administration: Current state of opioid drug approval, 2009. Available at www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm187976.htm. Accessed February 14, 2011.

Fudala PJ, Johnson RE: Development of opioid formulations with limited diversion and abuse potential. Drug Alcohol Depend. 2006; 83(Suppl 1): S40-S47.

Mendelson J, Jones RT: Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: Why the 4:1 ratio for treatment? Drug Alcohol Depend. 2003; 70(2 Suppl): S29-S37.

Strain EC, Stoller K, Walsh SL, et al.: Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl). 2000; 148(4): 374-383.

Weinhold LL, Preston KL, Farre M, et al.: Buprenorphine alone and in combination with naloxone in non-dependent humans. Drug Alcohol Depend. 1992; 30(3): 263-274.

Mallinckrodt Inc.: Naltrexone hydrochloride tables USP [package insert]. Hazelwood, MO: Mallinckrodt Inc., 2009.

Purdue Pharma L.P.: MS Contin [package insert]. Stamford, CT: Purdue Pharma L.P., 2009.

IMS Health: 2009. Available at www.imshealth.com/portal/site/imshealth. Accessed September 1, 2009.

Wesson DR, Ling W: The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003; 35(2): 253-259.

Ruan X, Chen T, Gudin J, et al.: Acute opioid withdrawal precipitated by ingestion of crushed Embeda (morphine extended release with sequestered naltrexone): Case report and the focused review of the literature. J Opioid Manag. 2010; 6(4): 300-303.

Jang DH, Robe JC, Hoffman RS: Severe opioid withdrawal due to misuse of new combined morphine and naltrexone product (Embeda). Ann Emerg Med. 2010; 55(3): 303-304.

American Psychiatric Association: 292.0 opioid withdrawal. In Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text rev. Washington, DC: American Psychiatric Association, 2000: 272-273.