FDA approves extended-release oxycodone combo to deter abuse

Development of opioids with abuse-deterrent properties is one goal of FDA’s campaign against the national epidemic of opioid misuse and abuse. The combination tablet oxycodone hydrochloride and naloxone hydrochloride extended-release (ON-ER) (Targiniq ER; Purdue Pharma) is an opioid agonist and antagonist (2:1 ratio, respectively) approved by FDA on July 23, 2014, for treatment of severe pain. ON-ER is not approved for as-needed pain relief.

As an opioid analgesic with an abuse deterrent, ON-ER exhibits properties that can deter, but not entirely prevent, abuse through snorting or injection.

Efficacy

When crushed or snorted, the naloxone contained in ON-ER blocks the euphoric effects of oxycodone, making it less attractive to abusers than oxycodone alone. Naloxone has low bioavailability due to extensive first-pass metabolism. This low oral availability reduces any risk of antagonism to the opioid.

ON-ER was administered to 2,396 patients in controlled or open-label clinical studies. One-third (n=794) were treated for approximately six months, and 26% (n=621) were treated for approximately one year.

A prospective study of two age groups (19-44 vs. 65-77) assessed age effects of the pharmacokinetics of ON-ER. Compared to younger subjects, elderly subjects showed a higher steady-state oxycodone AUC (18% increase) and higher steady-state naloxone AUC (82% increase). Elderly patients should therefore be monitored more frequently until stable drug effects are achieved.

Safety

Several black-box warning accompany ON-ER: risks of addiction, abuse, and misuse; serious, life-threatening, or fatal respiratory depression; accidental ingestion by children, resulting in a fatal overdose; neonatal opioid withdrawal syndrome; and fatal overdose concentrations of oxycodone resulting from initiation or discontinuation of CYP3A4 inhibitors.

As with other opioids, the most common adverse reactions with ON-ER were nausea and vomiting. ON-ER, like all opioids, can cause severe hypotension, and concern should be given to patients with reduced blood volume or concurrent administration of certain CNS depressant drugs.

ON-ER is a pregnancy category C. Oxycodone is likely to be present in breast milk, but it is unknown whether naloxone is present. To use or initiate ON-ER in nursing mothers is not recommended. ON-ER is contraindicated in patients with a history of significant respiratory depression, acute or severe bronchial asthma, known or suspected paralytic ileus and gastrointestinal obstruction, known hypersensitivity to oxycodone or naloxone, or moderate to severe hepatic impairment.

FDA is requiring post-marketing studies to assess the deterrent features of ON-ER on the risk of abuse, as well as the serious risks of misuse, abuse, increased sensitivity to pain, addiction, overdose, and death associated with use beyond 12 weeks. ON-ER is part of the ER/LA Opioid Analgesics Risk Evaluation and Mitigation Stategy (REMS).

Dosing

ON-ER is supplied as 10 mg/5 mg, 20 mg/10 mg, and 40 mg/20 mg of oxycodone/naloxone, respectively, in 100-count bottles. Opioid-naïve and opioid intolerant patients should be initiated on 10 mg/5 mg tablets orally every 12 hours. There are no well-controlled clinical studies evaluating the safety and efficacy of dosing more often than every 12 hours.

Standard opioid equivalencies are appropriate for ON-ER, just as for plain oxycodone ER. The ON-ER package insert contains initial ON-ER dose targets based on total daily morphine equivalency doses, and also specific guidelines for methadone, transdermal fentanyl, and transdermal buprenorphine conversions.

ON-ER can be up-titrated from the current dose by increasing the dose 10 mg/5 mg every 12 hours every one to two days; however, doses above 80 mg/40 mg have not been studied sufficiently for safety and thus should not be exceeded.

ON-ER is contraindicated in patients with moderate and severe hepatic impairment, and the starting dose should be reduced by one-third to one-half the usual starting dose in patients with mild hepatic impairment. When patients with renal impairment use ON-ER, the initial dose should be reduced to one-half the usual starting dose and followed by close titration.

When opioid therapy is no longer warranted, the dose should be reduced gradually to prevent signs and symptoms of withdrawal.

ON-ER tablets should be swallowed intact, and not crushed, dissolved, or chewed, due to the risk of rapid release and absorption of a potentially fatal dose of oxycodone.

Kevin W. Chamberlinis associate clinical professor and assistant department head, Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Connecticut.