Pfizer Inc. has reported the results from three phase IV studies of EMBEDA (morphine sulfate and naltrexone hydrochloride) extended release capsules CII designed to assess the effect of the drug when crushed and taken either orally or intranasally.

Studies ALO-01-10-4005 and ALO-01-10-4004 were double-blind cross-over designed studies in non-dependent, recreational opioid users that compared subjective measures relating to abuse potential of crushed EMBEDA to crushed extended-release morphine sulfate and placebo following oral (study 4005) and intranasal (study 4004) administration. In both studies, the use of EMBEDA was associated with significantly (p<0.01)lower scores on the primary endpoints of “drug liking” and “high,” as well as the secondary endpoints including “good effects,” “overall drug liking” and “take drug again” as compared with extended-release morphine sulfate. Both medications had significantly higher scores on all measures as compared with placebo. Common adverse events observed following oral administration of crushed EMBEDA in study ALO-01-10-4005 included somnolence, nausea, pruritis and dizziness, and in study ALO-01-10-4004 following intranasal administration of crushed EMBEDA included euphoric mood, somnolence and headache.

The third study, ALO-01-09-111, was a double-blind cross-over study in opioid-dependent patients with moderate-to-severe non-cancer chronic pain stabilized on EMBEDA therapy. This study used an opioid withdrawal scale to assess the ability of a single dose of crushed EMBEDA to induce withdrawal symptoms compared with intact EMBEDA swallowed whole, as crushing releases the sequestered naltrexone. The trial was not fully enrolled as the study was discontinued early due to the voluntary recall of EMBEDA.

Only six patients completed the study, compared with a target of 12 to 16 patients. Ingestion of crushed EMBEDA induced signs and symptoms of withdrawal of at least moderate intensity in three of the six patients. The most common adverse events reported in the trial following administration of crushed EMBEDA were anxiety, tremor, yawning, nausea, restlessness, diarrhoea and flushing.

EMBEDA is approved by the US Food and Drug Administration (FDA) for the management of moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. It is NOT intended for use as a prn analgesic. EMBEDA contains pellets of an extended-release oral formulation of morphine sulphate, an opioid receptor agonist, with a sequestered core of naltrexone hydrochloride, an opioid receptor antagonist. Proper use requires EMBEDA to be swallowed whole or the contents of the capsules to be sprinkled on apple sauce.

The pellets in the capsules are not to be crushed, dissolved, or chewed before swallowing. Misuse or abuse of EMBEDA by tampering with the formulation by crushing or chewing the pellets causes the rapid release and absorption of both morphine and naltrexone. The resulting morphine dose may be fatal, particularly in opioid-naïve individuals. In opioid-tolerant individuals, the absorption of naltrexone may increase the risk of precipitating withdrawal. There is no evidence that the naltrexone in EMBEDA reduces the abuse liability of EMBEDA.

In March 2011, Pfizer voluntarily recalled from US wholesalers and retailers all dosage forms of EMBEDA because a pre-specified stability requirement was not met during routine testing. Pfizer has been continuing its efforts to address the stability requirement and reintroduce EMBEDA to the US market as quickly as possible. There are several key decision points during 2012 that will determine the necessary corrective action and associated timing.

EMBEDA (morphine sulfate and naltrexone hydrochloride) extended release capsules contain morphine, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid agonists. It can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing EMBEDA in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

It contains pellets of an extended-release oral formulation of morphine sulfate, an opioid receptor agonist, surrounding an inner core of naltrexone hydrochloride, an opioid receptor antagonist indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

EMBEDA 100 mg/4 mg is for use in opioid-tolerant patients only. Ingestion of these capsules or the pellets within the capsules may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids.

Patients should not consume alcoholic beverages while on EMBEDA therapy. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on EMBEDA therapy. The co-ingestion of alcohol with EMBEDA may result in an increase of plasma levels and potentially fatal overdose of morphine. EMBEDA is to be swallowed whole or the contents of the capsules sprinkled on apple sauce. The pellets in the capsules are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of morphine.

Crushing, chewing, or dissolving EMBEDA will also result in the release of naltrexone which may precipitate withdrawal in opioid-tolerant individuals.

The common adverse events seen on initiation of therapy with EMBEDA are dose dependent, and their frequency depends on the clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as part of opioid analgesia. The most frequent of these include drowsiness, dizziness, constipation, and nausea. Additional common adverse events reported during clinical studies include constipation, nausea, and somnolence.

EMBEDA is an extended-release oral formulation of morphine sulfate and naltrexone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

EMBEDA is not indicated for acute/postoperative pain or if the pain is mild or not expected to persist for an extended period of time. It is only indicated for postoperative use if the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

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