IMPORTANT CORRECTION OF DRUG INFORMATION about EMBEDA(R) (morphine sulfate and naltrexone hydrochloride) Extended Release Capsules for oral use C-II

IMPORTANT

CORRECTION

OF DRUG

INFORMATION

about

EMBEDA® (morphine sulfate and naltrexone

hydrochloride) Extended Release Capsules for oral use

C-II

1.  

The news releases presented numerous efficacy claims regarding EMBEDA but entirely failed to disclose the potential for fatal risks associated with EMBEDA.

Important information regarding potentially fatal risks associated with EMBEDA follows:

• 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.
• EMBEDA 100 mg/4 mg IS FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. Ingestion of these capsules or pellets within the capsules may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids.
• Crushing, chewing, or dissolving EMBEDA will also result in the release of naltrexone which may precipitate withdrawal in opioid-tolerant individuals.

These are not all of the risks associated with EMBEDA. For a complete description, please see the additional risk disclosures below and the full Prescribing Information (PI).

2.  

The news releases failed to disclose important limitations to EMBEDA's indication. Therefore, the news releases implied that EMBEDA is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience.

The news releases failed to disclose that EMBEDA is not intended for acute/postoperative pain or if the pain is mild or not expected to persist for an extended period of time. EMBEDA is only indicated for postoperative pain when the patient is already receiving chronic opioid therapy or if the pain is expected to be moderate to severe and persist for an extended period of time. The FDA approved product labeling (PI) for EMBEDA specifically states:

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 intended for use as a prn analgesic.

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. EMBEDA 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. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate.

3.  

The news releases presented misleading claims that imply that EMBEDA's pharmacological properties have been shown to have a clinically significant effect in reducing liking and euphoria and that the naltrexone in EMBEDA will reverse the subjective and analgesic effects of morphine, thus reducing the likelihood of morphine overdose if the drug is crushed, chewed, or dissolved.

EMBEDA's formulation has not been shown to confer abuse resistance and reduced abuse liability. According to the FDA approved PI:

The pharmacodynamic effect of naltrexone in the setting of crushed EMBEDA was examined in two clinical trials. In a randomized double-blind, triple-dummy, four-way cross-over study, 32 non-dependent recreational opioid users received 120 mg of EMBEDA whole and crushed, 120 mg of immediate-release morphine sulfate and placebo. Overall, 87.5% of subjects had some degree of reduced drug liking after receiving crushed EMBEDA, while 12.5% had no reduction in drug liking. There was considerable individual variability in the degree of reduction in drug liking, ranging between 10 and 50%. Similarly, 69% of subjects showed some degree of a decrease in euphoria with crushed EMBEDA compared to IR morphine and 31% of subjects did not report a reduction in euphoria. There was similar individual variability in the degree of reduction in euphoria.

A randomized double-blind, placebo-controlled, three-way cross-over trial in 28 non-dependent recreational opioid users was performed using 30 mg of IV morphine alone and 30 mg of IV morphine in combination with 1.2 mg of IV naltrexone to simulate parenteral use of crushed EMBEDA. The combination of morphine with naltrexone resulted in 71% of subjects reporting a reduction in euphoria compared to morphine alone. Note that the intravenous injection of crushed EMBEDA may result in serious injury and death due to a morphine overdose or an embolic event. Intravenous injection of crushed EMBEDA may precipitate a severe withdrawal syndrome in opioid-dependent patients.

The clinical significance of the degree of reduction in drug liking and euphoria reported in these studies has not yet been established. There is no evidence that the naltrexone in EMBEDA reduces the abuse liability of EMBEDA.

4.  

Other important risks omitted from the news releases included the following:

The PI for EMBEDA includes the following boxed warning:

WARNING: EMBEDA® capsules contain morphine, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid agonists. EMBEDA 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.

EMBEDA 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 is NOT intended for use as a prn analgesic.

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.

Eric G. Carter, Ph.D., M.D.

Chief Science Officer

CONTACT:

Jack Howarth

Vice President

Investor Relations

+1-908-429-8350