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Serious adverse reactions that may be associated with EMBEDA (morphine sulfate and naltrexone hydrochloride) therapy in clinical use include: respiratory depression, respiratory arrest, apnea, circulatory depression, cardiac arrest, hypotension, and/or shock [see OVERDOSAGE, WARNINGS AND PRECAUTIONS].

The common adverse events seen on initiation of therapy with EMBEDA (morphine sulfate and naltrexone hydrochloride) 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 a part of opioid analgesia. The most frequent of these include drowsiness, dizziness, constipation, and nausea.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

There were 1251 subjects exposed to at least one dose of EMBEDA (morphine sulfate and naltrexone hydrochloride) in the clinical program. During late phase clinical development, 618 subjects received EMBEDA (morphine sulfate and naltrexone hydrochloride) in two randomized, controlled, double-blind studies in subjects with osteoarthritis of the hip or knee. An additional 465 subjects received EMBEDA (morphine sulfate and naltrexone hydrochloride) in an open-label, year-long safety study of subjects with chronic, non-cancer pain, 208 subjects for at least six months and 124 for 12 months. The remaining 168 subjects were exposed to a single dose of EMBEDA (morphine sulfate and naltrexone hydrochloride) in early PK/PD studies.

Short-Term (12-Week) Randomized Study

Adverse reactions observed in at least 2% of subjects treated with EMBEDA (morphine sulfate and naltrexone hydrochloride)

This study utilized an enriched enrollment with a randomized withdrawal design in which subjects were titrated to effect on open-label EMBEDA (morphine sulfate and naltrexone hydrochloride) for up to 45 days. Once their pain was controlled, subjects were randomized to either active treatment with EMBEDA (morphine sulfate and naltrexone hydrochloride) or were tapered off EMBEDA (morphine sulfate and naltrexone hydrochloride) using a double-dummy design and placed on placebo. The Maintenance Period was 12 weeks. The most common adverse reactions leading to study discontinuation were nausea, constipation, vomiting, fatigue, dizziness, pruritus, and somnolence. Adverse reactions, defined as treatment-related adverse events assessed by the investigators, reported by ≥ 2.0% of subjects in either the titration or maintenance phase of the 12-week study are presented in Table 1.

Table 1: Adverse Reactions Reported by ≥ 2.0% of Subjects in 12-Week Efficacy Study – Safety Population

Long-Term Open-Label Safety Study

In the long-term open-label safety study, 465 patients with chronic non-malignant pain were enrolled and 124 patients were treated for up to 1 year. The distributions of adverse events were similar to that of the randomized, controlled studies, and were consistent with the most common opioid related adverse events. Adverse reactions, defined as treatment-related adverse events assessed by the investigators, reported by ≥ 2.0% of subjects are presented in Table 2.

Table 2: Adverse Reactions Reported by ≥ 2.0% of Subjects in Long-Term Safety Study – Safety Population

Adverse Reactions Observed in the Phase 2/3 Studies

Most common ( ≥ 10%): constipation, nausea, somnolence

Common ( ≥ 1% to < 10%): vomiting, headache, dizziness, pruritus, dry mouth, diarrhea, fatigue, insomnia, hyperhidrosis, anxiety, chills, abdominal pain, lethargy, edema peripheral, dyspepsia, anorexia, muscle spasms, depression, flatulence, restlessness, decreased appetite, irritability, stomach discomfort, tremor, arthralgia, hot flush, sedation

Adverse Reactions Observed in the Phase 2/3 Studies

Most common ( ≥ 10%):

Gastrointestinal disorders: constipation, nausea;

Nervous system disorders: somnolence.

Common ( ≥ 1% to < 10%):

Gastrointestinal disorders: abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence, stomach discomfort, vomiting;

General disorders and administration site conditions: chills, edema peripheral, fatigue, irritability;

Metabolism and nutrition disorders: anorexia, decreased appetite;

Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms;

Nervous system disorders: dizziness, headache, lethargy, sedation, tremor;

Psychiatric disorders: anxiety, depression, insomnia, restlessness;

Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus;

Vascular disorders: hot flush.

Less Common ( < 1%):

Eye disorders: vision blurred, orthostatic hypotension;

Gastrointestinal disorders: abdominal distension, pancreatitis, abdominal discomfort, fecaloma, abdominal pain lower, abdominal tenderness;

General disorders and administration site conditions: malaise, asthenia, feeling jittery, drug withdrawal syndrome;

Hepatobiliary disorders: cholecystitis;

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased;

Musculoskeletal and connective tissue disorders: myalgia, muscular weakness;

Nervous system disorders: depressed level of consciousness, mental impairment, memory impairment, disturbance in attention, stupor, paraesthesia, coordination abnormal;

Psychiatric disorders: disorientation, thinking abnormal, mental status changes, confusional state, euphoric mood, hallucination, abnormal dreams, mood swings, nervousness;

Renal and urinary disorders: urinary retention, dysuria;

Reproductive system and breast disorders: erectile dysfunction;

Respiratory, thoracic and mediastinal disorders: dyspnea, rhinorrhoea;

Skin and subcutaneous tissue disorders: rash, piloerection, cold sweat, night sweats;

Vascular disorders: hypotension, flushing.

CNS Depressants

EMBEDA (morphine sulfate and naltrexone hydrochloride) should be used with great caution and in reduced dosage in patients who are concurrently receiving other central nervous system (CNS) depressants including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers, and alcohol because of the risk of respiratory depression, hypotension, and profound sedation or coma. When such combined therapy is contemplated, the initial dose of one or both agents should be reduced by at least 50%.

Muscle Relaxants

EMBEDA (morphine sulfate and naltrexone hydrochloride) may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression.

Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with EMBEDA (morphine sulfate and naltrexone hydrochloride) . In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of EMBEDA (morphine sulfate and naltrexone hydrochloride) and/or may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs have been reported to potentiate the effects of morphine anxiety, confusion, and significant depression of respiration or coma. EMBEDA (morphine sulfate and naltrexone hydrochloride) should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Cimetidine

There is an isolated report of confusion and severe respiratory depression when a hemodialysis patient was concurrently administered morphine and cimetidine.

Diuretics

Morphine can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with prostatism.

Anticholinergics

Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

P-Glycoprotein (PGP) Inhibitors

Based on published reports, PGP inhibitors (e.g. quinidine) may increase the absorption/exposure of morphine sulfate by about two fold. Therefore, caution should be exercised when morphine sulfate is co-administered with PGP inhibitors.

Drug Abuse And Dependence

Controlled Substance

EMBEDA (morphine sulfate and naltrexone hydrochloride) contains morphine, a mu-opioid agonist, and is a Schedule II controlled substance. EMBEDA (morphine sulfate and naltrexone hydrochloride) can be abused and is subject to criminal diversion.

Abuse

Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.

“Drug-seeking” behavior and attempts at wrongful procurement of prescription medicines are very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers. However, it is important to note that “drug-seeking behavior” may also be exhibited by patients who are experiencing under-treatment for their moderate to severe chronic pain.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. EMBEDA (morphine sulfate and naltrexone hydrochloride) , like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs.

EMBEDA (morphine sulfate and naltrexone hydrochloride) is intended for oral use only. Misuse or abuse of EMBEDA (morphine sulfate and naltrexone hydrochloride) by crushing or chewing the pellets will result in the uncontrolled release of both morphine and naltrexone, posing the risk of overdose and death. In opioid-tolerant individuals, the absorption of naltrexone may increase the risk of precipitating withdrawal. The risk of overdose and death is increased with concurrent abuse of alcohol and other central nervous system depressants. The sequestered naltrexone is intended to have no clinical effect when EMBEDA (morphine sulfate and naltrexone hydrochloride) is taken as directed; however, if crushed or chewed, up to 100% of the sequestered naltrexone dose could be released, bioequivalent to an immediate release naltrexone oral solution of the same dose.

Due to the presence of talc as one of the excipients in EMBEDA (morphine sulfate and naltrexone hydrochloride) , parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

In general, opioids should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 8/27/2009
This monograph has been modified to include the generic and brand name in many instances.