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Included as part of the PRECAUTIONS section.

EMBEDA (morphine sulfate and naltrexone hydrochloride) 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. 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.

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

Misuse, Abuse, and Diversion of Opioids

EMBEDA (morphine sulfate and naltrexone hydrochloride) contains morphine, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing EMBEDA (morphine sulfate and naltrexone hydrochloride) in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Abuse of EMBEDA (morphine sulfate and naltrexone hydrochloride) by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death [see Drug Abuse and Dependence].

Concerns about abuse and addiction should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse of this product.

Interactions with Alcohol and Drugs of Abuse

EMBEDA (morphine sulfate and naltrexone hydrochloride) may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression because respiratory depression, hypotension, and profound sedation or coma may result.

Patients should not consume alcoholic beverages, prescription or non-prescription medications containing alcohol while on EMBEDA (morphine sulfate and naltrexone hydrochloride) therapy. The co-ingestion of alcohol with EMBEDA (morphine sulfate and naltrexone hydrochloride) can result in an increase of morphine plasma levels and potentially fatal overdose of morphine [see CLINICAL PHARMACOLOGY].

Impaired Respiration

Respiratory depression is the chief hazard of all morphine preparations such as EMBEDA (morphine sulfate and naltrexone hydrochloride) . Respiratory depression occurs more frequently and is more dangerous in elderly and debilitated patients, and those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction (when even moderate therapeutic doses may significantly decrease pulmonary ventilation).

EMBEDA (morphine sulfate and naltrexone hydrochloride) should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve (e.g., severe kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of morphine may increase airway resistance and decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of morphine with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. EMBEDA (morphine sulfate and naltrexone hydrochloride) can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in pressure in patients with head injuries. EMBEDA (morphine sulfate and naltrexone hydrochloride) should only be administered under such circumstances when considered essential and then with extreme care.

Hypotensive Effect

EMBEDA (morphine sulfate and naltrexone hydrochloride) may cause severe hypotension. There is an added risk to individuals whose ability to maintain blood pressure has already been compromised by a reduced blood volume or a concurrent administration of drugs such as phenothiazines or general anesthetics [see DRUG INTERACTIONS]. EMBEDA (morphine sulfate and naltrexone hydrochloride) may produce orthostatic hypotension and syncope in ambulatory patients.

EMBEDA (morphine sulfate and naltrexone hydrochloride) should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Interactions with other CNS Depressants

EMBEDA (morphine sulfate and naltrexone hydrochloride) should be used with caution and in reduced dosage in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result [see DRUG INTERACTIONS].

Gastrointestinal Effects

EMBEDA (morphine sulfate and naltrexone hydrochloride) should not be given to patients with gastrointestinal obstruction, particularly paralytic ileus, as there is a risk of the product remaining in the stomach for an extended period and the subsequent release of a bolus of morphine when normal gut motility is restored. As with other solid morphine formulations diarrhea may reduce morphine absorption.

The administration of morphine may obscure the diagnosis or clinical course in patients with acute abdominal condition.

Cordotomy

Patients taking EMBEDA (morphine sulfate and naltrexone hydrochloride) who are scheduled for cordotomy or other interruption of pain transmission pathways should have EMBEDA (morphine sulfate and naltrexone hydrochloride) ceased 24 hours prior to the procedure and the pain controlled by parenteral short-acting opioids. In addition, the post- procedure titration of analgesics for such patients should be individualized to avoid either oversedation or withdrawal syndromes.

Use in Pancreatic/Biliary Tract Disease

EMBEDA (morphine sulfate and naltrexone hydrochloride) may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids may cause increases in the serum amylase level.

Tolerance and Physical 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 common 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.

EMBEDA should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION].

Special Risk Groups

EMBEDA (morphine sulfate and naltrexone hydrochloride) should be administered with caution, and in reduced dosages in elderly or debilitated patients; patients with severe renal or hepatic insufficiency; patients with Addison's disease; myxedema; hypothyroidism; prostatic hypertrophy or urethral stricture.

Caution should also be exercised in the administration of EMBEDA (morphine sulfate and naltrexone hydrochloride) to patients with CNS depression, toxic psychosis, acute alcoholism, and delirium tremens.

All opioids may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Driving and Operating Machinery

EMBEDA (morphine sulfate and naltrexone hydrochloride) may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Patients must be cautioned accordingly. Patients should also be warned about the potential combined effects of EMBEDA (morphine sulfate and naltrexone hydrochloride) with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see DRUG INTERACTIONS].

Anaphylaxis

Although extremely rare, cases of anaphylaxis have been reported with the use of a similar extended release morphine formulation.

Accidentally Precipitated Withdrawal

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.

Consuming EMBEDA (morphine sulfate and naltrexone hydrochloride) that have been tampered by crushing, chewing, or dissolving the extended-release formulation can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals. Symptoms of withdrawal usually appear within five minutes of ingestion of naltrexone and can last for up to 48 hours. Mental status changes can include confusion, somnolence, and visual hallucinations. Significant fluid losses from vomiting and diarrhea can require intravenous fluid administration. Patients should be closely monitored and therapy with non-opioid medications tailored to meet individual requirements.

Laboratory Tests

Naltrexone does not interfere with thin-layer, gas-liquid, and high pressure liquid chromatographic methods which may be used for the separation and detection of morphine, methadone, or quinine in the urine. Naltrexone may or may not interfere with enzymatic methods for the detection of opioids depending on the specificity of the test. Please consult the test manufacturer for specific details.

Patient Counseling Information

Patients receiving EMBEDA (morphine sulfate and naltrexone hydrochloride) should be given the following instructions by the physician:

• Patients should be advised that EMBEDA (morphine sulfate and naltrexone hydrochloride) contains morphine and naltrexone and should be taken only as directed.
• The dose of morphine sulfate should not be adjusted without consulting with a physician or other healthcare professional. EMBEDA (morphine sulfate and naltrexone hydrochloride) should be swallowed whole (not crushed, dissolved, or chewed) due to a risk of fatal morphine overdose or naltrexone precipitated withdrawal symptoms. Alternately, EMBEDA (morphine sulfate and naltrexone hydrochloride) Capsules may be opened and the entire contents sprinkled on a small amount of apple sauce immediately prior to ingestion [see DOSAGE AND ADMINISTRATION].
• Patients should not consume alcoholic beverages while on EMBEDA (morphine sulfate and naltrexone hydrochloride) therapy. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on EMBEDA (morphine sulfate and naltrexone hydrochloride) therapy. The co-ingestion of alcohol with EMBEDA (morphine sulfate and naltrexone hydrochloride) may result in an increase of plasma levels and potentially fatal overdose of morphine.
• Patients should be advised of the most common adverse reactions that may occur while taking EMBEDA (morphine sulfate and naltrexone hydrochloride) : constipation, nausea, somnolence, vomiting, dizziness, pruritus, and headache.
• Patients should be advised that EMBEDA (morphine sulfate and naltrexone hydrochloride) may cause drowsiness, dizziness, or lightheadedness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on EMBEDA (morphine sulfate and naltrexone hydrochloride) or patients whose dose has been adjusted should refrain from any potentially dangerous activity until it is established that they are not adversely affected.
• Patients should not combine EMBEDA (morphine sulfate and naltrexone hydrochloride) with central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician because dangerous additive effects may occur resulting in serious injury or death.
• Patients should be advised that EMBEDA (morphine sulfate and naltrexone hydrochloride) is a potential drug of abuse. They should protect it from theft.
• Special care must be taken to avoid accidental ingestion or use by individuals (including children) other than the patient for whom it was originally prescribed, as such unsupervised use may have severe, even fatal, consequences [see WARNINGS AND PRECAUTIONS].
• Patients should be advised that EMBEDA (morphine sulfate and naltrexone hydrochloride) 100 mg/4 mg is for use only in opioid-tolerant patients.
• Women of childbearing potential who become or are planning to become pregnant should consult a physician prior to initiating or continuing therapy with EMBEDA (morphine sulfate and naltrexone hydrochloride) .
• Safe use in pregnancy has not been established. Prolonged use of opioid analgesics during pregnancy may cause fetal neonatal physical dependence, and neonatal withdrawal may occur.
• As with other opioids, patients taking EMBEDA (morphine sulfate and naltrexone hydrochloride) should be advised of the potential for severe constipation; appropriate laxatives and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy.
• Patients should be advised to seek medical attention immediately if signs of a serious allergic reaction occur, such as swelling of the face, throat, or tongue, trouble breathing, feeling dizzy or faint, pounding heart beat, chest pain or feeling of doom. [see WARNINGS AND PRECAUTIONS].

Breakthrough Pain/Adverse Experiences

Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.

Mental and/or Physical Ability

Patients should be advised that EMBEDA (morphine sulfate and naltrexone hydrochloride) may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on EMBEDA (morphine sulfate and naltrexone hydrochloride) or whose dose has been changed should refrain from dangerous activity until it is established that they are not adversely affected [see WARNINGS AND PRECAUTIONS].

Avoidance of Alcohol or Other CNS Depressants

Patients should be advised that EMBEDA (morphine sulfate and naltrexone hydrochloride) should not be taken with alcohol, prescription or non-prescription medications containing alcohol, or other CNS depressants (sleeping medication, tranquilizers) except by the orders of the prescribing healthcare provider because dangerous additive effects may occur resulting in serious injury or death [see WARNINGS AND PRECAUTIONS].

Pregnancy

Women of childbearing potential who become or are planning to become pregnant, should consult their prescribing healthcare provider prior to initiating or continuing therapy with EMBEDA (morphine sulfate and naltrexone hydrochloride) [see Use in Specific Populations].

Cessation of Therapy

Patients should be advised that if they have been receiving treatment with EMBEDA (morphine sulfate and naltrexone hydrochloride) for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the EMBEDA (morphine sulfate and naltrexone hydrochloride) dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their prescribing healthcare provider should provide a dose schedule to accomplish a gradual discontinuation of the medication.

Drug of Abuse

Patients should be advised that EMBEDA (morphine sulfate and naltrexone hydrochloride) is a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed [see WARNINGS AND PRECAUTIONS].

Constipation

Patients should be advised that severe constipation could occur as a result of taking EMBEDA (morphine sulfate and naltrexone hydrochloride) and appropriate laxatives, stool softeners and other appropriate treatments should be initiated from the beginning of opioid therapy.

Storage/Destruction of Unused EMBEDA (morphine sulfate and naltrexone hydrochloride)

Patients should be instructed to keep EMBEDA (morphine sulfate and naltrexone hydrochloride) in a secure place out of the reach of children. When EMBEDA (morphine sulfate and naltrexone hydrochloride) is no longer needed, the unused capsules should be destroyed by flushing down the toilet.

FDA-Approved Patient Labeling

[See PATIENT INFORMATION section.]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies in animals to evaluate the carcinogenic potential of morphine have not been conducted.

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, in vitro studies have reported that morphine is non-mutagenic in Drosophila (no lethal mutation induction), in the Ames test with Salmonella, and induces chromosomal aberrations in human leukocytes. Morphine was found to be mutagenic in vitro in human T- cells, increasing the DNA fragmentation. In vivo, morphine was mutagenic in the mouse micronucleus test and induced chromosomal aberrations in spermatids and murine lymphocytes. Chronic opioid abusers (e.g., heroin abusers) and their offspring display higher rates of chromosomal damage. However, the rates of chromosomal abnormalities were similar in nonexposed individuals and in heroin users enrolled in long term opioid maintenance programs.

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. Studies from the literature have also reported changes in hormonal levels (i.e. testosterone, luteinizing hormone, serum corticosterone) following treatment with morphine. These changes may be associated with the reported effects on fertility in the rat.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C: Teratogenic effects of morphine have been reported in the animal literature. High parental doses during the second trimester were teratogenic in neurological, soft and skeletal tissue. The abnormalities included encephalopathy and axial skeletal fusions. These doses were often maternally toxic and were 0.3 to 3-fold the maximum recommended human dose (MRHD) on a mg/m² basis. The relative contribution of morphine-induced maternal hypoxia and malnutrition, each of which can be teratogenic, has not been clearly defined. Treatment of male rats with approximately 3-fold the MRHD for 10 days prior to mating decreased litter size and viability.

Nonteratogenic Effects

Morphine given subcutaneously, at non-maternally toxic doses, to rats during the third trimester with approximately 0.15-fold the MRHD caused reversible reductions in brain and spinal cord volume, and testes size and body weight in the offspring, and decreased fertility in female offspring. The offspring of rats and hamsters treated orally or intraperitoneally throughout pregnancy with 0.04-to 0.3-fold the MRHD of morphine have demonstrated delayed growth, motor and sexual maturation, and decreased male fertility. Chronic morphine exposure of fetal animals resulted in mild withdrawal, altered reflex and motor skill development, and altered responsiveness to morphine that persisted into adulthood.

There are no well-controlled studies of chronic in utero exposure to morphine sulfate in human subjects. However, uncontrolled retrospective studies of human neonates chronically exposed to other opioids in utero, demonstrated reduced brain volume which normalized over the first month of life. Infants born to opioid-abusing mothers are more often small for gestational age, have a decreased ventilatory response to CO₂, and increased risk of sudden infant death syndrome.

There are no adequate and well-controlled studies of naltrexone in pregnant women.

EMBEDA (morphine sulfate and naltrexone hydrochloride) should only be used during pregnancy if the need for strong opioid analgesia justifies the potential risk to the fetus.

Labor and Delivery

EMBEDA (morphine sulfate and naltrexone hydrochloride) is not recommended for use in women during and immediately prior to labor, where shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor. Neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. A specific opioid antagonist, such as naloxone or nalmefene, should be available for reversal of opioid-induced respiratory depression in the neonate.

Nursing Mothers

Morphine is excreted in the maternal milk, and the milk to plasma morphine AUC ratio is about 2.5:1. The amount of morphine received by the infant depends on the maternal plasma concentration, amount of milk ingested by the infant, and the extent of first pass metabolism.

Withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine sulfate is stopped. Because of the potential for adverse reactions in nursing infants from EMBEDA (morphine sulfate and naltrexone hydrochloride) , a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of EMBEDA (morphine sulfate and naltrexone hydrochloride) in individuals less than 18 years of age have not been established.

Geriatric Use

Clinical studies of EMBEDA (morphine sulfate and naltrexone hydrochloride) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. The pharmacokinetics of EMBEDA (morphine sulfate and naltrexone hydrochloride) have not been investigated in elderly patients ( > 65 years) although such patients were included in clinical studies. In a long-term open label safety study, the pre-dose plasma morphine concentrations after dose normalization were similar for subjects < 65 years and those 65 years of age. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Neonatal Withdrawal Syndrome

Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother's wborn. last dose, Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Race

Pharmacokinetic differences due to race may exist. Chinese subjects given intravenous morphine in one study had a higher clearance when compared to Caucasian subjects (1852 ± 116 mL/min versus 1495 ± 80 mL/min).

Hepatic Failure

The pharmacokinetics of morphine was found to be significantly altered in individuals with alcoholic cirrhosis. The clearance was found to decrease with a corresponding increase in half-life. The morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) to morphine plasma AUC ratios also decreased in these patients indicating a decrease in metabolic activity.

Renal Insufficiency

The pharmacokinetics of morphine is altered in renal failure patients. AUC is increased and clearance is decreased. The metabolites, M3G and M6G, accumulate several fold in renal failure patients compared with healthy subjects.

Adequate studies of naltrexone in patients with severe hepatic or renal impairment have not been conducted.

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