IMPORTANT SAFETY INFORMATION
WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Addiction, Abuse, and Misuse
EMBEDA exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing EMBEDA, and monitor all patients regularly for the development of these behaviors and conditions.
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
- complete a REMS compliant education program,
- counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
- emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
- consider other tools to improve patient, household, and community safety.
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of EMBEDA. Monitor for respiratory depression, especially during initiation of EMBEDA or following a dose increase. Instruct patients to swallow EMBEDA capsules whole, or to sprinkle the contents of the capsule on applesauce and swallow immediately without chewing. Crushing, chewing, or dissolving the pellets in EMBEDA can cause rapid release and absorption of a potentially fatal dose of morphine.
Accidental ingestion of even one dose of EMBEDA, especially by children, can result in a fatal overdose of morphine.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of EMBEDA during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Interaction With Alcohol
Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking EMBEDA. The co-ingestion of alcohol with EMBEDA may result in increased plasma levels and a potentially fatal overdose of morphine.
Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants
- Reserve concomitant prescribing of EMBEDA and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Limit dosages and durations to the minimum required.
- Follow patients for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when EMBEDA is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk of overdose and death associated with the use of additional CNS depressants, including alcohol and illicit drugs.
- Significant respiratory depression
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
- Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
- Known or suspected gastrointestinal obstruction, including paralytic ileus
- Hypersensitivity (eg, anaphylaxis) to morphine or naltrexone
WARNINGS AND PRECAUTIONS
The use of EMBEDA in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients With Chronic Pulmonary Disease: EMBEDA-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages of EMBEDA.
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
Monitor such patients closely, particularly when initiating and titrating EMBEDA and when EMBEDA is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs, including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
EMBEDA may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of EMBEDA. In patients with circulatory shock, EMBEDA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of EMBEDA in patients with circulatory shock.
Use in Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), EMBEDA may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with EMBEDA.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of EMBEDA in patients with impaired consciousness or coma.
Risks of Use in Patients With Gastrointestinal Conditions
EMBEDA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The morphine in EMBEDA may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
Increased Risk of Seizures in Patients With Seizure Disorders
The morphine in EMBEDA may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during EMBEDA therapy.
Consuming EMBEDA capsules that have been altered by crushing, chewing, or dissolving the pellets can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals. Symptoms of withdrawal usually appear within five minutes of ingestion of naltrexone, can last for up to 48 hours, and can include mental status changes, restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Significant fluid losses from vomiting and diarrhea can require intravenous (IV) fluid administration.
When discontinuing EMBEDA, gradually taper the dosage.
Risks of Driving and Operating Machinery
EMBEDA may impair the mental or physical abilities needed to perform potentially hazardous activities, such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of EMBEDA and know how they will react to the medication.
The following serious adverse reactions have occurred:
- Addiction, Abuse, and Misuse
- Life-threatening Respiratory Depression
- Neonatal Opioid Withdrawal Syndrome
- Interactions With Benzodiazepines or Other CNS Depressants
- Interaction with Monoamine Oxidase Inhibitors
- Adrenal Insufficiency
- Severe Hypotension
- Gastrointestinal Adverse Reactions
Most common (≥10%) adverse reactions in clinical studies were constipation, nausea, and somnolence.
Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue EMBEDA if serotonin syndrome is suspected.
Monoamine Oxidase Inhibitors (MAOIs) MAOI interactions with opioids may manifest as serotonin syndrome or may potentiate effects of morphine toxicity (eg, respiratory depression, coma, and confusion).
Do not use EMBEDA in patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics These may reduce the analgesic effect of EMBEDA and/or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who have received or are receiving a full opioid agonist analgesic, including EMBEDA.
Muscle Relaxants Opioids may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of EMBEDA and/or muscle relaxant as necessary.
Cimetidine The concomitant use of cimetidine can potentiate morphine effects and increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients for respiratory depression that may be greater than otherwise expected and decrease the dosage of EMBEDA and/or cimetidine as necessary.
Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when EMBEDA is used concomitantly with anticholinergic drugs.
P-Glycoprotein (PGP) Inhibitors The concomitant use of PGP inhibitors can increase the exposure of morphine by about two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of EMBEDA and/or the PGP inhibitor as necessary.
USE IN SPECIFIC POPULATIONS
Pregnancy Prolonged use of opioid analgesics, including EMBEDA, can cause neonatal opioid withdrawal syndrome. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
Lactation Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with EMBEDA. Morphine is present in breast milk. Monitor infants exposed to EMBEDA through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped.
Pediatric and Geriatric Patients Safety and efficacy in patients less than 18 years of age or more than 65 years of age have not been established.
EMBEDA is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Limitations of Use
- Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve EMBEDA for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
- EMBEDA is not indicated as an as-needed (prn) analgesic.