Dosing and uses of Embeda (morphine-naltrexone)
Adult dosage forms and strengths
morphine/naltrexone
extended-release capsule: Schedule II
- 20mg/0.8mg
- 30mg/1.2mg
- 50mg/2mg
- 60mg/2.4mg
- 80mg/3.2mg
- 100mg/4mg
Chronic Severe Pain
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
Opioid naïve: Initiate with lowest dose (ie, morphine/naltrexone 20 mg/0.8 mg PO q24hr); may adjust dose by titrating at 1-2 day intervals (steady-state plasma concentration are reached within 24-36 hr)
Conversion from other PO morphine: Administer one-half of daily dose q12hr OR administer total daily dose qDay
Conversion from PO opioids, parenteral morphine, or other parenteral opioids: Substantial inter-patient variation exist for conversion; for this reason, it is safer to underestimate patient’s 24-hour PO morphine dose during this transition and provide additional prompt-acting rescue analgesics until new daily dose established
Individualize dose
- Titrate no more frequently than q48hr to allow patient to stabilize before dose escalation
- For breakthrough pain, supplement with small dose (ie, <20% total daily dose) of short-acting analgesic
- If qDay dosing does not provide adequate analgesia, administer total daily dose divided q12hr
- Do not administer more frequently than q12hr
Opioid-tolerant definition
- Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression
- Patients who are opioid tolerant are those receiving, for 1 week or longer, at least 60 mg/day PO morphine, 25 mcg/hr transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, 25 mg/day PO oxymorphone, or an equianalgesic dose of another opioid
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 for patients whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain
- Not indicated as a PRN analgesic
- Not indicated for acute/postoperative pain, mild pain, or short-term pain relief; only indicated for postoperative use if patient already receiving chronic opioid therapy prior to surgery, or if postoperative pain is expected to be moderate-to-severe and persist for an extended period of time
Renal Impairment
Caution in severe impairment; information on renal impairment dosing not available from the manufacturer
Hepatic Impairment
Caution in severe impairment; information on hepatic impairment dosing not available from the manufacturer
Administration
Swallow capsule whole; chewing, crushing, or dissolving contents of capsules will result in uncontrolled delivery of morphine and can lead to overdose or death
The capsules contain pellets that consist of morphine and sequestered naltrexone; 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
Consuming capsules that have been altered by crushing, chewing, or dissolving the pellets can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals
May sprinkle capsule contents on apple sauce and swallow immediately; do not chew; rinse the mouth to ensure all pellets have been swallowed
Do not administer pellets through a nasogastric or gastric tube
May administer qDay or q12hr; do not administer more frequently than q12hr
Pediatric dosage forms and strengths
Safety and efficacy not established
Embeda (morphine-naltrexone) adverse (side) effects
>10%
Somnolence
Constipation
Nausea
1-10% (selected)
Edema peripheraL
Anxiety
Chills
Depression
Dizziness
Fatigue
Headache
Insomnia
Irritability
Lethargy
Restlessness
Sedation
Tremor
Hyperhidrosis
Pruritus
Hot flush
Abdominal pain
Anorexia
Dry mouth
Diarrhea
Dyspepsia
Decreased appetite
Flatulence
Stomach discomfort
Vomiting
Arthralgia
Muscle spasms
Frequency not defined
Cardiac arrest
Hypotension
Shock
Anaphylaxis
Apnea
Respiratory arrest
Respiratory depression
Opioid withdrawaL
Warnings
Black box warnings
Addiction, abuse, and misuse
- Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death
- Assess each patient’s risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions
Life-threatening respiratory depression
- Serious, life-threatening, or fatal respiratory depression may occur
- Monitor for respiratory depression, especially during initiation or following a dose increase
- Instruct patients to swallow tablet/capsule whole; crushing, chewing, or dissolving can cause rapid release and absorption of a potentially fatal morphine dose
Accidental exposure
- Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose
Neonatal opioid withdrawal syndrome
- Prolonged use 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
- Syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight
- Onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn
- 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 nonprescription products that contain alcohol
- Coingestion of alcohol may cause rapid release of opioid content from long-acting tablet/capsule and result in increased plasma levels and a potentially fatal overdose
Contraindications
Known hypersensitivity to morphine, morphine slats, naltrexone, or in any situation where opioids are contraindicated
Respiratory depression
Acute or severe asthma or hypercarbia
Paralytic ileus
Cautions
Abuse-deterrent properties: Releases only the morphine in the capsule when swallowed whole; when crushed, the naltrexone blocks some of the euphoric effects of the morphine and can precipitate withdrawal in persons dependent on opioids
Pharmacologic effects vary widely; in addition to its therapeutic analgesic effect, may cause adverse effects including dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release, physical dependence, & alterations of the endocrine and autonomic nervous systems
Use extreme caution in patients susceptible to intracranial effects of CO2 retention (eg, emphysema)
Do not use monoamine oxidase inhibitors concurrently or within 14 days of stopping morphine/naloxone
Not indicated for acute/postoperative pain, mild pain, or short-term pain relief; only indicated for postoperative use if patient already receiving chronic opioid therapy prior to surgery, or if postoperative pain is expected to be moderate-to-severe and persist for an extended period of time
Schedule II opioid analgesics expose users to the risks of addiction, abuse, and misuse; there is a greater risk for overdose and death with extended-release opioids due to the larger amount of active opioid present (see Black box warnings)
Addiction, abuse, and misuse risks are increased in patients with a personal or family history of substance abuse or mental illness (eg, major depression); the potential for these risks should not, however, prevent the prescribing of proper pain management in any given patient; intensive monitoring is necessary (see Black box warnings)
Serious, life-threatening, or fatal respiratory depression reported (see Black box warnings)
Accidental exposure reported, including fatalities (see Black box warnings)
Neonatal opioid withdrawal syndrome reported with long-term use during pregnancy (see Black box warnings)
Interactions with CNS depressants (eg, alcohol, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids) can cause additive effects and increase risk for respiratory depression, profound sedation, and hypotension; must not consume alcohol while taking morphine/naloxone
If the decision to begin morphine/naloxone is made, start with 20 mg/0.8 mg q24hr, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients
Pregnancy and lactation
Pregnancy: Category C
Lactation: morphine excreted into human milk (milk/plasma AUC ratio ~2.5:1); withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine is stopped; a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Embeda (morphine-naltrexone)
Mechanism of action
Morphine is a pure opioid agonist, relatively selective for the mu-opioid receptor; inhibits ascending pain pathways, which causes alteration in response to pain; produces analgesia, respiratory depression, and sedation
Naltrexone is a centrally acting mu-opioid antagonist; only becomes active and antagonizes opioid agonsists when the tablet is either chewed, crushed, or dissolved
Pharmacokinetics
Pharmacokinetic parameters are for morphine unless otherwise stated
Bioavailability: 20-40%
Peak Plasma Time: 7.5 hr
Protein Binding: 30-35%
Half-Life: 29 hr
Volume of distribution: 3-4 L/kg
Metabolism: Glucuronidation and sulfation in the liver to produce including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) or morphine-3-etheral sulfate; naltrexone extensively metabolized to 6-beta-naltrexoL
Clearance: 20-30 mL/min/kg
Excretion: Morphine: 10% excreted unchanged in urine, 55-65 metabolites excreted in urine
