Morphine Sulfate / Naltrexone Hydrochloride

Pronunciation

Pronunciation: MORE-feen SUL-fate/nal-TREX-one HYE-droe-KLOR-ide
Class: Opioid agonist/antagonist analgesic

Trade Names

Embeda 20/0.8 mg
- Capsules, ER morphine sulfate 20 mg/naltrexone hydrochloride 0.8 mg

Embeda 30/1.2 mg
- Capsules, ER morphine sulfate 30 mg/naltrexone hydrochloride 1.2 mg

Embeda 50/2 mg
- Capsules, ER morphine sulfate 50 mg/naltrexone hydrochloride 2 mg

Embeda 60/2.4 mg
- Capsules, ER morphine sulfate 60 mg/naltrexone hydrochloride 2.4 mg

Embeda 80/3.2 mg
- Capsules, ER morphine sulfate 80 mg/naltrexone hydrochloride 3.2 mg

Embeda 100/4 mg
- Capsules, ER morphine sulfate 100 mg/naltrexone hydrochloride 4 mg

Pharmacology

Morphine relieves pain by stimulating opiate receptors in CNS; also causes respiratory depression, peripheral vasodilation, inhibition of intestinal peristalsis, sphincter of Oddi spasm, stimulation of chemoreceptors that cause vomiting, and increased bladder tone. Naltrexone is an opioid receptor antagonist that reverses the subjective and analgesic effects of mu-opioid receptor agonists by competitively binding at mu-opioid receptors.

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Indications and Usage

Management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Contraindications

Acute or severe bronchial asthma, hypercapnia, or significant respiratory depression in unmonitored settings or in the absence of resuscitative equipment; patients who have or are suspected of having paralytic ileus; known hypersensitivity to morphine, morphine salts, or naltrexone; any situation where opioids are contraindicated.

Dosage and Administration

Moderate to severe pain
Adults

PO

Initial dosage

The lowest dose of morphine/naltrexone should be used. Do not dose more frequently than every 12 h. Titrate dose no more frequently than every other day to a once- or twice-daily dosage that adequately manages pain. Reduce dose in patients who show signs of excessive opioid adverse effects, such as sedation. Patients on a once-daily dosing regimen who experience inadequate analgesia should be switched to a twice-daily dosage regimen. If breakthrough pain occurs, supplement with a small dose (less than 20% of the total daily dose) of a short-acting analgesic.

Conversion from oral morphine

Administer one-half of the patients total daily oral morphine dose as morphine/naltrexone every 12 h or by administering the total daily oral morphine dose as morphine/naltrexone once daily.

Conversion from parenteral morphine

Generally, a dose of oral morphine 3 times the daily parenteral morphine requirement may a sufficient conversion. It is better to underestimate the patient's 24-hour oral morphine requirement and provide rescue medication.

Conversion from other opioids

Generally, it is safest to give half of the estimated daily morphine demand as the initial dose and manage inadequate analgesia by supplementation with immediate-release morphine.

Discontinuation

Do not abruptly discontinue morphine/naltrexone. Slowly taper daily dose.

General Advice

  • Administer without regard to meals, but administer with food if GI upset occurs.
  • Do not dose more frequently than every 12 h.
  • When converting patients from morphine or other opioids to morphine/naltrexone, the first dose of morphine/naltrexone may be taken with the last dose of immediate-release opioid medication.
  • Capsules and pellets should not be crushed, dissolved, or chewed before swallowing. Do not administer capsules or pellets through nasogastric or gastric tubes.
  • Capsules may be opened and the contents sprinkled on as small amount of applesauce and taken by mouth immediately. Entire portion should be consumed and not divided into separate doses. Rinse mouth to ensure all pellets have been swallowed.
  • The morphine 100 mg/naltrexone 4 mg capsules are for use only in opioid-tolerant patients.

Storage/Stability

Store at 59° to 86°F. Protect from light.

Drug Interactions

Alcohol

Additive CNS depressant effects, including respiratory depression, hypotension, and profound sedation and coma, may occur. In addition, morphine plasma concentrations may be elevated, increasing the risk of a potentially fatal overdose. Avoid coingestion of alcohol and morphine/naltrexone.

Anticholinergic agents (eg, atropine, benztropine)

Risk of urinary retention and/or severe constipation, leading to paralytic ileus, may be increased. Use with caution. If an interaction is suspected, it may be necessary to stop one or both drugs and treat the complication.

Cimetidine

Confusion and respiratory depression have been reported in a dialysis patient receiving morphine and cimetidine. Monitor patients. If excessive CNS or respiratory depression occurs, discontinue both drugs. Administer a narcotic antagonist, if needed.

CNS depressants (eg, hypnotic or sedatives, general anesthetics, other opioids, phenothiazines, tranquilizers)

Additive CNS depressant effects, including respiratory depression, hypotension, and profound sedation and coma, may occur. If coadministered, consider reducing the dose of one or both agents by at least 50%.

Diuretics (eg, furosemide)

Morphine may decrease diuretic efficacy by inducing the release of antidiuretic hormone. In addition, morphine may cause spasms of the bladder sphincter, causing acute urinary retention, especially in men with prostatitis. Use with caution and monitor diuretic response. Be prepared to stop one or both agents and treat the complication.

Mixed agonist/antagonist opioid analgesics (eg, pentazocine, nalbuphine, butorphanol)

The analgesic effect of morphine/naltrexone may be reduced. In addition, withdrawal symptoms may occur. Use with caution.

MAOIs (eg, phenelzine)

The effects of morphine may be potentiated, resulting in anxiety, confusion, respiratory depression, and coma. Do not administer morphine/naltrexone in patients receiving MAOIs or within 14 days of stopping such treatment.

P-glycoprotein inhibitors (eg, quinidine)

Morphine exposure may be increased about 2-fold, increasing the pharmacologic effects and risk of adverse reactions. Use with caution.

Rifamycins (eg, rifampin)

Morphine plasma concentrations may be reduced, decreasing the analgesic effect. Monitor the response of the patients. It may be necessary to increase the morphine/naltrexone dose or administer alternative treatment.

Skeletal muscle relaxants (eg, cyclobenzaprine)

Neuromuscular blocking action of skeletal muscle relaxants may be increased, producing respiratory depression. If coadministration is necessary, monitor neuromuscular function, titrate the muscle relaxant dose, and be prepared to provide mechanical respiratory support when needed.

Laboratory Test Interactions

Naltrexone may or may not interfere with enzymatic methods for the detection of opioids, depending on the specificity of the test. Consult the test manufacturer for specific details.

Adverse Reactions

Cardiovascular

Flushing (2%); hot flush (1% to less than 10%).

CNS

Somnolence (14%); psychiatric disorders (9%); dizziness (8%); headache (7%); fatigue (4%); insomnia (3%); anxiety (2%); depression, irritability, lethargy, restlessness, sedation, tremor (1% to less than 10%).

Dermatologic

Pruritus (6%); hyperhidrosis (3%).

GI

Constipation (31%); nausea (22%); vomiting (8%); diarrhea (7%); dry mouth (6%); upper abdominal pain (2%); dyspepsia, flatulence, stomach discomfort (1% to less than 10%).

Metabolic-Nutritional

Anorexia, decreased appetite (1% to less than 10%).

Musculoskeletal

Arthralgia, muscle spasms (1% to less than 10%).

Miscellaneous

Chills, peripheral edema (1% to less than 10%).

Precautions

Warnings

Morphine/naltrexone has an abuse liability similar to other opioid analgesics. Morphine/naltrexone is 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. Morphine/naltrexone is not intended for use as an as-needed analgesic. Morphine 100 mg/naltrexone 4 mg is for use in opioid-tolerant patients only. Patients should not consume alcoholic beverages or use medications containing alcohol while on therapy with morphine/naltrexone; this may result in a potentially fatal overdose of morphine. The pellets in the capsules are not to be crushed, dissolved, or chewed; rapid release and absorption may result in a potentially fatal dose of morphine and the release of naltrexone may precipitate withdrawal in opioid-tolerant patients.


Monitor

Asses pain type and intensity prior to administration. Assess efficacy of pain relief during therapy and monitor for adverse reactions.


Pregnancy

Category C .

Lactation

Excreted in breast milk (morphine); undetermined (naltrexone).

Children

Safety and efficacy not established.

Elderly

Use with caution and in reduced doses. Respiratory depression occurs more frequently and is more dangerous in elderly patients.

Hypersensitivity

Cases of anaphylaxis have been reported with use of a similar ER morphine formulation.

Renal Function

Use with caution and in reduced dosages in patients with severe renal impairment.

Hepatic Function

Use with caution and in reduced dosages in patients with severe hepatic impairment.

Special Risk Patients

Use with caution and in reduced dosages in elderly or debilitated patients; patients with Addison disease, hypothyroidism, myxedema, prostatic hypertrophy, or urethral stricture; use with caution in patients with acute alcoholism, CNS depression, delirium tremens, toxic psychosis, or seizure disorder.

Accidental precipitation of withdrawal

Severe opioid withdrawal syndromes may be precipitated in opioid-dependent patients by consuming morphine/naltrexone that has been crushed, chewed, or dissolved because of the release of naltrexone. Withdrawal symptoms may appear within 5 min and last 48 h.

Cordotomy

Discontinue therapy 24 h prior to cordotomy or other interruption of pain transmission pathways and control pain with parenteral short-acting opioids.

Drug dependence

Morphine/naltrexone has abuse potential.

GI effects

Avoid in patients with GI obstruction, particularly paralytic ileus. Morphine may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Head injury/increased intracranial pressure

Respiratory depressant effects with carbon dioxide retention and secondary elevation of CSF pressure may be exaggerated. Morphine/naltrexone may also produce effects on pupillary response and consciousness, obscuring neurologic signs of further increases in pressure in patients with head injuries.

Hypotension

May cause severe hypotension and syncope. Use with caution in patients with circulatory shock.

Pancreatic/Biliary tract disease

May cause spasm of the sphincter of Oddi; use with caution in patients with biliary tract disease, including pancreatitis.

Opioid withdrawal

May occur if abruptly discontinued; slowly taper to prevent withdrawal.

Respiratory depression

May occur; use with extreme caution in patients with COPD or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.

Overdosage

Symptoms

Bradycardia; cold and clammy skin; constricted pupils; hypotension; pulmonary edema; respiratory depression; skeletal muscle flaccidity; somnolence progressing to stupor or coma.

Patient Information

  • Advise patients to take only as directed and not to adjust the dose without consulting with their health care provider. If used for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the dose, rather than abruptly discontinue therapy.
  • Instruct patients to swallow capsules whole or open and sprinkle the contents on a small amount of applesauce immediately prior to ingestion. Capsules or the contents should not be crushed, dissolved, or chewed.
  • Advise patients not to consume alcoholic beverages or use medications containing alcohol while on this medication. Coingestion of alcohol may result in an increase of plasma levels and a potentially fatal overdose.
  • Advise patients of the most common adverse reactions, including constipation, dizziness, headache, nausea, pruritus, somnolence, and vomiting.
  • Advise patients that morphine/naltrexone may cause drowsiness, dizziness, or light-headedness, and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (eg, driving, operating machinery).
  • Advise patients not to combine with CNS depressants (eg, sleep aids, tranquilizers) except by the order of their health care provider because dangerous additive effects may occur, resulting in serious injury or death.
  • Inform patients that morphine/naltrexone is a potential drug of abuse and that they should protect it from theft.
  • Advise patients to take special care to avoid accidental ingestion or use by individuals, including children, other than the patient for whom it was originally prescribed, as such use may have potentially severe, even fatal, consequences.
  • Women of childbearing potential who become or plan to become pregnant should consult a health care provider prior to initiating or continuing therapy. Safe use in pregnancy has not been established; prolonged use of opioids during pregnancy may cause neonatal physical dependence and withdrawal.
  • Advise patients 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.
  • Advise patients to seek medical attention if signs of a serious allergic reaction occur, such as swelling of the face, throat, or tongue, trouble breathing, feeling dizzy or faint, pounding heartbeat, chest pain, or feeling of doom.
  • Advise patients to report episodes of breakthrough pain and adverse experiences during therapy.

Copyright © 2009 Wolters Kluwer Health.

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