Nalmefene (Monograph)

Brand name: Revex
Drug class: Opoid Antagonists
- Antidotes
VA class: CN102
Chemical name: (5α)-17-(Cyclopropylmethyl)-4,5-epoxy-6-methylene-morphinan-3,14-diol hydrochloride
Molecular formula: C₂₁H₂₅NO₃•HCl
CAS number: 58895-64-0

Introduction

Synthetic opiate antagonist.

Uses for Nalmefene

Postoperative Opiate Depression

Treatment of opiate-induced depression, including respiratory depression, caused by natural and synthetic opiates.

Opiate Overdosage

Management of known or suspected opiate overdosage.

Nalmefene Dosage and Administration

Administration

Principally administered by IV injection; can be administered by IM or sub-Q injection if venous access cannot be established.

For reversal of postoperative opiate depression, administer blue-labeled commercially available injection containing 100 mcg/mL nalmefene.

For management of known or suspected opiate overdose, administer green-labeled commercially available injection containing 1 mg/mL nalmefene.

Proper steps should be taken to prevent use of incorrect concentration of injection.

IV Administration

Administer as an IV bolus.

Dilution

When used for treatment of postoperative opiate-induced depression in patients with increased cardiovascular risk, it may be desirable to dilute to a final ratio of 1:1 in 0.9% sodium chloride injection or sterile water for injection. (See Cardiovascular Disease under Cautions.)

Dosage

Available as nalmefene hydrochloride; dosage expressed in terms of nalmefene.

Titrate dosage to reverse opiate-induced effects; when adequate opiate reversal has been established, additional doses of nalmefene are not required and may cause unwanted reversal of analgesia or precipitate withdrawal.

Adults

Postoperative Opiate Depression

IV

Initially, 0.25 mcg/kg given at 2- to 5-minute intervals until the desired response is obtained.

Cumulative total dosage >1 mcg/kg does not provide additional therapeutic effect.

Patients at increased cardiovascular risk: Initially, 0.1 mcg/kg given at 2- to 5- minute intervals until desired response is obtained.

Opiate Overdosage

IV

Opiate naive patients: Initially, 7.14 mcg/kg (0.5 mg/70 kg), followed by a second dose of 14.29 mcg/kg (1 mg/70 kg) 2–5 minutes later, if necessary.

If no response is observed after a total dose of 21.43 mcg/kg (1.5 mg/70 kg), additional doses are unlikely to provide therapeutic effect.

Patients suspected of opiate dependency: Initially, 1.43 mcg/kg (100 mcg/70 kg). If no withdrawal is observed within 2 minutes, 7.14 mcg/kg (0.5 mg/70 kg), followed by 14.29 mcg/kg (1 mg/70 kg) 2–5 minutes later, if necessary; observe closely for withdrawal symptoms.

If recurrence of respiratory depression occurs, titrate dosage incrementally to response to avoid over-reversal.

Prescribing Limits

Adults

Postoperative Opiate Depression

IV

Cumulative dosage >1 mcg/kg does not provide additional therapeutic effect.

Opiate Overdosage

IV

Cumulative dosages ≥21.43 mcg/kg (1.5 mg/70 kg) unlikely to increase therapeutic response.

Special Populations

Hepatic Impairment

Decreased clearance; however, dosage adjustment not required.

Renal Impairment

Decreased clearance. Dosage adjustment not required, however, administer incremental doses slowly (e.g., over 60 seconds) to minimize hypertension and dizziness associated with rapid administration in such patients.

Geriatric Patients

Dosage adjustment not required.

Cautions for Nalmefene

Contraindications

• Known hypersensitivity to nalmefene or any ingredient in the formulation.

Warnings/Precautions

Warnings

Additional Resuscitative Measures

When used in emergency settings, other resuscitative measures (e.g., maintenance of an adequate airway, artificial respiration, administration of oxygen, vasopressor agents) should be readily available and used first when necessary.

Respiratory Depression

Risk of recurrent respiratory depression in postoperative and overdose patients after initial response to nalmefene.

Carefully monitor patients who have responded to nalmefene since the duration of action of some opiates (e.g., methadone and levo-alpha-acetylmethadol [LAAM]) may exceed that of nalmefene; monitor patients until there is no reasonable risk of recurrent respiratory depression.

General Precautions

Cardiovascular Disease

Serious adverse cardiovascular effects (e.g., VT and VF, pulmonary edema, hypertension, hypotension, cardiovascular instability) reported in postoperative patients and in emergency department settings following administration of nalmefene; may be associated with excessive doses.

Use with caution in patients with preexisting cardiovascular disease or in those receiving potentially cardiotoxic drugs. Reduced dosage recommended in postoperative patients at high risk for cardiovascular complications. (See Adults under Dosage and Administration.)

Precipitation of Withdrawal

Possible precipitation of acute withdrawal symptoms. Use with extreme caution in patients with known physical dependence on opiates or following surgery involving high doses of opiates.

Observe patients suspected of opiate dependency for symptoms of withdrawal following initial and subsequent nalmefene injections.

Incomplete Reversal of Buprenorphine

Incomplete reversal of buprenorphine-induced analgesia reported in animal models; therefore, nalmefene may not completely reverse buprenorphine-induced respiratory depression.

Seizures

Possible risk of seizures.

Specific Populations

Pregnancy

Category B.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Use caution.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Safety and efficacy not established in neonates, however, nalmefene may be used in the resuscitation of neonates when benefits outweigh the risks.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. (See Special Populations under Pharmacokinetics.)

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Decreased clearance; however, dosage adjustments not recommended because nalmefene is administered as an acute course of therapy.

Renal Impairment

Decreased clearance; administer dosages slowly to minimize adverse effects. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, vomiting, tachycardia, hypertension.

Drug Interactions

Specific Drugs

Nalmefene Pharmacokinetics

Absorption

Bioavailability

Completely absorbed following IM or sub-Q administration; mean bioavailability is about 101.5% and 99.7%, respectively.

Onset

Therapeutic plasma concentrations occurred 5–15 minutes following administration of a single IM or sub-Q dose.

Duration

Duration of opiate antagonist activity is variable and depends on the dose, the half-life and plasma concentration of opiate being reversed, the presence or absence of other drugs affecting the brain or muscles of respiration, and the dose of nalmefene being administered.

Effects persist for not >30–60 minutes following administration of a partial reversing dose (i.e., 1 mcg/kg). Effects may persist for several hours following administration of a full reversing dose (i.e., 1 mg/70 kg).

Distribution

Extent

Rapidly distributed following IV administration, with 80% of brain opiate receptors blocked within 5 minutes of administration.

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

45%.

Elimination

Metabolism

Metabolized in the liver, primarily by glucuronide conjugation to nalmefene glucuronide, an inactive metabolite.

Elimination Route

Excreted principally in urine, mainly as metabolites, and in feces (17%).

Half-life

Biphasic; terminal half-life is approximately 10.8 hours.

Special Populations

In patients with end-stage renal disease, clearance of nalmefene is reduced by 25–27% compared with that in healthy adults and half-life is increased to around 26.1 hours.

In patients with hepatic impairment, clearance of nalmefene is reduced by 28.3%.

In geriatric patients, no substantial differences in clearance, steady-state volume of distribution, or half-life relative to younger adults.

Stability

Storage

Parenteral

Injection

15–30 ºC.

Actions

• A long-acting opiate antagonist.

• Antagonizes the effects of opiates (e.g., respiratory depression, sedation, hypotension).

• In patients who have not recently received opiates, nalmefene exerts no pharmacologic effect.

• Does not produce tolerance, physical dependence, or have abuse potential. May precipitate acute withdrawal in individuals physically dependent on opiates.

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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