Pharmacodynamics

Nalmefene hydrochloride injection prevents or reverses the effects of opioids, including respiratory depression, sedation, and hypotension. Pharmacodynamic studies have shown that Nalmefene hydrochloride injection has a longer duration of action than naloxone at fully reversing doses. Nalmefene hydrochloride injection has no opioid agonist activity.

Nalmefene hydrochloride injection is not known to produce respiratory depression, psychotomimetic effects, or pupillary constriction. No pharmacological activity was observed when nalmefene hydrochloride injection was administered in the absence of opioid agonists.

Nalmefene hydrochloride injection has not been shown to produce tolerance, physical dependence, or abuse potential.

Nalmefene hydrochloride injection can produce acute withdrawal symptoms in individuals who are opioid dependent.

Pharmacokinetics

Nalmefene exhibited dose proportional pharmacokinetics following intravenous administration of 0.5 mg to 2 mg. Pharmacokinetic parameters for nalmefene after a 1 mg intravenous administration in adult male volunteers are listed in Table 1.

Reversal of Postoperative Opioid Depression

Nalmefene hydrochloride injection (N=326) was studied in 5 controlled trials in patients who had received morphine or fentanyl intraoperatively. The primary efficacy criterion was the reversal of respiratory depression. A positive reversal was defined as both an increase in respiratory rate by 5 breaths per minute and a minimum respiratory rate of 12 breaths per minute. Five minutes after administration, initial single nalmefene hydrochloride injection doses of 0.1, 0.25, 0.5, or 1 mcg/kg had effectively reversed respiratory depression in a dose-dependent manner. Twenty minutes after initial administration, respiratory depression had been effectively reversed in most patients receiving cumulative doses within the recommended range (0.1 to 1 mcg/kg). Total doses of nalmefene hydrochloride injection above 1 mcg/kg did not increase the therapeutic response. The postoperative administration of nalmefene hydrochloride at the recommended doses did not prevent the analgesic response to subsequently administered opioids.

Reversal of the Effect of Intrathecally Administered Opioids

Intravenous nalmefene hydrochloride at doses of 0.5 and 1 mcg/kg was administered to 47 patients given intrathecal morphine. One to 2 doses of 0.5 and 1 mcg/kg nalmefene hydrochloride reversed respiratory depression in most patients. The administration of nalmefene hydrochloride at the recommended doses did not prevent the analgesic response to subsequently administered opioids.

Management of Known or Suspected Opioid Overdose

Nalmefene hydrochloride injection (N=284) at doses of 0.5 mg to 2 mg was studied in 4 trials of patients who were presumed to have taken an opioid overdose. Nalmefene hydrochloride injection doses of 0.5 mg to 1 mg effectively reversed respiratory depression within 2 to 5 minutes in most patients subsequently confirmed to have opioid overdose. A total dose greater than 1.5 mg did not increase the therapeutic response.

Use of Nalmefene Hydrochloride Injection in Emergencies

Nalmefene hydrochloride injection, like all drugs in this class, is not the primary treatment for ventilatory failure. In most emergency settings, treatment with nalmefene hydrochloride injection should follow, not precede, the establishment of a patent airway, ventilatory assistance, administration of oxygen, and establishment of circulatory access.

Risk of Recurrent Respiratory Depression

Accidental overdose with long acting opioids [such as methadone and levo-alpha-acetylmethadol (LAAM)] may result in prolonged respiratory depression. Respiratory depression in both the postoperative and overdose setting may be complex and involve the effects of anesthetic agents, neuromuscular blockers, and other drugs. While nalmefene hydrochloride injection has a longer duration of action than naloxone in fully reversing doses, the physician should be aware that a recurrence of respiratory depression is possible, even after an apparently adequate initial response to nalmefene hydrochloride injection treatment.

Patients treated with nalmefene hydrochloride injection should be observed until, in the opinion of the physician, there is no reasonable risk of recurrent respiratory depression.

General

Drug Interactions

Nalmefene hydrochloride injection has been administered after benzodiazepines, inhalational anesthetics, muscle relaxants, and muscle relaxant antagonists administered in conjunction with general anesthesia. It also has been administered in outpatient settings, both in trials in conscious sedation and in the emergency management of overdose following a wide variety of agents. No deleterious interactions have been observed.

Preclinical studies have shown that both flumazenil and nalmefene can induce seizures in animals. The coadministration of both flumazenil and nalmefene produced fewer seizures than expected in a study in rodents, based on the expected effects of each drug alone. Based on these data, an adverse interaction from the coadministration of the two drugs is not expected, but physicians should remain aware of the potential risk of seizures from agents in these classes.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Nalmefene did not have mutagenic activity in the Ames test with five bacterial strains or the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test or in the cytogenic bone marrow assay in rats. However, nalmefene did exhibit a weak but significant clastogenic activity in the human lymphocyte metaphase assay in the absence but not in the presence of exogenous metabolic activation. Oral administration of nalmefene up to 1200 mg/m2/day did not affect fertility, reproductive performance, and offspring survival in rats.

Use in Pregnancy

Reproduction studies have been performed in rats (up to 1200 mg/m2/day) and rabbits (up to 2400 mg/m2/day) by oral administration of nalmefene and in rabbits by intravenous administration up to 96 mg/m2/day (114 times the human dose). There was no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Nalmefene and its metabolites were secreted into rat milk, reaching concentrations approximately three times those in plasma at one hour and decreasing to about half the corresponding plasma concentrations by 24 hours following bolus administration. As no clinical information is available, caution should be exercised when nalmefene hydrochloride injection is administered to a nursing woman.

Use in Pediatric Patients

Safety and effectiveness of nalmefene hydrochloride injection in pediatric patients have not been established.

Use in Neonates

The safety and effectiveness of nalmefene hydrochloride injection in neonates have not been established in clinical studies. In a preclinical study, nalmefene was administered by subcutaneous injection to rat pups at doses up to 205 mg/m2/day throughout maternal lactation without producing adverse effects. A preclinical study evaluating the irritancy of the dosage form following arterial and venous administration in animals showed no vascular irritancy.

Nalmefene hydrochloride injection should only be used in the resuscitation of the newborn when, in the opinion of the treating physician, the expected benefits outweigh the risks.

Geriatric Use

Clinical studies of nalmefene hydrochloride injection did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.

Incidence less than 1%

CARDIOVASCULAR: Bradycardia, arrhythmia

DIGESTIVE: Diarrhea, dry mouth

NERVOUS SYSTEM: Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus

RESPIRATORY: Pharyngitis

SKIN: Pruritus

UROGENITAL: Urinary retention

The incidence of adverse events was highest in patients who received more than the recommended dose of nalmefene hydrochloride injection.

Important Information - Dosage Form

Nalmefene hydrochloride injection is supplied in a 2 mL vial as a 1 mg/mL concentration suitable for the management of overdose. Proper steps should be taken to prevent use of the incorrect concentration.

General Principles

Nalmefene hydrochloride injection should be titrated to reverse the undesired effects of opioids. Once adequate reversal has been established, additional administration is not required and may actually be harmful due to unwanted reversal of analgesia or precipitated withdrawal.

Duration of Action

The duration of action of nalmefene hydrochloride injection is as long as most opioid analgesics. The apparent duration of action of nalmefene hydrochloride injection will vary, however, depending on the half-life and plasma concentration of the narcotic being reversed, the presence or absence of other drugs affecting the brain or muscles of respiration, and the dose of nalmefene hydrochloride injection administered. Partially reversing doses of nalmefene hydrochloride injection (1 mcg/kg) lose their effect as the drug is redistributed through the body, and the effects of these low doses may not last more than 30 to 60 minutes in the presence of persistent opioid effects. Fully reversing doses (1 mg/70 kg) have been shown to last many hours in both experimental and clinical studies, but may complicate the management of patients who are in pain, at high cardiovascular risk, or who are physically dependent on opioids.

The recommended doses represent a compromise between a desirable controlled reversal and the need for prompt response and adequate duration of action. Using higher dosages or shorter intervals between incremental doses is likely to increase the incidence and severity of symptoms related to acute withdrawal such as nausea, vomiting, elevated blood pressure, and anxiety.

Patients Tolerant to or Physically Dependent on Opioids

Nalmefene hydrochloride injection may cause acute withdrawal symptoms in individuals who have some degree of tolerance to and dependence on opioids. These patients should be closely observed for symptoms of withdrawal following administration of the initial and subsequent injections of nalmefene hydrochloride injection. Subsequent doses should be administered with intervals of at least 2 to 5 minutes between doses to allow the full effect of each incremental dose of nalmefene hydrochloride injection to be reached.

Management of Known or Suspected Opioid Overdose

The recommended initial dose of nalmefene hydrochloride injection for non-opioid dependent patients is 0.5 mg/70 kg. If needed, this may be followed by a second dose of 1 mg/70 kg, 2 to 5 minutes later. If a total dose of 1.5 mg/70 kg has been administered without clinical response, additional nalmefene hydrochloride injection is unlikely to have an effect. Patients should not be given more nalmefene hydrochloride injection than is required to restore the respiratory rate to normal, thus minimizing the likelihood of cardiovascular stress and precipitated withdrawal syndrome.

If there is a reasonable suspicion of opioid dependency, a challenge dose of nalmefene hydrochloride injection 0.1 mg/70 kg should be administered initially. If there is no evidence of withdrawal in 2 minutes, the recommended dosing should be followed.

Nalmefene hydrochloride injection had no effect in cases where opioids were not responsible for sedation and hypoventilation. Therefore, patients should only be treated with nalmefene hydrochloride injection when the likelihood of an opioid overdose is high, based on a history of opioid overdose or the clinical presentation of respiratory depression with concurrent pupillary constriction.

Repeated Dosing

Nalmefene hydrochloride injection is the longest acting of the currently available parenteral opioid antagonists. If recurrence of respiratory depression does occur, the dose should again be titrated to clinical effect using incremental doses to avoid over-reversal.

Hepatic and Renal Disease

Hepatic disease and renal failure substantially reduce the clearance of nalmefene (see Pharmacokinetics). For single episodes of opioid antagonism, adjustment of nalmefene hydrochloride injection dosage is not required. However, in patients with renal failure, the incremental doses should be delivered slowly (over 60 seconds) to minimize the hypertension and dizziness reported following the abrupt administration of nalmefene to such patients.

Loss of Intravenous Access

Should intravenous access be lost or not readily obtainable, a pharmacokinetic study has shown that a single dose of nalmefene hydrochloride injection should be effective within 5 to 15 minutes after intramuscular or subcutaneous doses of 1 mg (see Pharmacokinetics).

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Store in original carton.

Protect from light.

Discard unused portion.

For additional information, contact Purdue Pharma's Medical Services Department @ 1-888-726-7535.