Nalmefene is an opioid antagonist, indicated for the complete or partial reversal of opioid drug effects (i.e., respiratory depression, sedation, hypotension) and for the management of known or suspected opioid overdose. The drug is a 6-methylene analog of naltrexone, that has a longer duration of action than naloxone at fully reversing doses. Nalmefene has no opioid agonist activity and does not produce tolerance, physical dependency, or abuse potential. The drug is available in a unit-dose nasal spray device and as a solution for injection. Although the solution for injection is primarily administered as an intravenous bolus injection, nalmefene can be given intramuscularly or subcutaneously if venous access cannot be established.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Primarily administered as a bolus intravenous injection; however, intramuscular or subcutaneous injections can be given if IV access is lost or not readily obtainable.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
IV Bolus Injection
-IV bolus injection is the primary route of administration.
-Incremental IV doses in patients with renal failure should be administered slowly (over 60 seconds) to minimize hypertension and dizziness.
Intramuscular Administration
-Inject into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.
-Therapeutic effects of a single IM dose should occur within 5 to 15 minutes.
-Due to the variable speed of drug absorption and the inability to titrate to effect, great care is advised if repeated IM doses must be administered.
Subcutaneous Administration
-Inject subcutaneously taking care not to inject intradermally.
-Therapeutic effects of a single subcutaneous dose should occur within 5 to 15 minutes.
-Due to the variable speed of drug absorption and the inability to titrate to effect, great care is advised if repeated subcutaneous doses must be administered.
Inhalation Administration
Intranasal Inhalation Administration
Preparation of Caregivers and Family
-Alert others about the presence of nalmefene nasal spray, as administration must be performed by someone other than the patient. Family members, caregivers, or other people who may have to use nalmefene in an opioid emergency should know the signs and symptoms of opioid overdose, where the nasal spray is stored, and how to administer the drug before an opioid emergency occurs. Once obtained, become familiar with how to use the nasal spray by reading the Instructions for Use.
-Those who administer nalmefene should be aware that its use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal can be life-threatening and must be treated immediately.
-Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Repeated administrations of nalmefene may be needed.
Administration
-Administer nalmefene nasal spray as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt. Prolonged respiratory depression may result in central nervous system damage or death.
-Hold the device with your thumb on the white plunger and your fingers on either side of the nozzle. DO NOT prime or test the device prior to administration.
-Place the patient on their back. Assure that the device nozzle is inserted into 1 of the patient's nostrils and provide support to the back of the neck to allow the head to tilt back.
-Press firmly on the device plunger to administer the dose. The dose has been delivered when the white plunger has been pushed all the way down until it stops.
-Remove the device nozzle from the nostril.
-Turn the patient on their side (recovery position) and seek immediate medical assistance after the first dose of nalmefene has been administered. Additional supportive and resuscitative measures may be helpful while awaiting emergency medical assistance. Keep the patient under continued surveillance until emergency personnel arrive and administer repeated nalmefene doses as necessary.
-Do NOT attempt to reuse the nalmefene nasal spray device; each device contains a single dose.
-Using a new nasal spray device, readminister nalmefene every 2 to 5 minutes if the patient does not respond or responds and then relapses into respiratory depression. The requirement for repeat doses depends on the amount, type, and route of administration of the opioid being antagonized.
-Administer the nasal spray in alternate nostrils with each dose.
-After use, put the device back into its box and dispose of properly.
-Replace the product before its expiration date.
Gastrointestinal (GI) adverse reactions reported with injectable nalmefene during clinical trials included nausea (18%), vomiting (9%), diarrhea (less than 1%), and xerostomia (less than 1%). The incidence of adverse reactions increased with doses higher than recommended. GI events reported during the nalmefene nasal spray clinical trials included nausea (4.2% to 16.7%), vomiting (4.3% to 6%), xerostomia (0.7% to 4.3%), constipation (4.2%), decreased appetite or anorexia (2%), and abdominal pain (1.3%).
Although not reported in humans, seizures have been associated with nalmefene use in animals. Use cautiously in patients with a history of seizures.
During clinical trials, elevated hepatic enzymes were reported in 0.3% of patients receiving either nalmefene or naloxone. The clinical significance of this finding is not known. No cases of hepatitis or hepatic injury due to either drug were observed.
The most common neurologic adverse reactions reported with injectable nalmefene during clinical trials included dizziness (3%) and headache (1%). Other less common neurologic reactions (less than 1%) included drowsiness, depression, agitation, nervousness, tremor, confusion, and myoclonia. The incidence of adverse reactions increased with doses higher than recommended. Neurologic reactions reported during the nalmefene nasal spray clinical trials included headache (4.3% to 26.7%), dizziness (4.2% to 9.3%), anxiety (4.7%), paresthesias (1.3% to 4.3%), presyncope (4.3%), fatigue (4%), dysgeusia (2%), agitation (1.3%), claustrophobia (1.3%), and insomnia (0.7% to 4.3%).
The most common cardiovascular adverse reactions reported with injectable nalmefene during clinical trials included sinus tachycardia (5%) and hypertension (5%). Other less common cardiovascular events (1% or less) included sinus bradycardia, arrhythmia exacerbation, hypotension, and peripheral vasodilation. The incidence of adverse reactions increased with doses higher than recommended. Cardiovascular reactions reported during the nalmefene nasal spray clinical trials included flushing (8%), chest pain (unspecified) (4.3%), and sinus tachycardia (4.3%).
Pruritus was reported by less than 1% of patients who received injectable nalmefene during clinical trials. Dermatologic reactions reported during the nalmefene nasal spray clinical trials included erythema (2% to 4.3%), hyperhidrosis (2% to 4.2%), and urticaria (4.2%).
Fever (3%), chills (1%), and pharyngitis (less than 1%) were reported by recipients of injectable nalmefene during clinical trials. The incidence of adverse reactions increased with doses higher than recommended. Adverse reactions reported during the nalmefene nasal spray clinical trials included nasal irritation or discomfort (13% to 28.7%), nasal congestion (4% to 16.7%), throat irritation (4%), rhinalgia (2.7% to 25%), dyspnea (1.3%), oropharyngeal pain (1.3% to 4.3%), chills (1.3%), and rhinitis (0.7% to 4.3%).
Postoperative pain (4%) and urinary retention (less than 1%) were reported by recipients of injectable nalmefene during clinical trials. The incidence of adverse reactions increased with doses higher than recommended. Dry eyes or xerophthalmia was reported by 4.3% of patients receiving nalmefene nasal spray during clinical trials.
Nalmefene will produce symptoms of opioid withdrawal if administered to an opioid-dependent person. Signs and symptoms of withdrawal in persons who are physically dependent on opioids have included body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia, and aggressive behavior. In neonates, opioid withdrawal symptoms also included convulsions, excessive crying, and hyperactive reflexes. Abrupt reversal of opioid depression using nalmefene in both postoperative and emergency department settings has resulted in nausea, vomiting, sweating, tremulousness, hypertension, hypotension, tachycardia, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequela of these events. Also, nalmefene at doses greater than recommended produced symptoms of endogenous opioid antagonism, which included nausea, chills, myalgia, dysphoria, abdominal cramps, and arthralgia.
Although the duration of action of nalmefene is as long as most opioids, recurrence of respiratory depression is possible, even after an adequate initial response to treatment. Therefore, emergency medical assistance must be sought immediately after delivering the first dose of nalmefene nasal spray. The patient must remain under continued surveillance, and repeat doses of nalmefene nasal spray should be administered as necessary. Additional supportive and resuscitative measures may be helpful while awaiting emergency medical assistance.
Reversal of respiratory depression by partial agonists or mixed agonist/antagonists (e.g., buprenorphine and pentazocine) may be incomplete. Repeat doses of nalmefene nasal spray may be required to antagonize buprenorphine because buprenorphine has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Antagonism of buprenorphine is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.
Seizures have been associated with nalmefene use in animals. Although they have not been reported in humans, use cautiously in patients with a history of a seizure disorder or receiving drugs known to induce seizures.
Administer nalmefene cautiously to patients with cardiac arrhythmias, other cardiac disease, or concurrently receiving potentially cardiotoxic drugs. In patients at high risk for cardiovascular complications, abrupt opioid reversal in the postoperative setting (through imprudent use or excessive doses of opioid antagonists) has been associated with nausea, vomiting, sweating, tremulousness, hypertension, hypotension, tachycardia, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequela of these events. After use of nalmefene in these patients, monitor for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting. The pathogenesis of nalmefene-associated pulmonary edema may be similar to neurogenic pulmonary edema (i.e., centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures).
Clinical studies of nalmefene did not include sufficient number of geriatric subjects (65 years and older) 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.
Although no adequate and well-controlled studies have been conducted to evaluate the use of nalmefene during human pregnancy, life-sustaining therapy for opioid overdose should not be withheld. In animal studies, no evidence of impaired fertility or harm to the fetus have been identified.
Administer nalmefene cautiously to patients with opioid dependence or known to have substance abuse habits, as use of the drug in these patients may precipitate acute opioid withdrawal. Closely monitor these patients for symptoms of withdrawal after administration of the initial and subsequent doses. Signs and symptoms of withdrawal include body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea, vomiting, nervousness, restlessness, irritability, shivering, trembling, abdominal cramps, weakness, and increased blood pressure. Patients who experience a withdrawal reaction after receiving nalmefene should receive symptomatic and supportive care. Administration of large amounts of opioids to patients receiving opioid antagonists, such as nalmefene, in an attempt to overcome a full blockade has resulted in adverse respiratory and circulatory reactions. Inform patients of the potential consequences of trying to overcome the opioid blockage.
The plasma clearance of nalmefene may be substantially reduced in patient with renal disease. Rapid administration of the drug to these patients may result in dizziness and hypertension. Administer incremental doses of nalmefene slowly (i.e., over 60 seconds) to patients with renal failure.
Because nalmefene is indicated for reversal of narcotic depressant effects or acute opioid overdose, treatment should not be withheld in a woman who is breast-feeding. There is no clinical information available on the use of nalmefene during breast-feeding or its presence in human milk. Nalmefene and its metabolites are excreted into rat milk, with peak concentrations of about 3-times those in plasma at 1 hour after administration. Naloxone, an alternate treatment for reversal of narcotic toxicity, has been administered to newborns following in utero exposure to narcotics with no adverse effects reported.
Nalmefene nasal spray is not approved for use in patients younger than 12 years. Additionally, safety and efficacy of the injectable formulation has not been established in any pediatric population (i.e., neonates, infants, children, and adolescents). However, in newborns, injectable nalmefene may be used for resuscitation ONLY WHEN, in the opinion of the treating physician, the expected benefits outweigh the risks. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Signs and symptoms of opioid withdrawal in neonates include convulsions, excessive crying, and hyperactive reflexes. Monitor for the development of opioid withdrawal. There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. In these settings, use an alternative opioid antagonist that can be titrated to effect and doses according to weight.
For known or suspected opioid overdose:
Intravenous dosage:
NOTE: Only use when the likelihood of an opioid overdose is high, based on a history of opioid overdose or clinical presentation of respiratory depression with concurrent pupillary constriction. Nalmefene provides no clinical benefit in cases where opioids were not responsible for sedation and hypoventilation.
Non-opioid-dependent Adults: 0.5 mg/70 kg IV. If needed, a second dose of 1 mg/70 kg IV may be given 2 to 5 minutes later. If no clinical response is observed, additional doses are unlikely to have an effect. Use the lowest effective dose.
Known or suspected opioid-dependent Adults: 0.1 mg/70 kg IV as an initial challenge dose. If there is no evidence of withdrawal after 2 minutes, give 0.5 mg/70 kg IV. If needed, a second dose of 1 mg/70 kg IV may be given 2 to 5 minutes later. If no clinical response is observed, additional doses are unlikely to have an effect. Use the lowest effective dose.
Intramuscular or Subcutaneous dosage (only if IV access is lost or not readily obtainable):
NOTE: Only use when the likelihood of an opioid overdose is high, based on a history of opioid overdose or clinical presentation of respiratory depression with concurrent pupillary constriction. Nalmefene provides no clinical benefit in cases where opioids were not responsible for sedation and hypoventilation.
Adults: 1 mg IM or subcutaneously as a single dose.
Intranasal dosage:
NOTE: Intended for immediate administration as emergency therapy in settings where opioids may be present. Administration of the nasal spray is not a substitute for emergency medical care.
Adults: 2.7 mg (1 spray) intranasally every 2 to 5 minutes in alternating nostrils as needed. Each device contains a single dose. Seek immediate medical assistance after administration of the first dose. Monitor the patient closely until emergency medical personnel arrive. If the patient responds to treatment and subsequently relapses back into respiratory depression before medical assistance arrives, administer an additional dose in the opposite nostril.
Children and Adolescents 12 to 17 years: 2.7 mg (1 spray) intranasally every 2 to 5 minutes in alternating nostrils as needed. Each device contains a single dose. Seek immediate medical assistance after administration of the first dose. Monitor the patient closely until emergency medical personnel arrive. If the patient responds to treatment and subsequently relapses back into respiratory depression before medical assistance arrives, administer an additional dose in the opposite nostril.
For complete or partial reversal of opiate agonist-induced respiratory depression, sedation, and hypotension:
Intravenous dosage:
Adults: Titrate to reverse the undesired opioid effects with a partial reversing dose of 1 mcg/kg or a full reversal dose of 1 mg/70 kg. Once adequate reversal has been established, additional administration is not required and may be harmful due to unwanted reversal of analgesia or precipitation of withdrawal. The duration of action depends 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 nalmefene dose being administered. If respiratory depression reoccurs, the dose should again be titrated to clinical effect using incremental doses to avoid over-reversal.
Maximum Dosage Limits:
-Adults
1 mcg/kg per dose IV for partial opioid reversal; 1 mg/70 kg per dose IV for full opioid reversal; 1 mg/70 kg per dose IV for opioid overdose; 1 mg IM or subcutaneously for opioid overdose; 2.7 mg (1 spray) per dose intranasally for opioid overdose.
-Geriatric
1 mcg/kg per dose IV for partial opioid reversal; 1 mg/70 kg per dose IV for full opioid reversal; 1 mg/70 kg per dose IV for opioid overdose; 1 mg IM or subcutaneously for opioid overdose; 2.7 mg (1 spray) per dose intranasally for opioid overdose.
-Adolescents
2.7 mg (1 spray) per dose intranasally for opioid overdose; safety and efficacy of injectable formulation have not been established.
-Children
12 years: 2.7 mg (1 spray) per dose intranasally for opioid overdose; safety and efficacy of injectable formulation have not been established.
1 to 11 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are required for single episodes of opioid antagonism.
Patients with Renal Impairment Dosing
No dosage adjustments are required for single episodes of opioid antagonism; however, in patients with renal failure, incremental intravenous doses should be delivered slowly (i.e., over 60 seconds) to minimize hypertension and dizziness.
*non-FDA-approved indication
Buprenorphine: (Major) Naloxone, nalmefene, and naltrexone act as opiate antagonists at all opiate receptors. Administration of an opiate antagonist will override the actions of mixed opiate agonist/antagonists and precipitate opioid withdrawal effects. While opiate antagonism may be desirable in a patient with respiratory depression caused by the mixed opiate agonist/antagonist, severe pain can be unmasked and opiate withdrawal symptoms may occur in patients who have received chronic opiate agonist therapy.
Buprenorphine; Naloxone: (Major) Naloxone, nalmefene, and naltrexone act as opiate antagonists at all opiate receptors. Administration of an opiate antagonist will override the actions of mixed opiate agonist/antagonists and precipitate opioid withdrawal effects. While opiate antagonism may be desirable in a patient with respiratory depression caused by the mixed opiate agonist/antagonist, severe pain can be unmasked and opiate withdrawal symptoms may occur in patients who have received chronic opiate agonist therapy.
Butorphanol: (Major) Naloxone, nalmefene, and naltrexone act as opiate antagonists at all opiate receptors. Administration of an opiate antagonist will override the actions of mixed opiate agonist/antagonists and precipitate opioid withdrawal effects. While opiate antagonism may be desirable in a patient with respiratory depression caused by the mixed opiate agonist/antagonist, severe pain can be unmasked and opiate withdrawal symptoms may occur in patients who have received chronic opiate agonist therapy.
Flumazenil: (Minor) Based on available animal data, an adverse interaction from the coadministration of these 2 drugs is not expected, but physicians should remain aware of the potential risk of seizures from agents in these classes. 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. In humans, nalmefene 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.
Methylnaltrexone: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Nalbuphine: (Major) Naloxone, nalmefene, and naltrexone act as opiate antagonists at all opiate receptors. Administration of an opiate antagonist will override the actions of mixed opiate agonist/antagonists and precipitate opioid withdrawal effects. While opiate antagonism may be desirable in a patient with respiratory depression caused by the mixed opiate agonist/antagonist, severe pain can be unmasked and opiate withdrawal symptoms may occur in patients who have received chronic opiate agonist therapy.
Naldemedine: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Naloxegol: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Opiate Agonists-Antagonists: (Major) Naloxone, nalmefene, and naltrexone act as opiate antagonists at all opiate receptors. Administration of an opiate antagonist will override the actions of mixed opiate agonist/antagonists and precipitate opioid withdrawal effects. While opiate antagonism may be desirable in a patient with respiratory depression caused by the mixed opiate agonist/antagonist, severe pain can be unmasked and opiate withdrawal symptoms may occur in patients who have received chronic opiate agonist therapy.
Pentazocine; Naloxone: (Major) Naloxone, nalmefene, and naltrexone act as opiate antagonists at all opiate receptors. Administration of an opiate antagonist will override the actions of mixed opiate agonist/antagonists and precipitate opioid withdrawal effects. While opiate antagonism may be desirable in a patient with respiratory depression caused by the mixed opiate agonist/antagonist, severe pain can be unmasked and opiate withdrawal symptoms may occur in patients who have received chronic opiate agonist therapy.
Nalmefene, like naloxone, is essentially a pure opioid receptor antagonist with little or no agonistic activity. In patients who have not recently received opiate agonists, nalmefene shows little or no pharmacological effects, even at high doses. Opioid receptors include mu, kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Mu receptors are responsible for analgesia, euphoria, respiratory depression, and miosis; kappa-receptors, are responsible for analgesia, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization) and sedation; and delta-receptors mediate analgesia, sedation, and possibly hormonal and neurotransmitter release. Since nalmefene has essentially the same effects as naloxone, it can be assumed that nalmefene antagonizes mu-, kappa-, and delta-receptors, however, unlike naloxone, this antagonism lasts longer. Thus, repeat doses of nalmefene may only be required when long-acting opioids (i.e., methadone) are involved. Nalmefene itself produces no physical or psychological dependence and will not worsen respiratory depression if administered for non-opioid overdose.
Based on pre-clinical trials, the manufacturer reports that nalmefene in doses of up to 10 mg/kg (437-times the recommended maximum human dosage) does not completely reverse butorphanol-induced analgesia in animal models. This occurs because of butorphanol's high affinity and slow displacement from opioid receptors. Therefore, nalmefene may not completely reverse the respiratory depression produced by butorphanol.
Nalmefene antagonizes both the toxic and clinical effects of opioids. Thus, not only are respiratory depression, hypotension, and sedation reversed, but so is analgesia. Clinicians should use discretion when considering administering nalmefene to patients who are sedated from opioids but do not exhibit respiratory depression. Reversal of analgesia is undesirable in patients known to be in severe pain. Nalmefene should not be used for drowsiness unless opioid-induced respiratory depression coexists.
Nalmefene is administered intravenously, subcutaneously, intramuscularly, or intranasally. Once absorbed, nalmefene is rapidly distributed with over 80% of brain opioid receptors occupied within 5 minutes of administration. The apparent volumes of distribution centrally and at steady-state are 3.9 +/- 1.1 L/kg and 8.6 +/- 1.7 L/kg, respectively. Nalmefene distributes 67% into red blood cells and 39% into plasma, with a plasma protein binding of approximately 45% over a concentration range of 0.1 to 2 mcg/mL. The whole blood to plasma ratio is 1.3. Metabolism occurs via the liver to a primary glucuronide conjugate and trace amounts of a N-dealkylated metabolite. These metabolites have minimal or no pharmacological activity. Less than 5% of nalmefene is excreted in the urine unchanged, and 17% of the nalmefene dose is excreted in the feces. Based on plasma concentration-time profiles in some patients, it is suggested that nalmefene undergoes enterohepatic recirculation. The redistribution and terminal elimination half-life after a 1 mg IV dose is 41 +/- 34 minutes and 10.8 +/- 5.2 hours, respectively.
Affected cytochrome P450 isoenzymes and/or drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
After a single 1 mg IV dose to 18 adult males, nalmefene concentrations were 3.7 ng/mL at 5 minutes post-dose and systemic exposure (AUC) was 16.6 ng/mL x hour.
Intramuscular Route
Nalmefene is completely bioavailable after IM administration, with a relative bioavailability of 101.5% +/- 8.1%. Although the time to reach maximum plasma concentrations (Cmax) after IM administration is 2.3 +/- 1.1 hours, therapeutic concentrations are achieved within 5 to 15 minutes.
Subcutaneous Route
Nalmefene is completely bioavailable after subcutaneous administration, with a relative bioavailability of 99.7% +/- 6.9%. Although the time to reach maximum plasma concentrations (Cmax) after subcutaneous administration is 1.5 +/- 1.2 hours, therapeutic concentrations are achieved within 5 to 15 minutes.
Other Route(s)
Intranasal Route
A study compared the pharmacokinetics of one 2.7 mg nalmefene nasal spray to a single 1 mg IM nalmefene injection in 68 healthy subjects. For the nasal spray, a maximum plasma concentration (Cmax) of 10.4 ng/mL was achieved in 0.25 hours (range: 0.08 to 2 hours). The Cmax for the IM injection was 1.5 ng/mL which was reached in 0.33 hours (range: 0.117 to 18 hours). Systemic exposures (AUC) for the nasal spray and IM injection were 40.6 ng x hour/mL and 16.8 ng x hour/mL, respectively. The half-live was 11.4 hours for the nasal spray and 10.6 hours for the IM injection.
A second study of 24 healthy subjects compared the pharmacokinetics of the following nalmefene doses: 2.7 mg dose (1 spray in a single nostril); 5.4 mg dose (1 spray in each nostril); 5.4 mg dose (2 sprays in a single nostril). The Cmax for the 2.7 mg dose, 5.4 mg dose (1 spray each nostril), and 5.4 mg dose (2 sprays single nostril) were 9.75 ng/mL, 18.9 ng/mL, and 16.1 ng/mL, respectively. The time to reach maximum plasma concentration was approximately 0.25 hours for each dose. The AUC for the 2.7 mg dose, 5.4 mg dose (1 spray each nostril), and 5.4 mg dose (2 sprays single nostril) were 45.8 ng x hour/mL, 88.1 ng x hour/mL, and 83.8 ng x hour/mL, respectively. The half-life was 11 hours for each dose.
-Special Populations
Hepatic Impairment
After a 1 mg dose, the plasma clearance of nalmefene is decreased by 28.3% (0.56 +/- 0.21 L/kg/hour/ vs. 0.78 +/- 0.24 L/kg/hour) and the terminal elimination half-life is increased to 11.9 +/- 2.0 hours in patients with hepatic impairment.
Renal Impairment
There is a statistically significant 27% decrease in the plasma clearance of nalmefene in patients with end-stage renal disease (ESRD) during interdialysis (0.57 +/- 0.2 L/kg/hour) and a 25% decreased plasma clearance in ESRD patients during intradialysis (0.59 +/- 0.18 L/kg/hour) as compared to normal controls (0.79 +/- 0.24 L/kg/hour). The terminal elimination half-life after a 1 mg dose is increased to 26.1 +/- 9.9 hours in end-stage renal disease patients.
Pediatrics
Nalmefene pharmacokinetic studies have not been conducted in pediatric patients. However, based on population pharmacokinetic simulations for nalmefene nasal spray, 12-year-old subjects (median weight: 50.6 kg, range: 27.6 to 126.8 kg) are expected to have 7.6% higher mean maximum plasma concentration (Cmax) and 25.5% higher exposure (AUC) as compared to the adult population (mean weight: 75.42 kg).
Geriatric
No significant differences between younger adults (19 to 32 years) and older patients (62 to 80 years) were observed with respect to nalmefene plasma clearance, steady-state volume of distribution, or half-life. There was an apparent age-related decrease in the central volume of distribution (young: 3.9 +/- 1.1 L/kg vs. elderly: 2.8 +/- 1.1 L/kg) that resulted in a greater initial nalmefene concentration in the elderly group. Despite this greater initial drug concentration, no dosage adjustments are required.
Other
Body Weight
The effects of body weight on the pharmacokinetics of a single 2.7 mg intranasal dose of nalmefene were assessed using population pharmacokinetic simulations. Compared to the mean pharmacokinetic values across the full population dataset (median weight 74.7 kg), the first quartile of body weight (50.4 to 64.8 kg) had a 5.2% higher maximum plasma concentrations (Cmax) and 15.7% higher systemic exposure (AUC). The fourth quartile of body weight (91 to 106.8 kg) had a 4.4% lower Cmax and 11.6% lower AUC.