nalmefene intranasal (Rx)

>10%

2.7 mg

• Headache (6.7-55.7%)
• Nasal discomfort (8.2-42.7%)
• Nausea (3.4-36.1%)
• Hot flush (8-19.7%)
• Dizziness (5.6-14.8%)
• Anxiety (4.7-11.5%)
• Vomiting (2.2-11.5%)

5.4 mg

• Rhinalgia (8.7-25%)
• Nausea (4.2-21.7%)
• Nasal congestion (4.3-16.7%)
• Nasal discomfort (12.5-13%)

1-10%

2.7 mg

• Hyperhidrosis (2-6.6%)
• Nasal congestion (3.3-4.5%)
• Throat irritation (3.4-4.9%)
• Fatigue (3.4-4.9%)
• Erythema (2-3.4%)
• Rhinalgia (1.6-3.4%)
• Dyspnea (1.3-3.3%)
• Oropharyngeal pain (1.3-3.3%)
• Paresthesia (1.3-3.3%)
• Agitation (1.3-3.3%)
• Chills (1.3-3.3%)
• Claustrophobia (1.3-3.3%)
• Dysgeusia (1.1-3.3%)
• Decreased appetite (1.1-3.3%)
• Abdominal pain (1.1-1.6%)
• Dry mouth (0.7-1.6%)
• Insomnia (0.7-1.1%)
• Rhinitis (0.7-1.1%)

5.4 mg

• Presyncope (4.3%)
• Headache (4.3%)
• Dry mouth (4.3%)
• Vomiting (4.3%)
• Insomnia (4.3%)
• Chest discomfort (4.3%)
• Rhinitis (4.3%)
• Dry eye (4.3%)
• Tachycardia (4.3%)
• Oropharyngeal pain (4.2-4.3%)
• Erythema (4.2-4.3%)
• Paresthesia (4.2-4.3%)
• Dizziness (4.2%)
• Constipation (4.2%)
• Hyperhidrosis (4.2%)
• Urticaria (4.2%)

<1%

• Bradycardia
• Arrhythmia
• Diarrhea
• Dry mouth
• Somnolence
• Depression
• Agitation
• Nervousness
• Tremor
• Confusion
• Withdrawal syndrome
• Myoclonus
• Pharyngitis
• Pruritus
• Urinary retention

Postmarketing Reports

Abrupt reversal of opioid depression: Nausea, vomiting, sweating, tremulousness, seizures, and cardiovascular instability including tachycardia, hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest

Death, coma, and encephalopathy reported as sequelae of these events; events primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects

In persons who were opioid dependent, abrupt reversal of opioid effects has precipitated an acute withdrawal syndrome

Signs and symptoms included: Body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shiver or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia

In neonates, opioid withdrawal symptoms also included convulsions, excessive crying, and hyperactive reflexes

Contraindications

Hypersensitivity to nalmefene or to any of other ingredients

Cautions

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists (eg, buprenorphine, pentazocine) may be incomplete; repeated doses of nalmefene intranasal may be necessary to antagonize buprenorphine owing to long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor

Risk of recurrent respiratory and CNS depression

• Recurrence of respiratory depression is possible, even after an adequate initial response to nalmefene intranasal
• Always seek out emergency medical assistance immediately after administering first dose and continue to monitor patient
• Additional doses may be necessary if symptoms of opioid overdose recur
• Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance

Precipitation of severe opioid withdrawal

• May precipitate opioid withdrawal in patients who are opioid dependent
• Signs and symptoms include body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure
• Abrupt postoperative reversal of opioid depression after use may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest
• After use, monitor patients with preexisting cardiac disease or patients who have received medications associated with cardiovascular effects such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting
• In neonates, opioid withdrawal may be life threatening if not recognized and properly treated and may include the following signs and symptoms: convulsions, excessive crying, and hyperactive reflexes
• Monitor for developing signs and symptoms of opioid withdrawal
• Use an alternative opioid antagonist product that can be titrated to effect and, where applicable, dosed according to weight

Risk of opioid overdose from attempts to overcome the blockade

• Unlikely to produce acute withdrawal symptoms in nonopioid-dependent patients
• Use in patients who are opioid dependent may precipitate opioid withdrawal
• Attempting to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of exogenous opioids could lead to opioid intoxication and death
• Inform patients of the potential consequences of trying to overcome the opioid blockade
• Get emergency medical assistance as soon as possible after using nalmefene nasal spray regardless of withdrawal symptoms

Pregnancy

Do not withhold life-sustaining therapy for opioid overdose

There are no available data on nalmefene use in pregnant females to evaluate for a drug-associated risk of major birth defects or miscarriage

Animal data

• No embryotoxic effects on embryofetal development were observed in rats and rabbits treated with nalmefene at exposures at least 6x (rats) and up to 20x (rabbits) the exposure at two human nasal doses of 5.4 mg

Clinical considerations

• An opioid overdose is a medical emergency and can be fatal for the pregnant female and fetus if left untreated

Lactation

There are no data on presence of nalmefene and its metabolites in human milk, the effects of nalmefene on breastfed children, or effects on milk production

Nalmefene and its metabolites are present in rat milk

When a drug is present in animal milk, drug is likely present in human milk

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.

Mechanism of Action

An opioid antagonist, is a 6-methylene analogue of naltrexone, prevents or reverses effects of opioids, including respiratory depression, sedation, and hypotension

Absorption

Bioavailability: 0.806 (relative to IM)

Peak plasma concentration

• 2.7-mg dose (1 spray in 1 nostril): 9.75 ng/mL
• 5.4-mg dose (1 spray in each nostril): 18.9 ng/mL
• 5.4-mg dose (2 sprays in 1 nostril): 16.1 ng/mL

Peak plasma time

• 2.7-mg dose (1 spray in 1 nostril): 0.267 hr
• 5.4-mg dose (1 spray in each nostril): 0.25 hr
• 5.4-mg dose (2 sprays in 1 nostril): 0.25 hr

AUC (0-inf)

• 2.7-mg dose (1 spray in 1 nostril): 45.8 ng⋅hr/mL
• 5.4-mg dose (1 spray in each nostril): 88.1 ng⋅hr/mL
• 5.4-mg dose (2 sprays in 1 nostril): 83.8 ng⋅hr/mL

Distribution

Vd: 3.9 L/kg

Vd (steady-state): 8.6 L/kg

Blood-to-plasma ratio: 1.3

Metabolism

Metabolized by the liver, primarily by glucuronide conjugation

Metabolized to trace amounts of an N-dealkylated metabolite

Nalmefene glucuronide is inactive and N-dealkylated metabolite has minimal pharmacological activity

Elimination

Clearance: 75.7 L/hr

Half-life

• 2.7-mg dose (1 spray in 1 nostril): 11.4 hr
• 5.4-mg dose (1 spray in each nostril): 11.3 hr
• 5.4-mg dose (2 sprays in 1 nostril): 11.3 hr

Excretion

• Nalmefene and its metabolites are excreted in urine
• Urine: <5% unchanged
• Feces: 17%

Intranasal Administration

Place patient in supine position

Before administering, ensure device nozzle is inserted in patient’s nose and provide support to back of the neck to allow head to tilt back

Do not prime or test device before administering

Press firmly on plunger and remove nozzle from nose after use

If patient responds (eg, waking up to voice or touch, starts breathing normally), place patient on their side (recovery position) as shown in prescribing information and call for emergency medical assistance immediately after administering first dose

Storage

Store in blister and cartons provided

Store at controlled room temperature 15-25ºC (59-77ºF); excursions permitted to 4- 40ºC (39-104ºF)

Do not freeze

Protect from light

Do not open individual blister packs or test nasal spray devices before use