naloxone intranasal (Rx, OTC)

Frequency Not Defined

Narcan

• Precipitation of severe opioid withdrawal
• Increased blood pressure
• Musculoskeletal pain
• Headache
• Nasal dryness
• Nasal edema
• Nasal congestion
• Nasal inflammation

Kloxxado

• Abdominal pain
• Asthenia
• Dizziness
• Headache
• Nasal discomfort
• Presyncope
• Nasal irritation
• Signs of nasal inflammation
• Nasal congestion

Postmarketing Reports

Narcan

• Aggressive behavior upon abrupt reversal of an opioid overdose
• Constipation
• Toothache
• Muscle spasms
• Rhinalgia
• Xeroderma

Kloxxado

• Hypotension
• Hypertension
• Ventricular tachycardia and fibrillation
• Dyspnea
• Pulmonary edema
• Cardiac arrest
• Death
• Coma
• Encephalopathy
• Agitation

All routes of administration

• Withdrawal syndrome
• Vomiting
• Nonresponsive to stimuli
• Drug ineffective
• Agitation
• Somnolence
• Loss of consciousness

Contraindications

Hypersensitivity

Cautions

Risk of recurrent respiratory and CNS depression

• There is limited data to inform if 2 mg dose will avoid precipitation of severe opioid withdrawal in setting of opioid dependence; however, the 2 mg dose may not provide adequate and timely reversal in persons who may be exposed to overdose of potent or very high dose of opioids
• Risk of recurrent respiratory and CNS depression exists because the duration of action of most opioids may exceed that of naloxone nasal spray
• Seek immediate emergency medical assistance following the first dose
• Administer additional doses and additional supportive and/or resuscitative measures while waiting for help

Reversing partial opioid agonists or mixed opioid agonist/antagonists

• Incomplete reversal of respiratory depression may be observed when attempting to reverse partial opioid agonists or mixed opioid agonist/antagonists
• Larger or repeat doses may be required to antagonize buprenorphine because the latter has a long duration of action owing to its slow rate of binding and subsequent slow dissociation from the opioid receptor

Precipitation of severe opioid withdrawal

• Use in patients who are opioid dependent may precipitate opioid withdrawal characterized by 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
• In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include convulsions, excessive crying, and hyperactive reflexes
• Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest; these events have primarily occurred in patients who had preexisting cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects
• Consider avoiding use in certain clinical settings (eg, postpartum period in neonates with known or suspected exposure to maternal opioid use) and using an alternant naloxone-containing product that can titrate to effect

Pregnancy

Limited available data are insufficient on use in pregnant females to inform a drug-associated risk regarding teratogenicity

Fetal/neonatal adverse reactions

• Crosses the placenta and may precipitate withdrawal in the fetus, as well as in the opioid-dependent mother
• Evaluate fetus for signs of distress after naloxone is used
• Careful monitoring is needed until the fetus and mother are stabilized

Animal studies

• No embryotoxic or teratogenic effects were observed in mice and rats treated during the period of organogenesis at doses equivalent to 6-12 times a human dose of 8 mg/day

Lactation

Unknown if distributed in human breast milk

Studies in nursing mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels

Minimally orally bioavailable and is unlikely to affect breastfed infants

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

Competitive opioid antagonist that antagonizes opioid effects by competing for the same receptor sites

It reverses the effects of opioids, including respiratory depression, sedation, and hypotension

Absorption

Peak plasma time

• Narcan: 0.33-0.5 hr
• Kloxxado: 0.25 hr

Peak plasma concentration

• Narcan: 4.83-9.7 ng/mL
• Kloxxado: 12.3-12.8 ng/mL

AUC

• Narcan: 7.87-15.3 hr·ng/mL
• Kloxxado: 16.7-19 hr·ng/mL

Bioavailability

• Kloxxado: 37%

Distribution

Protein bound

• Occurs, but is relatively weak
• Major binding constituent: Plasma albumin, but significant binding also occurs to plasma constituents other than albumin
• Unknown whether excreted into human milk

Metabolism

Metabolized in the liver, primarily by glucuronide conjugation

Metabolites: Naloxone-3-glucoronide

Elimination

Half-life

• Narcan: ~2 hr
• Kloxxado: 1.76-2.69 hr

Excretion in urine

• 6 hr: 25-40%
• 24 hr: 50%
• 72 hr: 60-70 %

Intranasal Administration

Intranasal use only

Ready for use; no additional device assembly required

Place patient in the supine position

Before administration, ensure insert device nozzle in either nostril, and provide support to back of neck to allow head to tilt back

Use each nasal spray only 1 time; do NOT test or prime before use; press firmly on device plunger to administer dose

Remove device nozzle from nostril after use

Do not attempt to reuse naloxone intranasal; each spray contains a single dose of naloxone and cannot be reused

Readminister using a new nasal spray every 2-3 minutes if the patient does not respond or responds and then relapses into respiratory depression

Administer in alternate nostrils with each dose

Turn patient on side and call for emergency medical assistance immediately after administration of first dose

Other instructions to consult patients and caregivers

• Administer as quickly as possible because prolonged respiratory depression may result in damage to the CNS or death
• Since duration of action of most opioids exceeds that of naloxone and suspected opioid overdose may occur outside of supervised medical settings, seek immediate emergency medical assistance, continue monitoring patient until emergency personnel arrive, and administer repeated doses of naloxone intranasal, as necessary
• Always seek emergency medical assistance if a potentially life-threatening opioid emergency is suspected after administration of the first dose of naloxone intranasal

Storage

Protect from light

Do not freeze

Freezes at temperatures below -15ºC (5ºF); if frozen, device will not spray

If frozen and is needed in an emergency, do NOT wait to thaw; get emergency medical help right away

Narcan nasal spray

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

Kloxxado

• Store at 20-25ºC (68-77ºF), with excursions permitted to 5-40ºC (41-104ºF)
• Not made of rubber latex