KLOXXADO

Clinical safety rating: caution

Comprehensive clinical and safety monograph for KLOXXADO (KLOXXADO).

How it works

KLOXXADO (flumazenil) is a benzodiazepine antagonist that competitively inhibits the activity at the benzodiazepine binding site on the GABA-A receptor, thereby reversing the effects of benzodiazepines.

What the body does with it

Metabolism	Hepatic metabolism via CYP1A2 and CYP3A4; undergoes extensive first-pass metabolism; major metabolites are inactive or less active.
Excretion	Hepatic metabolism primarily via CYP3A4 to inactive metabolites; renal excretion accounts for <1% of unchanged drug; fecal excretion accounts for approximately 50-60% of the dose as metabolites.
Half-life	Terminal elimination half-life is approximately 2 hours (range 1-4 hours); clinical context: short half-life supports rapid reversal of opioid effects but requires monitoring for renarcotization, especially with long-acting opioids.
Protein binding	Approximately 80% bound to plasma proteins, primarily albumin.
Volume of Distribution	Volume of distribution is approximately 2-4 L/kg; high Vd indicates extensive tissue distribution, which is consistent with rapid redistribution from brain to peripheral tissues, contributing to its short duration of action.
Bioavailability	Intranasal bioavailability is approximately 40-50% relative to intravenous administration; gastrointestinal absorption is limited due to first-pass metabolism, so oral bioavailability is <1%.
Onset of Action	Intranasal administration: rapid absorption, with peak plasma concentrations achieved within 15-30 minutes; clinical onset of reversal of opioid effects is typically observed within 2-5 minutes.
Duration of Action	Duration of opioid reversal is approximately 30-60 minutes, depending on the dose and the amount and type of opioid; clinical note: shorter duration than most opioids, necessitating repeat doses or continuous monitoring for recurrence of respiratory depression.

Classification & Brands

Dosing & administration

5 mg intranasally as a single dose; may repeat once after 2-3 minutes if response inadequate.

Dosage form	SPRAY
Renal impairment	No dose adjustment required for renal impairment.
Liver impairment	No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B); severe hepatic impairment (Child-Pugh C) has not been studied, use with caution.
Pediatric use	Weight ≥30 kg: 5 mg intranasally as single dose; weight 10-30 kg: 2.5 mg intranasally as single dose; may repeat once after 2-3 minutes if needed.
Geriatric use	No specific dose adjustment; elderly patients may be more sensitive to adverse effects, monitor for excessive sedation or respiratory depression.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for KLOXXADO (KLOXXADO).

Breastfeeding	Excreted in breast milk; M/P ratio unknown. Potential for infant sedation and withdrawal. Use caution; consider alternative agents or monitor for drowsiness and feeding difficulties.
Teratogenic Risk	Pregnancy category D: Positive evidence of human fetal risk in first trimester (increased risk of oral clefts), second and third trimesters (risk of maternal and neonatal respiratory depression, neonatal withdrawal syndrome). Avoid in pregnancy unless benefit outweighs risk.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

None.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Known hypersensitivity to flumazenil or benzodiazepines","Patients receiving benzodiazepines for control of life-threatening conditions (e.g., increased intracranial pressure, status epilepticus)","Evidence of serious tricyclic antidepressant overdose"]

Clinical Precautions

Precautions

["Risk of seizures, especially in patients with physical dependence on benzodiazepines, concurrent tricyclic antidepressant overdose, or history of seizures","Do not use for diagnostic purposes in suspected seizure disorders","May cause panic attacks in patients with anxiety disorders","Monitor for resedation due to shorter duration of action than benzodiazepines"]

Clinical Tips & Counseling

Drug interactions

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KLOXXADO

Clinical safety rating: caution

Comprehensive clinical and safety monograph for KLOXXADO (KLOXXADO).

How it works

What the body does with it

Metabolism	Hepatic metabolism via CYP1A2 and CYP3A4; undergoes extensive first-pass metabolism; major metabolites are inactive or less active.
Excretion	Hepatic metabolism primarily via CYP3A4 to inactive metabolites; renal excretion accounts for <1% of unchanged drug; fecal excretion accounts for approximately 50-60% of the dose as metabolites.
Half-life	Terminal elimination half-life is approximately 2 hours (range 1-4 hours); clinical context: short half-life supports rapid reversal of opioid effects but requires monitoring for renarcotization, especially with long-acting opioids.
Protein binding	Approximately 80% bound to plasma proteins, primarily albumin.
Volume of Distribution	Volume of distribution is approximately 2-4 L/kg; high Vd indicates extensive tissue distribution, which is consistent with rapid redistribution from brain to peripheral tissues, contributing to its short duration of action.
Bioavailability	Intranasal bioavailability is approximately 40-50% relative to intravenous administration; gastrointestinal absorption is limited due to first-pass metabolism, so oral bioavailability is <1%.
Onset of Action	Intranasal administration: rapid absorption, with peak plasma concentrations achieved within 15-30 minutes; clinical onset of reversal of opioid effects is typically observed within 2-5 minutes.
Duration of Action	Duration of opioid reversal is approximately 30-60 minutes, depending on the dose and the amount and type of opioid; clinical note: shorter duration than most opioids, necessitating repeat doses or continuous monitoring for recurrence of respiratory depression.

Classification & Brands

Dosing & administration

5 mg intranasally as a single dose; may repeat once after 2-3 minutes if response inadequate.

Dosage form	SPRAY
Renal impairment	No dose adjustment required for renal impairment.
Liver impairment	No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B); severe hepatic impairment (Child-Pugh C) has not been studied, use with caution.
Pediatric use	Weight ≥30 kg: 5 mg intranasally as single dose; weight 10-30 kg: 2.5 mg intranasally as single dose; may repeat once after 2-3 minutes if needed.
Geriatric use	No specific dose adjustment; elderly patients may be more sensitive to adverse effects, monitor for excessive sedation or respiratory depression.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for KLOXXADO (KLOXXADO).

Breastfeeding	Excreted in breast milk; M/P ratio unknown. Potential for infant sedation and withdrawal. Use caution; consider alternative agents or monitor for drowsiness and feeding difficulties.
Teratogenic Risk	Pregnancy category D: Positive evidence of human fetal risk in first trimester (increased risk of oral clefts), second and third trimesters (risk of maternal and neonatal respiratory depression, neonatal withdrawal syndrome). Avoid in pregnancy unless benefit outweighs risk.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

None.

Side Effect Profile

Serious Effects

Absolute Contraindications

Clinical Precautions

Precautions

Clinical Tips & Counseling

Drug interactions

Loading safety data…