Clonazepam (Monograph)

Brand name: KlonoPIN
Drug class: Benzodiazepines
VA class: CN400
CAS number: 1622-61-3

Medically reviewed by Drugs.com on Oct 30, 2024. Written by ASHP.

Warning

Concomitant use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death.
Reserve concomitant use for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation. (See Specific Drugs under Interactions.)

A boxed warning has been included in the prescribing information for all benzodiazepines describing risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions.
Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs.
Assess a patient’s risk of abuse, misuse, and addiction. Standardized screening tools are available ([Web]).
To reduce risk of acute withdrawal reactions, use a gradual dose taper when reducing dosage or discontinuing benzodiazepines. Take precautions when benzodiazepines are used in combination with opioid medications.

Introduction

Benzodiazepine; anticonvulsant, sedative, and anxiolytic.

Uses for Clonazepam

Seizure Disorders

Prophylactic management of Lennox-Gastaut syndrome and akinetic and myoclonic seizures.

Management of absence seizures in patients unresponsive to succinimides.

Some evidence of success in the management of refractory seizures^{† [off-label]}, including partial seizures with complex symptomatology and other partial seizures and some cases of infantile spasms^{† [off-label]}.

Useful in some patients with tonic-clonic seizures^{† [off-label]}.

Panic Disorder

Treatment of panic disorder with or without agoraphobia.

Catatonia

Also has been used for treatment of acute catatonic reactions^{† [off-label]}, whether associated with schizophrenia or other conditions.

Akathisia

May be helpful in patients experiencing akathisia^{† [off-label]} while receiving antipsychotic drugs (e.g., for management of schizophrenia).

Clonazepam Dosage and Administration

General

Adjust dosage carefully and slowly according to individual requirements and response.
Withdraw clonazepam slowly; avoid abrupt discontinuance, especially during long-term, high-dose therapy, to avoid precipitating seizures, status epilepticus, or withdrawal symptoms. During withdrawal of clonazepam in patients with seizure disorders, simultaneous substitution of another anticonvulsant may be indicated.

Administration

Oral Administration

Administer orally as conventional or orally disintegrating tablets.

Administer in 3 equally divided doses for the treatment of seizure disorders; if doses are not equally divided, give the largest dose at bedtime.

Administer in 2 equally divided doses for the management of panic disorder; alternatively, administer the entire dosage at bedtime to reduce the inconvenience of somnolence.

Conventional Tablets

Swallow tablet whole with water.

Orally Disintegrating Tablets

Just prior to administration, remove blister from aluminum pouch; with dry hands, peel open blister package, place orally disintegrating tablet in mouth to dissolve, and swallow with or without water.

Dosage

Pediatric Patients

Seizure Disorders

Oral

Infants and children <10 years of age or weighing <30 kg: Initially, 0.01–0.03 mg/kg daily; initial dosage should not exceed 0.05 mg/kg daily given in 2 or 3 divided doses.

Increase dosage by no more than 0.5 mg every third day until seizure control is achieved with minimal adverse effects. Maintenance dosage of 0.1–0.2 mg/kg daily.

Children ≥10 years of age or weighing ≥30 kg: Initial dosage should not exceed 1.5 mg daily given in 3 divided doses.

Increase dosage in increments of 0.5–1 mg every third day (up to a maximum dosage of 20 mg daily) until seizure control is achieved with minimal adverse effects.

Adults

Seizure Disorders

Oral

Initial dosage should not exceed 1.5 mg daily given in 3 divided doses. Increase dosage in increments of 0.5–1 mg every third day (up to a maximum dosage of 20 mg daily) until seizure control is achieved with minimal adverse effects.

Panic Disorder

Oral

Initially, 0.25 mg twice daily. After 3 days, increase dosage to usual maintenance dosage of 1 mg daily.

Some clinicians recommend dosages of 1–2 mg daily. Certain patients may benefit from dosages up to 4 mg daily. In such cases, increase dosage by 0.125–0.25 mg twice daily every 3 days until panic disorder is controlled with minimal adverse effects.

Discontinue therapy gradually by decreasing the dosage in increments of 0.125 mg twice daily every 3 days until the drug is completely withdrawn.

Prescribing Limits

Pediatric Patients

Seizure Disorders

Oral

Maximum 0.2 mg/kg daily.

Adults

Seizure Disorders

Oral

Maximum 20 mg daily.

Panic Disorder

Oral

Maximum 4 mg daily.

Special Populations

Geriatric Patients

Initiate therapy at low dosage and observe closely.

Cautions for Clonazepam

Contraindications

Known hypersensitivity to clonazepam or other benzodiazepines.
Clinical or biochemical evidence of substantial hepatic impairment.
Manufacturer states that clonazepam is contraindicated in patients with acute angle-closure glaucoma but may be administered to patients with open-angle glaucoma who are receiving appropriate therapy; however, clinical rationale for this contraindication has been questioned.

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including clonazepam, and opiates may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.

Reserve concomitant use of clonazepam and opiates for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)

CNS Effects

Performance of activities requiring mental alertness and physical coordination may be impaired.

Concurrent use of other CNS depressants may potentiate CNS depression. (See Concomitant Use with Opiates under Cautions and also see (See Specific Drugs under Interactions.)

Withdrawal Effects

Abrupt discontinuance may result in symptoms of withdrawal (similar to barbiturates or alcohol). Symptoms may be relieved by tapering the dosage.

General Precautions

Seizure Disorders

May increase the incidence or precipitate the onset of generalized tonic-clonic seizures in patients with multiple types of seizure disorders. Consider addition of appropriate anticonvulsants or an increase in their dosages.

Abrupt withdrawal, particularly in patients receiving long-term, high-dose therapy, may result in status epilepticus.

Concomitant use with valproic acid may produce absence status.

Laboratory Testing

Perform blood counts and liver function tests periodically during long-term therapy.

Hypersalivation

May increase salivation; use with caution in patients who have difficulty tolerating or clearing secretions.

Respiratory Effects

Possible hypersalivation and respiratory depression in patients with chronic respiratory disease; use with caution in such patients.

Abuse Potential

Psychologic and physical dependence may occur following prolonged use.

Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence; use only with careful surveillance in such patients.

Suicide

Use with caution in depressed patients; potential for suicidal tendencies. Prescribe drug in the smallest feasible quantity.

Psychiatric Indications

Do not use in patients with depressive neuroses or psychotic reactions in which anxiety is not prominent.

Specific Populations

Pregnancy

Category D.

Lactation

Distributed into milk; discontinue nursing or the drug.

Pediatric Use

Effects of long-term administration on physical and mental development have not been established. Administer to children with seizure disorders only if potential benefits outweigh possible risks.

Safety and efficacy for treatment of panic disorder not established in children <18 years of age; however, clonazepam has been effective in a limited number of adolescents with panic disorder.

Geriatric Use

Insufficient experience from clinical studies to determine whether patients ≥65 years of age respond differently than younger adults. Other clinical experience has not identified age-related differences in responses. Potential increased sensitivity (increased risk of oversedation and confusion) to sedatives.

Select dosage carefully, generally initiating therapy at low dosage; observe closely. Consider the increased incidence of hepatic and renal impairment, decreased cardiac function, and concomitant disease and drug therapy in the geriatric population. May be useful to assess hepatic and/or renal function when selecting dosage.

Hepatic Impairment

Prolonged elimination. Contraindicated in patients with clinical or biochemical evidence of substantial liver disease.

Renal Impairment

Elimination of metabolites may be decreased; use with caution.

Common Adverse Effects

Sedation/drowsiness, ataxia/hypotonia, behavioral disturbances (principally in children) including aggressiveness, irritability, agitation, hyperkinesis.

Drug Interactions

Metabolized by CYP enzymes, including CYP3A.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered plasma concentrations of clonazepam) with CYP inducers or inhibitors.

No evidence that clonazepam induces metabolism of other drugs.

Specific Drugs

Drug	Interaction	Comments
Antifungal agents, azole-type (e.g., itraconazole, ketoconazole)	Possible increase in plasma clonazepam concentrations	Use with caution
Carbamazepine	Decreased plasma clonazepam concentrations; carbamazepine pharmacokinetics not affected
CNS depressants (e.g., barbiturates, sedatives, anticonvulsants, alcohol)	Additive CNS effects	Use caution to avoid overdosage Avoid alcohol use
Disulfiram	Possible increase in plasma clonazepam concentrations	Reduce clonazepam dosage as necessary
Fluoxetine	Clonazepam pharmacokinetics not affected
Opiate agonists and partial agonists	Risk of profound sedation, respiratory depression, coma, or death	Whenever possible, avoid concomitant use Opiate analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation In patients receiving clonazepam, initiate opiate analgesic, if required, at reduced dosage and titrate based on clinical response In patients receiving an opiate analgesic, initiate clonazepam, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response Opiate antitussives: Avoid concomitant use Consider offering naloxone to patients receiving benzodiazepines and opiates concomitantly
Phenobarbital	Decreased plasma clonazepam concentrations; phenobarbital pharmacokinetics not affected
Phenytoin	Decreased plasma clonazepam concentrations; phenytoin pharmacokinetics not affected
Propantheline	Possible decrease in plasma clonazepam concentrations

Clonazepam Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration, with peak concentrations achieved within 1–4 hours. Absolute bioavailability is approximately 90%.

Onset

Anticonvulsant action occurs within 20–60 minutes following oral administration.

Duration

Duration of anticonvulsant action is 6–8 hours in infants and young children and up to 12 hours in adults.

Distribution

Extent

Apparently crosses the blood-brain barrier and the placenta.

Plasma Protein Binding

Approximately 85%.

Elimination

Metabolism

Extensively metabolized in the liver to several metabolites.

Elimination Route

Excreted in urine (<2% as unchanged drug).

Half-life

18–50 hours.

Stability

Storage

Oral

Conventional or Orally Disintegrating Tablets

25°C (may be exposed to 15–30°C).

Actions

Exact mechanism of anticonvulsant, sedative, and antipanic effects is unknown; however, mechanism appears to be related to the drug’s ability to enhance the activity of GABA, the principal inhibitory neurotransmitter in the CNS.

Advice to Patients

Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates either therapeutically or illicitly. Avoid concomitant use of opiate antitussives; also avoid concomitant use of opiate analgesics unless use is supervised by clinician.
Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.
Importance of not abruptly discontinuing therapy; consult clinician about discontinuing use.
Potential for psychologic or physiologic dependence.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and concomitant illnesses, particularly depression.
Importance of avoiding alcohol-containing beverages or products.
Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.
Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

clonazePAM
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	0.5 mg*	clonazePAM Tablets (C-IV)
			KlonoPIN (C-IV; scored)	Genentech
		1 mg*	clonazePAM Tablets (C-IV)
			KlonoPIN (C-IV)	Genentech
		2 mg*	clonazePAM Tablets (C-IV)
			KlonoPIN (C-IV)	Genentech
	Tablets, orally disintegrating	0.125 mg*	clonazePAM Orally Disintegrating Tablets (C-IV)
		0.25 mg*	clonazePAM Orally Disintegrating Tablets (C-IV)
		0.5 mg*	clonazePAM Orally Disintegrating Tablets (C-IV)
		1 mg*	clonazePAM Orally Disintegrating Tablets (C-IV)
		2 mg*	clonazePAM Orally Disintegrating Tablets (C-IV)