Clonazepam

Pronunciation

U.S. Brand Names

Klonopin®

Generic Available

Yes: Tablet

Canadian Brand Names

Alti-Clonazepam; Apo-Clonazepam®; Clonapam; Gen-Clonazepam; Klonopin®; Novo-Clonazepam; Nu-Clonazepam; PMS-Clonazepam; Rho-Clonazepam; Rivotril®

Use

Alone or as an adjunct in the treatment of petit mal variant (Lennox-Gastaut), akinetic, and myoclonic seizures; petit mal (absence) seizures unresponsive to succimides; panic disorder with or without agoraphobia

Use - Unlabeled/Investigational

Restless legs syndrome; neuralgia; multifocal tic disorder; parkinsonian dysarthria; bipolar disorder; adjunct therapy for schizophrenia

Restrictions

C-IV

Pregnancy Risk Factor

Pregnancy Implications

Clonazepam was shown to be teratogenic in some animal studies. Clonazepam crosses the placenta. Benzodiazepine use during pregnancy is associated with increased risk of congenital malformations. Nonteratogenic effects (including neonatal flaccidity, respiratory and feeding problems, and withdrawal symptoms) during the postnatal period have also been reported with benzodiazepine use. Epilepsy itself, number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy.

Lactation

Enters breast milk/not recommended

Contraindications

Hypersensitivity to clonazepam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); significant liver disease; narrow-angle glaucoma; pregnancy

Warnings/Precautions

Use with caution in elderly or debilitated patients, patients with hepatic disease (including alcoholics), or renal impairment. Use with caution in patients with respiratory disease or impaired gag reflex or ability to protect the airway from secretions (salivation may be increased). Worsening of seizures may occur when added to patients with multiple seizure types. Concurrent use with valproic acid may result in absence status. Monitoring of CBC and liver function tests has been recommended during prolonged therapy.

Causes CNS depression (dose-related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents. Effects with other sedative drugs or ethanol may be potentiated. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly).

Use caution in patients with depression, particularly if suicidal risk may be present. Use with caution in patients with a history of drug dependence. Benzodiazepines have been associated with dependence and acute withdrawal symptoms, including seizures, on discontinuation or reduction in dose. Acute withdrawal, including seizures, may be precipitated in patients after administration of flumazenil to patients receiving long-term benzodiazepine therapy.

Benzodiazepines have been associated with anterograde amnesia. Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.

Adverse Reactions

Reactions reported in patients with seizure and/or panic disorder. Frequency not defined.

Cardiovascular: Edema (ankle or facial), palpitation

Central nervous system: Amnesia, ataxia (seizure disorder ~30%; panic disorder 5%), behavior problems (seizure disorder ~25%), coma, confusion, depression, dizziness, drowsiness (seizure disorder ~50%), emotional lability, fatigue, fever, hallucinations, headache, hypotonia, hysteria, insomnia, intellectual ability reduced, memory disturbance, nervousness; paradoxical reactions (including aggressive behavior, agitation, anxiety, excitability, hostility, irritability, nervousness, nightmares, sleep disturbance, vivid dreams); psychosis, slurred speech, somnolence (panic disorder 37%), suicidal attempt, vertigo

Dermatologic: Hair loss, hirsutism, skin rash

Endocrine & metabolic: Dysmenorrhea, libido increased/decreased

Gastrointestinal: Abdominal pain, anorexia, appetite increased/decreased, coated tongue, constipation, dehydration, diarrhea, gastritis, gum soreness, nausea, weight changes (loss/gain), xerostomia

Genitourinary: Colpitis, dysuria, ejaculation delayed, enuresis, impotence, micturition frequency, nocturia, urinary retention, urinary tract infection

Hematologic: Anemia, eosinophilia, leukopenia, thrombocytopenia

Hepatic: Alkaline phosphatase increased (transient), hepatomegaly, transaminases increased (transient)

Neuromuscular & skeletal: Choreiform movements, coordination abnormal, dysarthria, muscle pain, muscle weakness, myalgia, tremor

Ocular: Blurred vision, eye movements abnormal, diplopia, nystagmus

Respiratory: Chest congestion, cough, bronchitis, hypersecretions, pharyngitis, respiratory depression, respiratory tract infection, rhinitis, rhinorrhea, shortness of breath, sinusitis

Miscellaneous: Allergic reaction, aphonia, dysdiadochokinesis, encopresis, "glassy-eyed" appearance, hemiparesis, lymphadenopathy

Overdosage/Toxicology

May produce somnolence, confusion, ataxia, diminished reflexes, or coma. Treatment for benzodiazepine overdose is supportive. Flumazenil has been shown to selectively block the binding of benzodiazepines to CNS receptors, resulting in a reversal of benzodiazepine-induced CNS depression, but not respiratory depression.

Drug Interactions

Substrate of CYP3A4 (major)

CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents; monitor for increased effect

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of clonazepam. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of clonazepam. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Disulfiram: Disulfiram may inhibit the metabolism of clonazepam; monitor for increased benzodiazepine effect

Levodopa: Therapeutic effects may be diminished in some patients following the addition of a benzodiazepine; limited/inconsistent data

Oral contraceptives: May decrease the clearance of some benzodiazepines (those which undergo oxidative metabolism); monitor for increased benzodiazepine effect

Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation

Valproic acid: The combined use of clonazepam and valproic acid has been associated with absence seizures

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Clonazepam serum concentration is unlikely to be increased by grapefruit juice because of clonazepam's high oral bioavailability.

Herb/Nutraceutical: St John's wort may decrease clonazepam levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Mechanism of Action

The exact mechanism is unknown, but believed to be related to its ability to enhance the activity of GABA; suppresses the spike-and-wave discharge in absence seizures by depressing nerve transmission in the motor cortex

Pharmacodynamics/Kinetics

Onset of action: 20-60 minutes

Duration: Infants and young children: 6-8 hours; Adults: 12 hours

Absorption: Well absorbed

Distribution: Adults: Vd: 1.5-4.4 L/kg

Protein binding: 85%

Metabolism: Extensively hepatic via glucuronide and sulfate conjugation

Half-life elimination: Children: 22-33 hours; Adults: 19-50 hours

Time to peak, serum: 1-3 hours; Steady-state: 5-7 days

Excretion: Urine (<2% as unchanged drug); metabolites excreted as glucuronide or sulfate conjugates

Dosage

Oral:

Children <10 years or 30 kg: Seizure disorders:

Initial daily dose: 0.01-0.03 mg/kg/day (maximum: 0.05 mg/kg/day) given in 2-3 divided doses; increase by no more than 0.5 mg every third day until seizures are controlled or adverse effects seen

Usual maintenance dose: 0.1-0.2 mg/kg/day divided 3 times/day, not to exceed 0.2 mg/kg/day

Adults:

Seizure disorders:

Initial daily dose not to exceed 1.5 mg given in 3 divided doses; may increase by 0.5-1 mg every third day until seizures are controlled or adverse effects seen (maximum: 20 mg/day)

Usual maintenance dose: 0.05-0.2 mg/kg; do not exceed 20 mg/day

Panic disorder: 0.25 mg twice daily; increase in increments of 0.125-0.25 mg twice daily every 3 days; target dose: 1 mg/day (maximum: 4 mg/day)

Discontinuation of treatment: To discontinue, treatment should be withdrawn gradually. Decrease dose by 0.125 mg twice daily every 3 days until medication is completely withdrawn.

Elderly: Initiate with low doses and observe closely

Hemodialysis: Supplemental dose is not necessary

Administration

Orally-disintegrating tablet: Open pouch and peel back foil on the blister; do not push tablet through foil. Use dry hands to remove tablet and place in mouth. May be swallowed with or without water. Use immediately after removing from package.

Monitoring Parameters

CBC, liver function tests; observe patient for excess sedation, respiratory depression

Reference Range

Relationship between serum concentration and seizure control is not well established

Timing of serum samples: Peak serum levels occur 1-3 hours after oral ingestion; the half-life is 20-40 hours; therefore, steady-state occurs in 5-7 days

Therapeutic levels: 20-80 ng/mL; Toxic concentration: >80 ng/mL

Patient Education

Take exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, loss of appetite, or dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help). If medication is used to control seizures, wear identification that you are taking an antiepileptic medication. Report excessive drowsiness, dizziness, fatigue, or impaired coordination; CNS changes (confusion, depression, increased sedation, excitation, headache, agitation, insomnia, or nightmares) or changes in cognition; respiratory difficulty or shortness of breath; changes in urinary pattern, changes in sexual activity; muscle cramping, weakness, tremors, or rigidity; ringing in ears or visual disturbances, excessive perspiration, or excessive GI symptoms (cramping, constipation, vomiting, anorexia); worsening of seizure activity, or loss of seizure control. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Additional Information

Ethosuximide or valproic acid may be preferred for treatment of absence (petit mal) seizures. Clonazepam-induced behavioral disturbances may be more frequent in mentally handicapped patients. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms. Flumazenil, a competitive benzodiazepine antagonist at the CNS receptor site, reverses benzodiazepine-induced CNS depression.

Anesthesia and Critical Care Concerns/Other Considerations

Ethosuximide or valproic acid may be preferred for treatment of absence (petit mal) seizures. Flumazenil, a competitive benzodiazepine antagonist at the CNS receptor site, reverses benzodiazepine-induced CNS depression. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Tablet: 0.5 mg, 1 mg, 2 mg

Tablet, orally-disintegrating [wafer]: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg

Extemporaneously Prepared

A 0.1 mg/mL oral suspension has been made using five 2 mg tablets, purified water USP (10 mL) and methylcellulose 1% (qs ad 100 mL); the expected stability of this preparation is 2 weeks if stored under refrigeration; shake well before use

Nahata MC and Hipple TF, Pediatric Drug Formulations , 2nd ed, Cincinnati, OH: Harvey Whitney Books Co, 1992.

References

Barnett AM, "Treatment of Epilepsy With Clonazepam," S Afr Med J , 1973, 47(37):1683-6.

Bladin PF, "The Use of Clonazepam as an Anticonvulsant - Clinical Evaluation," Med J Aust , 1973, 1(14):683-8.

Brogden RN and Goa KL, "Flumazenil. A Preliminary Review of Its Benzodiazepine Antagonist Properties, Intrinsic Activity, and Therapeutic Use," Drugs , 1988, 35(4):448-67.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

Sugai K, "Seizures With Clonazepam: Discontinuation and Suggestions for Safe Discontinuation Rates in Children," Epilepsia , 1993, 34(6):1089-97.

International Brand Names

Alti-Clonazepam (CA); Antelepsin® (DE, RO, RU); Apo-Clonazepam® (CA); Clonagin® (AR); Clonapam (CA, CL); Clonax® (AR); Clonazepam Duncan® (AR); Clonazepam Monte Verde® (AR); Clonazepam® (RO); Clonazepamum® (HU, PL); Clonogal® (HU); Clonotril® (CY, RO); Coquan® (CO); Diocam® (AR); Epitril® (IN); Gen-Clonazepam (CA); Iktorivil® (SE); Induzepam® (AR); Kenoket® (MX); Klonopin® (CA); Landsen® (JP); Lonazep® (BD); Neuryl® (AR); Novo-Clonazepam (CA); Nu-Clonazepam (CA); Paxam® (AU, NZ); PMS-Clonazepam (CA); Ravotril® (CL, CZ); Rho-Clonazepam (CA); Rivatril® (FI); Rivoril® (BE); Rivotril® (AR, AT, AU, BD, BE, BR, CA, CH, CO, CR, CZ, DE, DK, DO, ES, FR, GB, GT, HK, HN, HR, HU, ID, IE, IL, IT, LU, MX, NL, NO, NZ, PA, PL, PT, RO, RU, SI, SV, TH, TR, YU, ZA); Solfidin® (AR); Valpax® (CL)

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is the first of its kind, requiring compliance with 53 standards of quality and accountability, verified by independent audit. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial process . A.D.A.M. is also a founding member of Hi-Ethics (www.hiethics.com) and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2007 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

Home > Medical Reference > Complementary Medicine