No

Benzodiazepine

Seizure disorder: 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

C-IV

D

Clinical effects on the fetus: Two reports of cardiac defects; respiratory depression, lethargy, hypotonia may be observed in newborns exposed near time of delivery. Epilepsy itself, number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy. Benefit:risk ratio usually favors continued use during pregnancy and breast-feeding.

Breast-feeding/lactation: Crosses into breast milk

Clinical effects on the infant: CNS depression, respiratory depression reported. No recommendation from the American Academy of Pediatrics.

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

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.

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.

>10%: Central nervous system: Drowsiness

1% to 10%:

Central nervous system: Dizziness, abnormal coordination, ataxia, dysarthria, depression, memory disturbance, fatigue

Dermatologic: Dermatitis, allergic reactions

Endocrine & metabolic: Decreased libido

Gastrointestinal: Anorexia, constipation, diarrhea, xerostomia

Respiratory: Upper respiratory tract infection, sinusitis, rhinitis, coughing

<1%: Menstrual irregularities, blood dyscrasias

May produce somnolence, confusion, ataxia, diminished reflexes, or coma

Treatment for benzodiazepine overdose is supportive. Rarely is mechanical ventilation required. 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.

CYP3A3/4 enzyme substrate

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

Carbamazepine, rifampin, rifabutin may enhance the metabolism of clonazepam and decrease its therapeutic effect; consider using an alternative sedative/hypnotic agent

Cimetidine, ciprofloxacin, clarithromycin, clozapine, CNS depressants, diltiazem, disulfiram, digoxin, erythromycin, ethanol, fluconazole, fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, labetalol, levodopa, loxapine, metoprolol, metronidazole, miconazole, nefazodone, omeprazole, phenytoin, rifabutin, rifampin, troleandomycin, verapamil may increase the serum level and/or toxicity of clonazepam; monitor for altered benzodiazepine response

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

Onset of effect: 20-60 minutes

Duration: Up to 6-8 hours in infants and young children, up to 12 hours in adults

Absorption: Oral: Well absorbed

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

Protein binding: 85%

Metabolism: Extensive; glucuronide and sulfate conjugation

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

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

Elimination: <2% excreted unchanged in urine; metabolites excreted as glucuronide or sulfate conjugates

Oral:

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:

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

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

Hemodialysis: Supplemental dose is not necessary

Alcohol: Additive CNS depression has been reported with benzodiazepines; avoid or limit alcohol

Relationship between serum concentration and seizure control is not well established

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

No information available to require special precautions

No effects or complications reported

Take exactly as directed (do not increase dose or frequency); 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); constipation (increased exercise, fluids, or dietary fruit and 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; difficulty breathing 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 be pregnant. Breast-feeding is not recommended.

Observe patient for excess sedation, respiratory depression; raise bed rails, initiate safety measures, assist with ambulation

Tablet: 0.5 mg, 1 mg, 2 mg

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

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.

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