DRUG INTERACTIONS
Effect of Clonazepam on the Pharmacokineticsof Other Drugs
Clonazepam does not appear to alter the pharmacokineticsof phenytoin, carbamazepine or phenobarbital. The effect of clonazepamon the metabolism of other drugs has not been investigated.
Effect of Other Drugs on the Pharmacokineticsof Clonazepam
Literature reports suggest that ranitidine, an agentthat decreases stomach acidity, does not greatly alter clonazepampharmacokinetics.
In a study in which the 2mg clonazepam orally disintegrating tablet was administered with andwithout propantheline (an anticholinergic agent with multiple effectson the GI tract) to healthy volunteers, the AUC of clonazepam was10% lower and the Cmax of clonazepam was 20% lower whenthe orally disintegrating tablet was given with propantheline comparedto when it was given alone.
Fluoxetine doesnot affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers,such as phenytoin, carbamazepine and phenobarbital, induce clonazepammetabolism, causing an approximately 30% decrease in plasma clonazepamlevels. Although clinical studies have not been performed, based onthe involvement of the cytochrome P-450 3A family in clonazepam metabolism,inhibitors of this enzyme system, notably oral antifungal agents,should be used cautiously in patients receiving clonazepam.
Pharmacodynamic Interactions
The CNS-depressant action of the benzodiazepine classof drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbituratehypnotics, antianxiety agents, the phenothiazines, thioxanthene andbutyrophenone classes of antipsychotic agents, monoamine oxidase inhibitorsand the tricyclic antidepressants, and by other anticonvulsant drugs.
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OVERDOSAGE
Human Experience
Symptoms of clonazepam overdosage, like those producedby other CNS depressants, include somnolence, confusion, coma anddiminished reflexes.
Overdose Management
Treatment includes monitoring of respiration, pulseand blood pressure, general supportive measures and immediate gastriclavage. Intravenous fluids should be administered and an adequateairway maintained. Hypotension may be combated by the use of levarterenolor metaraminol. Dialysis is of no known value.
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicatedfor the complete or partial reversal of the sedative effects of benzodiazepinesand may be used in situations when an overdose with a benzodiazepineis known or suspected. Prior to the administration of flumazenil,necessary measures should be instituted to secure airway, ventilationand intravenous access. Flumazenil is intended as an adjunct to, notas a substitute for, proper management of benzodiazepine overdose.Patients treated with flumazenil should be monitored for resedation,respiratory depression and other residual benzodiazepine effects foran appropriate period after treatment. Theprescriber should be aware of a risk of seizure in association withflumazenil treatment, particularly in long-term benzodiazepine usersand in cyclic antidepressant overdose. The complete flumazenilpackage insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted priorto use.
Flumazenilis not indicated in patients with epilepsy who have been treated withbenzodiazepines. Antagonism of the benzodiazepine effect in such patientsmay provoke seizures.
Serious sequelaeare rare unless other drugs or alcohol have been taken concomitantly.
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