Veterinary Drug Handbook (VDH) is the reference veterinarians turn to when they want an independent source of information on the drugs that are used in veterinary medicine today.

CLONAZEPAM

Chemistry - A benzodiazepine anticonvulsant, clonazepam occurs as an off-white to light yellow, crystalline powder having a faint odor. It is insoluble in water and slightly soluble in alcohol.

Storage, Stability, Compatibility

Tablets should be stored in air-tight, light resistant containersat room temperature. After manufacture, a 5 year expiration date is assigned.

Pharmacology - CLONAZEPAM

The subcortical levels (primarily limbic, thalamic, and hypothalamic) of the CNSare depressed by diazepam and other benzodiazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant, and anticonvulsant effects seen. The exact mechanism of action isunknown, but postulated mechanisms include: antagonism of serotonin, increased release of and/orfacilitation of gamma-aminobutyric acid (GABA) activity and diminished release or turnover ofacetylcholine in the CNS. Benzodiazepine specific receptors have been located in the mammalianbrain, kidney, liver, lung and heart. In all species studied, receptors are lacking in the white matter.

Uses, Indications

Clonazepam is used primarily as an adjunctive anticonvulsant in dogs notcontrolled with other more standard therapies. Like diazepam, it may also be useful in the treatmentof status epilepticus.

Pharmacokinetics - CLONAZEPAM

In humans, the drug is well absorbed from the GI tract; crosses the blood-brain barrier and placenta; is metabolized in the liver to several metabolites that are excreted in the urine. Peak serum levels occur about 3 hours after oral dosing. Half-lives range from 19-40 hours.

Contraindications, Precautions, Reproductive Safety

Clonazepam is contraindicated in patients who are hypersensitive to it or other benzodiazepines, have significant liver dysfunction orhave acute narrow angle glaucoma. Benzodiazepines have been reported to exacerbate myastheniagravis.
Safe use during pregnancy has not been established; adverse effects have been seen in rabbits andrats. It is not known if the drug enters maternal milk, however several other benzodiazepines havebeen documented to enter maternal milk.

Adverse Effects, Warnings

There is very limited information on the adverse effect profile of thisdrug in domestic animals. Sedation (or excitement) and ataxia may occur. Clonazepam has beenreported to cause a multitude of various adverse effects in humans. Some of the more significantones include increased salivation, hypersecretion in upper respiratory passages, GI effects(vomiting, constipation, diarrhea, etc.), transient elevations of liver enzymes, hematologic effects(anemia, leukopenia, thrombocytopenia, etc.). Tolerance (usually noted after 3 months of therapy) tothe anticonvulsant effects has been reported in dogs.
Patients discontinuing clonazepam, particularly those who have been on the drug chronically athigh dosages, should be tapered off or status epilepticus may be precipitated. Vomiting and diarrheamay occur during this process.

Overdosage, Acute Toxicity

When used alone, clonazepam overdoses are generally limited tosignificant CNS depression (confusion, coma, decreased reflexes, etc). Treatment of significant oraloverdoses consists of standard protocols for removing and/or binding the drug in the gut andsupportive systemic measures. The use of analeptic agents (CNS stimulants such as caffeine, amphetamines, etc.) are generally not recommended.

Drug Interactions

If administered with other CNS depressant agents (barbiturates, narcotics, anesthetics, etc.) additive effects may occur. If used with phenytoin, increased serum phenytoin levels and decreased clonazepam levels may occur.
Rifampin may induce hepatic microsomal enzymes and decrease the pharmacologic effects ofbenzodiazepines. Cimetidine or Erythromycin has been reported to decrease the metabolism ofbenzodiazepines.Laboratory Considerations - Benzodiazepines may decrease the thyroidal uptake of I123 or I131.
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