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.

CLOMIPRAMINE HCL

Chemistry - A dibenzazepine-derivative tricyclic antidepressant, clomipramine HCl occurs as awhite to off-white crystalline powder and is freely soluble in water.

Storage, Stability, Compatibility

The commercially available capsules should be stored attemperatures less than 30°C in tight containers and protected from moisture. An expiration date of 3years from the date of manufacture is assigned to the commercially available capsules.

Pharmacology - CLOMIPRAMINE HCL

While the exact mechanism of action of tricyclic antidepressants is notfully understood, it is believed that their most significant effects result from their action in preventing the reuptake of norepinephrine and serotonin at the neuronal membrane. Clomipramine isapparently a selective inhibitor of serotonin (5-HT) reuptake.

Uses, Indications

In veterinary medicine, clomipramine is used primarily in dogs as a treatmentfor obsessive compulsive disorders (ritualistic stereotypical behaviors) and may also be useful fordominance aggression and anxiety (separation).
Clomipramine may also be useful in cats, but cats tend to be more sensitive to tricyclics antidepressant drugs and the commercially available dosage forms preclude convenient dosing in thisspecies.

Pharmacokinetics - CLOMIPRAMINE HCL

While no dog or cat pharmacokinetic data was located, in humans the drug iswell absorbed from the GI tract, but a substantial first pass effect reduces its systemic bioavailabilityto approximately 50%. The presence of food in the gut apparently does not significantly alter itsabsorption.
Clomipramine is highly lipophilic and widely distributed throughout the body with an apparentvolume of distribution of 17 L/kg. The drug crosses the placenta and into maternal milk. Plasmalevels have been detected in nursing babies of mothers taking the drug. Both clomipramine and itsactive metabolite (desmethylclomipramine) cross the blood-brain barrier and significant levels arefound in the brain. It should be noted that although therapeutic effects may take several weeks to beseen, adverse effects may occur early on in treatment.
Clomipramine is metabolized principally in the liver to several metabolites includingdesmethylclomipramine, which is active. About two-thirds of these metabolites are eliminated in theurine and the rest in the feces. After a single dose, the elimination half life of clomipramine averages32 hours and desmethylclomipramine averages 69 hours, but there is wide interpatient variation.

Contraindications, Precautions, Reproductive Safety

These agents are contraindicated if priorsensitivity has been noted with any other tricyclic. Concomitant use with monoamine oxidaseinhibitors is generally contraindicated.
In humans, these drugs (tricyclic antidepressants) may lower seizure threshold. Use with cautionin animals with preexisting seizure disorders. Because of their anticholinergic effects use withcaution in patients with decreased GI motility, urinary retention, cardiac rhythm disturbances orincreased intraocular pressure. In humans tricyclic antidepressants have caused hepaticabnormalities. Baseline and annual monitoring of liver enzymes is suggested for animals receivingclomipramine long term. Tricyclics should be used cautiously in patients with hyperthyroidism orthose that are receiving thyroid supplementation as there may be an increased risk of cardiac rhythmabnormalities developing.
No teratogenic effects were noted in mice and rats given clomipramine at dosages of up 20X usualmaximum human dosage. Data in other domestic species appear to be lacking.

Adverse Effects, Warnings

The primary adverse effects reported thus far with the use ofclomipramine in dogs is sedation and some anticholinergic (dry mouth etc.) effects. Cardiac effectssuch as tachycardia secondary to the drugs anticholinergic activity may also result.
Cats have been reported to be more susceptible to the adverse effects of clomipramine than aredogs.
Overdosage - Overdosage with tricyclics can be life-threatening (arrhythmias, cardiorespiratorycollapse). Because the toxicities and therapies for treatment are complicated and controversial, it isrecommended to contact a poison control center for further information in any potential overdosesituation.

Drug Interactions

Because of additive effects, use clomipramine cautiously with other agentswith anticholinergic or CNS depressant effects. Tricyclic antidepressants used with antithyroid agents may increase the potential risk of agranulocytosis. Cimetidine may inhibit tricyclicantidepressant metabolism and increase the risk of toxicity. Use in combination with sympathomimetic agents may increase the risk of cardiac effects (arrhythmias, hypertension, hyperpyrexia). Concomitant use with monoamine oxidase inhibitors (including selegiline/deprenyl) isgenerally contraindicated.
Laboratory Considerations - Tricyclics can widen QRS complexes, prolong PR intervals andinvert or flatten T-waves on ECG. The response to metapyrone may be decreased byclomipramine. Tricyclics may alter (increase or decrease) blood glucose levels.
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