Clomipramine Hydrochloride

Tricyclic Antidepressant (TCA) Serotonin and Norepinephrine Reuptake Inhibitor (SNRI-like)

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 1-3 mg/kg q12h (every 12 hours) Duration: Typically 2-4 weeks for initial response; may be used long-term for chronic conditions
Notes: Start at lower end of dose range and titrate up as needed. Administer with food to reduce GI upset. Maximum dose 3 mg/kg q12h.
Cat PO 0.5-1 mg/kg q24h (once daily) Duration: Usually 4-6 weeks for initial response; may be used long-term
Notes: Cats are more sensitive to side effects; use lower doses. Administer with food. Do not exceed 1 mg/kg/day.
Horse PO 0.5-1 mg/kg q12h Duration: Variable; limited studies
Notes: Off-label use; monitor for CNS effects. Not FDA-approved for horses.
Rabbit PO 1-2 mg/kg q24h Duration: Variable; limited data
Notes: Off-label use; use with caution due to limited safety data.

Clinical Indications & Species Uses

General Indications
  • Behavioral disorders involving anxiety, fear, and compulsions
  • As an adjunct to behavior modification therapy
Dog (Canine)
  • Separation anxiety
  • Compulsive behaviors (e.g., flank sucking, tail chasing, excessive licking)
  • Generalized anxiety disorders
  • Panic disorders
  • As an adjunct in behavioral modification programs
Cat (Feline)
  • Urine spraying (marking)
  • Anxiety-related inappropriate elimination
  • Compulsive behaviors (e.g., overgrooming, psychogenic alopecia)
  • Generalized anxiety

Pharmacology & Mechanism of Action

Drug Class: Tricyclic Antidepressant (TCA) | Pharmacological Group: Serotonin and Norepinephrine Reuptake Inhibitor (SNRI-like)

Mechanism of Action: Clomipramine is a dibenzazepine tricyclic antidepressant that primarily inhibits the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane, thereby increasing serotonergic neurotransmission. It also inhibits norepinephrine reuptake to a lesser extent. Its active metabolite, desmethylclomipramine, is a potent norepinephrine reuptake inhibitor. Chronic administration leads to downregulation of beta-adrenergic and serotonin receptors, contributing to its therapeutic effects. In veterinary medicine, it is used to manage behavioral disorders by modulating neurotransmitter levels in the brain.

Pharmacodynamics: Clomipramine exhibits antidepressant, anti-obsessional, and anti-panic properties. It reduces anxiety and compulsive behaviors by enhancing serotonergic and noradrenergic activity. It also has anticholinergic, antihistaminic, and alpha-adrenergic blocking effects, which account for many of its adverse effects. In dogs, it has been shown to reduce separation anxiety and compulsive behaviors. In cats, it is used for urine spraying and other anxiety-related behaviors. The onset of therapeutic effect is typically 2-4 weeks.

⚡ Pharmacokinetics Summary

Absorption: Clomipramine is well absorbed after oral administration in dogs and cats. Peak plasma concentrations occur approximately 2-3 hours after dosing. Food may delay absorption but not the extent.
Distribution: Clomipramine is widely distributed throughout the body, with high affinity for tissues, particularly the brain, lungs, and liver. It crosses the blood-brain barrier and placenta. It is approximately 97-99% protein-bound in plasma.
Metabolism: Extensively metabolized in the liver via cytochrome P450 enzymes, primarily CYP2D6 and CYP3A4, to form desmethylclomipramine (active) and other metabolites. First-pass metabolism is significant, reducing oral bioavailability.
Excretion: Metabolites are excreted primarily in the urine (about 60-70%) and feces (about 20-30%). A small amount is excreted unchanged. In dogs, the elimination half-life is approximately 4-8 hours for clomipramine and 8-12 hours for desmethylclomipramine. In cats, the half-life is longer, approximately 24-48 hours.
Half-Life: Dogs: 4-8 hours (clomipramine), 8-12 hours (desmethylclomipramine); Cats: 24-48 hours; Horses: ~2-4 hours (limited data).
Bioavailability: Oral bioavailability is low due to first-pass metabolism: approximately 20-30% in dogs and cats.
Protein Binding: 97-99% in plasma

Available Formulations & Strengths

Oral Tablet 10 mg, 25 mg, 50 mg, 75 mg (PO)
Capsule 25 mg, 50 mg, 75 mg (PO)
Oral Solution (compounded) Various (e.g., 5 mg/mL, 10 mg/mL) (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to clomipramine or other tricyclic antidepressants
  • Concurrent use of monoamine oxidase inhibitors (MAOIs) – risk of serotonin syndrome
  • Recent myocardial infarction or heart block
  • Severe hepatic or renal impairment
  • History of seizures or epilepsy (may lower seizure threshold)
  • Narrow-angle glaucoma (due to anticholinergic effects)
  • Urinary retention or prostatic hypertrophy (due to anticholinergic effects)
Warnings & Clinical Precautions:
  • Use with caution in patients with cardiovascular disease, as it may cause arrhythmias and hypotension.
  • May cause sedation or paradoxical excitation; monitor behavior.
  • Anticholinergic effects may cause dry mouth, constipation, and urinary retention.
  • Use with caution in geriatric patients and those with thyroid disease.
  • Do not discontinue abruptly; taper dose to avoid withdrawal symptoms.
  • In cats, monitor for signs of hepatic toxicity (rare).
  • Safety in pregnant or lactating animals has not been established; use only if benefits outweigh risks.
  • May interact with other CNS-active drugs; use with caution.

Adverse Effects & Reactions

Common:

  • Sedation or lethargy
  • Anticholinergic effects: dry mouth, constipation, urinary retention
  • Gastrointestinal upset: vomiting, diarrhea, decreased appetite
  • Mydriasis (pupil dilation)
  • Tachycardia

Serious / Severe:

  • Seizures (especially in animals with pre-existing seizure disorders)
  • Cardiac arrhythmias (including QT prolongation)
  • Hepatotoxicity (rare)
  • Serotonin syndrome (when combined with other serotonergic drugs)
  • Bone marrow suppression (rare)

Rare:

  • Allergic reactions (skin rash, urticaria)
  • Hyperthermia
  • Ataxia
  • Aggression or paradoxical excitation
  • Blood dyscrasias (eosinophilia, leukopenia)

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Monoamine oxidase inhibitors (MAOIs) e.g., selegiline Risk of serotonin syndrome (hyperthermia, agitation, tremors, seizures). Avoid concurrent use; allow at least 14 days between discontinuation of MAOI and start of clomipramine. High
Other serotonergic drugs (e.g., SSRIs, SNRIs, tramadol, amitraz) Additive serotonergic effects, increased risk of serotonin syndrome. High
Anticholinergic drugs (e.g., atropine, antihistamines) Additive anticholinergic effects (constipation, urinary retention, dry mouth). Moderate
CNS depressants (e.g., barbiturates, benzodiazepines, opioids) Additive sedation and respiratory depression. Moderate
Sympathomimetics (e.g., epinephrine, phenylpropanolamine) Increased risk of hypertension and cardiac arrhythmias. Moderate
Cimetidine, fluoxetine, quinidine May inhibit metabolism of clomipramine, increasing plasma levels and toxicity. Moderate
Thyroid medications (e.g., levothyroxine) May increase risk of cardiac arrhythmias. Mild

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe sedation or coma
  • Seizures
  • Cardiac arrhythmias (including QT prolongation, ventricular tachycardia)
  • Hypotension or hypertension
  • Respiratory depression
  • Hyperthermia
  • Mydriasis
  • Agitation or delirium

Emergency Treatment Protocol: Treatment is symptomatic and supportive. Induce emesis if recent ingestion and animal is conscious (within 1-2 hours). Administer activated charcoal to reduce absorption. Provide IV fluids for cardiovascular support. Monitor ECG and blood pressure. Treat seizures with diazepam or barbiturates. For cardiac arrhythmias, use lidocaine or propranolol (avoid class IA antiarrhythmics like quinidine). Sodium bicarbonate may be used for severe acidosis. In severe cases, consider hemodialysis (though protein binding limits efficacy). No specific antidote; physostigmine may be used for severe anticholinergic effects but is not routinely recommended.

Food Animal Withdrawal Times

Not approved for use in food animals. If used off-label in food animals, withdrawal times must be established based on pharmacokinetic data; however, due to long half-life and potential for residues, use is not recommended. Consult a veterinarian for specific withdrawal recommendations.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F).

Light Sensitivity: Light-sensitive — protect from direct exposure.

Handling & Special Conditions: Protect from light and moisture. Keep in tightly closed container. Keep out of reach of children and animals.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: FDA-approved for use in dogs and cats (Clomicalm®) for the treatment of separation anxiety in dogs and urine spraying in cats.

Extra-Label (Off-Label) Use: In the US, clomipramine is FDA-approved for use in dogs and cats (Clomicalm®). Extra-label use in other species is permitted under AMDUCA (Animal Medicinal Drug Use Clarification Act) for non-food animals, but for food animals, extra-label use is prohibited if the drug is not approved for that species and if it may cause residues. Since clomipramine is not approved for food animals, its use in food animals is not permitted.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Clomipramine is a valuable tool in managing behavioral disorders in companion animals, particularly separation anxiety and compulsive behaviors. It is most effective when combined with behavior modification therapy. The onset of action is delayed (2-4 weeks), so patience is required. Doses should be individualized, starting low and titrating to effect. Monitor for adverse effects, especially anticholinergic signs and sedation. In cats, use lower doses and monitor for signs of toxicity. Avoid use in animals with cardiac disease or seizure disorders. Regular veterinary follow-up is essential to assess efficacy and adjust treatment. Withdrawal should be gradual to avoid rebound anxiety. For food animals, use is contraindicated due to lack of residue data. Always consider the animal's overall health and concurrent medications to avoid interactions.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)