Doxepin Hydrochloride

Tricyclic Antidepressant (TCA) Dibenzoxepin derivative; serotonin and norepinephrine reuptake inhibitor

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 0.5-2 mg/kg q12h Duration: Variable; often 2-4 weeks for pruritus, may be longer for behavioral issues
Notes: Start at low end and titrate up. For pruritus, may take 1-2 weeks to see effect. For anxiety, may require 4-6 weeks.
Cat PO 0.5-1 mg/kg q12-24h Duration: Variable; often 2-4 weeks
Notes: Use cautiously in cats due to sensitivity to anticholinergic effects. Start with lowest dose.
Horse PO Not established Not established Duration: Not established
Notes: Not commonly used; no established dosage.
Cattle PO Not established Not established Duration: Not established
Notes: Not commonly used; no established dosage.
Small Ruminants PO Not established Not established Duration: Not established
Notes: Not commonly used; no established dosage.
Rabbit PO Not established Not established Duration: Not established
Notes: Not commonly used; no established dosage.
Bird/Poultry PO Not established Not established Duration: Not established
Notes: Not commonly used; no established dosage.
Exotic/Other PO Not established Not established Duration: Not established
Notes: Not commonly used; no established dosage.

Clinical Indications & Species Uses

General Indications
  • Antipruritic in allergic skin conditions
  • Sedation and anxiolysis
Dog (Canine)
  • Pruritus associated with allergic dermatitis (atopy, flea allergy, food allergy)
  • Anxiety and behavioral disorders (off-label)
  • Psychogenic alopecia (off-label)
Cat (Feline)
  • Pruritus associated with allergic dermatitis (off-label)
  • Anxiety and behavioral disorders (off-label)
  • Urine spraying (off-label)

Pharmacology & Mechanism of Action

Drug Class: Tricyclic Antidepressant (TCA) | Pharmacological Group: Dibenzoxepin derivative; serotonin and norepinephrine reuptake inhibitor

Mechanism of Action: Doxepin is a tricyclic antidepressant that primarily inhibits the reuptake of serotonin and norepinephrine at the presynaptic neuronal membrane, thereby increasing their concentrations in the synaptic cleft. It also has potent antihistaminic (H1 and H2) and anticholinergic properties, and blocks alpha-1 adrenergic receptors. In veterinary medicine, its primary use is for its antihistaminic and antipruritic effects, particularly in the management of pruritus associated with allergic dermatitis. It also has sedative and anxiolytic effects due to its central actions.

Pharmacodynamics: Doxepin exhibits high affinity for histamine H1 receptors, making it a potent antihistamine (up to 800 times more potent than diphenhydramine in vitro). It also blocks H2 receptors, reducing gastric acid secretion. Its anticholinergic activity can cause dry mouth, urinary retention, and tachycardia. It blocks alpha-1 adrenergic receptors leading to vasodilation and hypotension. Central effects include sedation, anxiolysis, and antidepressant activity. In dogs and cats, it is used primarily for its antipruritic and sedative properties.

⚡ Pharmacokinetics Summary

Absorption: Doxepin is well absorbed after oral administration. Peak plasma concentrations occur within 2-4 hours in dogs. Food may delay absorption but not the extent.
Distribution: Doxepin is highly lipophilic and widely distributed throughout the body. It crosses the blood-brain barrier and placenta, and is excreted in milk. Volume of distribution is large.
Metabolism: Extensively metabolized in the liver via oxidation and demethylation. The primary active metabolite is desmethyldoxepin (nordoxepin), which has similar pharmacological activity. CYP450 enzymes are involved.
Excretion: Excreted primarily in the urine as metabolites, with a small amount excreted in feces. Biliary excretion may occur.
Half-Life: Dog: approximately 8-12 hours for doxepin and 15-20 hours for nordoxepin. Cat: approximately 10-15 hours (estimated).
Bioavailability: Oral bioavailability is approximately 25-30% in dogs due to first-pass metabolism.
Protein Binding: Approximately 80-85% bound to plasma proteins.

Available Formulations & Strengths

Oral Capsule 10 mg, 25 mg, 50 mg, 75 mg, 100 mg (PO)
Oral Tablet 3 mg, 6 mg (as doxepin hydrochloride) (PO)
Oral Concentrate 10 mg/mL (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to doxepin or other tricyclic antidepressants
  • Concurrent use of MAO inhibitors (e.g., selegiline) - risk of severe serotonin syndrome
  • Severe urinary retention (e.g., prostatic hypertrophy, urethral obstruction)
  • Angle-closure glaucoma
  • Severe hepatic disease
  • Cardiac conduction abnormalities (e.g., bundle branch block)
  • Concurrent use of cisapride or other drugs that prolong QT interval
Warnings & Clinical Precautions:
  • Use with caution in patients with cardiovascular disease, arrhythmias, or hypotension.
  • May cause sedation; avoid use in working dogs or animals requiring alertness.
  • Anticholinergic effects may exacerbate constipation, urinary retention, and dry eye (keratoconjunctivitis sicca).
  • Use with caution in epileptics; may lower seizure threshold.
  • In cats, use with caution due to increased sensitivity to anticholinergic effects.
  • May cause serotonin syndrome when combined with other serotonergic drugs (e.g., SSRIs, tramadol).
  • Use with caution in geriatric patients; may cause paradoxical excitement.
  • Do not withdraw abruptly; taper dose to avoid withdrawal symptoms.
  • Safety in pregnant or lactating animals has not been established; use only if clearly needed.

Adverse Effects & Reactions

Common:

  • Sedation
  • Dry mouth
  • Increased thirst
  • Constipation
  • Urinary retention
  • Mydriasis
  • Tachycardia
  • Hypotension
  • Weight gain

Serious / Severe:

  • Cardiac arrhythmias (including QT prolongation)
  • Seizures
  • Serotonin syndrome (when combined with other serotonergic drugs)
  • Severe hypotension
  • Hepatotoxicity
  • Blood dyscrasias (rare)

Rare:

  • Paradoxical excitement
  • Aggression
  • Ataxia
  • Vomiting
  • Diarrhea
  • Skin reactions
  • Bone marrow suppression

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
MAO inhibitors (e.g., selegiline) Severe serotonin syndrome, hyperpyrexia, convulsions, death High
SSRIs (e.g., fluoxetine, paroxetine) Increased risk of serotonin syndrome High
Tramadol Increased risk of serotonin syndrome and seizures High
Anticholinergics (e.g., atropine) Additive anticholinergic effects (dry mouth, urinary retention, tachycardia) Moderate
CNS depressants (e.g., barbiturates, benzodiazepines, opioids) Additive sedation and respiratory depression Moderate
Sympathomimetics (e.g., epinephrine) Increased risk of hypertension and arrhythmias Moderate
Cimetidine May increase doxepin levels by inhibiting metabolism Moderate
Drugs that prolong QT interval (e.g., fluoroquinolones, macrolides) Increased risk of ventricular arrhythmias High

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe sedation
  • Coma
  • Respiratory depression
  • Cardiac arrhythmias (including QT prolongation, ventricular tachycardia)
  • Hypotension or hypertension
  • Seizures
  • Mydriasis
  • Dry mouth
  • Urinary retention
  • Hyperthermia or hypothermia

Emergency Treatment Protocol: Treatment is symptomatic and supportive. Induce vomiting if recent ingestion and patient is conscious. Administer activated charcoal to reduce absorption. Provide respiratory support, cardiac monitoring, and treat arrhythmias with appropriate antiarrhythmics (e.g., lidocaine for ventricular arrhythmias). Use sodium bicarbonate for metabolic acidosis and to counteract cardiotoxic effects. Control seizures with diazepam or barbiturates. Avoid physostigmine due to risk of bradycardia and asystole. Monitor for at least 24 hours.

Food Animal Withdrawal Times

Not approved for food animals. No withdrawal times established. Do not use in animals intended for food.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature 20-25°C (68-77°F)

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

Handling & Special Conditions: Protect from light and moisture. Keep container tightly closed.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Not FDA-approved for veterinary use; approved for human use. Used extra-label in veterinary medicine.

Extra-Label (Off-Label) Use: In the US, extra-label use in animals is permitted under AMDUCA (Animal Medicinal Drug Use Clarification Act) provided there is a valid veterinarian-client-patient relationship, and no approved animal drug is available. However, doxepin is not approved for veterinary use, so extra-label use is common. Withdrawal times must be considered for food animals, but since it is not used in food animals, no specific withdrawal times are established.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Doxepin is primarily used in veterinary dermatology for its potent antihistaminic and antipruritic effects, especially in dogs with allergic dermatitis. It is often used when conventional antihistamines are ineffective. It also has sedative and anxiolytic properties, making it useful for anxiety-related behaviors. Due to its anticholinergic effects, it should be used cautiously in patients with glaucoma, urinary retention, or cardiac disease. Dosing should be individualized, starting at the low end and titrating to effect. Clinical response for pruritus may take 1-2 weeks. For behavioral issues, it may take several weeks. Monitoring for adverse effects, especially sedation and anticholinergic signs, is recommended. Drug interactions, particularly with MAO inhibitors and other serotonergic drugs, must be avoided. Overdose can be life-threatening and requires aggressive supportive care. Not recommended for use in food animals.

References & Literature

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