Cyproheptadine Hydrochloride

Antihistamine (First-generation), Serotonin Antagonist Piperidine derivative; H1-receptor antagonist with antiserotonergic and anticholinergic properties

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 0.05-0.1 mg/kg (antihistamine); 0.1-0.5 mg/kg (appetite stimulant) q8-12h Duration: As needed; for pruritus, may be used for several weeks; for appetite, until improvement
Notes: Start at lower end for antihistamine effects; higher doses may cause sedation.
Cat PO 1-2 mg per cat (total dose) for appetite; 2-4 mg per cat for pruritus q12h Duration: As needed; for appetite, may be used for several weeks
Notes: Cats are sensitive to anticholinergic effects; monitor for urinary retention.
Horse PO 0.1-0.2 mg/kg q12h Duration: As needed
Notes: Limited data; use with caution.
Rabbit PO 0.5-1 mg/kg q12h Duration: As needed
Notes: May cause GI stasis; use with supportive care.

Clinical Indications & Species Uses

General Indications
  • Antihistamine for allergic reactions
  • Appetite stimulant
  • Antiserotonergic agent for serotonin syndrome
Dog (Canine)
  • Pruritus associated with allergic dermatitis
  • Urticaria
  • Appetite stimulation (especially in chronic illness or anorexia)
  • Serotonin syndrome (adjunctive therapy)
Cat (Feline)
  • Pruritus (especially in allergic skin disease)
  • Appetite stimulation (e.g., in chronic kidney disease or cancer)
  • Serotonin syndrome (adjunctive therapy)
  • Pica or inappropriate urination (off-label)
Rabbit & Small Mammals
  • Appetite stimulation (off-label)
  • Pruritus (off-label)
Exotic & Other Species
  • Appetite stimulation in small mammals (e.g., ferrets, guinea pigs) (off-label)
  • Pruritus in some exotic species (off-label)

Pharmacology & Mechanism of Action

Drug Class: Antihistamine (First-generation), Serotonin Antagonist | Pharmacological Group: Piperidine derivative; H1-receptor antagonist with antiserotonergic and anticholinergic properties

Mechanism of Action: Cyproheptadine is a first-generation antihistamine that competitively antagonizes histamine at H1 receptors, thereby reducing histamine-mediated effects such as vasodilation, increased vascular permeability, and bronchoconstriction. It also acts as a serotonin (5-HT2) receptor antagonist, which contributes to its appetite-stimulating effects and its use in conditions like serotonin syndrome. Additionally, it possesses weak anticholinergic (muscarinic) and sedative properties due to its ability to cross the blood-brain barrier and block central histamine and serotonin receptors.

Pharmacodynamics: Cyproheptadine produces dose-dependent antihistaminic effects, including reduction of pruritus, sneezing, and rhinorrhea. Its antiserotonergic activity can stimulate appetite by blocking serotonin's inhibitory effect on the feeding center. It also has anticholinergic effects leading to dry mouth, urinary retention, and tachycardia. In veterinary medicine, it is used for its antipruritic, appetite-stimulant, and antiserotonergic properties.

⚡ Pharmacokinetics Summary

Absorption: Cyproheptadine is well absorbed after oral administration. Peak plasma concentrations occur within 1-3 hours in most species. Food may slightly delay absorption but does not significantly affect overall bioavailability.
Distribution: It is widely distributed throughout the body, including the central nervous system. It crosses the blood-brain barrier and placenta. Volume of distribution is large, reflecting extensive tissue binding. Protein binding is approximately 96-99% in humans, but species-specific data are limited.
Metabolism: Extensively metabolized in the liver via oxidation, demethylation, and glucuronide conjugation. Multiple metabolites are formed, some of which may be pharmacologically active. Hepatic metabolism is the primary route of elimination.
Excretion: Metabolites are excreted primarily in the urine (about 40%) and feces (about 20%) in humans. In animals, biliary excretion may also occur. The elimination half-life is variable among species.
Half-Life: Dogs: approximately 3-4 hours; Cats: approximately 12-24 hours (may be longer); Humans: 8.6 hours (for reference).
Bioavailability: Oral bioavailability is estimated to be 50-80% in humans; species-specific data are limited but likely similar.
Protein Binding: Approximately 96-99% (human data; likely similar in animals).

Available Formulations & Strengths

Oral Tablet 4 mg, 8 mg (PO)
Oral Syrup 2 mg/5 mL (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to cyproheptadine or other antihistamines
  • Concurrent use with monoamine oxidase inhibitors (MAOIs)
  • Narrow-angle glaucoma
  • Gastrointestinal obstruction or stenosis
  • Severe cardiovascular disease (e.g., arrhythmias)
  • Pheochromocytoma
  • Pregnancy (unless benefits outweigh risks; safety not established)
Warnings & Clinical Precautions:
  • Use with caution in animals with hepatic or renal impairment.
  • May cause sedation; avoid concurrent use with other CNS depressants.
  • Anticholinergic effects may exacerbate conditions like urinary retention, constipation, or dry eye.
  • In cats, may cause hyperexcitability or agitation in some individuals.
  • Use with caution in animals with a history of seizures.
  • May mask signs of ototoxicity from other drugs.
  • In food animals, withdrawal times must be observed; extra-label use is prohibited in some countries.

Adverse Effects & Reactions

Common:

  • Sedation
  • Drowsiness
  • Dry mouth
  • Constipation
  • Urinary retention
  • Decreased tear production

Serious / Severe:

  • Tachycardia
  • Arrhythmias
  • Hypotension
  • Seizures (especially in overdose)
  • Paradoxical excitation (especially in cats)
  • Hepatotoxicity (rare)

Rare:

  • Blood dyscrasias
  • Allergic reactions (e.g., rash, anaphylaxis)
  • Photosensitivity

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Monoamine oxidase inhibitors (MAOIs) Increased risk of anticholinergic and CNS effects; may lead to hypertensive crisis. High
CNS depressants (e.g., barbiturates, benzodiazepines, opioids) Additive sedation and respiratory depression. Moderate
Anticholinergic drugs (e.g., atropine, tricyclic antidepressants) Additive anticholinergic effects (dry mouth, urinary retention, tachycardia). Moderate
Serotonergic drugs (e.g., SSRIs, SNRIs, tramadol) May antagonize serotonergic effects; risk of serotonin syndrome if used with other serotonergic agents. Moderate
Fluoxetine May increase cyproheptadine levels; monitor for toxicity. Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe sedation
  • Agitation or excitement (especially in cats)
  • Tachycardia
  • Arrhythmias
  • Hypotension
  • Seizures
  • Respiratory depression
  • Coma

Emergency Treatment Protocol: Treatment is symptomatic and supportive. Induce emesis if recent ingestion and animal is conscious. Administer activated charcoal to reduce absorption. Provide IV fluids and cardiovascular support. Use benzodiazepines for seizures. Monitor vital signs and ECG. In severe cases, consider gastric lavage. There is no specific antidote.

Food Animal Withdrawal Times

Cyproheptadine is not approved for use in food animals in many countries. If used extra-label, withdrawal times must be determined based on regulatory guidelines (e.g., FARAD in the US). Typically, a withdrawal period of at least 7 days for meat and 72 hours for milk is suggested, but consult local regulations.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature (20-25°C, excursions permitted to 15-30°C).

Handling & Special Conditions: Protect from moisture. Keep container tightly closed. Do not freeze oral syrup.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Approved for human use; not FDA-approved for veterinary use, but commonly used off-label in veterinary medicine.

Extra-Label (Off-Label) Use: In the US, extra-label use in food animals is permitted under AMDUCA only with a valid veterinary-client-patient relationship and if no approved drug is available. Withdrawal times must be extended based on FARAD recommendations. In the EU, extra-label use in food animals is restricted.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Cyproheptadine is a versatile drug in veterinary practice, primarily used for its antihistamine and appetite-stimulating effects. In cats, it is often used to stimulate appetite in chronic diseases like CKD or cancer, and for pruritus. In dogs, it is less commonly used for pruritus compared to other antihistamines, but may be tried. It is also an adjunct in serotonin syndrome. Dosing should be individualized, and owners should be warned about sedation and anticholinergic effects. In cats, paradoxical excitement may occur. For food animals, extra-label use is limited and withdrawal times must be carefully considered. Overall, it is a safe drug when used appropriately, but monitoring for adverse effects is recommended.

References & Literature

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