Clorazepate Dipotassium

Benzodiazepine Anxiolytic, Sedative, Anticonvulsant Rx Controlled C-IV (US)

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 0.5-2 mg/kg (anxiety); 0.5-1 mg/kg (seizure adjunct) q8-12h (anxiety); q8h (seizure adjunct) Duration: As needed for anxiety; for seizures, may be used short-term (e.g., 3-5 days) to break cluster seizures
Notes: Titrate to effect; taper dose when discontinuing to avoid withdrawal.
Cat PO 0.5-1 mg/kg q12-24h Duration: As needed for anxiety; short-term for seizures
Notes: Use with caution in cats with hepatic disease; may cause paradoxical excitation.
Horse PO 0.02-0.05 mg/kg q12-24h Duration: Short-term for anxiety/sedation
Notes: Not commonly used; IV formulation not available; oral only.
Cattle PO 0.05-0.1 mg/kg (off-label) q12-24h Duration: Short-term
Notes: Extra-label use; withdrawal times must be observed.
Small Ruminants PO 0.05-0.1 mg/kg (off-label) q12-24h Duration: Short-term
Notes: Limited data; use with caution.
Rabbit PO 0.5-1 mg/kg (off-label) q12-24h Duration: Short-term
Notes: Limited data; monitor for sedation.
Bird/Poultry PO 0.5-1 mg/kg (off-label) q12-24h Duration: Short-term
Notes: Limited data; not approved.

Clinical Indications & Species Uses

General Indications
  • Anxiolytic
  • Sedative
  • Anticonvulsant (adjunctive)
  • Muscle relaxant
Dog (Canine)
  • Anxiety disorders (separation anxiety, noise phobias)
  • Behavioral disorders (aggression, fear-based)
  • Adjunct in seizure management (especially for cluster seizures or status epilepticus when other drugs are ineffective)
  • Pre-anesthetic sedation (less common)
Cat (Feline)
  • Anxiety-related behavioral issues (e.g., inappropriate urination, aggression)
  • Adjunct in seizure management (less common)
  • Sedation for transport or veterinary visits (off-label)
Horse (Equine)
  • Anxiolytic for handling and transport
  • Sedative for minor procedures (off-label)
  • Adjunct in management of tetanus (muscle relaxation)

Pharmacology & Mechanism of Action

Drug Class: Benzodiazepine | Pharmacological Group: Anxiolytic, Sedative, Anticonvulsant

Mechanism of Action: Clorazepate dipotassium is a prodrug that is rapidly decarboxylated in the stomach to its active metabolite, N-desmethyldiazepam (nordazepam). Nordazepam is a long-acting benzodiazepine that binds to the benzodiazepine site on the gamma-aminobutyric acid type A (GABA-A) receptor, enhancing the inhibitory effects of GABA. This increases chloride ion influx, hyperpolarizing neurons and reducing neuronal excitability, leading to anxiolytic, sedative, muscle relaxant, and anticonvulsant effects.

Pharmacodynamics: Clorazepate produces dose-dependent central nervous system depression. It elevates the seizure threshold, reduces anxiety and aggression, and induces muscle relaxation. The onset of action after oral administration is relatively rapid (within 1-2 hours) due to rapid conversion to nordazepam. The duration of action is prolonged due to the long half-life of nordazepam and its active metabolites (e.g., oxazepam).

⚡ Pharmacokinetics Summary

Absorption: Clorazepate is well absorbed orally, but it is a prodrug that is rapidly decarboxylated in the acidic environment of the stomach to nordazepam, which is then absorbed. Food may delay absorption but not the extent.
Distribution: Nordazepam is highly lipophilic and distributes widely throughout the body, crossing the blood-brain barrier and placenta. It is also distributed into milk.
Metabolism: Clorazepate is metabolized in the stomach (non-enzymatic decarboxylation) to nordazepam. Nordazepam is then metabolized in the liver via hepatic microsomal enzymes (CYP450) to oxazepam, which is also active. Further metabolism includes glucuronidation.
Excretion: Metabolites are excreted primarily in the urine as glucuronide conjugates, with a small amount in feces. Enterohepatic recirculation may occur.
Half-Life: Dog: nordazepam half-life approximately 2-4 hours (but active metabolites may extend effects); Cat: approximately 5-8 hours; Horse: approximately 1-2 hours; Humans: 20-100 hours for nordazepam.
Bioavailability: Oral bioavailability is high (nearly complete) due to rapid conversion to nordazepam.
Protein Binding: Nordazepam is approximately 97-98% bound to plasma proteins.

Available Formulations & Strengths

Oral Tablet 3.75 mg, 7.5 mg, 15 mg (PO)
Oral Capsule 3.75 mg, 7.5 mg, 15 mg (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Known hypersensitivity to benzodiazepines
  • Severe hepatic insufficiency
  • Acute narrow-angle glaucoma
  • Myasthenia gravis
  • Severe respiratory insufficiency
  • Concurrent use with other CNS depressants (relative contraindication, use with caution)
Warnings & Clinical Precautions:
  • Use with caution in animals with hepatic or renal disease.
  • May cause paradoxical excitation (especially in cats and some dogs).
  • Prolonged use may lead to physical dependence and withdrawal symptoms upon abrupt discontinuation.
  • Use with caution in pregnant or lactating animals; potential teratogenic effects in early pregnancy.
  • May cause sedation and ataxia; avoid activities requiring coordination.
  • In food animals, observe withdrawal times; extra-label use requires veterinary oversight.
  • Benzodiazepines are controlled substances; handle and store securely.

Adverse Effects & Reactions

Common:

  • Sedation
  • Ataxia
  • Increased appetite
  • Paradoxical excitation (especially in cats)
  • Muscle weakness

Serious / Severe:

  • Respiratory depression (especially with high doses or concurrent CNS depressants)
  • Hepatic toxicity (rare)
  • Blood dyscrasias (rare)
  • Dependence and withdrawal seizures

Rare:

  • Hypotension
  • Gastrointestinal upset
  • Skin reactions
  • Bone marrow suppression

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Other CNS depressants (barbiturates, opioids, phenothiazines, alcohol) Additive CNS depression and respiratory depression High
Cimetidine May increase plasma levels of nordazepam by inhibiting hepatic metabolism Moderate
Fluoxetine May increase levels of benzodiazepines via CYP inhibition Moderate
Ketoconazole May increase benzodiazepine levels Moderate
Theophylline May reduce sedative effects of benzodiazepines Mild

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe sedation
  • Ataxia
  • Coma
  • Respiratory depression
  • Hypotension
  • Hypothermia

Emergency Treatment Protocol: Treatment is primarily supportive. Induce emesis if recent ingestion and animal is conscious. Administer activated charcoal to reduce absorption. Provide respiratory support (oxygen, ventilation) if needed. Flumazenil (benzodiazepine antagonist) can be administered at 0.01-0.02 mg/kg IV (dogs/cats) to reverse effects, but use with caution as it may precipitate seizures in animals with underlying seizure disorder. Monitor vital signs and provide fluid therapy for hypotension.

Food Animal Withdrawal Times

🥩 Meat: 7 days🥛 Milk: 3 days

Withdrawal times are not established for clorazepate in food animals; these are conservative estimates based on similar benzodiazepines. Extra-label use requires veterinary oversight and extended withdrawal periods may be necessary. Consult FARAD for specific 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).

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

Dispensing Status: Prescription Required (Rx Only)

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

Extra-Label (Off-Label) Use: In the US, extra-label use in food animals is permitted under AMDUCA with veterinary oversight, but requires a valid VCPR and extended withdrawal times. In non-food animals, extra-label use is common. In the EU, similar regulations apply under Cascade.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Clorazepate dipotassium is a long-acting benzodiazepine used in veterinary medicine primarily for anxiety and as an adjunctive anticonvulsant. Its active metabolite, nordazepam, has a long half-life, making it suitable for once or twice daily dosing. In dogs, it is particularly useful for managing separation anxiety and noise phobias, and can be used to break cluster seizures when combined with other anticonvulsants. In cats, it may be used for anxiety-related inappropriate urination, but paradoxical excitation can occur. Due to its potential for dependence, it should be tapered when discontinuing after prolonged use. It is a controlled substance (C-IV) and must be handled with care. In food animals, extra-label use is rare and withdrawal times must be observed. Always monitor for adverse effects, especially respiratory depression when used with other CNS depressants.

References & Literature

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