Anafranil

Approved Indications:

• Obsessive-Compulsive Disorder (OCD) in adults and adolescents (≥10 years)
• Major Depressive Disorder (MDD)
• Panic Disorder (with or without agoraphobia)

Clinically Accepted Off-Label Uses:

• Chronic Pain Syndromes (e.g., neuropathic pain, fibromyalgia)
• Cataplexy associated with narcolepsy
• Premature Ejaculation
• Social Anxiety Disorder
• Enuresis (nocturnal bedwetting) in children (typically after other options fail)
• Body Dysmorphic Disorder
• Trichotillomania
• Depression with Anxiety Features

Adults:

• OCD:
• Start with 25 mg/day (usually at bedtime).
• Increase gradually to 100 mg/day over 2 weeks.
• Typical effective dose: 100–250 mg/day (max: 250 mg/day), given in divided doses or single dose at bedtime.
• Depression, Panic Disorder:
• Initial: 25–50 mg/day
• Maintenance: 100–150 mg/day
• Maximum: 250 mg/day

Pediatrics (≥10 years for OCD):

• Initial: 25 mg/day
• Titrate gradually over 2 weeks up to 3 mg/kg/day (max: 200 mg/day)
• Divide doses or give at bedtime.

Elderly:

• Start low (10–25 mg/day); titrate slowly with close monitoring.
• Max: usually ≤150 mg/day

Hepatic Impairment:

• Use caution; reduce dose and monitor liver function.

Renal Impairment:

• No specific adjustments, but close monitoring is advised.

Administration:

• Oral only.
• Take with food to reduce GI irritation.
• Bedtime dosing may reduce daytime sedation.

Clomipramine inhibits the reuptake of serotonin (5-HT) and, to a lesser extent, norepinephrine (NE) at the presynaptic nerve terminals in the CNS. It binds strongly to the serotonin transporter (SERT), enhancing serotonergic neurotransmission, which plays a major role in reducing obsessive-compulsive behaviors. Clomipramine also has affinity for muscarinic, histaminergic, and adrenergic receptors, accounting for many of its side effects (e.g., anticholinergic, sedative, and cardiovascular effects).

• Absorption: Well absorbed orally (bioavailability ~50% due to first-pass metabolism)
• Peak Plasma Time: 2–6 hours
• Distribution: Widely distributed; crosses blood-brain barrier; plasma protein binding ~97%
• Metabolism: Hepatic via CYP2D6 to active metabolite desmethylclomipramine
• Half-life: Parent ~19–37 hours; active metabolite ~54 hours
• Excretion: Renal (mostly as metabolites)

• Pregnancy: Category C (use only if benefit outweighs risk); possible risk of neonatal withdrawal symptoms and cardiovascular effects with third-trimester use.
• Lactation: Excreted in breast milk; not recommended during breastfeeding due to potential for CNS effects in the infant (e.g., sedation, irritability).

• Primary Class: Tricyclic Antidepressant (TCA)
• Subclass: Serotonin Reuptake Inhibitor–dominant TCA

• Hypersensitivity to clomipramine or other TCAs
• Recent myocardial infarction
• Concomitant use of MAO inhibitors or within 14 days of stopping MAOIs
• Use with linezolid or IV methylene blue
• History of seizures
• Glaucoma (especially narrow-angle)
• Urinary retention

• Suicidal Ideation: Monitor closely in adolescents and young adults, especially during dose changes.
• Seizures: Dose-dependent risk; avoid in seizure-prone individuals.
• Serotonin Syndrome: Risk increases with serotonergic drugs.
• Orthostatic Hypotension & Arrhythmias: ECG monitoring recommended, especially in the elderly and patients with cardiac disease.
• Anticholinergic Effects: Dry mouth, constipation, urinary retention, blurred vision—use caution in elderly and those with prostatic hypertrophy.
• Hepatic Dysfunction: Monitor liver enzymes periodically.
• Withdrawal Symptoms: Avoid abrupt discontinuation; taper gradually.
• Photosensitivity: Use sunscreen or avoid prolonged sun exposure.

Very Common:

• Drowsiness
• Dry mouth
• Constipation
• Dizziness
• Weight gain
• Blurred vision

Common:

• Orthostatic hypotension
• Increased sweating
• Sexual dysfunction
• Tremors
• Nausea

Less Common/Rare:

• Seizures
• QT prolongation
• Cardiac arrhythmias
• Hypomania or mania
• Extrapyramidal symptoms
• Blood dyscrasias (e.g., agranulocytosis)
• Serotonin syndrome (when combined with SSRIs, MAOIs)

• MAO Inhibitors: Risk of serotonin syndrome—contraindicated.
• SSRIs/SNRIs: Increased risk of serotonin syndrome; caution with fluoxetine, sertraline, etc.
• CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine): May increase clomipramine levels.
• Anticholinergics: Additive effects (urinary retention, dry mouth).
• Antihypertensives: TCAs may reduce efficacy.
• CNS Depressants (alcohol, benzodiazepines): Enhanced sedation.
• QT-prolonging agents: Increased risk of torsades de pointes.

• FDA warning update: TCAs including clomipramine must carry black box warning about increased suicide risk in young adults and children.
• Updated TDM guidelines: Therapeutic plasma concentration range for OCD is 200–350 ng/mL for efficacy and safety balance.
• NICE & APA guidelines: Clomipramine is recommended as second-line treatment in OCD, especially when SSRIs fail.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Humidity & Light: Protect from moisture and light
• Handling: Keep tightly sealed; protect from children
• Formulations: Available as tablets and capsules; do not crush modified-release forms