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clomiPRAMINE

Class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA Class: CN601
Chemical Name: 3-Chloro-10,11-dihydro-N,N-dimethyl -5H-dibenz[b,f]azepine-5-propanamine monohydrochloride
Molecular Formula: C19H23ClN2•HCl
CAS Number: 17321-77-6
Brands: Anafranil

Medically reviewed by Drugs.com on May 24, 2021. Written by ASHP.

Warning

    Suicidality
  • Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need. Clomipramine is not approved for use in pediatric patients except patients with obsessive-compulsive disorder. (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.

  • Appropriately monitor and closely observe all patients who are started on clomipramine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process. (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Tricyclic antidepressant (TCA); pharmacologic profile resembles that of other TCAs, SSRIs, and trazodone.

Uses for clomiPRAMINE

Obsessive-Compulsive Disorder (OCD)

Among the drugs of choice for the management of OCD.

Reduces but does not completely eliminate obsessions and compulsions.

Panic Disorder

Has been used effectively for the management of panic disorder with or without agoraphobia.

Major Depressive Disorder

Has been used effectively for the management of major depressive disorder.

Despite comparable efficacy, the adverse effect profile (e.g., anticholinergic effects) of clomipramine may limit its usefulness relative to other antidepressants (e.g., TCAs, SSRIs).

Effective antidepressant when obsessive manifestations accompany episode of major depressive disorder.

Chronic Pain

Has been used for the management of chronic pain (e.g., central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, cancer pain) alone or as adjunct to conventional analgesics.

Cataplexy and Associated Narcolepsy

Has been used for the symptomatic management of cataplexy in a limited number of patients with cataplexy and associated narcolepsy.

Autistic Disorder

Has been used for the management of repetitive and obsessive-compulsive behaviors and hyperactivity associated with autistic disorder; does not treat core symptoms of autistic disorder.

Trichotillomania

Has been used for the management of trichotillomania (an urge to pull out one’s hair) in a limited number of patients with the disorder; relapse reported in some patients receiving long-term therapy.

Onychophagia

Has been used for the management of severe onychophagia (nail biting) without a history of OCD.

Associated with relatively high dropout rate because of adverse effects and drug intolerance; not considered first-line therapy in most patients with onychophagia.

Eating Disorders

Has been used for the management of anorexia nervosa in a limited number of patients with the disorder.

Initial therapeutic effects (e.g., improved eating behavior, weight gain) not sustained with long-term therapy (e.g., ≥8 weeks).

Avoid use in underweight individuals and in those exhibiting suicidal ideation.

Premature Ejaculation

Has been used for the management of premature ejaculation.

Premenstrual Syndrome

Has been used for the management of premenstrual syndrome.

clomiPRAMINE Dosage and Administration

General

  • Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of clomipramine and vice versa. Also allow at least 5 weeks to elapse when switching from fluoxetine.

  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments. (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Sustained therapy may be required; use lowest effective dosage and monitor periodically for need for continued therapy.

  • Avoid abrupt discontinuance of therapy. To avoid withdrawal reactions, taper dosage gradually (e.g., over a period of approximately 2 weeks).

Panic Disorder†

  • Transient increase in the number and intensity of panic attacks may occur during initial therapy with the drug.

Administration

Oral Administration

Administer orally; initially, in divided doses with meals to lessen adverse GI effects. After initial dosage titration, the total daily dose may be given once daily at bedtime to minimize adverse effects (e.g., sedation) during waking hours and enhance patient compliance.

Also has been administered IM or IV, but a parenteral dosage form is not commercially available in the US.

Dosage

Available as clomipramine hydrochloride; dosage is expressed in terms of the salt.

Individualize dosage carefully according to individual requirements and response.

Allow 2–3 weeks to elapse between any further dosage adjustments after the initial dosage titration period for achievement of steady-state plasma concentrations.

Pediatric Patients

OCD
Oral

Children >10 years of age: initially, 25 mg daily. Gradually increase dosage, as tolerated, during the first 2 weeks of therapy up to a maximum of 3 mg/kg or 100 mg daily, whichever is lower. Titrate dosage carefully. If necessary, dosages may be increased gradually during the next several weeks up to a maximum of 3 mg/kg or 200 mg daily (whichever is lower).

Optimum duration not established; some clinicians recommend that therapy be continued in responding patients at the minimally effective dosage for at least 18 months before attempting to discontinue.

Adults

OCD
Oral

Initially, 25 mg daily. Gradually increase dosage, as tolerated, during the first 2 weeks of therapy to approximately 100 mg daily. If necessary, dosages may be increased gradually during the next several weeks up to a maximum of 250 mg daily.

Optimum duration not established; some clinicians recommend that therapy be continued in responding patients at the minimally effective dosage for at least 18 months before attempting to discontinue.

Panic Disorder†
Oral

Usual dosage: ≤50 mg daily (range: 12.5–150 mg daily); patients with agoraphobia may require higher dosage.

Major Depressive Disorder†
Oral

100–250 mg daily.

Chronic Pain†
Oral

100–250 mg daily.

Cataplexy and Associated Narcolepsy†
Oral

25–200 mg daily.

Prescribing Limits

Pediatric Patients

OCD
Oral

Maximum 3 mg/kg or 200 mg daily, whichever is lower.

Adults

OCD
Oral

Maximum 250 mg daily.

Panic Disorder†
Oral

Maximum 200 mg daily.

Special Populations

Geriatric Patients

Manufacturer makes no specific recommendation for dosage adjustment but lower clomipramine hydrochloride dosages are recommended by some clinicians at least during initial therapy.

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Cautions for clomiPRAMINE

Contraindications

  • Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor. (See Specific Drugs under Interactions.)

  • During the acute recovery phase following MI.

  • Known hypersensitivity to clomipramine or other TCAs.

Warnings/Precautions

Warnings

Seizures

Risk of seizure; use with caution in patients with a history of seizures or other predisposing factors (e.g., brain damage of various etiology, alcoholism, concurrent use of other drugs that lower the seizure threshold).

Risk may be dose related. (See Prescribing Limits under Dosage and Administration.)

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients, whether or not they are taking antidepressants; may persist until clinically important remission occurs. However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

Appropriately monitor and closely observe patients receiving clomipramine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. (See Boxed Warning and also see Pediatric Use under Cautions.)

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality. Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms. (See General under Dosage and Administration and also see Withdrawal Reactions under Cautions.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, OCD) or nonpsychiatric disorders.

Bipolar Disorder

May unmask bipolar disorder. (See Activation of Mania or Hypomania under Cautions.) Clomipramine is not approved for use in treating bipolar depression.

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.

General Precautions

Cardiovascular Effects

Modest orthostatic decreases in BP, modest tachycardia, and/or ECG abnormalities (e.g., VPCs, ST-T wave changes, intraventricular conduction abnormalities) reported; use with caution in patients with known cardiovascular disease.

Titrate dosage carefully.

Neuropsychiatric Effects

Variety of neuropsychiatric manifestations (e.g., delusions, hallucinations, psychotic episodes, confusion, paranoia) reported.

May precipitate an acute psychotic episode in patients with unrecognized schizophrenia.

Activation of Mania or Hypomania

Risk of activation of mania or hypomania in patients with affective disorder. (See Bipolar Disorder under Cautions.)

Anticholinergic Effects

Use with caution in patients for whom excess anticholinergic activity could be harmful (e.g., history of urinary retention, increased intraocular pressure, angle-closure glaucoma).

Interactions

More than 30 cases of hyperthermia reported, most cases occurring in patients receiving clomipramine in combination with other drugs (e.g., antipsychotic agents). When clomipramine and an antipsychotic agent were used concomitantly, the cases sometimes were considered to be examples of neuroleptic malignant syndrome (NMS).

Hepatic Effects

Potentially clinically important elevations (e.g., >3 times ULN) in serum ALT and AST concentrations; severe hepatic injury and/or death rarely reported.

Possible cross hepatotoxicity (e.g., elevated values on hepatic function tests, abdominal pain) involving different TCAs including clomipramine. (See Hepatic Impairment under Cautions.)

Hematologic Effects

Bone marrow depression (e.g., leukopenia, agranulocytosis, thrombocytopenia, anemia, pancytopenia) rarely reported.

Obtain leukocyte and differential blood cell counts if fever and sore throat occur during therapy.

Sexual Dysfunction

Relatively high risk of sexual dysfunction (e.g., libido change, ejaculatory failure, impotence ) in male patients with OCD.

Normal sexual functioning usually returns within a few days after discontinuing therapy.

Weight Changes

Possible weight gain or weight loss.

Withdrawal Reactions

Withdrawal reactions (e.g., dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, sweating, irritability, seizures, worsening of psychiatric status) reported following abrupt discontinuance of therapy.

To avoid withdrawal reactions, taper dosage gradually and monitor patients carefully.

Electroconvulsive Therapy (ECT)

Possible increased ECT risks; limit to patients for whom concomitant use is essential.

Elective Surgery

Discontinue therapy for as long as is clinically feasible prior to surgery and advise the anesthetist of such action.

Thyroid Disease

Use with caution in hyperthyroid patients or patients receiving thyroid agents because of the possibility of cardiac toxicity.

Adrenal Medulla Tumors

Use with caution in patients with tumors of the adrenal medulla, in whom hypertensive crises may be provoked.

Specific Populations

Pregnancy

Category C.

Possible withdrawal symptoms (e.g., jitteriness, tremor, seizures ) in neonates whose mothers received clomipramine throughout pregnancy; avoid use during late pregnancy whenever possible.

Lactation

Distributed into milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy for OCD not established in children <10 years of age.

Potential risks associated with long-term use (e.g., effects on growth, development, or maturation) not systematically evaluated in children and adolescents.

Adverse effects in children and adolescents >10 years of age generally similar to those in adults.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, OCD, or other psychiatric disorders based on pooled analyses of 24 short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others). However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

Carefully consider these findings when assessing potential benefits and risks of clomipramine in a child or adolescent for any clinical use. (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo. (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Possible increased sensitivity to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotension, and sedative effects of TCAs.

Hepatic Impairment

Use with caution in patients with clinically important hepatic disease; periodically monitor hepatic enzyme concentrations.

Renal Impairment

Use with caution in patients with clinically important renal impairment.

Common Adverse Effects

Adverse GI (e.g., dry mouth, constipation, nausea, dyspepsia, anorexia, increased appetite), nervous system (e.g., somnolence, tremor, dizziness, nervousness, fatigue, myoclonus), or genitourinary (e.g., changed libido, ejaculatory failure, impotence, micturition disorder) effects; sweating; weight gain; visual changes.

Interactions for clomiPRAMINE

Extensively metabolized in the liver by various CYP isoenzymes (e.g., CYP1A2, CYP2C, CYP2D6, CYP3A4).

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6 and/or 1A2: Potential pharmacokinetic interaction (increased plasma clomipramine concentrations). Monitor plasma clomipramine concentrations whenever a CYP2D6 inhibitor is added or discontinued and adjust dosages as needed.

Drugs Associated with Serotonin Syndrome

Potential pharmacologic (serotonin syndrome) interaction with serotonergic agents. Avoid such use whenever clinically possible.

Drugs Affecting the Seizure Threshold

Use caution with concurrent administration of clomipramine and drugs (e.g., other antidepressants, antipsychotic agents) that lower the seizure threshold.

Protein-bound Drugs

Potential for clomipramine to displace or to be displaced by other protein-bound drugs. Observe patients for adverse effects.

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potential for increased CNS effects of alcohol

Limited data suggest that demethylation of clomipramine may be reduced with chronic alcohol consumption

Advise patients of risks of such concomitant use

Alprazolam

Adverse effects resembling serotonin syndrome

Antiarrhythmics: class 1C (e.g., flecainide, propafenone)

Potential for decreased clomipramine metabolism

Monitor for TCA toxicity

Anticholinergic agents

Potential for additive anticholinergic effects

Use with caution; dosage adjustment may be needed

Antipsychotic agents (e.g., phenothiazines)

Hyperthermia and adverse effects resembling NMS

Potential for decreased clomipramine metabolism

Dosage adjustment may be needed

Barbiturates (e.g., phenobarbital)

May be additive with or may potentiate CNS effects

Possible decreased plasma clomipramine concentrations

Increased plasma phenobarbital concentrations reported

Advise patients of risks associated with such concomitant use

Cimetidine

Potential increased plasma clomipramine concentrations

Use with caution; dosage adjustment may be needed

CNS depressants (e.g., alcohol, sedatives, hypnotics)

Potentiates effects of CNS depressants

Use with caution

Digoxin

Possible altered protein binding of clomipramine or digoxin

Monitor for adverse effects

Haloperidol

Potential for increased plasma clomipramine concentrations

Use with caution; dosage adjustment may be needed

Hypotensive agents (e.g., clonidine, guanethidine)

May antagonize antihypertensive effects

Monitor BP

Levodopa

May interfere with levodopa absorption

Monitor levodopa dosage carefully

Lithium

Adverse effects resembling serotonin syndrome

MAO inhibitors (e.g., phenelzine)

Potentially life-threatening serotonin syndrome

Status epilepticus reported with concomitant phenelzine use

Concomitant use contraindicated

Allow at least 14 days to elapse when switching to or from these drugs

Methylphenidate

Possible increased plasma clomipramine concentrations

Oral contraceptives

No evidence of interference with clomipramine therapeutic effects

Phenytoin

Possible decreased plasma clomipramine concentrations

SSRIs (e.g., fluoxetine, fluvoxamine)

Possible serotonin syndrome

Potential decreased clomipramine metabolism and increased plasma concentrations

Possible seizures with concomitant fluoxetine use

Severalfold elevation of plasma clomipramine concentration with concomitant fluvoxamine use

Use with caution; monitor for TCA toxicity

Allow at least 5 weeks to elapse when switching from fluoxetine

Smoking

Possible decreased plasma clomipramine concentrations

Sympathomimetic agents (e.g., amphetamines, epinephrine, isoproterenol, norepinephrine, phenylephrine)

Increased vasopressor, cardiac effects

Use with caution; dosage adjustment may be required

Thyroid agents (e.g., levothyroxine, liothyronine)

May accelerate the onset of therapeutic effects of TCA

Possible cardiac arrhythmias

Use with caution

Valproic acid

Possible elevated serum clomipramine concentrations; may precipitate seizures in predisposed individuals

Warfarin

Possible altered protein binding of clomipramine or warfarin

Monitor for adverse effects

clomiPRAMINE Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, with peak plasma concentrations usually attained within 2–6 hours (mean: 4.7 hours).

Oral bioavailability is about 50% because of extensive first-pass metabolism.

Onset

Therapeutic response in OCD generally occurs within 2–6 weeks, with maximal effects after 3–4 months.

Food

Food does not appear to substantially affect bioavailability from capsules.

Special Populations

In geriatric patients, plasma concentrations of clomipramine and its major active metabolite (desmethylclomipramine) are substantially higher than those in younger adults (18–40 years of age).

In children <15 years of age, plasma concentration-dose ratios of clomipramine are substantially lower than those of adults.

In smokers, steady-state plasma clomipramine concentrations are substantially lower than in nonsmokers; smoking appears to have less effect on plasma concentrations of desmethylclomipramine.

Distribution

Extent

Clomipramine and desmethylclomipramine widely distributed in body tissues, with moderate to high concentrations occurring in organs such as the lungs, adrenals, kidneys, heart, and brain.

Crosses the blood-brain barrier; desmethylclomipramine concentration in CSF is about 2.6 times higher than in plasma.

Crosses the placenta and distributes into milk.

Plasma Protein Binding

Approximately 97–98%, principally to albumin and possibly to α1-acid glycoprotein (α1-AGP).

Elimination

Metabolism

Extensively metabolized to active metabolites by various CYP isoenzymes (e.g., CYP1A2, CYP2C, CYP2D6, CYP3A4).

Exhibits nonlinear pharmacokinetics at dosages >150 mg daily. Metabolism of clomipramine and desmethylclomipramine may be capacity limited (saturable).

Elimination Route

Clomipramine and metabolites excreted in urine and in feces (via biliary elimination).

Half-life

Elimination half-lives of clomipramine and desmethylclomipramine are approximately 32 hours (range: 19–37 hours) and 69 hours (range: 54–77 hours), respectively, after a 150-mg oral dose.

Elimination half-lives may be considerably prolonged at dosages near upper limit of recommended dosage range (i.e., 200–250 mg daily).

Special Populations

Effects of renal and hepatic impairment on the disposition of clomipramine have not been fully elucidated.

Hemodialysis, peritoneal dialysis, forced diuresis, and/or exchange transfusion are unlikely to remove clomipramine and desmethylclomipramine substantially because of the drug’s rapid distribution into body tissues.

Stability

Storage

Oral

Capsules

Tightly closed container at ≤30°C. Protect from moisture.

Actions

  • Mechanism of action in the management of OCD unknown but may involve inhibition of reuptake of serotonin.

  • Desmethylclomipramine inhibits norepinephrine reuptake; therefore, clomipramine also shares pharmacologic profile of other tricyclic antidepressants.

  • Exhibits marked anticholinergic activity, which may account for sedation, adverse cardiovascular effects, and reduced seizure threshold (particularly at relatively high dosages).

Advice to Patients

  • Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment. FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.

  • Importance of informing patients about the risk of seizures associated with the drug.

  • Importance of discussing with patients the risk of serious injury to themselves or others resulting from sudden loss of consciousness (e.g., because of seizures) while engaged in certain complex and hazardous activities (e.g., operation of complex machinery, driving a motor vehicle, swimming, climbing).

  • Importance of cautioning patients about the use of alcohol, barbiturates, or other CNS depressants (see Interactions).

  • Importance of informing male patients about the relatively high incidence of sexual dysfunction associated with the drug.

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

clomiPRAMINE Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

25 mg*

Anafranil (with parabens)

Mallinckrodt

clomiPRAMINE Hydrochloride Capsules

Mylan, Sandoz, Taro, Teva, Watson

50 mg*

Anafranil (with parabens)

Mallinckrodt

clomiPRAMINE Hydrochloride Capsules

Mylan, Sandoz, Taro, Teva, Watson

75 mg*

Anafranil (with parabens)

Mallinckrodt

clomiPRAMINE Hydrochloride Capsules

Mylan, Sandoz, Taro, Teva, Watson

AHFS DI Essentials™. © Copyright 2021, Selected Revisions June 1, 2007. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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