Clomipramine Hydrochloride

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

• 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.^{d e} Clomipramine is not approved for use in pediatric patients except patients with obsessive-compulsive disorder.¹ (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.^{d e}

  
  


• 
  

  Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.^{d e f}

  
  


• 
  

  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.^{d e f} (See Worsening of Depression and Suicidality Risk under Cautions.)

  
  

Introduction

Tricyclic antidepressant (TCA);^{1 2 3 235} pharmacologic profile resembles that of other TCAs,^{235 238} SSRIs, and trazodone.^{2 3 4 212 213 214 220 221}

Uses for Clomipramine Hydrochloride

Obsessive-Compulsive Disorder (OCD)

Among the drugs of choice for the management of OCD.^{69 289 293 296 297}

Reduces but does not completely eliminate obsessions and compulsions.^{96 271 292 300}

Panic Disorder

Has been used effectively for the management of panic disorder† with or without agoraphobia†.^{2 3 4 104 105 106 107 108 109 110 116 347}

Major Depressive Disorder

Has been used effectively for the management of major depressive disorder†.^{2 3 254 255 256 257 258 259 260 267 277 278 282 288}

Despite comparable efficacy,^{2 3 255 256 257 258 260 277 282 283} the adverse effect profile (e.g., anticholinergic effects) of clomipramine may limit its usefulness relative to other antidepressants (e.g., TCAs, SSRIs).^{2 257 258 277 282 283 288 289}

Effective antidepressant when obsessive manifestations accompany episode of major depressive disorder.²⁸⁸

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.^{2 3 52 111 112 113 114 115 118 119 120 121 122 123 124 125 343 344}

Cataplexy and Associated Narcolepsy

Has been used for the symptomatic management of cataplexy† in a limited number of patients with cataplexy† and associated narcolepsy†.^{3 132 133 279}

Autistic Disorder

Has been used for the management of repetitive and obsessive-compulsive behaviors and hyperactivity associated with autistic disorder†;^{134 135 141 285 286} does not treat core symptoms of autistic disorder.^b

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;^{3 136 137 138 139} relapse reported in some patients receiving long-term therapy.¹⁴⁰

Onychophagia

Has been used for the management of severe onychophagia† (nail biting) without a history of OCD.¹⁴²

Associated with relatively high dropout rate because of adverse effects and drug intolerance; not considered first-line therapy in most patients with onychophagia.^{142 341}

Eating Disorders

Has been used for the management of anorexia nervosa† in a limited number of patients with the disorder.^{229 230 231}

Initial therapeutic effects (e.g., improved eating behavior, weight gain) not sustained with long-term therapy (e.g., ≥8 weeks).^{229 230 231 234}

Avoid use in underweight individuals and in those exhibiting suicidal ideation.^{288 341}

Premature Ejaculation

Has been used for the management of premature ejaculation†.^{3 128 129 130 131}

Premenstrual Syndrome

Has been used for the management of premenstrual syndrome†.^{261 262 263 264}

Clomipramine Hydrochloride 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.¹ Also allow at least 5 weeks to elapse when switching from fluoxetine.¹

  
  


• 
  

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

  
  


• 
  

  Sustained therapy may be required;^{2 4 33 78 80 81 82 148 341} use lowest effective dosage and monitor periodically for need for continued therapy.^{1 299}

  
  


• 
  

  Avoid abrupt discontinuance of therapy.^{1 2 78 148 301} To avoid withdrawal reactions, taper dosage gradually (e.g., over a period of approximately 2 weeks).^{1 2 78 148 301}

  
  

Panic Disorder†

• 
  

  Transient increase in the number and intensity of panic attacks may occur during initial therapy with the drug.^{4 104 105 106 288}

  
  

Administration

Oral Administration

Administer orally; initially, in divided doses with meals to lessen adverse GI effects.¹ After initial dosage titration, the total daily dose may be given once daily at bedtime^{1 2 4 271} to minimize adverse effects (e.g., sedation) during waking hours^{1 2} and enhance patient compliance.²

Also has been administered IM† or IV†, but a parenteral dosage form is not commercially available in the US.^{4 272}

Dosage

Available as clomipramine hydrochloride; dosage is expressed in terms of the salt.¹

Individualize dosage carefully according to individual requirements and response.¹

Allow 2–3 weeks to elapse between any further dosage adjustments after the initial dosage titration period for achievement of steady-state plasma concentrations.¹

Pediatric Patients

OCD

Oral

Children >10 years of age: initially, 25 mg daily.¹ 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.^{1 2 242} Titrate dosage carefully.¹ 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).^{1 2 3 4 66 67}

Optimum duration not established; ^{1 78 271} some clinicians recommend that therapy be continued in responding patients at the minimally effective dosage for at least 18 months before attempting to discontinue.^{1 271 299}

Adults

OCD

Oral

Initially, 25 mg daily.¹ Gradually increase dosage, as tolerated, during the first 2 weeks of therapy to approximately 100 mg daily.¹ If necessary, dosages may be increased gradually during the next several weeks up to a maximum of 250 mg daily.^{1 2 3 4 66 67}

Optimum duration not established; ^{1 78 271} some clinicians recommend that therapy be continued in responding patients at the minimally effective dosage for at least 18 months before attempting to discontinue.^{1 271 299}

Panic Disorder†

Oral

Usual dosage: ≤50 mg daily (range: 12.5–150 mg daily);^{2 4 104 105 106 107 108 110 116 272} patients with agoraphobia may require higher dosage.^{4 104 105 106}

Major Depressive Disorder†

Oral

100–250 mg daily.^{2 272 277 278 288}

Chronic Pain†

Oral

100–250 mg daily.^{2 115 272 288}

Cataplexy and Associated Narcolepsy†

Oral

25–200 mg daily.^{132 133 272 279}

Prescribing Limits

Pediatric Patients

OCD

Oral

Maximum 3 mg/kg or 200 mg daily, whichever is lower.^{1 2 3 4 66 67}

Adults

OCD

Oral

Maximum 250 mg daily.^{1 2 3 4 66 67}

Panic Disorder†

Oral

Maximum 200 mg daily.^{2 4 104 105 106 107 108 110 116 272}

Special Populations

Geriatric Patients

Manufacturer makes no specific recommendation for dosage adjustment^{1 41 240} but lower clomipramine hydrochloride dosages are recommended by some clinicians at least during initial therapy.^{2 4 272 282}

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.¹

Cautions for Clomipramine Hydrochloride

Contraindications

• 
  

  Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.¹ (See Specific Drugs under Interactions.)

  
  


• 
  

  During the acute recovery phase following MI.¹

  
  


• 
  

  Known hypersensitivity to clomipramine or other TCAs.¹

  
  

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).¹

Risk may be dose related.¹ (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.^{d e f g} However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.^{d e f}

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.^{d e f} (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.^{e f} 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.^{d e f} (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.^{1 e}

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

Bipolar Disorder

May unmask bipolar disorder.^e (See Activation of Mania or Hypomania under Cautions.) Clomipramine is not approved for use in treating bipolar depression.¹

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

General Precautions

Cardiovascular Effects

Modest orthostatic decreases in BP,^{1 193} modest tachycardia,¹ and/or ECG abnormalities (e.g., VPCs, ST-T wave changes, intraventricular conduction abnormalities) reported; use with caution in patients with known cardiovascular disease.¹

Titrate dosage carefully.¹

Neuropsychiatric Effects

Variety of neuropsychiatric manifestations (e.g., delusions, hallucinations, psychotic episodes, confusion, paranoia) reported.^{1 3 155 156 238}

May precipitate an acute psychotic episode in patients with unrecognized schizophrenia.^{1 3 155 156 295}

Activation of Mania or Hypomania

Risk of activation of mania or hypomania in patients with affective disorder.^{1 3 155 156 295} (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).¹

Interactions

More than 30 cases of hyperthermia reported,¹ most cases occurring in patients receiving clomipramine in combination with other drugs (e.g., antipsychotic agents).^{1 157 199} When clomipramine and an antipsychotic agent were used concomitantly, the cases sometimes were considered to be examples of neuroleptic malignant syndrome (NMS).^{1 157 199}

Hepatic Effects

Potentially clinically important elevations (e.g., >3 times ULN) in serum ALT^{1 65} and AST¹ concentrations;¹ severe hepatic injury and/or death rarely reported.¹

Possible cross hepatotoxicity (e.g., elevated values on hepatic function tests, abdominal pain) involving different TCAs including clomipramine.²⁰⁷ (See Hepatic Impairment under Cautions.)

Hematologic Effects

Bone marrow depression^{1 227} (e.g., leukopenia,¹ agranulocytosis,^{1 3 162 164 165 166} thrombocytopenia,¹ anemia,¹ pancytopenia)^{1 3 163} rarely reported.^{1 227}

Obtain leukocyte and differential blood cell counts if fever and sore throat occur during therapy.¹

Sexual Dysfunction

Relatively high risk of sexual dysfunction^{1 3 180} (e.g., libido change,^{1 65 189 251} ejaculatory failure,^{1 65 180 188 251} impotence^{1 65 189 245 270} ) in male patients with OCD.¹

Normal sexual functioning usually returns within a few days after discontinuing therapy.^{2 3 180}

Weight Changes

Possible weight gain^{1 242 245 247 249} or weight loss.¹

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.^{1 2 78 148 301}

To avoid withdrawal reactions, taper dosage gradually and monitor patients carefully.^{1 2 78 148 301}

Electroconvulsive Therapy (ECT)

Possible increased ECT risks; limit to patients for whom concomitant use is essential.¹

Elective Surgery

Discontinue therapy for as long as is clinically feasible prior to surgery and advise the anesthetist of such action.¹

Thyroid Disease

Use with caution in hyperthyroid patients or patients receiving thyroid agents because of the possibility of cardiac toxicity.^{1 1}

Adrenal Medulla Tumors

Use with caution in patients with tumors of the adrenal medulla, in whom hypertensive crises may be provoked.¹

Specific Populations

Pregnancy

Category C.¹

Possible withdrawal symptoms (e.g., jitteriness,^{1 71 152 158} tremor,^{1 71 153 154} seizures^{1 3 152 153} ) in neonates whose mothers received clomipramine throughout pregnancy;¹ avoid use during late pregnancy whenever possible.¹⁵³

Lactation

Distributed into milk;^{1 4 22 55 60 62 71 150} discontinue nursing or the drug.^{1 62 149 150 151}

Pediatric Use

Safety and efficacy for OCD not established in children <10 years of age.¹

Potential risks associated with long-term use (e.g., effects on growth, development, or maturation) not systematically evaluated in children and adolescents.¹

Adverse effects in children and adolescents >10 years of age generally similar to those in adults.¹

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).^e 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.^g No suicides occurred in these pediatric trials.^{e g}

Carefully consider these findings when assessing potential benefits and risks of clomipramine in a child or adolescent for any clinical use.^{d e f g} (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.¹

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.^{d e} (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.¹

Renal Impairment

Use with caution in patients with clinically important renal impairment.¹

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.^{1 2 35 65 242}

Interactions for Clomipramine Hydrochloride

Extensively metabolized in the liver by various CYP isoenzymes (e.g., CYP1A2,³⁴⁶ CYP2C,⁷³ CYP2D6,^{72 73} CYP3A4).^c

Drugs Affecting Hepatic Microsomal Enzymes

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

Drugs Associated with Serotonin Syndrome

Potential pharmacologic (serotonin syndrome) interaction with serotonergic agents.^{1 175 302 303} Avoid such use whenever clinically possible.^{1 302 303}

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.¹

Protein-bound Drugs

Potential for clomipramine to displace or to be displaced by other protein-bound drugs.¹ Observe patients for adverse effects.^{1 2}

Specific Drugs

Drug	Interaction	Comments
Alcohol	Potential for increased CNS effects of alcohol1 Limited data suggest that demethylation of clomipramine may be reduced with chronic alcohol consumption55 60 63 64	Advise patients of risks of such concomitant use1
Alprazolam	Adverse effects resembling serotonin syndrome174 178
Antiarrhythmics: class 1C (e.g., flecainide, propafenone)	Potential for decreased clomipramine metabolisma	Monitor for TCA toxicitya
Anticholinergic agents	Potential for additive anticholinergic effects1 2 c	Use with caution; dosage adjustment may be needed1 2 c
Antipsychotic agents (e.g., phenothiazines)	Hyperthermia and adverse effects resembling NMS1 157 199 Potential for decreased clomipramine metabolismc	Dosage adjustment may be neededc
Barbiturates (e.g., phenobarbital)	May be additive with or may potentiate CNS effects1 159 Possible decreased plasma clomipramine concentrations1 159 Increased plasma phenobarbital concentrations reported1	Advise patients of risks associated with such concomitant use1
Cimetidine	Potential increased plasma clomipramine concentrations1 159 c	Use with caution; dosage adjustment may be neededc
CNS depressants (e.g., alcohol, sedatives, hypnotics)	Potentiates effects of CNS depressants1 c	Use with cautionc
Digoxin	Possible altered protein binding of clomipramine or digoxin1 2	Monitor for adverse effects1 2
Haloperidol	Potential for increased plasma clomipramine concentrations1 2	Use with caution; dosage adjustment may be neededc
Hypotensive agents (e.g., clonidine, guanethidine)	May antagonize antihypertensive effects1 2 159	Monitor BPc
Levodopa	May interfere with levodopa absorptionc	Monitor levodopa dosage carefullyc
Lithium	Adverse effects resembling serotonin syndrome174 178
MAO inhibitors (e.g., phenelzine)	Potentially life-threatening serotonin syndrome1 2 159 160 Status epilepticus reported with concomitant phenelzine use2 3 161	Concomitant use contraindicated1 c Allow at least 14 days to elapse when switching to or from these drugs1 c
Methylphenidate	Possible increased plasma clomipramine concentrations1 159
Oral contraceptives	No evidence of interference with clomipramine therapeutic effects159
Phenytoin	Possible decreased plasma clomipramine concentrations1 159
SSRIs (e.g., fluoxetine, fluvoxamine)	Possible serotonin syndromec Potential decreased clomipramine metabolism and increased plasma concentrationsa c Possible seizures with concomitant fluoxetine use170 Severalfold elevation of plasma clomipramine concentration with concomitant fluvoxamine use171	Use with caution;c monitor for TCA toxicitya Allow at least 5 weeks to elapse when switching from fluoxetinea c
Smoking	Possible decreased plasma clomipramine concentrations1 2 41 55 60
Sympathomimetic agents (e.g., amphetamines, epinephrine, isoproterenol, norepinephrine, phenylephrine)	Increased vasopressor, cardiac effectsc	Use with caution; dosage adjustment may be requiredc
Thyroid agents (e.g., levothyroxine, liothyronine)	May accelerate the onset of therapeutic effects of TCAc Possible cardiac arrhythmiasc	Use with cautionc
Valproic acid	Possible elevated serum clomipramine concentrations; may precipitate seizures in predisposed individuals298
Warfarin	Possible altered protein binding of clomipramine or warfarin1 2	Monitor for adverse effects1 2

Clomipramine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration,^{2 3 4 5 10 55} with peak plasma concentrations usually attained within 2–6 hours (mean: 4.7 hours).^{1 10 11 12 25 29}

Oral bioavailability is about 50% because of extensive first-pass metabolism.^{1 2 25 55}

Onset

Therapeutic response in OCD generally occurs within 2–6 weeks, with maximal effects after 3–4 months.^{33 66 99 103}

Food

Food does not appear to substantially affect bioavailability from capsules.^{1 29}

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).^{1 41 60}

In children <15 years of age, plasma concentration-dose ratios of clomipramine are substantially lower than those of adults.^{1 43}

In smokers, steady-state plasma clomipramine concentrations are substantially lower than in nonsmokers;^{1 41 55 60} smoking appears to have less effect on plasma concentrations of desmethylclomipramine.⁶⁰

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.^{1 3 5 10 53}

Crosses the blood-brain barrier; desmethylclomipramine concentration in CSF is about 2.6 times higher than in plasma.¹

Crosses the placenta and distributes into milk.^{1 4 22 55 60 62 71}

Plasma Protein Binding

Approximately 97–98%, principally to albumin and possibly to α₁-acid glycoprotein (α₁-AGP).^{1 2 4 29 55 56}

Elimination

Metabolism

Extensively metabolized to active metabolites^{1 2 3 4 5 19 20 55 61 72 73} by various CYP isoenzymes (e.g., CYP1A2,³⁴⁶ CYP2C,⁷³ CYP2D6,^{72 73} CYP3A4).^c

Exhibits nonlinear pharmacokinetics at dosages >150 mg daily.^{1 8} Metabolism of clomipramine and desmethylclomipramine may be capacity limited (saturable).^{1 8 55}

Elimination Route

Clomipramine and metabolites excreted in urine and in feces (via biliary elimination).^{1 4 5 11 21 29 55 73}

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.^{1 2}

Elimination half-lives may be considerably prolonged at dosages near upper limit of recommended dosage range (i.e., 200–250 mg daily).^{1 8}

Special Populations

Effects of renal and hepatic impairment on the disposition of clomipramine have not been fully elucidated.^{1 60}

Hemodialysis, peritoneal dialy