Skip to main content

Imipramine (Monograph)

Brand names: Tofranil, Tofranil-PM
Drug class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA class: CN601
CAS number: 113-52-0

Medically reviewed by Drugs.com on Aug 22, 2024. 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. Imipramine is not approved for use in pediatric patients except patients ≥6 years of age with enuresis. (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 imipramine 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

Dibenzazapine-derivative tricyclic antidepressant (TCA).

Uses for Imipramine

Major Depressive Disorder

Management of major depressive disorder.

Results of several studies of TCAs in preadolescent and adolescent patients with major depression indicate lack of overall efficacy in this age group.

Enuresis

Temporary adjunctive therapy in the treatment of nocturnal enuresis (bed-wetting) in children ≥6 years of age.

Safety and efficacy of long-term use not established.

Panic Disorder

Management of panic disorder [off-label] with or without agoraphobia [off-label].

Attention Deficit Hyperactivity Disorder

Second-line agent in attention deficit hyperactivity disorder [off-label] (ADHD) in patients unable to tolerate or unresponsive to stimulants.

Associated with a narrower margin of safety than some other therapeutic agents; use only if clearly indicated and with careful monitoring, including baseline and subsequent determinations of ECG and other parameters.

Eating Disorders

Has been used for management of eating disorders [off-label] (e.g., bulimia [off-label], anorexia nervosa) with equivocal results; avoid use in underweight individuals and in those exhibiting suicidal ideation.

Bipolar Disorder

Has been used for the short-term management of acute depressive episodes in bipolar disorder.

TCAs associated with a greater risk of precipitating hypomania or manic episodes than other classes of antidepressants; should always be used in combination with a mood stabilizer (e.g., lithium).

Schizophrenia

Has been used for the management of acute depressive episodes (in combination with an antipsychotic) in patients with schizophrenia.

Anxiety Disorders

Has been used for the management of anxiety (in combination with an anxiolytic, a sedative, or an antipsychotic) in patients with depression.

Postherpetic Neuralgia

Among the drugs of choice for the symptomatic treatment of postherpetic neuralgia.

Insomnia

Less effective for insomnia and associated with more serious adverse reactions than conventional hypnotics.

Imipramine Dosage and Administration

General

Major Depressive Disorder

Enuresis

Administration

Oral Administration

Administer orally in up to 4 divided doses (without regard to meals) or as a single daily dose at bedtime to avoid daytime sedation.

Reserve use of Tofranil-PM capsules until recommended total daily imipramine hydrochloride dosage ≥75 mg. Tofranil-PM usually administered once daily, but divided doses may be necessary in some patients. Tofranil-PM should not be used in children of any age. (See Pediatric Warnings under Cautions.)

Dosage

Available as imipramine hydrochloride or imipramine pamoate; dosage is expressed in terms of imipramine hydrochloride.

Individualize dosage carefully according to individual requirements and response.

Pediatric Patients

Enuresis
Oral

Children ≥6 years of age: Initially, 25 mg daily, administered 1 hour prior to bedtime. If satisfactory response not obtained within 1 week, dosage may be increased to 50 mg nightly for children <12 years of age or 75 mg nightly for children ≥12 years of age. Higher dosages provide no additional therapeutic benefit but may increase risk of adverse effects. Maximum 2.5 mg/kg daily.

For children who are early-night bed-wetters, better results may be obtained by administering 25 mg in midafternoon and again at bedtime.

Adults

Major Depressive Disorder
Outpatients
Oral

Initially, 75 mg daily. May increase dosage to 150 mg daily and then if necessary to 200 mg daily.

Maintenance dosages: 50–150 mg daily.

Hospitalized Patients
Oral

Initially, 100–150 mg daily (administered in divided doses). May increase dosages to 200 mg daily and then if there is no response after 2 weeks to 250–300 mg daily.

Prescribing Limits

Pediatric Patients

Enuresis
Oral

Maximum 2.5 mg/kg daily.

Adults

Major Depressive Disorder
Outpatients
Oral

Maximum 200 mg daily.

Hospitalized Patients
Oral

Maximum 300 mg daily.

Special Populations

Geriatric Patients

Initially, 25–50 mg daily as imipramine hydrochloride (e.g., Tofranil). Increase dosage based on response and tolerance up to a maximum of 100 mg daily.

Cautions for Imipramine

Contraindications

Warnings/Precautions

Warnings

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 with major depressive disorder, 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 imipramine 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.)

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, obsessive-compulsive disorder [OCD]) or nonpsychiatric disorders.

Bipolar Disorder

May unmask bipolar disorder. (See Activation of Mania or Hypomania under Cautions.) Imipramine 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.

Cardiovascular Effects

Possible conduction defects, arrhythmias, CHF, MI, strokes, and tachycardia, particularly at higher dosages.

Patients with preexisting or prior history of cardiac disease, patients with disturbed eating behaviors (e.g., purging) that result in inadequate hydration and/or compromised cardiac status, geriatric patients, and children (see Pediatric Warnings) most at risk; use with caution and monitor closely (e.g., perform ECG at baseline and as appropriate during therapy).

Pediatric Warnings

ECG changes of unknown clinical importance reported in pediatric patients receiving twice the recommended maximum daily dosage for enuresis. Do not exceed maximum recommended pediatric dosage (i.e., 2.5 mg/kg daily). (See Pediatric Use under Cautions.)

Children may be more sensitive to an acute imipramine overdosage than adults; use of high-potency preparation, Tofranil-PM, not recommended for children of any age. (See Worsening of Depression and Suicidality Risk and also see Pediatric Use 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).

Seizures

Lowers seizure threshold; use with caution in patients with a history of seizures.

Interactions

May block hypotensive actions of clonidine, guanethidine, and similar agents.

Possible pharmacokinetic (decreased imipramine metabolism) interaction with methylphenidate; imipramine dosage adjustments may be required.

May enhance CNS depressant effects of alcohol. Use with caution in patients with a history of excessive alcohol consumption. (See Interactions.)

Hyperthyroidism

Use with caution and under close supervision in hyperthyroid patients or patients receiving thyroid agents; possible adverse cardiovascular effects.

Cognitive/Physical Impairment

Mental alertness or physical coordination required for performing hazardous tasks (e.g., driving or operating machinery) may be impaired.

Sensitivity Reactions

Cross-hypersensitivity

Possible cross-sensitivity to other dibenzazepine-derivative TCAs (e.g., clomipramine, desipramine, trimipramine).

Photosensitivity

Avoid excessive exposure to sunlight.

General Precautions

Adequate Patient Monitoring

Perform baseline ECG prior to initiation of therapy with larger than usual dosages and at periodic intervals thereafter until steady-state imipramine concentrations are achieved.

Close supervision and more frequent cardiac monitoring recommended for patients with any evidence of cardiovascular disease. (See Cardiovascular Effects.)

Activation of Mania or Hypomania

Possible activation of mania and hypomania, particularly in patients with bipolar disorder; decrease dosage and/or administer a benzodiazepine concomitantly. (See Bipolar Disorder under Cautions.)

Psychosis

Risk of manifestations of psychosis in patients with schizophrenia, particularly in patients with paranoid symptoms; decrease dosage and/or administer an antipsychotic (e.g., a phenothiazine) concomitantly.

Elective Surgery

Discontinue therapy several days prior to surgery whenever possible.

Electroconvulsive Therapy (ECT)

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

Hematologic Effects

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

If there is evidence of pathological neutrophil depression, discontinue therapy.

Blood Glucose Effects

Possible alterations in blood glucose concentrations.

Specific Populations

Pregnancy

Category D. Manifestations of withdrawal reported in neonates following maternal use of imipramine during pregnancy.

Lactation

Distributed into milk. Breast-feeding not recommended.

Pediatric Use

Safety and efficacy not established in treatment of enuresis in children <6 years of age or for treatment of any other disorders in children <18 years of age. (See Pediatric Warnings under Cautions.)

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 imipramine 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.

Titrate dosage carefully. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with moderate to severe hepatic impairment.

Renal Impairment

Use with caution in patients with moderate to severe renal impairment.

Common Adverse Effects

Anticholinergic effects (e.g., dry mouth, constipation, vision disturbance), orthostatic hypotension, sedation, weakness, lethargy, fatigue.

In children with enuresis: Nervousness, sleep disorders, tiredness, mild GI disturbances.

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

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: Potential pharmacokinetic interaction (increased plasma imipramine concentrations). Consider imipramine dosage adjustment whenever a CYP2D6 inhibitor is added or discontinued.

Inducers of CYP2D6: Potential pharmacokinetic interaction (decreased plasma imipramine concentrations). Consider imipramine dosage adjustment whenever a CYP2D6 inducer is added or discontinued.

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potentiates CNS depressant effects of alcohol

Increased risks if overdose or suicide attempt occurs

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

Potential for decreased imipramine metabolism

Monitor for TCA toxicity; dosage adjustment may be needed

Anticholinergic agents

Hyperthermia, particularly during hot weather, and paralytic ileus

Use with caution; dosage adjustment may be needed

Antipsychotics (e.g., phenothiazines)

Potential for decreased imipramine metabolism

Barbiturates

Potential for increased imipramine metabolism

Dosage adjustment may be needed

Cimetidine

Potential for decreased imipramine metabolism

Monitor for TCA toxicity; dosage adjustment may be needed

CNS depressants

Potentiates effects of CNS depressants

Use with caution

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

Antagonizes antihypertensive effects of clonidine or guanethidine

Use with caution

Levodopa

May interfere with levodopa absorption

Monitor levodopa dosage carefully

MAO inhibitors

Potentially life-threatening serotonin syndrome

Concomitant use contraindicated

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

Methylphenidate

Potential for decreased imipramine metabolism

Use with caution; decreased imipramine dosage may be required

Phenytoin

Potential for increased imipramine metabolism

Dosage adjustment may be needed

SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Potential for decreased imipramine metabolism and increased plasma concentrations

Use with caution; monitor for TCA toxicity; dosage adjustment may be needed

Allow at least 5 weeks to elapse when switching from fluoxetine

Smoking

Possible decreased steady-state imipramine concentrations

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

Increased vasopressor, cardiac effects

Avoid concomitant use

Thyroid agents

Possible cardiac arrhythmias

Use with caution and under close supervision

Imipramine Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract following oral administration, with peak plasma concentrations usually attained within 1–2 hours.

Bioavailability is approximately 43%.

Onset

Antidepressant effect usually occurs within 1–3 weeks.

Food

Food does not affect absorption.

Distribution

Extent

Widely distributed in the body.

Imipramine and its active metabolite, desipramine, are distributed into milk in concentrations similar to those present in maternal plasma.

Plasma Protein Binding

Approximately 60–96%.

Elimination

Metabolism

Extensively metabolized in the liver via demethylation to pharmacologically active metabolite, desipramine, by various CYP isoenzymes (e.g., CYP1A2, CYP2D6, CYP3A4, CYP2C).

Elimination Route

Excreted principally in urine as inactive metabolites within 24 hours (40%) and within 72 hours (70%); small amounts excreted in feces via biliary elimination.

Half-life

Imipramine: 8–20 hours.

Desipramine: Up to 125 hours.

Special Populations

Alcoholics found to have a threefold greater intrinsic clearance of imipramine.

Stability

Storage

Oral

Capsules

Tight containers at <30°C.

Tablets

Tight containers at 15–30°C.

Actions

Advice to Patients

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

Imipramine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg*

Imipramine Hydrochloride Tablets

Par

Tofranil (with povidone)

Mallinckrodt

25 mg*

Imipramine Hydrochloride Tablets

Par

Tofranil (with povidone)

Mallinckrodt

50 mg*

Imipramine Hydrochloride Tablets

Par

Tofranil (with povidone)

Mallinckrodt

Tablets, film-coated

10 mg*

Imipramine Hydrochloride Tablets

Sandoz

25 mg*

Imipramine Hydrochloride Tablets

Sandoz

50 mg*

Imipramine Hydrochloride Tablets

Sandoz

Imipramine Pamoate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

equivalent to imipramine hydrochloride 75 mg

Tofranil-PM (with parabens)

Mallinckrodt

equivalent to imipramine hydrochloride 100 mg

Tofranil-PM (with parabens)

Mallinckrodt

equivalent to imipramine hydrochloride 125 mg

Tofranil-PM (with parabens)

Mallinckrodt

equivalent to imipramine hydrochloride 150 mg

Tofranil-PM (with parabens)

Mallinckrodt

AHFS DI Essentials™. © Copyright 2024, Selected Revisions September 1, 2007. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

Reload page with references included