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, 2023. Written by ASHP.

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

• Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of imipramine 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; administer lowest effective dosage and monitor periodically for need for continued therapy.

• Avoid abrupt discontinuance of therapy in patients receiving high dosages for prolonged periods. To avoid withdrawal reactions, taper dosage gradually.

Enuresis

• Exclude organic causes of enuresis prior to initiation of therapy.

• If daytime urgency and frequency occur, perform appropriate examinations (e.g., voiding cystourethrography, cystoscopy).

• Tolerance (tachyphylaxis) to therapeutic effects possible with continuous administration of imipramine; consider instituting a drug-free period following an adequate therapeutic trial with favorable response.

• Long-term, chronic use not recommended; gradually discontinue therapy following a period of satisfactory response. To minimize risk of relapse, avoid abrupt discontinuance of therapy.

• Children who relapse when the drug is discontinued may not respond to subsequent treatment with imipramine.

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

• 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 imipramine, other dibenzazepine-derivative TCAs, or any ingredient in the formulation.

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

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

• Mechanism of action in the management of depression unknown but may involve inhibition of reuptake of norepinephrine and/or serotonin.

• Mechanism of action in the treatment of enuresis is not known but may involve inhibition of urination due to anticholinergic activity, CNS stimulant activity resulting in easier arousal by the stimulus of a full bladder, and/or other mechanisms that are presently unknown.

• Associated with more frequent anticholinergic, sedative, or cardiovascular effects and weight gain than SSRIs.

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 considering possible impaired ability to perform hazardous activities (e.g., operating hazardous machinery, driving a motor vehicle).

• Risk of concomitant use with alcohol.

• Risk of photosensitivity reactions.

• Importance of continuing imipramine therapy even if a response is not evident within 1–3 weeks, unless directed otherwise.

• Importance of women informing clinicians 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 or planned surgery.

• 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

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