Imipramine Pamoate

Name: Imipramine Pamoate

Warnings

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
< 18 14 additional cases
18-24 5 additional cases
Decreases Compared to Placebo
25-64 1 fewer case
≥ 65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for imipramine pamoate should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that imipramine pamoate is not approved for use in treating bipolar depression.

Extreme caution should be used when this drug is given to patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes, and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug; patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug's anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine pamoate may block the pharmacologic effects of these drugs; patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of imipramine pamoate, downward dosage adjustment of imipramine pamoate may be required when given concomitantly with methylphenidate hydrochloride.

Since imipramine pamoate may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly.

Tofranil-PM may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol (see PRECAUTIONS).

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Tofranil-PM, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Tofranil-PM with MAOIs intended to treat psychiatric disorders is contraindicated. Tofranil-PM should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Tofranil-PM. Tofranil-PM should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

If concomitant use of Tofranil-PM with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with Tofranil-PM and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

What is imipramine (tofranil, tofranil-pm)?

Imipramine is a tricyclic antidepressant. Imipramine affects chemicals in the brain that may become unbalanced.

Imipramine is used to treat symptoms of depression. Imipramine is sometimes used to treat bed-wetting in children ages 6 and older.

Imipramine may also be used for purposes not listed in this medication guide.

Introduction

Dibenzazapine-derivative tricyclic antidepressant (TCA).a b f

Cautions for Imipramine Pamoate

Contraindications

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

  • During the acute recovery phase following MI.a b

  • Known hypersensitivity to imipramine, other dibenzazepine-derivative TCAs, or any ingredient in the formulation.a b

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.i j k l However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.i j k

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.i j k (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.j k 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.i j k (See General under Dosage and Administration.)

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

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder [OCD]) or nonpsychiatric disorders.j

Bipolar Disorder

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

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

Cardiovascular Effects

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

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;a b c use with caution and monitor closely (e.g., perform ECG at baseline and as appropriate during therapy).a b c

Pediatric Warnings

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

Children may be more sensitive to an acute imipramine overdosage than adults;a b use of high-potency preparation, Tofranil-PM, not recommended for children of any age.b (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).a b

Seizures

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

Interactions

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

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

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

Hyperthyroidism

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

Cognitive/Physical Impairment

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

Sensitivity Reactions

Cross-hypersensitivity

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

Photosensitivity

Avoid excessive exposure to sunlight.a b

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.a

Close supervision and more frequent cardiac monitoring recommended for patients with any evidence of cardiovascular disease.a (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.a b (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.a b

Elective Surgery

Discontinue therapy several days prior to surgery whenever possible.a b

Electroconvulsive Therapy (ECT)

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

Hematologic Effects

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

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

Blood Glucose Effects

Possible alterations in blood glucose concentrations.a b

Specific Populations

Pregnancy

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

Lactation

Distributed into milk.a b e Breast-feeding not recommended.a b

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.a b (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).j 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.l No suicides occurred in these pediatric trials.j l

Carefully consider these findings when assessing potential benefits and risks of imipramine in a child or adolescent for any clinical use.i j k l (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.c

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.i j (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.c (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

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

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

Interactions for Imipramine Pamoate

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

Drugs Affecting Hepatic Microsomal Enzymes

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

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

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potentiates CNS depressant effects of alcohola b

Increased risks if overdose or suicide attempt occursa b

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

Potential for decreased imipramine metabolisma b

Monitor for TCA toxicity; dosage adjustment may be neededa b

Anticholinergic agents

Hyperthermia, particularly during hot weather, and paralytic ileusa b c

Use with caution; dosage adjustment may be neededc

Antipsychotics (e.g., phenothiazines)

Potential for decreased imipramine metabolisma b

Barbiturates

Potential for increased imipramine metabolisma b

Dosage adjustment may be neededa b

Cimetidine

Potential for decreased imipramine metabolisma b

Monitor for TCA toxicity; dosage adjustment may be neededc

CNS depressants

Potentiates effects of CNS depressantsa b

Use with cautiona b

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

Antagonizes antihypertensive effects of clonidine or guanethidinea b

Use with cautiona b

Levodopa

May interfere with levodopa absorption c

Monitor levodopa dosage carefullya

MAO inhibitors

Potentially life-threatening serotonin syndromea b

Concomitant use contraindicateda b

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

Methylphenidate

Potential for decreased imipramine metabolisma b

Use with caution; decreased imipramine dosage may be requireda b

Phenytoin

Potential for increased imipramine metabolisma b

Dosage adjustment may be neededa b

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

Potential for decreased imipramine metabolism and increased plasma concentrationsa b

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

Allow at least 5 weeks to elapse when switching from fluoxetinea b

Smoking

Possible decreased steady-state imipramine concentrationsg

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

Increased vasopressor, cardiac effectsc

Avoid concomitant usea b

Thyroid agents

Possible cardiac arrhythmiasc

Use with caution and under close supervisiona b

Actions

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

  • 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.c

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

Indications and Usage for Imipramine Pamoate

For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident.

Precautions

The 125 mg capsule contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

General

An ECG recording should be taken prior to the initiation of larger-than-usual doses of Imipramine Pamoate and at appropriate intervals thereafter until steady state is achieved. (Patients with any evidence of cardiovascular disease require cardiac surveillance at all dosage levels of the drug. SeeWARNINGS.) Elderly patients and patients with cardiac disease or a prior history of cardiac disease are at special risk of developing the cardiac abnormalities associated with the use of Imipramine Pamoate. It should be kept in mind that the possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Such patients should be carefully supervised during the early phase of treatment with Imipramine Pamoate and may require hospitalization. Prescriptions should be written for the smallest amount feasible.

Hypomanic or manic episodes may occur, particularly in patients with cyclic disorders. Such reactions may necessitate discontinuation of the drug. If needed, Imipramine Pamoate may be resumed in lower dosage when these episodes are relieved. Administration of a tranquilizer may be useful in controlling such episodes.

An activation of the psychosis may occasionally be observed in schizophrenic patients and may require reduction of dosage and the addition of a phenothiazine.

Concurrent administration of Imipramine Pamoate with electroshock therapy may increase the hazards: such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience.

Patients taking Imipramine Pamoate should avoid excessive exposure to sunlight since there have been reports of photosensitization.

Both elevation and lowering of blood sugar levels have been reported with Imipramine Pamoate use.

Imipramine Pamoate should be used with caution in patients with significantly impaired renal or hepatic function.

Patients who develop a fever and a sore throat during therapy with Imipramine Pamoate should have leukocyte and differential blood counts performed.

Imipramine Pamoate should be discontinued if there is evidence of pathological neutrophil depression.

Prior to elective surgery, Imipramine Pamoate should be discontinued for as long as the clinical situation will allow.

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Imipramine Pamoate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Imipramine Pamoate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Imipramine Pamoate.

Clinical Worsening and Suicide Risk

 Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Patients should be advised that taking Imipramine Pamoate can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Drug Interactions

Drugs Metabolized by P450 2D6

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.

The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary.

In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when Imipramine Pamoate is administered concomitantly with anticholinergic drugs.

Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines.

Caution should be exercised when Imipramine Pamoate is used with agents that lower blood pressure. Imipramine Pamoate may potentiate the effects of CNS depressant drugs.

Patients should be warned that Imipramine Pamoate may enhance the CNS depressant effects of alcohol (see WARNINGS).

Monoamine Oxidase Inhibitors (MAOIs)

(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)

Serotonergic Drugs

(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)

Pregnancy

Animal reproduction studies have yielded inconclusive results (see also ANIMAL PHARMACOLOGY & TOXICOLOGY).

There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine cannot be excluded. Therefore, imipramine should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus.

Nursing Mothers

Limited data suggest that imipramine is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNINGand WARNINGS:  Clinical Worsening and Suicide Risk).

It is generally recommended that Imipramine Pamoate should not be used in children because of the increased potential for acute overdosage due to the high unit potency (75 mg, 100 mg, 125 mg, and 150 mg). Each capsule contains Imipramine Pamoate equivalent to 75 mg, 100 mg, 125 mg, or 150 mg imipramine hydrochloride. Anyone considering the use of Imipramine Pamoate in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use

In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Imipramine Pamoate in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly.

Clinical studies of Imipramine Pamoate in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

(See also DOSAGE AND ADMINISTRATION: Adolescent and Geriatric Patients)

(See also PRECAUTIONS: General)

Medication Guide

Imipramine Pamoate Capsules

(im ip’ ra meen)

Rx Only

Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:

• all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions.Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood

Visual problems

• eye pain • changes in vision • swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

Who should not take Imipramine Pamoate capsules?

Do not take Imipramine Pamoate capsules if you:

• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. o Do not take an MAOI within 2 weeks of stopping Imipramine Pamoate capsules unless directed to do so by your physician. o Do not start Imipramine Pamoate capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10005901/05

Revised August 2016

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