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Medications: Tofranil® – imipramine

MEDICATIONS

Tofranil® – imipramine (View the FDA label)

Depression
Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission.

Usual Adult Dose

Hospitalized Patients
Initially, 100 mg/day in divided doses gradually increased to 200 mg/day as required. If no response after two weeks, increase to 250 to 300 mg/day.

Outpatients
Initially, 75 mg/day increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance, 50 to 150 mg/day.

Adolescent and Geriatric Patients
Initially, 30 to 40 mg/day; it is generally not necessary to exceed 100 mg/day.

Childhood Enuresis

Initially, an oral dose of 25 mg/day should be tried in children aged 6 and older. Medication should be given one hour before bedtime. If a satisfactory response does not occur within one week, increase the dose to 50 mg nightly in children under 12 years; children over 12 may receive up to 75 mg nightly. A daily dose greater than 75 mg does not enhance efficacy and tends to increase side effects. Evidence suggests that in early night bedwetters, the drug is more effective given earlier and in divided amounts, i.e., 25 mg in midafternoon, repeated at bedtime. Consideration should be given to instituting a drug free period following an adequate therapeutic trial with a favorable response, Dosage should be tapered off gradually rather than abruptly discontinued; this may reduce the tendency to relapse. Children who relapse when the drug is discontinued do not always respond to a subsequent course of treatment. A dose of 2.5 mg/kg/day should not be exceeded, ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.

The safety and effectiveness of Imipramine Hydrochloride Tablets USP as temporary adjunctive therapy for nocturnal enuresis in children less than 6 years of age has not been established.

Note — Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when Imipramine Hydrochloride Tablets USP is administered.

Cardiovascular: Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke.

Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis.

Neurological: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus.

Anticholinergic: Dry mouth, and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract.

Allergic: Skin rash, petechiae, urticaria, itching, photosensitization; edema (general or of face and tongue); drug fever; crosssensitivity with desipramine.

Hematologic: Bone marrow depression including agranulocytosis; eosinophilia; purpura; thrombocytopenia.

Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue.

Endocrine: Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; inappropriate antidiuretic hormone (ADH) secretion syndrome.

Other: Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling.

Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.

Note — In enuretic children treated with Imipramine Hydrochloride Tablets USP the most common adverse reactions have been nervousness, sleep disorders, tiredness, and mild gastrointestinal disturbances. These usually disappear during continued drug administration or when dosage is decreased. Other reactions which have been reported include constipation, convulsions, anxiety, emotional instability, syncope, and collapse. All of the adverse effects reported with adult use should be considered.

General

An ECG recording should be taken prior to the initiation of larger-than-usual doses of Imipramine Hydrochloride Tablets USP 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. See WARNINGS.) 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 Hydrochloride Tablets USP.

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 Hydrochloride Tablets USP, 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 Hydrochloride Tablets USP 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 Hydrochloride Tablets USP 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 Hydrochloride 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 Hydrochloride use. Imipramine Hydrochloride 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 Hydrochloride should have leukocyte and differential blood counts performed. Imipramine Hydrochloride should be discontinued if there is evidence of pathological neutrophil depression. Prior to elective surgery, Imipramine Hydrochloride 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 Hydrochloride 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 Hydrochloride. 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 Hydrochloride.

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.

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 Hydrochloride Tablets USP 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 Hydrochloride cannot be excluded. Therefore, Imipramine Hydrochloride Tablets USP 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 Hydrochloride Tablets USP 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 other than pediatric patients with nocturnal enuresis have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone considering the use of Imipramine Hydrochloride in a child or adolescent must balance the potential risks with the clinical need.

The safety and effectiveness of the drug as temporary adjunctive therapy for nocturnal enuresis in pediatric patients less than 6 years of age has not been established. The safety of the drug for long-term, chronic use as adjunctive therapy for nocturnal enuresis in pediatric patients 6 years of age or older has not been established; consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response.

A dose of 2, 5 mg/kg/day should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.

Geriatric Use

In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Imipramine Hydrochloride Tablets USP 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 Hydrochloride Tablets USP 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.)

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 206 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 interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration 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 Hydrochloride 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 Hydrochloride is used with agents that lower blood pressure. Imipramine Hydrochloride may potentiate the effects of CNS depressant drugs. Patients should be warned that Imipramine Hydrochloride may enhance the CNS depressant effects of alcohol (see WARNINGS).

Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible.

Children have been reported to be more sensitive than adults to an acute overdosage of Imipramine Hydrochloride. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal.

Manifestations

These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity.

Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements.

Cardiac abnormalities may include tachycardia and signs of congestive failure, Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present.

Management

Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at anytime during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.

Gastrointestinal Decontamination
All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.

Cardiovascular
A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/ hyperventilation may respond to lidocaine, bretylium, or phenytoin, Type lA and IC antiarrhythmics are generally contraindicated (e.g., quinidine, disopyrarnide, and procainamide).

In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning.

CNS
In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration, Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.

Psychiatric Follow-up
Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

Pediatric Management
The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

Uses

Depression
Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission.

Usual Adult Dose

Hospitalized Patients
Initially, 100 mg/day in divided doses gradually increased to 200 mg/day as required. If no response after two weeks, increase to 250 to 300 mg/day.

Outpatients
Initially, 75 mg/day increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance, 50 to 150 mg/day.

Adolescent and Geriatric Patients
Initially, 30 to 40 mg/day; it is generally not necessary to exceed 100 mg/day.

Childhood Enuresis

Initially, an oral dose of 25 mg/day should be tried in children aged 6 and older. Medication should be given one hour before bedtime. If a satisfactory response does not occur within one week, increase the dose to 50 mg nightly in children under 12 years; children over 12 may receive up to 75 mg nightly. A daily dose greater than 75 mg does not enhance efficacy and tends to increase side effects. Evidence suggests that in early night bedwetters, the drug is more effective given earlier and in divided amounts, i.e., 25 mg in midafternoon, repeated at bedtime. Consideration should be given to instituting a drug free period following an adequate therapeutic trial with a favorable response, Dosage should be tapered off gradually rather than abruptly discontinued; this may reduce the tendency to relapse. Children who relapse when the drug is discontinued do not always respond to a subsequent course of treatment. A dose of 2.5 mg/kg/day should not be exceeded, ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.

The safety and effectiveness of Imipramine Hydrochloride Tablets USP as temporary adjunctive therapy for nocturnal enuresis in children less than 6 years of age has not been established.

Side Effects

Note — Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when Imipramine Hydrochloride Tablets USP is administered.

Cardiovascular: Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke.

Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis.

Neurological: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus.

Anticholinergic: Dry mouth, and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract.

Allergic: Skin rash, petechiae, urticaria, itching, photosensitization; edema (general or of face and tongue); drug fever; crosssensitivity with desipramine.

Hematologic: Bone marrow depression including agranulocytosis; eosinophilia; purpura; thrombocytopenia.

Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue.

Endocrine: Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; inappropriate antidiuretic hormone (ADH) secretion syndrome.

Other: Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling.

Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.

Note — In enuretic children treated with Imipramine Hydrochloride Tablets USP the most common adverse reactions have been nervousness, sleep disorders, tiredness, and mild gastrointestinal disturbances. These usually disappear during continued drug administration or when dosage is decreased. Other reactions which have been reported include constipation, convulsions, anxiety, emotional instability, syncope, and collapse. All of the adverse effects reported with adult use should be considered.

Precautions

General

An ECG recording should be taken prior to the initiation of larger-than-usual doses of Imipramine Hydrochloride Tablets USP 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. See WARNINGS.) 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 Hydrochloride Tablets USP.

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 Hydrochloride Tablets USP, 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 Hydrochloride Tablets USP 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 Hydrochloride Tablets USP 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 Hydrochloride 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 Hydrochloride use. Imipramine Hydrochloride 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 Hydrochloride should have leukocyte and differential blood counts performed. Imipramine Hydrochloride should be discontinued if there is evidence of pathological neutrophil depression. Prior to elective surgery, Imipramine Hydrochloride 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 Hydrochloride 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 Hydrochloride. 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 Hydrochloride.

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.

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 Hydrochloride Tablets USP 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 Hydrochloride cannot be excluded. Therefore, Imipramine Hydrochloride Tablets USP 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 Hydrochloride Tablets USP 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 other than pediatric patients with nocturnal enuresis have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone considering the use of Imipramine Hydrochloride in a child or adolescent must balance the potential risks with the clinical need.

The safety and effectiveness of the drug as temporary adjunctive therapy for nocturnal enuresis in pediatric patients less than 6 years of age has not been established. The safety of the drug for long-term, chronic use as adjunctive therapy for nocturnal enuresis in pediatric patients 6 years of age or older has not been established; consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response.

A dose of 2, 5 mg/kg/day should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.

Geriatric Use

In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Imipramine Hydrochloride Tablets USP 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 Hydrochloride Tablets USP 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.)

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 206 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 interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration 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 Hydrochloride 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 Hydrochloride is used with agents that lower blood pressure. Imipramine Hydrochloride may potentiate the effects of CNS depressant drugs. Patients should be warned that Imipramine Hydrochloride may enhance the CNS depressant effects of alcohol (see WARNINGS).

Overdose

Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible.

Children have been reported to be more sensitive than adults to an acute overdosage of Imipramine Hydrochloride. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal.

Manifestations

These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity.

Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements.

Cardiac abnormalities may include tachycardia and signs of congestive failure, Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present.

Management

Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at anytime during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.

Gastrointestinal Decontamination
All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.

Cardiovascular
A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/ hyperventilation may respond to lidocaine, bretylium, or phenytoin, Type lA and IC antiarrhythmics are generally contraindicated (e.g., quinidine, disopyrarnide, and procainamide).

In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning.

CNS
In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration, Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.

Psychiatric Follow-up
Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

Pediatric Management
The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

Interpreting the GeneSight® Test:
Gene-Drug Interaction Chart

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