Tofranil (Imipramine)

TOFRANIL® Novartis Pharmaceuticals Imipramine HCl Antidepressant

Action and Clinical

Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin.

It possesses anticholinergic properties which are responsible for certain of its side effects. The mechanism of action of imipramine and other tricyclic antidepressants is not well established, but it is thought that it might be related to their action on the transmitter-uptake mechanism of monoaminergic neurons. The mechanism of action in childhood nocturnal enuresis is not fully known.

Imipramine is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma levels are reached in 2 to 5 hours, and plasma half-life ranges from 9 to 20 hours. After oral administration of 50 mg 3 times daily for 10 days, the mean steady-state plasma concentration was 33 to 85 ng/mL for imipramine and 43 to 109 ng/mL for desmethylimipramine, an active metabolite. Approximately 86% of imipramine is bound to plasma proteins. It is excreted primarily as inactive metabolites, up to 80% in the urine and up to 20% in the feces.

Owing to the lower clearance of imipramine in plasma, elderly patients require lower doses of imipramine than patients in younger age groups.

Indications And Clinical Uses:

For the relief of symptoms of depression.

Imipramine may also be useful as temporary adjunctive therapy in reducing enuresis in children aged 5 years and older, after possible organic causes have been excluded by appropriate tests. In patients having daytime symptoms of frequency and urgency, examination should include voiding cystourethrography and cytoscopy, as necessary. The effectiveness of treatment may decrease with continued drug administration.

Contra-Indications:

In patients who have known or suspected hypersensitivity to the drug or its excipients, or have known or suspected hypersensitivity to tricyclic antidepressants belonging to the dibenzazepine group.

Imipramine should not be given in conjunction with, or within 14 days before or after treatment with a MAO inhibitor (see Precautions, Drug Interactions). The concomitant treatment with selective reversible MAO A inhibitors, such as moclobemide, is also contraindicated. Hypertensive crises, hyperactivity, hyperpyrexia, spasticity, severe convulsions or coma, and death have been reported in patients receiving such combinations.

Imipramine is contraindicated for use during the acute recovery phase following a myocardial infarction and in the presence of acute congestive heart failure.

Imipramine is contraindicated in patients with existing liver or kidney damage and should not be administered to patients with a history of blood dyscrasias.

Imipramine is contraindicated in patients with glaucoma, as the condition may be aggravated due to the atropine-like effects of the drug.

Warnings in Clinical States:

Seizures: Tricyclic agents are known to lower the convulsive threshold and imipramine should, therefore, be used with extreme caution in patients with a history of convulsive disorders and other predisposing factors, e.g., brain damage of varying etiology, concomitant use of neuroleptics, alcoholism and withdrawal from alcohol, and concomitant use with other drugs that lower the seizure threshold. It appears that the occurrence of seizures is dose dependent. Therefore, the recommended total daily doses should not be exceeded (see Dosage).

Concurrent administration of electroconvulsive therapy and imipramine may be hazardous and such treatment should be limited to patients for whom it is essential. Physicians should discuss with patients the risk of taking imipramine while engaging in activities in which a sudden loss of consciousness could result in serious injury to the patient or others e.g., the operation of complex machinery, driving, swimming, or climbing.

Cardiovascular: Tricyclic antidepressants particularly in high doses, have been reported to produce sinus tachycardia, changes in conduction time and arrhythmias. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with drugs of this class. Therefore, imipramine should be administered with extreme caution to patients with a history of cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders (e.g., atrioventricular block grades I to III) or other arrhythmias, those with circulatory lability and elderly patients. Imipramine also has a hypotensive action which may be detrimental in these circumstances. In such cases, treatment should be initiated at low doses with progressive increases only if required and tolerated, and the patients should be under close surveillance at all dosage levels. Monitoring of cardiac function and the ECG is indicated in such patients as well as in the elderly.

Concomitant Illness: Caution should be observed when prescribing imipramine for hyperthyroid patients or for patients receiving thyroid medication. Transient cardiac arrhythmias have occurred in rare instances in patients who have been receiving other tricyclic compounds concomitantly with thyroid medication.

Because of its anticholinergic properties, imipramine should be used with caution in patients wiith increased intraocular pressure, narrow angle glaucoma or urinary retention, particularly in the presence of prostatic hypertrophy.

Tricyclic antidepressants may give rise to paralytic ileus, particularly in the elderly and in hospitalized patients. Therefore, appropriate measures should be taken if constipation occurs.

Caution is called for when employing imipramine in patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma), in whom the drug may provoke hypertensive crisis.

Children: Effectiveness of imipramine in children for conditions other than nocturnal enuresis has not been established. The safety and effectiveness of the drug as temporary adjunctive therapy for nocturnal enuresis in children under 5 years of age has not been established.

The safety of imipramine for long-term chronic use as adjunctive therapy for nocturnal enuresis in children 5 years of age or older has not been established; consideration should be given to establishing a drug free period following an adequate therapeutic trial with a favorable response. Recommended doses should not be exceeded in childhood, because ECG changes of unknown significance have been reported with higher doses in pediatric patients. To guard against possible cardiotoxic effects, a daily dosage of 2.5 mg/kg should not be exceeded in children.

Imipramine should be kept in a safe place, well out of the reach of children.

Pregnancy: The safety of use in pregnant women has not been established. Therefore, imipramine should not be administered to women of childbearing potential, or during pregnancy, unless in the opinion of the physician the expected benefit to the patient outweighs the potential risk to the fetus. Withdrawal symptoms including: tremors, dyspnea, lethargy, colic, irritability, hypotonia/hypertonia, convulsions and respiratory depression have been reported in neonates whose mothers received tricyclic antidepressants during the third trimester of pregnancy. To avoid such symptoms, imipramine should, if possible, be gradually withdrawn at least 7 weeks before the calculated date of confinement.

Lactation: Since imipramine passes into the breast milk, imipramine should be gradually withdrawn or the infant should be weaned if the patient is breast-feeding.

Precautions:

Suicide: The possibility of a suicide attempt is inherent in depression. These patients should be carefully supervised during treatment with imipramine and hospitalization or concomitant electroconvulsive therapy may be required. To minimize the risk of an intentional overdose by a depressed patient, prescriptions for imipramine should be written for the smallest possible quantity of the drug consistent with good patient management.

Psychosis, Mania-Hypomania and Other Neuropsychiatric Phenomena: In patients treated with tricyclic antidepressants, activation of latent schizophrenia or aggravation of existing psychotic manifestations in schizophrenic patients may occur. Patients with manic-depressive tendencies may experience hypomanic or manic shifts. Hyperactive or agitated patients may become over stimulated. A reduction in dose or discontinuation of imipramine should be considered under these circumstances.

In predisposed and elderly patients, tricyclic antidepressants may, particularly at night, provoke pharmacogenic (delirious) psychoses that disappear within a few days of withdrawing the drug.

Occupational Hazards: Since imipramine may produce sedation, particularly during the initial phase of therapy, patients should be cautioned about the danger of engaging in activities requiring mental alertness, judgment and physical coordination.

Cardiovascular: Before initiating treatment, it is advisable to check the patient’s blood pressure, because individuals with hypotension or a labile circulation may react to the drug with a fall in blood pressure. Regular measurements of blood pressure should be performed in susceptible patients.

Postural hypotension may be controlled by reducing the dosage or administering circulatory stimulants.

ECG abnormalities have been observed in patients treated with imipramine. The most common ECG changes were premature ventricular contractions (PVCs), ST T wave changes, and abnormalities in intraventricular conduction. These changes were rarely associated with significant clinical symptoms. Nevertheless, caution is necessary when treating patients with heart disease, as well as elderly subjects. In these patients cardiac function should be monitored and ECG examinations performed during long-term therapy. Gradual dose titration is also recommended.

Hepatic Changes: Isolated cases of obstructive jaundice have been reported. Caution is indicated in treating patients with known liver disease and periodic monitoring of hepatic function is recommended in such patients.

Hematological Changes: Isolated cases of bone marrow depression with agranulocytosis have been reported. Leukocyte and differential blood cell counts are recommended in patients receiving treatment with imipramine over prolonged periods, and should be performed for patients who develop fever, an influenzal infection or sore throat. In the event of an allergic skin reaction, imipramine should be withdrawn.

Withdrawal Symptoms: A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of imipramine, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia and irritability. In addition, such patients may experience a worsening of psychiatric status. While the withdrawal effects of imipramine have not been systematically evaluated in controlled trials, they are well known with closely related tricyclic antidepressants, and it is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation.

Metabolic Effects: Tricyclic antidepressants have been associated with porphyrinogenicity in susceptible patients.

Renal Function: It is advisable to monitor renal function during long-term therapy with tricyclic antidepressants.

Dental Effects: Lengthy treatment with tricyclic antidepressants can lead to an increased incidence of dental caries.

Lacrimation: Decreased lacrimation and accumulation of mucoid secretions due to the anticholinergic properties of tricyclic antidepressants may cause damage to the corneal epithelium in patients with contact lenses.

Drug Interactions:

Patients should be warned that, while taking imipramine their responses to alcoholic beverages, other CNS depressants (e.g., barbiturates, benzodiazepines or general anesthetics) or anticholinergic agents (e.g., atropine, biperiden, levodopa) may be exaggerated. When tricyclic antidepressants are given in combination with anticholinergics or neuroleptics with an anticholinergic action, hyperexcitation states or delirium may occur, as well as attacks of glaucoma.

Tricyclic antidepressants should not be employed in combination with antiarrhythmic agents of the quinidine type (see Warnings, Cardiovascular).

Since imipramine may diminish or abolish the antihypertensive effects of guanethidine, bethanidine, clonidine, reserpine, or alpha-methyldopa, patients requiring concomitant treatment for hypertension should be given antihypertensives of a different type (e.g., diuretics, vasodilators, beta-blockers).

Imipramine may potentiate the cardiovascular effects of norepinephrine or epinephrine, amphetamine, as well as nasal drops and local anesthetics containing sympathomimetics (e.g., isoprenaline, ephedrine, phenylephrine).

Fluoxetine, fluvoxamine and other selective serotonin reuptake inhibitors (SSRIs) may increase the activity and plasma concentrations of tricyclic antidepressants with corresponding adverse effects.

Caution should be exercised if imipramine is administered together with cimetidine or methylphenidate since these drugs have been shown to inhibit the metabolism of several tricyclic antidepressants. Clinically significant increases in plasma levels of imipramine may occur, necessitating a dosage reduction.

Substances which activate the hepatic mono-oxygenase enzyme system (e.g., barbiturates, carbamazepine, phenytoin, nicotine and oral contraceptives) may lower plasma concentrations of tricyclic antidepressants and so reduce their antidepressive effects. In addition, imipramine may increase plasma levels of phenytoin and carbamazepine, therefore, it may be necessary to adjust the dosage of these drugs.

Imipramine should not be administered for a period of at least 14 days after the discontinuation of treatment with MAO inhibitors due to the potential for severe interactions (see Contraindications). The same caution should also be observed when administering a MAO inhibitor after previous treatment with imipramine.

Imipramine should be discontinued prior to elective surgery for as long as clinically feasible, since little is known about the interaction between imipramine and general anesthetics.

Concomitant treatment with neuroleptic agents (e.g., phenothiazines and butyrophenones) may result in increased plasma concentrations of imipramine, a lowered convulsion threshold and seizures. Combination with thioridazine may produce severe cardiac arrhythmias. No such effects are known to occur in combination with diazepam, but it might be necessary to lower the dosage of imipramine if administered concomitantly with alprazolam or disulfiram.

Tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs by inhibiting hepatic metabolism of these drugs. Careful monitoring of plasma prothrombin is therefore advised.

If administered concomitantly with estrogens, the dose of imipramine should be reduced since steroid hormones inhibit the metabolism of imipramine.

Adverse Reactions:

If severe neurological or psychiatric reactions occur, imipramine should be withdrawn.

Elderly patients are particularly susceptible to anticholinergic, psychiatric, neurological and cardiovascular effects.

The following adverse reactions have been reported with imipramine or other tricyclic antidepressants. (Frequency estimates: Frequent: >10%; Occasional: between 1 to 10%; Rare: between 0.01 to 1%; Isolated cases: <0.01%.)

Neurological: Frequent: tremors. Occasional: drowsiness, headache, paresthesia (numbness, tingling sensation, symptoms suggestive of peripheral neuropathy), delirium. Rare: epileptic seizures. Isolated cases: tinnitus, incoordination, ataxia, alterations in EEG patterns, extrapyramidal symptoms, myoclonus, speech disorders, weakness.

Behavioral: Occasional: drowsiness, fatigue, insomnia, confusional states with hallucinations (particularly in geriatric patients suffering from Parkinson’s disease), anxiety, agitation, restlessness, nightmares, hypomania, mania, decrease in memory, feeling of unreality. Rare: activation of latent psychosis. Isolated cases: aggressiveness.

Anticholinergic: dry mouth and rarely associated sublingual adenitis, blurred vision, disturbances of visual accommodation, constipation, perspiration, hot flushes. Occasional: delayed micturition, dilation of the urinary tract. Isolated cases: mydriasis, glaucoma, paralytic ileus.

Cardiovascular: Frequent: hypotension, particularly orthostatic hypotension with associated vertigo, sinus tachycardia, ECG changes (including flattening or inversion of T wave, depressed S T segments) in patients of normal cardiac status. Occasional: arrhythmia, disturbances in cardiac conduction (e.g., widening of QRS complex, PQ changes, bundle-branch block), palpitation, syncope. Isolated cases: hypertension, congestive heart failure, myocardial infarction, heart block, asystole, stroke, peripheral vasospastic reactions.

Hematologic: Isolated cases: agranulocytosis, eosinophilia, leukopenia, purpura and thrombocytopenia may occur as an idiosyncratic response.

Gastrointestinal: Occasional: nausea, vomiting, anorexia, abdominal cramps. Rare: diarrhea, elevated transaminases. Isolated cases: bitter taste, stomatitis, epigastric distress, black tongue, dysphagia, increased salivation, hepatitis with or without jaundice.

Respiratory: Isolated cases: bronchospasm.

Endocrine: Frequent: weight gain. Occasional: increased or decreased libido, impotence. Isolated cases: gynecomastia in the male, breast enlargement and galactorrhea in the female, testicular swelling, elevation or depression of blood sugar levels, weight loss, inappropriate antidiuretic hormone (SIADH) secretion syndrome.

Allergic or Toxic: Occasional: skin rash, urticaria. Isolated cases: petechiae, itching, photosensitization (avoid excessive exposure to sunlight), edema (general or of face and tongue), drug fever, obstructive jaundice, nasal congestion, alopecia, cross-sensitivity with desipramine, allergic alveolitis (pneumonia) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions including hypotension.

Withdrawal Symptoms: Abrupt cessation of treatment with tricyclic antidepressants after prolonged administration may occasionally produce nausea, vomiting, abdominal pain, diarrhea, insomnia, nervousness, anxiety, headache and malaise. These symptoms are not indicative of addiction.

Symptoms And Treatment Of Overdose:

Since children may be more sensitive than adults to acute overdosage with tricyclic antidepressants, and since fatalities in children have been reported, effort should be made to avoid potential ovedose, particularly in this age group.

Symptoms:

These may vary in severity depending upon factors such as the amount of drug absorbed, the interval between drug ingestion and the start of treatment and the age of the patient. Accidental ingestion in children should be regarded as serious and potentially fatal.

Symptoms generally appear within 4 hours of ingestion and reach maximum severity after 24 hours. Owing to delayed absorption (increased anticholinergic effect due to overdose), long half-life and enterohepatic recycling of the drug, the patient may be at risk for up to 4 to 6 days.

Symptoms may include drowsiness, stupor, ataxia, vomiting, cyanosis, restlessness, agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements and/or convulsions. Hyperpyrexia, mydriasis, bowel and bladder paralysis, oliguria or anuria and respiratory depression may occur.

Hypotension and initial hypertension may occur. However, the usual finding is increasing hypotension which may eventually lead to shock. Serious cardiovascular disturbances are frequently present, including tachycardia, cardiac arrhythmias (flutter, atriofibrillation, premature ventricular beats and ventricular tachycardia), as well as impaired myocardial conduction, atrioventricular and intraventricular block, ECG abnormalities (such as widened QRS complexes and marked S T shifts), signs of congestive heart failure and cardiac arrest. Coma may ensue.

Treatment: Patients in whom overdosage is suspected should be admitted to hospital without delay. No specific antidote is available and treatment is essentially symptomatic and supportive.

Gastric lavage or aspiration should be performed promptly and is recommended up to 12 hours or even more after the overdose, since the anticholinergic effect of the drug may delay gastric emptying. Administration of activated charcoal may help reduce absorption of the drug. As imipramine is largely protein bound, forced diuresis, peritoneal dialysis and hemodialysis are unlikely to be of value.

Treatment should be designed to insure maintenance of the vital functions. An open airway should be maintained in comatose patients and assisted ventilation instituted, if necessary, but respiratory stimulants should not be used. Hyperpyrexia should be controlled by external measures, such as ice packs and cooling sponge baths. Acidosis may be treated by cautious administration of sodium bicarbonate. Adequate renal function should be maintained.

ECG monitoring in an intensive care unit is recommended in all patients, particularly in the presence of ECG abnormalities, and should be maintained for several days after the cardiac rhythm has returned to normal. Unexpected deaths attributed to cardiac arrhythmias have been reported several days following an apparent recovery from tricyclic antidepressant overdose. Correction of hypoxia and acidosis, if present, may be beneficial. Correction of metabolic acidosis and low potassium concentrations by means of bicarbonate i.v. and potassium substitution may also be effective for treatment of arrhythmias. If bradyarrhythmia or AV block ocur, consider temporary insertion of a cardiac pacemaker. Because of its effect on cardiac conduction, digitalis should be used only, with caution. If rapid digitalization is required for the treatment of congestive heart failure, special care should be exercised in using the drug.

External stimulation should be minimized to reduce the tendency to convulsions. If convulsions occur, anticonvulsants (preferably i.v. diazepam) should be administered. Barbiturates may intensify respiratory depression, particularly in children, and aggravate hypotension and coma. Paraldehyde may be used in some children to counteract muscular hypertonus and convulsions with less likelihood of causing respiratory depression. If the patient fails to respond rapidly to anticonvulsants, artificial ventilation should be instituted. Prompt control of convulsions is essential since they aggravate hypoxia and acidosis and may thereby precipitate cardiac arrhythmias and arrest.

Shock should be treated with supportive measures such as i.v. fluids, plasma expanders, and oxygen. The use of corticosteroids in shock is controversial and may be contraindicated in tricyclic antidepressant overdose. Hypotension usually responds to elevation of the foot of the bed. Pressor agents, (but not epinephrine) should be given cautiously, if indicated. In the event of a reduced myocardial function, consider recourse to treatment with dopamine or dobutamine by i.v. drip.

Since it has been reported that physostigmine may cause severe bradycardia, asystole and seizures, its use is not recommended in cases of overdosage with imipramine.

Deaths by deliberate or accidental overdosage have occurred with this class of drugs. Since the propensity for suicide is high in depressed patients, a suicide attempt by other means may occur during the recovery phase. The possibility of simultaneous ingestion of other drugs should also be considered.

Dosage And Administration:

Depression: The dosage should be individualized according to the requirements of each patient. Treatment should be initiated at the lowest recommended dose and increased gradually noting carefully the clinical response and any evidence of intolerance, particularly when treating elderly and adolescent patients. It should be kept in mind that a lag in therapeutic response usually occurs at the onset of therapy, lasting from several days to a few weeks. Increasing the dosage does not normally shorten this latent period and may increase the incidence of side effects.

Initial Dosage: Adults: 25 mg 3 times daily. This should be increased gradually as required and tolerated, up to 150 mg/day. Dosages over 200 mg/day are not recommended. In severely ill, hospitalized patients, initially 100 mg/day in divided doses, gradually increasing to 200 mg/day, if required. If no significant response is observed after 3 weeks, dosage may be increased up to 250 to 300 mg/day.

Elderly and Debilitated Patients: 30 to 40 mg/day, in divided doses, gradually increasing dosage if necessary, and tolerated; it is generally not necessary to exceed 100 mg/day. Maintenance Dosage: Dosage during maintenance therapy should be kept at the lowest effective level. Medication should be continued for the expected duration of the depressive episode in order to minimize the possibility of relapse following clinical improvement.

When a maintenance dosage has been established as described above, imipramine may be administered in a single daily dose at bedtime, provided such a dosage regimen is well tolerated.

Childhood Enuresis: For persistent functional enuresis which has not responded to other forms of management, a therapeutic trial with imipramine may be considered for children between 5 and 15 years of age, who are not mentally defective, and in whom organic causes of enuresis have been excluded.

The recommended dosage is 10 to 25 mg/day for children 5 years of age and older. If a satisfactory response does not occur within 1 week, the dosage may be increased up to 75 mg/day in children over 12 years of age. A daily dose greater than 75 mg does not enhance efficacy and tends to increase side effects. ECG changes of unknown significance have been reported with doses higher than those recommended in pediatric patients. The trial period should be 2 to 4 weeks. Medication should be given in a single dose 1 hour before bedtime, however, in children subject to enuresis early on in the night, part of the dose should be taken between 15 and 17 h.

Consideration should be given to instituting a drug free period following an adequate therapeutic trial with a favorable response, in order to assess the need for further drug treatment.

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.

The safety and effectiveness of imipramine as temporary adjunctive treatment for nocturnal enuresis in children less than 5 years of age has not been established.

Availability And Storage:

10 mg: Each reddish brown, sugar-coated, triangular tablet, branded Geigy in white and coded FT, contains: imipramine HCl USP 10 mg. Energy: 1.3 kJ (0.32 kcal). Bottles of 100.

25 mg: Each reddish brown, sugar-coated, round, biconvex tablet, contains: imipramine HCl 25 mg. Energy: 1 kJ (0.25 kcal). Bottles of 100.

50 mg: Each reddish brown, sugar-coated, round, biconvex tablet, branded Geigy on one side and LB on the other side in white, contains: imipramine HCl 50 mg. Energy: 3.77 kJ (0.90 kcal). Bottles of 100.

75 mg: Each reddish brown, sugar-coated, round, biconvex tablet, branded Geigy on one side and ATA on the other side in white, contains: imipramine HCl 75 mg. Energy: 3.3 kJ (0.8 kcal). Bottles of 30.

Nonmedicinal ingredients: cellulose compounds, colloidal silicon dioxide, cornstarch, glycerin, iron oxides, lactose, magnesium stearate, polyethylene glycol, povidone, stearic acid, sucrose, talc and titanium dioxide. All are alcohol-, bisulfite-, gluten-, parabens-, sodium- and tartrazine-free.

Protect from heat (store between 2 and 30°C) and humidity. Keep out of reach of children.

TOFRANIL® Novartis Pharmaceuticals Imipramine HCl Antidepressant

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