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Imipramine Withdrawal
Brand name (Janimine and Tofranil)

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Pharmacology

Antidepressant

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 well absorbed from the gastrointestinal tract. Following 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. Peak plasma levels are reached in 2 to 5 hours, and plasma half-life ranges from 9 to 20 hours. 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.

 


Indications

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.

 


Contraindications

Imipramine should not be given in conjunction with, or within 14 days of treatment with a MAO inhibitor. Combined therapy of this type could lead to the appearance of serious interactions such as hypertensive crises, hyperactivity, hyperpyrexia, spasticity, severe convulsions or coma and death may occur.

Imipramine is contraindicated in patients with existing severe hepatic or renal damage, and those with a history of blood dyscrasias.

Imipramine is contraindicated in patients who have shown hypersensitivity to the drug or hypersensitivity to tricyclic antidepressants belonging to the dibenzazepine group.

Imipramine is contraindicated for use during the acute recovery phase following a myocardial infarction.

It should not be used in patients with convulsive disorders or glaucoma.

 


Warnings

Extreme caution should be used when imipramine is given to patients with known cardiovascular disease including a history of myocardial infarction, arrhythmias, atrioventricular-block (grades I-III) and/or ischemic heart disease. These patients require cardiac surveillance at all dosage levels of the drug. Imipramine may induce or exacerbate an arrhythmia or lead to a hypotensive episode, thus making its use hazardous in these conditions.

Imipramine should be used with caution in hyperthyroid patients and in those on thyroid medication because of the possibility of cardiovascular toxicity.

Particularly in the elderly and in hospitalized patients the tricyclic antidepressants may give rise to paralytic ileus and therefore appropriate measures should be taken if constipation occurs. Imipramine may produce urinary retention and should be used with caution in patients with urinary pathology, particularly in the presence of prostatic hypertrophy.

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.

Concomitant treatment with imipramine and electroconvulsive therapy should only be resorted to under careful supervision.

Caution is called for when treating patients with low convulsion thresholds (e.g., due to brain damage of varying etiology, alcoholism).

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

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. In order to guard against possible cardiotoxic effects, a daily dosage of 2.5 mg/kg should not be exceeded in children.

Pregnancy:
The safety of imipramine in pregnancy has not been established. Neonates whose mothers had taken imipramine up until delivery have shown symptoms such as dyspnea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms during the first few hours or days.

Therefore, imipramine should not be administered to women of childbearing potential, particularly during the first trimester and the last 7 weeks of pregnancy, unless in the opinion of the physician the potential benefit to the patient outweighs the possible hazards to the fetus.

Lactation:
Imipramine passes into the breast milk, in the case of nursing mothers the infant should be weaned or the drug withdrawn.

Imipramine should be kept out of the reach of children.

 


Precautions

The possibility of suicide in seriously depressed patients is inherent in their illness and may persist until significant remission occurs. Therefore, patients must be carefully supervised during all phases of treatment with imipramine and may require hospitalization. Prescriptions should be written for the smallest amount and consistent with good management.

Activation of latent schizophrenia or aggravation of existing psychotic manifestations in schizophrenic patients may occur; hyperactive or agitated patients may become over-stimulated; and patients with manic-depressive tendencies may experience hypomanic or manic shifts. Discontinuation of imipramine should be considered under these circumstances.

In predisposed and elderly patients, imipramine may, particularly at night, provoke pharmacogenic (delirious) psychoses which disappear without treatment within a few days of withdrawing the drug.

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 the blood pressure should be performed in patients susceptible to postural hypotension. Postural hypotension may be controlled by reducing the dosage or administering circulatory stimulants.

Particularly in patients with heart diseases, especially those who have a history of conduction disorders, as well as in elderly subjects, cardiac function should be monitored and ECG examinations performed during long-term treatment.

Periodic blood cell counts and liver function tests are recommended with prolonged therapy.

An abrupt discontinuation of treatment should be avoided as it may give rise to withdrawal symptoms.

Occupational Hazards:
Since imipramine may produce sedation and decrease alertness, patients should be cautioned against driving an automobile, operating heavy machinery or performing potentially dangerous tasks that require mental alertness, judgment and physical co-ordination.

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

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 combinations 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 anti-arrhythmic agents of the quinidine type.

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

Imipramine may potentiate the cardiovascular effects of noradrenaline or adrenaline, amphetamine, as well as nasal drops and local anesthetics containing sympathomimetics.

Methylphenidate may increase the activity and plasma concentrations of tricyclic antidepressants.

Caution should be exercised if imipramine is administered together with cimetidine since cimetidine has been shown to inhibit the metabolism of several tricyclic antidepressants and clinically significant increases in plasma levels of imipramine may occur; ranitidine was not observed to alter the kinetics of imipramine.

Substances which activate the hepatic mono-oxygenase enzyme system (e.g., barbiturates, phenytoin, nicotine) may lower plasma concentrations of tricyclic antidepressants and so reduce their antidepressive effects.

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 an MAO inhibitor after previous treatment with imipramine.

The use of imipramine on a once-a-day dosage regimen in geriatric patients, patients with intercurrent illnesses, or patients taking other medications should be adjusted carefully, based on the patient's condition. This is especially important if the patient is receiving other medications with anticholinergic effects.

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 administration of imipramine and phenytoin may lead to elevated serum phenytoin concentration. If necessary, the phenytoin dosage should be adjusted accordingly.

Neuroleptic agents (e.g., phenothiazines) may increase the plasma concentration of imipramine. 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.

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

 


Adverse Effects

The following adverse effects have been reported with imipramine or other tricyclic antidepressants.

CNS:
Frequently: Tremors. Occasionally: drowsiness, fatigue, insomnia, dizziness, headache, paresthesia (numbness, tingling sensation, symptoms suggestive of peripheral neuropathy). Rarely: Epileptic seizures. In isolated cases: Tinnitus, incoordination, ataxia, alterations in EEG patterns, extrapyramidal symptoms, myoclonus, speech disorders.

Behavioral:
Occasionally: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions, anxiety, agitation, restlessness, nightmares, hypomania, mania, exacerbation of psychosis, decrease in memory, feeling of unreality. In isolated cases: Feeling of weakness, aggressiveness.

Autonomic:
Frequently: Dry mouth and rarely associated sublingual adenitis, blurred vision, disturbances of accommodation, constipation, perspiration, flushing. Occasionally: Delayed micturition, dilation of the urinary tract. In isolated cases: Mydriasis, glaucoma, paralytic ileus, urinary frequency.

Cardiovascular:
Frequently: Hypotension, particularly orthostatic hypotension with associated vertigo, tachycardia, ECG changes (including flattening or inversion of T wave). Occasionally: Arrhythmia, disturbances in cardiac conduction, palpitation, syncope. In isolated cases: Hypertension, congestive heart failure, myocardial infarction, heart block, asystole, stroke, peripheral vasospastic reactions.

Hematologic:
In isolated cases: Agranulocytosis, eosinophilia, leukopenia, purpura and thrombocytopenia may occur as an idiosyncratic response.

Gastrointestinal:
Occasionally: Nausea, vomiting, anorexia. Rarely: Elevated transaminases. In isolated cases: Diarrhea, bitter taste, stomatitis, epigastric distress, abdominal cramps, black tongue, dysphagia, increased salivation, hepatitis with or without jaundice.

Endocrine:
Frequently: Weight gain. Occasionally: Increased or decreased libido, impotence. In 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 (ADH) secretion syndrome.

Allergic or Toxic:
Occasionally: Skin rash, urticaria. In 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.

If treatment is terminated abruptly, withdrawal symptoms, such as gastrointestinal upsets, nervousness, anxiety, and muscle twitching may occur.

 


Overdose

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

Symptoms:
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. Blood and urine levels of imipramine may not reflect the severity of poisoning; they have chiefly a qualitative rather than quantitative value, and are unreliable indicators in the clinical management of the patient.

Drowsiness, stupor, ataxia, vomiting, cyanosis, restlessness, agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, athetoid movements, convulsions, respiratory depression, hyperpyrexia, hypothermia, mydriasis, and bowel and bladder paralysis may occur.

Serious cardiovascular disturbances are frequently present, including tachycardia, cardiac arrhythmia (flutter, atriofibrillation, ventricular premature 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 and signs of congestive heart failure and cardiac arrest). Hypotension and initial hypertension may occur. However, the usual finding is increasing hypotension which may lead eventually to shock. Coma may ensue.

Treatment:
Symptomatic and supportive. Cardiac arrhythmias and CNS involvement pose the greatest threat with tricyclic antidepressant overdosage and may occur suddenly even when initial symptoms appear to be mild. Therefore, patients who may have ingested an overdosage of imipramine, particularly children, should be hospitalized and kept under close surveillance.

If the patient is conscious, induced emesis followed by gastric lavage, with appropriate precautions to prevent pulmonary aspiration, should be accomplished as soon as possible. Following lavage, activated charcoal may be administered to reduce absorption. An adequate airway should be established 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.

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.

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. A patient who has ingested a toxic overdose of a tricyclic antidepressant may remain medically and psychiatrically unstable for several days due to sustained excessive drug levels. Unexpected cardiac deaths have occurred up to 6 days after overdosage with other antidepressants. The QRS interval of the electrocardiogram appears to be a reliable correlate of the severity of overdosage. If the QRS interval exceeds 100 milliseconds any time during the first 24 hours after overdosage, cardiac function should be continuously monitored for 5 or 6 days. Correction of hypoxia, 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 for arrhythmia. If bradyarrhythmia or AV-block occur, 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.

Shock should be treated with supportive measures such as i.v. fluids, plasma expanders, oxygen and corticosteroids. Hypotension usually responds to elevation of the foot of the bed. Pressor agents, such as norepinephrine (but not epinephrine), are rarely indicated and should be given only after careful consideration and under continuous monitoring. In the event of a reduced myocardial function, consider recourse to treatment with dopamine or dobutamine by i.v. drip.

Physostigmine i.v. has been used in the treatment of tricyclic-induced anticholinergic toxicity. Its use is controversial and should be reserved for life-threatening situations. Physostigmine is not innocuous and carries the risk of inducing seizures, bronchospasm, hypertension and severe arrhythmias. It should not be used routinely or to reverse coma. However, it may be indicated in the treatment of seizures or combative hallucinations. It should not be used in patients who are acidemic or who have cardiac conduction defects.

Adults:
A test dose of 0.5 mg i.v. is given initially. Give 1 to 2 mg slowly i.v. (over 2 minutes). If no clinical changes or cholinergic signs occur within 15 to 30 minutes, an additional 1 to 2 mg may be cautiously administered. Repeat doses of 1 to 2 mg i.v. every 30 minutes up to 2 hours.

Children:
0.5 mg i.v. is given initially.

As the CNS effects of physostigmine may wear off rapidly, it is important to monitor the patient continuously.

Physostigmine is the only drug of this class that may be used. Neostigmine should not be used as it does not have any CNS effects.

If symptoms of cholinergic toxicity develop, physostigmine should be discontinued.

Peritoneal and hemodialysis are of no value because of low plasma concentrations of the drug. Most of the administered dose is distributed in tissue and not in plasma. When aggressive medical management is inadequate, hemoperfusion, but not hemodialysis, has shown some good results.

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

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.

Adults:
Initial dosage:
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 one 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 one 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.

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

 


Supplied

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 and 500.

25 mg:
Each reddish brown, sugar-coated, round tablet, branded Geigy in white and coded CZ, contains: Imipramine HCl USP 25 mg. Energy: 1 kJ (0.25 kcal). Bottles of 100 and 1000.

50 mg:
Each reddish brown, sugar-coated, round tablet, branded Geigy in white and coded LB, contains: Imipramine HCl USP 50 mg. Energy: 3.77 kJ (0.90 kcal). Bottles of 100 and 500.

75 mg:
Each reddish brown, sugar-coated, round tablet, branded Geigy in white and coded ATA, contains: Imipramine HCl USP 75 mg. Energy: 3.3 kJ (0.8 kcal). Bottles of 30.

All strengths contain lactose. All are alcohol-free, bisulfite-free, gluten-free, parabens-free, sodium-free and tartrazine-free.