Indications and Usage
For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident.
Dosage and Administration
The following recommended dosages for imipramine pamoate should be modified as necessary by the clinical response and any evidence of intolerance.
Initial Adult Dosage
Outpatients:
Therapy should be initiated at 75 mg/day. Dosage may be increased to 150 mg/day which is the dose level at which optimum response is usually obtained. If necessary, dosage may be increased to 200 mg/day.
Dosage higher than 75 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule.
As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.
Hospitalized Patients:
Therapy should be initiated at 100 to 150 mg/day and may be increased to 200 mg/day. If there is no response after two weeks, dosage should be increased to 250 to 300 mg/day.
Dosage higher than 150 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule.
As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.
Adult Maintenance Dosage:
Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased.
The usual maintenance dosage is 75 to 150 mg/day. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.
In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted.
Adolescent and Geriatric Patients:
Therapy in these age groups should be initiated with imipramine pamoate tablets at a total daily dosage of 25 to 50 mg, since imipramine pamoate capsules are not available in these strengths. Dosage may be increased according to response and tolerance, but it is generally unnecessary to exceed 100 mg/day in these patients. Imipramine pamoate capsules may be used when total daily dosage is established at 75 mg or higher.
The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.
As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.
Adolescent and geriatric patients can usually be maintained at lower dosage. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased.
The total daily maintenance dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.
In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with imipramine pamoate. Conversely, at least 14 days should be allowed after stopping imipramine pamoate before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ).
Use of Imipramine Pamoate With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start imipramine pamoate in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ).
In some cases, a patient already receiving imipramine pamoate therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, imipramine pamoate should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with imipramine pamoate may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS ).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with imipramine pamoate is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS ).
Contraindications
Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with imipramine pamoate or within 14 days of stopping treatment with imipramine pamoate is contraindicated because of an increased risk of serotonin syndrome. The use of imipramine pamoate within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION ).
Starting imipramine pamoate in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION ).
Myocardial Infarction
The drug is contraindicated during the acute recovery period after a myocardial infarction.
Hypersensitivity to Tricyclic Antidepressants
Patients with a known hypersensitivity to this compound should not be given the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind.
Adverse Reactions
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 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; cross-sensitivity 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; hyponatremia.
Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise.
Postmarketing Experience
The following adverse drug reaction has been reported during post-approval use of imipramine pamoate. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency.
Eye Disorders: Angle-closure glaucoma
Overdosage
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 pamoate. 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 any time 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 ≥0.1 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 >7.6 or a pCO2 <20 mmHg is undesirable.
Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, 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.
Description
Imipramine Pamoate Capsules, USP are a tricyclic antidepressant, available as capsules for oral administration. The 75 mg, 100 mg, 125 mg, and 150 mg capsules contain imipramine pamoate, USP equivalent to 75 mg, 100 mg, 125 mg, and 150 mg of imipramine hydrochloride. Imipramine pamoate, USP is 5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine 4, 4'-methylenebis-(3-hydroxy-2-naphthoate) (2:1), and its structural formula is:
(C19H24N2)2●C23H16O6 M.W. = 949.18
Imipramine pamoate, USP is a slightly yellow, crystalline powder. It is soluble in ethanol, in acetone, in ether, in chloroform, and in carbon tetrachloride, and is insoluble in water.
Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, pregelatinized starch, sodium starch glycolate and talc.
Gelatin capsule shells contain FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, and titanium dioxide. The 100 mg capsules also contain FD&C Yellow No. 10. The 125 mg capsules also contain FD&C Yellow No. 5.
In addition to the ingredients listed above, each capsule contains iron oxide used in the black monogramming ink.
structural formulaClinical Pharmacology
The mechanism of action of imipramine is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings.
How Supplied / Storage and Handling
Imipramine Pamoate Capsules, USP
75 mg capsules are supplied as light caramel opaque cap and light caramel opaque body with “54 591” printed on the cap and body, containing a light yellow to yellow powder.
NDC 0054-0273-13: Bottle of 30 Capsules
NDC 0054-0273-25: Bottle of 100 Capsules
100 mg capsules are supplied as light caramel opaque cap and rich yellow opaque body with “54 758” printed on the cap and body, containing a light yellow to yellow powder.
NDC 0054-0274-13: Bottle of 30 Capsules
NDC 0054-0274-25: Bottle of 100 Capsules
125 mg capsules are supplied as light caramel opaque cap and ivory opaque body with “54 466” printed on the cap and body, containing a light yellow to yellow powder.
NDC 0054-0275-13: Bottle of 30 Capsules
150 mg capsules are supplied as light caramel opaque cap and light caramel opaque body with “54 161” printed on the cap and body, containing a light yellow to yellow powder.
NDC 0054-0276-13: Bottle of 30 Capsules
NDC 0054-0276-25: Bottle of 100 Capsules
Storage
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, child-resistant container as defined in the USP/NF.
Patient Counseling Information
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with imipramine pamoate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for imipramine pamoate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking imipramine pamoate.
Clinical Worsening and Suicide Risk:
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Patients should be advised that taking imipramine pamoate can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.