Imipramine Pamoate, Tofranil-PM™®

• Tofranil-PM™®

• Tricyclic Antidepressant (TCA)

• Capsules 75 mg, 100 mg, 125 mg and 150 mg

• Major Depression Disorder (MDD)

Mechanism of action:

• potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings

• Absorption:
  • Bioavailability: From GI tract (approximately 43%)
  • Peak Plasma Time: within 1–2 hours
  • Onset: within 1–3 weeks
  • Food: does not affect absorptio

• Distribution
  • Extent:
    • Widely distributed in the body
    • Distributed into milk in concentrations similar to maternal plasma
  • Plasma Protein Binding: 60–96%

• Metabolism:
  • In the liver by various CYP isoenzymes (CYP1A2, CYP2D6, CYP3A4, CYP2C)
  • Metabolites: Desipramine

• Elimination:
  • Excretion: principally in urine, small amounts excreted in feces
  • Half-life: 8–20 hours

Initial Adult Dosage:

• Outpatients:
• Start dose: 75 mg/day
• Optimum dose level: 150 mg/day
• Max dose: 200 mg/day.
• Hospitalized Patients:
• Start dose: 100 to 150 mg/day (may be increased to 200 mg/day)
• Max dose: 250 to 300 mg/day (If there is no response after two weeks)

Adult Maintenance Dosage:

• Usual dose: 75 to 150 mg/day
• Following remission for a longer period of time at the lowest dose
• Should decrease gradually

Adolescent and Geriatric Patients:

• Start dose: 25 to 50 mg/day (Because Tofranil-PM capsules are not available in these strengths >>> Should be treat with Tofranil-TM, brand of imipramine hydrochloride tablets)
• Max dose: 100 mg/day

1. Monoamine Oxidase Inhibitors (MAOIs)
2. Serotonergic Drugs
3.  Drugs Metabolized by P450 2D6:

Caucasian population: 7% to 10% of Caucasians are “poor metabolizers >>> higher plasma concentrations of tricyclic antidepressants (TCAs)

Certain drugs:

• Quinidine
• Cimetidine
• Phenothiazine
• Type 1C Anti-arrhythmic (e.g., Propafenone)
• Flecainide
• Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, sertraline, and paroxetine
• Hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine)
• epatic enzyme inducers (e.g., barbiturates, phenytoin)
• Anticholinergic drugs (including anti-parkinsonism agents)
• Decongestants and local anesthetic (contain sympathomimetic amine: (e.g., epinephrine, norepinephrine)
• Anti-hypertension agents
• CNS depressant

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, paresthesia 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.

1- Monoamine Oxidase Inhibitors (MAOIs):

• Such as linezolid or intravenous methylene blue
• Contraindicated within 14 days of stopping treatment with Tofranil-PM (increased risk of serotonin syndrome)

2- Myocardial Infarction:

• Drug is contraindicated during the acute recovery period after a myocardial infarction.

3- Hypersensitivity to Tricyclic Antidepressants

• Pregnancy: Category D
• Lactation: not recommended in nursing mothers

1- Clinical Worsening and Suicide Risk:

• Suicidal ideation and behavior (suicidality):
  • In patients with Major depressive disorder (MDD) and other psychiatric disorders.
  • might persist until significant remission occurs
  • Patients should be supervised during the early phase of treatment (may require hospitalization)
  • Symptoms should be reported to the patient’s prescriber or health professional
  • Occur during early antidepressant treatment and when the dose is adjusted up or down
• Symptoms:
  • anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness)
• Management:
  • close monitoring
  • changes in the medication

2- Dosage administration:

• Daily dosage could be given as single dose at bedtime
• Divide dosage schedule (if needed)

3- Antidepressant effect:

• Might takes one to three weeks

4- ECG should be taken:

• Prior to the initiation of larger-than-usual doses
• At appropriate intervals after until steady state is achieved
• Elderly patients
• Patients with history of cardiac disease

5- Hypomanic or manic episodes:

• Occur in patients with cyclic disorders
• Necessitate discontinuation of the drug. (Drug could be resumed in lower dosage when these episodes are relieved.)
• Tranquilizer is useful in controlling such episodes.

 6- Activation of the psychosis:

• Might be observed in schizophrenic patients
• Require reduction of dosage and the addition of a phenothiazine.

 7- Concurrent use of imipramine pamoate with electroshock therapy:

• Increase the hazards >>> treatment should be limited

 8- Sunlight exposure:

• should avoid excessive exposure to sunlight (because of photosensitization)

 9- Blood sugar level:

• Risk of elevation and lowering of blood sugar levels

 10- Renal and Hepatic impairment:

• Drug should be used with caution

 11- Pathological Neutrophil Depression:

• Signs: fever and sore throat during therapy with imipramine pamoate
• Investigation: leukocyte and differential blood counts
• Discontinue drug if there is evidence of pathological neutrophil depression.

 12- Prior to elective surgery:

• Should be discontinued for as long as the clinical situation will allow.

13- Pediatric Use:

• should not be used in children >>> because of increased potential risk for acute over-dosage

 14- Geriatric Use:

• Dose selection for the elderly should be cautious >>> starting at the low end of the dosing range

 15- In the case of relapse (due to premature withdrawal of the drug):

• The effective dosage of imipramine should be reinstituted.

 16- Switching From a Monoamine Oxidase Inhibitor (MAOI) to Imipramine:

• At least 14 days should elapse

 17- Caution of usage With Other MAOIs (Such as Linezolid or Methylene Blue):

• Should not start Tofranil-PM in a patient treated with linezolid or intravenous methylene blue >>> because of increasing risk of serotonin syndrome.

 18- Over dose:

• Manifestations:
  • Symptoms might vary depends on Amount of drug absorbed, Age of the patient, Interval between drug ingestion and treatment.
• Signs and symptoms:
  • Critical manifestations: Cardiac Dysrhythmias, Severe Hypotension, Convulsions, CNS Depression, Coma
• Toxicity indicator:
  • Changes in the electrocardiogram (particularly in QRS axis or width)
• Management
  • No specific antidote
  • Supportive therapy

 19- Withdrawal Symptoms:

• Abrupt cessation may produce nausea, headache and malaise.