TOFRANIL-PM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TOFRANIL-PM (TOFRANIL-PM).
Tofranil-PM (imipramine pamoate) is a tricyclic antidepressant that inhibits the reuptake of norepinephrine and serotonin from the synaptic cleft, increasing their concentrations in the central nervous system. It also has anticholinergic, antihistaminergic, and alpha-1 adrenergic blocking effects.
| Metabolism | Primarily hepatic via cytochrome P450 enzymes, especially CYP2D6, CYP1A2, CYP2C9, and CYP3A4. Active metabolite: desipramine. Imipramine undergoes N-demethylation to desipramine. |
| Excretion | Renal: 40-70% as metabolites; biliary/fecal: 20-30%; unchanged drug: <5%. |
| Half-life | Terminal elimination half-life: 8-30 hours (mean 21 hours); clinical context: steady-state reached in 5-7 days; extended half-life in elderly and hepatic impairment. |
| Protein binding | 90-95% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 10-20 L/kg; indicates extensive tissue binding and distribution. |
| Bioavailability | Oral: 30-70% due to first-pass metabolism; bioavailability increased in elderly and hepatic disease. |
| Onset of Action | Oral: 2-4 weeks for antidepressant effect; intramuscular: 2-4 weeks; plasma levels detectable within 1-2 hours. |
| Duration of Action | Antidepressant effect: 2-4 weeks to peak; sustained with chronic dosing; single dose: therapeutic plasma levels sustained for 12-24 hours. |
100-200 mg orally once daily at bedtime, starting at 25-50 mg/day and titrating up by 25-50 mg every 2-3 weeks. Maximum 300 mg/day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 10-50 mL/min: reduce dose by 50%; GFR <10 mL/min: reduce dose by 75% or avoid use. |
| Liver impairment | Child-Pugh Class A: reduce dose by 50%; Class B: reduce dose by 75%; Class C: contraindicated. |
| Pediatric use | Not recommended for children under 12; for adolescents, initial 25-50 mg/day, titrate up to 100-200 mg/day, maximum 200 mg/day. |
| Geriatric use | Initial dose 10-25 mg at bedtime, titrate slowly, maximum 100-150 mg/day; monitor for anticholinergic effects and orthostatic hypotension. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TOFRANIL-PM (TOFRANIL-PM).
| Breastfeeding | Excreted in breast milk; M/P ratio approximately 0.5–1.5. Relative infant dose 1–2% of maternal weight-adjusted dose. Monitor infant for sedation, irritability, and feeding difficulties. Use only if clearly needed; consider monitoring infant serum levels if toxicity suspected. |
| Teratogenic Risk | Pregnancy Category D. First trimester: Limited human data; animal studies show fetal abnormalities (cardiovascular, skeletal). Second/third trimester: Neonatal withdrawal (tachycardia, irritability, respiratory depression) and anticholinergic effects (ileus, urinary retention) reported. Risk of persistent pulmonary hypertension of the newborn (PPHN) with late exposure. |
■ FDA Black Box Warning
Suicidality: Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Monitor for clinical worsening, suicidality, or unusual changes in behavior.
| Serious Effects |
Absolute: Hypersensitivity to imipramine or any component, concomitant use with MAOIs (within 14 days), recent myocardial infarction, concurrent use of linezolid or intravenous methylene blue. Relative: History of seizure disorder, narrow-angle glaucoma, urinary retention, prostatic hypertrophy, hyperthyroidism, cardiovascular disease, hepatic or severe renal impairment.
| Precautions | Cardiovascular: risk of QTc prolongation, arrhythmias, and sudden death; avoid in recent myocardial infarction. Suicidality: monitor for worsening depression or suicidal ideation. Serotonin syndrome: risk when co-administered with other serotonergic drugs. Seizure threshold lowering: use cautiously in patients with seizure disorders. Anticholinergic effects: urinary retention, angle-closure glaucoma, constipation, dry mouth. Withdrawal symptoms: abrupt discontinuation may cause nausea, headache, malaise. Activation of mania/hypomania in bipolar disorder. Hepatic impairment: reduce dose. Renal impairment: use with caution. Leukopenia/agranulocytosis: monitor CBC if fever or sore throat develops. |
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| Fetal Monitoring | Maternal: ECG for QTc prolongation at baseline and periodically; liver function tests; blood glucose (may cause hypoglycemia); thyroid function (may alter thyroid hormone levels). Fetal: Serial ultrasound for growth restriction; fetal echocardiography if QTc prolongation concerns; neonatal ECG after delivery if maternal QTc prolonged. |
| Fertility Effects | Imipramine may inhibit ovulation via prolactin elevation; reversible upon discontinuation. Animal studies show reduced fertility at high doses. Human data limited; may affect sperm motility in males (case reports). No established permanent effect. |