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. |
| Molecular Weight | 280.41 |
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 | Avoid; associated with congenital malformations in animal studies and limited human data; consider risk-benefit. |
| 2nd trimester | Avoid; use only if clearly needed due to risk of fetal tachycardia and neonatal withdrawal. |
| 3rd trimester | Avoid in third trimester due to risk of neonatal withdrawal, tachycardia, and irritability. |
Clinical note
Comprehensive clinical and safety monograph for TOFRANIL-PM (TOFRANIL-PM).
| Placental transfer | Crosses placenta; measurable fetal serum concentrations. |
| Breastfeeding | Imipramine and its metabolite desipramine are excreted into breast milk in small amounts; monitor infant for sedation, poor feeding, and respiratory depression; consider risk-benefit. |
| Lactation Rating |
■ 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 |
Hypersensitivity to imipramine or any componentConcomitant use with MAOIs or within 14 days of MAOI discontinuationRecent myocardial infarctionAcute recovery phase after myocardial infarctionUse in children <6 years for enuresis (safety not established)
| 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. |
Loading safety data…
| L3 (Moderately Safe) |
| 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. |
| 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. |
| Food/Dietary | Avoid alcohol and grapefruit juice. Alcohol can potentiate CNS depression and increase sedation. Grapefruit juice may inhibit CYP3A4 and CYP2D6, increasing imipramine levels. High-fiber meals may reduce absorption; take consistently with respect to meals. Avoid excessive caffeine as it may increase anxiety and cardiac effects. |
| Clinical Pearls | Tofranil-PM (imipramine pamoate) is a tricyclic antidepressant used primarily for major depressive disorder and enuresis. Due to its long half-life, once-daily dosing is sufficient, but it may take 2-4 weeks for antidepressant effects. Monitor for anticholinergic effects (constipation, urinary retention, dry mouth), orthostatic hypotension, and cardiac arrhythmias. ECG is recommended before initiating in patients over 40 or with cardiac history. Avoid abrupt discontinuation to prevent withdrawal symptoms. It has a narrow therapeutic index; plasma levels of imipramine plus desipramine should be kept between 150-300 ng/mL. |
| Patient Advice | Take this medication exactly as prescribed, typically once daily at bedtime to minimize daytime sedation. · Do not stop taking this medication abruptly; taper under your doctor's guidance to avoid withdrawal symptoms. · Avoid alcohol and grapefruit juice, which can increase side effects and affect drug levels. · This drug may cause drowsiness, dizziness, or blurred vision; do not drive until you know how it affects you. · Report any signs of mania, worsening depression, or suicidal thoughts immediately. · Common side effects include dry mouth, constipation, and weight gain; these may improve over time. · Use caution when getting up from a sitting or lying position to prevent falls due to blood pressure changes. · Notify your doctor if you experience rapid or irregular heartbeat, difficulty urinating, or severe constipation. |