TOFRANIL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TOFRANIL (TOFRANIL).
Inhibits the reuptake of norepinephrine and serotonin at the presynaptic neuronal membrane, increasing synaptic concentrations of these neurotransmitters. Metabolite desipramine is more selective for norepinephrine reuptake inhibition.
| Metabolism | Primarily metabolized by CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 to active metabolite desipramine. Also undergoes N-demethylation and hydroxylation. |
| Excretion | Primarily renal (70% as metabolites, <5% unchanged); 20% biliary/fecal. |
| Half-life | Terminal elimination half-life 8–20 hours (mean 12 hours); clinical context: steady-state achieved in 3–7 days; active metabolite desipramine half-life 12–28 hours. |
| Protein binding | 80–95% bound primarily to albumin and alpha1-acid glycoprotein. |
| Volume of Distribution | Vd 9–23 L/kg (mean 15 L/kg); high Vd indicates extensive tissue distribution. |
| Bioavailability | Oral bioavailability 22–77% (mean 50%) due to extensive first-pass metabolism. |
| Onset of Action | Oral: antidepressant effect 1–3 weeks; IM: no advantage; sedation within hours. |
| Duration of Action | Terminal elimination half-life 12 hours; clinical effect persists for days due to active metabolite; dosing interval 1–4 times daily. |
| Molecular Weight | 280.41 |
Initial: 75-150 mg/day orally in divided doses; maintenance: 50-150 mg/day; maximum: 200 mg/day. For depression, dose may be increased gradually to 300 mg/day if needed.
| Dosage form | TABLET |
| Renal impairment | eGFR 30-59 mL/min: use 50% of normal dose; eGFR <30 mL/min: avoid use due to risk of accumulation. |
| Liver impairment | Child-Pugh A: reduce dose by 50%; Child-Pugh B: reduce dose by 75%; Child-Pugh C: contraindicated. |
| Pediatric use | For enuresis: age 6-12 years: 25-50 mg/day orally at bedtime; age 12+: 50-75 mg/day. Not recommended for depression in children <12 years. |
| Geriatric use | Initial: 30-40 mg/day orally in divided doses or at bedtime; increase gradually; maximum: 100 mg/day due to increased sensitivity and risk of side effects. |
| 1st trimester | Avoid; limited studies suggest possible association with cardiovascular malformations, but not conclusively proven. Use only if clearly needed. |
| 2nd trimester | Use with caution; associated with anticholinergic effects, potential for fetal tachycardia, and possible association with preterm labor. Monitor as needed. |
| 3rd trimester | Avoid near term; risk of neonatal withdrawal (irritability, tremor, respiratory distress), anticholinergic effects, and cardiac abnormalities. May cause neonatal tachycardia, hypotonia, and poor feeding. |
Clinical note
Comprehensive clinical and safety monograph for TOFRANIL (TOFRANIL).
| Placental transfer | Yes; imipramine and its active metabolite desipramine cross the placenta. Cord blood concentrations approximate maternal plasma levels, indicating significant placental transfer. |
| Breastfeeding | Imipramine is excreted into breast milk in small amounts (milk-to-plasma ratio ~0.1). Infant plasma levels are low to undetectable. No adverse effects reported in most nursing infants; however, monitor for sedation, irritability, and poor feeding. American Academy of Pediatrics considers it compatible with breastfeeding, but weigh risks/benefits. Prefer lower doses and monitor infant for side effects. |
■ FDA Black Box Warning
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Monitor closely for clinical worsening, suicidality, or unusual changes in behavior.
| Serious Effects |
Hypersensitivity to imipramine or any tricyclic antidepressantConcomitant use of MAO inhibitors (within 14 days); risk of serotonin syndromeRecent myocardial infarction (within 6 weeks)Acute recovery phase after MIConcurrent use of fluoxetine or other SSRIs (increased risk of toxicity, serotonin syndrome)Severe hepatic impairment (child-pugh class C)Narrow-angle glaucomaUncontrolled angle-closure glaucomaUrinary retention due to benign prostatic hyperplasia or other obstructive uropathyUntreated epilepsy or seizure disorder (lowers seizure threshold)
| Precautions | Activation of mania/hypomania, Seizure threshold lowering, Cardiovascular effects (QT prolongation, arrhythmias, orthostatic hypotension), Anticholinergic effects (urinary retention, constipation, blurred vision), Serotonin syndrome when combined with other serotonergic drugs, Angle-closure glaucoma in susceptible patients, Pediatric use: increased risk of suicidality |
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| Lactation Rating | L2 (Safer) |
| Teratogenic Risk | First trimester: Limited data; no clear teratogenicity. Second and third trimesters: Risk of neonatal withdrawal symptoms (tachycardia, irritability, respiratory distress) and anticholinergic effects (ileus, urinary retention). |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and ECG for arrhythmias. Fetal monitoring for heart rate variability and growth (third trimester). |
| Fertility Effects | May cause sexual dysfunction (libido, ejaculation) in both sexes; reversible upon discontinuation. No direct evidence of impaired fertility. |
| Food/Dietary | Avoid or limit tyramine-rich foods (aged cheese, cured meats, pickled foods, soy products, draft beer) due to risk of hypertensive crisis. Grapefruit may increase drug levels. High-fiber foods may reduce absorption. Take with food to reduce gastrointestinal upset. |
| Clinical Pearls | For enuresis, start at low dose (25 mg) and titrate slowly; taper discontinuation to avoid withdrawal. Use with caution in patients with cardiovascular disease, narrow-angle glaucoma, urinary retention, or hyperthyroidism. Monitor for suicidal ideation in young adults and serotonin syndrome if combined with other serotonergic drugs. Check plasma levels for therapeutic window (150-250 ng/mL). |
| Patient Advice | Take this medication exactly as prescribed, usually 1-3 times daily. Do not stop abruptly. · Avoid consuming alcohol while taking TOFRANIL. · You may experience drowsiness, dizziness, or blurred vision; avoid driving until you know how the medication affects you. · Contact your doctor immediately if you experience chest pain, fast heartbeat, confusion, or difficulty urinating. · Tell your doctor about all other medications you are taking, especially MAOIs, SSRIs, and blood pressure medications. |