TOFRANIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for TOFRANIL (TOFRANIL).

How it works

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.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for TOFRANIL (TOFRANIL).

Breastfeeding	Enters breast milk; M/P ratio ~1.0. Limited data; use with caution, monitor infant for sedation, poor feeding, and anticholinergic effects.
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

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to imipramine or any component","Concomitant use with MAOIs (risk of serotonin syndrome) - avoid within 14 days of MAOI discontinuation","Recent myocardial infarction","Concurrent use of linezolid or intravenous methylene blue"]

Clinical Precautions

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"]

Clinical Tips & Counseling

Drug interactions

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TOFRANIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for TOFRANIL (TOFRANIL).

How it works

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for TOFRANIL (TOFRANIL).

Breastfeeding	Enters breast milk; M/P ratio ~1.0. Limited data; use with caution, monitor infant for sedation, poor feeding, and anticholinergic effects.
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