ENDEP

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ENDEP (ENDEP).

How it works

Increases synaptic concentrations of serotonin and norepinephrine by inhibiting their reuptake in the central nervous system.

What the body does with it

Metabolism	Hepatic via CYP2D6, CYP2C19, and CYP3A4; active metabolite nortriptyline.
Excretion	Renal: 70-80% as metabolites (including glucuronides, unchanged drug <5%); Biliary/Fecal: 20-30%.
Half-life	Terminal elimination half-life: 15-40 hours (mean ~24 h); clinical context: steady-state achieved in 5-7 days; prolonged in elderly and CYP2D6 poor metabolizers.
Protein binding	85-95% bound primarily to alpha-1-acid glycoprotein and albumin.
Volume of Distribution	10-30 L/kg (mean 15 L/kg); clinical meaning: extensive tissue distribution, particularly in lungs, heart, and brain.
Bioavailability	Oral: 30-60% due to extensive first-pass metabolism.
Onset of Action	Oral: 2-4 weeks for antidepressant effect; IV/IM (not typical): within 24 hours for sedation; analgesic effect may begin within 1 week.
Duration of Action	Oral: 24-48 hours; clinical note: continued pharmacologic effects (e.g., anticholinergic) persist for several days after cessation due to long half-life of active metabolite nortriptyline.

Classification & Brands

Action Class	Selective Seretonin Reuptake inhibitors (SSRIs)
Brand Substitutes	Pronil 20mg Capsule, Fluox 20mg Capsule, Persona 20mg Capsule, Flunat 20mg Capsule, Flonol 20mg Capsule

Dosing & administration

Initial 75 mg/day orally in divided doses, increased gradually to 150-200 mg/day; maintenance 50-150 mg/day as single dose at bedtime or in divided doses.

Dosage form	TABLET
Renal impairment	GFR 30-50 mL/min: reduce dose by 25-50%; GFR <30 mL/min: use with caution, consider alternative; not dialyzable.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated.
Pediatric use	Weight <25 kg: 1-2 mg/kg/day in 3 divided doses; >25 kg: start 30 mg/day, increase to 60-100 mg/day in 3-4 divided doses. Not recommended for children <6 years.
Geriatric use	Start 10-25 mg/day at bedtime; increase by 10-25 mg every 3-7 days; max 100 mg/day in divided doses; monitor for QT prolongation and anticholinergic effects.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for ENDEP (ENDEP).

Breastfeeding	Excreted in breast milk in low quantities; M/P ratio 0.5-1.5. American Academy of Pediatrics classifies as compatible, but monitor infant for sedation and poor feeding. Use lowest effective dose.
Teratogenic Risk	First trimester: Limited human data; animal studies show embryotoxicity and delayed ossification at high doses. Second/third trimester: Risk of neonatal withdrawal syndrome (irritability, hypertonia, respiratory depression) and anticholinergic effects if used near term. Consider risks vs benefits.

Warnings & precautions

■ FDA Black Box Warning

Suicidality and Antidepressant Drugs: Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders.

Side Effect Profile

Serious Effects

Absolute Contraindications

Concomitant use with MAOIs, recent myocardial infarction, hypersensitivity to tricyclic antidepressants.

Clinical Precautions

Precautions	Activation of mania/hypomania, QT interval prolongation, serotonin syndrome, angle-closure glaucoma, urinary retention, seizures.
Food/Dietary	Avoid high-tyramine foods (aged cheeses, cured meats, fermented products) as concurrent use with MAOIs can precipitate hypertensive crisis, but this interaction is less relevant when MAOIs have been discontinued. Consume grapefruit and grapefruit juice with caution due to potential CYP3A4 inhibition affecting amitriptyline metabolism.

Clinical Tips & Counseling

Drug interactions

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ENDEP

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ENDEP (ENDEP).

How it works

Increases synaptic concentrations of serotonin and norepinephrine by inhibiting their reuptake in the central nervous system.

What the body does with it

Metabolism	Hepatic via CYP2D6, CYP2C19, and CYP3A4; active metabolite nortriptyline.
Excretion	Renal: 70-80% as metabolites (including glucuronides, unchanged drug <5%); Biliary/Fecal: 20-30%.
Half-life	Terminal elimination half-life: 15-40 hours (mean ~24 h); clinical context: steady-state achieved in 5-7 days; prolonged in elderly and CYP2D6 poor metabolizers.
Protein binding	85-95% bound primarily to alpha-1-acid glycoprotein and albumin.
Volume of Distribution	10-30 L/kg (mean 15 L/kg); clinical meaning: extensive tissue distribution, particularly in lungs, heart, and brain.
Bioavailability	Oral: 30-60% due to extensive first-pass metabolism.
Onset of Action	Oral: 2-4 weeks for antidepressant effect; IV/IM (not typical): within 24 hours for sedation; analgesic effect may begin within 1 week.
Duration of Action	Oral: 24-48 hours; clinical note: continued pharmacologic effects (e.g., anticholinergic) persist for several days after cessation due to long half-life of active metabolite nortriptyline.

Classification & Brands

Action Class	Selective Seretonin Reuptake inhibitors (SSRIs)
Brand Substitutes	Pronil 20mg Capsule, Fluox 20mg Capsule, Persona 20mg Capsule, Flunat 20mg Capsule, Flonol 20mg Capsule

Dosing & administration

Initial 75 mg/day orally in divided doses, increased gradually to 150-200 mg/day; maintenance 50-150 mg/day as single dose at bedtime or in divided doses.

Dosage form	TABLET
Renal impairment	GFR 30-50 mL/min: reduce dose by 25-50%; GFR <30 mL/min: use with caution, consider alternative; not dialyzable.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated.
Pediatric use	Weight <25 kg: 1-2 mg/kg/day in 3 divided doses; >25 kg: start 30 mg/day, increase to 60-100 mg/day in 3-4 divided doses. Not recommended for children <6 years.
Geriatric use	Start 10-25 mg/day at bedtime; increase by 10-25 mg every 3-7 days; max 100 mg/day in divided doses; monitor for QT prolongation and anticholinergic effects.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for ENDEP (ENDEP).

Breastfeeding	Excreted in breast milk in low quantities; M/P ratio 0.5-1.5. American Academy of Pediatrics classifies as compatible, but monitor infant for sedation and poor feeding. Use lowest effective dose.
Teratogenic Risk	First trimester: Limited human data; animal studies show embryotoxicity and delayed ossification at high doses. Second/third trimester: Risk of neonatal withdrawal syndrome (irritability, hypertonia, respiratory depression) and anticholinergic effects if used near term. Consider risks vs benefits.

Warnings & precautions

■ FDA Black Box Warning

Side Effect Profile

Serious Effects

Absolute Contraindications

Concomitant use with MAOIs, recent myocardial infarction, hypersensitivity to tricyclic antidepressants.

Clinical Precautions

Precautions	Activation of mania/hypomania, QT interval prolongation, serotonin syndrome, angle-closure glaucoma, urinary retention, seizures.
Food/Dietary	Avoid high-tyramine foods (aged cheeses, cured meats, fermented products) as concurrent use with MAOIs can precipitate hypertensive crisis, but this interaction is less relevant when MAOIs have been discontinued. Consume grapefruit and grapefruit juice with caution due to potential CYP3A4 inhibition affecting amitriptyline metabolism.

Clinical Tips & Counseling

Drug interactions

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Clinical Pearls	ENDEP (amitriptyline) is a tricyclic antidepressant with strong anticholinergic effects; avoid in narrow-angle glaucoma and urinary retention. Monitor ECG for QTc prolongation, especially in elderly or with concurrent QTc-prolonging drugs. Start low (25 mg HS) and go slow; therapeutic response may take 2–4 weeks. Abrupt discontinuation can cause withdrawal symptoms.
Patient Advice	Take ENDEP at bedtime to reduce daytime sedation. · Do not stop abruptly; taper under doctor's guidance. · Avoid alcohol and other CNS depressants. · Report suicidal thoughts, worsened depression, or unusual behavior. · May cause dry mouth, constipation, blurred vision; use sugar-free gum and increase fiber intake. · Avoid driving or operating machinery until you know how ENDEP affects you.