ZONALON

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ZONALON (ZONALON).

How it works

Doxepin is a tricyclic antidepressant (TCA) that inhibits the reuptake of serotonin and norepinephrine, and acts as a potent histamine H1 receptor antagonist.

What the body does with it

Metabolism	Metabolized primarily by CYP2D6 and CYP2C19; major metabolite is N-desmethyldoxepin.
Excretion	Primarily renal (approximately 70-80% as unchanged drug and metabolites), with about 20-30% eliminated via feces. Less than 2% excreted unchanged in urine.
Half-life	Terminal elimination half-life is approximately 20-30 hours in healthy adults, which supports once-daily dosing but requires dose adjustment in hepatic impairment.
Protein binding	Approximately 85-90% bound primarily to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Volume of distribution is approximately 5-7 L/kg, indicating extensive tissue distribution and accumulation in peripheral compartments.
Bioavailability	Oral: Absolute bioavailability is approximately 30-40% due to extensive first-pass metabolism. Topical: Systemic absorption is minimal (<5%) with normal skin application.
Onset of Action	Oral: Onset of antipruritic effect is typically within 1-3 hours after a single dose. Topical: Onset of local anesthetic effect is within 15-30 minutes.
Duration of Action	Oral: Duration of antipruritic effect is approximately 24 hours with once-daily dosing. Topical: Duration of local anesthetic effect is 4-6 hours.

Classification & Brands

Dosing & administration

Apply a thin layer to the affected area 3-4 times daily; maximum daily dose is 200 mg (5% cream, 5 g).

Dosage form	CREAM
Renal impairment	No dose adjustment required for GFR ≥30 mL/min; data insufficient for GFR <30 mL/min.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B or C: reduce dosing frequency to 2-3 times daily.
Pediatric use	Not recommended for children under 12 years; for ages 12-18, use same as adult dosing.
Geriatric use	No specific dose adjustment; use caution due to possible increased sedation 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 ZONALON (ZONALON).

Breastfeeding	Doxepin (active metabolite) is excreted into breast milk; M/P ratio not determined. Case reports of infant sedation and respiratory depression. American Academy of Pediatrics recommends caution; avoid breastfeeding if maternal dose ≥ 10 mg/day or if infant is premature or has respiratory issues. Consider alternative agents.
Teratogenic Risk	First trimester: No adequate studies; animal data not available. Potential risk based on class (antihistamine) cannot be ruled out. Second and third trimesters: Limited data; no known association with major malformations. However, use only if clearly needed due to potential for uterine irritability or neonatal effects (e.g., irritability, respiratory depression) with high doses near term.

Warnings & precautions

■ FDA Black Box Warning

None.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to doxepin or other TCAs; concomitant use with MAOIs; narrow-angle glaucoma; severe urinary retention; use in children under 12 years.

Clinical Precautions

Precautions

Anticholinergic effects (urinary retention, constipation, blurred vision), drowsiness/sedation, risk of suicidal thinking and behavior in children, adolescents, and young adults with depression, cardiovascular effects (QT prolongation, arrhythmias), photosensitivity, and withdrawal symptoms if abruptly discontinued.

Clinical Tips & Counseling

Drug interactions

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ZONALON

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ZONALON (ZONALON).

How it works

Doxepin is a tricyclic antidepressant (TCA) that inhibits the reuptake of serotonin and norepinephrine, and acts as a potent histamine H1 receptor antagonist.

What the body does with it

Metabolism	Metabolized primarily by CYP2D6 and CYP2C19; major metabolite is N-desmethyldoxepin.
Excretion	Primarily renal (approximately 70-80% as unchanged drug and metabolites), with about 20-30% eliminated via feces. Less than 2% excreted unchanged in urine.
Half-life	Terminal elimination half-life is approximately 20-30 hours in healthy adults, which supports once-daily dosing but requires dose adjustment in hepatic impairment.
Protein binding	Approximately 85-90% bound primarily to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Volume of distribution is approximately 5-7 L/kg, indicating extensive tissue distribution and accumulation in peripheral compartments.
Bioavailability	Oral: Absolute bioavailability is approximately 30-40% due to extensive first-pass metabolism. Topical: Systemic absorption is minimal (<5%) with normal skin application.
Onset of Action	Oral: Onset of antipruritic effect is typically within 1-3 hours after a single dose. Topical: Onset of local anesthetic effect is within 15-30 minutes.
Duration of Action	Oral: Duration of antipruritic effect is approximately 24 hours with once-daily dosing. Topical: Duration of local anesthetic effect is 4-6 hours.

Classification & Brands

Dosing & administration

Apply a thin layer to the affected area 3-4 times daily; maximum daily dose is 200 mg (5% cream, 5 g).

Dosage form	CREAM
Renal impairment	No dose adjustment required for GFR ≥30 mL/min; data insufficient for GFR <30 mL/min.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B or C: reduce dosing frequency to 2-3 times daily.
Pediatric use	Not recommended for children under 12 years; for ages 12-18, use same as adult dosing.
Geriatric use	No specific dose adjustment; use caution due to possible increased sedation 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 ZONALON (ZONALON).

Breastfeeding	Doxepin (active metabolite) is excreted into breast milk; M/P ratio not determined. Case reports of infant sedation and respiratory depression. American Academy of Pediatrics recommends caution; avoid breastfeeding if maternal dose ≥ 10 mg/day or if infant is premature or has respiratory issues. Consider alternative agents.
Teratogenic Risk	First trimester: No adequate studies; animal data not available. Potential risk based on class (antihistamine) cannot be ruled out. Second and third trimesters: Limited data; no known association with major malformations. However, use only if clearly needed due to potential for uterine irritability or neonatal effects (e.g., irritability, respiratory depression) with high doses near term.

Warnings & precautions

■ FDA Black Box Warning

None.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to doxepin or other TCAs; concomitant use with MAOIs; narrow-angle glaucoma; severe urinary retention; use in children under 12 years.