ZONALON
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZONALON (ZONALON).
Doxepin is a tricyclic antidepressant (TCA) that inhibits the reuptake of serotonin and norepinephrine, and acts as a potent histamine H1 receptor antagonist.
| 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. |
| Molecular Weight | 279.38 |
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. |
| 1st trimester | Avoid; doxepin is teratogenic in animal studies and there is a risk of fetal cardiac malformations. |
| 2nd trimester | Caution; risk of neonatal withdrawal syndrome, especially if used near term. Weigh benefits vs risks. |
| 3rd trimester | Avoid; risk of neonatal withdrawal syndrome, respiratory depression, and poor fetal adaptation. |
Clinical note
Comprehensive clinical and safety monograph for ZONALON (ZONALON).
| Placental transfer | Doxepin and its active metabolite cross the placenta; drug levels in fetal circulation are similar to maternal levels. |
| Breastfeeding | Doxepin is excreted into breastmilk at low levels, but its active metabolite may accumulate. Cases of drowsiness in infants have been reported; avoid use in breastfeeding or monitor closely. |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to doxepin or any tricyclic antidepressantConcurrent use with MAOIs or within 14 days of MAOI therapyUntreated narrow-angle glaucomaUrinary retention (benign prostatic hyperplasia, prostatic hypertrophy)
| 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. |
| Food/Dietary | No specific food interactions are known with topical doxepin. However, alcohol may increase the risk of sedation and should be avoided during treatment. |
Loading safety data…
| Lactation Rating |
| L2 - Limited data (possibly compatible, but use with caution) |
| 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. |
| Fetal Monitoring | Maternal: Monitor for sedation, anticholinergic effects (dry mouth, blurred vision), and cardiac arrhythmias (prolonged QTc, tachycardia). Fetal: Ultrasound for growth and amniotic fluid volume if used long-term; fetal heart rate monitoring if high doses near term due to risk of neonatal withdrawal or respiratory depression. |
| Fertility Effects | No specific data on ZONALON. Class effects of tricyclic antidepressants may cause hyperprolactinemia, galactorrhea, menstrual irregularities, and sexual dysfunction, potentially impairing fertility. Animal studies: no direct fertility impairment reported, but caution is advised. |
| Clinical Pearls | Zonalon (doxepin cream 5%) is a topical tricyclic antidepressant used for pruritus in adults. Avoid application to large body surface areas (>10%) or for prolonged periods due to risk of systemic absorption, especially in elderly or those with hepatic impairment. Do not use with occlusive dressings. Monitor for anticholinergic effects (dry mouth, urinary retention) if used extensively. Discontinue if rash or irritation occurs. |
| Patient Advice | Apply a thin layer only to affected skin, not to broken or infected areas. · Do not cover with bandages or airtight dressings. · Wash hands after application unless treating hands. · Avoid contact with eyes, mouth, or mucous membranes. · Do not use more than 10% of body surface area or for longer than 8 days without consulting a doctor. · Do not take oral doxepin or other tricyclic antidepressants while using this cream unless directed by a physician. · May cause drowsiness; avoid driving or operating machinery if affected. · Report signs of allergic reaction or worsening itching. |