ZONALON^® (doxepin hydrochloride) CREAM, 5%

Zonalon^® (doxepin hydrochloride) Cream, 5% is a topical cream. Each gram contains: 50 mg of doxepin hydrochloride (equivalent to 44.3 mg of doxepin).

Doxepin hydrochloride is one of a class of agents known as dibenzoxepin tricyclic antidepressant compounds. It is an isomeric mixture of N,N-dimethyldibenz[b,e]oxepin-Δ^11(6H),γ-propylamine hydrochloride. Doxepin hydrochloride has an empirical formula of C₁₉H₂₁NO•HCl and a molecular weight of 316.

Zonalon^® Cream also contains sorbitol, cetyl alcohol, isopropyl myristate, glyceryl stearate, PEG-100 stearate, petrolatum, benzyl alcohol, titanium dioxide and purified water.

Although doxepin HCl does have H₁ and H₂ histamine receptor blocking actions, the exact mechanism by which doxepin exerts its antipruritic effect is unknown. Zonalon^® Cream can produce drowsiness which may reduce awareness, including awareness of pruritic symptoms. In 19 pruritic eczema patients treated with Zonalon^® Cream, plasma doxepin concentrations ranged from nondetectable to 47 ng/mL from percutaneous absorption. Plasma levels from topical application of Zonalon^® Cream can result in CNS and other systemic side effects.

Once absorbed into the systemic circulation, doxepin undergoes hepatic metabolism that results in conversion to pharmacologically-active desmethyldoxepin. Further glucuronidation results in urinary excretion of the parent drug and its metabolites. Desmethyldoxepin has a half-life that ranges from 28 to 52 hours and is not affected by multiple dosing. Plasma levels of both doxepin and desmethyldoxepin are highly variable and are poorly correlated with dosage. Wide distribution occurs in body tissues including lungs, heart, brain, and liver. Renal disease, genetic factors, age, and other medications affect the metabolism and subsequent elimination of doxepin. (See PRECAUTIONS - Drug Interactions.)

Zonalon^® Cream is indicated for the short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus. (See DOSAGE AND ADMINISTRATION.)

Because doxepin HCl has an anticholinergic effect and because significant plasma levels of doxepin are detectable after topical Zonalon^® Cream application, the use of Zonalon^® Cream is contraindicated in patients with untreated narrow angle glaucoma or a tendency to urinary retention.

Zonalon^® Cream is contraindicated in individuals who have shown previous sensitivity to any of its components.

Drowsiness occurs in over 20% of patients treated with Zonalon^® Cream, especially in patients receiving treatment to greater than 10% of their body surface area. Patients should be warned about the possibility of sedation and cautioned against driving a motor vehicle or operating hazardous machinery while being treated with Zonalon^® Cream.

The sedating effects of alcoholic beverages, antihistamines, and other CNS depressants may be potentiated when Zonalon^® Cream is used.

If excessive drowsiness occurs it may be necessary to reduce the frequency of applications, the amount of cream applied, and/or the percentage of body surface area treated, or discontinue the drug. However, the efficacy with reduced frequency of applications has not been established.

Keep this product away from the eyes.

Studies have not been performed examining drug interactions with Zonalon^® Cream. However, since plasma levels of doxepin following topical application of Zonalon^® Cream can reach levels obtained with oral doxepin HCl therapy, the following drug interactions are possible following topical Zonalon^® Cream application:

Carcinogenesis, mutagenesis, and impairment of fertility studies have not been conducted with doxepin hydrochloride.

Doxepin is excreted in human milk after oral administration. It is possible that doxepin may also be excreted in human milk following topical application of Zonalon^® Cream.

One case has been reported of apnea and drowsiness in a nursing infant whose mother was taking an oral dosage form of doxepin HCl.

Because of the potential for serious adverse reactions in nursing infants from doxepin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The use of Zonalon^® Cream in pediatric patients is not recommended. Safe conditions for use of Zonalon^® Cream in children have not been established. One case has been reported of a 2.5-year-old child who developed somnolence, grand mal seizure, respiratory depression, ECG abnormalities, and coma after treatment with Zonalon^® Cream. A total of 27 grams had been applied over three days for eczema. He was treated with supportive care, activated charcoal, and systemic alkalization and recovered.

Clinical studies of Zonalon^® Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

The extent of renal excretion of doxepin has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections.

Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on Zonalon^® Cream. (See WARNINGS.) An 80-year-old male nursing home patient developed probable systemic anticholinergic toxicity which included urinary retention and delirium after Zonalon^® Cream had been applied to his arms, legs and back three times daily for two days.

Twenty-six cases of allergic contact dermatitis have been reported in patients using Zonalon^® Cream, twenty of which were documented by positive patch test to doxepin 5% cream.

Deaths may occur from overdosage with this class of drugs. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible.

Should overdosage with topical application of Zonalon^® Cream occur, the signs and symptoms may include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.

Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms uled under ADVERSE REACTIONS.

A thin film of Zonalon^® Cream should be applied four times each day with at least a 3 to 4 hour interval between applications. There are no data to establish the safety and effectiveness of Zonalon^® Cream when used for greater than 8 days. Chronic use beyond eight days may result in higher systemic levels and should be avoided. Use of Zonalon^® Cream for longer than 8 days may result in an increased likelihood of contact sensitization.

The risk for sedation may increase with greater body surface area application of Zonalon^® Cream (See WARNINGS section). Clinical experience has shown that drowsiness is significantly more common in patients applying Zonalon^® Cream to over 10% of body surface area; therefore, patients with greater than 10% of body surface area (see WARNINGS section) affected should be particularly cautioned concerning possible drowsiness and other systemic adverse effects of doxepin. If excessive drowsiness occurs, it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug.

Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings should not be utilized with Zonalon^® Cream.

Zonalon^® Cream is available in 30 g (NDC 10337-804-03) and 45 g (NDC 10337-804-45) tubes. Store at or below 27°C (80°F).