Zonalon

ZONALON- doxepin hydrochloride cream
Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC

FOR TOPICAL DERMATOLOGIC USE ONLY —
NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE.

Rx Only

DESCRIPTION

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-Δ11(6H),γ -propylamine hydrochloride. Doxepin hydrochloride has an empirical formula of C19 H21 NO•HCl and a molecular weight of 316.

Structural Formula

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

CLINICAL PHARMACOLOGY

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.)

INDICATIONS AND USAGE

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.)

CONTRAINDICATIONS

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.

WARNINGS

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.

PRECAUTIONS

General

Drowsiness

Since drowsiness may occur with the use of Zonalon® Cream, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while using this drug. Patients should also be cautioned that their response to alcohol may be potentiated.

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 PRECAUTIONS — Geriatric Use.)

Use under occlusion

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

Contact sensitization

Use of Zonalon® Cream can cause Type IV hypersensitivity reactions (contact sensitization) to doxepin.

Drug Interactions

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:

Drugs Metabolized by P450 2D6

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7-10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dosage regimen of a TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.

MAO Inhibitors

Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with Zonalon® Cream. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved.

Cimetidine

Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine.

Alcohol

Alcohol ingestion may exacerbate the potential sedative effects of Zonalon® Cream. This is especially important in patients who may use alcohol excessively.

Tolazamide

A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of oral doxepin (75 mg/day).

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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