PRUDOXIN Dailymed

PRUDOXIN^® doxepin hydrochloride cream Prestium Pharma, Inc.

Rx only

PRUDOXIN^®  (doxepin hydrochloride) Cream, 5%

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

Description

PRUDOXIN^® (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, USP 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 a molecular formula of C₁₉H₂₁NO•HCl and a molecular weight of 316.

PRUDOXIN^® 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. PRUDOXIN^® Cream can produce drowsiness which may reduce awareness, including awareness of pruritic symptoms. In 19 pruritic eczema patients treated with PRUDOXIN^® Cream, plasma doxepin concentrations ranged from nondetectable to 47 ng/mL from percutaneous absorption. Plasma levels from topical application of PRUDOXIN^® 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.)

Indicationsandusage

PRUDOXIN^® 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 PRUDOXIN^® Cream application, the use of PRUDOXIN^® Cream is contraindicated in patients with untreated narrow angle glaucoma or a tendency to urinary retention.

PRUDOXIN^® 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 PRUDOXIN^® 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 PRUDOXIN^® Cream.

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

Contact sensitization: Use of PRUDOXIN^® Cream can cause Type IV hypersensitivity reactions (contact sensitization) to doxepin.

Drug Interactions

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

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

Pregnancy

Reproduction studies have been performed in which doxepin was orally administered to rats and rabbits at doses up to 0.6 and 1.2 times, respectively, the estimated exposure to doxepin that results from use of 16 grams of PRUDOXIN^® Cream per day (four applications of four grams of cream per day; dose multiples reflect comparisons made following normalization of the data on the basis of body surface area estimates) and have revealed no evidence of harm to rat or rabbit fetuses due to doxepin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

NursingMothers

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 PRUDOXIN^® 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.

PediatricUse

The use of PRUDOXIN^® Cream in pediatric patients is not recommended. Safe conditions for use of PRUDOXIN^® 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 PRUDOXIN^® 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.

GeriatricUse

Clinical studies of PRUDOXIN^® 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 PRUDOXIN^® Cream. (See WARNINGS.) An 80-year old male nursing home patient developed probable systemic anticholinergic toxicity which included urinary retention and delirium after PRUDOXIN^® Cream had been applied to his arms, legs and back three times daily for two days.

Adversereactions

Controlled Clinical Trials

Systemic Adverse Effects: In controlled clinical trials of patients treated with PRUDOXIN^® Cream, the most common systemic adverse event reported was drowsiness. Drowsiness occurred in 71 of 330 (22%) of patients treated with PRUDOXIN^® Cream compared to 7 of 334 (2%) of patients treated with vehicle cream. Drowsiness resulted in the premature discontinuation of the drug in approximately 5% of patients treated with PRUDOXIN^® Cream in controlled clinical trials.

Local Site Adverse Effects: In controlled clinical trials of patients treated with PRUDOXIN^® Cream, the most common local site adverse event reported was burning and/or stinging at the site of application.

These occurred in 76 of 330 (23%) of patients treated with PRUDOXIN^® Cream compared to 54 of 334 (16%) of patients treated with vehicle cream. Most of these reactions were categorized as "mild"; however, approximately 25% of patients who reported burning and/or stinging reported the reaction as "severe". Four patients treated with PRUDOXIN^® Cream withdrew from the study because of the burning and/or stinging.

The table below presents the adverse events reported at an incidence of ≥ 1 % in either PRUDOXIN^® or vehicle cream treatment groups during the trials:

Adverse Event	PRUDOXIN® N=330	VehicleN=334
Burning /Stinging	76 (23.0%)	54 (16.2%)
Drowsiness	71 (21.5%)	7 (2.1%)
Dry Mouth1	32 (9.7%)	4 (1.2%)
Pruritus2	13 (3.9%)	20 (6.0%)
Fatigue/Tiredness	10 (3.0%)	5 (1.5%)
Exacerbated Eczema	10 (3.0%)	8 (2.4%)
Other Application Site Reaction3	10 (3.0%)	16 (4.8%)
Dizziness4	7 (2.1%)	3 (0.9%)
Mental/Emotional Changes	6 (1.8%)	1 (0.3%)
Taste Perversion5	5 (1.5%)	1 (0.3%)
Edema	4 (1.2%)	1 (0.3%)
Headache	3 (0.9%)	14 (4.2%)
1Includes reports of “dry lips”, “dry throat”, and “thirst”
2Includes reports of “pruritus exacerbated”
3Includes report of “increased irritation at application site”
4Includes reports of “lightheadedness” and “dizziness/vertigo”
5Includes reports of “bitter taste” and “metallic taste in mouth”

Adverse events occurring in 0.5% to < 1.0% of PRUDOXIN^® Cream treated patients in the controlled clinical trials included: nervousness/anxiety, tongue numbness, fever, and nausea.