Zonalon

Oral:

• Doxepin is a prescription medication used to treat adults who are having difficulty staying asleep.

Topical:

• Doxepin cream is a prescription medication used to treat itching of the skin.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Oral:

• Common side effects of doxepin include sleepiness, nausea and upset stomach.

Topical:

• Common side effects of doxepin cream include burning or stinging at site of application, dry mouth, and drowsiness.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of doxepin. For more information ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects.

Oral:

• Tablets (Silenor) for Insomnia
  • Take within 30 minutes of bedtime.
  • Should not be taken within 3 hours of a meal.
• Capsules and Oral Solution
  • In more severely ill patients higher doses may be required with a gradual increase to 300 mg/day if necessary.
  • If taking once a day, take the dose at bedtime.
  • Anti-anxiety effect will be seen before the antidepressant effect. The antidepressant effect may take 2 to 3 weeks to occur.

Topical:

• A thin film of doxepin 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 doxepin cream when used for greater than 8 days. Use beyond eight days should be avoided. Use of doxepin cream for longer than 8 days may result in an increased likelihood of a hypersensitivity reaction.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Serious overdose symptoms can occur if too much of this medicine is absorbed through your skin. Overdose symptoms may include extreme dizziness or drowsiness, feeling hot or cold, vomiting, confusion, agitation, trouble concentrating, irregular heartbeats, hallucinations, fainting, dilated pupils, muscle stiffness, or seizure (convulsions).

Rinse with water if this medicine gets in your eyes.

Absorbing large amounts of this medicine through your skin may cause side effects that can impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol with this medicine can cause side effects.

Using doxepin topical with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking a sleeping pill, narcotic medication, muscle relaxer, or medicine for anxiety, depression, or seizures.

Before using doxepin topical, tell your doctor if you have used an MAO inhibitor in the past 14 days, such as isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• cimetidine;

• heart rhythm medication; or

• any antidepressant medication you take by mouth.

This list is not complete. Other drugs may interact with doxepin topical, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Feeling very sleepy.
• Feeling confused.
• Very bad skin irritation.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling sleepy.
• Dry mouth.
• More thirst.
• Burning.
• Stinging.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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

Rx Only

General

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.)

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

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:

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.

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.

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

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.

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 Zonalon® 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.

Nursing Mothers

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.

Pediatric Use

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.

Geriatric Use

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.