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Doxepin (Topical)


VA CLASSIFICATION
Primary: DE900

Commonly used brand name(s): Zonalon.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antipruritic (topical){01}

Indications

Accepted

Pruritus associated with eczema (treatment)—Doxepin is indicated for the short-term (up to 8 days) topical treatment of moderate pruritus in adult patients with eczematous dermatitis, e.g., atopic dermatitis and lichen simplex chronicus. {01} {04} {05}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    A dibenzoxepin tricyclic antidepressant {01} {05}.
Molecular weight—
    316 {01}

Mechanism of action/Effect:

The exact mechanism by which topical doxepin exerts its antipruritic effect is unknown. However, doxepin has potent antihistaminic (H 1- and H 2-receptor) activity. As a histamine-blocking agent, doxepin appears to bind to histamine receptor sites and competitively inhibits the biological activation of histamine receptors. {01} {05} Because topical doxepin produces drowsiness in significant numbers of patients, it is believed that this sedative property may also have an effect on certain pruritic symptoms. {01}


Other actions/effects:

Topical doxepin may be absorbed into the systemic circulation {01} and, therefore, may have the potential for causing peripheral and central anticholinergic effects {08} {09} due to its potent and high binding affinity for muscarinic receptors. {08} It may also have the potential to produce prominent cardiovascular effects as a result of its anticholinergic activity on the heart and a `quinidine-like' myocardial depressant action, as well as inhibition of norepinephrine uptake at adrenergic synapses. {02} {03} {08} {09}

Absorption:

Doxepin applied topically is absorbed through the skin. {01} As with most topical agents, occlusive dressings may increase the absorption of topical doxepin. {01} {06}

Distribution:

Once absorbed, doxepin may be distributed in body tissues including lungs, heart, brain, and liver. {01}

Biotransformation:

Once absorbed into the systemic circulation, doxepin undergoes hepatic metabolism that results in the conversion to the pharmacologically active metabolite, desmethyldoxepin. The parent compound and its metabolite also undergo glucuronidation. {01}

Half-life:

Desmethyldoxepin—Ranges from 28 to 52 hours. {01}

Peak plasma concentration

For both doxepin and its active metabolite, desmethyldoxepin, plasma concentrations are highly variable and are poorly correlated with dosage. In 19 patients with pruritic eczema treated with topical doxepin, plasma doxepin concentrations ranged from nondetectable to 47 nanograms per mL {01} {05} (168.2 nanomoles per L) with a mean of 10.8 nanograms per mL, {05} (38.6 nanomoles per L) after percutaneous absorption. (For oral doxepin, the target therapeutic plasma concentrations for the treatment of depression range from 30 to 150 nanograms per mL [107.3 to 536.8 nanomoles per L]). {01}

Elimination:
    Renal for both the parent compound and its metabolites. {01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other dibenzoxepines (tricyclic antidepressants) may also be sensitive to doxepin. {02}

Carcinogenicity

Studies on carcinogenicity have not been conducted with topical doxepin. {01}

Mutagenicity

Studies on mutagenicity have not been conducted with topical doxepin. {01}

Pregnancy/Reproduction
Fertility—
Studies have not been conducted with topical doxepin in humans. {01}

Studies in rats and rabbits given oral doses of doxepin up to 8 times the topical human dose (on a milligram per kilogram of body weight [mg/kg] basis) have shown no evidence of impaired fertility. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. {01}

Studies in rats and rabbits given oral doses of doxepin up to 8 times the topical human dose (on a milligram per kilogram of body weight [mg/kg] basis) have shown no evidence of harm to the fetus. {01}

FDA Pregnancy Category B. {01}

Breast-feeding

No studies have been done to determine if doxepin is distributed into human milk following topical administration. However, doxepin is distributed into human milk after oral administration. Because significant systemic concentrations of doxepin are obtained when this agent is applied topically, it is possible that this medication could be distributed into human milk after topical administration. {01}

Apnea and drowsiness have been reported in 1 nursing infant whose mother was taking an oral dosage form of doxepin. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of topical doxepin have not been performed in the pediatric population. Safety and efficacy have not been established. {01}


Geriatrics


Appropriate studies on the relationship of age to the effects of topical doxepin have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. ( {11}See also Antidepressants, Tricyclic [Systemic] monograph for oral doxepin drug interactions). {13}

» Alcohol or
» CNS depression-producing medications, other (See Appendix II )    (concurrent use with tricyclic antidepressants may result in serious potentiation of CNS depression, respiratory depression, and hypotensive effects; caution is recommended, and dosage of one or both agents should be reduced {01} {03} {06})


» Cimetidine    (cimetidine may inhibit the metabolism and increase the plasma concentration of doxepin, leading to toxicity; {01} {03} {06} serious anticholinergic effects have been associated with concurrent use of cimetidine and tricyclic antidepressants {01} {02} {06})


» Medications metabolized by cytochrome P 450 isoenzyme P 450IID 6 such as
Antiarrhythmic agents, Type 1C, including encainide, flecainide, and propafenone
Antidepressants, other
Carbamazepine
Debrisoquine
Dextromethorphan
Phenothiazines
Quinidine    (although no studies have been done on the use of topical doxepin with these medications, caution is recommended because experience with oral tricyclic antidepressants has shown that concurrent use with other medications that are metabolized via the cytochrome P 450 isoenzyme P 45011D 6 may result in mutual inhibition of metabolism and in toxicity of either or both medications, especially in patients known to have genetically determined defects in oxidative metabolism involving this enzyme, if dosage of either or both medications is not reduced; the risk may be particularly high with quinidine and with other tricyclic antidepressants because of additive toxicities {01} {03} {07})


» Monoamine oxidase (MAO) inhibitors    (concurrent use with orally administered tricyclic antidepressants has resulted in serious side effects {01} {02} {03} {06} [convulsions, excitation, hyperpyrexia, and mania] {03} and even death {01} {02} {06} [although there have been patients who have received combinations of these medications without ill effects]; {03}MAO inhibitors should be discontinued at least 2 weeks prior to the initiation of treatment with topical doxepin {01} {06})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Glaucoma, narrow-angle, untreated or
» Urinary retention    (doxepin may aggravate these conditions {01} {06})


Sensitivity to doxepin or other ingredients of the preparation, or history of{01}{06}


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
—approximately 1 to 10%    
Edema at site of application (swelling at site of application)
    
exacerbation of pruritus (worsening of itching)
    
exacerbation of eczema (worsening of eczema)
    
paresthesias (burning, crawling, or tingling sensation of the skin){01}

Incidence rare
—less than 1%    
Fever{01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—1 to 10%, or as specified    
Burning and/or stinging at the site of application{01}{04}{06} —approximately 21%{01}{04}{05}
    
changes in taste
    
dizziness
    
drowsiness{01}{04} —22%
    
dryness and tightness of skin
    
dryness of mouth and/or lips
    
emotional changes
    
fatigue (unusual tiredness or weakness)
    
headache
    
thirst{01}

Note: Drowsiness is the most common adverse effect reported with the use of topical doxepin, especially in those patients receiving treatment over more than 10% of their body surface area. {01} {05} {06} However, this effect was observed to be mild and temporary, usually lasting 1 or 2 days, as reported by the vast majority of patients who experienced drowsiness during the clinical trials. {01} {04} {05} Burning and/or stinging at the site of application is the second most common adverse effect reported. {01} {04} {05} In clinical trials, most patients characterized this reaction as mild and about 25% reported it as severe. {01} {05}


Incidence less frequent or rare
—less than 1%{01}    
Anxiety
    
irritation, tingling, scaling, or cracking of skin
    
nausea{01}





Overdose
For specific information on the agent used in the management of doxepin overdose, see:
   • Physostigmine (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Note: Signs and symptoms of overdose are generally related to the anticholinergic effects of this medication. {01} {09}

Mild effects
    
Blurred vision
    
drowsiness
    
dryness of mouth, excessive
    
stupor (decreased awareness or responsiveness){01}

Severe effects
    
Cardiac arrhythmias (irregular heartbeat)
    
coma (unconsciousness)
    
dilated pupils (enlarged pupils)
    
hyperactive reflexes (increased or excessive unconscious or jerking movements)
    
hypertension (increased blood pressure)
    
hyperthermia (extremely high fever or body temperature)
    
hypotension (dizziness, fainting, or lightheadedness)
    
hypothermia (extremely low body temperature; weak or feeble pulse)
    
paralytic ileus (abdominal pain and swelling; intractable constipation; vomiting)—may lead to intestinal obstruction
    
respiratory depression (difficulty in breathing)
    
seizures (convulsions)
    
tachycardia (fast heartbeat)
    
urinary retention due to bladder atony (difficulty in passing urine){01}


Treatment of overdose
For mild effects, observation and supportive therapy are recommended. It may be necessary to reduce the percent of body surface area treated or the frequency of application. A thinner layer of cream should be applied. {01}

For severe effects, medical management should consist of aggressive supportive therapy.

To decrease absorption—The area of skin covered with topical doxepin should be thoroughly washed {01} with soap and water. {12}

To enhance elimination—Enhancing elimination of absorbed doxepin through dialysis and forced diuresis have not been successful due to the high tissue and protein binding, {01} {08} large volume of distribution, and limited water solubility of this agent. {08}

Specific treatment—Cardiac arryhthmias should be treated with the appropriate antiarrhythmic agents. It has been reported that many of the anticholinergic effects (cardiovascular and central nervous system [CNS] symptoms) of tricyclic antidepressant overdose in adults may be reversed by the slow intravenous administration of physostigmine. The dose should be repeated as required because physostigmine is rapidly metabolized. {01} However, physostigmine should be used with caution because this agent may also increase the risk of cardiac toxicity if used indiscriminately. ( {08} {09}See the package insert or Physostigmine [Systemic] monograph for specific dosing guidelines for use of this product.) Convulsions may be treated with anticonvulsant agents, such as diazepam or lorazepam; {01} {09} however, barbiturates are not recommended because they may potentiate respiratory depression. {01} If there is any suspicion that the patient may have taken a benzodiazepine in addition to doxepin, flumazenil should not be used to reverse the effects of the benzodiazepine. Administration of flumazenil in such cases has been shown to increase the risk of seizures and/or cardiac arrhythmias. {09} {10}

Monitoring—Vital signs, especially cardiovascular and respiratory functions, should be constantly monitored. {08} Because relapse after apparent recovery has been reported with oral doxepin, electrocardiogram (ECG) monitoring may be required for several days. {01}

Supportive care—For comatose patients, an adequate airway should be established and assisted ventilation should be used if necessary. {01} {08} {09} Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation. {11}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Doxepin (Topical).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to doxepin or other ingredients of the preparation {01}





Breast-feeding—May be distributed into breast milk {01}
Other medications, especially alcohol and other CNS depression-producing medications, cimetidine, medications metabolized by cytochrome P 450 isoenzyme P 45011D 6, and monoamine oxidase (MAO) inhibitors {01}
Other medical problems, especially untreated narrow-angle glaucoma and urinary retention {01}

Proper use of this medication
» For external use only; not for ophthalmic, oral, or intravaginal use {01}

» Using this medication exactly as directed; not using more of it, not using it more often, and not using it for more than 8 days; not applying medication to an area of skin larger than recommended by physician {01}

Applying a thin film of doxepin cream to only affected area(s) of skin and rubbing in gently {01}

Compliance with full course of therapy

» Not using occlusive dressings, which may increase absorption of medication {01} {06}

» Proper dosing{01}
Missed dose

» Proper storage{01}

Precautions while using this medication
Checking with physician if skin problem does not improve after 8 days or if it becomes worse

» Avoiding alcoholic beverages or other alcohol-containing preparations while using topical doxepin; not taking other medications unless prescribed by physician {01} {06}

» Caution if drowsiness occurs; not driving, using machines, or doing anything else that requires alertness while using topical doxepin; if excessive drowsiness occurs, reducing the number of applications per day, the amount of cream applied, and/or the percentage of body surface area treated, or discontinuing medication after checking with physician {01}

» Possible dryness of mouth; {01} using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks


Side/adverse effects
Signs of potential side effects, especially edema at site of application, exacerbation of pruritus, exacerbation of eczema, paresthesias, and fever {01}


General Dosing Information
Topical doxepin is for external use only. It is not for ophthalmic, oral, or intravaginal use. {01}

A thin film of doxepin cream should be applied to the affected area(s) of skin. {01}

Drowsiness may occur, especially in patients receiving treatment over more than 10% of their body surface area. Patients should be warned of this possibility and cautioned against driving a motor vehicle or operating hazardous machinery while being treated with topical doxepin. If excessive drowsiness occurs, it may be necessary to reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the medication. {01} {06}

Topical doxepin should not be used for more than 8 days. Chronic use beyond 8 days may result in higher systemic concentrations of the medication because of increased absorption. {01}


Topical Dosage Forms

DOXEPIN HYDROCHLORIDE CREAM

Usual adult dose
Antipruritic (topical)
Topical, a thin film applied to the affected area(s) of skin four times a day, with an interval of at least three to four hours between applications. Treatment may be continued for up to eight days. {01}


Usual pediatric dose
Safety and efficacy have not been established. {01}

Strength(s) usually available
U.S.—


5% (Rx) [Zonalon (benzyl alcohol) (cetyl alcohol) (glyceryl stearate) (isopropyl myristate) (petrolatum) (PEG-100 stearate) (purified water) (sorbitol) (titanium dioxide){01}]

Canada—


5% (Rx) [Zonalon{06}]

Packaging and storage:
Store at or below 27 °C (80 °F). {01}

Auxiliary labeling:
   • For external use only. {01}
   • May cause drowsiness. {01}
   • Avoid alcoholic beverages. {01}



Developed: 05/26/1995



References
  1. Zonalon package insert (GenDerm—US), Rev 1/94, Rec 8/94.
  1. Sinequan (Roerig). In: PDR Physicians' desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data, 1995: 2098-9.
  1. Katzung BG, editor. Basic and clinical pharmacology. 5th ed. Norwalk: Appleton and Lange, 1992: 56, 700-3, 932.
  1. Drake LA, Fallon JD, Sober A, et al. Relief of pruritus in patients with atopic dermatitis after treatment with topical doxepin cream. J Am Acad Dermatol 1994; 31(4): 613-6.
  1. Zonalon Cream (doxepin hydrochloride), 5%. A clinical review. Genderm Corporation, 1994: 6.
  1. Zonalon package insert (GenDerm—Canada), Rec 4/95.
  1. DeVane CL. Pharmacokinetics of the newer antidepressants: clinical relevance. Am J Med 1994; 97(suppl 6A): 13S-23S.
  1. Goldfrank LR, Flomenbaum NE, Lewis NA, et al. Goldfrank's toxicologic emergencies. 5th ed. Norwalk, CT: Appleton & Lange, 1994: 327-44.
  1. Gossel TA, Bricker JD. Principles of clinical toxicology. 3rd ed. New York: Raven Press, 1994: 725-34.
  1. Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther 1992; 292-305.
  1. Reviewers' consensus on monograph revision of 4/95.
  1. Panel comment, 4/95.
  1. Panel comment, 4/95.
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