AHFS Class:

• Tricyclics and Other Norepinephrine-reuptake Inhibitors 28:16.04.28

Generic Name(s):

• Doxepin Hydrochloride

Doxepin hydrochloride is a dibenzoxepin-derivative tricyclic antidepressant.

Depressive and Anxiety Disorders

Doxepin shares the pharmacologic actions of the other tricyclic antidepressants and is used principally in the treatment of depression and/or anxiety in psychoneurotic patients, depression and/or anxiety associated with alcoholism or organic disease, and psychotic depressive disorders with associated anxiety, including involutional depression and manic-depressive disorders.102,110 Symptoms of psychoneurosis that respond well to doxepin include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension, and worry.102,110

For further information on treatment of major depression and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidality risks, see Considerations in Choosing Antidepressants under Uses: Major Depressive Disorder, in the Tricyclic Antidepressants General Statement 28:16.04.28.

Chronic Idiopathic Urticaria

Doxepin also has been effective in the management of chronic idiopathic urticaria† and may be used as an alternative to antihistamines, which generally are considered as first-line therapy in patients with this condition.111,112,113,114

Administration

Doxepin hydrochloride is administered orally.102,110,123 Although doxepin has been administered in up to 3 divided doses throughout the day, it is long-acting and the entire daily dose may be administered at one time.102,110,123 Administration of the entire daily dose at bedtime may reduce daytime sedation.

Each dose of the oral concentrate should be diluted with approximately 120 mL of water, whole or skimmed milk, or orange, grapefruit, tomato, prune, or pineapple juice just prior to administration; the solution is physically incompatible with many carbonated beverages.102,123 For patients requiring doxepin therapy while on methadone maintenance, doxepin solution and methadone syrup can be mixed together with Gatorade^®, lemonade, orange juice, sugar water, Tang^®, or water, but not with grape juice.102,123 Bulk dilution and storage are not recommended by the manufacturers.102,123

Doxepin is applied topically to the skin as an antipruritic. (See Doxepin Hydrochloride 84:08.)

Dosage

Dosage of doxepin hydrochloride is expressed in terms of doxepin.102,110,123 There is a wide range of dosage requirements, and dosage must be carefully individualized. Initial dosages should be low and generally range from 30-150 mg daily, depending on the severity of the condition being treated. Dosage may be gradually adjusted to the level which produces maximal therapeutic effect with minimal toxicity and may range up to 300 mg daily. The manufacturers state that dosages exceeding 300 mg daily rarely produce additional therapeutic benefits.102 Hospitalized patients under close supervision may generally be given higher dosages than outpatients. Patients with very mild symptomatology or organic brain syndrome should usually be given lower than average dosages and may obtain satisfactory improvement with 25-50 mg of doxepin daily. The manufacturers state that appropriate dosage in geriatric patients should be selected with caution, usually initiating therapy at the low end of the dosage range since decreased hepatic, renal, or cardiac function occurs more frequently in these patients.102

When doxepin is administered as a single daily dose, the maximum daily dose recommended by the manufacturers is 150 mg. Commercially available 150-mg capsules of doxepin are intended for maintenance therapy only and are not recommended for initial therapy. Maximum antidepressant effects may not occur for 2 or more weeks after therapy is begun, although anxiolytic effects may develop more rapidly.

After symptoms are controlled, dosage should be gradually reduced to the lowest level which will maintain relief of symptoms. To avoid the possibility of precipitating withdrawal symptoms, doxepin should not be terminated abruptly in patients who have received high dosages for prolonged periods.

Patients should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.106,107,108 (See Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Doxepin shares the pharmacologic actions and toxic potentials of the tricyclic antidepressants, and the usual precautions of tricyclic antidepressant administration should be observed. Patients should be fully advised about the risks, especially suicidal thinking and behavior (suicidality), associated with tricyclic antidepressant therapy.107,108 For a complete discussion, see Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.

Pediatric Precautions

Safety of doxepin in children younger than 12 years of age has not been established.102

The US Food and Drug Administration (FDA) has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.107 However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.107 Anyone considering the use of doxepin in a child or adolescent for any clinical use must therefore balance the potential risk of therapy with the clinical need.107,108,110 (See Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Lactation

Lactation

Limited data indicate that doxepin and its active N -demethylated metabolite are distributed into milk.100,101,102,110,115,116,117 Sedation and serious respiratory depression were reported in a nursing infant whose mother was receiving 75 mg of doxepin daily; substantial concentrations of the active metabolite of the drug were detected in the infant's serum and urine.100 In addition, poor sucking and swallowing while nursing, drowsiness, muscle hypotonia, and vomiting were reported in a nursing infant whose mother was receiving 35 mg of doxepin daily.116 Because of the potential for serious adverse reactions to doxepin and/or its active metabolite in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.115,116,117

Pharmacokinetics

Absorption

The pharmacokinetics of doxepin have not been extensively studied, but the drug is well absorbed from the GI tract in animals. Peak plasma concentrations usually occur within 2 hours after oral administration of the drug.118,120,122

Distribution

Doxepin is highly bound to plasma proteins.120

Limited data indicate that doxepin and its active N -demethylated metabolite are distributed into milk in concentrations reportedly ranging from about 30-140% and 10-115%, respectively, of those in maternal serum and that substantial concentrations of the active metabolite have been detected in the serum and urine of nursing infants whose mothers were receiving 75-150 mg of doxepin daily.100,101,102,110,115,116,117

Elimination

The plasma half-life of doxepin is 6-24.5 hours.118,119,120,121 The drug appears to be metabolized via the same pathways as are other tricyclic antidepressants; its N -demethylated metabolite is pharmacologically active.

Chemistry and Stability

Chemistry

Doxepin hydrochloride is a dibenzoxepin-derivative tricyclic antidepressant. The drug occurs as a white powder, is freely soluble in water and in alcohol, and has a pK_a of 8. Doxepin hydrochloride oral concentrate has a pH of 4-7.

Stability

Doxepin hydrochloride capsules should be stored in tight, light-resistant containers at a temperature between 15-30°C110 and the oral concentrate should be stored at a temperature between 20-25°C.123 Commercially available doxepin hydrochloride capsules have an expiration date of 36 months and the oral concentrate has an expiration date of 24 months following the date of manufacture.

Doxepin hydrochloride oral concentrate is physically incompatible with many carbonated beverages, but is compatible with some other beverages.102,123 (See Dosage and Administration: Administration.) Bulk preparation and storage of dilutions of the commercially available oral concentrate are not recommended by the manufacturers.102,123

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of doxepin, see the Tricyclic Antidepressants General Statement 28:16.04.28.

Only references cited for selected revisions after 1984 are available electronically.

100. Matheson I, Pande H, Alertsen AR. Respiratory depression caused by N-desmethyldoxepin in breast milk. Lancet . 1985; 2:1124. [PubMed 2865592]

101. Kemp J, Ilett KF, Booth J et al. Excretion of doxepin and N -desmethyldoxepin in human milk. Br J Clin Pharmacol . 1985; 20:497-9. [PubMed 4074620][PubMedCentral]

102. Pfizer Roerig. Sinequan^® (doxepin hydrochloride) capsules and oral concentrate prescribing information. New York, NY; 2005 Jan.

103. Food and Drug Administration. Class suicidality labeling language for antidepressants. From the FDA website. [Web]

104. Food and Drug Administration. Public health advisory: suicidality in children and adolescents being treated with antidepressant medications. Rockville, MD; 2004 Oct 15. From the FDA website. [Web]

105. Food and Drug Administration. Medication guide: about using antidepressants in children or teenagers. Rockville, MD; 2005 Jan 16. From the FDA website. [Web]

106. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

107. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

108. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

109. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA . 2007; 297:1683-96. [PubMed 17440145]

110. Watson Laboratories, Inc. Doxepin hydrochloride capsules prescribing information. Corona, CA; 2005 May.

111. Greene SL, Reed CE, Schroeter AL. Double-blind crossover study comparing doxepin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Dermatol . 1985; 12:669-75. [PubMed 3886724]

112. Goldsobel AB, Rohr AS, Siegel SC et al. Efficacy of doxepin in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol . 1986; 78:867-73. [PubMed 3782654]

113. Ormerod AD. Urticaria: recognition, causes and treatment. Drugs . 1994; 48:717-30. [PubMed 7530629]

114. Pons G, Greene SL, Reed CE, Schroeter AL. Double-blind crossover study comparing doxepin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Dermatol . 1985; 12:669-75. [PubMed 3886724]

115. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:513-16.

116. Frey OR, Scheidt P, von Brenndorff AI. Adverse effects in a newborn infant breast-fed by a mother treated with doxepin. Ann Pharmacother . 1999; 33:690-3. [PubMed 10410181]

117. Pons G, Rey E, Matheson I et al. Excretion of psychoactive drugs into breast milk: pharmacokinetic principles and recommendations. Clin Pharmacokinet . 1994; 27:270-89. [PubMed 7834964]

118. Yan JH, Hubbard JW, McKay G et al. Absolute bioavailability and stereoselective pharmacokinetics of doxepin. Xenobiotica. 2002; 32:615-23. [PubMed 12162857]

119. Greene SL, Reed CE, Schroeter AL. Double-blind crossover study comparing doxepin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Dermatol . 1985; 12:669-75. [PubMed 3886724]

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121. Ziegler VE, Biggs JT, Wylie LT et al. Doxepin kinetics. Clin Pharmacokinet . 1978; 23:573-9.

122. Rudorfer MV, Potter WZ. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol . 1999; 19:373-409. [PubMed 10319193]

123. Teva Pharmaceuticals USA. Doxepin hydrochloride oral concentrate prescribing information. Sellersville, PA; 2005 Jul.