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Doxepin (Monograph)

Brand name: SINEquan
Drug class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
- TCAs
VA class: CN601
Chemical name: 1-Propamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride
Molecular formula: C19H21NO HCL
CAS number: 1229-29-4

Medically reviewed by Drugs.com on Sep 25, 2023. Written by ASHP.

Warning

    Suicidality
  • Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need. Doxepin is not approved for use in pediatric patients <12 years of age. (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.

  • Appropriately monitor and closely observe all patients who are started on doxepin therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process. (See Worsening of Depression and Suicidality Risk and Pediatric Use under Cautions.)

Introduction

Dibenzoxepin-derivative tricyclic antidepressant (TCA).

Uses for Doxepin

Depressive and Anxiety Disorders

Treatment of depression and/or anxiety in psychoneurotic patients. Psychoneurosis symptoms that respond well to doxepin include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension, and worry.

Treatment of depression and/or anxiety associated with alcoholism. (See Specific Drugs under Interactions.)

Treatment of depression and/or anxiety associated with organic disease; consider possible drug interactions if receiving other drugs concomitantly.

Treatment of psychotic depressive disorders with associated anxiety, including involutional depression and manic-depressive disorders.

Chronic Idiopathic Urticaria

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

Doxepin Dosage and Administration

General

Depressive and Anxiety Disorders

Administration

Oral Administration

Administer orally in up to 3 divided doses or as a single daily dose (if ≤150 mg); may administer once-daily doses at bedtime to reduce daytime sedation.

Dilute each dose of oral concentrate with 120 mL of water, whole or skim milk, or orange, grapefruit, tomato, prune, or pineapple juice just prior to administration; solution is physically incompatible with many carbonated beverages. Patients on methadone maintenance may mix doxepin oral concentrate and methadone syrup with Gatorade, lemonade, orange juice, sugar water, Tang, or water but not with grape juice. Bulk dilution and storage not recommended by manufacturer.

Dosage

Available as doxepin hydrochloride; dosage expressed in terms of doxepin.

Individualize dosage carefully according to individual requirements and response.

When administered as a single daily dose, the maximum daily dose recommended is 150 mg. Commercially available 150-mg capsules of doxepin are intended for maintenance therapy only and are not recommended for initial therapy.

Pediatric Patients

Depressive and Anxiety Disorders
Oral

Adolescents ≥12 years of age should receive dosage recommended for adults. (See Adults under Dosage.)

Adults

Depressive and Anxiety Disorders
Oral

Patients with illness of mild to moderate severity: Initially, 75 mg daily. May adjust dosage as necessary based on response. Usual maintenance dosage: 75–150 mg daily.

More seriously ill patients: Higher dosages may be necessary; gradually increase dosage to ≤300 mg daily, if necessary.

Dosages >300 mg daily rarely provide additional therapeutic effect.

Patients with very mild symptomatology or emotional symptoms associated with organic brain syndrome: Lower dosages may be adequate; some patients respond to 25–50 mg daily.

Prescribing Limits

Pediatric Patients

Depressive and Anxiety Disorders
Oral

Adolescents ≥12 years of age: Maximum 300 mg daily.

Adults

Oral

Maximum 300 mg daily.

Special Populations

Geriatric Patients

Select dosage at the lower end of recommended range since decreased hepatic, renal, or cardiac function and concomitant illness and medications are more frequent; increase dosage more gradually and monitor closely. May administer before bedtime. (See Geriatric Use under Cautions.)

Cautions for Doxepin

Contraindications

Warnings/Precautions

Warnings

Shares the toxic potentials of other TCAs; observe the usual precautions of TCA therapy.

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs. However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

Appropriately monitor and closely observe patients receiving doxepin for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. (See Boxed Warning and also see Pediatric Use under Cautions.)

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality. Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms. (See General under Dosage and Administration.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder [OCD]) or nonpsychiatric disorders.

Bipolar Disorder

May unmask bipolar disorder. (See Activation of Mania or Hypomania under Cautions.) Doxepin is not approved for use in treating bipolar depression.

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.

Sensitivity Reactions

Possible sensitivity reactions including skin rash, photosensitization, edema, and pruritus.

General Precautions

Activation of Mania or Hypomania

Possible activation of mania and hypomania, particularly in patients with bipolar disorder; decrease dosage and/or administer an antipsychotic agent concomitantly. (See Bipolar Disorder under Cautions.)

Cognitive/Physical Impairment

Mental alertness or physical coordination required for performing hazardous tasks (e.g., driving, operating machinery) may be impaired.

Response to alcohol may be potentiated.

Anticholinergic Effects

Use with caution in patients for whom excess anticholinergic activity could be harmful (e.g., history of urinary retention, increased IOP). (See Contraindications under Cautions.)

Withdrawal of Therapy

Possibly severe withdrawal reactions; avoid abrupt discontinuance of therapy and taper dosage gradually.

Psychosis

Possible exacerbation of psychosis in patients with schizophrenia; decrease dosage or administer an antipsychotic agent concomitantly.

Specific Populations

Pregnancy

Category C.

Lactation

Distributes into milk; some clinicians recommend that breast-feeding be avoided during doxepin therapy.

Pediatric Use

Safety of doxepin in pediatric patients <12 years of age has not been established.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, OCD, or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others). However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

Carefully consider these findings when assessing potential benefits and risks of doxepin in a child or adolescent for any clinical use. (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo. (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Doxepin generally is well tolerated in geriatric patients. Possible increased sensitivity to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotension, and sedative effects of TCAs.

Titrate dosage carefully. (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Drowsiness, anticholinergic effects (e.g., dry mouth, constipation, blurred vision), GI effects (e.g., nausea, vomiting, diarrhea).

Drug Interactions

Metabolized in the liver by various CYP isoenzymes (e.g., CYP1A2, CYP2D6, CYP3A4).

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: potential pharmacokinetic interaction (increased plasma doxepin concentrations) with concomitant use of CYP2D6 inhibitors; use with caution. Consider doxepin dosage adjustment whenever a CYP2D6 inhibitor is added or discontinued.

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potentiates the effects of alcohol

Avoid concomitant use

Increased risks if overdose or suicide attempt occurs

Antiarrhythmics: class 1C (e.g., flecainide, propafenone); quinidine

Potential for decreased doxepin metabolism

Monitor for TCA toxicity; dosage adjustment may be needed

Anticholinergic agents

Hyperthermia, particularly during hot weather, and paralytic ileus possible

Use with caution; dosage adjustment may be needed

Antipsychotics (e.g., phenothiazines)

Potential for decreased doxepin metabolism

Dosage adjustment may be needed

Cimetidine

Possible increased plasma doxepin concentrations

Potential for tricyclic toxicity, particularly anticholinergic adverse effects

Monitor for TCA toxicity; dosage adjustment may be needed

CNS depressants (e.g., analgesics, antihistamines, barbiturates, general anesthetics, opiates)

Potentiates the effects of CNS depressants

Guanethidine and related compounds

Antagonizes the antihypertensive effects of guanethidine and related compounds at doxepin dosages >150 mg daily; at dosages ≤150 mg daily, antagonism of antihypertensive effects not reported

Levodopa

May interfere with levodopa absorption

Monitor levodopa dosage carefully

MAO inhibitors

Potentially life-threatening serotonin syndrome

Concomitant use with TCAs generally contraindicated

Allow at least 2 weeks to elapse when switching to or from these drugs

Methylphenidate

Potential for decreased metabolism and increased therapeutic efficacy and toxicity of TCAs

SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Possible serotonin syndrome

Potential for decreased doxepin metabolism and increased plasma concentrations

Use with caution and monitor for TCA toxicity; dosage adjustment may be needed

Allow at least 5 weeks to elapse when switching from fluoxetine

Sympathomimetic agents (e.g., amphetamines, epinephrine, isoproterenol, norepinephrine, phenylephrine)

Increased vasopressor and/or cardiac effects

Use with caution; dosage adjustment may be required

Thyroid agents

Possible cardiac arrhythmias

Use with caution

Tolazamide

Severe hypoglycemia reported in at least one patient

Doxepin Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract following oral administration; bioavailability averages approximately 30%.

Peak plasma concentrations usually occur within 2 hours after oral administration.

Onset

Anxiolytic effect occurs prior to antidepressant effect; antidepressant effect usually occurs within 2–3 weeks.

Distribution

Extent

Doxepin and its active N-demethylated metabolite are distributed into milk in concentrations ranging from about 30–140% and 10–115%, respectively, of those in maternal serum. 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.

Plasma Protein Binding

Highly bound to plasma protein.

Elimination

Metabolism

Extensively metabolized in the liver by various CYP isoenzymes (principally CYP2D6; also CYP1A2, CYP3A4); undergoes demethylation to pharmacologically active metabolite, N-desmethyldoxepin. Poor metabolizers of CYP2D6 metabolize the drug more slowly than normal metabolizers.

Elimination Route

Excreted principally in urine.

Half-life

6–24.5 hours.

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 15–30°C.

Oral Concentrate

Tight, light-resistant containers at 20–25°C.

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Doxepin Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

10 mg (of doxepin)*

SINEquan (with parabens)

Pfizer

Doxepin Hydrochloride Capsules

Watson

25 mg (of doxepin)*

SINEquan (with parabens)

Pfizer

Doxepin Hydrochloride Capsules

Watson

50 mg (of doxepin)*

SINEquan (with parabens)

Pfizer

Doxepin Hydrochloride Capsules

Watson

75 mg (of doxepin)*

SINEquan (with parabens)

Pfizer

Doxepin Hydrochloride Capsules

Watson

100 mg (of doxepin)*

SINEquan (with parabens)

Pfizer

Doxepin Hydrochloride Capsules

Watson

150 mg (of doxepin)*

SINEquan (with parabens)

Pfizer

Solution, concentrate

10 mg (of doxepin) per mL*

SINEquan Oral Concentrate (with parabens)

Pfizer

Doxepin Hydrochloride Oral Solution (Concentrate) (with parabens)

Teva

AHFS DI Essentials™. © Copyright 2024, Selected Revisions October 3, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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