Doxepin

Special Alerts

Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes (either increases or decreases). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.

Pronunciation

(DOKS e pin)

U.S. Brand Names

Prudoxin™; Sinequan®; Zonalon®

Synonyms

Doxepin Hydrochloride

Generic Available

Yes: Capsule, solution

Canadian Brand Names

Apo-Doxepin®; Novo-Doxepin; Sinequan®; Zonalon®

Use

Oral: Depression

Topical: Short-term (<8 days) management of moderate pruritus in adults with atopic dermatitis or lichen simplex chronicus

Use - Unlabeled/Investigational

Analgesic for certain chronic and neuropathic pain; anxiety

Pregnancy Risk Factor

B (cream); C (all other forms)

Pregnancy Implications

Teratogenic effects were not observed in animal studies; however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed.

Lactation

Enters breast milk/not recommended (AAP rates "of concern")

Contraindications

Hypersensitivity to doxepin, drugs from similar chemical class, or any component of the formulation; narrow-angle glaucoma; urinary retention; use of MAO inhibitors within 14 days; use in a patient during acute recovery phase of MI

Warnings/Precautions

Often causes sedation, which may result in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is very high relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disease. May increase the risks associated with electroconvulsive therapy. This agent should be discontinued, when possible, prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.

May cause orthostatic hypotension (risk is moderate relative to other antidepressants) - use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is high relative to other cyclic antidepressants - use caution in patients with benign prostatic hyperplasia, xerostomia, visual problems, constipation, or history of bowel obstruction.

The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide should be dispensed with each prescription. Doxepin is approved for treatment of depression in adolescents.

Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk conduction abnormalities with this agent is moderate relative to other antidepressants. Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.

Cream formulation is for external use only (not for ophthalmic, vaginal, or oral use). Do not use occlusive dressings. Use for >8 days may increase risk of contact sensitization. Doxepin is significantly absorbed following topical administration; plasma levels may be similar to those achieved with oral administration.

Adverse Reactions

Oral: Frequency not defined.

Cardiovascular: Hyper-/hypotension, tachycardia

Central nervous system: Drowsiness, dizziness, headache, disorientation, ataxia, confusion, seizure

Dermatologic: Alopecia, photosensitivity, rash, pruritus

Endocrine & metabolic: Breast enlargement, galactorrhea, SIADH, increase or decrease in blood sugar, increased or decreased libido

Gastrointestinal: Xerostomia, constipation, vomiting, indigestion, anorexia, aphthous stomatitis, nausea, unpleasant taste, weight gain, diarrhea, trouble with gums, decreased lower esophageal sphincter tone may cause GE reflux

Genitourinary: Urinary retention, testicular edema

Hematologic: Agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, purpura

Neuromuscular & skeletal: Weakness, tremor, numbness, paresthesia, extrapyramidal symptoms, tardive dyskinesia

Ocular: Blurred vision

Otic: Tinnitus

Miscellaneous: Diaphoresis (excessive), allergic reactions

Topical:

>10%:

Central nervous system: Drowsiness (22%)

Dermatologic: Stinging/burning (23%)

1% to 10%:

Cardiovascular: Edema: (1%)

Central nervous system: Dizziness (2%), emotional changes (2%)

Gastrointestinal: Xerostomia (10%), taste alteration (2%)

<1%: Contact dermatitis, tongue numbness, anxiety

Overdosage/Toxicology

Symptoms of overdose include confusion, hallucinations, seizures, urinary retention, hypothermia, hypotension, tachycardia, and cyanosis. Following initiation of essential overdose management, toxic symptoms should be treated symptomatically.

Drug Interactions

Substrate (major) of CYP1A2, 2D6, 3A4

Altretamine: Concurrent use may cause orthostatic hypertension

Amphetamines: TCAs may enhance the effect of amphetamines; monitor for adverse CV effects

Anticholinergics: Combined use with TCAs may produce additive anticholinergic effects

Antihypertensives: TCAs may inhibit the antihypertensive response to bethanidine, clonidine, debrisoquin, guanadrel, guanethidine, guanabenz, guanfacine; monitor BP; consider alternate antihypertensive agent

Beta-agonists (nonselective): When combined with TCAs may predispose patients to cardiac arrhythmias

Bupropion: May increase the levels of tricyclic antidepressants; based on limited information; monitor response

Carbamazepine: Tricyclic antidepressants may increase carbamazepine levels; monitor

Cholestyramine and colestipol: May bind TCAs and reduce their absorption; monitor for altered response

Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis, amitriptyline may enhance the response

CNS depressants: Sedative effects may be additive with TCAs; monitor for increased effect; includes benzodiazepines, barbiturates, antipsychotics, ethanol and other sedative medications

CYP1A2 inducers: May decrease the levels/effects of doxepin. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of doxepin. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

CYP2D6 inhibitors: May increase the levels/effects of doxepin. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of doxepin. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of doxepin. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Epinephrine (and other direct alpha-agonists): Pressor response to I.V. epinephrine, norepinephrine, and phenylephrine may be enhanced in patients receiving TCAs ( Note: Effect is unlikely with epinephrine or levonordefrin dosages typically administered as infiltration in combination with local anesthetics)

Fenfluramine: May increase tricyclic antidepressant levels/effects

Hypoglycemic agents (including insulin): TCAs may enhance the hypoglycemic effects of tolazamide, chlorpropamide, or insulin; monitor for changes in blood glucose levels; reported with chlorpropamide, tolazamide, and insulin

Levodopa: Tricyclic antidepressants may decrease the absorption (bioavailability) of levodopa; rare hypertensive episodes have also been attributed to this combination

Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with agents which inhibit MAO (serotonin syndrome); this combination should be avoided

Lithium: Concurrent use with a TCA may increase the risk for neurotoxicity

MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported (serotonin syndrome); this combination is contraindicated

Methylphenidate: Metabolism of TCAs may be decreased

Phenothiazines: Serum concentrations of some TCAs may be increased; in addition, TCAs may increase concentration of phenothiazines; monitor for altered clinical response

QTc-prolonging agents: Concurrent use of tricyclic agents with other drugs which may prolong QTc interval may increase the risk of potentially fatal arrhythmias; includes type Ia and type III antiarrhythmics agents, selected quinolones (sparfloxacin, gatifloxacin, moxifloxacin, grepafloxacin), cisapride, and other agents

Ritonavir: Combined use of high-dose tricyclic antidepressants with ritonavir may cause serotonin syndrome in HIV-positive patients; monitor

Sucralfate: Absorption of tricyclic antidepressants may be reduced with coadministration

Sympathomimetics, indirect-acting: Tricyclic antidepressants may result in a decreased sensitivity to indirect-acting sympathomimetics; includes dopamine and ephedrine; also see interaction with epinephrine (and direct-acting sympathomimetics)

Tramadol: Tramadol's risk of seizures may be increased with TCAs

Valproic acid: May increase serum concentrations/adverse effects of some tricyclic antidepressants

Warfarin (and other oral anticoagulants): TCAs may increase the anticoagulant effect in patients stabilized on warfarin; monitor INR

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Grapefruit juice may inhibit the metabolism of some TCAs and clinical toxicity may result.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation).

Stability

Protect from light

Mechanism of Action

Increases the synaptic concentration of serotonin and norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane

Pharmacodynamics/Kinetics

Onset of action: Peak effect: Antidepressant: Usually >2 weeks; Anxiolytic: may occur sooner

Absorption: Following topical application, plasma levels may be similar to those achieved with oral administration

Distribution: Crosses placenta; enters breast milk

Protein binding: 80% to 85%

Metabolism: Hepatic; metabolites include desmethyldoxepin (active)

Half-life elimination: Adults: 6-8 hours

Excretion: Urine

Dosage

Oral (entire daily dose may be given at bedtime):

Depression or anxiety:

Children (unlabeled use): 1-3 mg/kg/day in single or divided doses

Adolescents: Initial: 25-50 mg/day in single or divided doses; gradually increase to 100 mg/day

Adults: Initial: 25-150 mg/day at bedtime or in 2-3 divided doses; may gradually increase up to 300 mg/day; single dose should not exceed 150 mg; select patients may respond to 25-50 mg/day

Elderly: Use a lower dose and adjust gradually

Chronic urticaria, angioedema, nocturnal pruritus: Adults and Elderly: 10-30 mg/day

Dosing adjustment in hepatic impairment: Use a lower dose and adjust gradually

Topical: Pruritus: Adults and Elderly: Apply a thin film 4 times/day with at least 3- to 4-hour interval between applications; not recommended for use >8 days. Note: Low-dose (25-50 mg) oral administration has also been used to treat pruritus, but systemic effects are increased.

Administration

Oral: Do not mix oral concentrate with carbonated beverages (physically incompatible).

Topical: Apply thin film to affected area; use of occlusive dressings is not recommended.

Monitoring Parameters

Monitor blood pressure and pulse rate prior to and during initial therapy; monitor mental status, weight; ECG in older adults; adverse effects may be increased if topical formulation is applied to >10% of body surface area

Reference Range

Proposed therapeutic concentration (doxepin plus desmethyldoxepin): 110-250 ng/mL. Toxic concentration (doxepin plus desmethyldoxepin): >500 ng/mL. Utility of serum level monitoring is controversial.

Test Interactions

Increased glucose

Patient Education

Oral: Take exactly as directed; do not increase dose or frequency. It may take several weeks to achieve desired results. Avoid alcohol, caffeine, and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); constipation (increased exercise, fluids, fruit, or fiber may help); urinary retention (void before taking medication); postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing); altered sexual drive or ability (reversible); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report persistent CNS effects (eg, nervousness, restlessness, insomnia, anxiety, excitation, headache, agitation, impaired coordination, changes in cognition); muscle cramping, weakness, tremors, or rigidity; chest pain, palpitations, or irregular heartbeat; blurred vision or eye pain; yellowing of skin or eyes; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Topical: Use as directed. Apply in thin layer; do not overuse. Report increased skin irritation, worsening of condition or lack of improvement.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation).

Oral: Aphthous stomatitis, unpleasant taste, trouble with gums.

Topical: Taste alteration

Long-term treatment with TCAs increases the risk of caries by reducing salivation and salivary buffer capacity.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Use with caution; epinephrine, norepinephrine and levonordefrin have been shown to have an increased pressor response in combination with TCAs

Dosage Forms

[DSC] = Discontinued product

Capsule, as hydrochloride: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

Sinequan®: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg [DSC], 150 mg [DSC]

Cream, as hydrochloride:

Prudoxin™: 5% (45 g) [contains benzyl alcohol]

Zonalon®: 5% (30 g, 45 g) [contains benzyl alcohol]

Solution, oral concentrate, as hydrochloride (Sinequan®): 10 mg/mL (120 mL)

References

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Galynker II, Rosenthal RN, Perkel C, et al, "Doxepin Withdrawal Mania," J Clin Psychiatry , 1995, 56(3):122-3.

Jastak JT and Yagiela JA, "Vasoconstrictors and Local Anesthesia: A Review and Rationale for Use," J Am Dent Assoc , 1983, 107(4):623-30.

Jefferson JW, "Tamoxifen-Associated Reduction in Tricyclic Antidepressant Levels in Blood," J Clin Psychopharmacol , 1995, 15(3):223-4.

Lakshmanan M, Mion LC, and Frengley JD, "Effective Low-Dose Tricyclic Antidepressant Treatment for Depressed Geriatric Rehabilitation Patients. A Double-Blind Study," J Am Geriatr Soc , 1986, 34(6):421-6.

Larochelle P, Hamet P, and Enjalbert M, "Responses to Tyramine and Norepinephrine After Imipramine and Trazodone," Clin Pharmacol Ther , 1979, 26(1):24-30.

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Mitchell JR, "Guanethidine and Related Agents. III Antagonism by Drugs Which Inhibit the Norepinephrine Pump in Man," J Clin Invest , 1970, 49(8):1596-604.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

Roose SP, Glassman AH, Attia E, et al, "Comparative Efficacy of Selective Serotonin Reuptake Inhibitors and Tricyclics in the Treatment of Melancholia," Am J Psychiatry , 1994, 151(12):1735-9.

Rundegren J, van Dijken J, Mörnstad H, et al, "Oral Conditions in Patients Receiving Long-Term Treatment With Cyclic Antidepressant Drugs," Swed Dent J , 1985, 9(2):55-64.

Svedmyr N, "The Influence of a Tricyclic Antidepressive Agent (Protriptyline) on Some of the Circulatory Effects of Noradrenaline and Adrenalin® in Man," Life Sci , 1968, 7(1):77-84.

Tran P, Panacek EA, Rhee KJ, et al, "Is Norepinephrine More Efficacious Than Dopamine in Reversing Hypotension Caused by Cyclic Antidepressant Overdose?" Ann Emerg Med , 1995, 25(1):128-30.

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Williams JO, "Respiratory Depression in Tricyclic Overdose," Br Med J , 1972, 1(800):631.

International Brand Names

Anten® (NZ); Apo-Doxepin® (CA); Aponal® (DE, LU); Deptran® (AU); Doneurin® (DE); Doxal® (FI); Doxederm® (AR); Doxepia® (DE); Doxepin 1A Pharma® (DE); Doxepin AL® (DE); Doxepin AZU® (DE); Doxepin beta® (DE); doxepin-biomo® (DE); Doxepin dura® (DE); Doxepin Holsten® (DE); Doxepin Lindo® (DE); Doxepin-neuraxpharm® (DE); Doxepin® (PL, RO, RU); Doxepin-ratiopharm® (DE); Doxepin-RPh® (DE); Doxepin Sandoz® (DE); Doxepin Stada® (DE); Doxepin-TEVA® (DE); Doxe TAD® (DE); Espadox® (DE); Expan® (CO); Gilex® (IL); Mareen® (DE); Novo-Doxepin (CA); Poldoxin® (PL); Quitaxon® (FR); Sinequan® (AT, AU, BE, CA, DO, ES, FR, GB, HK, IE, LU, NL, NO, PL, SI, TH); Sinquan® (DE, DK, FR); Spectra® (IN); Xepin® (GB, IE); Zonalon® (CA, IL)

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