Doxepin is available in 3 mg and 6 mg strength tablets for oral administration. Each tablet contains 3.39 mg or 6.78 mg doxepin hydrochloride, USP equivalent to 3 mg and 6 mg of doxepin, respectively. Chemically, doxepin hydrochloride, USP is an (E) and (Z) geometric, isomeric mixture of 1-propanamine, 3-dibenz[ b ,e]oxepin-11(6 H )ylidene- N,N -dimethyl-hydrochloride. It has the following structure: Doxepin hydrochloride USP is a white or almost white crystalline powder, that is freely soluble in water, ethanol and dichloromethane, soluble in chloroform and in methanol. It has a molecular weight of 315.84 and molecular formula of C 19 H 21 NO•HCl. Each doxepin tablet includes the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate and microcrystalline cellulose. The 6 mg tablet contains D&C Yellow No. 10 alum lake. doxepin-tabs-structure

Doxepin tablets are indicated for the treatment of insomnia characterized by difficulty with sleep maintenance. The clinical trials performed in support of efficacy were up to 3 months in duration. Doxepin tablets are indicated for the treatment of insomnia characterized by difficulties with sleep maintenance. ( 1 , 14 )

Doxepin tablets are an immediate-release, oval-shaped, tablet for oral administration available in strengths of 3 mg and 6 mg. The tablets are white (3 mg) or light yellow (6 mg) and are debossed with “134” or “135”, respectively, on one side and “m” on the other side. Doxepin tablets are not scored. 3 mg and 6 mg tablets. Tablets not scored.

The dose of doxepin tablets should be individualized. Initial dose: 6 mg, once daily for adults and 3 mg, once daily for the elderly. Take within 30 minutes of bedtime. Total daily dose should not exceed 6 mg. Should not be taken within 3 hours of a meal. ( 2.3 , 12.3 ) 2.1 Dosing in Adults The recommended dose of doxepin tablets for adults is 6 mg once daily. A 3 mg once daily dose may be appropriate for some patients, if clinically indicated

Dosing in the Elderly The recommended starting dose of doxepin tablets in elderly patients (≥65 years old) is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically indicated

Administration Doxepin tablets should be taken within 30 minutes of bedtime. To minimize the potential for next day effects, doxepin tablets should not be taken within 3 hours of a meal [ see Clinical Pharmacology ]. The total doxepin tablets dose should not exceed 6 mg per day.

Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use. Abnormal thinking, behavioral changes, complex behaviors: May include “Sleep-driving” and hallucinations. Immediately evaluate any new onset behavioral changes. Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount feasible to avoid intentional overdose. CNS-depressant effects: Use can impair alertness and motor coordination. Avoid engaging in hazardous activities such as operating a motor vehicle or heavy machinery after taking drug. Do not use with alcohol. Potential additive effects when used in combination with CNS depressants or sedating antihistamines. Dose reduction may be needed. Patients with severe sleep apnea: Doxepin is ordinarily not recommended for use in this population. 5.1 Need to Evaluate for Comorbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Exacerbation of insomnia or the emergence of new cognitive or behavioral abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with hypnotic drugs

Abnormal Thinking and Behavioral Changes Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a hypnotic, with amnesia for the event) have been reported with hypnotics. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with hypnotics appears to increase the risk of such behaviors, as does the use of hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of doxepin should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic. As with “sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably

Suicide Risk and Worsening of Depression In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of hypnotics. Doxepin, the active ingredient in doxepin tablets, is an antidepressant at doses 10- to 100-fold higher than in doxepin. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Risk from the lower dose of doxepin in doxepin tablets can not be excluded. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation

CNS Depressant Effects After taking doxepin, patients should confine their activities to those necessary to prepare for bed. Patients should avoid engaging in hazardous activities, such as operating a motor vehicle or heavy machinery, at night after taking doxepin, and should be cautioned about potential impairment in the performance of such activities that may occur the day following ingestion. When taken with doxepin, the sedative effects of alcoholic beverages, sedating antihistamines, and other CNS depressants may be potentiated [ see Warnings and Precautions and Drug Interactions (7.3 , 7.4 )]. Patients should not consume alcohol with doxepin [ see Warnings and Precautions and Drug Interactions (7.3 )]. Patients should be cautioned about potential additive effects of doxepin used in combination with CNS depressants or sedating antihistamines [ see Warnings and Precautions and Drug Interactions ].

MAO inhibitors: Doxepin should not be administered in patients on MAOIs within the past two weeks. Cimetidine: Increases exposure to doxepin. Alcohol: Sedative effects may be increased with doxepin. CNS Depressants and Sedating Antihistamines: Sedative effects may be increased with doxepin Tolazamide: A case of severe hypoglycemia has been reported

Cytochrome P450 Isozymes Doxepin is primarily metabolized by hepatic cytochrome P450 isozymes CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Inhibitors of these isozymes may increase the exposure of doxepin. Doxepin is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations. The ability of doxepin to induce CYP isozymes is not known

Cimetidine Doxepin exposure is doubled with concomitant administration of cimetidine, a nonspecific inhibitor of CYP isozymes. A maximum dose of 3 mg is recommended in adults and elderly when cimetidine is co-administered with doxepin 7.3 Alcohol When taken with doxepin, the sedative effects of alcohol may be potentiated [ see Warnings and Precautions (5.2 , 5.4 )]

CNS Depressants and Sedating Antihistamines When taken with doxepin, the sedative effects of sedating antihistamines and CNS depressants may be potentiated [ see Warnings and Precautions (5.2 , 5.4 ) ]

Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 g/day) 11 days after the addition of oral doxepin (75 mg/day).