Silenor
(doxepin)Silenor Prescribing Information
Doxepin hydrochloride 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 [see Clinical Studies (14)].
The dose of doxepin hydrochloride tablets should be individualized.
. Dosing in Adults
The recommended dose of doxepin hydrochloride 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 hydrochloride 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 hydrochloride tablets should be taken within 30 minutes of bedtime.
To minimize the potential for next day effects, doxepin hydrochloride tablets should not be taken within 3 hours of a meal [see Clinical Pharmacology (12.3)].
The total doxepin hydrochloride tablets dose should not exceed 6 mg per day.
Doxepin Hydrochloride Tablets are available containing 3.39 mg or 6.78 mg of doxepin hydrochloride, equivalent to 3 mg or 6 mg of doxepin, respectively.
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- The 3 mg tablets are blue, oval shaped, unscored tablets debossed with 3 on one side of the tablet and SP on the other side.
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- The 6 mg tablets are green, oval shaped, unscored tablets debossed with 6 on one side of the tablet and SP on the other side.
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of doxepin hydrochloride tablets in pregnant women. Doxepin hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of doxepin to pregnant animals resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 6 mg/day.
When doxepin (30, 100 and 150 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, developmental toxicity (increased incidences of fetal structural abnormalities and decreased fetal body weights) was noted at ≥ 100 mg/kg/day. The plasma exposures (AUC) at the no-effect dose for embryo-fetal developmental toxicity in rats (30 mg/kg/day) are approximately 6 and 3 times the plasma AUCs for doxepin and nordoxepin (the primary metabolite in humans), respectively, at the MRHD. When administered orally to pregnant rabbits (10, 30 and 60 mg/kg/day) during the period of organogenesis, fetal body weights were reduced at the highest dose in the absence of maternal toxicity. The plasma exposures (AUC) at the no-effect dose for developmental effects (30 mg/kg/day) are approximately 6 and 18 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD. Oral administration of doxepin (10, 30 and 100 mg/kg/day) to rats throughout the pregnancy and lactation periods resulted in decreased pup survival and transient growth delay at the highest dose. The plasma exposures (AUC) at the no-effect dose for adverse effects on pre- and postnatal development in rats (30 mg/kg/day) are approximately 3 and 2 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD.
Labor and Delivery
The effects of doxepin hydrochloride tablets on labor and delivery in pregnant women are unknown.
Nursing Mothers
Doxepin is excreted in human milk after oral administration. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking the higher dose of doxepin used to treat depression. Caution should be exercised when doxepin hydrochloride tablets are administered to nursing women.
Pediatric Use
The safety and effectiveness of doxepin hydrochloride tablets in pediatric patients have not been evaluated.
Geriatric Use
A total of 362 subjects who were ≥ 65 years and 86 subjects who were ≥ 75 years received doxepin hydrochloride tablets in controlled clinical studies. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects. Greater sensitivity of some older individuals cannot be ruled out.
Sleep-promoting drugs may cause confusion and over-sedation in the elderly. A starting dose of 3 mg is recommended in this population and evaluation prior to considering dose escalation is recommended [see Dosage and Administration (2.2)].
Use in Patients with Hepatic Impairment
Patients with hepatic impairment may display higher doxepin concentrations than healthy individuals. Initiate doxepin hydrochloride tablets treatment with 3 mg in patients with hepatic impairment and monitor closely for adverse daytime effects [see Clinical Pharmacology (12.5)].
Use in Patients with Sleep Apnea
Doxepin hydrochloride tablets have not been studied in patients with obstructive sleep apnea. Since hypnotics have the capacity to depress respiratory drive, precautions should be taken if doxepin hydrochloride tablets are prescribed to patients with compromised respiratory function. In patients with severe sleep apnea, doxepin hydrochloride tablets are ordinarily not recommended for use.
. Hypersensitivity
Doxepin hydrochloride tablets are contraindicated in individuals who have shown hypersensitivity to doxepin HCl, any of its inactive ingredients, or other dibenzoxepines.
. Co-administration with Monoamine Oxidase Inhibitors (MAOIs)
Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Do not administer doxepin hydrochloride tablets if patient is currently on MAOIs or has used MAOIs within the past two weeks. The exact length of time may vary depending on the particular MAOI dosage and duration of treatment.
. Glaucoma and Urinary Retention
Doxepin hydrochloride tablets are contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention.
. 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 hydrochloride tablets 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 hydrochloride tablets, is an antidepressant at doses 10- to 100-fold higher than in doxepin hydrochloride tablets. 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 hydrochloride 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 hydrochloride tablets, 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 hydrochloride tablets, and should be cautioned about potential impairment in the performance of such activities that may occur the day following ingestion.
When taken with doxepin hydrochloride tablets, the sedative effects of alcoholic beverages, sedating antihistamines, and other CNS depressants may be potentiated [see Warnings and Precautions (5.2) and Drug Interactions (7.3, 7.4)]. Patients should not consume alcohol with doxepin hydrochloride tablets [see Warnings and Precautions (5.2) and Drug Interactions (7.3)]. Patients should be cautioned about potential additive effects of doxepin hydrochloride tablets used in combination with CNS depressants or sedating antihistamines [see Warnings and Precautions (5.2) and Drug Interactions (7.4)].
The following serious adverse reactions are discussed in greater detail in other sections of labeling:
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- Abnormal thinking and behavioral changes [see Warnings and Precautions (5.2)].
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- Suicide risk and worsening of depression [see Warnings and Precautions (5.3)].
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- CNS Depressant effects [see Warnings and Precautions (5.4)].
. Clinical Trials Experience
The pre-marketing development program for doxepin hydrochloride tablets included doxepin HCl exposures in 1017 subjects (580 insomnia patients and 437 healthy subjects) from 12 studies conducted in the United States. 863 of these subjects (580 insomnia patients and 283 healthy subjects) participated in six randomized, placebo-controlled efficacy studies with doxepin hydrochloride tablets doses of 1 mg, 3 mg, and 6 mg for up to 3-months in duration.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. However, data from the doxepin hydrochloride tablets studies provide the physician with a basis for estimating the relative contributions of drug and non-drug factors to adverse reaction incidence rates in the populations studied.
Associated with Discontinuation of Treatment
The percentage of subjects discontinuing Phase 1, 2, and 3 trials for an adverse reaction was 0.6% in the placebo group compared to 0.4%, 1.0%, and 0.7% in the doxepin hydrochloride tablets 1 mg, 3 mg, and 6 mg groups, respectively. No reaction that resulted in discontinuation occurred at a rate greater than 0.5%.
Adverse Reactions Observed at an Incidence of ≥ 2% in Controlled Trials
Table 1 shows the incidence of treatment-emergent adverse reactions from three long-term (28 to 85 days) placebo-controlled studies of doxepin hydrochloride tablets in adult (N = 221) and elderly (N = 494) subjects with chronic insomnia.
Reactions reported by Investigators were classified using a modified MedDRA dictionary of preferred terms for purposes of establishing incidence. The table includes only reactions that occurred in 2% or more of subjects who received doxepin hydrochloride tablets 3 mg or 6 mg in which the incidence in subjects treated with doxepin hydrochloride tablets was greater than the incidence in placebo-treated subjects.
| |||
System Organ Class | Placebo | Doxepin Hydrochloride Tablets | Doxepin Hydrochloride Tablets |
Nervous System Disorders | |||
| 4 | 6 | 9 |
Infections and Infestations | |||
| 2 | 4 | 2 |
| 0 | 2 | 0 |
Gastrointestinal Disorders | |||
| 1 | 2 | 2 |
Vascular Disorders | |||
| 0 | 3 | < 1 |
The most common treatment-emergent adverse reaction in the placebo and each of the doxepin hydrochloride tablets dose groups was somnolence/sedation.
. Studies Pertinent to Safety Concerns for Sleep-promoting Drugs
Residual Pharmacological Effect in Insomnia Trials
Five randomized, placebo-controlled studies in adults and the elderly assessed next-day psychomotor function within 1 hour of awakening utilizing the digit-symbol substitution test (DSST), symbol copying test (SCT), and visual analog scale (VAS) for sleepiness, following night time administration of doxepin hydrochloride tablets.
In a one-night, double-blind study conducted in 565 healthy adult subjects experiencing transient insomnia, doxepin hydrochloride tablets 6 mg showed modest negative changes in SCT and VAS.
In a 35-day, double-blind, placebo-controlled, parallel group study of doxepin hydrochloride tablets 3 and 6 mg in 221 adults with chronic insomnia, small decreases in the DSST and SCT occurred in the 6 mg group.
In a 3-month, double-blind, placebo-controlled, parallel group study in 240 elderly subjects with chronic insomnia, doxepin hydrochloride tablets 1 mg and 3 mg was comparable to placebo on DSST, SCT, and VAS.
. Other Reactions Observed During the Pre-marketing Evaluation of Silenor
Doxepin hydrochloride tablets were administered to 1017 subjects in clinical trials in the United States. Treatment-emergent adverse reactions recorded by clinical investigators were standardized using a modified MedDRA dictionary of preferred terms. The following is a list of MedDRA terms that reflect treatment-emergent adverse reactions reported by subjects treated with doxepin hydrochloride tablets.
Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 subjects; Infrequent adverse reactions are those that occurred in fewer than 1/100 subjects and more than 1/1000 subjects. Rare adverse reactions are those that occurred in fewer than 1/1000 subjects. Adverse reactions that are listed in Table 1 are not included in the following listing of frequent, infrequent, and rare AEs.
Blood and Lymphatic System Disorders: Infrequent: anemia; Rare: thrombocythemia.
Cardiac Disorders: Rare: atrioventricular block, palpitations, tachycardia, ventricular extrasystoles.
Ear and Labyrinth Disorders: Rare: ear pain, hypoacusis, motion sickness, tinnitus, tympanic membrane perforation.
Eye Disorders: Infrequent: eye redness, vision blurred; Rare: blepharospasm, diplopia, eye pain, lacrimation decreased.
Gastrointestinal Disorders: Infrequent: abdominal pain, dry mouth, gastroesophageal reflux disease, vomiting; Rare: dyspepsia, constipation, gingival recession, haematochezia, lip blister.
General Disorders and Administration Site Conditions: Infrequent: asthenia, chest pain, fatigue; Rare: chills, gait abnormal, edema peripheral.
Hepatobiliary Disorders: Rare: hyperbilirubinemia.
Immune System Disorders: Rare: hypersensitivity.
Infections and Infestations: Infrequent: bronchitis, fungal infection, laryngitis, sinusitis, tooth infection, urinary tract infection, viral infection; Rare: cellulitis staphylococcal, eye infection, folliculitis, gastroenteritis viral, herpes zoster, infective tenosynovitis, influenza, lower respiratory tract infection, onychomycosis, pharyngitis, pneumonia.
Injury, Poisoning and Procedural Complications: Infrequent: back injury, fall, joint sprain; Rare: bone fracture, skin laceration.
Investigations: Infrequent: blood glucose increased; Rare: alanine aminotransferase increased, blood pressure decreased, blood pressure increased, electrocardiogram ST-T segment abnormal, electrocardiogram QRS complex abnormal, heart rate decreased, neutrophil count decreased, QRS axis abnormal, transaminases increased.
Metabolism and Nutrition Disorders: Infrequent: anorexia, decreased appetite, hyperkalemia, hypermagnesemia, increased appetite; Rare: hypokalemia.
Musculoskeletal and Connective Tissue Disorders: Infrequent: arthralgia, back pain, myalgia, neck pain, pain in extremity; Rare: joint range of motion decreased, muscle cramp, sensation of heaviness.
Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps): Rare: lung adenocarcinoma stage I, malignant melanoma.
Nervous System Disorders: Frequent: dizziness; Infrequent: dysgeusia, lethargy, parasthesia, syncope; Rare: ageusia, ataxia, cerebrovascular accident, disturbance in attention, migraine, sleep paralysis, syncope vasovagal, tremor.
Psychiatric Disorders: Infrequent: abnormal dreams, adjustment disorder, anxiety, depression; Rare: confusional state, elevated mood, insomnia, libido decreased, nightmare.
Reproductive System and Breast Disorders: Rare: breast cyst, dysmenorrhea.
Renal and Urinary Disorders: Rare: dysuria, enuresis, hemoglobinuria, nocturia.
Respiratory, Thoracic and Mediastinal Disorders: Infrequent: nasal congestion, pharyngolaryngeal pain, sinus congestion, wheezing; Rare: cough, crackles lung, nasopharyngeal disorder, rhinorrhea, dyspnea.
Skin and Subcutaneous Tissue Disorders: Infrequent: skin irritation; Rare: cold sweat, dermatitis, erythema, hyperhidrosis, pruritis, rash, rosacea.
Surgical and Medical Procedures: Rare: arthrodesis.
Vascular Disorders: Infrequent: pallor; Rare: blood pressure inadequately controlled, hematoma, hot flush.
In addition, the reactions below have been reported for other tricyclics and may be idiosyncratic (not related to dose).
Allergic: photosensitization, skin rash.
Hematologic: agranulocytosis, eosinophilia, leukopenia, purpura, thrombocytopenia.
. Cytochrome P450 Isozymes
Doxepin hydrochloride 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 hydrochloride is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations. The ability of doxepin hydrochloride to induce CYP isozymes is not known.
. Cimetidine
Doxepin hydrochloride 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 hydrochloride tablets [see Clinical Pharmacology (12.4)].
. Alcohol
When taken with doxepin hydrochloride tablets, 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 hydrochloride tablets, 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).
Doxepin hydrochloride tablets are available in 3 mg and 6 mg strength tablets for oral administration. Each tablet contains 3.39 mg or 6.78 mg doxepin hydrochloride, equivalent to 3 mg and 6 mg of doxepin, respectively.
Chemically, doxepin hydrochloride is an (E) and (Z) geometric, isomeric mixture of 1 propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-hydrochloride. It has the following structure:
Doxepin hydrochloride is a white crystalline powder, with a slight amine-like odor, that is readily soluble in water. It has a molecular weight of 315.84 and molecular formula of C19 H21 NO•HCl.
Each doxepin hydrochloride tablet includes the following inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. The 3 mg tablet also contains FD&C Blue No.1. The 6 mg tablet also contains D&C Yellow No. 10 and FD&C Blue No. 1.
Mechanism of Action
Doxepin binds with high affinity to the histamine H1 receptor (Ki < 1 nM) where it functions as an antagonist. The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but is believed due to its antagonism of the H1 receptor.
Pharmacodynamics
Cardiac Safety
In a thorough QTc prolongation clinical study in healthy subjects, doxepin had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 50 mg.
Pharmacokinetics
Absorption
The median time to peak concentrations (Tmax) of doxepin occurred at 3.5 hours postdose after oral administration of a 6 mg dose to fasted healthy subjects. Peak plasma concentrations (Cmax) of doxepin hydrochloride increased in approximately a dose-proportional manner for 3 mg and 6 mg doses. The AUC was increased by 41% and Cmax by 15% when 6 mg doxepin hydrochloride tablets were administered with a high fat meal. Additionally, compared to the fasted state, Tmax was delayed by approximately 3 hours. Therefore, for faster onset and to minimize the potential for next day effects, it is recommended that doxepin hydrochloride tablets not be taken within 3 hours of a meal [see Dosage and Administration (2.3)].
Distribution
Doxepin hydrochloride is widely distributed throughout the body tissues. The mean apparent volume of distribution following a single 6 mg oral dose of doxepin hydrochloride tablets to healthy subjects was 11,930 liters. Doxepin hydrochloride is approximately 80% bound to plasma proteins.
Metabolism
Following oral administration, doxepin hydrochloride is extensively metabolized by oxidation and demethylation. The primary metabolite is N-desmethyldoxepin (nordoxepin).
The primary metabolite undergoes further biotransformation to glucuronide conjugates.
In vitro studies have shown that CYP2C19 and CYP2D6 are the major enzymes involved in doxepin metabolism, and that CYP1A2 and CYP2C9 are involved to a lesser extent.
Doxepin appears not to have inhibitory effects on human CYP enzymes at therapeutic concentrations. The potential of doxepin to induce metabolizing enzymes is not known. Doxepin is not a Pgp substrate.
Excretion
Doxepin is excreted in the urine mainly in the form of glucuronide conjugates.
Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. The apparent terminal half-life (t ½) of doxepin was 15.3 hours and for nordoxepin was 31 hours.
. Drug Interactions
Since doxepin is metabolized by CYP2C19 and CYP2D6, inhibitors of these CYP isozymes may increase the exposure of doxepin.
Cimetidine
The effect of cimetidine, a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4, on doxepin hydrochloride plasma concentrations was evaluated in healthy subjects. When cimetidine 300 mg BID was co-administered with a single dose of doxepin hydrochloride tablets 6 mg, there was approximately a 2-fold increase in doxepin hydrochloride Cmax and AUC compared to doxepin hydrochloride tablets given alone. A maximum dose of doxepin in adults and elderly should be 3 mg, when doxepin is co-administered with cimetidine.
Sertraline
The effect of sertraline HCl, a selective serotonin reuptake inhibitor, on doxepin plasma concentrations was evaluated in a daytime study conducted with 24 healthy subjects. Following co-administration of doxepin 6 mg with sertraline 50 mg (at steady-state), the doxepin mean AUC and Cmax estimates were approximately 21% and 32% higher, respectively, than those obtained following administration of doxepin alone. Psychomotor function as measured by the digit symbol substitution test and symbol copy test performance was decreased more at 2-4 hours post dosing for the combination of sertraline and doxepin as compared to doxepin alone, but subjective measures of alertness were comparable for the two treatments.
. Special Populations
Renal Impairment
The effects of renal impairment on doxepin pharmacokinetics have not been studied. Because only small amounts of doxepin and nordoxepin are eliminated in the urine, renal impairment would not be expected to result in significantly altered doxepin concentrations.
Hepatic Impairment
The effects of doxepin hydrochloride tablets in patients with hepatic impairment have not been studied. Because doxepin is extensively metabolized by hepatic enzymes, patients with hepatic impairment may display higher doxepin concentrations than healthy individuals.
Poor Metabolizers of CYPs
Poor metabolizers of CYP2C19 and CYP2D6 may have higher doxepin plasma levels than normal subjects.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
No evidence of carcinogenic potential was observed when doxepin was administered orally to hemizygous Tg.rasH2 mice for 26 weeks at doses of 25, 50, 75 and 100 mg/kg/day.
Mutagenesis
Doxepin was negative in in vitro (bacterial reverse mutation, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays.
Impairment of Fertility
When doxepin (10, 30 and 100 mg/kg/day) was orally administered to male and female rats prior to, during and after mating, adverse effects on fertility (increased copulatory interval and decreased corpora lutea, implantation, viable embryos and litter size) and sperm parameters (increased percentages of abnormal sperm and decreased sperm motility) were observed. The plasma exposures (AUC) for doxepin and nordoxepin at the no-effect dose for adverse effects on reproductive performance and fertility in rats (10 mg/kg/day) are less than those in humans at the maximum recommended human dose of 6 mg/day.
. Controlled Clinical Trials
The efficacy of doxepin hydrochloride tablets for improving sleep maintenance was supported by six randomized, double-blind studies up to 3 months in duration that included 1,423 subjects, 18 to 93 years of age, with chronic (N = 858) or transient (N = 565) insomnia. Doxepin hydrochloride tablets were evaluated at doses of 1 mg, 3 mg, and 6 mg relative to placebo in inpatient (sleep laboratory) and outpatient settings.
The primary efficacy measures for assessment of sleep maintenance were the objective and subjective time spent awake after sleep onset (respectively, objective Wake After Sleep Onset [WASO] and subjective WASO).
Subjects in studies of chronic insomnia were required to have at least a 3-month history of insomnia.
Chronic Insomnia
Adults
A randomized, double-blind, parallel-group study was conducted in adults (N = 221) with chronic insomnia. Doxepin hydrochloride tablets 3 mg and 6 mg were compared to placebo out to 30 days.
Doxepin hydrochloride tablets 3 mg and 6 mg were superior to placebo on objective WASO. Doxepin hydrochloride tablets 3 mg were superior to placebo on subjective WASO at night 1 only. Doxepin hydrochloride tablets 6 mg were superior to placebo on subjective WASO at night 1, and nominally superior at some later time points out to Day 30.
Elderly
Elderly subjects with chronic insomnia were assessed in two parallel-group studies.
The first randomized, double-blind study assessed doxepin hydrochloride tablets 1 mg and 3 mg relative to placebo for 3 months in inpatient and outpatient settings in elderly subjects (N = 240) with chronic insomnia. Doxepin hydrochloride tablets 3 mg were superior to placebo on objective WASO.
The second randomized, double-blind study assessed doxepin hydrochloride tablets 6 mg relative to placebo for 4 weeks in an outpatient setting in elderly subjects (N = 254) with chronic insomnia. On subjective WASO, doxepin hydrochloride tablets 6 mg was superior to placebo.
Transient Insomnia
Healthy adult subjects (N = 565) experiencing transient insomnia during the first night in a sleep laboratory were evaluated in a randomized, double-blind, parallel-group, single-dose study of doxepin hydrochloride tablets 6 mg relative to placebo. Doxepin hydrochloride tablets 6 mg were superior to placebo on objective WASO and subjective WASO.
Withdrawal Effects
Potential withdrawal effects were assessed in a 35-day double blind study of adults with chronic insomnia who were randomized to placebo, doxepin hydrochloride tablets 3 mg, or doxepin hydrochloride tablets 6 mg. There was no indication of a withdrawal syndrome after discontinuation of doxepin hydrochloride tablets treatment (3 mg or 6 mg), as measured by the Tyrer’s Symptom Checklist. Discontinuation-period emergent nausea and vomiting occurred in 5% of subjects treated with 6 mg doxepin hydrochloride tablets, versus 0% in 3 mg and placebo subjects.
Rebound Insomnia Effects
Rebound insomnia, defined as a worsening in WASO compared with baseline following discontinuation of treatment, was assessed in a double-blind, 35-day study in adults with chronic insomnia. Doxepin hydrochloride tablets 3 mg and 6 mg showed no evidence of rebound insomnia.
. How Supplied
Doxepin Hydrochloride Tablets are available containing 3.39 mg or 6.78 mg of doxepin hydrochloride equivalent to 3 mg or 6 mg of doxepin, respectively.
The 3 mg tablets are blue, oval shaped, unscored tablets debossed with 3 on one side of the tablet and SP on the other side. They are available as follows:
NDC 0378-4810-93
bottles of 30 tablets
The 6 mg tablets are green, oval shaped, unscored tablets debossed with 6 on one side of the tablet and SP on the other side.
NDC 0378-4811-93
bottles of 30 tablets
. Storage and Handling
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from light.
Mechanism of Action
Doxepin binds with high affinity to the histamine H1 receptor (Ki < 1 nM) where it functions as an antagonist. The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but is believed due to its antagonism of the H1 receptor.