Doxepin

INDICATIONS AND USAGE Doxepin Hydrochloride Capsules, USP are recommended for the treatment of: 1. Psychoneurotic patients with depression and/or anxiety. 2. Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol). 3. Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly). 4. Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders. The target symptoms of psychoneurosis that respond particularly well to doxepin hydrochloride capsules include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry. Clinical experience has shown that doxepin hydrochloride capsules are safe and well tolerated even in the elderly patient. Owing to lack of clinical experience in the pediatric population, doxepin hydrochloride capsules are not recommended for use in children under 12 years of age.

DOSAGE AND ADMINISTRATION • Prior to initiating treatment with doxepin hydrochloride capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania. ( 2.1 ) • Recommended starting oral dosage is 25 mg three times daily or 75 mg once daily. ( 2.2 ) • Recommended target total dosage range is between 75 mg/day and 150 mg/day (may be given once daily or in divided doses). ( 2.2 ) • Maximum recommended dosage is 100 mg three times daily. ( 2.2 ) • Wait at least 14 days after discontinuation of a monoamine oxidase inhibitor (MAOI) before initiating therapy with doxepin hydrochloride capsules. ( 2.3 ) • See the Full Prescribing Information for dosage modifications intended to reduce the risk of anticholinergic effects, for strong CYP2D6 inhibitors, and in known CYP2D6 and CYP2C19 poor metabolizers. ( 2.4 , 2.5 , 2.6 ). • When discontinuing doxepin hydrochloride capsules, gradually reduce the dosage until discontinued. ( 2.7 ) 2.1 Screen for Bipolar Disorder Prior to Starting Doxepin Hydrochloride Capsules Prior to initiating treatment with doxepin hydrochloride capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.5) ]. 2.2 Recommended Dosage The recommended starting oral dosage for doxepin hydrochloride capsules is 25 mg three times daily or 75 mg once daily. The recommended target total oral dosage range for doxepin hydrochloride capsules is between 75 mg/day and 150 mg/day (may be given once daily or in divided doses). The maximum recommended oral dosage for doxepin hydrochloride capsules is 100 mg three times daily. 2.3 Switching Patients to or from a Monoamine Oxidase Inhibitor Wait at least 14 days after discontinuation of a monoamine oxidase inhibitor (MAOI) before initiating therapy with doxepin hydrochloride capsules [see Contraindications (4) , Warnings and Precautions (5.2) , and Drug Interactions (7) ] . Wait at least 14 days after discontinuation of doxepin hydrochloride capsules before initiating therapy with an MAOI [see Contraindications (4) , Warnings and Precautions (5.2) , and Drug Interactions (7) ]. 2.4 Dosage Modifications Intended to Reduce the Risk of Anticholinergic Effects If anticholinergic effects (e.g., dry mouth, blurred vision, constipation) develop, reduce the doxepin hydrochloride capsules dosage [see Adverse Reactions (6.1) ] . 2.5 Dosage Modifications for Strong CYP2D6 Inhibitors Reduce the doxepin hydrochloride capsules dosage based on doxepin plasma concentrations when used concomitantly with strong CYP2D6 inhibitors [see Drug Interactions (7) ] . 2.6 Dosage Modifications in Known CYP2D6 and CYP2C19 Poor Metabolizers Reduce the doxepin hydrochloride capsules dosage based on doxepin plasma concentrations in patients who are known CYP2D6 and CYP2C19 poor metabolizers [see Use in Specific Populations (8.7) ] . 2.7 Discontinuation of Doxepin Hydrochloride Capsules Treatment When discontinuing doxepin hydrochloride capsules, gradually reduce the dosage until discontinued [see Adverse Reactions (6) ] .

WARNINGS AND PRECAUTIONS • Suicidal Thoughts and Behaviors : Monitor for clinical worsening and suicide thoughts and behaviors. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride capsules, in patients who are experiencing emergent suicidal thoughts or behaviors. ( 5.1 ) • Serotonin Syndrome : Risk increases with concomitant use of other serotonergic drugs. Monitor all patients taking doxepin hydrochloride capsules for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride capsules and any concomitant serotonergic agents immediately and initiate supportive treatment if serotonin syndrome occurs. ( 5.2 , 7 ) • Angle-Closure Glaucoma : Avoid use of doxepin hydrochloride capsules in patients with untreated anatomically narrow angles. ( 5.3 ) • Sedation and Driving Risks : Because doxepin hydrochloride capsules can cause sedation, warn patients against driving a car or operating dangerous machinery while taking doxepin hydrochloride capsules. ( 5.4 ) • Activation of Mania or Hypomania : Prior to initiating antidepressant therapy, screen for bipolar disorder. Doxepin hydrochloride capsules are not approved for use in treating bipolar depression. ( 5.5 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs including tricyclic antidepressants and other antidepressant classes that included approximately 77,000 adult patients and 4,500 pediatric patients (doxepin hydrochloride capsules are not approved for use in pediatric patients), the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient ≥ 65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression. Monitor all doxepin hydrochloride capsules-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of doxepin hydrochloride capsules therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the health care provider. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride capsules, in patients who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Tricyclic antidepressants, including doxepin hydrochloride capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitant use of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans, tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue) [see Drug Interactions (7) ] . Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of doxepin hydrochloride capsules with MAOIs is contraindicated. The use of doxepin hydrochloride capsules within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride capsules in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloride capsules, discontinue doxepin hydrochloride capsules before initiating treatment with the MAOI [see Dosage and Administration (2.4) and Drug Interactions (7) ] . Monitor all patients taking doxepin hydrochloride capsules for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride capsules treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride capsules with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms . 5.3 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride capsules may trigger an angle closure glaucoma attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Doxepin hydrochloride capsules are contraindicated in patients with glaucoma. Avoid use of doxepin hydrochloride capsules in patients with untreated anatomically narrow angles. 5.4 Sedation and Driving Risks Because doxepin hydrochloride capsules can cause sedation, warn patients of the risk of sedation and caution patients against driving a car or operating dangerous machinery while taking doxepin hydrochloride capsules. Also caution patients that their response to alcohol may be potentiated. Sedating drugs, including doxepin hydrochloride capsules, may cause oversedation in geriatric patients. 5.5 Activation of Mania or Hypomania In patients with bipolar disorder, treating MDD with doxepin hydrochloride capsules may precipitate a mixed/manic episode. Prior to initiating treatment with doxepin hydrochloride capsules, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. doxepin hydrochloride capsules are not approved for use in treating bipolar depression . 5.6 Risk of Seizures Caution should be used when doxepin hydrochloride capsules are given to patients with a history of seizure disorder, because this drug may lower the seizure threshold. Patients with a history of seizures should be monitored during doxepin hydrochloride capsules use to identify recurrence of seizures or increase in frequency of seizures. 5.7 Psychosis In patients with schizophrenia, treatment with doxepin hydrochloride capsules for MDD may activate psychosis. If this occurs, stop doxepin hydrochloride capsules and consider alternative treatment options.

4. CONTRAINDICATIONS Hypersensitivity to doxepin hydrochloride, inactive ingredients, or other dibenzoxepines. ( 4.1 ) Co-administration with Monoamine Oxidase Inhibitors (MAOIs): Do not administer if patient is taking MAOIs or has used MAOIs within the past two weeks. ( 4.2 ) Untreated narrow angle glaucoma or severe urinary retention. ( 4.3 ) 4.1. Hypersensitivity Doxepin HCl Tablets is contraindicated in individuals who have shown hypersensitivity to doxepin HCl, any of its inactive ingredients, or other dibenzoxepines. 4.2. 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 HCl 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. 4.3. Glaucoma and Urinary Retention Doxepin HCl Tablets is contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention.

Drug Interactions: Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of Doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with Doxepin has not been systematically evaluated. MAO Inhibitors: Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with Doxepin. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine: Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol: It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional Doxepin overdosage. This is especially important in patients who may use alcohol excessively. Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of Doxepin (75 mg/day). Drowsiness : Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of Doxepin and observed closely. (See PRECAUTIONS−Geriatric Use.) Suicide : Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount. Psychosis : Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer to the dosage regimen. Geriatric Use: A determination has not been made whether controlled clinical studies of Doxepin included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of Doxepin has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of Doxepin and observed closely. (See WARNINGS.)

ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of labeling: Abnormal thinking and behavioral changes [see Warnings and Precautions (5.2)] . Suicide risk and worsening of depression [ see Warnings and Precautions (5.3) ] . CNS Depressant effects [ see Warnings and Precautions (5.4) ] . The most common treatment-emergent adverse reactions, reported in ≥ 2% of patients treated with doxepin, and more commonly than in patients treated with placebo, were somnolence/sedation, nausea, and upper respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 and or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience The pre-marketing development program for doxepin 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 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 trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. However, data from the doxepin 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 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 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 3 mg or 6 mg in which the incidence in subjects treated with doxepin was greater than the incidence in placebo-treated subjects. Table 1 Incidence (%) of Treatment-Emergent Adverse Reactions in Long-term Placebo-Controlled Clinical Trials System Organ Class Preferred Term* Placebo (N=278) Doxepin 3 mg (N=157) Doxepin 6 mg (N=203) Nervous System Disorders Somnolence/Sedation 4 6 9 Infections and Infestations Upper Respiratory Tract Infection/Nasopharyngitis 2 4 2 Gastroenteritis 0 2 0 Gastrointestinal Disorders Nausea 1 2 2 Vascular Disorders Hypertension 0 3 < 1 * Includes reactions that occurred at a rate of ≥2% in any doxepin-treated group and at a higher rate than placebo. The most common treatment-emergent adverse reaction in the placebo and each of the doxepin dose groups was somnolence/sedation. 6.2 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. In a one-night, double-blind study conducted in 565 healthy adult subjects experiencing transient insomnia, doxepin 6 mg showed modest negative changes in SCT and VAS. In a 35-day, double-blind, placebo-controlled, parallel group study of doxepin 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 1 mg and 3 mg was comparable to placebo on DSST, SCT, and VAS. 6.3 Other Reactions Observed During the Pre-marketing Evaluation of Doxepin Doxepin was 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. 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, enur

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of the doxepin hydrochloride in the treatment of MDD in adult patients is not well understood. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of doxepin have not been fully characterized. 12.3 Pharmacokinetics Absorption In healthy volunteers, a single oral doxepin hydrochloride dose of 75 mg resulted in peak plasma doxepin concentrations that ranged from 8.8 ng/mL to 45.8 ng/mL (mean 26.1 ng/mL). Peak levels were reached between 2 and 4 hours (mean 2.9 hours) after doxepin hydrochloride administration. Peak levels for the primary active metabolite N-desmethyldoxepin (nordoxepin) ranged from 4.8 ng/mL to 14.5 ng/mL (mean 9.7 ng/mL) and were achieved between 2 and 10 hours after doxepin hydrochloride administration. Distribution The mean apparent volume of distribution for doxepin was approximately 20 L/kg. The protein binding for doxepin was approximately 76%. Elimination In healthy volunteers, the plasma elimination half-life of doxepin ranged from 8 to 24 hours (mean 17 hours). The half-life of nordoxepin ranged from 33 to 80 hours (mean 51 hours). The mean plasma clearance for doxepin was approximately 0.84 L/hour/kg. Metabolism After oral doxepin hydrochloride administration, approximately 55% to 87% of doxepin undergoes first-pass metabolism in the liver, forming the primary active metabolite nordoxepin. Metabolic pathways of doxepin include demethylation, N-oxidation, hydroxylation and glucuronide formation. Excretion Doxepin is excreted primarily in the urine, mainly as its metabolites, either free or in conjugate form. Specific Populations Patients with Hepatic Impairment : Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with hepatic impairment. Patients with hepatic impairment may have a greater systemic doxepin exposure than those with normal liver function [see Use in Specific Populations (8.6)]. Patients with Renal Impairment : The extent of renal excretion of doxepin is unknown. Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with renal impairment compared to those with normal renal function. Drug Interactions Studies Carbamazepine : After concomitant use of doxepin hydrochloride and carbamazepine, the combined exposure of doxepin and nordoxepin (12 hours after the last dose) was decreased by 55% compared to that after the use of doxepin hydrochloride alone [see Drug Interactions (7)]. Strong CYP2D6 Inhibitors : CYP2D6 contributes to the metabolism of doxepin and concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase doxepin exposure [see Drug Interactions (7)]. Cimetidine : Cimetidine is a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4. When cimetidine 300 mg twice daily was administered concomitantly with a single 6 mg dose of another oral doxepin product, there was approximately a 2-fold increase in doxepin Cmax and AUC compared to doxepin without cimetidine [see Drug Interactions (7)]. CYP2D6 Substrates : Concomitant use of doxepin hydrochloride and other CYP2D6 substrates may have impact on the plasma doxepin concentrations. The clinical significance of this possible impact is unknown.