Taro-Doxepin Product Monograph

RECENT MAJOR LABEL CHANGES

None at time of the most recent authorization.

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES.........................................................................................................2

TABLE OF CONTENTS ..........................................................................................................................2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................................4

1 INDICATIONS ..........................................................................................................................4

1.1 Pediatrics ............................................................................................................................. 4

1.2 Geriatrics ............................................................................................................................. 4

2 CONTRAINDICATIONS .............................................................................................................4

4 DOSAGE AND ADMINISTRATION .............................................................................................4

4.1 Dosing Considerations ......................................................................................................... 4

4.2 Recommended Dose and Dosage Adjustment .................................................................... 4

4.5 Missed dose ......................................................................................................................... 5

5 OVERDOSAGE .........................................................................................................................5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ..............................................6

7 WARNINGS AND PRECAUTIONS ..............................................................................................6

7.1 Special Populations ............................................................................................................. 8

7.1.1 Pregnant Women ................................................................................................................ 8

7.1.2 Breast-feeding ..................................................................................................................... 9

7.1.3 Pediatrics ............................................................................................................................. 9

7.1.4 Geriatrics ............................................................................................................................. 9

8 ADVERSE REACTIONS ..............................................................................................................9

8.1 Adverse reaction overview .................................................................................................. 9

8.2 Clinical Trial Adverse Reactions ........................................................................................... 9

8.3 Less Common Clinical Trial Adverse Reactions ................................................................. 11

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................................................... 12

8.5 Post-Market Adverse Reactions ........................................................................................ 12

9 DRUG INTERACTIONS ........................................................................................................... 13

9.1 Serious drug interactions .................................................................................................. 13

9.2 Drug Interactions Overview .............................................................................................. 13

9.3 Drug-Behavioural Interactions .......................................................................................... 13

9.4 Drug-Drug Interactions ...................................................................................................... 13

9.5 Drug-Food Interactions ..................................................................................................... 14

9.6 Drug-Herb Interactions ..................................................................................................... 15

9.7 Drug-Laboratory Test Interactions .................................................................................... 15

10 CLINICAL PHARMACOLOGY ................................................................................................... 15

10.1 Mechanism of Action ........................................................................................................ 15

10.2 Pharmacodynamics ........................................................................................................... 15

10.3 Pharmacokinetics .............................................................................................................. 16

11 STORAGE, STABILITY AND DISPOSAL ..................................................................................... 17

12 SPECIAL HANDLING INSTRUCTIONS ....................................................................................... 17

PART II: SCIENTIFIC INFORMATION ................................................................................................... 19

13 PHARMACEUTICAL INFORMATION ........................................................................................ 19

14 CLINICAL TRIALS ................................................................................................................... 19

14.1 Clinical Trial by Indication ................................................................................................. 19

14.2 Comparative Bioavailability Studies .................................................................................. 20

15 MICROBIOLOGY ................................................................................................................... 21

16 NON-CLINICAL TOXICOLOGY ................................................................................................. 21

17 SUPPORTING PRODUCT MONOGRAPHS ................................................................................ 22

Patient Medication Information ........................................................................................................ 23

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

TARO-DOXEPIN (doxepin tablets) is indicated for:

• the treatment and symptomatic relief of insomnia characterized by frequent nocturnal awakening, and/or early morning awakenings.

The clinical trials performed in support of efficacy were up to 1 month duration in adults and 3 months in duration in the elderly (≥ 65 years of age).

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): During clinical trials, no overall differences in safety or effectiveness were observed in elderly and adult patients, however greater sensitivity of some older individuals cannot be ruled out.

2 CONTRAINDICATIONS

TARO-DOXEPIN is contraindicated in patients:

• with known intolerance or hypersensitivity to doxepin hydrochloride, other dibenzoxepine compounds or to any ingredient in the formulation or component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• with untreated narrow angle glaucoma.
• with severe urinary retention.
• currently taking monoamine oxidase inhibitors (MAOIs) or who have used MAOIs within the past two weeks. Serious side effects and even death have been reported following the concomitant use of certain drugs with MAOIs.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

TARO-DOXEPIN should be taken within 30 minutes of bedtime. To minimize the potential for next day effects, TARO-DOXEPIN should not be taken within 3 hours of a meal (see 10.3 Pharmacokinetics). If symptoms fail to remit after 7-10 days, alternative primary psychiatric or medical illness should be considered.

4.2 Recommended Dose and Dosage Adjustment

Adults: The recommended dose of TARO-DOXEPIN for adults is 6 mg once daily. A 3 mg once daily dose may be appropriate for some patients, if clinically indicated.

Geriatrics (≥ 65 years old): The recommended starting dose of TARO-DOXEPIN in geriatric patients is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically indicated.

The safety and efficacy of doxepin tablets in the treatment of insomnia at doses higher than 6 mg has not been established and is therefore not recommended.

Pediatrics (< 18 years of age): TARO-DOXEPIN is not indicated for patients less than 18 years of age.

Use in Patients with Hepatic Impairment: Patients with hepatic impairment may display higher doxepin concentrations than healthy individuals. Initiate TARO-DOXEPIN treatment with 3 mg in patients with hepatic impairment and monitor closely for adverse daytime effects.

4.5 Missed dose

If a dose is missed, the patient should be instructed to take the next dose when it is due. The patient should be instructed to not make up for a missed dose by taking double dose next time.

5 OVERDOSAGE

Doxepin is routinely administrated for indications other than insomnia at doses 10- to 50-fold higher than the highest recommended dose of TARO-DOXEPIN (6 mg).

Symptoms: Excessive drowsiness leading to minor alterations of consciousness and even unresponsiveness could be an early indication of excessive dosage. However, overdosage with doxepin hydrochloride is more likely to be manifested by increased psychomotor agitation and convulsions leading to apnea and coma. The electrocardiogram (ECG) changes (broadening of QRS and T-wave abnormalities) tend to be a late finding and are not always accompanied by cardiovascular hemodynamic changes.

The following adverse effects have been associated with use of doxepin at doses higher than 6 mg.

Anticholinergic Effects: constipation and urinary retention

Central Nervous System: disorientation, hallucinations, numbness, paresthesias, extrapyramidal symptoms, seizures, tardive dyskinesia

Cardiovascular: hypotension

Gastrointestinal: aphthous stomatitis, indigestion

Endocrine: raised libido, testicular swelling, gynecomastia in males, enlargement of breasts and galactorrhea in the female, raising or lowering of blood sugar levels, and syndrome of inappropriate antidiuretic hormone secretion

Other: weight gain, sweating, flushing, jaundice, alopecia, exacerbation of asthma, and hyperpyrexia (in association with chlorpromazine)

Treatment: In general, treatment of overdosage should be symptomatic and supportive. Cardiac arrhythmias and central nervous system (CNS) involvement pose the greatest threat with tricyclic antidepressant overdosage and may occur suddenly even when initial symptoms appear to be mild. Therefore, patients who may have ingested an overdosage of doxepin hydrochloride, particularly children, should be hospitalized and kept under close surveillance.

If the patient is conscious, induced emesis followed by gastric lavage, with appropriate precautions to prevent pulmonary aspiration, should be accomplished as soon as possible. Following lavage, activated charcoal may be administered to reduce absorption. An adequate airway should be established in comatose patients and assisted ventilation instituted, if necessary. The possibility of occurrence of seizures should be kept in mind. External stimulation should be minimized to reduce the tendency to convulsions. Convulsions, should they occur, may respond to standard anticonvulsant therapy. However, barbiturates should be avoided since they may potentiate respiratory depression, particularly in children, and aggravate hypotension and coma.

ECG monitoring in an intensive care unit is recommended in all patients, particularly in the presence of ECG abnormalities, and should be maintained for several days after the cardiac rhythm has returned to normal. A patient who has ingested a toxic overdose of a tricyclic antidepressant may remain medically and psychiatrically unstable for several days due to sustained excessive drug levels. Unexpected cardiac deaths have occurred up to 6 days after overdosage with other antidepressants. The QRS interval of the electrocardiogram appears to be a reliable correlate of the severity of overdosage. If the QRS interval exceeds 100 milliseconds any time during the first 24 hours after overdosage, cardiac function should be continuously monitored for 5 or 6 days. Because of its effect on cardiac conduction, digitalis should be used only with caution. If rapid digitalization is required for the treatment of congestive heart failure, special care should be exercised in using the drug.

Shock should be treated with supportive measures such as intravenous fluids, oxygen and corticosteroids. Pressor agents, such as noradrenaline (but not adrenaline), are rarely indicated and should be given only after careful consideration and under continuous monitoring.

The slow intravenous administration of physostigmine salicylate has been reported to reverse most of the cardiovascular and CNS anticholinergic manifestations of tricyclic overdose. The recommended dosage in adults has been 1 mg to 2 mg in very slow intravenous injection. In children, the initial dosage should not exceed 0.5 mg and should be adjusted to age and response. Since physostigmine has a short duration of action, administration may have to be repeated at 30 to 60 minute intervals.

Deaths by deliberate or accidental overdosage have occurred with this class of drugs. Since the propensity for suicide is high in depressed patients, a suicide attempt by other means may occur during the recovery phase. The possibility of simultaneous ingestion of other drugs should also be considered.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

TARO-DOXEPIN is formulated as an oval shaped tablet available in two strengths, 3 mg and 6 mg, and showing the following distinguishable characteristics:

• 3 mg tablet is blue and identified with debossed markings of “T” & “S” on one side and blank on the other

• 6 mg tablet is green and identified with debossed markings of “T” & “S” on one side and “6” on

  the other

TARO-DOXEPIN is supplied in bottles of 30 tablets.

7 WARNINGS AND PRECAUTIONS

General

CNS depressant effects: When taken with TARO-DOXEPIN, the sedative effects of other CNS depressants, sedating antihistamines and alcoholic beverages may be potentiated (see 9.4 Drug- Drug Interactions). Patients should not consume alcohol with TARO-DOXEPIN (see 9.4 Drug-Drug Interactions). Patients should be cautioned about potential additive effects of TARO-DOXEPIN used in combination with CNS depressants or sedating antihistamines.

Complex sleep-related behaviours: Complex behaviours 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. Other potentially dangerous behaviours have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with “sleep-driving”, patients usually do not remember these events. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Although behaviours 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 behaviours, 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 TARO-DOXEPIN should be strongly considered for patients who report a “sleep- driving” episode or other complex behaviours episode.

Dependence/Tolerance

Potential withdrawal effects were assessed in a 35-day double blind study of adults with chronic insomnia who were randomized to placebo, doxepin tablets 3 mg, or doxepin tablets 6 mg. There was no indication of a withdrawal syndrome after discontinuation of doxepin 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 doxepin tablets 6 mg, versus 0 % in 3 mg and placebo subjects.

Doxepin tablets has not been demonstrated to produce tolerance or physical dependence. In a brief assessment of adverse events observed during discontinuation of doxepin following chronic administration, no symptoms indicative of a withdrawal syndrome were observed.

Abuse potential: Doxepin is not associated with abuse potential in animals or in humans. Healthcare professionals should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of doxepin (e.g., escalation of dose, drug-seeking behaviours).

Driving and Operating Machinery

Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug. This includes potential impairment of the performance of such activities that may occur the day following ingestion of TARO-DOXEPIN.

Hepatic/Biliary/Pancreatic

The effects of hepatic impairment on the pharmacokinetics of doxepin tablets have not been studied. Because doxepin is extensively metabolized by hepatic enzymes, patients with hepatic impairment may display higher doxepin concentrations than healthy individuals (see 4.2 Recommended Dose and Dosage Adjustment).

Psychiatric

Depression: TARO-DOXEPIN should be administered with caution when prescribed to patients with signs and symptoms of depression that could be intensified by hypnotic drugs. The potential for self-harm (e.g., intentional overdose) is high in patients with depression and thus, the least amount of drug should be available to them at any given time.

Worsening of depression and suicidal ideation: In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions have been reported. As with other hypnotics, TARO-DOXEPIN should be administered with caution in patients with depression. The risk of suicide due to pre-existing psychiatric disorders remains, even when the patient's insomnia improves.

Doxepin, the active ingredient in TARO-DOXEPIN, is an antidepressant at doses 10- to 100-fold higher than TARO-DOXEPIN. Antidepressants increased the risk compared to placebo of suicidal thinking and behaviours (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 TARO-DOXEPIN cannot be excluded.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviours listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behaviours sign or symptom of concern requires careful and immediate evaluation.

Renal

The effects of renal impairment on the pharmacokinetics of doxepin tablets have not been studied. Because only small amounts of doxepin and nordoxepin are eliminated in the urine, renal impairment is not expected to result in significantly altered doxepin concentrations.

Respiratory

Patients with sleep apnea: Doxepin tablets has not been studied in patients with obstructive sleep apnea. Since hypnotics have the capacity to depress respiratory drive, precautions should be taken if TARO-DOXEPIN is prescribed to patients with compromised respiratory function. In patients with severe sleep apnea, TARO-DOXEPIN is not recommended for use.

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate and well-controlled studies of doxepin tablets in pregnant women. TARO-DOXEPIN 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/or Delivery: The effects of doxepin tablets on labor and delivery in pregnant women have not been studied.

7.1.2 Breast-feeding

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 higher dose of doxepin to treat depression. Therefore, the administration of TARO-DOXEPIN to nursing mothers is not recommended.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety and effectiveness of doxepin tablets in pediatric patients have not been evaluated. Therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (≥ 65 years of age): A total of 362 subjects who were ≥ 65 years and 86 subjects who were ≥ 75 years received doxepin tablets in controlled clinical studies. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects but greater sensitivity of some older individuals cannot be ruled out as sleep-promoting drugs may cause confusion and over-sedation in elderly (see 4.2 Recommended Dose and Dosage Adjustment).

8 ADVERSE REACTIONS

8.1 Adverse reaction overview

The most common reported adverse drug reactions with doxepin tablets were somnolence, sedation and nausea. There was no apparent overall relationship to dose for any adverse reaction other than for the combined adverse events of somnolence and sedation.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful for identifying and approximating rates of adverse drug reactions in real-world use.

During the doxepin tablets clinical development program, a total of 1,017 subjects were exposed to doses of 1 mg to 6 mg of doxepin. The safety of doxepin tablets has been evaluated in three Phase 3 long-term placebo-controlled clinical trials (ranging from 28 to 85 days) conducted in adults (n = 221) and elderly (n = 494) subjects with chronic insomnia.

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 %, 1.3 %, and 0.8 % in the doxepin tablets 1 mg, 3 mg, and 6 mg groups, respectively. No reaction that resulted in discontinuation occurred at a rate greater than 0.5 %.

Table 2 lists the treatment-emergent adverse events, regardless of causality, reported by at least 1% of subjects who received doxepin tablets (3 mg or 6 mg) in the three long-term chronic insomnia studies (n = 221 for adult; and n = 417 for elderly).

Table 2 – Treatment-Emergent Adverse Events Reported at a Frequency ≥ 1 % of Subjects in Long-Term Chronic Insomnia Studies

Table 3 lists the treatment-emergent adverse events, regardless of causality, by age group reported by at least 2 % of subjects who received doxepin tablets in the three long-term chronic insomnia studies.

Table 3 – Treatment-Emergent Adverse Events Reported at a Frequency ≥ 2 % of Adults or Elderly Subjects in the Three Long-Term Chronic Insomnia Studies

*includes doxepin tablets doses ranging from 3 mg to 6 mg.

Treatment-emergent adverse events generally occurred with similar incidence in adults and elderly subjects with the exception with nausea (4.7 % in adults versus 0.5 % in elderly).

8.3 Less Common Clinical Trial Adverse Reactions

The following adverse events were reported in the administration of doxepin tablets at a frequency < 1 % in the three long-term chronic insomnia safety and efficacy studies.

Cardiac disorders: atrioventricular block, tachycardia

Ear and labyrinth disorders: hypoacusis, motion sickness, tinnitus

Eye disorders: blepharospasm, diplopia, eye pain, vision blurred, visual disturbance

Gastrointestinal disorders: abdominal pain upper, diarrhoea, gastroesophageal reflux disease, gingival recession, toothache, tooth fracture

General disorders: fatigue, feeling abnormal, hangover, oedema peripheral, pitting oedema, sluggishness

Infections and infestations: bronchitis, eye infection, fungal infection, gastroenteritis viral, herpes zoster, infective tenosynovitis, influenza, laryngitis, lower respiratory tract infection, onychomycosis, sinusitis, tooth abscess, urinary tract infection, viral infection

Injury, poisoning and procedural complications: back injury, excoriation, foot fracture, hand fracture, skin laceration, upper limb fracture

Investigations: blood pressure decreased, electrocardiogram abnormal

Metabolism and nutrition disorders: decreased appetite, hypokalemia, increased appetite

Musculoskeletal and connective tissue disorders: joint range of motion decreased, muscle cramp, myalgia, neck pain, pain in extremity

Neoplasm benign, malignant and unspecified (including cysts and polyps): lung adenocarcinoma stage I, malignant melanoma

Nervous system disorders: ageusia, ataxia, disturbance in attention, lethargy, migraine, sleep paralysis, tremor

Psychiatric disorders: depression, elevated mood, libido decreased, nightmare

Renal and urinary disorders: enuresis

Reproductive system and breast disorders: breast cyst

Respiratory, thoracic and mediastinal disorders: cough, nasal congestion, nasopharyngeal disorder, pharyngolaryngeal pain, sinus congestion

Skin and subcutaneous tissue disorders: dermatitis contact, erythema, pruritus generalized, rash, rosacea, skin lesion

Vascular disorders: blood pressure inadequately controlled, hematoma

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

There were no clinically relevant findings in the mean values and mean changes in clinical laboratory data after any of the treatments.

8.5 Post-Market Adverse Reactions

The following adverse events have been reported in users of doxepin tablets in the post marketing period. These adverse events are compiled from spontaneous reports and are listed regardless of frequency and whether or not a causal relationship with doxepin tablets has been established.

Adverse events previously observed in clinical trials are not duplicated below.

Cardiac disorders: palpitations

Eye disorders: dry eye, lacrimation decreased, ocular hyperemia, visual acuity reduced

Gastrointestinal disorders: abdominal discomfort, bowel movement irregularity, dyspepsia, flatulence

General disorders: energy increased, epistaxis, feeling drunk, hypotrichosis, irritability, stress symptoms

Injury, poisoning and procedural complications: intentional overdose

Investigations: dysuria, hyperglycemia, hypoglycemia, swollen tongue, urine output decreased, urine output increased, weight increased

Musculoskeletal and connective tissue disorders: muscle spasms

Nervous system disorders: drowsiness, dyskinesia, head discomfort, nervousness, poor quality sleep, psychomotor hyperactive, restless leg syndrome, restlessness

Psychiatric disorders: amnesia, hallucination, insomnia, mental impairment, mood altered, sleep disorder, suicidal ideation, suicidal thoughts, thinking abnormal

Renal and urinary disorders: micturition urgency, urinary hesitation

Respiratory, thoracic and mediastinal disorders: dyspnea, hoarseness, pharyngeal hypoesthesia, pharyngeal edema, throat irritation

Skin and subcutaneous tissue disorders: hyperhidrosis, night sweats, rash generalized

Vascular disorders: hot flush

9 DRUG INTERACTIONS

9.1 Serious drug interactions

9.2 Drug Interactions Overview

Doxepin tablets 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 tablets is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations. The ability of doxepin tablets to induce CYP isozymes is not known.

Since doxepin is metabolized by CYP2C19 and CYP2D6, inhibitors of these CYP isozymes may increase the exposure of doxepin.

9.3 Drug-Behavioural Interactions

TARO-DOXEPIN may potentiate the sedative effects of alcohol. Patients should not consume alcohol with TARO-DOXEPIN.

9.4 Drug-Drug Interactions

TARO-DOXEPIN may potentiate the sedative effects of sedating antihistamines and other CNS depressants.

Table 4 – Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Doxepin tablets is readily absorbed from the gastrointestinal tract. When administered with a high-fat meal, the AUC for a single 6 mg dose was increased by 41 % and the C_max was 15 % higher than when given in a fasted state. Additionally, compared to the fasted state, the time to reach maximum plasma concentration (T_max) was delayed by approximately 3 hours. Therefore, for faster onset and to minimize the potential for next day effects, it is recommended not to take TARO-DOXEPIN within 3 hours of a meal (see 4.1 Dosing Considerations and 10.3 Pharmacokinetics).

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but it is well established that doxepin is one of the most potent H₁ antagonist and has a substantial selectivity for H₁ receptors (Ki < 1 nM) versus other CNS and peripheral targets. Doxepin has an affinity toward the human 5-HT_2a receptor; this property could play a role in promoting sleep maintenance, as several studies have proposed that antagonism at this site promotes restorative Stage III-IV sleep.

10.2 Pharmacodynamics

Cardiovascular

Cardiac safety: In a thorough QTc prolongation study in healthy subjects, doxepin had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses of 6 mg or 50 mg.

In vitro studies: The effect of doxepin on IKr channels (encoded by HERG; human ether-à-go-go related gene) has been investigated. Doxepin was found to inhibit IHERG channels with an IC₅₀ of 6.5 ± 1.4 mcM and native IKr with an IC₅₀ of 4.4 ± 0.6 mcM. This concentration is approximately 1300-fold higher than the concentration reached with the highest strength of doxepin tablets (6 mg tablets, approximately 3.4 nM C_max=1.094 ng/mL).

In vivo studies: Doxepin elicits either positive or negative inotropic effects depending on species, decreases in blood pressure, and dysrhythmias characterized by broadening of the QRS complex and QT prolongation. In studies where plasma concentrations are reported, these events typically occur at concentrations well in excess of 1000 ng/mL, or more than 1000 times the maximum mean concentrations (at 6 mg).

Clinical electrocardiography studies: In a double-blind, randomized, placebo-controlled, parallel group study in healthy subjects (n = 44-50/treatment arm), serial ECG recordings were collected on day 7 of treatment with doxepin at a therapeutic dose of 6 mg and a supratherapeutic dose of 50 mg. Doxepin 6 mg and doxepin 50 mg did not affect the QTc interval, the QRS duration, or the PR interval. Heart rate was not affected at the 6 mg dose, but statistically significant increases in heart rate were observed at the 50 mg dose, with a maximum placebo-adjusted mean change from baseline of 6.5 bpm (90% CI 4.3, 8.6).

Doxepin was associated with a blood pressure-lowering effect. Serial blood pressure measurements were performed on day 1 of treatment at predose and at 2, 4, 8, 12, and 24 h post-dosing. Doxepin 6 mg was associated with a statistically significant placebo-adjusted decrease from baseline in systolic blood pressure at 4 h post-dosing: mean -2.92 mmHg (90 % CI -5.39, -0.45). Statistically significant reductions in diastolic blood pressure were reported at 4, 8, and 12 h post-dosing with doxepin 6 mg, with a maximum decrease at 8 h post-dosing: mean - 4.67 mmHg (90 % CI -6.78, -2.55).

Doxepin 50 mg was associated with statistically significant placebo-adjusted decreases from baseline in systolic blood pressure at all post-dose time points on day 1. The largest observed decrease in systolic blood pressure occurred at 8 h post-dose: mean -7.09 mmHg (90 % CI -9.56,

-4.62). Diastolic blood pressure was significantly reduced at 2, 4, 8, and 12 h post-dosing in the doxepin 50 mg group. The maximum observed decrease in diastolic blood pressure occurred at 8 h post-dosing: mean -6.68 mmHg (90 % CI -8.80, -4.57).

The C_max and AUC values of doxepin following treatment with the 50 mg dose for 7 days were 12-fold higher than for the 6 mg dose.

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 tablets.

In a one-night, double-blind study conducted in 565 healthy adult subjects experiencing transient insomnia, doxepin tablets 6 mg showed modest negative changes in SCT and VAS.

In a 35-day, double-blind, placebo-controlled, parallel group study of doxepin 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 tablets 1 mg and 3 mg was comparable to placebo on DSST, SCT, and VAS.

10.3 Pharmacokinetics

The pharmacokinetics of doxepin tablets 3 mg and 6 mg have been characterized in healthy subjects.

Table 5 – Summary of Doxepin Pharmacokinetic Parameters in Healthy Volunteers Following a Single Dose of 6 mg

Estimates presented are arithmetic mean (CV %) for AUC, C_max, and t_1/2 and median (range) for T_max.

Absorption: After oral administration of a 6 mg dose to fasted healthy subjects, doxepin plasma concentrations increase rapidly, with peak concentrations (median T_max) occurring 3.5 hours postdose. Peak plasma concentrations (C_max) and total exposure (AUC) of doxepin tablets increased in a dose-proportional manner for 3 mg and 6 mg doses.

Doxepin tablets is readily absorbed from the gastrointestinal tract. When administered with a high-fat meal, the AUC for a single 6 mg dose was increased by 41 % and the C_max was 15 % higher than when given in a fasted state. Additionally, compared to the fasted state, the time to reach maximum plasma concentration (T_max) was delayed by approximately 3 hours. Therefore, for faster onset and to minimize the potential for next day effects, it is recommended not to take TARO-DOXEPIN within 3 hours of a meal.

Distribution: Doxepin tablets is highly lipophilic and widely distributed throughout the body tissues.

The mean apparent volume of distribution following a single 6 mg oral dose of doxepin tablets in healthy subjects was 11,930 liters. Doxepin tablets is approximately 80% bound to plasma proteins.

Metabolism: Following oral administration, doxepin tablets is extensively metabolized by oxidation and demethylation. The primary metabolite is N-desmethyldoxepin (nordoxepin). The primary metabolites undergo 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.

In animals, data shows that doxepin is well absorbed, widely distributed, moderately protein bounded, and undergoes extensive Phase I and Phase II metabolism, the most important pathways being demethylation, hydroxylation and glucuronidation. Doxepin metabolism appears to be similar for humans and animal species and is isomer specific, with demethylation reactions occurring for both isomers primarily via CYP2C19 (with contribution of 1A2, 2C9 and possibly 3A4), while only the E isomer is hydroxylated via CYP2D6. Doxepin, as well as oxidative metabolites and conjugates of doxepin and its isomers are rapidly eliminated and the majority of drug products are recovered in urine.

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_1/2) of doxepin is 15.3 hours and 31 hours for nordoxepin.

Special Populations and Conditions

• Pediatrics: The pharmacokinetics of doxepin tablets have not been studied in subjects under 18 years of age.
• Geriatrics: The pharmacokinetics of doxepin tablets have not been studied in elderly subjects. Elimination of doxepin may be slower and the terminal half-life may be longer in the elderly, which may result in drug accumulation and a greater risk of undesirable effects.
• Gender: No gender effect was observed in healthy subject/patients after repeated administration of doxepin tablets.
• Hepatic Insufficiency: No studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of doxepin tablets. Because doxepin is extensively metabolized by hepatic enzymes, patients with hepatic insufficiency may display higher doxepin concentrations than healthy individuals.
• Renal Insufficiency: No studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of doxepin tablets. 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.
• Genetic Polymorphism: Poor metabolizers of CYP2C19 and CYP2D6 may have higher doxepin plasma levels than normal subjects.
• Drug Interactions: Since doxepin is metabolized by CYP2C19 and CYP2D6, inhibitors of theses CYP isozymes may increase the exposure of doxepin.

11 STORAGE, STABILITY AND DISPOSAL

Keep TARO-DOXEPIN out of reach and sight of children. Store TARO-DOXEPIN at room temperature between 15°C and 30°C. Protect from light.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: doxepin hydrochloride

Chemical name: doxepin hydrochloride is an (E) and (Z) geometric, isomeric mixture of 1 propanamine, 3-Dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl 1-Propanamine, Hydrochloride

Molecular formula and molecular mass: C₁₉H₂₁NO·HCl and 315.84 g/mol

Structural formula:

Physicochemical properties: Doxepin hydrochloride appears as white or almost white crystalline powder, that is freely soluble in water.

14 CLINICAL TRIALS

14.1 Clinical Trial by Indication

Insomnia

The efficacy of doxepin 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 experimentally induced transient (n = 565) insomnia. Doxepin tablets was 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.

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 (followed by 2 days of drug discontinuation – i.e.: Day 36 and 37) in adults with chronic insomnia. Doxepin tablets 3 mg and 6 mg showed little evidence of rebound insomnia in the two nights following discontinuation. However, there was evidence of mild discontinuation effects on latency to persistent sleep (LPS) in the two nights following doxepin tablets discontinuation.

Study Results

Chronic Insomnia

Adults: A randomized, double-blind, parallel-group study was conducted in adults (n = 221) with chronic insomnia. Doxepin tablets 3 mg and 6 mg was compared to placebo out to 30 days. Doxepin tablets 3 mg and 6 mg were superior to placebo on objective WASO and TST (total sleep time). Doxepin tablets 3 mg was superior to placebo on subjective WASO at night 1 only. Doxepin tablets 6 mg was superior to placebo on subjective WASO at night 1, and nominally superior at some later time points out to Day 30. Doxepin tablets 3 mg was superior to placebo on subjective TST at night 1 only. Doxepin tablets 6 mg was superior to placebo on subjective TST at night 1, and at some later time points. On other secondary subjective outcome measures a similar pattern was observed, suggesting superior efficacy of the doxepin tablets 6 mg dose compared to the 3 mg dose.

Elderly: Elderly subjects with chronic insomnia were assessed in two parallel-group studies.

The first randomized, double-blind study assessed doxepin 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 tablets 3 mg, but not 1 mg, was superior to placebo on objective and subjective WASO. The second randomized, double-blind study assessed doxepin 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 tablets 6 mg was superior to placebo.

Transient Insomnia

Healthy adult subjects (n = 565) experiencing transient insomnia (induced by a 3 hour phase advance) during the first night in a sleep laboratory were evaluated in a randomized, double- blind, parallel-group, single-dose study of doxepin tablets 6 mg relative to placebo. Doxepin tablets 6 mg was superior to placebo on objective WASO and subjective WASO.

14.2 Comparative Bioavailability Studies

A double blind, randomized, two-period, two-treatment, two-sequence, crossover, oral comparative bioavailability study of TARO-DOXEPIN 6 mg tablets (Taro Pharmaceuticals Inc.) and SILENOR 6 mg tablets (Currax™ Pharmaceuticals LLC, USA), was conducted in healthy, adult, male and female subjects under fasting conditions. Comparative bioavailability data from 69 subjects that were included in the statistical analysis are presented in the following table:

Table 6 Summary Table of the Comparative Bioavailability Data

¹ TARO-DOXEPIN (doxepin, as doxepin hydrochloride) tablets, 6 mg (Taro Pharmaceuticals Inc.).

² SILENOR (doxepin, as doxepin hydrochloride) tablets, 6 mg (Currax™ Pharmaceuticals LLC, USA).

³ Expressed as the median (range) only.

⁴ Expressed as the arithmetic mean (CV%) only.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Repeat Dose Toxicity: In multiple-dose studies in rats, clinical signs of CNS depression were observed, with the addition of decreases in body weight and food consumption. However, there was no consistent evidence of target organ toxicity. Doxepin-related decreased body weight and body weight gain was also noted in animals receiving 100 mg/kg/day. Alkaline phosphatase was increased in males at 100 mg/kg/day. There were no doxepin-related macroscopic findings in either sex. There were no effects on hematology, coagulation, or urinalysis parameters. Possible doxepin-related organ weight changes were present in the liver, spleen, and thymus. Increases in liver weight were present in males and females at 25, 50, and 100 mg/kg/day. Decreased spleen weights were observed in males and females at 100 mg/kg/day and in females only at 25 and 50 mg/kg/day. No correlative microscopic findings were present in the livers or spleens. Thymus weight was decreased in both sexes at 100 mg/kg/day. These decreases in thymus weights corresponded with minimal to mild lymphoid depletion microscopically.

Carcinogenicity: 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. Doxepin has shown no oncogenic effect when administered daily to rats for 104 weeks at doses of 10, 30 and 75 mg.

Genotoxicity: Doxepin was negative in in vitro (bacterial reverse mutation, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays.

Reproductive and Developmental Toxicology: 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 (approx. 53 to 61-fold).

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. SILENOR® (tablets, 3 mg and 6 mg), control 290257, product monograph, Endo Operations Ltd. (2025-02-27)