Taro-Duloxetine Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults

Major Depressive Disorder

Taro-Duloxetine (duloxetine hydrochloride) is indicated for the symptomatic relief of major depressive disorder (MDD).

The efficacy of duloxetine hydrochloride in maintaining an antidepressant response for up to 12 months in patients who have shown initial treatment response following up to 34 weeks of open-label acute treatment was demonstrated in 2 placebo-controlled trials.

The efficacy of duloxetine hydrochloride in hospitalized patients with MDD has not been studied.

Generalized Anxiety Disorder

Taro-Duloxetine is indicated for the symptomatic relief of anxiety causing clinically significant distress in patients with generalized anxiety disorder (GAD).

The efficacy of duloxetine hydrochloride in maintaining anxiolytic response for up to 6 months in patients with GAD was demonstrated in a long-term placebo-controlled trial in patients who had initially responded to duloxetine hydrochloride during a 6-month open-label phase.

Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

Taro-Duloxetine is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN).

Fibromvalgia

Taro-Duloxetine is indicated for the management of pain associated with fibromyalgia (FM).

Chronic Low Back Pain

Taro-Duloxetine is indicated for the management of chronic low back pain (CLBP).

Osteoarthritis of the Knee

Taro-Duloxetine is indicated for the management of chronic pain associated with osteoarthritis (OA) of the knee.

Long-Term Use of Taro-Duloxetine

The efficacy of duloxetine hydrochloride in long-term use for MDD has been demonstrated in controlled clinical trials for up to 12 months. Physicians should periodically re-evaluate the long-term usefulness of Taro-Duloxetine for the individual patient.

The efficacy of duloxetine hydrochloride has been demonstrated in controlled clinical trials for up to 12 weeks in DPN and FM and up to 13 weeks in patients with CLBP and OA. The physician who elects to use Taro-Duloxetine for extended periods in DPN, FM, CLBP or OA should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Geriatrics (≥65 years of age)

Pharmacokinetic results suggest no overall differences between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see WARNINGS AND PRECAUTIONS: Special Populations: Geriatrics and ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions).

Pediatrics (<18 years of age)

The safety and efficacy of duloxetine hydrochloride in pediatric patients (<18 years of age) have not been established and its use in this patient population is not indicated. See WARNINGS AND PRECAUTIONS: General, Potential Association with Behavioural and Emotional Changes, including Self-Harm; see also DOSAGE AND ADMINISTRATION section.

CONTRAINDICATIONS

Hypersensitivity

Taro-Duloxetine (duloxetine hydrochloride) is contraindicated in patients with a known hypersensitivity to the drug or the other components of the product.

Monoamine Oxidase Inhibitors (MAOIs)

Taro-Duloxetine should not be used concomitantly with a monoamine oxidase inhibitor (MAOI), including the antibiotic linezolid and the thiazine dye methylthioninium chloride (methylene blue) which are less well-known examples of MAOIs, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping Taro-Duloxetine before starting an MAOI (see WARNINGS AND PRECAUTIONS: General: MAOIs).

Hepatic Impairment

Taro-Duloxetine is contraindicated in patients with any liver disease resulting in hepatic impairment (see WARNINGS and PRECAUTIONS: General: Hepatic Impairment; and DOSAGE AND ADMINISTRATION: Dosage for Patients with Hepatic Impairment).

Uncontrolled Narrow-Angle Glaucoma

In clinical trials, duloxetine hydrochloride was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma (see WARNINGS AND PRECAUTIONS: General: Ophthalmologic).

Severe Renal Impairment

Taro-Duloxetine is contraindicated in patients with severe renal impairment (i.e. creatinine clearance <30 mL/min) or end-stage renal disease (see WARNINGS AND PRECAUTIONS: Renal Impairment).

Thioridazine

Concomitant use of Taro-Duloxetine and thioridazine is contraindicated (see WARNINGS AND PRECAUTIONS: General: Thioridazine).

CYP1A2 Inhibitors

Taro-Duloxetine should not be used concomitantly with potent CYP1A2 inhibitors (e.g. fluvoxamine) and some quinolone antibiotics (e.g. ciprofloxacin or enoxacin) (see DRUG INTERACTIONS).

WARNINGS AND PRECAUTIONS

General

Potential Association with Behavioural and Emotional Changes, Including Self-Harm

Pediatrics: Placebo-Controlled Clinical Trial Data

• Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.
• The small denominators in the clinical trials database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

Adults and Pediatrics: Additional data

• There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, and depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients ages 18 to 24 years with psychiatric disorder showed an increased risk of suicidal behaviour with antidepressants compared to placebo.

Akathisia/Psychomotor Restlessness

The use of SSRI’s and other newer antidepressants, including duloxetine, has been very rarely associated with the development of akathisia, which is characterized by a subjectively unpleasant or distressing restlessness and a need to move, often accompanied by an inability to sit or stand. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Discontinuation Symptoms

Patients currently taking SSRIs or newer antidepressants should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended (see WARNINGS AND PRECAUTIONS: Dependence: Discontinuation of Treatment; ADVERSE REACTIONS: Adverse Events Following Discontinuation of Treatment; and DOSAGE AND ADMINISTRATION: Discontinuation of Treatment).

Monoamine Oxidase Inhibitors (MAOIs):

In patients receiving a serotonin reuptake inhibitor in combination with a MAOI, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of Taro-Duloxetine (duloxetine hydrochloride) and MAOIs have not been evaluated in humans or animals. Therefore, because duloxetine hydrochloride is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that duloxetine hydrochloride not be used in combination with a MAOI, including the antibiotic linezolid and methylene blue, a surgical dye, or within at least 14 days of discontinuing treatment with a MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping Taro-Duloxetine before starting a MAOI (see CONTRAINDICATIONS: MAOIs; and DRUG INTERACTIONS).

Hepatic Impairment:

Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single non-therapeutic (20 mg) dose of duloxetine hydrochloride, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer. Taro-Duloxetine is contraindicated in patients with any liver disease resulting in hepatic impairment (see CONTRAINDICATIONS: Hepatic Impairment; ACTION AND CLINICAL PHARMACOLOGY: Hepatic Impairment; and DOSAGE AND ADMINISTRATION: Dosage for Patients with Hepatic Impairment).

Hepatotoxicity:

Duloxetine hydrochloride increases the risk of elevation of serum aminotransferase levels. In clinical trials, the median time to detection of the aminotransferase elevation was about two months. In most patients, these were usually transient and self-limiting with continued use, or resolved upon discontinuation of Duloxetine hydrochloride. Liver aminotransferase elevations resulted in the discontinuation of 0.3% (89/29,435) of duloxetine hydrochloride-treated patients.

In placebo-controlled trials in MDD, elevations of alanine aminotransferase (ALT) to >3 times the upper limit of normal occurred in 0.4% (8/1902) of duloxetine hydrochloride-treated patients and in 0.2% (2/1200) of placebo-treated patients. In placebo-controlled trials in DPN, elevations of ALT to >3 times the upper limit of normal occurred in 2% (13/662) of duloxetine hydrochloride-treated patients and in 0% (0/281) of placebo-treated patients.

In the full cohort of placebo-controlled trials in any indication for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.37% (132/9611) of duloxetine hydrochloride-treated patients compared with 0.49%

(35/7182) of placebo-treated patients. In placebo-controlled studies using a fixed-dose design, there was evidence of a dose-response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.

Postmarketing reports have described cases of hepatitis with abdominal pain, hepatomegaly and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported (see ADVERSE REACTIONS: Post-Market Adverse Drug Reactions: Hepatic).

The combination of aminotransferase elevations and elevated bilirubin, without evidence of cholestasis, is generally recognized as an important predictor of severe liver injury. In clinical trials, 7 duloxetine hydrochloride patients had elevations of aminotransferase and bilirubin, but 5 of 7 also had elevation of alkaline phosphatase, suggesting an obstructive process; in 3 of these 7 patients, there was evidence of heavy alcohol use and this may have contributed to the abnormalities seen. Two placebo-treated patients also had aminotransferase elevations with elevated bilirubin.

Post-marketing reports indicate that elevated aminotransferase, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Severe elevations of liver enzymes (>10 times the upper limit of normal) or liver injury with a cholestatic or mixed pattern have been rarely reported, in some cases associated with excessive alcohol use or pre-existing liver disease. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Taro-Duloxetine should ordinarily not be prescribed to patients with substantial alcohol use (see Special Populations: Use in Patients with Substantial Alcohol Use). Taro-Duloxetine should not be used in patients with any liver disease resulting in hepatic impairment (see CONTRAINDICATIONS: Hepatic Impairment). Taro-Duloxetine should be used with caution in patients treated with other drugs associated with hepatic injury (see ADVERSE REACTIONS: Post-Market Adverse Drug Reactions: Hepatic).

Severe hepatic injury, associated with jaundice, has been reported very rarely in patients with non-alcoholic fatty liver disease (NAFLD). It is not clear whether these events are related to use of duloxetine or to other factors.

Physicians should be aware of the signs and symptoms of liver damage (e.g. pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained "flu-like" symptoms) and should investigate such symptoms promptly. Taro-Duloxetine should be discontinued and should not be restarted in patients with jaundice.

Thioridazine:

Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This effect appears to be dose-related.

An in vivo study suggests that drugs which inhibit P4502D6, including certain SSRIs such as paroxetine, fluoxetine, and fluvoxamine, will elevate plasma levels of thioridazine. Therefore, as duloxetine hydrochloride is a moderate inhibitor of CYP2D6 and increases the AUC and Cmax of drugs metabolized by CYP2D6, Taro-Duloxetine should not be used in combination with thioridazine. See CONTRAINDICATIONS and DRUG INTERACTIONS sections.

Inhibitors of CYP1A2:

Because CYP1A2 is involved in duloxetine metabolism, the potential exists for increased concentrations of duloxetine when co-administered with a CYP1A2 inhibitor. Fluvoxamine (100 mg QD), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77%. Taro-Duloxetine should not be used concomitantly with potent CYP1A2 inhibitors (e.g. fluvoxamine) and some quinolone antibiotics (e.g. ciprofloxacin or enoxacin). See CONTRAINDICATIONS and DRUG INTERACTIONS.

Sucrose:

Taro-Duloxetine capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

Bone Fracture Risk

Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs/SNRIs. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with Taro-Duloxetine. Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal. Preliminary data from observational studies show association of SSRIs/SNRIs and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long term treatment with SSRIs/SNRIs, including Taro-Duloxetine, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.

Cardiovascular

Blood Pressure and Heart Rate: Duloxetine hydrochloride has been associated with an increase in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of duloxetine.

In placebo-controlled clinical trials across all approved indications for change from baseline to endpoint, duloxetine hydrochloride treatment was associated with mean increases of 0.09 mm Hg in systolic and 0.65 mm Hg in diastolic blood pressure compared to mean decreases of 1.35 mm Hg systolic and 0.79 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure (see ADVERSE REACTIONS: Vital Sign Changes). There was no significant difference between treatment groups in the rate of discontinuation due to elevated blood pressure.

Duloxetine hydrochloride treatment, for up to 26 weeks in placebo-controlled trials across all approved indications was associated with an increase in heart rate of 1.39 beats per minute (mean change from baseline to endpoint).

Cases of hypertensive crisis have been reported very rarely with duloxetine hydrochloride, especially in patients with pre-existing hypertension. Taro-Duloxetine should be used with caution in patients with uncontrolled hypertension as it may expose them to hypertensive crisis (see ADVERSE REACTIONS: Post-Market Adverse Drug Reactions).

Blood pressure and heart rate should be evaluated prior to initiating treatment and periodically measured throughout treatment, especially in patients with known hypertension and/or other cardiac disease. Taro-Duloxetine should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when duloxetine hydrochloride is used with drugs that may impair its metabolism (see DRUG INTERACTIONS). For patients who experience a sustained increase in blood pressure while receiving Taro-Duloxetine either dose reduction or gradual discontinuation should be considered.

Electrocardiogram Changes: Duloxetine hydrochloride has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s pre-marketing testing.

Electrocardiograms of 321 patients who received duloxetine hydrochloride in MDD placebo-controlled clinical trials and 728 patients who received duloxetine hydrochloride in DPN placebo-controlled clinical trials were evaluated; duloxetine hydrochloride was not associated with the development of clinically significant ECG abnormalities (see ADVERSE REACTIONS: Electrocardiogram Changes). Additionally a clinical pharmacology study was conducted to assess the safety of duloxetine at the highest tolerable level of exposure of duloxetine (200 mg BID) and to measure QT interval. QT interval at doses up to 200 mg BID was not prolonged (see ACTION AND CLINICAL PHARMACOLOGY: Clinical Safety Pharmacology).

In MDD and DPN placebo-controlled clinical trials, duloxetine hydrochloride-treated patients did not develop abnormal ECGs at a rate different from that in placebo-treated patients (see ADVERSE REACTIONS, Electrocardiogram Changes).

Concomitant Illness

Clinical experience with duloxetine hydrochloride in patients with concomitant systemic illnesses is limited. Caution is advisable when using duloxetine hydrochloride in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. For example, caution should be exercised in using Taro-Duloxetine in patients with conditions that slow gastric emptying (e.g., some patients with diabetic gastroparesis) (see DRUG INTERACTIONS: Potential for Interaction with Drugs That Affect Gastric Acidity).

Dependence

Dependence Liability: In animal studies, duloxetine did not demonstrate stimulant or barbiturate-like (depressant) abuse potential. Duloxetine did produce reductions in activity in rodents and monkeys. In drug dependence studies, duloxetine did not demonstrate any dependence-producing potential in monkeys or rats.

While duloxetine hydrochloride has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behaviour in the clinical trials. However, it is not possible to predict on the basis of pre-marketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of duloxetine hydrochloride (e.g. development of tolerance, incrementation of dose, drug-seeking behaviour).

Discontinuation of Treatment: Discontinuation symptoms have been systematically evaluated in patients taking duloxetine hydrochloride. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate in duloxetine hydrochloride-treated patients compared with those discontinuing from placebo: dizziness, nausea, headache, paresthesia, fatigue, vomiting, irritability, nightmare, insomnia, diarrhea, anxiety, hyperhidrosis, vertigo, somnolence, and myalgia.

Patients should be monitored for these symptoms when discontinuing treatment with Taro-Duloxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see ADVERSE REACTIONS: Adverse Events Following Discontinuation of Treatment; and DOSAGE and ADMINISTRATION: Discontinuation of Treatment).

Endocrine

Glucose Regulation: In DPN trials, duloxetine hydrochloride treatment worsened glycemic control in some diabetic patients. In three clinical trials of duloxetine hydrochloride for the management of pain associated with DPN, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 9.8 mmol/L (176 mg/dL), and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, duloxetine hydrochloride was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 0.67 mmol/L (12 mg/dL) in the duloxetine hydrochloride group and decreased by 0.64 mmol/L (11.5 mg/dL) in the routine care group, which was statistically significantly different. HbA1c increased by 0.5% in the duloxetine hydrochloride group and by 0.2% in the routine care groups.

Hematologic

Abnormal Bleeding: SSRIs and SNRIs, including duloxetine hydrochloride, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDS), warfarin and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding (see ADVERSE REACTIONS: Other Adverse Events – Gastrointestinal Bleeding, and Post Market Adverse Drug Reactions). Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening haemorrhages. An observational study showed an association between the occurrence of postpartum hemorrhage and exposure to duloxetine hydrochloride close to delivery (see WARNINGS AND PRECAUTIONS: Special Populations: Labour and Delivery).

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Taro-Duloxetine and NSAIDS, ASA, or other drugs that affect coagulation (see DRUG

INTERACTIONS – Potential for Duloxetine to Affect Other Drugs). Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g. thrombocytopenia).

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Taro-Duloxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when duloxetine hydrochloride was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Taro-Duloxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death (see ADVERSE REACTIONS, Post-Marketing Adverse Drug Reactions).

Neurologic

Seizures: Although anticonvulsant effects of duloxetine have been observed in animal studies, duloxetine hydrochloride has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product’s premarketing testing. In placebo-controlled clinical trials across all indications, seizures/convulsions occurred in 0.03% (3/10,524) of patients treated with duloxetine and 0.01% (1/7699) of patients treated with placebo. As with other CNS active drugs, Taro-Duloxetine should be used with caution in patients with a history of a seizure disorder.

Serotonin Syndrome/Neuroleptic Malignant Syndrome: On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment with SSRIs, particularly when given in combination with other serotonergic and/or neuroleptic drugs. Serotonin syndrome symptoms may include mental status changes (e.g., confusion, irritability, extreme agitation progressing to delirium and coma), autonomic instability with rapid fluctuations of vital signs (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., rigidity, myoclonus, hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). As these syndromes may result in potentially life-threatening conditions, treatment with duloxetine hydrochloride should be discontinued if such events occur and supportive symptomatic treatment should be initiated. Taro-Duloxetine should not be used in combination with MAOIs, including the antibiotic linezolid and the thiazine dye methylthioninium chloride (methylene blue) which are less well-known examples of MAOIs,) or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Triptans (5HT₁ Agonists): Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with duloxetine hydrochloride and a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. See WARNINGS AND PRECAUTIONS: Serotonin Syndrome/Neuroleptic Malignant Syndrome, and DRUG INTERACTIONS: Triptans (5HT₁ agonists).

Effects on Ability to Drive and Use Machines: Any psychoactive drug may impair judgment, thinking, or motor skills. Duloxetine hydrochloride may be associated with undesirable effects such as sedation and dizziness. Therefore, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that duloxetine hydrochloride therapy does not affect their ability to engage in such activities.

Ophthalmologic

Angle-Closure Glaucoma: As with other antidepressants, duloxetine hydrochloride can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.

Psychiatric

Suicide: The possibility of a suicide attempt is inherent in MDD and other psychiatric disorders and may persist until significant remission occurs.

As with other drugs with similar pharmacological action (inhibitor of serotonin reuptake [SSRI] or inhibitor of serotonin and norepinephrine reuptake [SNRI]), isolated cases of suicidal ideation and suicidal behaviours have been reported during duloxetine hydrochloride therapy or early after treatment discontinuation.

Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose (see WARNINGS AND PRECAUTIONS: General: Potential Association With Behavioural And Emotional Changes, Including Self-Harm; ADVERSE REACTIONS: Adverse Events Following Discontinuation of Treatment; and DOSAGE AND ADMINISTRATION: Discontinuation of Treatment).

Because of the well established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders (see WARNINGS AND PRECAUTIONS: General: Potential Association with Behavioural and Emotional Changes, Including Self-Harm section).

Physicians should encourage patients to report any distressing thoughts or feelings at any time.

Activation of Mania/Hypomania: In placebo-controlled trials in patients with MDD, activation of mania or hypomania was reported in 0.1% (2/2489) of duloxetine hydrochloride-treated patients and 0.1% (1/1625) of placebo-treated patients. No activation of mania or hypomania was reported in GAD, DPN, FM, CLBP or OA placebo-controlled trials. Activation of mania/hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of

MDD. As with similar CNS active drugs, Taro-Duloxetine should be used cautiously in patients with a history of mania.

A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should be made only after patients have been adequately assessed to determine if they are at risk for bipolar disorder.

Renal

Increased plasma concentrations of duloxetine occur in patients with end-stage renal disease (requiring dialysis). For this reason Taro-Duloxetine is not recommended for patients with end-stage renal disease or severe renal impairment (see CONTRAINDICATIONS: Severe Renal Impairment; ACTION AND CLINICAL PHARMACOLOGY: Renal Impairment; and DOSAGE AND ADMINISTRATION: Dosage for Patients with Renal Impairment).

Urinary Hesitation and Retention

Duloxetine hydrochloride is in a class of drugs known to affect urethral resistance. Urinary hesitation and retention have been observed in clinical trials for various indications. Spontaneous post-marketing cases of urinary hesitation and retention have been reported. In some instances of urinary retention associated with duloxetine hydrochloride therapy, hospitalization and/or catheterization was required. If symptoms of urinary hesitation develop during treatment with Taro-Duloxetine, discontinuation or dose-reduction should be considered. Caution should also be exercised in prescribing Taro-Duloxetine to patients who use concomitant medications that may affect voiding (e.g., anticholinergics; see ADVERSE REACTIONS: Other Adverse Events).

Sexual Function

Refer to ADVERSE REACTIONS: Sexual Function.

Skin

Serious Dermatological Reactions

There have been very rare post-marketing reports of serious cutaneous reactions including Stevens-Johnson Syndrome (SJS) and erythema multiforme in patients treated with duloxetine hydrochloride (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Post-market reporting rate is generally accepted to be an underestimate due to under-reporting. In some cases, causality in relation to duloxetine hydrochloride could not be established. Patients should be advised that if they experience a skin rash, they should discontinue Taro-Duloxetine treatment and contact their physician for assessment and advice.

Carcinogenesis, Mutagenesis and Impairment of Fertility

For animal data, see TOXICOLOGY.

Special Populations

Pregnant Women:

Safe use of duloxetine hydrochloride during pregnancy has not been established. Therefore, Taro-Duloxetine should not be administered to pregnant women or those intending to become pregnant, unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus.

There are no adequate and well-controlled studies in pregnant women. In animal reproductive studies, duloxetine and/or its metabolites were found to cross the placenta in rats and duloxetine has been shown to have adverse effects on embryo/fetal and post-natal development (see TOXICOLOGY). Because animal reproduction studies are not always predictive of human response and because of the possibility that duloxetine and/or its metabolites may have adverse effects on the newborn, the use of this drug during pregnancy should only be considered if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Post-marketing reports indicate that some neonates exposed to SSRIs or newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see CONTRAINDICATIONS: MAOIs). When treating a pregnant woman with Taro-Duloxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION: Treatment of Pregnant Women During the Third Trimester).

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Labour and Delivery: An observational study evaluating the risks of maternal outcomes associated with exposure to duloxetine during pregnancy demonstrated an increased risk of postpartum hemorrhage for women exposed to duloxetine. The risk of postpartum hemorrhage was 36/1000 (95% confidence interval 24.8-49.4) women exposed to duloxetine close to delivery (final 30 days of pregnancy) compared to 23/1000 (95% confidence interval 23.1-23.4) women who were not exposed to duloxetine during pregnancy [adjusted relative risk 1.53 (95% confidence interval 1.08-2.18)].

In observational study data, maternal exposure to duloxetine during pregnancy was associated with an increased risk for preterm birth (less than 2-fold). The majority of the premature births occurred between 35 and 36 weeks of gestation.

When treating a pregnant woman, the use of duloxetine should only be considered if the potential benefit justifies the potential risk to the fetus.

Nursing Women:

Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on Taro-Duloxetine is not recommended.

Patients should be advised to notify their physician if they are breast-feeding.

Pediatrics (<18 years of age):

The safety and efficacy of duloxetine hydrochloride in pediatric patients (<18 years of age) have not been established and its use in this patient population is not indicated. See WARNINGS AND PRECAUTIONS: General, Potential Association with Behavioural and Emotional Changes, including Self-Harm. See also DOSAGE AND ADMINISTRATION, Dosage for Pediatric Patients; and INDICATIONS AND CLINICAL USE, Pediatrics sections.

Geriatrics (≥65 years of age):

Of the 2418 duloxetine hydrochloride-treated patients in the MDD clinical studies 5.9% (143) were 65 years of age or over. Of the 1169 duloxetine hydrochloride-treated patients in the acute placebo-controlled GAD studies, 17.2% (201) were 65 years of age or over. Of the 1429 duloxetine hydrochloride-treated patients in the DPN studies, 31.9% (456) were 65 years of age or over. Of the 1226 duloxetine hydrochloride treated patients in FM studies, 7.9% (97) were 65 years of age or over. Of the 600 duloxetine hydrochloride-treated patients in CLBP placebo-controlled clinical studies, 22.3% (134) were 65 years of age or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and although other reported clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out (see WARNINGS AND PRECAUTIONS: Bone Fracture Risk; WARNINGS AND PRECAUTIONS: Hyponatremia).

Use In Patients With Substantial Alcohol Use:

Use of duloxetine hydrochloride in patients who consume substantial amounts of alcohol may be associated with severe liver injury. Isolated cases of liver failure, including fatal cases, have been reported. Taro-Duloxetine should only be used in exceptional circumstances and with extreme caution in these patients (see WARNINGS and PRECAUTIONS: Hepatotoxicity, and ADVERSE REACTIONS: Post-Market Adverse Drug Reactions: Hepatic).

Monitoring and Laboratory Tests

No specific laboratory tests are recommended.

Patient Counseling Information

Consumer Information is included in the package of Taro-Duloxetine dispensed to the patient. Patients should be advised to read this sheet prior to using Taro-Duloxetine.

Patients who are prescribed Taro-Duloxetine should be given the following instructions by the physician:

1. 1. Proper Administration

Taro-Duloxetine is usually taken once a day. Taro-Duloxetine capsules may be taken with or without food; however, food may help reduce the incidence of initial nausea.

Taro-Duloxetine should be swallowed whole and should not be chewed or crushed, nor should the contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.

1. 2. Continued Therapy

While patients may notice improvement with Taro-Duloxetine therapy in 1 to 4 weeks, they should be advised to continue therapy for several months or longer as directed.

1. 3. New or Worsened Emotional or Behavioural Problems

Patients should be advised that they may experience new or worsened feelings of agitation, hostility, anxiety, impulsivity, or thoughts about suicide, self-harm or harm to others, particularly in the first few weeks of treatment or when doses are adjusted. Patients should inform their doctor of any changes in their emotional status, including any distressing thoughts or feelings, after starting the medication. Physicians should advise patients to not discontinue Taro-Duloxetine on their own without consulting their physician.

1. 4. Discontinuation Symptoms

Patients should be advised that discontinuation of Taro-Duloxetine may be associated with symptoms such as dizziness, nausea, diarrhea, headache, paresthesia, vomiting, irritability, anxiety, excessive sweating, fatigue, insomnia, and nightmare. These symptoms usually disappear without needing treatment. Patients should be instructed to contact their doctor immediately if they have these or any other symptoms. Physicians should advise patients to not discontinue Taro-Duloxetine on their own without consulting their physician.

1. 5. Hepatotoxicity

Patients should be informed that severe liver problems, sometimes fatal, have been reported in patients treated with Taro-Duloxetine. Patients should be instructed to talk to their doctor about the signs and symptoms of liver damage. Use of Taro-Duloxetine in patients who consume substantial amounts of alcohol may be associated with severe liver injury.

1. 6. Alcohol Use

Patients should be advised to keep use of alcohol to a minimum while taking Taro-Duloxetine.

1. 7. Effects on Blood Pressure

Patients should be cautioned that Taro-Duloxetine may cause an increase in blood pressure.

1. 8. Abnormal Bleeding

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Taro-Duloxetine and NSAIDS, ASA, or other drugs that affect coagulation.

1. 9. Serotonin Syndrome/Neuroleptic Malignant Syndrome

Patients should be cautioned about the risk of serotonin syndrome associated with the concomitant use of Taro-Duloxetine and other serotonergic and/or neuroleptic drugs. Patients should be advised of the signs and symptoms associated with serotonin syndrome and to seek medical care immediately if they experience the symptoms.

1. 10. Hyponatremia

Patients should be advised that hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Taro-Duloxetine. Patients should be advised of the signs and symptoms associated with hyponatremia.

1. 11. Urinary Hesitation and Retention

Patients should be instructed to consult with their doctor if they develop any problems with urine flow.

1. 12. Bone Fractures

Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal.

1. 13. Serious Skin Reactions

Patients should be advised that if they experience a skin rash, they should discontinue Taro-Duloxetine treatment and contact their physician for assessment and advice.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Major Depressive Disorder (MDD):

Duloxetine hydrochloride has been evaluated for safety in 2418 patients diagnosed with MDD who participated in multiple-dose pre-marketing trials, representing 1099 patient-years of exposure. Among these 2418 duloxetine hydrochloride-treated patients, 1139 patients participated in eight 8- or 9-week, placebo-controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1-year in an open-label safety study using flexible doses between 80 and 120 mg/day. Two placebo-controlled studies with doses of 80 and 120 mg/day had 6-month maintenance extensions. Of these 2418 patients, 993 duloxetine hydrochloride-treated patients were exposed for at least 180 days and 445 duloxetine hydrochloride-treated patients were exposed for at least 1 year. The long-term safety of duloxetine hydrochloride in MDD patients has also been evaluated in 533 patients in one long-term maintenance of effect study consisting of a 12-week, open-label, acute phase followed by a 26-week, double-blind continuation phase and in 514 patients in another long-term maintenance of effect study consisting of a 4 to 10 week, open-label, acute phase, a 24-week, open-label, continuation phase followed by a 52-week, double-blind, maintenance phase.

Generalized Anxiety Disorder (GAD):

Duloxetine hydrochloride has also been evaluated for safety in 1797 patients with GAD. Most patients in the acute placebo-controlled studies received duloxetine hydrochloride 60 mg QD or 120 mg QD as their final dose.

Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (DPN):

Duloxetine hydrochloride has also been evaluated for safety in 1429 patients with neuropathic pain associated with DPN representing 894.13 patient-years of exposure. Among these 1429 duloxetine hydrochloride-treated patients, 800 patients participated in three 12- to 13-week, placebo-controlled trials at doses ranging from 20 to 120 mg/day. An additional 449 patients were enrolled in an open-label safety study using 120 mg/day for a duration of 6 months (87 patients continued on to an open-label extension phase for an additional 24 weeks). Another 57 patients, originally treated with placebo, were exposed to duloxetine hydrochloride for up to 12 months at 60 mg twice daily in an extension phase. Among these 1429 patients, 881 had ≥6 months of exposure to duloxetine hydrochloride, and 515 had greater than 12 months of exposure.

Fibromyalgia:

Duloxetine hydrochloride has also been evaluated for safety in 1236 patients with fibromyalgia. In placebo-controlled trials, 369 patients received duloxetine hydrochloride 60 mg QD (120.08 patient-years), 221 patients received duloxetine hydrochloride 120 mg QD (102.18 patient-years), and 220 patients received duloxetine hydrochloride 60 mg BID (36.49 patient-years) as a maximum dose.

Chronic Low Back Pain:

Duloxetine hydrochloride has been evaluated for safety in 698 patients with CLBP (representing 237.99 patient-years exposure to duloxetine). In 12- to 13-week placebo-controlled studies, the majority of the duloxetine hydrochloride-treated patients (428, 71.3%) received duloxetine hydrochloride 60 mg QD. Approximately a quarter of duloxetine hydrochloride-treated patients (139, 23.2%) received duloxetine 120 mg QD at some point during the acute phase.

Chronic Pain Associated with Osteoarthritis (OA) of the Knee:

Duloxetine hydrochloride has been evaluated for safety in 503 duloxetine-treated patients with OA of the knee in two 13-week, placebo-controlled trials and one 10-week placebo-controlled “add-on” trial with NSAIDs (see CLINICAL TRIALS).

Clinical Trial Adverse Drug Reactions

The data in the following tables and text cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. The cited data provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence in the population studied.

Adverse Events Reported as Reasons for Discontinuation of Treatment

Placebo-Controlled MDD Trials: Approximately 10% of the 1139 patients who received Duloxetine hydrochloride in acute placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients receiving placebo. Nausea (duloxetine hydrochloride 1.4%, placebo 0.1%) was the only common adverse event reported as reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine hydrochloride-treated patients and at a rate of at least twice that of placebo).

Placebo-Controlled GAD Trials: Approximately 14% of the 910 patients who received duloxetine hydrochloride in acute placebo-controlled trials for GAD discontinued treatment due to an adverse event, compared with 5.3% of the 665 patients receiving placebo. Nausea (duloxetine hydrochloride 3.3%, placebo 0.5%) and dizziness (duloxetine hydrochloride 1.0%, placebo 0.5%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (as defined under MDD Trials, above).

Placebo-Controlled Trials for Neuropathic Pain Associated with DPN: Approximately 12% of the 800 patients who received duloxetine hydrochloride in acute placebo-controlled trials discontinued treatment due to an adverse event, compared with 5% of the 339 patients receiving placebo. Nausea (duloxetine hydrochloride 3.0%, placebo 0.3%), dizziness

(duloxetine hydrochloride 1.1%, placebo 0.3%), and somnolence (duloxetine hydrochloride 1.2%, placebo 0%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (as defined under MDD Trials, above).

Placebo-Controlled FM Trials: Approximately 19% of the 876 patients who received duloxetine hydrochloride in placebo-controlled trials for FM discontinued treatment due to an adverse event, compared with 11.8% of the 535 patients receiving placebo. Nausea (duloxetine hydrochloride 1.9%, placebo 0.7%), fatigue (duloxetine hydrochloride 1.3%, placebo 0.2%) and somnolence (duloxetine hydrochloride 1.5%, placebo 0%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (as defined under MDD Trials, above).

Placebo-Controlled CLBP Trials: Approximately 17% of the 600 patients who received duloxetine hydrochloride in 13-week placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% of the 441 patients receiving placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine hydrochloride 3.0%, placebo 0.7%) and somnolence (duloxetine hydrochloride 1.0%, placebo 0.0%).

Placebo-Controlled OA Trials: Approximately 16% of the 239 patients who received duloxetine hydrochloride in 13 week placebo-controlled trials for chronic pain due to OA of the knee discontinued treatment due to an adverse reaction, compared with 5.6% of the 248 patients receiving placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine hydrochloride 2.9%, placebo 0.8%) and asthenia (duloxetine hydrochloride 1.3%, placebo 0.0%). Similarly, more patients taking duloxetine hydrochloride (40/264, or 15.2%) discontinued from the 10 week placebo-controlled, “add-on” trial with NSAIDs due to adverse events than did patients in the placebo group (23/260, or 8.8%).

Adverse Events Following Discontinuation of Treatment

Discontinuation symptoms have been systematically evaluated in patients taking duloxetine hydrochloride. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate in duloxetine hydrochloride-treated patients compared with those discontinuing from placebo: dizziness, nausea, headache, paresthesia, fatigue, vomiting, irritability, nightmare, insomnia, diarrhea, anxiety, hyperhidrosis, vertigo, somnolence, and myalgia. Although these events are generally self-limiting, some have been reported to be severe. (See WARNINGS AND PRECAUTIONS: Discontinuation of Treatment and DOSAGE AND ADMINISTRATION).

Adverse Events Occurring Among Duloxetine Hydrochloride-Treated Patients in Placebo-Controlled Major Depressive Disorder (MDD) Trials

Table 1 lists the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with duloxetine hydrochloride in the acute phase of MDD placebo-controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in duloxetine hydrochloride-treated MDD patients (incidence 5% or greater and at least twice the incidence in placebo patients) were: nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating. MedDRA terminology has been used to classify reported adverse events.

Table 1: Treatment-Emergent Adverse Events Incidence in the Acute Phase of MDD Placebo-Controlled Trials¹

1 Events reported by at least 2% of patients treated with duloxetine hydrochloride and more often than with placebo. The following events were reported by at least 2% of patients treated with duloxetine hydrochloride for MDD and had an incidence equal to or less than placebo: upper abdominal pain, palpitations, dyspepsia, back pain, arthralgia, headache, pharyngitis, cough, nasopharyngitis, and upper respiratory tract infection.

2 Term includes anorexia

3 Term includes middle insomnia

4 Male patients only

5 Term includes ejaculation disorder and ejaculation failure

Adverse events seen in men and women were generally similar except for effects on sexual function (see ADVERSE REACTIONS: Sexual Function). Clinical studies of duloxetine hydrochloride did not suggest a difference in adverse event rates in people over or under 65 years of age. There were too few non-Caucasian patients studied to determine if these patients responded differently from Caucasian patients.

Table 2 lists the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with duloxetine hydrochloride in a long-term maintenance of effect study in MDD patients. The most commonly observed adverse events in duloxetine hydrochloride-treated MDD patients (incidence 5% or greater) during the double-blind maintenance phase included back pain, headache, nasopharyngitis, and fatigue.

Table 2: Treatment-Emergent Adverse Events Incidence from a Long-term Maintenance of MDD Effect Study

Adverse Events Occurring Among Duloxetine Hydrochloride-Treated Patients in Placebo-Controlled Generalized Anxiety Disorder (GAD) Trials

Table 3 lists the incidence of treatment-emergent adverse events that occurred in ≥2% of patients treated with duloxetine hydrochloride in the GAD acute placebo-controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in duloxetine hydrochloride-treated GAD patients (incidence 5% or greater and at least twice the incidence in placebo patients) included nausea, dizziness, dry mouth, fatigue, constipation, somnolence and increased sweating.

Table 3: Treatment-Emergent Adverse Events Incidence in the Acute Phase of GAD Placebo-Controlled Trials¹

1 Events reported by at least 2% of patients treated with duloxetine hydrochloride and more often than with placebo.

2 Term includes anorexia

3 Term includes middle insomnia

4 Male patients only

5 Term includes ejaculation disorder and ejaculation failure

Dose Dependency of Adverse Events in GAD

Adverse events that occurred in the duloxetine 120 mg/day group at an incidence rate that was 5% or greater, and approximately twice that of the duloxetine 60 mg/day group included the following: increased sweating (15.3% versus 8.3%), diarrhea (7.6% versus 3.0%), and vomiting (6.5% versus 3.0%).

Adverse Events Occurring Among Duloxetine Hydrochloride-Treated Patients in Placebo-Controlled Trials of Pain Associated with Diabetic Peripheral Neuropathy (DPN):

Table 4 lists the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with duloxetine hydrochloride in the acute phase (12-week) of DPN placebo-controlled trials (doses of 20 to 120 mg/day) and with an incidence greater than placebo. The most commonly observed adverse events in duloxetine hydrochloride-treated DPN patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea, constipation, dry mouth, vomiting, fatigue, decreased appetite, somnolence, erectile dysfunction, and hyperhidrosis. MedDRA terminology has been used to classify reported adverse events.

Table 4: Treatment-Emergent Adverse Events Incidence in the Acute Phase of Neuropathic Pain Associated with DPN Placebo-Controlled Trials¹

* Includes all doses used in DPN studies (i.e. 20mg QD, 60mg QD and 60mg BID)

1 Events reported by at least 2% of patients treated with duloxetine hydrochloride and more often than placebo. The following events were reported by at least 2% of patients treated with duloxetine hydrochloride for DPNP and had an incidence equal to or less than placebo: pain in extremity, upper respiratory tract infection, arthralgia, cough, influenza, pruritus, musculoskeletal pain (includes myalgia and neck pain), and edema peripheral.

2 Includes stomach discomfort.

3 Also includes asthenia.

4 Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.

5 2.8% of patients treated with duloxetine hydrochloride; 2.7% of patients who received placebo.

6 Includes anorexia.

7 Includes hypersomnia, sedation.

8 Includes hypoesthesia, hypoesthesia facial, and paresthesia oral.

9 Also includes middle insomnia, early morning awakening, and initial insomnia.

10 Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation.

11 Male patients only. (duloxetine hydrochloride 60 mg QD, N=201; duloxetine hydrochloride 60 mg BID, N=190; all duloxetine hydrochloride, N=466; placebo, N=181).

12 3.9% of patients treated with duloxetine hydrochloride; 3.8% of patients who received placebo.

Adverse Events Occurring Among Duloxetine Hydrochloride-Treated Patients in Placebo-Controlled Fibromyalgia (FM) Trials

Table 5 lists the incidence of treatment-emergent adverse events (TEAEs) that occurred in 2% of patients treated with duloxetine hydrochloride in the fibromyalgia (FM) placebo-controlled trials and with an incidence greater than placebo. The following TEAEs had an incidence in the duloxetine hydrochloride treatment group ≥ 5.0% and were significantly more frequent with duloxetine hydrochloride than with placebo: nausea, headache, dry mouth, insomnia, fatigue, constipation, diarrhoea, dizziness, somnolence, hyperhidrosis, and decreased appetite.

Table 5: Treatment-Emergent Adverse Events Incidence in the FM Placebo-Controlled

Trials*

* Events reported by at least 2% of patients treated with duloxetine hydrochloride and more often than with placebo. The following events were reported by at least 2% of patients treated with duloxetine hydrochloride for FM and had an incidence equal to or less than placebo: nasopharyngitis, back pain, sinusitis, anxiety, arthralgia, depression, pain in extremity, vomiting, pain, abdominal pain, bronchitis, abdominal pain upper

1 Male patients only (N = 46 duloxetine-treated patients versus 26 placebo patients)

a Also includes asthenia

b Also includes anorexia

c Also includes hypersomnia and sedation

d Also includes middle insomnia, early morning awakening, and initial insomnia

e Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation

f Also includes nightmare

g Also includes anorgasmia

h Also includes loss of libido

I Also includes ejaculation failure and ejaculation dysfunction

Dose Dependency of Adverse Events in Fibromyalgia

In one fibromyalgia study the most common adverse events that occurred in the duloxetine 120 mg QD group at an incidence rate that was 5% or greater, and approximately twice that of the duloxetine 60 mg/day group included the following: constipation (21.1% versus 10.0%; p=.01) and somnolence (15.0% versus 7.3%, p=.043).

In another fibromyalgia study somnolence was the most common adverse event that occurred in the duloxetine 60 mg BID group at an incidence rate that was 5% or greater, and approximately twice that of the duloxetine 60 mg QD group (12.1% versus 5.1%, p=.064).

Adverse Events Occurring Among Duloxetine Hydrochloride-Treated Patients in Placebo-Controlled CLBP Trials

Table 6 lists the incidence of treatment-emergent adverse events (TEAEs) that occurred in ≥2% of patients treated with duloxetine hydrochloride in the CLBP placebo-controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in duloxetine hydrochloride-treated CLBP patients (incidence 5% or greater and at least twice the incidence in placebo patients) included nausea, insomnia, somnolence, constipation, dry mouth, fatigue, and dizziness.

Table 6: Treatment-Emergent Adverse Events Incidence in the CLBP Placebo-Controlled Trials*

* Events reported by at least 2% of patients treated with duloxetine hydrochloride and more often than placebo. The following events were reported by at least 2% of patients treated with duloxetine hydrochloride and CLBP and had an incidence equal to or less than placebo: arthralgia; and nasopharyngitis

1 Also includes abdominal pain upper, abdominal discomfort, and gastrointestinal pain

2 Also includes initial insomnia, middle insomnia, terminal insomnia

Adverse Events Occurring Among Duloxetine Hydrochloride-Treated Patients in Placebo-Controlled OA Trials

Table 7 lists the incidence of treatment-emergent adverse events (TEAEs) that occurred in ≥2% of patients treated with duloxetine hydrochloride in three placebo-controlled OA trials (treatment duration = 10 to 13 weeks) with an incidence greater than placebo. The most commonly observed adverse events in duloxetine hydrochloride-treated OA patients (incidence 5% or greater and at least twice the incidence in placebo patients) were: nausea, constipation, dry mouth, diarrhea, abdominal pain, fatigue, dizziness, insomnia, decreased appetite and erectile dysfunction.

Table 7: Treatment-Emergent Adverse Events in Clinical Trials of Patients with Pain due to Osteoarthritis of the Knee

a. Also includes Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain.

b. Also includes Asthenia

c. Also includes Hypersomnia, Sedation.

d. Also includes Initial insomnia, Middle insomnia, Terminal insomnia.

e. Also includes Ejaculation failure

f. Male only (N=173 for Placebo, N=192 for Duloxetine).

Other Adverse Events

Urinary Hesitation: Duloxetine hydrochloride is in a class of drugs known to affect urethral resistance during the filling stage of the bladder. Spontaneous post-marketing cases of urinary hesitation and retention have been reported. In some instances of urinary retention associated with duloxetine hydrochloride therapy, hospitalization and/or catheterization was required. If symptoms of urinary hesitation develop during treatment with duloxetine hydrochloride, consideration should be given to the possibility that they might be drug-related. Dose-reduction or discontinuation should also be considered (see WARNINGS AND PRECAUTIONS: Renal; Urinary Hesitation and Retention).

Gastrointestinal Bleeding: In placebo-controlled clinical trials across all indications, gastrointestinal hemorrhage was reported in 0.23% of duloxetine hydrochloride-treated patients compared with 0.15% of placebo-treated patients (p=.198). The term gastrointestinal hemorrhage is a combined term consisting of diarrhea hemorrhagic, lower gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, melena, rectal hemorrhage, and ulcer hemorrhage. A statistically significant difference in the incidence of gastrointestinal hemorrhage between duloxetine hydrochloride-treated patients compared with placebo-treated patients was only seen in MDD placebo-controlled trials (duloxetine hydrochloride 0.3% [9/3007 patients] versus 0.05% [1/1883 patients], p=.031) but not the other indications. In fibromyalgia placebo-controlled trials, 0.44% (5/1139) patients experienced gastrointestinal bleeding compared to 0.12% (1/802) patients in the placebo arm; this difference was not statistically significant (p = .328). Post-marketing cases of gastrointestinal bleeding have also been reported (see ADVERSE REACTIONS: Post-Marketing Adverse Drug Reactions).

Laboratory Changes: Duloxetine hydrochloride treatment in placebo-controlled clinical trials across indications was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, transient, abnormal values were observed for these analytes in duloxetine hydrochloride-treated patients, compared with placebo-treated patients (see WARNINGS AND PRECAUTIONS: Hepatotoxicity). In placebo-controlled clinical trials across all indications, treatment-emergent high potassium levels were observed more frequently in duloxetine-treated patients than placebo patients (2.2% with duloxetine versus 1.6% with placebo, p=.016). In addition, the treatment-emergent adverse event “Blood potassium increased”, including the individual terms Hyperkalemia and Blood potassium increased, was reported more frequently in duloxetine-treated patients than placebo patients (0.11% with duloxetine versus 0.05% with placebo, p=.146).

Vital Sign Changes: In placebo-controlled clinical trials across all approved indications for change from baseline to endpoint, duloxetine hydrochloride treatment was associated with mean increases of 0.09 mm Hg in systolic blood pressure and 0.65 mm Hg in diastolic blood pressure compared to mean decreases of 1.35 mm Hg systolic and 0.79 mm Hg diastolic in placebo-treated patients.

Sustained elevations of either systolic or diastolic blood pressure were also measured in placebo-controlled studies. A patient was considered to have sustained elevation in blood pressure if either of the following criteria for sustained elevation in systolic blood pressure or diastolic blood pressure was met.

• Sustained elevation in systolic blood pressure was defined as a value ≥140 mm Hg with an increase ≥10 mm Hg from baseline for three consecutive visits.
• Sustained elevation in diastolic blood pressure was defined as a value ≥90 mm Hg with an increase of ≥10 mm Hg from baseline for three consecutive visits.

In placebo-controlled trials across all approved indications, there was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure.

There was no significant difference between treatment groups in the frequency of elevated blood pressure as a reason for discontinuation.

Duloxetine hydrochloride treatment, for up to 26 weeks in placebo-controlled trials across all approved indications, was associated with an increase in heart rate of 1.39 beats per minute (mean change from baseline to endpoint).

Weight Changes: Duloxetine hydrochloride had minimal effect on weight. In MDD and GAD placebo-controlled clinical trials, patients treated with duloxetine hydrochloride for up to 9 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.35 kg in placebo-treated patients. This represents a small but significant decrease in weight compared with placebo-treated patients. Long-term trials over 52 weeks in duration demonstrated a mean weight gain of 2.4 kg but this was not clinically significant.

In DPN, FM, CLBP and OA studies, patients treated with duloxetine hydrochloride (N=3160) for up to 26 weeks experienced a mean weight loss of approximately 0.63 kg compared with a mean weight gain of approximately 0.15 kg in placebo-treated patients.

In 3 placebo-controlled DPN clinical trials, patients treated with duloxetine hydrochloride for up to 13 weeks experienced a mean weight loss of 0.92 kg, compared with a mean weight gain of 0.16 kg in placebo-treated patients. In long-term trials of up to 52 weeks in duration, the mean decrease in weight was 0.35 kg for duloxetine hydrochloride-treated patients.

In FM studies, patients treated with duloxetine hydrochloride for up to 26-weeks experienced a mean weight loss of approximately 0.4 kg compared with a mean weight gain of approximately 0.3 kg in placebo-treated patients. In one long-term FM 60-week uncontrolled study, (195 patients completed the study) duloxetine hydrochloride patients had a mean weight increase of 0.7 kg.

In one long-term CLBP 54-week study (13-week, placebo-controlled acute phase and 41-week uncontrolled extension phase), duloxetine hydrochloride-treated patients (N=109) experienced a mean weight decrease of 0.6 kg compared with a mean weight increase of 0.1 kg in placebo-treated patients (N=116) during the acute phase of the study. In the open-label phase, all patients treated with duloxetine hydrochloride (N=178) had a mean weight increase of 0.4 kg.

Electrocardiogram Changes: Electrocardiograms were obtained from duloxetine hydrochloride-treated patients and placebo-treated patients in clinical trials across all indications. No clinically significant differences were observed for QTc, QT, PR, and QRS intervals between duloxetine hydrochloride-treated and placebo-treated patients. There were no differences in clinically meaningful QTcF elevations between duloxetine hydrochloride and placebo.

Additionally a clinical pharmacology study was conducted to assess the safety of duloxetine at the highest tolerable level of exposure of duloxetine (200 mg BID) and to measure QT interval. QT interval at doses up to 200 mg BID was not prolonged (see ACTION AND CLINICAL PHARMACOLOGY: Clinical Safety Pharmacology).

Glucose Regulation: In DPN trials, duloxetine hydrochloride treatment worsened glycemic control in some diabetic patients. In three clinical trials of duloxetine hydrochloride for the management of pain associated with DPN, the mean duration of diabetes was approximately

12 years, the mean baseline fasting blood glucose was 9.8 mmol/L (176 mg/dL), and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, duloxetine hydrochloride was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 0.67 mmol/L (12 mg/dL) in the duloxetine hydrochloride group and decreased by 0.64 mmol/L (11.5 mg/dL) in the routine care group, which was statistically different. HbA1c increased by 0.5% in the duloxetine hydrochloride group and by 0.2% in the routine care groups.

Sexual Function: Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Table 8 displays the incidence of sexual side effects spontaneously reported by at least 2% of either male or female patients taking duloxetine hydrochloride in MDD placebo-controlled trials.

Table 8: Treatment-Emergent Sexual Dysfunction-Related Adverse Events Incidence in MDD Placebo-Controlled Trials¹

1 Events reported by at least 2% of patients treated with duloxetine hydrochloride and more often than with placebo.

2 Term includes anorgasmia.

3 Term includes ejaculation disorder and ejaculation failure.

NA=Not applicable

Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine

The following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials across all indications, 34,756 patients were treated with duloxetine. Of these, 26.9% (9337) took duloxetine for at least 6 months, and 12.4% (4317) for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labelling, (2) for which a drug cause was remote, (3) which were so general that they were uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: common adverse reactions are those occurring in at least 1/100 patients; uncommon adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in less than 1/1000 patients.

Cardiac Disorders — Common: palpitations; Uncommon: myocardial infarction, tachycardia.

Ear and Labyrinth Disorders — Common: vertigo; Uncommon: ear pain, tinnitus.

Endocrine Disorders — Rare: hypothyroidism.

Eye Disorders — Uncommon: diplopia, visual impairment, mydriasis, dry eye.

Gastrointestinal Disorders — Common: flatulence; Uncommon: eructation, gastritis, halitosis, gastroenteritis; Rare: gastric ulcer, melena, stomatitis.

General Disorders and Administration Site Conditions — Common: chills (includes rigors); Uncommon: falls (falls were more common in the elderly, ≥ 65 years old), feeling abnormal, feeling hot and/or cold, malaise, thirst, dysphagia; Rare: gait disturbance.

Infections and Infestations — Uncommon: laryngitis.

Investigations — Uncommon: weight increased, blood cholesterol increased.

Metabolism and Nutrition Disorders — Uncommon: dehydration, hyperlipidemia; Rare: dyslipidemia.

Musculoskeletal and Connective Tissue Disorders — Common: musculoskeletal pain; Uncommon: muscle tightness (includes musculoskeletal stiffness), muscle twitching.

Nervous System Disorders — Common: dysgeusia, lethargy, paresthesia/hypoesthesia; Uncommon: disturbance in attention, dyskinesia, myoclonus, poor quality sleep; Rare: dysarthria.

Psychiatric Disorders — Common: abnormal dreams (includes nightmares), sleep disorder; Uncommon: apathy, bruxism, disorientation (includes confusional state), irritability, mood swings, suicide attempt; Rare: completed suicide.

Renal and Urinary Disorders — Common: Urinary frequency; Uncommon: dysuria, micturition urgency, nocturia, polyuria, urine flow decreased, urine odour abnormal.

Reproductive System and Breast Disorders — Common: anorgasmia/orgasm abnormal; Uncommon: menopausal symptoms, sexual dysfunction, testicular pain; Rare: menstrual disorder.

Respiratory, Thoracic and Mediastinal Disorders — Common: Oropharyngeal pain; Uncommon: throat tightness.

Skin and Subcutaneous Tissue Disorders — Uncommon: cold sweat, dermatitis contact, increased tendency to bruise, night sweats, photosensitivity reaction; Rare: ecchymosis.

Vascular Disorders — Common: flushing (includes hot flush); Uncommon: peripheral coldness, orthostatic hypotension.

Post-Market Adverse Drug Reactions

Since the first approval of duloxetine hydrochloride on 03 August 2004 through 31 July 2013, it is estimated that 63.8 million patients have been treated with duloxetine hydrochloride worldwide, accounting for over 23.8 million patient-years of therapy.

Hepatic: Post-marketing surveillance has identified reports of hepatic injury, including hepatocellular, pure cholestatic and mixed injury ranging from mild elevations in laboratory values to more severe clinical signs and symptoms of liver injury. Isolated cases of liver failure, including fatal cases, have been reported. Most of these cases have been reported in patients with past or current medical and other risk factors for liver injury, including alcohol abuse, hepatitis, or exposure to drugs with known adverse effects on the liver and it is unclear to what extent duloxetine may have played a contributing role (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Hepatotoxicity).

Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including duloxetine hydrochloride. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when duloxetine hydrochloride was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Taro-Duloxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death (see WARNINGS AND PRECAUTIONS).

Gastrointestinal bleeding: Post-marketing cases of gastrointestinal bleeding have been reported very rarely (Table 9) (see also Clinical Trial Adverse Drug Reactions: Other Adverse Events, Gastrointestinal Bleeding).

Serious Dermatological Reactions: There have been very rare post-marketing reports of serious cutaneous reactions including Stevens-Johnson Syndrome (SJS) and erythema multiforme in patients treated with duloxetine hydrochloride (see WARNINGS AND PRECAUTIONS). Post-market reporting rate is generally accepted to be an underestimate due to under-reporting. In some cases, causality in relation to duloxetine hydrochloride could not be established. Patients should be advised that if they experience a skin rash, they should discontinue Taro-Duloxetine treatment and contact their physician for assessment and advice.

Table 9 is based on post-market spontaneous adverse event reports. The percentages shown are calculated by dividing the number of adverse events reported to the company by the estimated number of patients exposed to the drug during the same time period. A causal relationship between duloxetine hydrochloride and the emergence of these events has not been clearly established.

Table 9: Duloxetine Hydrochloride Post-Market Spontaneous Adverse Event Reports For All Indications

DRUG INTERACTIONS

Overview

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications.

Potential for Other Drugs to Affect Duloxetine

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Inhibitors of CYP1A2: When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased by approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t½ was increased by approximately 3-fold. Taro-Duloxetine should not be used concomitantly with potent CYP1A2 inhibitors (e.g. fluvoxamine) and some quinolone antibiotics (e.g. ciprofloxacin, or enoxacin).

Inhibitors of CYP2D6: Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average 60%) of duloxetine. Paroxetine (20 mg QD) increased duloxetine (40 mg QD) AUC and Cmax by 60%. Caution is advised if administering duloxetine with inhibitors of CYP2D6 (e.g., SSRIs).

Dual Inhibition of CYP1A2 and CYP2D6: Concomitant administration of duloxetine 40 mg BID with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.

Potential for Duloxetine to Affect Other Drugs

Drugs Metabolized by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine (60 mg BID) was co-administered with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 mg BID) increased steady-state AUC of tolterodine (2 mg BID) by 71% but did not affect the pharmacokinetics of the 5-hydroxyl metabolite. Therefore, caution should be used if duloxetine is co-administered with medications that are predominately metabolized by the CYP2D6 system or have a narrow therapeutic index such as antiarrhythmics (e.g., flecainide and encainide) (see DRUG INTERACTIONS: Tricyclic Antidepressants).

Drugs Metabolized by CYP1A2: In vitro drug interaction studies demonstrate that duloxetine does not induce catalytic activity associated with the CYP1A2 isoform. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline and caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine has been shown to be a potential inhibitor of the CYP1A2 isoform in in vitro studies. However, in a clinical study, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg BID). These results suggest that duloxetine is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates.

Drugs Metabolized by CYP2C9: Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C9 activity.

Drugs Metabolized by CYP3A: Results of in vitro studies demonstrate that duloxetine does not inhibit or induce the catalytic activity of CYP3A. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.

Drugs Metabolized by CYP2C19: Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.

CNS Drugs: Caution is advised when Taro-Duloxetine is taken in combination with other centrally acting drugs and substances, especially those with a similar mechanism of action, including alcohol. Concomitant use of other drugs with serotonergic activity (e.g., SNRIs, SSRIs, triptans, or tramadol) may result in serotonin syndrome.

Drugs Highly Bound to Plasma Protein: Duloxetine is highly bound to plasma proteins (>90%). Therefore, administration of Taro-Duloxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of either drug.

Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of electroconvulsive therapy and duloxetine.

Benzodiazepines

Lorazepam: Under steady-state conditions, duloxetine (60 mg Q 12 hours) had no effect on lorazepam (2 mg Q 12 hours) pharmacokinetics and lorazepam had no effect on duloxetine pharmacokinetics. The combination of duloxetine and lorazepam resulted in increased sedation compared with lorazepam alone.

Temazepam: Under steady-state conditions, duloxetine (60 mg qhs) had no effect on temazepam (2 mg qhs) kinetics and temazepam had no effect on duloxetine pharmacokinetics.

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS: MAOIs and WARNINGS AND PRECAUTIONS: MAOIs.

Serotonergic Drugs: Based on the mechanism of action of duloxetine and the potential for serotonin syndrome, caution is advised when Taro-Duloxetine is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, tramadol, fentanyl and its analogues, dextromethorphan, tapentadol, meperidine, methadone, pentazocine or St. John's Wort (see WARNINGS AND PRECAUTIONS: Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Triptans (5HT₁ agonists): Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with Taro-Duloxetine and a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS AND PRECAUTIONS: Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Tricyclic Antidepressants (TCA): Caution is advised in the co-administration of tricyclic antidepressants (TCAs) (e.g. amitriptyline, desipramine, nortriptyline) with duloxetine, because duloxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with duloxetine (see DRUG INTERACTIONS: Drugs Metabolized by CYP2D6).

Drugs Affecting Platelet Function (e.g., NSAIDs, ASA, and other anticoagulants): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate this risk of bleeding.

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Taro-Duloxetine is initiated or discontinued (See WARNINGS AND PRECAUTIONS).

Potential for Interaction with Drugs that Affect Gastric Acidity: Duloxetine hydrochloride has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, duloxetine hydrochloride, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Taro-Duloxetine in patients with conditions that may slow gastric emptying (e.g. some patients with diabetic gastroparesis). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of duloxetine hydrochloride with aluminum- and magnesium-containing antacids (51 mEq) or duloxetine hydrochloride with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40-mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption.

Drug-Food Interactions

Food delays the time for duloxetine to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11%) (see ACTION AND CLINICAL PHARMACOLOGY). However food does not affect the Cmax of duloxetine. Taro-Duloxetine may be taken with or without food.

Drug-Herb Interactions

In common with other SSRIs and SNRIs, pharmacodynamic interactions between duloxetine and the herbal remedy St. John’s Wort may occur and may result in an increase in undesirable effects. Interactions with other herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Smoking: Duloxetine bioavailability appears to be about 34% lower in smokers than in nonsmokers, although dosage modifications are not routinely recommended.

Alcohol: Although duloxetine does not increase the impairment of mental and motor skills caused by alcohol, the concomitant use of duloxetine and substantial amounts of alcohol is not recommended.

In the duloxetine hydrochloride clinical trials database, three duloxetine hydrochloride-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of cholestasis. Substantial inter-current ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen (see WARNINGS AND PRECAUTIONS: Hepatotoxicity).

DOSAGE AND ADMINISTRATION

Dosage Considerations

• Taro-Duloxetine (duloxetine hydrochloride) is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS: General: Potential Association with Behavioural and Emotional Changes, Including Self-Harm).
• Taro-Duloxetine may be administered with or without food; however, food may help reduce the incidence of initial nausea. Results from a well-controlled dose comparison study (N=647) have demonstrated that patients taking duloxetine hydrochloride 60 mg/day with food experienced similar rates of nausea as patients treated with duloxetine hydrochloride 30 mg/day with or without food.
• Taro-Duloxetine should be swallowed whole and should not be chewed or crushed, nor should the contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.
• All patients who participated in the chronic low back pain clinical trials had a clinical diagnosis of CLBP with pain present on most days for at least 6 months and no signs of radiculopathy or spinal stenosis (see CLINICAL TRIALS).

Recommended Dose and Dose Adjustment

Adults:

Major Depressive Disorder

The recommended dose is 60 mg once daily. A lower starting dose of 30 mg may be considered for tolerability reasons in some patients, with a target dose of 60 mg/day within 1-2 weeks. Therapeutic response is usually seen after 1-4 weeks of treatment. There is no evidence that doses greater than 60 mg/day conferred additional benefits (see CLINICAL TRIALS).

Generalized Anxiety Disorder

The recommended dose is 60 mg once daily. A lower starting dose of 30 mg may be considered for tolerability reasons in some patients, with a target dose of 60 mg/day within 1-2 weeks (see Dosage for Elderly Patients). Therapeutic response is usually seen after 1-4 weeks of treatment. While a 120 mg once daily dose was shown to be safe and effective, there is no evidence that doses greater than 60 mg/day confer additional benefit and the higher dose is less well tolerated. Daily doses above 120 mg have not been evaluated for safety or efficacy and are not recommended (see CLINICAL TRIALS).

Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

The recommended dose is 60 mg once daily. A lower starting dose of 30 mg may be considered for tolerability reasons in some patients, with a target dose of 60 mg/day within 1-2 weeks. Efficacy of duloxetine hydrochloride has been demonstrated within the first week.

Some patients may benefit from dosages above the recommended 60 mg once daily up to a maximum dose of 120 mg per day. While a 120 mg/day dose was shown to be safe and effective, there is no evidence that doses greater than 60 mg/day confer additional significant benefit, and the higher dose is less well tolerated (see ADVERSE EVENTS, Table 3). Daily doses above 120 mg have not been evaluated for safety or efficacy and are not recommended (see CLINICAL TRIALS).

Fibromyalgia

The recommended dose is 60 mg once daily. A lower starting dose of 30 mg may be considered for tolerability reasons in some patients, with a target dose of 60 mg/day within 1-2 weeks. Some patients may respond within the first week. There is no evidence that doses greater than 60 mg/day (e.g., 120 mg/day) confer additional benefit. Additionally, patients who do not respond to 60 mg/day may not respond to 120 mg/day (see CLINICAL TRIALS). Furthermore, doses higher than 60 mg/day are associated with more severe and frequent rate of adverse reactions (see ADVERSE REACTIONS). Daily doses above 120 mg have not been evaluated for safety or efficacy and are not recommended (see CLINICAL TRIALS

Chronic Low Back Pain:

The recommended dose is 60 mg once daily. A lower starting dose of 30 mg may be considered for tolerability reasons in some patients, with a target dose of 60 mg/day within 1-2 weeks. Some patients may respond within the first week. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions. Daily doses above 120 mg have not been evaluated for safety or efficacy and are not recommended (see CLINICAL TRIALS).

Chronic Pain Associated with Osteoarthritis of the Knee

The recommended dose is 60 mg once daily. A lower starting dose of 30 mg may be considered for tolerability reasons in some patients, with a target dose of 60 mg/day within 1-2 weeks. Some patients may respond within the first week. Some patients may benefit from dosages above the recommended 60 mg once daily up to a maximum dose of 120 mg per day, although the higher dose has been associated with a higher rate of adverse reactions. Daily doses above 120 mg have not been evaluated for safety or efficacy and are not recommended (see CLINICAL TRIALS).

Maintenance/Continuation/Extended Treatment

Major Depressive Disorder

It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy beyond response to the acute episode. There is insufficient evidence available to answer the question of how long a patient should continue to be treated with Taro-Duloxetine. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

Generalized Anxiety Disorder

During long-term therapy, the dosage should be maintained at the lowest effective level and patients should be periodically re-assessed to determine the need to continue treatment (see CLINICAL TRIALS).

Fibromyalgia, Chronic Low Back Pain, Chronic Pain Associated with Osteoarthritis of the Knee, and Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

The efficacy of duloxetine hydrochloride beyond 12 weeks in DPN or FM and 13 weeks in CLBP or OA has not been evaluated in controlled clinical trials. The physician who elects to use Taro-Duloxetine for extended periods in the treatment of FM, DPN, CLBP and OA should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

General Considerations for Dosing in Special Populations

Dosage for Patients with Renal Impairment: Taro-Duloxetine is not recommended for patients with end-stage renal disease (requiring dialysis) or in severe renal impairment (estimated creatinine clearance <30 mL/min) (see CONTRAINDICATIONS: Severe Renal Impairment; WARNINGS AND PRECAUTIONS: Renal and ACTION AND CLINICAL PHARMACOLOGY).

Dosage for Patients with Hepatic Impairment: Taro-Duloxetine should not be used in patients with any liver disease resulting in hepatic impairment (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Dosage for Elderly Patients: For GAD, Taro-Duloxetine should be initiated at a dose of 30 mg once daily for 2 weeks. For patients showing a response, 30 mg once daily may then be continued. For others, the dose can be increased to the target dose of 60 mg/day. In patients who continue to show insufficient response, patients may benefit from doses above 60 mg once daily. The maximum dose studied is 120 mg per day. For all other indications, no dose adjustment is recommended for elderly patients on the basis of age. Caution should be exercised in treating the elderly. Pharmacokinetic results suggest no overall differences between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. When individualizing the dosage, extra care should be taken when increasing the dose.

Dosage for Pediatric Patients: The safety and efficacy of duloxetine hydrochloride in pediatric patients (<18 years of age) have not been established and its use in this patient population is not indicated (see WARNINGS and PRECAUTIONS: General: Potential Association With Behavioural And Emotional Changes, Including Self-Harm).

Treatment of Pregnant Women During the Third Trimester: Post-marketing reports indicate that some neonates exposed to SSRIs or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS AND PRECAUTIONS: Special Populations: Pregnant Women). When treating pregnant women with Taro-Duloxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Taro-Duloxetine in the third trimester.

Discontinuation of Treatment

When discontinuing Taro-Duloxetine after more than 1 week of therapy, it is recommended that the dose be tapered to minimize the risk of discontinuation symptoms (see WARNINGS AND PRECAUTIONS: General: Discontinuation Symptoms; WARNINGS AND

PRECAUTIONS: Dependance: Discontinuation of Treatment; and ADVERSE REACTIONS: Adverse Events Following Discontinuation of Treatment). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Taro-Duloxetine. In addition, at least 5 days should be allowed after stopping Taro-Duloxetine before starting an MAOI (see CONTRAINDICATIONS: MAOIs and WARNINGS AND PRECAUTIONS: General: MAOIs).

OVERDOSAGE

Human Experience: In clinical trials, cases of acute ingestions above 3000 mg, alone or in combination with other drugs, were reported, with none being fatal. However, in post marketing experience fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, serotonin syndrome, seizures, vomiting, and tachycardia.

Animal Experience: In animal studies, the major signs of overdose toxicity related to the central nervous and gastrointestinal systems. These included central nervous system effects such as tremors, clonic convulsions, ataxia, emesis, and decreased appetite.

Management of Overdose

No specific antidote is known, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. An airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution and forced diuresis, hemoperfusion, and exchange perfusion are unlikely to be beneficial.

In managing overdose, consider the possibility of multiple drug involvement. A specific caution involves patients who are taking or have recently taken duloxetine and might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see DRUG INTERACTIONS).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Taro-Duloxetine (duloxetine hydrochloride) is a serotonin and norepinephrine reuptake inhibitor, and weakly inhibits dopamine uptake with no significant affinity for histaminergic, dopaminergic, cholinergic, and adrenergic receptors. Duloxetine is also a potent in vitro inhibitor of transporter binding, with 5-HT and transporter NE inhibition constants (Ki) of 0.8 and 7.5 nM, respectively. Duloxetine dose-dependently increases extracellular levels of serotonin and norepinephrine in various brain areas of animals. The exact mechanism of action of duloxetine in humans is unknown. It is chemically unrelated to other SNRIs, tricyclic, tetracyclic, or other available drugs effective in the treatment of MDD.

Pharmacodynamics

The effectiveness of duloxetine in the treatment of MDD is presumed to be linked to inhibition of central nervous system (CNS) neuronal uptake of serotonin and norepinephrine, and a resultant increase in serotonin and norepinephrine neurotransmission. The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system. Studies at clinically relevant doses in humans (i.e., 40-60 mg BID) have shown that duloxetine decreases 5-hydroxytryptamine concentration in the blood and decreases the urinary excretion of norepinephrine and its metabolites, consistent with blockade of serotonin and norepinephrine uptake processes, respectively. Duloxetine undergoes extensive metabolism; however, the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Neurochemical and behavioural studies in laboratory animals showed an enhancement of both serotonin and norepinephrine neurotransmission in the CNS. Responses consistent with enhanced serotonergic and noradrenergic neurotransmission include lowered food intake, body weight, and alcohol intake. Duloxetine also normalized pain thresholds in several preclinical models of neuropathic [L5/L6 spinal nerve ligation model and partial sciatic nerve ligation model] and inflammatory pain [carrageenan model and acetic-acid induced writhing model] and attenuated pain behaviour in a model of persistent pain [formalin model, late phase] at doses that are consistent with in vivo blockade of 5HT and NE reuptake sites].

Duloxetine’s affinity for dopamine uptake sites is low. Nevertheless, animal studies have shown increases in extracellular levels of dopamine in prefrontal cortex in addition to increases in norepinephrine and serotonin levels. This is presumed to be associated with the known propensity of cortical norepinephrine transporters to take up dopamine as well as norepinephrine, rather than an effect on dopamine transporters themselves.

Pharmacokinetics

Absorption: In humans, orally administered duloxetine hydrochloride is well absorbed, with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine. However, food delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11%). Duloxetine plasma exposure increases in proportion to dose for doses up to 60 mg twice a day. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Based upon AUC, multiple once daily doses of 60 mg produce steady-state concentrations that are approximately 1.5 times higher than that predicted from a 60 mg single dose. Average minimum and maximum steady-state concentrations for the 60 mg QD dose are 27.0 and 89.5 ng/mL, respectively. There is no clinically important difference in the pharmacokinetic parameters of morning and evening doses.

Distribution: The apparent volume of distribution ranges from 701 to 3800 L (5th to 95th percentile, mean of 1640 L). Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.

Metabolism: Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labelled duloxetine. Integrated over time, duloxetine comprises about 3% of the total radiolabelled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the formation of 2 major metabolites found in plasma and urine (glucuronide conjugate of 4-hydroxy duloxetine, and the sulfate conjugate of 5-hydroxy,6-methoxy duloxetine). The major circulating metabolites are not pharmacologically active.

Excretion: The elimination half-life of duloxetine ranges from 8.1 to 17.4 hours (5th to 95th percentile, mean of 12.1 hours) and the apparent plasma clearance ranges from 33 to 261 L/hr (5th to 95th percentile, mean of 101 L/hr). Apparent plasma clearance of duloxetine does not differ between once daily and twice daily dosing. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine following single dose administration of ¹⁴C-labelled duloxetine. The majority (72%) of the duloxetine dose is recovered in the urine as metabolites of duloxetine and approximately 19% is recovered in the feces.

Special Populations and Conditions

Pediatrics: Safety and efficacy in pediatric patients have not been established.

In a Phase 2, 6-month, open-label pharmacokinetic, safety and tolerability study in pediatric patients (ages 7-17 years) with MDD, duloxetine hydrochloride 30 mg QD to 120 mg QD was administered to 72 patients. The median steady state duloxetine concentrations in pediatric patients receiving 60 mg QD duloxetine were ~29% lower than in previous data for adults. Duloxetine apparent oral clearance (CL/F) in pediatric patients was nearly twice the value estimated from previous data in adults. Similarly, median body weight normalized CL/F was nearly four times and two times higher in children and adolescents respectively, as compared with adults. The pharmacokinetic results in pediatric patients from this study and the comparison with adults should be considered preliminary (see DOSAGE AND ADMINISTRATION: Dosage Considerations).

Geriatrics: The pharmacokinetics of duloxetine after a single dose of 40 mg were evaluated in 12 healthy elderly females (65 to 77 years) and 12 healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was 24% higher and the half-life 4.3 hours longer in the elderly females. Pharmacokinetic results suggest no overall differences between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment based on the age of the patient is not necessary (see DOSAGE AND ADMINISTRATION: Dosage for Elderly Patients).

Gender: In clinical pharmacology studies, the mean apparent clearance of duloxetine was 9 to 55% lower in females as compared with males. In these studies, duloxetine half-life was similar between males and females. A similar effect of gender on the apparent plasma clearance was identified in patients with MDD. Since exposure in males and females spans a similar range, these differences in average clearance values do not appear to be clinically significant. Dosage adjustment based on gender is not necessary.

Race: No specific pharmacokinetic study was conducted to investigate the effects of race. Due to large interpatient variability, clinically significant differences in drug level exposure among ethnic groups are not likely.

Hepatic Impairment: Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single, non-therapeutic (20 mg) dose of duloxetine hydrochloride, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer. Taro-Duloxetine is contraindicated in patients with any liver disease resulting in hepatic impairment (see CONTRAINDICATIONS: Hepatic Impairment; WARNINGS AND PRECAUTIONS: Hepatic Impairment; and DOSAGE AND ADMINISTRATION: Dosage for Patient with Hepatic Impairment).

Renal Impairment: Duloxetine Cmax and AUC values were approximately 2-fold higher in patients with end stage renal disease (ESRD) receiving chronic intermittent hemodialysis, compared with subjects with normal renal function. In contrast, the elimination half-life was similar in both groups. Studies have not been conducted in patients with a moderate degree of renal dysfunction. Population PK analyses suggest that mild renal dysfunction has no significant effect on duloxetine apparent clearance. Taro-Duloxetine is not recommended for patients with end-stage renal disease or severe renal impairment (see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS: Renal; and DOSAGE AND ADMINISTRATION: Dosage for Patients with Renal Impairment).

Smoking Status: Duloxetine bioavailability appears to be about 34% lower in smokers than in nonsmokers, although dosage modifications are not routinely recommended.

Clinical Safety Pharmacology

Effect on QTc Interval: A clinical pharmacology study was conducted to assess the safety of duloxetine at the highest tolerable level of exposure of duloxetine and measure QT interval. Of the 117 subjects enrolled, 84 were available for statistical analysis at the maximum dosage of 200 mg BID, and 91 on placebo. Seventy subjects (approximately 60%) completed the entire protocol. Compared with placebo, the mean change in the QTcF interval decreased at each time point with duloxetine 200 mg BID, ranging between -3.0 and -6.4 msec. The upper limit of the two-sided 90% confidence intervals was less than 5 msec at each time point, indicating no clinically relevant increase in the QTcF interval. Similar results were found with the covariance approach and the individual correction method.

No individual QTcF exceeded 470 msec on either duloxetine or placebo, and only 2 subjects had a categorical QTcF increase >30 msec at either 160 mg BID or 200 mg BID dosages (n=84), compared with 6 subjects (n=97) at placebo. Furthermore, no subject had a maximal QTc interval greater than 450 msec based on the average of replicate QTcF and QTcI values on day four of duloxetine 200 mg BID. The ability to detect relevant changes in QTc intervals in this study was confirmed by observing significant differences in the QTc interval at two time points (mean change in QTcF = 6.7 msec at 2 hours, p<0.0001 and 2.7 msec at 6 hours, p=0.0186) with moxifloxacin as compared with placebo. QT interval at doses up to 200 mg BID was not prolonged.

STORAGE AND STABILITY

Store between 15° and 30°C.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

Taro-Duloxetine (duloxetine hydrochloride) delayed-release capsules are available in 30 mg and 60 mg strengths.

30 mg: The 30 mg capsule has a white coloured body and blue coloured cap, and is imprinted with “382” on the body and on the cap. It is available in bottles of 30 and 90 capsules.

60 mg: The 60 mg capsule has a green coloured body and blue coloured cap, and is imprinted with “383” on the body and on the cap. It is available in bottles of 30 and 90 capsules.

Not all pack sizes and presentations may be marketed.

Composition

Each capsule contains enteric-coated pellets of duloxetine hydrochloride equivalent to 30 mg or 60 mg of duloxetine that are designed to prevent degradation of the drug in the acidic environment of the stomach.

Nonmedicinal ingredients include ascorbic acid, FD&C Blue No.2, gelatin, hydroxypropyl methylcellulose, mannitol, methacrylic acid ethyl acrylate co-polymer, sodium hydroxide, sodium lauryl sulphate, sucrose, sugar spheres, talc, titanium dioxide and triethyl citrate. The 60 mg capsules also contain iron oxide yellow.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: duloxetine hydrochloride

Chemical name: (+)-(S)-N-methyl-γ-(1-naphthalenyloxy)-2-thiophenepropanamine hydrochloride

Molecular formula and Molecular mass: C18H19NOS•HCl

333.88

Structural formula:

Physicochemical properties:

Description: White to slightly brownish white solid

Solubility of duloxetine hydrochloride:

CLINICAL TRIALS

Major Depressive Disorder (MDD) Studies

Study Demographics And Trial Design:

The efficacy of Duloxetine (duloxetine hydrochloride) as a treatment for MDD was assessed in 6 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for MDD, and having baseline scores of ≥15 on the 17-Item Hamilton Depression Rating Scale and ≥4 on the Clinic Global Impression Severity Score. Primary efficacy was evaluated using the mean total scores of the HAMD17.

In two studies of identical design, patients were randomized to Duloxetine hydrochloride 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in a second set of 2 studies of identical design patients were randomized to Duloxetine hydrochloride 20 mg (N=91 and N=86) or 40 mg twice daily (N=84 and N=91) or placebo (N=90 and N=89) for 8 weeks; in a third set of studies of identical design, patients were randomized to Duloxetine hydrochloride 40 mg (N=95 and N=93) or 60 mg twice daily (N=93 and N=103) or placebo (N=93 and N=99) for 8 weeks. The design of the six studies is summarized in Table 10.

Table 10: Clinical Trials Supporting Efficacy of Duloxetine Hydrochloride in the Treatment of MDD

Study Results:

The HAMD17 total score was the primary efficacy measure for the assessment of duloxetine hydrochloride effectiveness in the treatment of MDD. Additional secondary efficacy measures that supported the emotional and physical symptoms of MDD included: HAMD17 Depressed Mood Item (Item 1), HAMD17 Core and Anxiety subscales, Global Impression Scales (Patient Global Impressions (PGI) Improvement and CGI-Severity), and the Quality of Life in Depression (QLDS) rating scale.

In four of the six studies, duloxetine hydrochloride demonstrated statistical superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (see Table 11). The secondary efficacy outcomes were supportive of the primary efficacy outcomes.

Table 11: Mean Change in Hamilton Depression Rating Scale (HAMD-17) Total Score

In comparison with placebo, duloxetine hydrochloride at doses of 60 mg once daily and 40 mg and 60 mg twice daily produced a significantly higher rate of response and remission as defined respectively by ≥50% decrease in the HAMD-17 total score and a total endpoint HAMD-17 score of ≤7.

There was no evidence that doses of greater than 60 mg/day conferred any additional benefit.

Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

Study in Elderly Patients with Depression:

In a study comparing duloxetine hydrochloride 60mg QD (n=207) and placebo (n=104) in the acute treatment (study duration 8 weeks) of elderly patients with MDD (>65 years of age, mean age 72.9 years), the efficacy of duloxetine hydrochloride 60 mg once a day in treating depression symptoms was demonstrated by a statistically significant difference in the reduction of the HAMD17 score for duloxetine-treated patients compared to placebo (p<0.001). Tolerability of duloxetine hydrochloride 60 mg once daily in elderly patients in this study was comparable to that seen in younger adults, but greater sensitivity of some older individuals cannot be ruled out.

Long-Term Maintenance of Effect Studies:

The efficacy of duloxetine hydrochloride in maintaining antidepressant effect was assessed in two long-term studies.

Study HMBC: Patients responding to 12 weeks of acute treatment with open-label duloxetine hydrochloride at a dose of 60 mg once daily were randomly assigned to either duloxetine hydrochloride 60 mg once daily or placebo for a further 6 months (continuation phase) and time to relapse in each group was compared. Of 533 subjects who enrolled in the study, 278 responded and were randomized to duloxetine hydrochloride 60 mg once daily (n=136) or placebo (N=142). Response during the open-label phase was defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD. The estimated probability of depressive relapse at 6 months for duloxetine hydrochloride was 19.7% and for placebo was 38.3% (p=0.004). During the 6-month continuation therapy phase of this study, 17.4% of duloxetine hydrochloride-treated patients met the a priori-defined criteria for relapse compared with 28.5% on placebo. Median duration of treatment was 64 days for placebo and 178 days for duloxetine, with 74 (54%) patients on duloxetine and 47 (33%) patients on placebo completing the 6 month, double-blind continuous phase. Relapse during the continuation phase was defined as an increase in the CGI-S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit.

Study HMDI: Patients with at least 3 episodes of MDD in the past 5 years (and were in remission between the episodes) who responded to duloxetine hydrochloride at a dose of 60 to 120 mg QD during an initial 4- to 10-week, open-label, acute treatment period, and who continued to respond to the same dose during a further 24-week, open-label, continuation treatment period, were randomized to duloxetine hydrochloride or placebo for a 52-week, double-blind, maintenance phase. Response during the acute and continuation phases was defined as: HAMD17 total score ≤9, a CGI-S score ≤2, and not meeting DSM-IV criteria for MDD. During the maintenance phase, patients continued on the duloxetine hydrochloride dose to which they had responded (N=146) or underwent a 4-week down-titration to placebo (N=142). For the purposes of this study, recurrence during the maintenance phase was defined as: CGI-S score >4 and meeting DSM-IV criteria for MDD for at least 2 weeks; or 3 consecutive visits that met re-emergence criteria (CGI-S score >4 but not meeting DSM-IV criteria for MDD) or 10 total re-emergence visits; or discontinued due to lack of efficacy. Time to depressive recurrence, as defined in the study (see above), was statistically significantly longer in duloxetine hydrochloride-treated patients compared with placebo-treated patients (p<0.001) and significantly fewer patients treated with duloxetine hydrochloride experienced a return of their depressive symptoms (14.4%) compared to patients treated with placebo (33.1%).

Secondary efficacy measures that supported the primary outcome included: HAMD17 total score and subscales, CGI-Severity scale, PGI Improvement scale, and Sheehan Disability Scale (SDS) global functional impairment score.

The criteria for relapse and recurrence used in these studies were specified for these study protocols only; clinical criteria may vary.

Generalized Anxiety Disorder (GAD) Studies

The efficacy of duloxetine hydrochloride as a treatment for GAD was assessed in four acute, randomized, double-blind, placebo-controlled studies (duration: 9-10 weeks) in adult outpatients (ages 18 to 84 years) meeting DSM-IV criteria for GAD, and having baseline

Hamilton Anxiety Rating Scale (HAMA) total score of ≥18 (moderate severity) and ≥4 on the Clinical Global Impression of Severity Score. The primary efficacy end-point was mean change from baseline to end-point on the HAMA total score versus placebo. Treatment difference was determined by calculating the difference between mean change in anxiety scores at end-point between duloxetine hydrochloride and placebo arms (Drug-Placebo; see Table 12). The main secondary efficacy measure was improvement in the Sheehan Disability Scale (SDS) global functional impairment score. The SDS measures the extent to which emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities.

Table 12: Clinical Trials Supporting Efficacy of Duloxetine Hydrochloride in the Treatment of GAD

Abbr: DLX = duloxetine; QD = once daily.

Study Results: In all 4 studies, duloxetine hydrochloride 60 mg to 120 mg once daily demonstrated statistically significant superiority over placebo as measured by improvement in the primary outcome measure, the HAMA total score, and improvement in secondary outcome measures, including the SDS global functional impairment score and the Clinical Global Impression of Change (CGI-Improvement). The results on the other secondary outcome measures were supportive of the positive primary outcome.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

Maintenance of Response: In a long-term, relapse observation study, patients diagnosed with GAD who had responded during an initial 6 months of open-label duloxetine hydrochloride treatment, were randomized to receive either their optimized dose of duloxetine hydrochloride or placebo in a double-blind phase for an additional 6-months. There were statistically significantly (p<0.001) more relapses on placebo (42%) as compared to duloxetine hydrochloride 60 mg to 120 mg once daily (14%) during the double-blind continuation therapy phase.

Study in Elderly Patients with GAD:

Study HMGF: The efficacy of duloxetine hydrochloride 30 to 120 mg once daily (n=151) versus placebo (n=140) in elderly patients (>65 years, mean age 71.6 years) with GAD was evaluated in a 12-week randomized, double-blind, placebo-controlled, flexible dose study. The primary efficacy endpoint was the HAMA total score at week 10. The key secondary efficacy measure was the improvement in SDS global functional impairment score. At week 10, duloxetine hydrochloride was superior to placebo on least squares mean change from baseline in HAMA total scores (-15.9 vs. -11.7, p<0.001) and in SDS global functional impairment scores (-8.6 vs. -5.4, p<0.001). The efficacy and safety of duloxetine hydrochloride 30 to 120 mg once daily in elderly patients with GAD was similar to that seen in younger adult patients but greater sensitivity of some older individuals cannot be ruled out.

Neuropathic Pain Associated With Diabetic Peripheral Neuropathy (DPN) Studies

Study Demographics and Trial Design: The efficacy of duloxetine hydrochloride for the management of neuropathic pain associated with DPN was established in three randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients (20 to 84 years) having neuropathic pain associated with DPN for at least 6 months. All studies compared duloxetine hydrochloride 60 mg once daily or 60 mg twice daily with placebo. One of the studies also compared duloxetine hydrochloride 20 mg with placebo. The design of the three studies is summarized in Table 13.

The three studies enrolled a total of 1139 patients, of whom 888 (78%) completed the studies. Patients enrolled had Type 1 or 2 diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to duloxetine hydrochloride. Patients recorded their pain daily in a diary.

Table 13: Study Design of Clinical Trials Supporting Efficacy of Duloxetine Hydrochloride in the Management of Neuropathic Pain Associated with DPN

Study Results: The 24-hour average pain severity was the primary efficacy measure for the assessment of duloxetine hydrochloride’s effectiveness for the management of neuropathic pain associated with DPN. Evidence of efficacy from the primary efficacy measure was confirmed by comprehensive results from the secondary pain and DPN symptom measures.

In all 3 studies, duloxetine hydrochloride 60 mg QD and duloxetine hydrochloride 60 mg BID were statistically significantly superior to placebo at 12 weeks as assessed by the reduction from baseline in the 24 hour average pain severity (p<0.001).

Duloxetine hydrochloride’s effect on pain was apparent at the first weekly visit. In all studies, a statistically significant difference (p<0.001) between duloxetine hydrochloride 60 mg QD versus placebo and 60 mg BID versus placebo was observed at the first week of treatment and persisted to week 12.

In all studies, both duloxetine hydrochloride 60 mg QD and 60 mg BID were statistically significantly superior to placebo as assessed by response rate, which was defined as a 30% reduction in pain severity (Table 14).

Table 14: 24-Hour Average Pain Severity; 30% Response Rate at Endpoint All Randomized Patients

1 p=0.003; 2 p<0.001; 3 p=0.002; 4 p=0.01; 5 p=0.007

Secondary measures which further support the efficacy of duloxetine hydrochloride in the management of neuropathic pain associated with DPN included: 24-hour worst pain severity, night pain severity, and Patient’s Global Impressions of Improvement (PGI-Improvement). In all studies, the results from these secondary measures were statistically significant for both duloxetine hydrochloride 60 mg QD and 60 mg BID when compared to placebo.

In HMAW-Acute, there was a statistically significant difference in 24-hour worst pain severity and PGI-Improvement (p<0.001 for both duloxetine hydrochloride 60 mg QD and 60 mg BID versus placebo), and for night pain severity (duloxetine hydrochloride 60 mg QD, p=0.025 and duloxetine hydrochloride 60 mg BID, p<0.001 versus placebo).

In HMAV(a)-Acute, there was a statistically significant difference in 24-hour worst pain severity (duloxetine hydrochloride 60 mg QD, p=0.002 and duloxetine hydrochloride 60 mg BID, p<0.001 versus placebo) and PGI-Improvement (p<0.001 for both duloxetine hydrochloride 60 mg BID and 60 mg QD versus placebo) and night pain severity (duloxetine hydrochloride 60 mg QD, p=0.009 and duloxetine hydrochloride 60 mg BID, p<0.001 versus placebo).

In HMAV(b)-Acute, there was a statistically significant difference in 24-hour worst pain severity (duloxetine hydrochloride 60 mg QD, p=0.002 and duloxetine hydrochloride 60 mg BID, p =0.003 versus placebo) and PGI-Improvement (Duloxetine hydrochloride 60 mg QD, p=0.002 and Duloxetine hydrochloride 60 mg BID, p<0.001 versus placebo) and night pain severity (Duloxetine hydrochloride 60 mg QD, p=0.003 and Duloxetine hydrochloride 60 mg BID, p=0.002 versus placebo).

Summary: In controlled DPN clinical trials, Duloxetine hydrochloride, at doses of 60 mg QD and 60 mg BID, was statistically significantly more effective than placebo in reducing 24-hour average pain severity (primary efficacy measure), 24-hour worst pain severity, night pain severity, and improving PGI scores.

These findings demonstrate the clinical relevance of the reductions in pain severity observed.

Fibromyalgia (FM) Studies

Study Demographics And Trial Design: The efficacy of duloxetine hydrochloride in the management of pain associated with FM was established in two randomized, double-blind, placebo-controlled studies (HMCA and HMCJ) in 874 adult patients (19-80 years of age). To enter the study, patients had to have moderate to severe pain, i.e., baseline average pain of the past week prior to study medication of ≥4, and a diagnosis of fibromyalgia based on the American College of Rheumatology criteria (history of widespread pain for 3 months, and pain present at 11 or more out of 18 specific tender points). During the two studies (HMCA and HMCJ) described below, patients were allowed to take acetaminophen up to 4 g per day, as needed, for pain relief.

The primary efficacy end-point for study HMCA was Brief Pain Inventory (BPI) - Modified Short Form that measures severity and interference of pain on function. The Severity scores range from 0 (no pain) to 10 (pain as bad as you can imagine). The Interference scores range from 0 (does not interfere) to 10 (completely interferes). Treatment differences, defined as change in endpoint mean pain scores for duloxetine hydrochloride versus placebo (drug – placebo), were calculated. Co-primary efficacy end-points for study HMCJ were BPI and PGI-I (Patient Global Impression of Improvement).

Supplemental and secondary efficacy endpoints included Responder Rates (patients reporting at least 30% or 50% reduction in endpoint mean pain score compared to baseline), Clinical Global Impressions of Severity (CGI), Fibromyalgia Impact Questionnaire (FIQ) and BPI Average Interference Score.

The safety and tolerability of duloxetine hydrochloride in patients with fibromyalgia were further established in the long term study (HMEH) which enrolled 307 patients for 60 weeks (64% completed this study).

The design of the placebo-controlled studies is summarized in Table 15.

Table 15: Clinical Trials Supporting Efficacy of Duloxetine Hydrochloride in the Management of pain associated with Fibromyalgia (FM)

QD= once daily; BID = twice daily; DLX = duloxetine; PBO = placebo; BPI = Brief Pain Inventory; PGI= Patient Global Impression of Improvement;

*PGI-Improvement scale range from 1 (very much better) to 7 (very much worse).

Study Results

Study HMCA: In this all female, placebo-controlled study, patients were treated with duloxetine hydrochloride 60 mg BID, 60 mg QD (total of 234 patients; 63% completed) or placebo (120 patients; 57% completed). The primary efficacy end-point was BPI average pain severity score. At end-point (3 months of therapy), both duloxetine hydrochloride 60 mg QD and BID doses were significantly better than placebo with treatment difference of –1.23 (p≤0.001) and –1.24 (p≤0.001) respectively. Some patients on duloxetine hydrochloride experienced a decrease in pain as early as week 1, which persisted throughout the study. Most supplemental and secondary endpoints were supportive of the primary efficacy measure. A dose-related increase in adverse events and withdrawals due to adverse events was observed.

Study HMCJ: In this controlled study, patients were randomized to duloxetine hydrochloride 20, 60, and 120 mg daily (total of 376 patients; 64% completed 3 month therapy phase) or placebo (144 patients; 58% completed 3 month therapy phase). Co-primary efficacy end-points were BPI average pain severity score and PGI-I at the end of 3 months of therapy. Both duloxetine hydrochloride 60 and 120 mg once daily doses were significantly better than placebo at end-point for BPI and PGI-I with treatment differences for BPI ranging between –0.62 (p= 0.02) for 60 mg QD and –0.93 (p≤0.001) for 120 mg QD. Some patients on duloxetine hydrochloride experienced a decrease in pain as early as week 1, which persisted throughout the study. Most supplemental and secondary endpoints were supportive of the primary efficacy measure. A dose-related increase in adverse events and withdrawals due to adverse events was observed.

Study HMEH: This 60-week study examined the benefit of up-titration in non-responders to duloxetine hydrochloride at 60 mg/day. It consisted of an 8-week open-label period, during which all patients received duloxetine hydrochloride 60 mg once daily, and a 52-week randomized, double-blind phase. At the end of the open-label phase, response status, defined as at least a 50% reduction in pain score from baseline, was determined. All completers (responders and non-responders) of the open-label phase were then randomized to double-blind treatment with duloxetine hydrochloride at either 60 mg once daily or 120 mg once daily. Those who were considered non-responders at the end of the open-label phase, were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to duloxetine hydrochloride 120 mg as compared to those who were blindly continued on duloxetine hydrochloride 60 mg. No new safety issues were identified in this study.

Chronic Low Back Pain (CLBP) Studies

Study Demographics and Trial Design: The efficacy of Duloxetine hydrochloride in the management of CLBP was established in two randomized, double-blind, 12-13 weeks, placebo-controlled studies (HMEN and HMGC) in 637 adult patients (18-89 years of age). To enter the study, patients had to have a clinical diagnosis of CLBP with pain present on most days for at least 6 months and no signs of radiculopathy or spinal stenosis.

The primary efficacy endpoint in both studies was a reduction in pain severity as measured by the BPI 24-hour average pain rating on the 11-point Likert scale (0 = no pain; 10 = worst possible pain). Some of the supplemental and secondary efficacy endpoints were the Patient’s Global Impression of Improvement (PGI-I), Responder Rates (patients reporting at least 30% or 50% reduction in endpoint average pain score compared to baseline), and BPI Severity and Interference Score.

The design of the studies is summarized in Table 16.

Table 16: Clinical Trial Supporting Efficacy of Duloxetine in the Management of Chronic Low Back Pain

*Treatment group of 60/120mg QD is the combined population for patients who stayed on 60mg QD or increased to 120mg QD.

QD= once daily; DLX = duloxetine; PBO = placebo; BPI = Brief Pain Inventory

Study Results:

Study HMGC: In this fixed-dose study, patients were not permitted to use any other analgesic agent while taking Duloxetine. After 12 weeks of treatment, patients taking Duloxetine hydrochloride 60 mg QD had significantly greater pain reduction compared to placebo (see Table 16). Some patients on duloxetine hydrochloride experienced pain reduction as early as week one which persisted throughout the study. Most supplemental and secondary efficacy measures were supportive of the primary end-point.

Study HMEN: In this flexible-dose study, patients assigned to duloxetine hydrochloride started treatment at a dose of 30 mg once daily for one week to improve tolerability, then increased to 60 mg once daily (QD). After 7 weeks of treatment with Duloxetine hydrochloride 60 mg QD, patients with sub-optimal response to treatment (<30% pain reduction) and who tolerated Duloxetine hydrochloride 60 mg once daily had their dose increased to 120 mg. Patients were permitted to continue on their stable therapeutic dose of NSAIDs or acetaminophen while taking Duloxetine hydrochloride.

After 13 weeks of treatment, patients taking Duloxetine hydrochloride 60-120 mg daily had a significantly greater pain reduction compared to placebo (see Table 16). Some patients on Duloxetine hydrochloride experienced pain reduction in the first week after starting the 60 mg dose which continued throughout the 13 weeks of the acute therapy phase. Most supplemental and secondary efficacy measures were supportive of the primary end-point.

Osteoarthritis (OA) studies

Study Demographics and Trial Design: The efficacy of Duloxetine hydrochloride in the management of chronic pain associated with osteoarthritis of the knee was established in two, randomized, double-blind, placebo-controlled studies in 780 adult patients (40 to 92 years). To enter these studies, patients had to meet the American College of Rheumatology (ACR)

clinical and radiographic criteria for the diagnosis of osteoarthritis of the knee with pain for ≥14 days of each month for 3 months prior to study entry. In both studies, the 11-point Likert scale (0 = no pain; 10 = worst possible pain) was used to measure pain severity. Some of the supplemental and secondary efficacy endpoints were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Patient’s Global Impression of Improvement (PGI-I), Responder Rates (patients reporting at least 30% or 50% reduction in endpoint average pain score compared to baseline), and BPI Severity and Interference Score.

The design of these studies is summarized in Table 17.

Table 17: Clinical Trials Supporting Efficacy of Duloxetine Hydrochloride in the Management of Pain due to Osteoarthritis of the Knee

*Treatment group of 60/120mg QD is the combined population for patients who stayed on 60mg QD or increased to 120mg QD.

QD= once daily; DLX = duloxetine; PBO = placebo; BPI = Brief Pain Inventory

Study HMFG: In this 13-week long, flexible-dose study, 256 patients were initially randomized to receive Duloxetine (128 patients; 73% completed) or placebo (128 patients, 87% completed). Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). Patients randomized to Duloxetine hydrochloride started treatment at a dose of 30 mg once daily for one week, then increased to 60 mg once daily (QD). After 7 weeks of treatment with Duloxetine hydrochloride 60 mg QD, patients with sub-optimal response to treatment (<30% pain reduction) had their dose increased to 120 mg for the remainder of the study, while the remaining patients who responded continued on Duloxetine hydrochloride 60 mg QD. For efficacy analyses, data from both Duloxetine doses were combined and compared to placebo. Patients administered Duloxetine hydrochloride 60/120 mg QD reported significantly greater pain reduction compared to those on placebo as assessed by the primary efficacy end-point, Brief Pain

Inventory (BPI) 24-hour average pain rating (Table 17). Secondary efficacy measures were supportive of the primary end-point.

Study HMGL: In this 10 week, placebo-controlled, flexible-dose study, patients with OA pain of the knee, who had inadequate pain relief from an optimized dose of NSAID therapy for two weeks, received Duloxetine hydrochloride 60/120 mg/day or placebo. After 8 weeks of double-blind treatment, duloxetine-treated patients experienced significantly greater pain reduction compared with placebo on the weekly 24 hour average pain rating (primary efficacy measure). Results of the two gatekeeper efficacy end-points, Western Ontario and McMaster Universities (WOMAC) index of osteoarthritis and Patient Global Impression of Improvement (PGI-I) also demonstrated significantly greater improvement in Duloxetine hydrochloride-treated patients compared with placebo. Secondary efficacy measures (example BPI) were also supportive of the primary endpoint.

Comparative Bioavailability Studies

Fasting study:

A randomized, two treatment, two period, two sequence, single dose, crossover, bioequivalence study of Duloxetine hydrochloride 60 mg delayed release capsules of Taro Pharmaceuticals Inc., Canada and ^prCymbalta^® (Duloxetine Hydrochloride) 60 mg delayed release capsules of Eli Lilly Canada Inc., in 60 healthy human adult subjects under fasting conditions.

Number of subject completed both period of the study: 56

Number of subjects whose data used to calculate pharmacokinetic parameters: 56

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

[Table for single dose studies]

^* Duloxetine hydrochloride 60 mg DR Capsule of Taro Pharmaceuticals Inc., Canada.

^{† Pr}Cymbalta^® (Duloxetine hydrochloride) 60 mg DR Capsule of Eli Lilly Canada Inc., Toronto, Ontario, M1N 2E8

^§ Expressed as arithmetic mean (CV%)

^# 90% Geometric C.I

Fed study:

A randomized, two treatment, two period, two sequence, single dose, crossover, bioequivalence study of Duloxetine hydrochloride 60 mg delayed release capsules of Taro Pharmaceuticals Inc., Canada and ^PrCymbalta^® (Duloxetine Hydrochloride) 60 mg delayed release capsules of Eli Lilly Canada Inc., in 52 healthy human adult subjects under fed conditions.

Number of subject completed both period of the study: 51

Number of subjects whose data used to calculate pharmacokinetic parameters: 51

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

[Table for single dose studies]

^* Duloxetine hydrochloride 60 mg DR Capsule of Taro Pharmaceuticals Inc., Canada.

^{† Pr}Cymbalta^® (Duloxetine hydrochloride) 60 mg DR Capsule of Eli Lilly Canada Inc., Toronto, Ontario, M1N 2E8

^§ Expressed as arithmetic mean (CV%)

^# 90% Geometric C.I

DETAILED ANIMAL PHARMACOLOGY

Pharmacodynamics Studies

Nonclinical studies indicate that duloxetine has the following neuropharmacologic attributes:

1. 1. Potently inhibits the uptake of serotonin (5-HT) and norepinephrine (NE) in vitro in a relatively balanced manner and has lower affinity for dopamine uptake
2. 2. Has low affinity for a number of neuronal receptors including those which are associated with adverse events such as cholinergic, histaminergic, or α-adrenergic receptors
3. 3. Blocks 5-HT and NE ex vivo uptake as well as 5-HT and NE depletion induced by transporter-dependent neurotoxins, demonstrating in vivo blockade of the respective transporters
4. 4. Increases extracellular levels of 5-HT and NE in brain regions. Dopamine extracellular levels in prefrontal cortex were increased, consistent with noradrenergic uptake processes regulating dopamine extracellular levels in cortical areas
5. 5. Is active in behaviour models indicative of enhancement of central 5-HT and NE neurotransmission and also in behavioural models of depression

Duloxetine is active in several models of chronic pain at doses that are consistent with in vivo uptake blockade of 5-HT and NE. This is in keeping with the known role of 5-HT and NE in enhancing endogenous analgesia mechanisms via descending spinal inhibitory pain pathways:

1. 1. Duloxetine is an effective inhibitor of the second phase of the formalin test, the capsaicin test, the acetic-acid writhing test, the carrageenan test and nerve ligation injury tests (both the Chung and Seltzer models) indicative of analgesic effects in neurological, inflammatory, and neuropathic pains.
2. 2. Full efficacy occurs at doses that do not impair motor performance on the rotorod test.
3. 3. There is no evidence of reduction in effect with subchronic dosing in the nerve ligation models.

Thus, the activity of duloxetine in nonclinical models suggests that it would have antidepressant activity as well as utility in treating persistent/chronic pain.

Safety Pharmacology Studies

The potential of duloxetine to alter cardiovascular, central nervous system (CNS), smooth muscle, renal, immune, and gastrointestinal motility functions was examined to provide a profile of possible secondary pharmacologic effects of this compound. Smooth and cardiac muscle function was unaffected at concentrations of 1 nM to 1 µM duloxetine. At the maximum clinically achieved unbound plasma concentration of duloxetine (90 nM or 30 ng/ml), duloxetine had no effect on any of the human cardiac ion channels tested. Significant cardiovascular effects were observed at intravenous doses of 2 mg/kg of duloxetine in anesthetized dogs. Cardiovascular function was not significantly altered following oral administration of 7 or 20 mg duloxetine/kg in the conscious rat. Intravenous doses of 0.4 mg/kg of duloxetine in the anesthetized dog stimulated respiratory rate. However, in conscious dogs, intravenous (2 mg/kg) or oral (10 mg/kg) administration of duloxetine had no effect on pulmonary or systemic arterial pressure or on heart rate. Duloxetine did not adversely affect the CNS functions of mice at acute oral doses of 3 mg/kg. In addition, multiple (5-day) oral administration of duloxetine in mice resulted in tolerance to its adrenergic activity, depressed CNS activity (as evaluated using hexobarbital-induced sleep), and enhanced anticonvulsive properties. Gastrointestinal motility was not affected at oral doses of up to 30 mg/kg. An increase in sodium excretion was the only effect on renal function observed at 3 mg/kg. Immune functions were unaltered at an oral dose of 130 mg/kg.

Based upon the results of these studies, therapeutically relevant doses of duloxetine would not be predicted to significantly alter the CNS, smooth muscle, renal, immune, or gastrointestinal functions tested. Potential secondary pharmacologic reactions of duloxetine at clinical doses would appear to be limited to increases in pulmonary pressure, pulmonary vascular resistance, and respiratory rate, effects which are attributable to the known actions of norepinephrine and serotonin. It should be noted, however, that these effects were only observed in anesthetized animals.

Pharmacokinetics

The absorption, distribution, metabolism, and excretion of duloxetine have been extensively evaluated in mice, rats, and dogs. After an oral gavage dose or daily oral or dietary doses, duloxetine is well absorbed in mice, rats, and dogs, but extensively metabolized. The percent of the dose undergoing biotransformation after oral administration is >90% in all 3 species, with dogs exhibiting the highest degree of metabolism. After an intravenous dose to both rats and dogs, duloxetine is also extensively metabolized with approximately 75% to 81% of the dose circulating as metabolites. The elimination half-life of duloxetine ranges from 1.5 hours in rats to 4 hours in dogs after administration of an oral dose. The half-life of radioactivity is much longer (27 to 122 hours) in all three species and is reflective of the elimination of multiple metabolites. The major route of elimination in mice, rats, and dogs is via the feces (46% to 77%) with 14% to 43% of the radioactivity appearing in the urine. The elimination routes of radioactivity are similar after both an intravenous dose and an oral dose of 14C-duloxetine. In bile duct cannulated rats, the majority of the radioactivity is excreted in the bile indicating that radioactivity eliminated in the feces of noncannulated rats is due to biliary excretion and not to poor absorption.

Duloxetine is extensively metabolized in mice, rats, and dogs to numerous metabolites. In all three species, the major biotransformation pathways involve several oxidations, especially in the naphthyl ring followed by conjugation. The major metabolites in dogs are a dihydrodiol and cysteinylhydroxy derivative of duloxetine. The dihydrodiol of duloxetine is found in all three species, but the cysteinylhydroxy of duloxetine is only found in the dog. The major metabolites in mice and rats are glucuronide conjugates of 4-hydroxy duloxetine, and 6-hydroxy duloxetine, and the des(aminomethyl) acid metabolite. The 5-hydroxy related metabolites tended to predominate in the dog.

Tissue distribution studies indicate that after a dose of 14C-duloxetine, radioactivity is not widely distributed into tissues of rats and that the highest concentrations of radioactivity were observed in the liver, kidney, lung and gastrointestinal tract. Radioactivity does distribute into the brain, but at low levels. Duloxetine is highly bound to plasma proteins, which may account for some of its lower distribution. Duloxetine does cross the placenta and is excreted into milk of lactating rats. Although duloxetine appeared to be a mixed cytochrome P450 inducer (CYP1A and CYP2B) in rats at elevated doses, the data indicated that duloxetine has a very low potential for P450 induction in humans.

The disposition of duloxetine has been investigated in mice, rats, dogs and monkeys. The primary species used in studying duloxetine have been the rat and dog. Monkeys were only used in a pilot study determining the disposition and metabolism of 14C-duloxetine. Plasma concentrations of duloxetine have been quantitated utilizing HPLC with UV or fluorescence detection and HPLC with tandem mass spectrometry methods. 14C-duloxetine was synthesized with the radiolabel in various positions, 14C-alkyl, 14C-naphthyl and 14C at the chiral carbon. Radiolabelled drug was administered in the pharmacokinetic, metabolism, excretion and tissue distribution studies. The metabolism and excretion of 14C-duloxetine has been investigated in mice, rats, dogs and monkeys. The plasma protein binding of 14C-duloxetine has been determined in mouse, rat, dog and human plasma. Additional studies have investigated the placental transfer of 14C-duloxetine in rats and the excretion of 14C-duloxetine into milk of lactating rats.

TOXICOLOGY

Acute Toxicology Studies

The primary findings following acute oral administration of duloxetine to mice, rats, dogs, and monkeys were related to central nervous system (CNS) effects (i.e., tremors, convulsions, emesis, mydriasis, salivation, and hyperresponsiveness). In rats and mice, the median lethal dose ranged from 279 mg/kg to 595 mg/kg. No deaths occurred in single-dose studies in dogs or monkeys at doses up to 100 mg/kg, the highest dose tested.

Important toxicologic effects in rats following the dietary administration of duloxetine hydrochloride for 1, 3, or 6 months occurred primarily in the high-dose group of 0.08% or approximately 50 mg/kg. These effects were decreased mean body weight, body weight gain, and food consumption; moderate hepatic microsomal enzyme induction with correlated increased liver weights, and minimal-to-moderate midzonal hepatocellular lipid vacuolation primarily in males.

Subacute and Long-Term Toxicology Studies

Administration of duloxetine to dogs for 1, 6, or 12 months at doses of 3, 10, or 30 mg/kg caused dose-related clinical signs of the CNS as a result of the pharmacologic action of this compound, including decreased food consumption, abnormal stools, emesis, and mydriasis. The frequency of emesis increased in a dose-related manner and was the dose-limiting effect. Additional findings were related to the liver (hepatic microsomal enzyme induction, increased liver weight, increased liver phospholipid phosphorus, and increased numbers of secondary lysosomes) and were limited primarily to the 30-mg/kg group. Dogs treated with 3 mg/kg had no adverse signs of toxicity.

Other Toxicology Studies

The toxicity of duloxetine following intravenous administration was evaluated in rats and dogs. Administration of duloxetine to male and female Fischer 344 rats via a daily 30-minute intravenous infusion at dose levels of 1, 5, or 10 mg/kg/day resulted in excessive irritation at the injection sites. Systemic toxicity was not observed at a dose of 1 mg/kg/day for 15 days. Similarly, daily intravenous administration of duloxetine over an approximate 30-minute period to beagle dogs at doses of 1, 2.5, or 5 mg/kg/day for up to 15 days resulted in no evidence of systemic toxicity. However, local irritation at the injection sites precluded dosing of the 5-mg/kg/day group for more than 10 days.

Antigenicity studies indicated that the hypersensitivity-eliciting antigenicity of duloxetine in guinea pigs was restricted to active systemic anaphylaxis when immunized with a hapten-protein conjugate with adjuvant. Duloxetine was nonimmunogenic and did not possess hypersensitivity-eliciting antigenicity in mice. As a result, the overall risk of duloxetine causing allergic adverse reactions clinically is considered minimal.

Dependence studies indicated that duloxetine did not demonstrate any dependence-producing potential in monkeys or rats.

Dermal toxicity and dermal and ocular irritancy were determined to assess the occupational hazard of duloxetine. In the rabbit, duloxetine was considered to be nontoxic and a very slight irritant when administered dermally. Duloxetine was also determined to be corrosive ocularly.

Carcinogenicity Studies

Duloxetine was administered in the diet to rats and mice for 2 years. In rats, dietary doses of duloxetine up to approximately 27 mg/kg/day in females (2.0 times the maximum recommended human dose [MRHD] on a mg/m² basis) or approximately 36 mg/kg/day in males (2.6 times the MRHD on a mg/m2 basis) did not cause any increase in incidence of expected or unusual neoplasms or decrease in the latency for any tumour type. Rats receiving dietary concentrations of approximately 30 mg/kg/day had plasma concentrations of duloxetine that were 3.5 to 12 times the plasma concentrations of patients receiving the MRHD.

In female mice receiving duloxetine at approximately 144 mg/kg/day (5 times MRHD on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas, but these were considered to be secondary to hepatic enzyme induction with associated centrilobular hypertrophy and vacuolation. Mice receiving dietary concentrations of approximately 144 mg/kg/day had plasma concentrations of duloxetine that were 3 to 11 times the plasma concentrations of patients receiving the MRHD. The relevance of this mouse data in humans is unknown.

Mutagenicity Studies

Duloxetine demonstrated no mutagenic potential in a battery of genotoxicity tests which included the Ames bacterial mutagenesis assay, the Chinese hamster ovary (CHO) chromosomal aberration assay, the mouse lymphoma cell mutagenesis assay, the in vivo mouse micronucleus assay, the rat hepatocyte unscheduled DNA synthesis assay, and the in vivo CHO sister chromatid exchange assay.

Reproductive and Teratogenicity Studies

Reproductive performance was not affected in male rats receiving duloxetine orally at doses up to 45 mg/kg/day or approximately 3.3 times the MRHD on a mg/m2 basis. In female rats receiving 45 mg/kg/day duloxetine orally (3.3 times the MRHD on a mg/m2 basis), reproductive toxicity was demonstrated by a decrease in maternal food consumption and body weight, estrous cycle disruption, depressions in live birth indices and progeny survival, and progeny growth retardation. The no-observed-effect level (NOEL) for maternal toxicity, reproductive toxicity, and developmental toxicity in the female fertility study was 10 mg/kg/day (approximately 0.7 times the MRHD on a mg/m² basis).

In embryo-fetal development studies in rats and rabbits there was no evidence of teratogenicity following the oral administration of up to 45 mg/kg/day (3.3 times the MRHD on a mg/m² basis). In rat reproduction studies, mating and fertility indices and reproductive parameters were not affected by duloxetine administration of up to 30 mg/kg/day (2.2 times the MRHD on a mg/m² basis). A decrease in pup survival to 1 day postpartum and a decrease in mean litter body weights during the lactation period occurred following maternal exposure to 30 mg/kg/day (2.2 times the MRHD on a mg/m² basis). Increased reactivity was observed in pups following maternal exposure to 10 and 30 mg/kg/day (0.7 and 2.2 times the MRHD on a mg/m2 basis, respectively). Growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.

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