Drizalma Sprinkle Drug Information

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, a treatment-emergent adverse reaction of the type listed. Adverse Reactions in Adults The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled trials for MDD (N = 3779), GAD (N = 1018), OA (N = 503), CLBP (N = 600), and DPNP (N = 906), and FM (N = 1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively.

Most patients received doses of a total of 60 to 120 mg per day . The data below do not include results of the trial examining the efficacy of duloxetine delayed-release in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population. A dverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials Major Depressive Disorder: Approximately 8.4% (319/3779) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo-treated patients. Nausea (duloxetine delayed-release capsules 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine delayed-release capsules-treated patients and at a rate of at least twice that of placebo). Generalized Anxiety Disorder: Approximately 13.7% (139/1018) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) of placebo-treated patients.

Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.3%, placebo 0.4%), and dizziness (duloxetine delayed-release capsules 1.3%, placebo 0.4%). Diabetic Peripheral Neuropathic Pain: Approximately 12.9% (117/906) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.5%, placebo 0.7%), dizziness (duloxetine delayed-release capsules 1.2%, placebo 0.4%), and somnolence (duloxetine delayed-release capsules 1.1%, placebo 0.0%). Fibromyalgia: Approximately 17.5% (227/1294) of the duloxetine delayed-release capsules-treated patients in 3-to 6-month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 2.0%, placebo 0.5%), headache (duloxetine delayed-release capsules 1.2%, placebo 0.3%), somnolence (duloxetine delayed-release capsules 1.1%, placebo 0%), and fatigue (duloxetine delayed-release capsules 1.1%, placebo 0.1%). Chronic Pain due to Osteoarthritis: Approximately 15.7% (79/503) of the duloxetine delayed-release capsules-treated patients in 13 week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo-treated patients.

Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 2.2%, placebo 1.0%). Chronic Low Back Pain: Approximately 16.5% (99/600) of the duloxetine delayed-release capsules-treated patients in 13 week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.0%, placebo 0.7%), and somnolence (duloxetine delayed-release capsules 1.0%, placebo 0.0%). M ost Common Adverse Reactions (Adults) Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Fibromyalgia: nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.

Chronic Pain due to Osteoarthritis: nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness. Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue. A dverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine Delayed-Release Capsules Treated Patients in Adult Placebo-Controlled Trials The most commonly observed adverse reactions in duloxetine delayed-release capsule-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.

Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo-treated patients. T able 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations a A dverse Reaction P ercentage of Patients Reporting Reaction Duloxetine delayed - release capsules (N = 8100) P lacebo ( N = 5655) Nausea c 23 8 Headache 14 12 Dry mouth 13 5 Somnolence e 10 3 Fatigue b,c 9 5 Insomnia d 9 5 Constipation c 9 4 Dizziness c 9 5 Diarrhea 9 6 Decreased appetite c 7 2 Hyperhidrosis c 6 1 Abdominal pain f 5 4 a Includes adults with MDD, GAD, DPNP, FM, and chronic musculoskeletal pain. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b Also includes asthenia. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. d Also includes initial insomnia, middle insomnia, and early morning awakening. e Also includes hypersomnia and sedation. f Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.

A dverse Reactions in Pooled MDD and GAD Trials in Adults Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo-treated patients. T able 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults a,b S y stem Organ Class / Adverse Reaction P ercentage of Patients Reporting Reaction Duloxetine delayed - release capsules (N = 4797) P lacebo ( N = 3303) Cardiac Disorders Palpitations 2 1 E y e Disorders Vision blurred 3 1 G astrointestinal Disorders Nausea c 23 8 Dry mouth 14 6 Constipation c 9 4 Diarrhea 9 6 Abdominal pain d 5 4 Vomiting 4 2 G eneral Disorders and Administration Site Conditions Fatigue e 9 5 M etabolism and Nutrition Disorders Decreased appetite c 6 2 Nervous System Disorders Headache 14 14 Dizziness c 9 5 Somnolence f 9 3 Tremor 3 1 P s ychiatric Disorders Insomnia g 9 5 Agitation h 4 2 Anxiety 3 2 Reproductive System and Breast Disorders Erectile dysfunction 4 1 Ejaculation delayed c 2 1 Libido decreased i 3 1 Orgasm abnormal j 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 S kin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b For GAD, there were no adverse reactions that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65 years. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. d Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain e Includes asthenia f Includes hypersomnia and sedation g Includes initial insomnia, middle insomnia, and early morning awakening h Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity i Includes loss of libido j Includes anorgasmia Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials: Table 4 displays the incidence of adverse reactions that occurred in 2% or more of duloxetine delayed-release capsules-treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients. T able 4: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials in Adults a S y stem Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N = 3303) Placebo (N = 2352) G astrointestinal Disorders Nausea Dry Mouth b Constipation b Diarrhea Abdominal Pain c Vomiting Dyspepsia 23 11 10 9 5 3 2 7 3 3 5 4 2 1 G eneral Disorders and Administration Site Conditions Fatigue d 11 5 Infections and Infestations Nasopharyngitis Upper Respiratory Tract Infection Influenza 4 3 2 4 3 2 M etabolism and Nutrition Disorders Decreased Appetite b 8 1 M usculoskeletal and Connective Tissue Musculoskeletal Pain e Muscle Spasms 3 2 3 2 Nervous System Disorders Headache Somnolence b,f Dizziness Paraesthesia g Tremor b 13 11 9 2 2 8 3 5 2 <1 P s ychiatric Disorders Insomnia b,h Agitation i 10 3 5 1 Reproductive System and Breast Disorders Erectile Dysfunction b Ejaculation Disorder j 4 2 <1 <1 Respiratory, Thoracic, and Mediastinal Disorders Cough 2 2 S kin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 V ascular Disorders Flushing k Blood pressure increased l 3 2 1 1 a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day. c Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness and gastrointestinal pain d Includes asthenia e Includes myalgia and neck pain f Includes hypersomnia and sedation g Includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia oral h Includes initial insomnia, middle insomnia, and early morning awakening. i Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity j Includes ejaculation failure k Includes hot flush l Includes blood pressure diastolic increased, blood pressure systolic increased, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension E ff ects on Male and Female Sexual Function in Adults with MDD Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment.

Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled adult trials . The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from baseline level of sexual dysfunction from baseline, which is commonly seen in depressed patients.

In these trials, male patients treated with duloxetine delayed-release capsules experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than did placebo-treated male patients (see Table 5). Female patients treated with duloxetine delayed-release capsules did not experience more sexual dysfunction than on placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in patients treated with duloxetine delayed-release capsules. T able 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials Male Patients a Female Patients a Duloxetine delayed - release capsules (n = 175) Placebo (n = 83) Duloxetine delayed - release capsules (n = 241) Placebo (n = 126) ASEX Total (Items 1-5) Item 1 - Sex drive Item 2 - Arousal Item 3 - Ability to achieve erection (men); Lubrication (women) Item 4 - Ease of reaching orgasm Item 5 - Orgasm satisfaction 0.56 b -0.07 0.01 0.03 0.40 c 0.09 -1.07 -0.12 -0.26 -0.25 -0.24 -0.13 -1.15 -0.32 -0.21 -0.17 -0.09 -0.11 -1.07 -0.24 -0.18 -0.18 -0.13 -0.17 a n = Number of patients with non-missing change score for ASEX total b p = 0.013 versus placebo c p<0.001 versus placebo V ital Sign Changes in Adults In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, duloxetine delayed-release capsules-treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg SBP and 0.55 mm Hg in DBP placebo-treated patients.

There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure . Duloxetine delayed-release capsules treatment, for up to 26 weeks in placebo-controlled trials across approved adult populations, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine delayed-release capsules-treated patients, decrease of 0.17 beats per minute in placebo-treated patients). Laboratory Changes in Adults Duloxetine delayed-release capsules treatment in placebo-controlled clinical trials across approved adult populations, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in duloxetine delayed-release capsules-treated patients when compared with placebo-treated patients . High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in duloxetine delayed-release capsules treated patients compared to placebo-treated patients. Ot her Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine Delayed-Release Capsules in Adults Following is a list of adverse reactions reported by patients treated with duloxetine delayed-release capsules in clinical trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine delayed-release capsules.

Of these, 26.9% took duloxetine delayed-release capsules for at least 6 months, and 12% for at least one year. The following listing is not intended to include reactions already listed in previous tables or elsewhere in labeling, for which a drug cause was remote, which were so general as to be uninformative, which were not considered to have significant clinical implications, or which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Cardiac Disorders - Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy. Ear and Labyrinth Disorders - Frequent: vertigo; Infrequent: ear pain and tinnitus. Endocrine Disorders - Infrequent: hypothyroidism.

Eye Disorders - Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment. Gastrointestinal Disorders - Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer. General Disorders and Administration Site Conditions - Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.

Infections and Infestations - Infrequent: gastroenteritis and laryngitis. Investigations - Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased. Metabolism and Nutrition Disorders - Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.

Musculoskeletal and Connective Tissue Disorders - Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching. Nervous System Disorders - Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; R are: dysarthria. Psychiatric Disorders - Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.

Renal and Urinary Disorders - Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal. Reproductive System and Breast Disorders - Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder. Respiratory, Thoracic and Mediastinal Disorders - Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness.

Skin and Subcutaneous Tissue Disorders - Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis. Vascular Disorders - Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness. A dverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients The data described below reflect exposure to duloxetine delayed-release capsules in pediatric, 10 week, placebo-controlled trials for MDD (N = 341) and GAD (N = 135). The population studied (N = 476) was 7 to 17 years of age with 42.4% children age 7 to 11 years of age, 50.6% female, and 68.6% white.

Patients received 30 to 120 mg per day during placebo-controlled acute treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41.7% children age 7 to 11 years of age and 51.8% female exposed to duloxetine delayed-release capsules in MDD and GAD clinical trials up to 36 weeks in length, in which most patients received 30 to 120 mg per day. The safety and effectiveness of DRIZALMA SPRINKLE have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain.

Pediatric Clinical Trial Database The adverse drug reaction profile observed in pediatric clinical trials in pediatric patients aged 7 to 17 years old was consistent with the adverse drug reaction profile observed in adult clinical trials. The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients . The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness. Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD Table 6 provides the incidence of adverse reactions in MDD and GAD pediatric placebo- controlled trials that occurred in greater than 2% of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo.

DRIZALMA SPRINKLE is not approved for the treatment of MDD in pediatric patients T able 6: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10 week Pediatric Placebo-Controlled Trialsin MDD a and GAD b System Organ Class/Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Duloxetine delayed - release capsules (N = 476) Placebo (N = 362) Gastrointestinal Disorders Nausea Abdominal Pain c Vomiting Diarrhea Dry Mouth 18 13 9 6 2 8 10 4 3 1 General Disorders and Administration Site Conditions Fatigue d 7 5 Investigations Decreased Weight e 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache Somnolence f Dizziness 18 11 8 13 6 4 Psychiatric Disorders Insomnia g 7 4 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain Cough 4 3 2 1 a DRIZALMA SPRINKLE is not approved for the treatment of pediatric MDD . b The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. c Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. d Also includes asthenia. e Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N = 467 duloxetine delayed-release capsules; N = 354 Placebo). f Also includes hypersomnia and sedation. g Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia. Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine delayed-release capsules treated patients than placebo treated patients in pediatric MDD and GAD clinical trials included abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (DRIZALMA SPRINKLE is not approved for the treatment of pediatric MDD). The most commonly reported symptoms following discontinuation of duloxetine delayed-release capsules in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain . Gr owth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Pediatric patients treated with duloxetine delayed-release capsules in clinical trials experienced a 0.1kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated patients.

The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the duloxetine delayed-release capsules group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine delayed-release capsules-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers. In studies up to 9 months, duloxetine delayed-release capsules-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients and 1.3 cm increase in patients ). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in patients and increase of 0.3% in patients ). Weight and height should be monitored regularly in pediatric patients treated with DRIZALMA SPRINKLE. Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine delayed-release capsules). However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of duloxetine delayed-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally related to duloxetine delayed-release capsules therapy and not mentioned elsewhere in labeling include: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.

• Potent CYP1A2 Inhibitors: Avoid concomitant use (2.6, 7)
• CYP2D6 Substrates: Consider dose reduction with concomitant use (7) 7.1 Drugs Having Clinically Important Interactions with DRIZALMA SPRINKLE Table 7: Clinically Important Drug Interactions Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of SSRIs and SNRIs including duloxetine with MAOIs increases the risk of serotonin syndrome. Intervention
• The use of MAOIs intended to treat psychiatric disorders with duloxetine or within 5 days of stopping treatment with duloxetine is contraindicated [see Contraindications (4) and Warnings and Precautions (5.4)] .
• The use of duloxetine delayed-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Contraindications (4) and Warnings and Precautions (5.4)] .
• Starting duloxetine in a patient who is being treated with MAOIs is also contraindicated [see Dosage and Administration (2.10), Contraindications (4), Warnings and Precautions (5.4)] . Examples Selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, intravenous methylene blue Other Serotonergic Drugs Clinical Impact Concomitant use of duloxetine with other serotonergic drugs increases the risk of serotonin syndrome. Intervention
• Patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
• Monitor for symptoms of serotonin syndrome when duloxetine is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems.
• Treatment with duloxetine delayed-release capsules and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated [see Warnings and Precautions (5.4)] . Examples Other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort Inhibitors of CYP1A2 Clinical Impact Concomitant use of duloxetine with CYP1A2 inhibitors increases AUC, C max , t 1/2 of duloxetine. Intervention Avoid concomitant use of duloxetine delayed-release capsules with potent CYP1A2 inhibitors [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)]. Examples Fluvoxamine, cimetidine, ciprofloxacin, enoxacin Dual Inhibition of CYP1A2 and CYP2D6 Clinical Impact Concomitant administration of duloxetine with potent CYP1A2 inhibitors to CYP2D6 poor metabolizers results in increased AUC and C max of duloxetine. Intervention Avoid co-administration of duloxetine delayed-release capsules and potent CYP1A2 inhibitors to CYP2D6 poor metabolizers [see Clinical Pharmacology (12.3)] . Examples Fluvoxamine, cimetidine, ciprofloxacin, enoxacin Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of duloxetine with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when duloxetine is initiated or discontinued [Warnings and Precaution (5.5)] . Examples NSAIDs, aspirin, warfarin Inhibitors of CYP2D6 Clinical Impact Concomitant use of duloxetine with CYP2D6 inhibitors increase AUC of duloxetine. Greater degrees of inhibition are expected with higher doses of CYP2D6 inhibitors. Intervention Exercise caution when co-administering duloxetine delayed-release capsules and potent CYP2D6 inhibitors [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)]. Examples Paroxetine, fluoxetine, quinidine Drugs Metabolized by CYP2D6 Clinical Impact Concomitant use of duloxetine increases AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug. Intervention Monitor plasma concentrations of CYP2D6 substrate and reduce dosage of CYP2D6 substrate drug if necessary [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)] . Examples TCAs (nortriptyline, amitriptyline, imipramine, desipramine); phenothiazines (thioridazine); Type 1C antiarrhythmics (propafenone, flecainide) Drugs that Affect Gastric Acidity Clinical Impact In patients with conditions that may slow gastric emptying (e.g., some diabetics) and drugs that raise the gastrointestinal pH may lead to earlier the release of duloxetine. Intervention Use with caution [see Clinical Pharmacology (12.3)]. Examples Aluminum-and magnesium-containing antacids, famotidine, proton pump inhibitors Drugs Metabolized by CYP1A2 Clinical Impact Concomitant use of duloxetine with CYP1A2 substrates may increase the AUC of CYP1A2 substrate. Intervention Use with caution [see Clinical Pharmacology (12.3)]. Examples Theophylline, caffeine CNS Drugs Clinical Impact Concomitant use of duloxetine with other centrally acting drugs may increase the CNS effects of duloxetine. Intervention Use with caution [see Warnings and Precautions (5.12)] . Examples Centrally acting CNS drugs Drugs Highly Bound to Plasma Protein Clinical Impact Concomitant use of duloxetine with highly protein bound drugs may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. Intervention Use with caution [see Clinical Pharmacology (12.3)]. Examples Highly plasma protein binding drugs Alcohol Clinical Impact Concomitant use of duloxetine and alcohol may cause liver injury or aggravate pre-existing liver disease. Intervention Avoid use patients with chronic liver disease or heavy alcohol use [see Dosage and Administration (2.7), Warnings and Precautions (5.2, 5.12)] .

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ Risk Summary Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage . Data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. Data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes ( see Data ). There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including DRIZALMA SPRINKLE, during pregnancy (see Clinical Considerations). In rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to 3 and 6 times, respectively, the maximum recommended human dose (MRHD) of 120 mg/day given to adolescents on a mg/m 2 basis.

When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected.

The estimated of background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Women who discontinued antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continued antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum.

Pregnant women with fibromyalgia are at increased risk for adverse maternal and infant outcomes including preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, and venous thrombosis. It is not known if these adverse maternal and fetal outcomes are a direct result of fibromyalgia or other comorbid factors. Maternal Adverse Reactions Use of DRIZALMA SPRINKLE in the month before delivery may be associated with an increased risk of postpartum hemorrhage . Fetal/Neonatal Adverse Reaction Neonates exposed to duloxetine and other SNRIs or SSRIs 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 findings are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome.

It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome . Data Human Data Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% CI: 1.08-2.18). The same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. Methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures. A nimal Data In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.

When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of malformations or developmental variations at doses up to 45 mg/kg/day (3 and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m 2 basis. However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (approximately equal to the MRHD in rats and 2 times the MRHD in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD given to adolescents on a mg/m 2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day.

Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.

Pediatric Use The safety and effectiveness of DRIZALMA SPRINKLE have been established for treatment of generalized anxiety disorder (GAD) in pediatric patients ages 7 to 17 years of age. The safety and effectiveness of DRIZALMA SPRINKLE have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain. Antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients.

Monitor all pediatric patients being treated with antidepressants for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, or at times of dosage changes . Perform regular monitoring of weight and growth in pediatric patients treated with DRIZALMA SPRINKLE . Generalized Anxiety Disorder Use of DRIZALMA SPRINKLE for the treatment of GAD in patients 7 to 17 years of age is supported by one 10-week, placebo- controlled trial (GAD-6). The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age (53% were 12 to 17 years of age). Duloxetine delayed-release capsules demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score . The safety and effectiveness of DRIZALMA SPRINKLE for the treatment of GAD in pediatric patients less than 7 years of age have not been established. Fibromyalgia The safety and effectiveness of DRIZALMA SPRINKLE for the treatment of fibromyalgia in patients less than 13 years of age have not been established. Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine delayed-release capsules). However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Major Depressive Disorder The safety and effectiveness of DRIZALMA SPRINKLE have not been established in pediatric patients for the treatment of MDD. Efficacy of duloxetine delayed-release capsules was not demonstrated in two 10 week, placebo-controlled trials with 800 pediatric patients with MDD, aged 7 to 17 years old with MDD. Neither duloxetine delayed-release capsules nor an active control (approved for treatment of pediatric MDD) was superior to placebo. The most frequently observed adverse reactions in the clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs.

Juvenile Animal Toxicology Data Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child).

The use of MAOIs intended to treat psychiatric disorders with DRIZALMA SPRINKLE, or within 5 days of stopping treatment with DRIZALMA SPRINKLE, are contraindicated because of an increased risk of serotonin syndrome. The use of DRIZALMA SPRINKLE within 14 days of stopping an MAOI intended to treat psychiatric disorders is contraindicated . Starting DRIZALMA SPRINKLE in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is contraindicated because of an increased risk of serotonin syndrome . Serotonin Syndrome and MAOIs : Do not use MAOIs intended to treat psychiatric disorders with DRIZALMA SPRINKLE or within 5 days of stopping treatment with DRIZALMA SPRINKLE. Do not use DRIZALMA SPRINKLE within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start DRIZALMA SPRINKLE in a patient who is being treated with linezolid or intravenous methylene blue

Signs and Symptoms

In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

Management of Overdose

There is no specific antidote to a duloxetine overdosage, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug, such as assuring an an adequate airway, oxygenation, and ventilation and monitoring cardiac rhythm and vital signs. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Induction of emesis is not recommended. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and C max by an average of one-third, although some patients had a limited effect of activated charcoal.

Due to the large volume of distribution of duloxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who overdose with duloxetine delayed-release capsules and tricyclic antidepressants.

In such a case, decreased clearance 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 . In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org) for up-to-date guidance and advice.