Data from FDA - Curated by Marshall Pearce - Last updated 09 October 2017

Indication(s)

1 INDICATIONS AND USAGE CYMBALTA ® is indicated for the treatment of: Major Depressive Disorder [see Clinical Studies ( 14.1)] Generalized Anxiety Disorder [see Clinical Studies ( 14.2)] Diabetic Peripheral Neuropathy [see Clinical Studies ( 14.3)] Fibromyalgia [see Clinical Studies ( 14.4)] Chronic Musculoskeletal Pain [see Clinical Studies ( 14.5)] CYMBALTA ® is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: Major Depressive Disorder (MDD) ( 1) Generalized Anxiety Disorder (GAD) ( 1) Diabetic Peripheral Neuropathic Pain (DPNP) ( 1) Fibromyalgia (FM) ( 1) Chronic Musculoskeletal Pain ( 1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOIs) — The use of MAOIs intended to treat psychiatric disorders with CYMBALTA or within 5 days of stopping treatment with CYMBALTA is contraindicated because of an increased risk of serotonin syndrome. The use of CYMBALTA within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration ( 2.8) and Warnings and Precautions ( 5.4)] . Starting CYMBALTA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration ( 2.9) and Warnings and Precautions ( 5.4)] . Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with CYMBALTA or within 5 days of stopping treatment with CYMBALTA. Do not use CYMBALTA within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start CYMBALTA in a patient who is being treated with linezolid or intravenous methylene blue ( 4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions ( 5.1)] Hepatotoxicity [see Warnings and Precautions ( 5.2)] Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions ( 5.3)] Serotonin Syndrome [see Warnings and Precautions ( 5.4)] Abnormal Bleeding [see Warnings and Precautions ( 5.5)] Severe Skin Reactions [see Warnings and Precautions ( 5.6)] Discontinuation of Treatment with CYMBALTA [see Warnings and Precautions ( 5.7)] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.8)] Angle-Closure Glaucoma [see Warnings and Precautions ( 5.9)] Seizures [see Warnings and Precautions ( 5.10)] Effect on Blood Pressure [see Warnings and Precautions ( 5.11)] Clinically Important Drug Interactions [see Warnings and Precautions ( 5.12)] Hyponatremia [see Warnings and Precautions ( 5.13)] Urinary Hesitation and Retention [see Warnings and Precautions ( 5.15)] Most common adverse reactions (≥5% and at least twice the incidence of placebo patients): nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis ( 6.3). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Data Sources 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 individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality. Adults — The data described below reflect exposure to CYMBALTA in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), 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 [see Clinical Studies ( 14)] .The data below do not include results of the trial examining the efficacy of CYMBALTA 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. Children and Adolescents — The data described below reflect exposure to CYMBALTA 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 30-120 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 CYMBALTA in MDD and GAD clinical trials up to 36-weeks in length, in which most patients received 30-120 mg per day. 6.2 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials Major Depressive Disorder — Approximately 8.4% (319/3779) of the patients who received CYMBALTA in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (CYMBALTA 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the CYMBALTA-treated patients and at a rate of at least twice that of placebo). Generalized Anxiety Disorder — Approximately 13.7% (139/1018) of the patients who received CYMBALTA in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 3.3%, placebo 0.4%), and dizziness (CYMBALTA 1.3%, placebo 0.4%). Diabetic Peripheral Neuropathic Pain — Approximately 12.9% (117/906) of the patients who received CYMBALTA in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 3.5%, placebo 0.7%), dizziness (CYMBALTA 1.2%, placebo 0.4%), and somnolence (CYMBALTA 1.1%, placebo 0.0%). Fibromyalgia — Approximately 17.5% (227/1294) of the patients who received CYMBALTA in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 2.0%, placebo 0.5%), headache (CYMBALTA 1.2%, placebo 0.3%), somnolence (CYMBALTA 1.1%, placebo 0.0%), and fatigue (CYMBALTA 1.1%, placebo 0.1%). Chronic Pain due to Osteoarthritis — Approximately 15.7% (79/503) of the patients who received CYMBALTA in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 2.2%, placebo 1.0%). Chronic Low Back Pain — Approximately 16.5% (99/600) of the patients who received CYMBALTA in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 3.0%, placebo 0.7%), and somnolence (CYMBALTA 1.0%, placebo 0.0%). 6.3 Most Common Adult Adverse Reactions Pooled Trials for all Approved Indications — The most commonly observed adverse reactions in CYMBALTA-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. Diabetic Peripheral Neuropathic Pain — The most commonly observed adverse reactions in CYMBALTA-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Fibromyalgia — The most commonly observed adverse reactions in CYMBALTA-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation. Chronic Pain due to Osteoarthritis — The most commonly observed adverse reactions in CYMBALTA-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness. Chronic Low Back Pain — The most commonly observed adverse reactions in CYMBALTA-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue. 6.4 Adverse Reactions Occurring at an Incidence of 5% or More Among CYMBALTA-Treated Patients in Adult Placebo-Controlled Trials Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with CYMBALTA and with an incidence greater than placebo. Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Indications a 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 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. Percentage of Patients Reporting Reaction Adverse Reaction CYMBALTA (N=8100) Placebo (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 6.5 Adverse Reactions Occurring at an Incidence of 2% or More Among CYMBALTA-Treated Patients in Adult Placebo-Controlled Trials Pooled MDD and GAD Trials — Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with CYMBALTA and with an incidence greater than placebo. Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials a,b 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 events 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 Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain e Also includes asthenia f Also includes hypersomnia and sedation g Also includes initial insomnia, middle insomnia, and early morning awakening h Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity i Also includes loss of libido j Also includes anorgasmia Percentage of Patients Reporting Reaction System Organ Class / Adverse Reaction CYMBALTA (N=4797) Placebo (N=3303) Cardiac Disorders Palpitations 2 1 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nausea c 23 8 Dry mouth 14 6 Constipation c 9 4 Diarrhea 9 6 Abdominal pain d 5 4 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue e 9 5 Metabolism 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 Psychiatric 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 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 DPNP, FM, OA, and CLBP — Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with CYMBALTA (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo. Table 4: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials a 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 Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness and gastrointestinal pain d Also includes asthenia e Also includes myalgia and neck pain f Also includes hypersomnia and sedation g Also includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia oral h Also includes initial insomnia, middle insomnia, and early morning awakening. i Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity j Also includes ejaculation failure k Also includes hot flush l Also 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 Percentage of Patients Reporting Reaction System Organ Class / Adverse Reaction CYMBALTA (N=3303) Placebo (N=2352) Gastrointestinal Disorders Nausea 23 7 Dry Mouth b 11 3 Constipation b 10 3 Diarrhea 9 5 Abdominal Pain c 5 4 Vomiting 3 2 Dyspepsia 2 1 General Disorders and Administration Site Conditions Fatigue d 11 5 Infections and Infestations Nasopharyngitis 4 4 Upper Respiratory Tract Infection 3 3 Influenza 2 2 Metabolism and Nutrition Disorders Decreased Appetite b 8 1 Musculoskeletal and Connective Tissue Musculoskeletal Pain e 3 3 Muscle Spasms 2 2 Nervous System Disorders Headache 13 8 Somnolence b,f 11 3 Dizziness 9 5 Paraesthesia g 2 2 Tremor b 2 <1 Psychiatric Disorders Insomnia b,h 10 5 Agitation i 3 1 Reproductive System and Breast Disorders Erectile Dysfunction b 4 <1 Ejaculation Disorder j 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Cough 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders Flushing k 3 1 Blood pressure increased l 2 1 6.6 Effects on Male and Female Sexual Function in Adults 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 trials. In these trials, as shown in Table 5 below, patients treated with CYMBALTA experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with CYMBALTA experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on CYMBALTA than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects. Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials 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 Male Patients a Female Patients a CYMBALTA (n=175) Placebo (n=83) CYMBALTA (n=241) Placebo (n=126) ASEX Total (Items 1-5) 0.56 b -1.07 -1.15 -1.07 Item 1 — Sex drive -0.07 -0.12 -0.32 -0.24 Item 2 — Arousal 0.01 -0.26 -0.21 -0.18 Item 3 — Ability to achieve erection (men); Lubrication (women) 0.03 -0.25 -0.17 -0.18 Item 4 — Ease of reaching orgasm 0.40 c -0.24 -0.09 -0.13 Item 5 — Orgasm satisfaction 0.09 -0.13 -0.11 -0.17 6.7 Vital Sign Changes in Adults In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, CYMBALTA treatment was associated with mean increases of 0.23 mm Hg in systolic blood pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg systolic and 0.55 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions ( 5.3, 5.11)] . CYMBALTA treatment, for up to 26 weeks in placebo-controlled trials across approved indications, 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 CYMBALTA - treated patients, decrease of 0.17 beats per minute in placebo-treated patients). 6.8 Laboratory Changes in Adults CYMBALTA treatment in placebo-controlled clinical trials across approved indications, 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 CYMBALTA-treated patients when compared with placebo-treated patients [see Warnings and Precautions ( 5.2)] . High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in CYMBALTA treated patients compared to placebo. 6.9 Electrocardiogram Changes in Adults The effect of CYMBALTA 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected. CYMBALTA appears to be associated with concentration-dependent but not clinically meaningful QT shortening. 6.10 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of CYMBALTA in Adults Following is a list of treatment-emergent adverse reactions reported by patients treated with CYMBALTA in clinical trials. In clinical trials of all indications, 34,756 patients were treated with CYMBALTA. Of these, 26.9% (9337) took CYMBALTA 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 labeling, (2) for which a drug cause was remote, (3) which were so general as to be 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: 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 and tachycardia. 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; Rare: 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. 6.11 Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical Trials The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) 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 (children and adolescents) [see Adverse Reactions ( 6.5)] . The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness. Table 6 provides the incidence of treatment-emergent adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with CYMBALTA and with an incidence greater than placebo. Table 6: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10-week Pediatric Placebo-Controlled Trials a 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 Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. c Also includes asthenia. d Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=467 CYMBALTA; N=354 Placebo). e Also includes hypersomnia and sedation. f Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia. Percentage of Pediatric Patients Reporting Reaction System Organ Class/Adverse Reaction CYMBALTA (N=476) Placebo (N=362) Gastrointestinal Disorders Nausea 18 8 Abdominal Pain b 13 10 Vomiting 9 4 Diarrhea 6 3 Dry Mouth 2 1 General Disorders and Administration Site Conditions Fatigue c 7 5 Investigations Decreased Weight d 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache 18 13 Somnolence e 11 6 Dizziness 8 4 Psychiatric Disorders Insomnia f 7 4 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain 4 2 Cough 3 1 Other adverse reactions that occurred at an incidence of less than 2% but were reported by more CYMBALTA treated patients than placebo treated patients and are associated CYMBALTA treatment: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor. Discontinuation-emergent symptoms have been reported when stopping CYMBALTA. The most commonly reported symptoms following discontinuation of CYMBALTA in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions ( 5.7) and Adverse Reactions ( 6.2)] . Growth (Height and Weight) — Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Pediatric patients treated with CYMBALTA 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 CYMBALTA group than in the placebo group (14% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, CYMBALTA-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, CYMBALTA-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in children [7 to 11 years of age] and 1.3 cm increase in adolescents [12 to 17 years of age]). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in children [7 to 11 years of age] and increase of 0.3% in adolescents [12 to 17 years of age]). Weight and height should be monitored regularly in children and adolescents treated with CYMBALTA. 6.12 Postmarketing Spontaneous Reports The following adverse reactions have been identified during post approval use of CYMBALTA. 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 CYMBALTA 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Swallow CYMBALTA whole. Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric coating. CYMBALTA can be given without regard to meals. If a dose of CYMBALTA is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of CYMBALTA at the same time. Take CYMBALTA once daily, with or without food. Swallow CYMBALTA whole; do not crush or chew, do not open capsule. Take a missed dose as soon as it is remembered. Do not take two doses of CYMBALTA at the same time. ( 2) Indication Starting Dose Target Dose Maximum Dose MDD ( 2.1) 40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD ( 2.2) Adults 60 mg/day 60 mg/day (once daily) 120 mg/day Elderly 30 mg/day 60 mg/day (once daily) 120 mg/day Children and Adolescents (7 to 17 years of age) 30 mg/day 30 to 60 mg/day (once daily) 120 mg/day DPNP ( 2.3) 60 mg/day 60 mg/day (once daily) 60 mg/day FM ( 2.4) 30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain ( 2.5) 30 mg/day 60 mg/day (once daily) 60 mg/day Some patients may benefit from starting at 30 mg once daily ( 2) There is no evidence that doses greater than 60 mg/day confers additional benefit, while some adverse reactions were observed to be dose-dependent ( 2) Discontinuing CYMBALTA: Gradually reduce dosage to avoid discontinuation symptoms ( 2.7, 5.7) Hepatic Impairment: Avoid use in patients with chronic liver disease or cirrhosis ( 5.14) Renal Impairment: Avoid use in patients with severe renal impairment, GFR <30 mL/min ( 5.14) 2.1 Dosage for Treatment of Major Depressive Disorder Administer CYMBALTA at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies ( 14.1)] . 2.2 Dosage for Treatment of Generalized Anxiety Disorder Adults — For most patients, initiate CYMBALTA 60 mg once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies ( 14.2)] . Elderly — Initiate CYMBALTA at a dose of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies ( 14.2)] . Children and Adolescents (7 to 17 years of age) — Initiate CYMBALTA at a dose of 30 mg once daily for 2 weeks before considering an increase to 60 mg. The recommended dose range is 30 to 60 mg once daily. Some patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. The safety of doses above 120 mg once daily has not been evaluated [see Clinical Studies ( 14.2)] . 2.3 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain Administer CYMBALTA 60 mg once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies ( 14.3)] . For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, consider a lower starting dose and gradual increase in dose for patients with renal impairment [see Dosage and Administration ( 2.6), Use in Specific Populations ( 8.10), and Clinical Pharmacology ( 12.3)] . 2.4 Dosage for Treatment of Fibromyalgia Administer CYMBALTA 60 mg once daily. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day 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 [see Clinical Studies ( 14.4)] . 2.5 Dosage for Treatment of Chronic Musculoskeletal Pain Administer CYMBALTA 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. 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 [see Clinical Studies ( 14.5)] . 2.6 Dosing in Special Populations Hepatic Impairment — Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions ( 5.14) and Use in Specific Populations ( 8.9)] . Severe Renal Impairment — Avoid use in patients with severe renal impairment, GFR <30 mL/min [see Warnings and Precautions ( 5.14) and Use in Specific Populations ( 8.10)] . 2.7 Discontinuing CYMBALTA Adverse reactions after discontinuation of CYMBALTA, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions ( 5.7)] . 2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with CYMBALTA. Conversely, at least 5 days should be allowed after stopping CYMBALTA before starting an MAOI intended to treat psychiatric disorders [see Contraindications ( 4)]. 2.9 Use of CYMBALTA with Other MAOIs such as Linezolid or Methylene Blue Do not start CYMBALTA in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications ( 4)]. In some cases, a patient already receiving CYMBALTA therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, CYMBALTA should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with CYMBALTA may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions ( 5.4)] . The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with CYMBALTA is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions ( 5.4)] .
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data may cause fetal harm ( 8.1) Nursing Mothers: Exercise caution when administered to a nursing woman ( 8.3) 8.1 Pregnancy Pregnancy Category C Pregnancy Exposure Registry — There is a pregnancy registry that monitors the pregnancy outcomes in women exposed to CYMBALTA during pregnancy. To enroll, contact the CYMBALTA Pregnancy Registry at 1-866-814-6975 or www.cymbaltapregnancyregistry.com. Risk Summary — There are no adequate and well-controlled studies of CYMBALTA administration in pregnant women. In animal studies with duloxetine, fetal weights were decreased but there was no evidence of teratogenicity in pregnant rats and rabbits at oral doses administered during the period of organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day, respectively. 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. 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. CYMBALTA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reaction — Neonates exposed during pregnancy to serotonin - norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding which 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 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 [see Warnings and Precautions ( 5.4)] . Data Animal 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 teratogenicity at doses up to 45 mg/kg/day (4 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m 2 basis, in rat; 7 times the MRHD in rabbit). 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; 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); 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. 8.3 Nursing Mothers Risk Summary CYMBALTA is present in human milk. In a published study, lactating women who were weaning their infants were given CYMBALTA. At steady state, the concentration of CYMBALTA in breast milk was approximately 25% that of maternal plasma. The estimated daily infant dose was approximately 0.14% of the maternal dose. The developmental and health benefits of human milk feeding should be considered along with the mother's clinical need for CYMBALTA and any potential adverse effects on the milk-fed child from the drug or from the underlying maternal condition. Exercise caution when CYMBALTA is administered to a nursing woman. Data The disposition of CYMBALTA was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. The women were given 40 mg of CYMBALTA twice daily for 3.5 days. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose. The amount of CYMBALTA in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day. The presence of CYMBALTA metabolites in breast milk was not examined. 8.4 Pediatric Use Generalized Anxiety Disorder — In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10-week, placebo-controlled trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age. CYMBALTA demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies ( 14.2)] . The safety and effectiveness in pediatric patients less than 7 years of age have not been established. Major Depressive Disorder — Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7 to 17. Neither CYMBALTA nor an active control (indicated for treatment of pediatric depression) was superior to placebo. The safety and effectiveness in pediatric patients less than 7 years of age have not been established. 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. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as CYMBALTA [see Adverse Reactions ( 6.11)] . Use of CYMBALTA in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions ( 5.1)] . Animal 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). 8.5 Geriatric Use Of the 2,418 patients in premarketing clinical studies of CYMBALTA for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or over. In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and 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. SSRIs and SNRIs, including CYMBALTA have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions ( 5.13)] . In an analysis of data from all placebo-controlled-trials, patients treated with CYMBALTA reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient's underlying risk for falls. Underlying risk appears to increase steadily with age. As elderly patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during treatment with CYMBALTA is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Warnings and Precautions ( 5.3) and Adverse Reactions ( 6.10)] . The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the C max, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary. 8.6 Gender Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary. 8.7 Smoking Status Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers. 8.8 Race No specific pharmacokinetic study was conducted to investigate the effects of race. 8.9 Hepatic Impairment Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single 20 mg dose of CYMBALTA, 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 C max was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see Dosage and Administration ( 2.6) and Warnings and Precautions ( 5.14)] . 8.10 Severe Renal Impairment Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, C max and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal impairment (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance [see Dosage and Administration ( 2.6) and Warnings and Precautions ( 5.14)] .
Pregnancy and lactation
8.3 Nursing Mothers Risk Summary CYMBALTA is present in human milk. In a published study, lactating women who were weaning their infants were given CYMBALTA. At steady state, the concentration of CYMBALTA in breast milk was approximately 25% that of maternal plasma. The estimated daily infant dose was approximately 0.14% of the maternal dose. The developmental and health benefits of human milk feeding should be considered along with the mother's clinical need for CYMBALTA and any potential adverse effects on the milk-fed child from the drug or from the underlying maternal condition. Exercise caution when CYMBALTA is administered to a nursing woman. Data The disposition of CYMBALTA was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. The women were given 40 mg of CYMBALTA twice daily for 3.5 days. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose. The amount of CYMBALTA in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day. The presence of CYMBALTA metabolites in breast milk was not examined.

Interactions

7 DRUG INTERACTIONS Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potent inhibitors of CYP1A2 should be avoided ( 7.1). Potent inhibitors of CYP2D6 may increase CYMBALTA concentrations ( 7.2). CYMBALTA is a moderate inhibitor of CYP2D6 ( 7.9). 7.1 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 approximately 6-fold, the C max was increased about 2.5-fold, and duloxetine t 1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions ( 5.12)] . 7.2 Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions ( 5.12)] . 7.3 Dual Inhibition of CYP1A2 and CYP2D6 Concomitant administration of duloxetine 40 mg twice daily 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 C max. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) 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 or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUC τ,ss, C max,ss or t max,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see Warnings and Precautions ( 5.5)] . 7.5 Lorazepam Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration. 7.6 Temazepam Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. 7.7 Drugs that Affect Gastric Acidity CYMBALTA 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, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of CYMBALTA with aluminum- and magnesium-containing antacids (51 mEq) or CYMBALTA 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 [see Warnings and Precautions ( 5.14)] . 7.8 Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily). 7.9 Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions ( 5.12)] . 7.10 Drugs Metabolized by CYP2C9 Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine [see Drug Interactions ( 7.4)] . 7.11 Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. 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. 7.12 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. 7.13 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration ( 2.8, 2.9), Contraindications ( 4), and Warnings and Precautions ( 5.4)] . 7.14 Serotonergic Drugs [See Dosage and Administration ( 2.8, 2.9), Contraindications ( 4), and Warnings and Precautions ( 5.4)] . 7.15 Alcohol When CYMBALTA and ethanol were administered several hours apart so that peak concentrations of each would coincide, CYMBALTA did not increase the impairment of mental and motor skills caused by alcohol. In the CYMBALTA clinical trials database, three CYMBALTA-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions ( 5.2, 5.12)] . 7.16 CNS Drugs [See Warnings and Precautions ( 5.12)] . 7.17 Drugs Highly Bound to Plasma Protein Because duloxetine is highly bound to plasma protein, administration of CYMBALTA to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see Drug Interactions ( 7.4)] .

More information

Category Value
Authorisation number NDA021427
Agency product number 9044SC542W
Orphan designation No
Product NDC 55289-028
Date Last Revised 03-10-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 615186
Storage and handling 16.2 Storage and Handling Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Marketing authorisation holder PD-Rx Pharmaceuticals, Inc.
Warnings WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions ( 5.1)] . In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions ( 5.1)] . WARNING: SUICIDALTHOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants ( 5.1) Monitor for worsening and emergence of suicidal thoughts and behaviors ( 5.1)