1
`
`
`-------------------DOSAGE FORMS AND STRENGTHS------------------------
`
`• 20 mg, 30 mg, and 60 mg capsules (3)
`
`
`----------------------------CONTRAINDICATIONS-------------------------------
`• Use of a monoamine oxidase inhibitor concomitantly or in close temporal
`
`
`proximity (4.1)
`
`• Use in patients with uncontrolled narrow-angle glaucoma (4.2)
`
`----------------------WARNINGS AND PRECAUTIONS-------------------------
`• Suicidality: Monitor for clinical worsening and suicide risk (5.1).
`• Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in
`patients treated with Cymbalta. Cymbalta should be discontinued in
`patients who develop jaundice or other evidence of clinically significant
`
`liver dysfunction and should not be resumed unless another cause can be
`established. Cymbalta should not be prescribed to patients with substantial
`alcohol use or evidence of chronic liver disease (5.2).
`
`• Orthostatic Hypotension and Syncope: Cases have been reported with
`duloxetine therapy (5.3).
`
`• Serotonin Syndrome, or Neuroleptic Malignant Syndrome (NMS)-like
`reactions: Serotonin syndrome or NMS-like reactions have been reported
`with SSRIs and SNRIs. Discontinue Cymbalta and initiate supportive
`treatment (5.4, 7.14).
`• Abnormal Bleeding: Cymbalta may increase the risk of bleeding events.
`
`Patients should be cautioned about the risk of bleeding associated with the
`concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that
`affect coagulation (5.5, 7.4).
`
`• Discontinuation: May result in symptoms, including dizziness, nausea,
`
`headache, paresthesia, fatigue, vomiting, irritability, insomnia, diarrhea,
`anxiety, and hyperhidrosis(5.6).
`
`• Activation of mania or hypomania has occurred (5.7).
`
`• Seizures: Prescribe with care in patients with a history of seizure disorder
`
`(5.8).
`• Blood Pressure: Monitor blood pressure prior to initiating treatment and
`periodically throughout treatment (5.9).
`
`Inhibitors of CYP1A2 or Thioridazine: Should not administer with
`Cymbalta (5.10).
`• Hyponatremia: Cases of hyponatremia have been reported (5.11).
`
`• Hepatic Insufficiency and Severe Renal Impairment: Should ordinarily not
`be administered to these patients (5.12).
`
`• Controlled Narrow-Angle Glaucoma: Use cautiously in these patients
`(5.12).
`
`• Glucose Control in Diabetes: In diabetic peripheral neuropathic pain
`patients, small increases in fasting blood glucose, HbA1c, and total
`
`cholesterol have been observed (5.12).
`• Conditions that Slow Gastric Emptying: Use cautiously in these patients
`
`(5.12).
`
`• Urinary Hesitation and Retention (5.13).
`--------------------------------ADVERSE REACTIONS-----------------------------
`
`• Most common adverse reactions (≥5% and at least twice the incidence of
`
`
`placebo patients): nausea, dry mouth, somnolence, fatigue, constipation,
`decreased appetite, and hyperhidrosis (6.3).
`
`•
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
`
`Company at 1-800-LillyRx or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`--------------------------------DRUG INTERACTIONS-----------------------------
`• Potent inhibitors of CYP1A2 should be avoided (7.1).
`
`• Potent inhibitors of CYP2D6 may increase duloxetine concentrations (7.2).
`• Duloxetine is a moderate inhibitor of CYP2D6 (7.9).
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`• Pregnancy and Nursing Mothers: Use only if the potential benefit justifies
`the potential risk to the fetus or child (2.3, 8.1, 8.3).
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`Revised: 10/2010
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`Cymbalta safely and effectively. See full prescribing information for
`Cymbalta.
`
`Cymbalta (duloxetine hydrochloride) Delayed-Release Capsules for Oral
`Use.
`Initial U.S. Approval: 2004
`
`WARNING: Suicidality and Antidepressant Drugs
`See full prescribing information for complete boxed warning.
`
`
`
`
`• Increased risk of suicidal thinking and behavior in children,
`adolescents, and young adults taking antidepressants for major
`depressive disorder (MDD) and other psychiatric disorders. Cymbalta
`
`is not approved for use in pediatric patients (5.1).
`
`
`
`
`
`
`--------------------------RECENT MAJOR CHANGES----------------------------
`Indications and Usage, Generalized Anxiety Disorder (1.2)
`11/2009
`
`Indications and Usage, Chronic Musculoskeletal Pain (1.5)
`10/2010
`Dosage and Administration, Chronic Musculoskeletal Pain (2.1, 2.2) 10/2010
`Dosage and Administration, Maintenance/Continuation/Extended
`11/2009
`Treatment (2.2)
`10/2010
`Warnings and Precautions, Effect on Blood Pressure (5.9)
`
`--------------------------INDICATIONS AND USAGE-----------------------------
`Cymbalta® is a serotonin and norepinephrine reuptake inhibitor (SNRI)
`
`indicated for:
`
`
`• Major Depressive Disorder (MDD) (1.1)
`
`Efficacy was established in four short-term and one maintenance trial in
`
`adults (14.1).
`• Generalized Anxiety Disorder (GAD) (1.2)
`
`Efficacy was established in three short-term and one maintenance trial in
`
`adults (14.2).
`• Diabetic Peripheral Neuropathic Pain (DPNP) (1.3)
`
`• Fibromyalgia (FM) (1.4)
`
`• Chronic Musculoskeletal Pain (1.5)
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`• Cymbalta should generally be administered once daily without regard to
`meals. Cymbalta should be swallowed whole and should not be chewed or
`crushed, nor should the capsule be opened and its contents be sprinkled on
`
`
`food or mixed with liquids (2.1).
`
`
`
`Indication
`
`
`Starting Dose
`
`Target Dose
`
`
`Maximum
`Dose
`120 mg/day
`
`
`120 mg/day
`
`
`60 mg/day
`
`
`60 mg/day
`
`
`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
`60 mg/day (once
`
`daily)
`60 mg/day (once
`
`daily)
`60 mg/day (once
`
`daily)
`60 mg/day (once
`
`daily)
`
`
`
`MDD (2.1, 2.2)
`
`
`40mg/day to
`60mg/day
`
`
`GAD (2.1)
`
`60 mg/day
`
`
`DPNP (2.1)
`
`
`60 mg/day
`
`
`FM (2.1)
`
`
`
`30 mg/day
`
`
`30 mg/day
`
`
`Chronic
`Musculoskeletal
`Pain (2.1)
`• Some patients may benefit from starting at 30 mg once daily.
`• There is no evidence that doses greater than 60 mg/day confers additional
`benefit, while some adverse reactions were observed to be dose-dependent.
`
`• Discontinuing Cymbalta: A gradual dose reduction is recommended to
`avoid discontinuation symptoms (5.6).
`
`
`
`Reference ID: 2860327
`
`
`MYLAN - EXHIBIT 1037
`Mylan et al. v. AstraZeneca
`IPR2015-01340
`
`

`
`
`
`
`
`
`
`
`
`
` 2
`
`9
`
`8
`
`Serotonergic Drugs
`7.14
`Triptans
`7.15
`7.16 Alcohol
`7.17
`CNS Drugs
`7.18 Drugs Highly Bound to Plasma Protein
`
`
`USE IN SPECIFIC POPULATIONS
` Pregnancy
`
`8.1
`
`Labor and Delivery
`
`8.2
`
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`Gender
`
`8.6
`
`Smoking Status
`8.7
`8.8
`Race
`8.9
` Hepatic Insufficiency
`
`
`Severe Renal Impairment
`8.10
`
`DRUG ABUSE AND DEPENDENCE
`9.2
` Abuse
`
`9.3
` Dependence
`
`10 OVERDOSAGE
`
`Signs and Symptoms
`
`10.1
`
`
`10.2 Management of Overdose
`
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`13.1
`
`
`14 CLINICAL STUDIES
`14.1 Major Depressive Disorder
`
`
`
`14.2 Generalized Anxiety Disorder
`
`
`
`14.3 Diabetic Peripheral Neuropathic Pain
`
`
`
`14.4
`Fibromyalgia
`14.5 Chronic Musculoskeletal Pain
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`16.2
`Storage
`17 PATIENT COUNSELING INFORMATION
`
`17.1
`Information on Medication Guide
`
`
`17.2
`Clinical Worsening and Suicide Risk
`
`17.3 Medication Administration
`17.4 Continuing the Therapy Prescribed
`
`
`
`17.5 Abnormal Bleeding
`17.6 Concomitant Medications
`
`Serotonin Syndrome
`17.7
`17.8
`Pregnancy and Breast Feeding
`
`
`17.9 Alcohol
`17.10 Orthostatic Hypotension and Syncope
`
`
`
`17.11
`Interference with Psychomotor Performance
`
`
`* Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`6.3
`6.4
`
`6.5
`
`
`
`2
`
`3
`4
`
`6
`
`7
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`
` Major Depressive Disorder
`1.1
`
`
` Generalized Anxiety Disorder
`1.2
`
`
`Diabetic Peripheral Neuropathic Pain
`
`1.3
`
`1.4
` Fibromyalgia
`1.5
`Chronic Musculoskeletal Pain
`
`DOSAGE AND ADMINISTRATION
`2.1
` Initial Treatment
`2.2
` Maintenance/Continuation/Extended Treatment
`2.3
`Dosing in Special Populations
`2.4
` Discontinuing Cymbalta
`2.5
`Switching Patients to or from a Monoamine Oxidase Inhibitor
`
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1
`Monoamine Oxidase Inhibitors
`
`
`Uncontrolled Narrow-Angle Glaucoma
`
`4.2
`
`5 WARNINGS AND PRECAUTIONS
`5.1
`Clinical Worsening and Suicide Risk
`
` Hepatotoxicity
`
`5.2
`
`Orthostatic Hypotension and Syncope
`
`5.3
`
`Serotonin Syndrome or Neuroleptic Malignant Syndrome
`5.4
`(NMS)-like Reactions
`
`5.5
` Abnormal Bleeding
`5.6
`Discontinuation of Treatment with Cymbalta
`
`5.7
`Activation of Mania/Hypomania
`
`5.8
` Seizures
`5.9
`Effect on Blood Pressure
`
`
`5.10 Clinically Important Drug Interactions
`
`
`
`5.11 Hyponatremia
`5.12 Use in Patients with Concomitant Illness
`
`5.13 Urinary Hesitation and Retention
`
`5.14
`Laboratory Tests
`ADVERSE REACTIONS
`6.1
`Clinical Trial Data Sources
`
`6.2
`Adverse Reactions Reported as Reasons for Discontinuation of
`Treatment in Placebo-Controlled Trials
`Most Common Adverse Reactions
`Adverse Reactions Occurring at an Incidence of 5% or More
`
`
`Among Duloxetine-Treated Patients in Placebo-Controlled
`Trials
`
`Adverse Reactions Occurring at an Incidence of 2% or More
`
`
`Among Duloxetine-Treated Patients in Placebo-Controlled
`
`Trials
`
`6.6
`Effects on Male and Female Sexual Function
`
`6.7
`Vital Sign Changes
`
`6.8
` Weight Changes
`6.9
` Laboratory Changes
`6.10
`Electrocardiogram Changes
`
`6.11 Other Adverse Reactions Observed During the Premarketing
`
`
`and Postmarketing Clinical Trial Evaluation of Duloxetine
`
`Postmarketing Spontaneous Reports
`
`6.12
`
`DRUG INTERACTIONS
`
`7.1
`Inhibitors of CYP1A2
`
`7.2
`Inhibitors of CYP2D6
`
`7.3
`Dual Inhibition of CYP1A2 and CYP2D6
`
`7.4
`Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin,
`
`and Warfarin)
`
` Lorazepam
`
`7.5
`
` Temazepam
`
`7.6
`
`Drugs that Affect Gastric Acidity
`
`7.7
`
`Drugs Metabolized by CYP1A2
`
`7.8
`Drugs Metabolized by CYP2D6
`
`7.9
`7.10 Drugs Metabolized by CYP2C9
`
`7.11 Drugs Metabolized by CYP3A
`
`7.12 Drugs Metabolized by CYP2C19
`
`7.13 Monoamine Oxidase Inhibitors
`
`
`
`Reference ID: 2860327
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`
`
`
`
`
`
`
`
`
`
` 3
`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
`
`
`
`(suicidality) in children, adolescents, and young adults in short-term studies of major depressive
`
`
`disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any
`
`
`other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical
`
`need. Short-term studies did not show an increase in the risk of suicidality with antidepressants
`compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants
`
`
`compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders
`are themselves associated with increases in the risk of suicide. Patients of all ages who are started on
`
`antidepressant therapy should be monitored appropriately and observed closely for clinical
`worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of
`
`
`the need for close observation and communication with the prescriber. Cymbalta is not approved for
`use in pediatric patients. [see Warnings and Precautions (5.1), Use in Specific Populations (8.4), and
`
`Information for Patients (17.2).]
`
`
`1
`INDICATIONS AND USAGE
`
`1.1 Major Depressive Disorder
`Cymbalta is indicated for the treatment of major depressive disorder (MDD). The efficacy of
`Cymbalta was established in four short term and one maintenance trial in adults [see Clinical Studies
`(14.1)].
`A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every
`
`
`
`day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and
`includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities,
`
`
`
`significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or
`retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration,
`or a suicide attempt or suicidal ideation.
`1.2
`Generalized Anxiety Disorder
`
`Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD). The efficacy of
`Cymbalta was established in three short-term trials and one maintenance trial in adults [see Clinical Studies
`
`(14.2)].
`Generalized anxiety disorder is defined by the DSM-IV as excessive anxiety and worry, present
`
`
`
`more days than not, for at least 6 months. The excessive anxiety and worry must be difficult to control and
`
`
`
`must cause significant distress or impairment in normal functioning. It must be associated with at least 3 of
`
`
`
`
`the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty
`
`
`
`concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance.
`
`
`
`Diabetic Peripheral Neuropathic Pain
`1.3
`
`Cymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic
`
`peripheral neuropathy [see Clinical Studies (14.3)].
`
`Fibromyalgia
`1.4
`
`Cymbalta is indicated for the management of fibromyalgia (FM) [see Clinical Studies (14.4)].
`
`
`1.5
`Chronic Musculoskeletal Pain
`
`
`Cymbalta is indicated for the management of chronic musculoskeletal pain. This has been
`established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis [see
`
`
`
`Clinical Studies (14.5)].
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`Cymbalta should be swallowed whole and should not be chewed or crushed, nor should the capsule
`
`
`
`be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric
`
`coating. Cymbalta can be given without regard to meals.
`2.1
`Initial Treatment
`
`
`
`Reference ID: 2860327
`
`

`
`
`
`
`
`
`
`
`
`
` 4
`
`
`
`
`Major Depressive Disorder — Cymbalta should be administered 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 [see Clinical Studies (14.1)].
`Generalized Anxiety Disorder — For most patients, the recommended starting dose for Cymbalta is
`
`
`60 mg administered 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, dose
`
`increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has
`
`
`
`not been adequately evaluated [see Clinical Studies (14.2)].
`
`
`Diabetic Peripheral Neuropathic Pain — The recommended dose for Cymbalta is 60 mg
`
`administered 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, a lower starting dose and gradual
`increase in dose should be considered for patients with renal impairment [see Clinical Pharmacology (12.3)
`
`
`
`and Dosage and Administration (2.3)].
`Fibromyalgia — The recommended dose for Cymbalta is 60 mg administered once daily.
`
`Treatment should begin 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)].
`
`
`Chronic Musculoskeletal Pain — The recommended dose for Cymbalta is 60 mg once daily.
`
`
`Dosing may be started 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)].
`
`2.2 Maintenance/Continuation/Extended Treatment
`
`Major Depressive Disorder — It is generally agreed that acute episodes of major depression require
`several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was
`
`
`demonstrated with Cymbalta as monotherapy. Cymbalta should be administered at a total dose of 60 mg
`
`
`
`once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and
`the appropriate dose for such treatment [see Clinical Studies (14.1)].
`
`Generalized Anxiety Disorder — It is generally agreed that episodes of generalized anxiety
`
`disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in
`GAD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered in a dose range
`
`
`
`of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for
`
`maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].
`
`
`
`
`Diabetic Peripheral Neuropathic Pain — As the progression of diabetic peripheral neuropathy is
`
`
`highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed
`
`individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.
`
`Fibromyalgia — Fibromyalgia is recognized as a chronic condition. The efficacy of Cymbalta in
`the management of fibromyalgia has been demonstrated in placebo-controlled studies up to 3 months. The
`
`
`efficacy of Cymbalta was not demonstrated in longer studies; however, continued treatment should be
`
`based on individual patient response.
`
`Chronic Musculoskeletal Pain — The efficacy of Cymbalta has not been established in placebo-
`
`
`controlled studies beyond 13 weeks.
`Dosing in Special Populations
`2.3
`
`
`
`
`Hepatic Insufficiency — It is recommended that Cymbalta should ordinarily not be administered to
`
`
`patients with any hepatic insufficiency [see Warnings and Precautions (5.12) and Use in Specific
`Populations (8.9)].
`
`Reference ID: 2860327
`
`

`
`
`
`
`
`
`
`
`
`
` 5
`
`
` Severe Renal Impairment — Cymbalta is not recommended for patients with end-stage renal
`
`
`disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see Warnings and
`
`Precautions (5.12) and Use in Specific Populations (8.10)].
`Elderly Patients — No dose adjustment is recommended for elderly patients on the basis of age. As
`
`with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in
`
`elderly patients, extra care should be taken when increasing the dose [see Use in Specific Populations
`
`
`
`(8.5)].
`
`
`
`Pregnant Women — There are no adequate and well-controlled studies in pregnant women;
`
`
`therefore, Cymbalta should be used during pregnancy only if the potential benefit justifies the potential risk
`
`to the fetus [see Use in Specific Populations (8.1)].
`Nursing Mothers — Because the safety of duloxetine in infants is not known, nursing while on
`
`Cymbalta is not recommended [see Use in Specific Populations (8.3)].
`
`Discontinuing Cymbalta
`2.4
`
`Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been
`
`
`
`
`
`
`reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible
`
`
`
`
`[see Warnings and Precautions (5.6)].
`Switching Patients to or from a Monoamine Oxidase Inhibitor
`2.5
`
`At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with
`
`
`
`Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI
`
`
`[see Contraindications (4.1) and Warnings and Precautions (5.4)].
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`Cymbalta is available as delayed release capsules:
`
`20mg opaque green capsules imprinted with “Lilly 3235 20mg”
`
`
`
`
`30mg opaque white and blue capsules imprinted with “Lilly 3240 30mg”
`
`
`
`
`
`
`60mg opaque green and blue capsules imprinted with “Lilly 3237 60mg”
`
`
`
`
`
`
`
`60mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”
`
`
`
`
`
`
`
`
`4
`CONTRAINDICATIONS
`
`4.1 Monoamine Oxidase Inhibitors
`Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated due
`
`to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions may
`
`include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital
`signs, and mental status changes that include extreme agitation progressing to delirium and coma. These
`reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors
`
`
`
`and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant
`
`
`
`syndrome [see Dosage and Administration (2.5) and Warnings and Precautions (5.4)].
`
`Uncontrolled Narrow-Angle Glaucoma
`4.2
`
`
`In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use
`
`
`
`should be avoided in patients with uncontrolled narrow-angle glaucoma [see Warnings and Precautions
`
`
`
`(5.12)].
`5
`WARNINGS AND PRECAUTIONS
`
`5.1
`Clinical Worsening and Suicide Risk
`
`Patients with major depressive disorder (MDD), both adult and pediatric, may experience
`
`
`
`
`worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or
`
`unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may
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`persist until significant remission occurs. Suicide is a known risk of depression and certain other
`
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`
`
`psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been
`a long-standing concern, however, that antidepressants may have a role in inducing worsening of
`
`
`
`depression and the emergence of suicidality in certain patients during the early phases of treatment.
`
`
`Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
`showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children,
`
`
`adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric
`
`
`
`
`disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants
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`Reference ID: 2860327
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`

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` 6
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` compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to
`
`placebo in adults aged 65 and older.
`
`The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
`
`
`
`compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9
`
`
`
`
`antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with
`
`MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months)
`
`
`
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`of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality
`
`
`among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There
`
`
`were differences in absolute risk of suicidality across the different indications, with the highest incidence in
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`
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`MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and
`
`
`across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per
`
`
`1000 patients treated) are provided in Table 1.
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`
`
`
`
`Table 1
`
`
`Drug-Placebo Difference in Number of Cases of
`Suicidality per 1000 Patients Treated
`Increases Compared to Placebo
`14 additional cases
`5 additional cases
`Decreases Compared to Placebo
`1 fewer case
`6 fewer cases
`
`Age Range
`
`
`<18
`
`18-24
`
`25-64
`≥65
`
`
`
`No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
`number was not sufficient to reach any conclusion about drug effect on suicide.
`It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
`However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression
`
`
`that the use of antidepressants can delay the recurrence of depression.
`All patients being treated with antidepressants for any indication should be monitored
`
`
`appropriately and observed closely for clinical worsening, suicidality, and unusual changes in
`
`
`
`behavior, especially during the initial few months of a course of drug therapy, or at times of dose
`
`
`changes, either increases or decreases.
`
`
`The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
`
`aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
`
`
`
`
`
`reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as
`
`well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the
`
`emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal
`
`
`impulses has not been established, there is concern that such symptoms may represent precursors to
`emerging suicidality.
`
`
`
`Consideration should be given to changing the therapeutic regimen, including possibly
`
`
`discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing
`
`
`
`
`
`emergent suicidality or symptoms that might be precursors to worsening depression or suicidality,
`
`
`
`especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting
`
`symptoms.
`
`
`
`If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as
`is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Dosage
`
`
`
`and Administration (2.4) and Warnings and Precautions (5.6) for descriptions of the risks of
`
`discontinuation of Cymbalta].
`
`Families and caregivers of patients being treated with antidepressants for major depressive
`
`disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need
`to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the
`other symptoms described above, as well as the emergence of suicidality, and to report such
`
`symptoms immediately to health care providers. Such monitoring should include daily observation
`
`by families and caregivers. Prescriptions for Cymbalta should be written for the smallest quantity of
`capsules consistent with good patient management, in order to reduce the risk of overdose.
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`Reference ID: 2860327
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` 7
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` Screening Patients for Bipolar Disorder — A major depressive episode may be the initial
` presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that
`
`
`
`
`
`
` treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a
` mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above
`
`
`
` represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant,
`
` patients with depressive symptoms should be adequately screened to determine if they are at risk for
`
`
`
`
` bipolar disorder; such screening should include a detailed psychiatric history, including a family history of
`
`
` suicide, bipolar disorder, and depression. It should be noted that Cymbalta (duloxetine) is not approved for
`
`
`
`
`use in treating bipolar depression.
`
`Hepatotoxicity
`5.2
`
`
`
`There have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta.
`
`
`
`These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase
`
`
`
`
`
`levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or
`
`
`
`hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or
`
`
`
`
`other evidence of clinically significant liver dysfunction and should not be resumed unless another cause
`can be established.
`
`
`Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been
`
`reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline
`
`phosphatase have occurred in patients with chronic liver disease or cirrhosis.
`
`
`
`
`Cymbalta increased the risk of elevation of serum transaminase levels in development program
`clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (89/29,435) of
`
`
`Cymbalta-treated patients. In most patients, the median time to detection of the transaminase elevation was
`
`
`about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal
`
`
`
`
`baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.37% (132/9611) of
`Cymbalta-treated patients compared to 0.49% (35/7182) of placebo-treated patients. In placebo-controlled
`
`
`
`
`studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST
`
`elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.
`
`Because it is possible that duloxetine and alcohol may interact to cause liver injury or that
`
`
`duloxetine may aggravate pre-existing liver disease, Cymbalta should not be prescribed to patients with
`
`substantial alcohol use or evidence of chronic liver disease.
`
`5.3
`Orthostatic Hypotension and Syncope
`
`
`
`
`Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine.
`
`
`
`
`
`
`Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any
`
`
`time during duloxetine treatment, particularly after dose increases. The risk of blood pressure decreases
`
`
`may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as
`
`
`antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions (5.10) and Drug
`Interactions (7.1)] and in patients taking duloxetine at doses above 60 mg daily. Consideration should be
`
`
`
`
`
`
`given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or
`syncope during duloxetine therapy.
`5.4
`Serotonin Syndrome or Neuroleptic Malign