HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to
`use CYMBALTA safely and effectively. See full prescribing
`infonnation for CYMBALTA.
`
`CYMBALTA (Duloxetine hydrochloride) Delayed-Release
`Capsules) for Oral Use.
`Initial U.S. Approval: 2004
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`Cymbalta is not approved for use in pediatric patients (8.4)
`
`See full prescribing infonnation 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)
`
`RECENT MAJOR CHANGES
`
`Contraindications:
`Removed: Uncontrolled Narrow-Angle Glaucoma (4.2) 00/0000
`Warnings and Precautions:
`AngIe—CIosure Glaucoma (5.9)
`INDICA11ONS AND USAGE
`
`00/0000
`
`Cymbalta’ is a serotonin and norepinephrine reuptake inh bitor
`(SNRI) indicated for.
`Major Depressive Disorder (MDD) (1.1)
`Generalized Anxiety Disorder (GAD) (1.2)
`Diabefic Peripheral Neuropatlic Pain (DPNP) (1.3)
`fibromyalgia (FM) (1.4)
`Chronic Musculoskeletal Pail (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)
`Indication
`
`Target Dose
`
`Starting
`Dose
`
`aximum
`M
`ose
`D
`120
`mg/day
`
`0 Ida
`
`60 mg/day
`
`60 mg/day
`60 mg/day
`
`WARNINGS AND PRECAUTIONS
`Suicidality: Monitor for clinical worsening and suicide risk (5.1)
`Hepatotoxicity: Hepatic failure, sometimes fatal, has been
`reported in patients trwted 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)
`Orthostafic Hypotension and Syncope: Cases have been
`reported with duloxetine therapy (5.3)
`Serotonin Syndrome: Serotonin syndrome has been reported
`with SSRls and SNRls, including with Cymbalta, both when
`taken alone, but especially when coadministered with other
`serotonergic agents (includng triptans, tricyclic antidepressants,
`fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's
`Wort). If such symptoms occur, discontinue Cymbalta and
`initiate supportive trlment If concomitant use of Cymbalta with
`other serotonergic dnrgs is clinically warranted, patients sholld
`be made aware of a potential increased risk for serotonin
`syndrome, particularly during treatment initiation and dose
`increases (5.4)
`Abnomial Bleeding: Cymbalta may hcrease the risk of bleediig
`events. Patients should be cautioned about the risk of bleeding
`associated with the concomitant use of duloxefine and NSAIDS,
`aspirin, or other dmgs that attect coagulation (5.5, 7.4)
`Severe Skin Reactions: Severe skin reactions, hduding
`erythema multifomie and Stevensdohnson Syndrome (SJS),
`can occurwith Cymbalta. Cymbalta should be discontinued at
`the first appearance of blisters, peeling rash, mucosal erosions,
`or any other sign of hypersensitivity if no other etiology can be
`identified. (5.6)
`Discontinuation: May result in symptoms, incluring dizziness,
`headache, nausea, dianhea, paresthesia, initability, vomiting,
`insomnia, anxiety, hyperhidrosis, and fatigue (5.7)
`Activation of mania or hypomania has occurred (5.8)
`Angleclosure Glaucoma: Angle4:losure glaucoma has occurred
`in patients with untreated anatomically narrow angles treated
`with antidepressants. (5.9)
`Seizures: Prescribe with care in patients with a history of seizure
`disorder (5.10)
`Blood Pressure: Monitor blood pressure prior to initiating
`treatment and periodlly throughout treatment (5.11)
`Inh bitors of CYP1A2 or Thioridazine: Should not administer with
`
`_
`Cymbalta (5.12)
`Hyponatremra: Cases of hyponatremra have been reported
`(5. 1 3)
`Hepatic lnsufficiency and Severe Renal lmpainnent: Should
`ordinarily not be administered to these patients (514)
`Glucose Control in Diabetes: In diabetic perpheral neuropathic
`pain patients, small increases in fasting blood glucose, and
`HbA.. have been observed (5.14)
`Conditions that Slow Gastric Emptyhg: Use cautiously in these
`patients (5.1_4)_
`_
`Unnary Hesrtation and Retention (5.15)
`ADVERSE REAC11ONS
`
`incidence of placebo patients): nausea, dry mouth, somnolence,
`consfipation, decreased appetite, and hypemidrosis (6.3).
`To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly
`and Company at 1-800-LillyRx (1 -800-5455979) or FDA at 1-800-
`FDA-1088 or www.fda.gov/medwatch.
`—————— DRUG lN'l'ERACTlONS
`-
`Potent inhibitors of CYP1A2 should be avoided (7.1).
`-
`Potent inhibitors of CYP2D6 may increase dubxetine
`concentrations (7.2).
`Duloxetine is a moderate inhbitor of CYP2D6 (7.9).
`
`-
`
`Most common adverse reactions (25% and at lst twice the Chronic
`
`MDD (2.1, 2.2)
`
`GAD (2.1)
`DPNP (2.1)
`
`FM (2.1)
`
`60 mg/day
`60 mg/day
`
`30 mg/day
`30 mg/day
`
`Acute Treatment:
`40 mg/day (20 mg
`twice daily) to 60
`mg/day (once <_iai|v
`or as 30 mg twice
`daily); Maintenance
`Treatment: 60
`mg/day
`60 mg/day (once
`dai
`60 mg/day (once
`dai
`
`at
`g0_mg/day (once
`60 mg/day (once
`daily)
`
`Musculoskeletal
`Pain 2.1
`Some patients may benefit from starting at 30 mg once daily
`(2.1)
`There is no evidence that doses greater than 60 mg/day confers
`additional benefit, while some adverse reactions were observed
`to be dose-dependent (2.1)
`Discontinuing Cymbalta: A gradual dose reduction is
`recommended to avoid discontinuation symptoms (24, 5.7)
`
`-
`
`-
`
`-
`
`TDOSAGE FORMS AND STRENGTHS
`20 mg’ 30 mg_ and 60 mg capsules (3)
`
`_
`ScoNTRA|N[)|cA1'|oNsS T U35 'N_ SPECIFIC l’°PUU\T_'°Ns
`-
`Serotonin Syndrome and MAOls: Do not use MA0ls intended to
`‘
`P'°9“a"CY and N“'5'"9 M°"'°'5- U59 °“'Y '7 the P°t°"t'a' bmem
`1]-eat psychiamc disorders with cylnbalta or within 5 days of
`the potential H-Sk t0 the fetus Of Child (2.3, 8.1,
`stopping treatment with Cymbalta. Do not use Cymbalta within
`See 17 for PATIENT COUNSELING INFORMATION and
`14 days of stopping an MAOI iitended to treat psychiatric
`Medication Guide
`disorders. In addition, do not start Cymbalta in a patient who is
`being treated with linezolid or htravenous methylene blue (4.1)
`
`Revised: 00/0000
`
`Reference ID: 3594216
`
`Depomed Exhibit 2072
`
`

`
`2
`
`
`7.10 Drugs Metabolized by CYP2C9
`
`
`7.11 Drugs Metabolized by CYP3A
`
`
`7.12 Drugs Metabolized by CYP2C19
`
`
`7.13 Monoamine Oxidase Inhibitors (MAOIs)
`
`7.14
` Serotonergic Drugs
`7.15
` Alcohol
`7.16
` CNS Drugs
`7.17 Drugs Highly Bound to Plasma Protein
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.2
`Labor and Delivery
`
`
` Nursing Mothers
`
`8.3
`8.4
` Pediatric Use
`
`8.5
` Geriatric Use
`
`
` Gender
`
`8.6
` Smoking Status
`8.7
`8.8
` Race
`8.9
` Hepatic Insufficiency
`
`8.10 Severe Renal Impairment
`
`
`9 DRUG ABUSE AND DEPENDENCE
`9.2
` Abuse
`
`9.3
` Dependence
`
`
`10 OVERDOSAGE
`10.1 Signs and Symptoms
`
`
`
` Management of Overdose
`
`10.2
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2
` Pharmacodynamics
`12.3
` Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`14.1 Major Depressive Disorder
`
`14.2 Generalized Anxiety Disorder
`
`14.3 Diabetic Peripheral Neuropathic Pain
`
`14.4
` F bromyalgia
`14.5 Chronic Musculoskeletal Pain
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
` How Supplied
`
`16.1
`16.2 Storage and Handling
`
`
`17 PATIENT COUNSELING INFORMATION
`
`Information on Medication Guide
`
`17.1
`17.2 Suicidal Thoughts and Behaviors
`
`17.3
` Medication Administration
`17.4 Continuing the Therapy Prescribed
`
`17.5
` Hepatotoxicity
`17.6
` Alcohol
`17.7 Orthostatic Hypotension and Syncope
`
`17.8
` Serotonin Syndrome
`17.9
` Abnormal Bleeding
`17.10 Severe Skin Reaction
`
`
`17.11 Discontinuation of Treatment
`
`
`
`17.12 Activation of Mania or Hypomania
`
`17.13 Angle-Closure Glaucoma
`
`17.14 Seizures
`
`17.15 Effects on Blood Pressure
`
`
`
`17.16 Concomitant Medications
`
`
`17.17 Hyponatremia
`
`17.18 Concomitant Illnesses
`
`
`
`17.19 Urinary Hesitancy and Retention
`
`
`
`
`17.20 Pregnancy and Breast Feeding
`
`
`
`17.21
`Interference with Psychomotor Performance
`
`
`
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`INDICATIONS AND USAGE
`1
`
`Major Depressive Disorder
`
`1.1
`Generalized Anxiety Disorder
`
`1.2
`1.3
`Diabetic Peripheral Neuropathic Pain
`
`1.4
` F bromyalgia
`1.5
`Chronic Musculoskeletal Pain
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
` Initial Treatment
`
`2.1
`
` Maintenance/Continuation/Extended Treatment
`
`2.2
`2.3
`Dosing in Special Populations
`
`2.4
` Discontinuing Cymbalta
`2.5
`Switching a Patient To or From a Monoamine Oxidase
`
`Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
`
`Use of Cymbalta with Other MAOIs such as Linezolid or
`
`
`Methylene Blue
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`Monoamine Oxidase Inhibitors (MAOIs)
`
`4.1
`
`5 WARNINGS AND PRECAUTIONS
`5.1
`Suicidal Thoughts and Behaviors in Adolescents and
`
`Young Adults
`
` Hepatotoxicity
`5.2
`Orthostatic Hypotension and Syncope
`
`5.3
` Serotonin Syndrome
`5.4
` Abnormal Bleeding
`5.5
`Severe Skin Reactions
`
`5.6
`
`Discontinuation of Treatment with Cymbalta
`
`5.7
`
`Activation of Mania/Hypomania
`
`5.8
` Angle-Closure Glaucoma
`5.9
` Seizures
`5.10
`
`5.11 Effect on Blood Pressure
`
`5.12 Clinically Important Drug Interactions
`
`
` Hyponatremia
`
`5.13
`5.14 Use in Patients with Concomitant Illness
`
`5.15 Urinary Hesitation and Retention
`
`
` Laboratory Tests
`5.16
`
`6 ADVERSE REACTIONS
`Clinical Trial Data Sources
`
`6.1
`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
`
`6.12 Postmarketing Spontaneous Reports
`
`
`7 DRUG INTERACTIONS
`Inhibitors of CYP1A2
`
`7.1
`
`Inhibitors of CYP2D6
`
`7.2
`
`Dual Inhibition of CYP1A2 and CYP2D6
`
`7.3
`Drugs that Interfere with Hemostasis (e.g., NSAIDs,
`
`7.4
`
`Aspirin, and Warfarin)
`
`
` Lorazepam
`
`
` Temazepam
`
`Drugs that Affect Gastric Acidity
`
`Drugs Metabolized by CYP1A2
`
`Drugs Metabolized by CYP2D6
`
`
`2.6
`
`6.3
`6.4
`
`6.5
`
`7.5
`7.6
`7.7
`7.8
`7.9
`
`Reference ID: 3594216
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults
`in short-terrn 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)].
`
`Cymbalta is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].
`
`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-tenn 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.
`
`1.3
`
`Diabetic Peripheral Neuropathic Pain
`Cymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral
`neuropathy [see Clinical Studies (14. 3)].
`
`1.4
`
`1.5
`
`Fibromyalgia
`Cymbalta is indicated for the management of fibromyalgia (FM) [see Clinical Studies (14. 4)].
`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 (CLBP) and chronic pain due to osteoarthritis [see Clinical Studies (14. 5)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`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
`
`Major Depressive Disorde — Cymbalta should be administered at a total dose of 40 mglday (given as 20 mg
`twice daily) to 60 mglday (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 mglday dose was shown to be effective, there is no evidence that doses greater than 60 mglday confer any
`additional benefits. The safety of doses above 120 mglday has not been adequately evaluated [see Clinical Studies
`(14.1)].
`
`Generalized Anxiety Disorde — 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 mglday 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 Pai — 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
`
`Reference ID: 3594216
`
`

`
`4
`
`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 Dosage and Administration (2.3), Use in Specific Populations
`(8.10), and Clinical Pharmacology (12.3)].
`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 (5.14) and Use in Specific Populations (8.9)].
`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 (5.14) 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)].
`Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Cymbalta while
`pregnant. Healthcare providers are encouraged to register any patient who is exposed to Cymbalta during pregnancy by
`calling the Cymbalta Pregnancy Registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com
`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)].
`2.4
` Discontinuing Cymbalta
`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 (5.7)].
`Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric
`2.5
`
`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 (4.1)].
`
`Use of Cymbalta with Other MAOIs such as Linezolid or Methylene Blue
`2.6
`
`Reference ID: 3594216
`
`

`
`5
`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 (4.1)].
`
`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)].
`3
`DOSAGE FORMS AND STRENGTHS
`Cymbalta is available as delayed release capsules:
`
`20 mg opaque green capsules imprinted with “Lilly 3235 20mg”
`30 mg opaque white and blue capsules imprinted with “Lilly 3240 30mg”
`60 mg opaque green and blue capsules imprinted with “Lilly 3237 60mg”
`60 mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”
`4
`CONTRAINDICATIONS
`
`4.1 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 (2.5) 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 (2.6) and
`Warnings and Precautions (5.4)].
`WARNINGS AND PRECAUTIONS
`5
`
`Suicidal Thoughts and Behaviors in Adolescents and Young Adults
`5.1
`
`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 persist until significant remission occurs. Suicide is a
`known risk of depression and certain other 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 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) 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 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.
`
`
`
`
`Age Range
`
`
`
`<18
`
`18-24
`
`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
`
`Reference ID: 3594216
`
`

`
`
`25-64
`≥65
`
`
`Decreases Compared to Placebo
`1 fewer case
`
`6 fewer cases
`
`6
`
`
`
`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 (5.7) 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.
`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.
`Orthostatic Hypotension and Syncope
`5.3
`
`Reference ID: 3594216
`
`

`
`7
`
`Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and
`orthostatic hypotension tend