`
`
` These highlights do not include all the information needed to use
`CYMBALTA safely and effectively. See full prescribing
`
`
` information for CYMBALTA.
`
`•
`
`
` In linezolid- or intravenous methylene blue-treated patients,
`
`
`
`
` initiation of CYMBALTA is contraindicated (4)
`
`
`
` 1
`
`
`
`
`
` CYMBALTA (duloxetine delayed-release capsules), for oral use
`
` Initial U.S. Approval: 2004
`
`
`
`
`
` WARNING: SUICIDAL THOUGHTS 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)
`
`•
`
`
`
`
`•
`
`
`
`
`
`
`
` ------------------------ WARNINGS AND PRECAUTIONS -----------------------
`• Hepatotoxicity: Hepatic failure, sometimes fatal, has been
`
`reported. Discontinue CYMBALTA in patients who develop
`
` jaundice or other evidence of clinically significant liver dysfunction
`and should not be resumed unless another cause can be
`
` established. Avoid use in patients with substantial alcohol use or
` evidence of chronic liver disease (5.2)
`
`• Orthostatic Hypotension, Falls and Syncope: Consider dosage
`
`
` reduction or discontinuation if these events occur (5.3)
`
`
`• Serotonin Syndrome: Increased risk when co-administered with
`
`
` other serotonergic agents, but also when taken alone. If it occurs,
`
`
` discontinue CYMBALTA and serotonergic agents (5.4)
`
`
`
`
`Increased Risk of Bleeding: May increase the risk of bleeding
` events. Concomitant use of antiplatelet drugs and anticoagulants
`
` may increase this risk (5.5, 7.4, 8.1)
`
`• Severe Skin Reactions: Severe skin reactions, including erythema
`
`
`
` multiforme and Stevens-Johnson Syndrome (SJS), can occur;
`
`Discontinue 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)
`
`
`• Activation of Mania or Hypomania: Prior to initiating, screen
`
`
`patients for personal or family history of bipolar disorder, mania, or
`
`
` hypomania (5.8)
`• Angle-Closure 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 Increases: Monitor blood pressure prior to initiating
`
`
` treatment and periodically throughout treatment (5.11)
`
` Inhibitors of CYP1A2 or Thioridazine: Avoid co-administration with
`
`
`
` CYMBALTA (5.12)
`• Hyponatremia: Can occur in association with SIADH; consider
`
`
`
` discontinuation (5.13)
`• Glucose Control in Diabetes: In DPNP patients, increases in
`
`
` fasting blood glucose, and HbA1c have been observed (5.14)
`
`
`
`
`• Conditions that Slow Gastric Emptying: Use cautiously in these
`
`
` patients (5.14)
`• Sexual Dysfunction: CYMBALTA may cause symptoms of sexual
`
`
`
`
` dysfunction (5.16)
`
`
`
`
`
`
`
` --------------------------- RECENT MAJOR CHANGES --------------------------
`
`
`
`
`
` Warnings and Precautions (5.4, 5.5)
`
`
`
` 8/2023
`
` ---------------------------- INDICATIONS AND USAGE ---------------------------
`
`
`
`
` CYMBALTA® is a serotonin and norepinephrine reuptake inhibitor
` (SNRI) indicated for the treatment of the following conditions:
`
`
`• Major depressive disorder (MDD) in adults (1)
`
`
`
`• Generalized anxiety disorder (GAD) in adults and pediatric patients
`
`
`
` 7 years of age and older (1)
`
`• Diabetic peripheral neuropathic pain (DPNP) in adults (1)
`
`
`
`
`
`
`• Fibromyalgia (FM) in adults and pediatric patients 13 years of age
`
` and older (1)
`
`• Chronic musculoskeletal pain in adults (1)
`
`
`
`
`
`
`
`
`
`
`
` ------------------------DOSAGE AND ADMINISTRATION -----------------------
`• Take CYMBALTA once daily, with or without food. Swallow whole;
`
`
`
`
`
` do not crush, chew, or open capsule (2.1)
`
`
`
`
`
` Indication
`
`
`
` MDD (2.2)
`
`Starting
`
` Dose
`
`
`
` Target Dose
`
`
`
` 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
`
`
`
`Maximum
`
` Dose
`
`
`
` 120 mg/day
`
`
`
` GAD (2.3)
`
`
`
`
`
`
`
` Adults
`
` 60 mg/day
`
`
`
` 60 mg/day (once daily)
`
`
`
` 120 mg/day
`
`•
`
`
`
`
`
`
`
`
` ------------------------------- ADVERSE REACTIONS ------------------------------
`Most common adverse reactions (≥5% and at least twice the incidence
`
`
`
` of placebo-treated patients): (6.1)
` Adults: nausea, dry mouth, somnolence, constipation, decreased
`
` appetite, and hyperhidrosis
`Pediatric Patients: decreased weight, decreased appetite, nausea,
`
` vomiting, fatigue, and diarrhea
`
`
`
`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.
`
`
`
`
` ------------------------------- DRUG INTERACTIONS ------------------------------
`• 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)
`
`
`
`
`
`
` ------------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`
`
`
`Pregnancy: Third trimester use may increase risk for symptoms of poor
`adaptation (respiratory distress, temperature instability, feeding
`
`
` difficulty, hypotonia, tremor, irritability) in the neonate (8.1)
`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/minute (5.14)
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
` approved Medication Guide.
`
`
`
` Revised: 8/2023
`
`
`
`
`
`
`
` Geriatric
`
`
`
` 30 mg/day
`
`
`
` 60 mg/day (once daily)
`
`
`
` 120 mg/day
`
` Pediatrics (7
`
`to 17 years
`
` of age)
`
`
`
` 30 mg/day
`
`
`
` 30 to 60 mg/day (once
`
` daily)
`
`
`
` 120 mg/day
`
`
`
` DPNP (2.4)
`
`
`
` 60 mg/day
`
`
`
` 60 mg/day (once daily)
`
`
`
` 60 mg/day
`
`
`
` FM (2.5)
`
`
`
` 30 mg/day
`
`
`
` 60 mg/day (once daily)
`
`
`
` 60 mg/day
`
`
`
`
`
`
`
`Adults and
`
` Pediatrics
`
` (13 to 17
` years of
`
`
` age)
`
`
`
` 30 mg/day
`
`
`
` 60 mg/day (once daily)
`
` Chronic
`
`Musculoskel
`etal Pain
`
` (2.6)
`• Discontinuing CYMBALTA: Gradually reduce dosage to avoid
`
`
`
` discontinuation symptoms (2.8, 5.7)
`
`
`
` 60 mg/day
`
` ----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`
` Delayed-release capsules: 20 mg, 30 mg, and 60 mg (3)
`
`
`
`
`
`
` ------------------------------- CONTRAINDICATIONS ------------------------------
`• Concomitant use of an MAOI antidepressant with CYMBALTA is
`
`
`
` contraindicated
`• Use of CYMBALTA within 14 days of stopping an MAOI
`
`
` antidepressant is contraindicated
`
`
`
`
`
`
`
`Reference ID: 5229383
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`
`
`
`
` 2
`
` 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 (MAOIs)
`
`
` 7.14 Other 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
`
` Lactation
`
` 8.4
` Pediatric Use
`
`
` 8.5
`
` Geriatric Use
`
` 8.6
`
` Gender
`
` 8.7
` Smoking Status
`
` 8.8
`
` Race
`
`
`
` 8.9
` Hepatic Impairment
` 8.10 Severe Renal Impairment
`
`
`
`
`
`
`
`
`
`
`
`
` 9 DRUG ABUSE AND DEPENDENCE
`
`
` 9.2
` Abuse
`
` 9.3
` Dependence
`
`
`
`
`
` 10 OVERDOSAGE
`
`
`
` 10.1 Signs and Symptoms
`
` 10.2 Management of Overdose
`
`
`
`
`
`
` 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 Overview of the Clinical Trials
`
` 14.2 Major Depressive Disorder in Adults
`
`
` 14.3 Generalized Anxiety Disorder
`
`
` 14.4 Diabetic Peripheral Neuropathic Pain in Adults
`
` 14.5 Fibromyalgia
`
`
` 14.6 Chronic Musculoskeletal Pain in Adults
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
` 16.1 How Supplied
`
` 16.2 Storage and Handling
`
`
`
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
` 2.1
` Important Administration Instructions
`
`
` 2.2
`
`
` Dosage for Treatment of Major Depressive Disorder in
`
` Adults
` Dosage for Treatment of Generalized Anxiety Disorder
`
`
`
` Dosage for Treatment of Diabetic Peripheral Neuropathic
`
`
` Pain in Adults
` Dosage for Treatment of Fibromyalgia
`
` Dosage for Treatment of Chronic Musculoskeletal Pain in
`
` Adults
`Dosage in Patients with Hepatic Impairment or Severe
`
` Renal Impairment
` Discontinuing CYMBALTA
`
`
` Switching a Patient to or from a Monoamine Oxidase
` Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
`
`
`
` 2.10 Use of CYMBALTA with Other MAOIs such as Linezolid or
`
` Methylene Blue
`
`
`
`
`
`
`
`
`
`
` 2.3
`
` 2.4
`
`
` 2.5
`
` 2.6
`
`
`
` 2.7
`
`
` 2.8
`
` 2.9
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
` 5.1
`Suicidal Thoughts and Behaviors in Children,
`
`
` Adolescents, and Young Adults
` Hepatotoxicity
`
`
` 5.2
` Orthostatic Hypotension, Falls and Syncope
`
` 5.3
`
` Serotonin Syndrome
`
` 5.4
` Increased Risk of Bleeding
`
`
` 5.5
`
` Severe Skin Reactions
`
` 5.6
` Discontinuation Syndrome
`
`
` 5.7
` Activation of Mania/Hypomania
`
` 5.8
`
` Angle-Closure Glaucoma
`
` 5.9
`
`
` 5.10 Seizures
` Increases in Blood Pressure
`
`
`
` 5.11
`
` 5.12 Clinically Important Drug Interactions
`
` 5.13 Hyponatremia
`
`
` 5.14 Use in Patients with Concomitant Illness
`
` 5.15 Urinary Hesitation and Retention
`
`
` 5.16 Sexual Dysfunction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
`
` 6.1
` Clinical Trials Experience
`
` 6.2
` Postmarketing Experience
`
`
`
`
` 7 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
` Temazepam
`
`
`
` 7.5
`
` 7.6
`
`
`
`Reference ID: 5229383
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 3
`
`
`
` 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)].
`
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
` CYMBALTA® is indicated for the treatment of:
`
`
`
`• Major depressive disorder in adults
`
`
`
`• Generalized anxiety disorder in adults and pediatric patients 7 years of age and older
`
`
`
`• Diabetic peripheral neuropathic pain in adults
`
`
`
`• Fibromyalgia in adults and pediatric patients 13 years of age and older
`
`
`
`• Chronic musculoskeletal pain in adults
`
`
`
`
`
`
` 2
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
` 2.1
`
`
`
` Important Administration Instructions
`
`
`
`
`
`
`
` Administer CYMBALTA orally (with or without meals) and swallow whole. Do not chew or crush, and do not open the
`
` delayed-release capsule and sprinkle its contents on food or mix with liquids because these actions might affect the
`
`
`
`enteric coating. 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.
`
`
`
` 2.2
`
`
`
` Dosage for Treatment of Major Depressive Disorder in Adults
`
`
`
` The recommended starting dosage in adults with MDD is 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 CYMBALTA 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. Periodically reassess
` to determine the need for maintenance treatment and the appropriate dosage for such treatment.
`
`
`
`
`
`
` 2.3
`
`
`
` Dosage for Treatment of Generalized Anxiety Disorder
`
`
`
`
`
` Recommended Dosage in Adults Less than 65 Years of Age
`
`
`
`
`
`
`
` For most adults less than 65 years of age with GAD, 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 CYMBALTA before increasing to 60 mg
` once daily. While a 120 mg once daily dosage 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 dosage beyond 60 mg once daily,
`
`
` increase dosage in increments of 30 mg once daily. Periodically reassess to determine the continued need for
`
`
`
`
` maintenance treatment and the appropriate dosage for such treatment.
`
`
`
`
`
`
` Recommended Dosage in Geriatric Patients
`
` In geriatric patients with GAD, initiate CYMBALTA at a dosage of 30 mg once daily for 2 weeks before considering an
`
`
`
`
` increase to the target dose of 60 mg/day. 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.
`
`
`
`
`
`
`
`
` Recommended Dosage in Pediatric Patients 7 to 17 Years of Age
`
`
`
`
`
`
`
`
`
` Initiate CYMBALTA in pediatric patients 7 to 17 years of age with GAD at a dosage of 30 mg once daily for 2 weeks
` before considering an increase to 60 mg once daily. The recommended dosage range is 30 to 60 mg once daily. Some
`
`
`
`
`
`
` patients may benefit from dosages above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg
` once daily, increase dosage in increments of 30 mg once daily. The maximum dose studied was 120 mg per day.
`
`
`
`Reference ID: 5229383
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`
`
`
`
` 2.4
`
`
`
` Dosage for Treatment of Diabetic Peripheral Neuropathic Pain in Adults
`
`
`
` Administer 60 mg once daily in adults with diabetic peripheral neuropathic pain. There is no evidence that doses higher
`
`
`
`
`
`
` than 60 mg once daily confer additional significant benefit and the higher dosage is clearly less well tolerated. 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 dosage and gradual increase in
`
`
`
`
` dosage for patients with renal impairment [see Dosage and Administration (2.7) and Use in Specific Populations (8.10)].
`
`
`
`
`
` 2.5
`
`
`
` Dosage for Treatment of Fibromyalgia
`
`
`
` 4
`
`
`
` Recommended Dosage in Adults
`
`
`
`
`
`
`
`
`
`
` The recommended CYMBALTA dosage is 60 mg once daily in adults with fibromyalgia. Begin treatment at 30 mg once
` daily for 1 week, to allow patients to adjust to CYMBALTA before increasing to 60 mg once daily. Some patients may
`
`
`
` respond to the starting dosage. There is no evidence that dosages greater than 60 mg/day confer additional benefit, even
` in patients who do not respond to a 60 mg/day dosage, and higher dosages were associated with a higher rate of adverse
`
`
`
`
`
`
` reactions.
`
`
`
`
`
` Recommended Dosage in Pediatric Patients 13 to 17 Years of Age
`
`
`
`
`
`
`
`
`
` The recommended starting CYMBALTA dosage in pediatric patients 13-17 years of age with fibromyalgia is 30 mg once
`
`
`
` daily. The dosage may be increased to 60 mg once daily based on response and tolerability.
`
`
`
`
`
` 2.6
`
`
`
` Dosage for Treatment of Chronic Musculoskeletal Pain in Adults
`
`
`
`
`
` The recommended CYMBALTA dosage is 60 mg once daily in adults with chronic musculoskeletal pain. Begin treatment
`
`
`
`
`
`
`
`
` at 30 mg once daily for one week, to allow patients to adjust to CYMBALTA before increasing to 60 mg once daily. There
` is no evidence that higher dosages confer additional benefit, even in patients who do not respond to a 60 mg once daily
`
`
`
`
` dosage, and higher dosages are associated with a higher rate of adverse reactions [see Clinical Studies (14.6)].
`
`
`
` 2.7
`
`
`
` Dosage in Patients with Hepatic Impairment or Severe Renal Impairment
`
`
`
`
`
` Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions (5.14) and Use in Specific
`
` Populations (8.9)].
`
` Avoid use in patients with severe renal impairment, GFR <30 mL/minute [see Warnings and Precautions (5.14) and Use in
`
`
` Specific Populations (8.10)].
`
`
`
`
`
`
`
`
`
` 2.8
`
`
`
` 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)].
`
`
`
` 2.9
`
`
`
` 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)].
`
`
`
` 2.10 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)].
`
`
`
`Reference ID: 5229383
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`
`
` The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in
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`
`
` 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)].
`
`
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`
`
` 5
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`
`
` 3
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` DOSAGE FORMS AND STRENGTHS
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`
`
` CYMBALTA is available as delayed-release capsules:
`
`
`
`
`
`•
`
`•
`
`•
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`
`20 mg opaque green capsules imprinted with “Lilly 3235 20mg”
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`30 mg opaque white and blue capsules imprinted with “Lilly 3240 30mg”
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`60 mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”
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`
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` 4
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`
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` CONTRAINDICATIONS
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` 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 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)].
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` 5
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` WARNINGS AND PRECAUTIONS
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` 5.1
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`
`
` Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
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` Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression
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`
`
` 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
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`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
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`
`
` treated) are provided in Table 1.
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`
`
`
`
`Reference ID: 5229383
`
`
`
` Age Range
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`
` <18
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` 18-24
`
`
`
` 25-64
`≥65
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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
`
`
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`
`
`
` 6
` No suicides occurred in any of the pediatric CYMBALTA trials. There were suicides in the adult CYMBALTA trials, but the
`
`
`
`
`
` number was not sufficient to reach any conclusion about CYMBALTA effect on suicide.
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` 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
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` 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 (2.8) and
`
`
`
` Warnings and Precautions (5.7)] for descriptions of the risks of discontinuation of CYMBALTA.
`
`
`
`
`
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` Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications,
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` 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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`
`
` Screening Patients for Bipolar Disorder
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`
`
`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 is not approved for use in treating bipolar depression.
`
`
`
` 5.2
`
`
`
` Hepatotoxicity
`
` 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 (ULN) 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% (92/34,756) of CYMBALTA-treated patients. In most
` patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled
`
`
`
`
` trials, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the ULN occurred in 1.25%
` (144/11,496) of CYMBALTA-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo-
`
`controlled studies using a fixed dose design, there was evidence of a CYMBALTA dose response relationship for ALT and
`
`
` AST elevation of >3 times the ULN and >5 times the ULN, respectively.
`
`
`
`
`
`
` Because it is possible that CYMBALTA and alcohol may interact to cause liver injury or that CYMBALTA may aggravate
`
` pre-existing liver disease, CYMBALTA should not be prescribed to patients with substantial alcohol use or evidence of
`
`
` chronic liver disease.
`
`Reference ID: 5229383
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`
`
`
`
` 5.3
`
`
`
` Orthostatic Hypotension, Falls and Syncope
`
`
`
` 7
`
`
`
`
`
` Orthostatic hypotension, falls, and syncope have been reported in patients treated with the recommended CYMBALTA
`
` dosages. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time
` during CYMBALTA treatment, particularly after dose increases. The risk of falling appears to be related to the degree of
`
` orthostatic decrease in blood pressure (BP) as well as other factors that may increase the underlying risk of falls.
`
`
`
`
`
`
` In an analysis of patients from all placebo-controlled trials, patients treated with CYMBALTA reported a higher rate of falls
`
`
`
` compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in BP. The
` risk of BP 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 (5.12) and Drug Interactions (7.1)]
` and in patients taking CYMBALTA at doses above 60 mg daily. Consideration should be given to dose reduction or
`
`
`
`
`
` discontinuation of CYMBALTA in patients who experience symptomatic orthostatic hypotension, falls and/or syncope
` during CYMBALTA therapy.
`
`
`
`Risk of falling also appeared to be proportional to a patient’s underlying risk for falls and appeared to increase steadily
`
` with age. As geriatric patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such
`as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is
`
` unclear. Falls with serious consequences including fractures and hospitalizations have been reported with CYMBALTA
`
`
` use [see Adverse Reactions (6.1)].
`
`
`
` 5.4
`
`
`
` Serotonin Syndrome
`
` Serotonin-norepinephrine reuptake inhibitors (SNRIs), including CYMBALTA, can precipitate serotonin syndrome, a
`
`
`
` potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including
` triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone,
`
`
`
`
`
` amphetamines, and St. John’s Wort) and