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Drug Safety-related Labeling Changes (SrLC)

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CYMBALTA (NDA-021427)

(DULOXETINE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/20/2021 (SUPPL-56)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.16 Sexual Dysfunction

(Newly added subsection)

Use of SNRIs, including CYMBALTA, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of CYMBALTA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

  • Sexual Dysfunction [see Warnings and Precautions (5.16)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

sexual problems (dysfunction). Taking serotonin and norepinephrine reuptake inhibitors (SNRIs), including CYMBALTA, may cause sexual problems.

Symptoms in males may include:

  • delayed ejaculation or inability to have an ejaculation
  • decreased sex drive
  • problems getting or keeping an erection

Symptoms in females may include:

  • decreased sex drive
  • delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with CYMBALTA. There may be treatments your healthcare provider can suggest.

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

  • Sexual Dysfunction — Advise patients that use of CYMBALTA may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.16)].

04/20/2020 (SUPPL-52)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Serotonin Syndrome

Additions and/or revisions underlined:

… The concomitant use of CYMBALTA with MAOI antidepressants is contraindicated.

5.11 Increases in Blood Pressure

In adult placebo-controlled clinical trials across the approved adult populations from baseline to endpoint, CYMBALTA treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of CYMBALTA on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily (approximately 3.3 times the maximum recommended dosage).

6 Adverse Reactions

Additions and/or revisions to the bulleted line listing:

  • Increased Risk of Bleeding [see Warnings and Precautions (5.5)]

  • Discontinuation Syndrome [see Warnings and Precautions (5.7)]

  • Increases in Blood Pressure [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

Extensive changes made to this section in both the adult and pediatric sections to reflect the new provision of use of Cymbalta in pediatric patients ages 13 to 17 years with fibromyalgia.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of CYMBALTA have been established for treatment of generalized anxiety disorder (GAD) in patients 7 to 17 years of age and for treatment of juvenile fibromyalgia syndrome in patients 13 to 17 years of age. The safety and effectiveness of CYMBALTA have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain.

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients. Monitor all pediatric patients being treated with antidepressants for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, or at times of dosage changes [see Warnings and Precautions (5.1)]. Perform regular monitoring of weight and growth in pediatric patients treated with CYMBALTA [see Adverse Reactions (6.1)].

Generalized Anxiety Disorder

Use of CYMBALTA for the treatment of GAD in patients 7 to 17 years of age is supported by one 10-week, placebo- controlled trial (GAD-6). The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age (53% were 12 to 17 years of age). CYMBALTA demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies (14.3)].

The safety and effectiveness of CYMBALTA for the treatment of GAD in pediatric patients less than 7 years of age have not been established.

Fibromyalgia

Use of CYMBALTA for treatment of fibromyalgia in patients 13 to 17 years of age is supported by a 13-week placebo- controlled trial in 184 patients with juvenile fibromyalgia syndrome (Study FM-4). CYMBALTA showed improvement over placebo on the primary endpoint, change from baseline to end-of-treatment on the Brief Pain Inventory (BPI) – Modified Short Form: Adolescent Version 24-hour average pain severity rating [see Clinical Studies (14.5)].

The safety and effectiveness of CYMBALTA for the treatment of fibromyalgia in patients less than 13 years of age have not been established.

Major Depressive Disorder

The safety and effectiveness of CYMBALTA have not been established in pediatric patients for the treatment of MDD. Efficacy of CYMBALTA was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients aged 7 to 17 years old with MDD (MDD-6 and MDD-7). Neither CYMBALTA nor an active control (approved for treatment of pediatric MDD) was superior to placebo.

The most frequently observed adverse reactions in the MDD pediatric clinical trials included nausea, headache,

decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs.

Juvenile Animal Toxicology Data

Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

  • ‘Increased Risk of Bleeding’ replaces ‘Abnormal Bleeding’

Pregnancy

Additions and/or revisions underlined:

  • Advise pregnant women or patients who intend to become pregnant that CYMBALTA use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.

10/04/2019 (SUPPL-51)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Increased Risk of Bleeding

(additions and/or revisions are underlined)

Drugs that interfere with serotonin reuptake inhibition, including CYMBALTA, may increase the risk of bleeding events. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. A post-marketing study showed a higher incidence of postpartum hemorrhage in mothers taking duloxetine. Other bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk.

Inform patients about the risk of bleeding associated with the concomitant use of CYMBALTA and NSAIDs, aspirin, or other drugs that affect coagulation.

6 Adverse Reactions

6.1 Clinical Studies Experience

(renaming of subsection title)

6.2 Postmarketing Experience

(renaming of subsection title)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors the pregnancy outcomes in women exposed to CYMBALTA during pregnancy. To enroll, contact the CYMBALTA Pregnancy Registry at 1-866-814-6975 or www.cymbaltapregnancyregistry.com.

Risk Summary

Data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. Data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes. There are risks associated with untreated depression and fibromyalgia in pregnancy, and with exposure to SNRIs and SSRIs, including CYMBALTA, during pregnancy.

In rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to 3 and 6 times, respectively, the maximum recommended human dose (MRHD) of 120 mg/day given to adolescents on a mg/m^2 basis. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD given to adolescents on a mg/m^2 basis. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected.

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

Clinical Considerations

Disease-associated Maternal and/or Embryo/Fetal Risk

Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Pregnant women with fibromyalgia are at increased risk for adverse maternal and infant outcomes including preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, and venous thrombosis. It is not known if these adverse maternal and fetal outcomes are a direct result of fibromyalgia or other comorbid factors.

Maternal Adverse Reactions

Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

Fetal/Neonatal Adverse Reaction

Neonates exposed to CYMBALTA and other SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.


Data

Human Data

Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% CI: 1.08-2.18). The same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. Methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures.

Animal Data

In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.

When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of malformations or developmental variations at doses up to 45 mg/kg/day [3 and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m^2 basis]. However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (approximately equal to the MRHD in rats and 2 times the MRHD in rabbits).

When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD given to adolescents on a mg/m^2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

Data from published literature report the presence of duloxetine in human milk. There are reports of sedation, poor feeding, and poor weight gain in infants exposed to duloxetine through breast milk. There are no data on the effect of duloxetine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CYMBALTA and any potential adverse effects on the breastfed child from CYMBALTA or from the underlying maternal condition.

Clinical Considerations

Infants exposed to CYMBALTA should be monitored for sedation, poor feeding and poor weight gain.

Data

Disposition of CYMBALTA was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. The women were given 40 mg of CYMBALTA twice daily for 3.5 days. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose. The amount of CYMBALTA in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day, which is less than 1% of the maternal dose. The presence of CYMBALTA metabolites in breast milk was not examined.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(addition of medication guide; please refer to labeling for complete information)

PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

  • Suicidal Thoughts and Behaviors Advise patients, their families, and their caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down and instruct them to report such symptoms to their healthcare provider.

 

 

  • Pregnancy

    • Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with CYMBALTA.

    • Advise patients that CYMBALTA use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.

    • Advise pregnant women that there is a risk of relapse with discontinuation of antidepressants.

    • Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to duloxetine during pregnancy.

  • Lactation - Advise breastfeeding women using CYMBALTA to monitor infants for sedation, poor feeding and poor weight gain and to seek medical care if they notice these signs.

12/19/2017 (SUPPL-50)

Approved Drug Label (PDF)

6 Adverse Reactions

6.10 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of CYMBALTA in Adults

(Additions and/or revisions are underlined)

Cardiac Disorders Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy.

01/04/2017 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Serotonin Syndrome

(additions underlined)

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including CYMBALTA, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

…If concomitant use of CYMBALTA with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with CYMBALTA and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(addition underlined)

          Serotonin Syndrome —Caution patients about the risk of serotonin syndrome with the concomitant use of CYMBALTA and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort


Medication Guide

Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Cymbalta and some medicines may interact with each other, may not work as well, or may cause serious side

effects.

Especially tell your healthcare provider if you take:

  • triptans used to treat migraine headache
  • medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs or MAOIs
  • tramadol and fentanyl
  • amphetamines


...

09/02/2016 (SUPPL-48)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Spontaneous Reports
  • Adverse reactions reported since market introduction that were temporally related to CYMBALTA therapy and not mentioned elsewhere in labeling include:
    • acute pancreatitis (addition)