Drug Safety-related Labeling Changes (SrLC)

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DRIZALMA SPRINKLE (NDA-212516)

(DULOXETINE HYDROCHLORIDE)

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

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08/18/2023 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Serotonin Syndrome

Additions and/or revisions underlined:

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including DRIZALMA SPRINKLE, 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 with drugs that impair metabolism of serotonin [see Contraindications (4), Drug Interactions (7)]. Serotonin syndrome can also occur when these drugs are used alone.

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5.5 Increased Risk of Bleeding

Additions and/or revisions underlined:

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Inform patients about the increased risk of bleeding associated with the concomitant use of DRIZALMA SPRINKLE and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.1)].

7 Drug Interactions

7.1 Drugs Having Clinically Important Interactions with DRIZALMA SPRINKLE

Addition of Other SNRIs and SSRIs to the examples section of other serotonergic drugs in table 7; please refer to label for complete information

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Serotonin Syndrome - Caution patients about the risk of serotonin syndrome with the concomitant use of DRIZALMA SPRINKLE and other serotonergic agents including triptans, tricyclic antidepressants, opioids, lithium, buspirone, tryptophan, amphetamines, and St. John’s Wort [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7)].

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All other trademarks are the property of their respective owners.

MEDICATION GUIDE

Additions and/or revisions underlined:

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Especially tell your healthcare provider if you take:

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• tramadol, fentanyl, meperidine, methadone, or other opioids

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07/23/2021 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Activation of Mania/Hypomania

Additions and/or revisions underlined:

… No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials.

Prior to initiating treatment with DRIZALMA SPRINKLE, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

Additions and/or revisions underlined:

5.11 Increases in Blood Pressure

In adult placebo-controlled clinical trials across the approved adult populations from baseline to endpoint, duloxetine treatment was associated with mean increases …

Newly added subsection:

5.16 Sexual Dysfunction

Use of SNRIs, including DRIZALMA SPRINKLE, 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 DRIZALMA SPRINKLE 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

Newly added to bulleted line listing:

·         Sexual Dysfunction [See Warnings and Precautions (5.16)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials

Diabetic Peripheral Neuropathic Pain:

Approximately 12.9% (117/906) of the duloxetine delayed-release capsules-treated patients in placebo- controlled adult trials for DPNP discontinued treatment due to an adverse reaction …

Fibromyalgia

Approximately 17.5% (227/1294) of the duloxetine delayed-release capsules-treated patients in 3-to 6- month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 2.0%, placebo 0.5%), headache (duloxetine delayed-release capsules 1.2%, placebo 0.3%), somnolence (duloxetine delayed-release capsules 1.1%, placebo 0%), and fatigue (duloxetine delayed-release capsules 1.1%, placebo 0.1%).

Chronic Pain due to Osteoarthritis:

Approximately 15.7% (79/503) of the duloxetine delayed-release capsules-treated patients in 13 week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction …

Most Common Adverse Reactions (Adults)

Fibromyalgia: nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.

Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine Delayed-Release Capsules Treated Patients in Adult Placebo-Controlled Trials

The most commonly observed adverse reactions in duloxetine delayed-release capsule-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis. Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo-treated patients.

Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-

Controlled Trials of Approved Adult Populations

Pooled MDD and GAD Trials in Adults

Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults

Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials:

Table 4: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials in Adults

Effects on Male and Female Sexual Function in Adults with MDD

Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment.

Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled adult trials [see Clinical Studies (14.1)]. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from baseline level of sexual dysfunction from baseline, which is commonly seen in depressed patients.

In these trials, male patients treated with duloxetine delayed-release capsules experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than did placebo-treated male patients (see Table 5). Female patients treated with duloxetine delayed- release capsules did not experience more sexual dysfunction than on placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in patients treated with duloxetine delayed-release capsules.

Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials

Vital Sign Changes in Adults

In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, duloxetine delayed-release capsules-treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg SBP and 0.55 mm Hg in DBP placebo-treated patients.

Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine Delayed-Release Capsules in Adults

Following is a list of adverse reactions reported by patients treated with duloxetine delayed-release capsules in clinical trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine delayed-release capsules …

Adverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients

The data described below reflect exposure to duloxetine delayed-release capsules in pediatric, 10 week, placebo-controlled trials for MDD (N = 341) and GAD (N = 135). The population studied (N = 476) was 7 to 17 years of age with 42.4% children age 7 to 11 years of age, 50.6% female, and 68.6% white.

Patients received 30 to 120 mg per day during placebo-controlled acute treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41.7% children age 7 to 11 years of age and 51.8% female exposed to duloxetine delayed-release capsules in MDD and GAD clinical trials up to 36 weeks in length, in which most patients received 30 to 120 mg per day. The safety and effectiveness of DRIZALMA SPRINKLE have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain.

Pediatric Clinical Trial Database

The adverse drug reaction profile observed in pediatric clinical trials in pediatric patients aged 7 to 17 years old was consistent with the adverse drug reaction profile observed in adult clinical trials …

Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD

Table 6 provides the incidence of adverse reactions in MDD and GAD pediatric placebo- controlled trials that occurred in greater than 2% of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo. DRIZALMA SPRINKLE is not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4)]

Table 6: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10 week Pediatric Placebo-Controlled Trials in MDD and GAD

 Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine delayed-release capsules treated patients than placebo treated patients in pediatric MDD and GAD clinical trials included abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (DRIZALMA SPRINKLE is not approved for the treatment of pediatric MDD).

Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD

 …The proportion of patients who experienced a clinically significant decrease in  weight (?3.5%) was greater in the duloxetine delayed-release capsules group than in the placebo group (16% and 6%, respectively) …

In studies up to 9 months, duloxetine delayed-release capsules-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients [7 to 11 years of age] and 1.3 cm increase in patients [12 to 17 years of age]). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in patients [7 to 11 years of age] and increase of 0.3% in patients [12 to 17 years of age]). Weight and height should be monitored regularly in pediatric patients treated with DRIZALMA SPRINKLE.

Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine delayed-release capsules). However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8 Use in Specific Populations

8.1 Pregnancy

Clinical Considerations

Disease-associated Maternal and/or Embryo/Fetal Risk

Additions and/or revisions underlined:

… Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the 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.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of DRIZALMA SPRINKLE have been established for treatment of generalized anxiety disorder (GAD) in pediatric patients ages 7 to 17 years of age. The safety and effectiveness of DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE [see Adverse Reactions (6.1)].

Generalized Anxiety Disorder

Use of DRIZALMA SPRINKLE 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). Duloxetine delayed-release capsules 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 DRIZALMA SPRINKLE for the treatment of GAD in pediatric patients less than 7 years of age have not been established.

Fibromyalgia

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

Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine delayed-release capsules). However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Major Depressive Disorder

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

Juvenile Animal Toxicology Data

Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood …

8.5 Geriatric Use

Additions and/or revisions underlined, and ‘geriatric’ replaces ‘elderly’ throughout subsection:

Geriatric Exposure in Premarketing Clinical Trials of duloxetine delayed-release capsules

• Of the 2,418 patients in MDD trials, 6% (143) were 65 years of age or over.

• Of the 1041 patients in CLBP trials, 21%(221) were 65 years of age or over.

• Of the 487 patients in OA trials, 41% (197) were 65 years of age or over.

• Of the 1,074 patients in the DPNP trials, 33% (357) were 65 years of age or over.

• Of the 1,761 patients in FM trials, 8% (140) were 65 years of age or over.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is DRIZALMA SPRINKLE?

DRIZALMA SPRINKLE is prescription medicine used to treat:

• Fibromyalgia (FM) in adults

Before taking DRIZALMA SPRINKLE, tell your healthcare provider about all your medical conditions, including if you:

Especially tell your healthcare provider if you take:

• medicines to treat migraine headaches known as triptans

• tricyclic antidepressants

What are the possible side effects of DRIZALMA SPRINKLE? DRIZALMA SPRINKLE may cause serious side effects, including:

• Eye problems (angle-closure glaucoma). DRIZALMA SPRINKLE may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Seizures (convulsions).

• Sexual problems (dysfunction). Taking serotonin and norepinephrine reuptake inhibitors (SNRIs), including DRIZALMA SPRINKLE, 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 DRIZALMA SPRINKLE. There may be treatments your healthcare provider can suggest.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

… Concomitant Illnesses - Advise patients to inform their healthcare provider about all of their medical conditions [see Warnings and Precautions (5.14)].

Urinary Hesitation and Retention - DRIZALMA SPRINKLE are in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see Warnings and Precautions (5.15)].

Sexual Dysfunction - Advise patients that use of DRIZALMA SPRINKLE 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 (516)].

Pregnancy

Newly added:

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

06/24/2020 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Increased Risk of Bleeding

(Additions and/or revisions underlined)

Drugs that interfere with serotonin reuptake inhibition, including duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk. 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 SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the risk of bleeding associated with the concomitant use of DRIZALMA Sprinkle and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.1)].

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at  https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/

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 (see Data). There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including DRIZALMA Sprinkle, during pregnancy (see Clinical Considerations).

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 of 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 discontinued antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continued 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 the postpartum.

Maternal Adverse Reactions

Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)].

Fetal/Neonatal Adverse Reaction

Neonates exposed to duloxetine 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 [see Warnings and Precautions (5.4)].

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/m2 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/m2 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

(Additions and/or revisions underlined)

Risk Summary

Data from the published literature report the presence of duloxetine in human milk (see Data). There are reports of sedation, poor feeding, and poor weight gain in infants exposed to duloxetine through breast milk (see Clinical Considerations). 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 DRIZALMA Sprinkle and any potential adverse effects on the breastfed child from DRIZALMA Sprinkle or from the underlying maternal condition.

Clinical Considerations

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

Data

Disposition of duloxetine 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 duloxetine delayed-release capsules 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 duloxetine 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 duloxetine metabolites in breast milk was not examined.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

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 [see Boxed Warning, and Warnings and Precautions (5.1)].

Hepatotoxicity - Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with duloxetine delayed-release capsules. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking DRIZALMA Sprinkle which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of DRIZALMA Sprinkle with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions (5.2)].

Alcohol - Although duloxetine delayed-release capsules does not increase the impairment of mental and motor skills caused by alcohol, use of DRIZALMA Sprinkle concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, DRIZALMA Sprinkle should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

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Pregnancy

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

• Advise patients that DRIZALMA Sprinkle 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 patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to duloxetine during pregnancy [see Use in Specific Populations (8.1)].

Lactation- Advise breastfeeding women using DRIZALMA Sprinkle to monitor infants for sedation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Pediatric Use - Safety and efficacy of duloxetine delayed-release capsules in patients 7 to 17 years of age have been established for the treatment of GAD. The types of adverse reactions observed with duloxetine delayed-release capsules in children and adolescents were generally similar to those observed in adults. The safety and effectiveness of DRIZALMA Sprinkle have not been established in pediatric patients less than 18 years of age with other indications. [see Use in Specific Populations (8.4)].

Interference with Psychomotor Performance - Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies duloxetine delayed-release capsules has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that DRIZALMA Sprinkle therapy does not affect their ability to engage in such activities.