DRIZALMA SPRINKLE (duloxetine hydrochloride 30 mg) Dailymed

Recent Major Changes Section

Warnings and Precautions (5.4, 5.5)       08/2023

Warning: Suicidal Thoughts And Behaviors

• Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies.

Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)].


WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

•Increased risk of suicidal thinking and behavior in pediatric and young adult patients taking antidepressants (5.1)

•Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors (5.1)

DRIZALMA SPRINKLE 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 Neuropathy in adults
• • Fibromyalgia in adults
• •Chronic Musculoskeletal Pain in adults

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.


DRIZALMA SPRINKLE is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of following conditions:• Major Depressive Disorder (MDD) in adults (1)• Generalized Anxiety Disorder (GAD) in adults and pediatric patients ages 7 years of age and older (1)• Diabetic Peripheral Neuropathic Pain (DPNP) in adults (1)• Fibromyalgia (FM) in adults (1)• Chronic Musculoskeletal Pain in adults (1)

2 Dosage And Administration

• •Take DRIZALMA SPRINKLE with or without food (2.1)
• •DRIZALMA SPRINKLE may be: swallowed whole (do not crush or chew capsule); opened and sprinkled over applesauce; or administered via nasogastric tube (2.1)
• •Take a missed dose as soon as it is remembered. Do not take two doses of DRIZALMA SPRINKLE at the same time (2.1)

Indication	Starting Dose	Target Dose	Maximum Dose
MDD (2.2) Adults	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	120 mg/day
GAD (2.3)
Adults	60 mg/day	60 mg/day (once daily)	120 mg/day
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) Adults	30 mg/day	60 mg/day (once daily)	60 mg/day
Chronic Musculoskeletal Pain (2.6) Adults	30 mg/day	60 mg/day (once daily)	60 mg/day

• •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)
• •Discontinuing DRIZALMA SPRINKLE: Gradually reduce dosage to avoid discontinuation symptoms (2.8, 5.7)

2.1Important Administration Instructions

Administer DRIZALMA SPRINKLE with or without food. Swallow DRIZALMA SPRINKLE whole (do not chew or crush the capsule). For patients unable to swallow an intact capsule, refer to the alternative administration instructions below.

Directions for use with applesauce

For patients with swallowing difficulty, DRIZALMA SPRINKLE can be opened and the contents sprinkled over applesauce. The contents of the capsules should be swallowed along with a small amount (tablespoonful) of applesauce. The drug/food mixture should be swallowed immediately and not stored for future use.

Nasogastric tube administration

Open and add contents of capsule to an all plastic catheter tip syringe and add 50 mL of water. Gently shake the syringe for approximately 10 seconds. Promptly deliver through a 12 French or larger nasogastric tube. Ensure no pellets are left in the syringe. Rinse with additional water (about 15 mL) if needed.

If a dose of DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE at the same time.

2.2Dosage for Treatment of Major Depressive Disorder in Adults

The recommended starting dosage in adults with MDD is 40 mg per day (given as 20 mg twice daily) to 60 mg per 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 DRIZALMA SPRINKLE before increasing to 60 mg once daily. While a 120 mg per day dose was shown to be effective, there is no evidence that doses greater than 60 mg per day confer any additional benefits. Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment [see Clinical Studies (14.1)].

2.3Dosage 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 DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE 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 per 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. The safety of doses above 120 mg once daily has not been adequately evaluated. 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 DRIZALMA SPRINKLE at a dosage of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg per 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 DRIZALMA SPRINKLE 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.

2.4Dosage for Treatment of Diabetic Peripheral Neuropathic Pain in Adults

Administer DRIZALMA SPRINKLE 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 (2.8) and Use in Specific Populations (8.10)].

2.5 Dosage for Treatment of Fibromyalgia in Adults

Recommended Dosage in Adults

The recommended DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE 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.

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.

2.6Dosage for Treatment of Chronic Musculoskeletal Pain in Adults

The recommended DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE before increasing to 60 mg once daily. There is no evidence that higher dosage 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 (14.5)].

2.7Dosage Recommendations for Concomitant Use with Potent CYP1A2 Inhibitors

Coadministration with potent CYP1A2 Inhibitors: Avoid concomitant use of DRIZALMA SPRINKLE with potent CYP1A2 inhibitors.

2.8 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)].

2.9Screen for Bipolar Disorder Prior to Starting DRIZALMA SPRINKLE

Prior to initiating treatment with DRIZALMA SPRINKLE or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.8)].

2.10Discontinuing DRIZALMA SPRINKLE

Adverse reactions may occur upon discontinuation of DRIZALMA SPRINKLE [see Warnings and Precautions (5.7)]. Gradually reduce the dosage rather than stopping DRIZALMA SPRINKLE abruptly whenever possible [see Warnings and Precautions (5.7)].

2.11Switching 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 DRIZALMA SPRINKLE. Conversely, at least 5 days should be allowed after stopping DRIZALMA SPRINKLE before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4).

2.12 Use of DRIZALMA SPRINKLE with Other MAOIs such as Linezolid or Methylene Blue

Do not start DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE 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, DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE 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

20 mg: hard gelatin capsules with green cap imprinted with “RG53” and green body imprinted with “RG53” containing off-white to pale-yellow colored pellets. Each capsule contains 22.4 mg of duloxetine hydrochloride, USP equivalent to 20 mg duloxetine.

30 mg: hard gelatin capsules with blue cap imprinted with “RG54” and white body imprinted with “RG54” containing off-white to pale-yellow colored pellets. Each capsule contains 33.6 mg of duloxetine hydrochloride, USP equivalent to 30 mg duloxetine.

40 mg: hard gelatin capsules with white cap imprinted with “RL85” and white body imprinted with “RL 85” containing off-white to pale-yellow colored pellets. Each capsule contains 44.9 mg of duloxetine hydrochloride, USP equivalent to 40 mg duloxetine.

60 mg: hard gelatin capsules with blue cap imprinted with “RG55” and green body imprinted with “RG55” containing off-white to pale-yellow colored pellets. Each capsule contains 67.3 mg of duloxetine hydrochloride, USP equivalent to 60 mg duloxetine.


Delayed-release capsules: 20 mg, 30 mg, 40 mg, and 60 mg (3)

4 Contraindications

The use of MAOIs intended to treat psychiatric disorders with DRIZALMA SPRINKLE, or within 5 days of stopping treatment with DRIZALMA SPRINKLE, are contraindicated because of an increased risk of serotonin syndrome. The use of DRIZALMA SPRINKLE within 14 days of stopping an MAOI intended to treat psychiatric disorders is contraindicated [see Dosage and Administration (2.10), Warnings and Precautions (5.4), Drug Interactions (7)].

Starting DRIZALMA SPRINKLE in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is contraindicated because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.4)].

• Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with DRIZALMA SPRINKLE or within 5 days of stopping treatment with DRIZALMA SPRINKLE. Do not use DRIZALMA SPRINKLE within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start DRIZALMA SPRINKLE in a patient who is being treated with linezolid or intravenous methylene blue (4)

5 Warnings And Precautions

• Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported. Discontinue DRIZALMA SPRINKLE 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)
  • S ero t on in Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue DRIZALMA SPRINKLE and serotonergic agents and initiate supportive treatment (5.4)
  • Increased Risk of B leeding: May increase the risk of bleeding events. Concomitant use of antiplatelet drugs and anticoagulants may increase this risk (5.5, 7, 8.1)
  • S ever e Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with duloxetine. Discontinue at the first appearance of bulers, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified (5.6)
  • D iscontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms (5.7)
  • Activation of Mania or Hypomania: Prior to initiating, screen patients for personal or family history of bipolar disorder, mania, or hypomania (5.8)
  • A ng le-Closure Glaucoma: Has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.9)
  • S e izures: Prescribe with care in patients with a history of seizure disorder (5.10)
  • B lood Pressure Increases: Monitor blood pressure prior to initiating treatment and periodically throughout treatment (5.11)
  • Inhibitors of CYP1A2 or Thioridazine: Avoid co-administration with DRIZALMA SPRINKLE (5.12)
    • Hypona t r emia: Can occur in association with SIADH; consider discontinuation (5.13)
    • Glucose Control in Diabetes: In DPNP patients, increase 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: DRIZALMA SPRINKLE may cause symptoms of sexual dysfunction (5.16)

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated
	Increases Compared to Placebo
<18	14 additional patients
18 to 24	5 additional patients
	Decreases Compared to Placebo
25 to 64	1 fewer patients
≥65	6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing DRIZALMA SPRINKLE, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2Hepatotoxicity

There have been reports of hepatic failure, sometimes fatal, in patients treated with duloxetine delayed-release capsules. 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. Discontinue DRIZALMA SPRINKLE in patients who develop jaundice or other evidence of clinically significant liver dysfunction and do not resume unless another cause can be established.

Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other post-marketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.

Duloxetine delayed-release capsules 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 duloxetine delayed-release capsules-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult 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 1.25% (144/11,496) of duloxetine delayed-release capsules-treated patients compared to 0.45% (39/8716) of placebo- treated patients. In adult placebo-controlled studies with duloxetine delayed-release capsules using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the ULN and >5 times the ULN, respectively.

Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, DRIZALMA SPRINKLE should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

5.3Orthostatic Hypotension, Falls and Syncope

Orthostatic hypotension, falls, and syncope have been reported in patients treated with the recommended duloxetine delayed-release capsules dosage. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during DRIZALMA SPRINKLE 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 duloxetine delayed-release capsules 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 anti-hypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions (5.12) and Drug Interactions (7.1)] and in patients taking DRIZALMA SPRINKLE at doses above 60 mg daily. Consider dose reduction or discontinuation of DRIZALMA SPRINKLE in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during DRIZALMA SPRINKLE 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 duloxetine delayed-release capsules use [see Adverse Reactions (6.1)].

5.4Serotonin Syndrome

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.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of DRIZALMA SPRINKLE with MAOI antidepressant is contraindicated. In addition, do not initiate DRIZALMA SPRINKLE in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking DRIZALMA SPRINKLE, discontinue DRIZALMA SPRINKLE before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)].

Monitor all patients taking DRIZALMA SPRINKLE for the emergence of serotonin syndrome. Discontinue treatment with DRIZALMA SPRINKLE capsules immediately if the above symptoms occur and initiate supportive symptomatic treatment. If concomitant use of DRIZALMA SPRINKLE with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.5Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including DRIZALMA SPRINKLE, 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 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)].

5.6Severe Skin Reactions

Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with DRIZALMA SPRINKLE. The reporting rate of SJS associated with duloxetine use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.

DRIZALMA SPRINKLE should be discontinued at the first appearance of bulers, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

5.7Discontinuation Syndrome

Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.

Monitor patients for these symptoms when discontinuing treatment with DRIZALMA SPRINKLE [see Dosage and Administration (2.10)]. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.9)].

5.8Activation of Mania/Hypomania

In patients with bipolar disorder, treating a depressive episode with DRIZALMA SPRINKLE or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials in adult patients with major depressive disorder, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.1% of patients treated with duloxetine delayed-release capsules. 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.

5.9Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs, including DRIZALMA SPRINKLE, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including DRIZALMA SPRINKLE, in patients with anatomically narrow angles.

5.10Seizures

Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with duloxetine delayed-release capsules and 0.01% (1/9513) of patients treated with placebo. DRIZALMA SPRINKLE should be prescribed with care in patients with a history of a seizure disorder.

5.11Increases 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 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.

Patients receiving DRIZALMA SPRINKLE should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies [see Adverse Reactions (6.1)]. Pre-existing hypertension should be controlled before initiating treatment with DRIZALMA SPRINKLE. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure.

Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving DRIZALMA SPRINKLE, either dose reduction or discontinuation should be considered [see Adverse Reactions (6.1), Drug Interactions (7.1)]].

5.12Clinically Important Drug Interactions

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Potential for Other Drugs to Affect DRIZALMA SPRINKLE

CYP1A2 Inhibitors – Avoid concomitant use of DRIZALMA SPRINKLE with potent CYP1A2 inhibitors [see Drug Interactions (7.1)].

CYP2D6 Inhibitors - Concomitant use of DRIZALMA SPRINKLE with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine [see Drug Interactions (7.1)].

Potential for DRIZALMA SPRINKLE to Affect Other Drugs

Drugs Metabolized by CYP2D6 - Co-administration of DRIZALMA SPRINKLE with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with DRIZALMA SPRINKLE. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, DRIZALMA SPRINKLE and thioridazine should not be co-administered [see Drug Interactions (7.1)].

Other Clinically Important Drug Interactions

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)].

When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.

In the duloxetine clinical trials database, three duloxetine-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions (5.2), Drug Interactions (7.1)].

CNS Acting Drugs - Given the primary CNS effects of duloxetine, DRIZALMA SPRINKLE should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see Drug Interactions (7.1)].

5.13Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including DRIZALMA SPRINKLE. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Geriatric patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of DRIZALMA SPRINKLE should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have been included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.14Use in Patients with Concomitant Illness

Clinical experience with duloxetine delayed-release capsules in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of DRIZALMA SPRINKLE enteric coating. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using DRIZALMA SPRINKLE in patients with conditions that may slow gastric emptying (e.g., some diabetics).

DRIZALMA SPRINKLE has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing.

Hepatic Impairment

Avoid use in patients with chronic liver disease or cirrhosis [see Dosage and Administration (2.7), Warnings and Precautions (5.2), and Use in Specific Populations (8.9)].

Severe Renal Impairment

Avoid use in patients with severe renal impairment, GFR < 30 mL/minute. Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration (2.7) and Use in Specific Populations (8.10)].

Glycemic Control in Patients with Diabetes

As observed in DPNP trials, duloxetine delayed-release capsules treatment worsened glycemic control in some patients with diabetes. In three clinical trials of duloxetine delayed-release capsules for the management of neuropathic pain associated with diabetic peripheral neuropathy [see clinical studies (14.3)], the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A_1c (HbA_1c) was 7.8%. In the 12 week acute treatment phase of these studies, duloxetine delayed-release capsules was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the duloxetine delayed-release capsules group and decreased by 11.5 mg/dL in the routine care group. HbA_1c increased by 0.5% in the duloxetine delayed-release group and by 0.2% in the routine care group.

5.15Urinary Hesitation and Retention

DRIZALMA SPRINKLE is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with DRIZALMA SPRINKLE, consideration should be given to the possibility that they might be drug-related.

In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine delayed-release capsules use, hospitalization and/or catheterization has been needed.

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

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.2)]
• Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions (5.3)]
• Serotonin Syndrome [see Warnings and Precautions (5.4)]
• Increased Risk of Bleeding [see Warnings and Precautions (5.5)]
• Severe Skin Reactions [see Warnings and Precautions (5.6)]
• Discontinuation Syndrome [see Warnings and Precautions (5.7)]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.8)]
• Angle-Closure Glaucoma [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Increases in Blood Pressure [see Warnings and Precautions (5.11)]
• Clinically Important Drug Interactions [see Warnings and Precautions (5.12)]
• Hyponatremia [see Warnings and Precautions (5.13)]
• Urinary Hesitation and Retention [see Warnings and Precautions (5.15)]
• Sexual Dysfunction [see Warnings and Precautions (5.16)]

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: nausea, diarrhea, decreased weight

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, a treatment-emergent adverse reaction of the type uled.

Adverse Reactions in Adults

The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled trials for MDD (N = 3779), GAD (N = 1018), OA (N = 503), CLBP (N = 600), and DPNP (N = 906), and FM (N = 1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies (14)]. The data below do not include results of the trial examining the efficacy of duloxetine delayed-release in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population.

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

Major Depressive Disorder:

Approximately 8.4% (319/3779) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo-treated patients. Nausea (duloxetine delayed-release capsules 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine delayed-release capsules-treated patients and at a rate of at least twice that of placebo).

Generalized Anxiety Disorder:

Approximately 13.7% (139/1018) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) of placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.3%, placebo 0.4%), and dizziness (duloxetine delayed-release capsules 1.3%, placebo 0.4%).

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, compared with 5.1% (23/448) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.5%, placebo 0.7%), dizziness (duloxetine delayed-release capsules 1.2%, placebo 0.4%), and somnolence (duloxetine delayed-release capsules 1.1%, placebo 0.0%).

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, compared with 7.3% (37/508) 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 2.2%, placebo 1.0%).

Chronic Low Back Pain:

Approximately 16.5% (99/600) of the duloxetine delayed-release capsules-treated patients in 13 week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) 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 3.0%, placebo 0.7%), and somnolence (duloxetine delayed-release capsules 1.0%, placebo 0.0%).
M ost Common Adverse Reactions (Adults)
Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.

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

Chronic Pain due to Osteoarthritis: nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.

Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.
A dverse 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.

T able 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations^a

A dverse Reaction	P ercentage of Patients Reporting Reaction
	Duloxetine delayed - release capsules (N = 8100)	P lacebo ( N = 5655)
Nauseac	23	8
Headache	14	12
Dry mouth	13	5
Somnolencee	10	3
Fatigueb,c	9	5
Insomniad	9	5
Constipationc	9	4
Dizzinessc	9	5
Diarrhea	9	6
Decreased appetitec	7	2
Hyperhidrosisc	6	1
Abdominal painf	5	4

^a Includes adults with MDD, GAD, DPNP, FM, and chronic musculoskeletal pain. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.

^b Also includes asthenia.

^c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.

^d Also includes initial insomnia, middle insomnia, and early morning awakening.

^e Also includes hypersomnia and sedation.               

^f Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.
A dverse Reactions in Pooled MDD and GAD Trials in Adults
Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo-treated patients.

T able 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults^a,b

S y stem Organ Class / Adverse Reaction	P ercentage of Patients Reporting Reaction
	Duloxetine delayed-release capsules (N = 4797)	P lacebo ( N = 3303)
Cardiac Disorders Palpitations	2	1
E y e Disorders Vision blurred	3	1
G astrointestinal Disorders
Nauseac	23	8
Dry mouth	14	6
Constipationc	9	4
Diarrhea	9	6
Abdominal paind	5	4
Vomiting	4	2
G eneral Disorders and Administration Site Conditions Fatiguee	9	5
M etabolism and Nutrition Disorders Decreased appetitec	6	2
Nervous System Disorders
Headache	14	14
Dizzinessc	9	5
Somnolencef	9	3
Tremor	3	1
P s ychiatric Disorders
Insomniag	9	5
Agitationh	4	2
Anxiety	3	2
Reproductive System and Breast Disorders
Erectile dysfunction	4	1
Ejaculation delayedc	2	1
Libido decreasedi	3	1
Orgasm abnormalj	2	<1
Respiratory, Thoracic, and Mediastinal Disorders Yawning	2	<1
S kin and Subcutaneous Tissue Disorders Hyperhidrosis	6	2

^a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in  the table are rounded to the nearest integer.

^b For GAD, there were no adverse reactions that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65 years.

^c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.

^d Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain

^e Includes asthenia

^f Includes hypersomnia and sedation

^g Includes initial insomnia, middle insomnia, and early morning awakening

^h Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity

ⁱ Includes loss of libido

^j Includes anorgasmia

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

Table 4 displays the incidence of adverse reactions that occurred in 2% or more of duloxetine delayed-release capsules-treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients.

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

S y stem Organ Class / Adverse Reaction	Percentage of Patients Reporting Reaction
	Duloxetine delayed-release capsules (N = 3303)	Placebo (N = 2352)
G astrointestinal Disorders Nausea Dry Mouthb Constipationb Diarrhea Abdominal Painc Vomiting Dyspepsia	23 11 10 9 5 3 2	7 3 3 5 4 2 1
G eneral Disorders and Administration Site Conditions Fatigued	11	5
Infections and Infestations Nasopharyngitis Upper Respiratory Tract Infection Influenza	4 3 2	4 3 2
M etabolism and Nutrition Disorders Decreased Appetiteb	8	1
M usculoskeletal and Connective Tissue Musculoskeletal Paine Muscle Spasms	3 2	3 2
Nervous System Disorders Headache Somnolenceb,f Dizziness Paraesthesiag Tremorb	13 11 9 2 2	8 3 5 2 <1
P s ychiatric Disorders Insomniab,h Agitationi	10 3	5 1
Reproductive System and Breast Disorders Erectile Dysfunctionb Ejaculation Disorderj	4 2	<1 <1
Respiratory, Thoracic, and Mediastinal Disorders Cough	2	2
S kin and Subcutaneous Tissue Disorders Hyperhidrosis	6	1
V ascular Disorders Flushingk Blood pressure increasedl	3 2	1 1

^a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.

^b Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day.

^c Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness and gastrointestinal pain

^d Includes asthenia

^e Includes myalgia and neck pain

^f Includes hypersomnia and sedation

^g Includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia oral

^h Includes initial insomnia, middle insomnia, and early morning awakening.

ⁱ Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity

^j Includes ejaculation failure

^k Includes hot flush

^l Includes blood pressure diastolic increased, blood pressure systolic increased, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension
E ff ects 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.

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

	Male Patientsa		Female Patientsa
	Duloxetine delayed-release capsules (n = 175)	Placebo (n = 83)	Duloxetine delayed-release capsules (n = 241)	Placebo (n = 126)
ASEX Total (Items 1-5) Item 1 - Sex drive Item 2 - Arousal Item 3 - Ability to achieve erection (men); Lubrication (women) Item 4 - Ease of reaching orgasm Item 5 - Orgasm satisfaction	0.56b -0.07 0.01 0.03 0.40c 0.09	-1.07 -0.12 -0.26 -0.25 -0.24 -0.13	-1.15 -0.32 -0.21 -0.17 -0.09 -0.11	-1.07 -0.24 -0.18 -0.18 -0.13 -0.17

^a n = Number of patients with non-missing change score for ASEX total

^b p = 0.013 versus placebo

^c p<0.001 versus placebo
V ital 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. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3, 5.11)].

Duloxetine delayed-release capsules treatment, for up to 26 weeks in placebo-controlled trials across approved adult populations, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine delayed-release capsules-treated patients, decrease of 0.17 beats per minute in placebo-treated patients).
Laboratory Changes in Adults
Duloxetine delayed-release capsules treatment in placebo-controlled clinical trials across approved adult populations, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in duloxetine delayed-release capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5.2)]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in duloxetine delayed-release capsules treated patients compared to placebo-treated patients.
Ot her Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine Delayed-Release Capsules in Adults
Following is a ul 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. Of these, 26.9% (9337) took duloxetine delayed-release capsules for at least 6 months, and 12% (4317) for at least one year. The following uling is not intended to include reactions (1) already uled in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

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

Ear and Labyrinth Disorders- Frequent: vertigo; Infrequent: ear pain and tinnitus.

Endocrine Disorders- Infrequent:hypothyroidism.

Eye Disorders- Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment.

Gastrointestinal Disorders- Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.

General Disorders and Administration Site Conditions- Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.

Infections and Infestations- Infrequent: gastroenteritis and laryngitis.

Investigations - Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased.

Metabolism and Nutrition Disorders- Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.

Musculoskeletal and Connective Tissue Disorders- Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.

Nervous System Disorders- Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent:

disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; R are: dysarthria.

Psychiatric Disorders- Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.

Renal and Urinary Disorders- Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.

Reproductive System and Breast Disorders- Frequent: anorgasmia/orgasm abnormal; Infrequent:

menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.

Respiratory, Thoracic and Mediastinal Disorders- Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness.

Skin and Subcutaneous Tissue Disorders- Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.

Vascular Disorders- Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.
A dverse 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. The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients [see Adverse Reactions (6.1)]. The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness.

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)]

T able 6: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10 week Pediatric Placebo-Controlled Trialsin MDD^a and GAD^b

System Organ Class/Adverse Reaction	Percentage of Pediatric Patients Reporting Reaction
	Duloxetine delayed - release capsules (N = 476)	Placebo (N = 362)
Gastrointestinal Disorders Nausea Abdominal Painc Vomiting Diarrhea Dry Mouth	18 13 9 6 2	8 10 4 3 1
General Disorders and Administration Site Conditions Fatigued	7	5
Investigations Decreased Weighte	14	6
Metabolism and Nutrition Disorders Decreased Appetite	10	5
Nervous System Disorders Headache Somnolencef Dizziness	18 11 8	13 6 4
Psychiatric Disorders Insomniag	7	4
Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain Cough	4 3	2 1

^a DRIZALMA SPRINKLE is not approved for the treatment of pediatric MDD [see Use in Specific Populations (8.4)] .

^bThe inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.

^c Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.

^d Also includes asthenia.

^e Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss

(N = 467 duloxetine delayed-release capsules; N = 354 Placebo).

^f Also includes hypersomnia and sedation.

^g Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia.

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).

The most commonly reported symptoms following discontinuation of duloxetine delayed-release capsules in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions (5.7)].

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

Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Pediatric patients treated with duloxetine delayed-release capsules in clinical trials experienced a 0.1kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated patients. 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). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine delayed-release capsules-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers.

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.

6.2Postmarketing Experience

The following adverse reactions have been identified during post approval use of duloxetine delayed-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally related to duloxetine delayed-release capsules therapy and not mentioned elsewhere in labeling include: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.