DRIZALMA SPRINKLE- duloxetine capsule, delayed release
SUN PHARMACEUTICAL INDUSTRIES, INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use DRIZALMA SPRINKLE safely and effectively. See full prescribing information for DRIZALMA SPRINKLE.
DRIZALMA SPRINKLE™ (duloxetine delayed-release capsules), for oral use. Initial U.S. Approval: 2004 WARNING: SUICIDAL THOUGHTS AND BEHAVIORSSee full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGEDRIZALMA SPRINKLE is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of following conditions: (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHSDelayed-release capsules: 20 mg, 30 mg, 40 mg, and 60 mg (3) (3) CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSMost 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. DRUG INTERACTIONS
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 7/2021 |
Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)].
DRIZALMA SPRINKLE is indicated for the treatment of:
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.
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)].
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)].
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.
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 [seeClinical Studies (14.5)].
Coadministration with potent CYP1A2 Inhibitors: Avoid concomitant use of DRIZALMA SPRINKLE with potent CYP1A2 inhibitors.
Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions (5.14) and Use in Specific Populations (8.9)].
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)].
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)].
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).
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)].
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.
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)].
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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.
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)].
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, 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.
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 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)].
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 blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.
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)].
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.
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.
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.
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)]].
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)].
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.
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 A1c (HbA1c) 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. HbA1c increased by 0.5% in the duloxetine delayed-release group and by 0.2% in the routine care group.
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.
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.
Most Common Adverse Reactions (Adults)
Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine Delayed-Release Capsules Treated Patients in Adult Placebo-Controlled Trials
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Adverse Reactions in Pooled MDD and GAD Trials in Adults
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Duloxetine delayed-release capsules (N = 4797) |
Placebo (N = 3303) |
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23 |
8 |
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14 |
6 |
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9 |
4 |
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9 |
6 |
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5 |
4 |
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4 |
2 |
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9 |
5 |
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6 |
2 |
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14 |
14 |
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9 |
5 |
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9 |
3 |
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3 |
1 |
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9 |
5 |
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4 |
2 |
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3 |
2 |
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4 |
1 |
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2 |
1 |
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3 |
1 |
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2 |
<1 |
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2 |
<1 |
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6 |
2 |
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Percentage of Patients Reporting Reaction |
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Duloxetine delayed-release capsules (N = 3303) |
Placebo (N = 2352) |
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Gastrointestinal Disorders
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23 11 10 9 5 3 2 |
7 3 3 5 4 2 1 |
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11 |
5 |
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4 3 2 |
4 3 2 |
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8 |
1 |
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3 2 |
3 2 |
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13 11 9 2 2 |
8 3 5 2 <1 |
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10 3 |
5 1 |
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4 2 |
<1 <1 |
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2 |
2 |
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6 |
1 |
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3 2 |
1 1 |
Effects on Male and Female Sexual Function in Adults with MDD
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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 |
Vital Sign Changes in Adults
Laboratory Changes in Adults
Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine Delayed-Release Capsules in Adults
Adverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients
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Percentage of Pediatric Patients Reporting Reaction |
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Duloxetine delayed-release capsules (N = 476) |
Placebo (N = 362) |
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18 13 9 6 2 |
8 10 4 3 1 |
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7 |
5 |
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14 |
6 |
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10 |
5 |
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18 11 8 |
13 6 4 |
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7 |
4 |
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4 3 |
2 1 |
Monoamine Oxidase Inhibitors (MAOIs) |
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Clinical Impact |
Concomitant use of SSRIs and SNRIs including duloxetine with MAOIs increases the risk of serotonin syndrome. |
Intervention |
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Examples |
Selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, intravenous methylene blue |
Serotonergic Drugs |
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Clinical Impact |
Concomitant use of duloxetine with other serotonergic drugs increases the risk of serotonin syndrome. |
Intervention |
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Examples |
Triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, other SNRIs or SSRIs, and St. John’s Wort |
Inhibitors of CYP1A2 |
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Clinical Impact |
Concomitant use of duloxetine with CYP1A2 inhibitors increases AUC, Cmax, t1/2 of duloxetine. |
Intervention |
Avoid concomitant use of duloxetine delayed-release capsules with potent CYP1A2 inhibitors [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)]. |
Examples |
Fluvoxamine, cimetidine, ciprofloxacin, enoxacin |
Dual Inhibition of CYP1A2 and CYP2D6 |
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Clinical Impact |
Concomitant administration of duloxetine with potent CYP1A2 inhibitors to CYP2D6 poor metabolizers results in increased AUC and Cmax of duloxetine. |
Intervention |
Avoid co-administration of duloxetine delayed-release capsules and potent CYP1A2 inhibitors to CYP2D6 poor metabolizers [see Clinical Pharmacology (12.3)]. |
Examples |
Fluvoxamine, cimetidine, ciprofloxacin, enoxacin |
Drugs that Interfere with Hemostasis |
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Clinical Impact |
Concomitant use of duloxetine with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. |
Intervention |
Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when duloxetine is initiated or discontinued [Warnings and Precaution (5.5)]. |
Examples |
NSAIDs, aspirin, warfarin |
Inhibitors of CYP2D6 |
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Clinical Impact |
Concomitant use of duloxetine with CYP2D6 inhibitors increase AUC of duloxetine. Greater degrees of inhibition are expected with higher doses of CYP2D6 inhibitors. |
Intervention |
Exercise caution when co-administering duloxetine delayed-release capsules and potent CYP2D6 inhibitors [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)]. |
Examples |
Paroxetine, fluoxetine, quinidine |
Drugs Metabolized by CYP2D6 |
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Clinical Impact |
Concomitant use of duloxetine increases AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug. |
Intervention |
Monitor plasma concentrations of CYP2D6 substrate and reduce dosage of CYP2D6 substrate drug if necessary [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)]. |
Examples |
TCAs (nortriptyline, amitriptyline, imipramine, desipramine); phenothiazines (thioridazine); Type 1C antiarrhythmics (propafenone, flecainide) |
Drugs that Affect Gastric Acidity |
|
Clinical Impact |
In patients with conditions that may slow gastric emptying (e.g., some diabetics) and drugs that raise the gastrointestinal pH may lead to earlier the release of duloxetine. |
Intervention |
Use with caution [see Clinical Pharmacology (12.3)]. |
Examples |
Aluminum-and magnesium-containing antacids, famotidine, proton pump inhibitors |
Drugs Metabolized by CYP1A2 |
|
Clinical Impact |
Concomitant use of duloxetine with CYP1A2 substrates may increase the AUC of CYP1A2 substrate. |
Intervention |
Use with caution [see Clinical Pharmacology (12.3)]. |
Examples |
Theophylline, caffeine |
CNS Drugs |
|
Clinical Impact |
Concomitant use of duloxetine with other centrally acting drugs may increase the CNS effects of duloxetine. |
Intervention |
Use with caution [see Warnings and Precautions (5.12)]. |
Examples |
Centrally acting CNS drugs |
Drugs Highly Bound to Plasma Protein |
|
Clinical Impact |
Concomitant use of duloxetine with highly protein bound drugs may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. |
Intervention |
Use with caution [see Clinical Pharmacology (12.3)]. |
Examples |
Highly plasma protein binding drugs |
Alcohol |
|
Clinical Impact |
Concomitant use of duloxetine and alcohol may cause liver injury or aggravate pre-existing liver disease. |
Intervention |
Avoid use patients with chronic liver disease or heavy alcohol use [see Dosage and Administration (2.7), Warnings and Precautions (5.2, 5.12)]. |
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 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.
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.
The most frequently observed adverse reactions in the clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Juvenile Animal Toxicology Data
Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child).
Geriatric Exposure in Premarketing Clinical Trials of duloxetine delayed-release capsules
In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between these geriatric and younger adult patients, but greater sensitivity of some older patients cannot be ruled out.
SSRIs and SNRIs, including duloxetine delayed-release capsules have been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.13)].
In an analysis of data from all placebo-controlled-trials, patients treated with duloxetine delayed-release capsules reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient’s underlying risk for falls. Underlying risk appears to increase steadily with age. As geriatric patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during treatment with duloxetine delayed-release capsules is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported with duloxetine delayed-release capsules use [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].
The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the adult patient is not necessary.
Duloxetine’s half-life is similar in men and women. Dosage adjustment based on gender is not necessary.
Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.
Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single 20 mg dose of duloxetine delayed-release capsules, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5 fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see Dosage and Administration (2.8) and Warnings and Precautions (5.14)].
Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7 to 9 fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal impairment (estimated CrCl 30 to 80 mL/min) have no significant effect on duloxetine apparent clearance [see Dosage and Administration (2.8) and Warnings and Precautions (5.14)].
In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.
While duloxetine delayed-release capsules have not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of duloxetine delayed-release capsules (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).
In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.
Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). The chemical name of duloxetine hydrochloride is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The molecular formula is C18H19NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is:
Duloxetine hydrochloride, USP is a white to off-white powder, which is freely soluble in methanol, soluble in dichloromethane, and slightly soluble in water. The molecular formula of duloxetine free base is C18H19NOS and its molecular weight is 297.38.
Each DRIZALMA SPRINKLE (duloxetine delayed-release capsule) for oral administration contains enteric-coated pellets containing a total of 22.4 mg, 33.6 mg, 44.9 mg or 67.3 mg of duloxetine hydrochloride, equivalent to 20 mg, 30 mg, 40 mg or 60 mg of duloxetine free base, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients of the pellets include hypromellose, hypromellose phthalate, polyethylene glycol, starch, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The capsule shell ingredients for 20 mg strength are D&C Yellow 10, FD &C Blue 1, FD &C Red 40, gelatin, sodium lauryl sulfate and titanium dioxide. The capsule shell ingredients for 30 mg strength are FD &C Blue 1, FD &C Red 40 and FD &C Red 3 (present in cap), gelatin, sodium lauryl sulfate and titanium dioxide. The capsule shell ingredients for 40 mg strength are gelatin, sodium lauryl sulfate and titanium dioxide. The capsule shell ingredients for 60 mg strength are D&C Yellow 10 (present in body), FD &C Blue 1, FD &C Red 40, FD &C Red 3 (present in cap), gelatin, sodium lauryl sulfate and titanium dioxide.
The imprinting ink for 20 mg, 30 mg, 40 mg, and 60 mg strength capsules was made of ammonia solution, black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol and shellac.
DRIZALMA SPRINKLE does not comply with the USP dissolution test.
Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.
Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).
Duloxetine is in a class of drugs known to affect urethral resistance [see Warnings and Precautions (5.15)].
Cardiac Electrophysiology
The effect of duloxetine delayed-release capsules 160 mg and 200 mg administered twice daily (2.7 and 3.3 times the maximum recommended dosage, respectively) to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female adult subjects. No QT interval prolongation was detected. Duloxetine delayed-release capsules appears to be associated with concentration-dependent but not clinically meaningful QT shortening.
Duloxetine hydrochloride pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing.
Absorption
After oral duloxetine delayed-release capsules administration, duloxetine hydrochloride is well absorbed. Peak plasma concentration of duloxetine is attained at 5 hours following administration of duloxetine delayed-release capsules. There is a 3 hour delay in absorption and a one- third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.
Effect of food
Compared to fasted state administration, high-fat, high-calorie meal (containing approximately 150 kcal from protein, 250 kcal from carbohydrates and 500 kcal from fat) did not have a significant effect on Cmax and AUC of duloxetine hydrochloride. However, Tmax of duloxetine hydrochloride delayed by approximately 1.7 hours with the administration of high-fat, high-calorie meal.
Duloxetine delayed-release capsules administered under fasting conditions to healthy adults by sprinkling the entire contents on one-tablespoon (15 mL) of applesauce did not significantly affect Tmax, Cmax, and AUC of duloxetine.
Distribution
The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.
Elimination
Metabolism
Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
Excretion
Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Mean terminal half-life was 12.4 hours (range 7.8 to 22.2 hour) in subjects receiving a single dose DRIZALMA SPRINKLE.
Specific Populations
Pediatric Patients
Duloxetine steady-state plasma concentration was comparable in pediatric patients7 to 17 years of age) and adult patients. The average steady-state duloxetine concentration was approximately 30% lower in the pediatric population relative to the adults. The model-predicted duloxetine steady state plasma concentrations in pediatric patients 7 to 17 years of age were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.
Drug Interaction Studies
Clinical Studies: Effect of other drugs on duloxetine
Fluvoxamine:
When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n = 14) duloxetine AUC was increased approximately 6 fold, the Cmax was increased about 2.5 fold, and duloxetine t1/2 was increased approximately 3 fold [see Dosage and Administration (2.6) and Drug Interactions (7.1)].
Fluvoxamine in CYP2D6 poor metabolizer subjects:
Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n = 14) resulted in a 6 fold increase in duloxetine AUC and Cmax[see Dosage and Administration (2.6) and Drug Interactions (7.1)].
Paroxetine:
Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily), a strong CYP2D6 inhibitor, increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine [see Drug Interactions (7.1)].
Lorazepam:
Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.
Temazepam:
Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.
Drugs that Affect Gastric Acidity:
Co-administration of duloxetine delayed-release capsules with aluminum- and magnesium-containing antacids (51 mEq) or duloxetine delayed-release capsules with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose [see Drug Interactions (7.1)].
Clinical Studies: Effect of duloxetine on other drugs
Theophylline:
In two clinical studies the average (90% confidence interval) increase in theophylline (a CYP1A2 substrate) AUC was 7% (1% to 15%) and 20% (13% to 27%) when co-administered with duloxetine (60 mg twice daily) [see Drug Interactions (7.1)].
Desipramine:
When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3 fold [see Drug Interactions (7.1)].
Warfarin:
Under steady-state condition for warfarin (2 to 9 mg once daily) and duloxetine (60 or 120 mg once daily), the total warfarin (protein bound plus free drug) pharmacokinetics (AUCτ,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin (a CYP2C9 substrate) were not altered by duloxetine [see Drug Interactions (7.1)].
In vitro Studies
Results of in vitro studies demonstrate that duloxetine does not inhibit activity of drugs metabolized by CYP3A (e.g., oral contraceptives and other steroidal agents) and drugs metabolized by CYP2C19.
Alcohol:
An in vitro study showed significant increases of duloxetine hydrochloride release from DRIZALMA SPRINKLE at 2 hours to approximately 86% and 56% of the drug release in the presence of 40% and 20% alcohol, respectively. Effect of 5% alcohol on drug release was not observed at 2 hours. There is no in vivo study conducted for the effect of alcohol on drug exposure.
Carcinogenesis - Duloxetine was administered in the diet to mice and rats for 2 years.
In female mice receiving duloxetine at 140 mg/kg/day (3 times the MRHD of 120 mg/day given to children on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (1 times the MRHD given to children). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (2 times the MRHD given to children).
In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (1 times the MRHD given to children) and up to 36 mg/kg/day in males (1.4 times the MRHD given to children) did not increase the incidence of tumors.
Mutagenesis - Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo.
Impairment of Fertility - Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (3 times the MRHD given to adolescents on a mg/m2 basis) did not alter mating or fertility.
Study Number |
Treatment Group |
Primary Efficacy Measure: HAMD-17 |
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Mean Baseline Score (SD) |
LS Mean Change from Baseline (SE) |
Placebo-subtracted Differencea (95% CI) |
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21.5 (4.10) 21.1 (3.71) |
-10.9 (0.70) -6.1 (0.69) |
-4.9 (-6.8, -2.9) - |
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20.3 (3.32) 20.5 (3.42) |
-10.5 (0.71) -8.3 (0.67) |
-2.2 (-4.0, -0.3) - |
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18.6 (5.85) 18.1 (4.52) 17.2 (5.11) |
-7.4 (0.80) -8.6 (0.81) -5.0 (0.81) |
-2.4 (-4.7, -0.2) -3.6 (-5.9, -1.4) -‑ |
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19.9 (3.54) 20.2 (3.41) 19.9 (3.58) |
-11.0 (0.49) -12.1 (0.49) -8.8 (0.50) |
-2.2 (-3.6, -0.9) -3.3 (-4.7, -1.9) -‑ |
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Figure 3: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – Study DPNP-1
Figure 4: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-2
The efficacy of duloxetine delayed-release capsules for the management of fibromyalgia in adults was established in two randomized, double-blind, placebo-controlled, fixed-dose trials in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in duration and enrolled female patients only. Study FM-2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of MDD. Studies FM-1 and FM-2 enrolled a total of 874 patients of whom 541 (62%) completed the trials. A total of 354 patients (234 duloxetine, 120 placebo) were enrolled in Study FM-1 and a total of 520 patients (376 duloxetine, 144 placebo) were enrolled in Study FM-2 (5% male, 95% female). The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain).
Both trials compared duloxetine 60 mg once daily or 120 mg daily (given in divided doses in Study FM-1 and as a single daily dose in Study FM-2) with placebo. Study FM-2 additionally compared duloxetine 20 mg with placebo during the initial three months of a six-month trial.
Treatment with duloxetine 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients achieving that degree of improvement in Studies FM-1 and FM-2, respectively. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the trial. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither trial demonstrated a benefit of 120 mg compared to 60 mg, and a higher dosage was associated with more adverse reactions and premature discontinuations of treatment.
Figure 5: Percentage of Adult Fibromyalgia Patients Achieving Various Levels of Pain Relief at Study Endpoint as Measured by 24-Hour Average Pain Severity (Study FM-1)
Figure 6: Percentage of Adult Fibromyalgia Patients Achieving Various Levels of Pain Relief at Study Endpoint as Measured by 24-Hour Average Pain Severity (Study FM-2)
Figure 8: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – Study CLBP-3
Features |
Strengths |
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20 mg a |
30 mg a |
40 mg a |
60 mg a |
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Body color |
Green |
White |
White |
Green |
Cap color |
Green |
Blue |
White |
Blue |
Cap imprint |
RG53 |
RG54 |
RL85 |
RG55 |
Body imprint |
RG53 |
RG54 |
RL85 |
RG55 |
Presentations and NDC Codes |
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Bottles of 30 |
47335-616-30 |
47335-617-30 |
47335-618-30 |
47335-619-30 |
Bottles of 60 |
47335-616-60 |
47335-617-60 |
47335-618-60 |
47335-619-60 |
Bottles of 90 |
47335-616-90 |
47335-617-90 |
47335-618-90 |
47335-619-90 |
Bottles of 1000 |
47335-616-10 |
47335-617-10 |
47335-618-10 |
47335-619-10 |
DRIZALMA SPRINKLE (dri zal' mah)
(duloxetine delayed-release capsules)
What is the most important information I should know about DRIZALMA SPRINKLE?
DRIZALMA SPRINKLE may cause serious side effects, including:
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What is DRIZALMA SPRINKLE?
DRIZALMA SPRINKLE is prescription medicine used to treat:
It is not known if DRIZALMA SPRINKLE is safe and effective for use to treat MDD, DPNP, and Chronic Musculoskeletal Pain in children.
Do not take DRIZALMA SPRINKLE if you:
Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue.
Do not start taking an MAOI for a least 5 days after you stop treatment with DRIZALMA SPRINKLE.
Before taking DRIZALMA SPRINKLE, tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
DRIZALMA SPRINKLE and other medicines may affect each other causing possible serious side effects. DRIZALMA SPRINKLE may affect the way other medicines work and other medicines may affect the way DRIZALMA SPRINKLE works.
Especially tell your healthcare provider if you take:
Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take DRIZALMA SPRINKLE with your other medicines.
Do not start or stop any other medicines during treatment with TREATMENT without talking to your healthcare provider first. Stopping DRIZALMA SPRINKLE suddenly may cause you to have serious side effects. See, “What are the possible side effects of DRIZALMA SPRINKLE?”
Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.
How should I take DRIZALMA SPRINKLE?
If you take too much DRIZALMA SPRINKLE, call your healthcare provider or poison control center at 1800-222-1222 right away, or go to the nearest hospital emergency room.
What are the possible side effects of DRIZALMA SPRINKLE? DRIZALMA SPRINKLE may cause serious side effects, including:
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Your healthcare provider may tell you to stop taking DRIZALMA SPRINKLE if you develop serious side effects during treatment with DRIZALMA SPRINKLE. The most common side effects of DRIZALMA SPRINKLE in adults include: The most common side effects of DRIZALMA SPRINKLE in children include: Height and weight changes in children and adolescents may happen during treatment with DRIZALMA SPRINKLE. Your healthcare provider should check your child’s or adolescent’s height and weight during treatment with DRIZALMA SPRINKLE. These are not all the possible side effects of DRIZALMA SPRINKLE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
How should I store DRIZALMA SPRINKLE?
General information about the safe and effective use of DRIZALMA SPRINKLE.
What are the ingredients in DRIZALMA SPRINKLE?
Active ingredient: duloxetine hydrochloride
Inactive ingredients: hypromellose, hypromellose phthalate, polyethylene glycol, starch, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate.
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: July/2021
DRIZALMA SPRINKLE (dri zal' mah)
(duloxetine delayed-release capsules)
Taking DRIZALMA SPRINKLE with applesauce:
Giving DRIZALMA SPRINKLE through a nasogastric tube (NG tube) 12 French or larger as prescribed by your healthcare provider:
For people who have a NG tube in place, DRIZALMA SPRINKLE may be given as follows:
How should I store DRIZALMA SPRINKLE?
This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: July/2021
NDC 47335-616-30
Drizalma Sprinkle™
(duloxetine delayed-release capsules)
20 mg
30 Capsules
NDC 47335-617-30
Drizalma Sprinkle™
(duloxetine delayed-release capsules)
30 mg
90 Capsules
DRIZALMA SPRINKLE
duloxetine capsule, delayed release |
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DRIZALMA SPRINKLE
duloxetine capsule, delayed release |
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DRIZALMA SPRINKLE
duloxetine capsule, delayed release |
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DRIZALMA SPRINKLE
duloxetine capsule, delayed release |
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Labeler - SUN PHARMACEUTICAL INDUSTRIES, INC. (146974886) |
Registrant - SUN PHARMACEUTICAL INDUSTRIES, INC. (146974886) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Sun Pharmaceutical Industries Limited | 650456002 | MANUFACTURE(47335-616, 47335-617, 47335-618, 47335-619) |