DULOXETINE- duloxetine hydrochloride capsule, delayed release

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

DULOXETINE HYDROCHLORIDE (UNII: 9044SC542W) (DULOXETINE - UNII:O5TNM5N07U)

Available from:

REMEDYREPACK INC.

INN (International Name):

DULOXETINE HYDROCHLORIDE

Composition:

DULOXETINE 60 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Duloxetine delayed-release capsules are indicated for the treatment of: - Major depressive disorder in adults - Generalized anxiety disorder in adults and pediatric patients 7 years of age and older - Diabetic peripheral neuropathic pain in adults - Fibromyalgia in adults and pediatric patients 13 years of age and older - Chronic musculoskeletal pain in adults The use of MAOIs intended to treat psychiatric disorders with duloxetine delayed-release capsules or within 5 days of stopping treatment with duloxetine delayed-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of duloxetine delayed-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is contraindicated [see  Dosage and Administration (2.8)and Warnings and Precautions (5.4)] . Starting duloxetine delayed-release capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see  Dosage and Administration (2.9)and Warnings and Precautions (5.4)] . Risk Summary Data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. Data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes (see Data) . There are risks associated with untreated depression and fibromyalgia in pregnancy, and with exposure to SNRIs and SSRIs, including duloxetine delayed-release capsules, during pregnancy (see Clinical Considerations) . In rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to 3 and 6 times, respectively, the maximum recommended human dose (MRHD) of 120 mg/day given to adolescents on a mg/m 2 basis. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Pregnant women with fibromyalgia are at increased risk for adverse maternal and infant outcomes including preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, and venous thrombosis. It is not known if these adverse maternal and fetal outcomes are a direct result of fibromyalgia or other comorbid factors. Maternal Adverse Reactions Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)] . Fetal/Neonatal Adverse Reaction Neonates exposed to duloxetine delayed-release capsules and other SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.4)] . Data Human Data Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% CI: 1.08 to 2.18). The same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. Methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures. Animal Data In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of malformations or developmental variations at doses up to 45 mg/kg/day [3 and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m 2 basis]. However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (approximately equal to the MRHD in rats and 2 times the MRHD in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD given to adolescents on a mg/m 2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. Risk Summary Data from 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 duloxetine delayed-release capsules and any potential adverse effects on the breastfed child from duloxetine delayed-release capsules or from the underlying maternal condition. Clinical Considerations Infants exposed to duloxetine delayed-release capsules should be monitored for sedation, poor feeding and poor weight gain. Data Disposition of duloxetine delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules metabolites in breast milk was not examined. The safety and effectiveness of duloxetine delayed-release capsules have been established for treatment of generalized anxiety disorder (GAD) in patients 7 to 17 years of age and for treatment of juvenile fibromyalgia syndrome in patients 13 to 17 years of age. The safety and effectiveness of duloxetine delayed-release capsules 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 duloxetine delayed-release capsules [see Adverse Reactions (6.1)] . Generalized Anxiety Disorder Use of duloxetine delayed-release capsules 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 duloxetine delayed-release capsules for the treatment of GAD in pediatric patients less than 7 years of age have not been established. Fibromyalgia Use of duloxetine delayed-release capsules for treatment of fibromyalgia in patients 13 to 17 years of age is supported by a 13-week placebo-controlled trial in 184 patients with juvenile fibromyalgia syndrome (Study FM-4). Duloxetine delayed-release capsules showed improvement over placebo on the primary endpoint, change from baseline to end-of-treatment on the Brief Pain Inventory (BPI) – Modified Short Form: Adolescent Version 24-hour average pain severity rating [see Clinical Studies (14.5)] . The safety and effectiveness of duloxetine delayed-release capsules for the treatment of fibromyalgia in patients less than 13 years of age have not been established. Major Depressive Disorder The safety and effectiveness of duloxetine delayed-release capsules 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 aged 7 to 17 years old with MDD (MDD-6 and MDD-7). 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 MDD pediatric clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Juvenile Animal Toxicology Data Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted 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 - Of the 2,418 patients in MDD trials, 6% (143) were 65 years of age or over. - Of the 1041 patients in CLBP trials, 21% (221) were 65 years of age or over. - Of the 487 patients in OA trials, 41% (197) were 65 years of age or over. - Of the 1,074 patients in the DPNP trials, 33% (357) were 65 years of age or over. - Of the 1,761 patients in FM trials, 8% (140) were 65 years of age or over. 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, duloxetine delayed-release capsules-treated patients reported a higher rate of falls compared to placebo-treated patients. 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 duloxetine delayed-release capsules treatment 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 C max , 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. No specific pharmacokinetic study was conducted to investigate the effects of race. 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 C max was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see  Dosage and Administration (2.7)and Warnings and Precautions (5.14)] . Limited data are available on the effects of duloxetine delayed-release capsules in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine delayed-release capsules, C max and AUC values were approximately 100% greater in patients with ESRD 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 (2.7)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 drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

Product summary:

Duloxetine Delayed-Release Capsules USP, 60 mg are blue opaque/green opaque, size ‘1’ hard gelatin capsule filled with white to off-white pellets and imprinted with ‘X’ on blue opaque cap and ‘03’ on green opaque body with black ink. NDC: 70518-0937-00 NDC: 70518-0937-01 NDC: 70518-0937-02 NDC: 70518-0937-03 NDC: 70518-0937-04 NDC: 70518-0937-05 NDC: 70518-0937-06 PACKAGING: 30 in 1 BLISTER PACK PACKAGING: 30 in 1 BOX PACKAGING: 1 in 1 POUCH PACKAGING: 30 in 1 BOTTLE PLASTIC PACKAGING: 30 in 1 BLISTER PACK PACKAGING: 90 in 1 BOTTLE PLASTIC PACKAGING: 60 in 1 BOTTLE PLASTIC Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

DULOXETINE- DULOXETINE HYDROCHLORIDE CAPSULE, DELAYED RELEASE
REMEDYREPACK INC.
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MEDICATION GUIDE
Duloxetine Delayed-Release Capsules USP
(doo lox' e teen)
Read this Medication Guide before you start taking duloxetine
delayed-release capsules and each time
you get a refill. There may be new information. This information does
not take the place of talking to
your healthcare provider about your medical condition or treatment.
Talk to your healthcare provider about:
•
all risks and benefits of treatment with antidepressant medicines
•
all treatment choices for depression or other serious mental illness
What is the most important information I should know about
antidepressant medicines, depression, other
serious mental illnesses, and suicidal thoughts or actions?
1. Duloxetine delayed-release capsules and other antidepressant
medicines may increase suicidal thoughts
or actions in some children, teenagers, or young adults within the
first few months of treatment or when
the dose is changed.
2. Depression and other serious mental illnesses are the most
important causes of suicidal thoughts or
actions. Some people may have a particularly high risk of having
suicidal thoughts or actions.These
include people who have (or have a family history of) bipolar illness
(also called manic-depressive
illness).
3. How can I watch for and try to prevent suicidal thoughts and
actions?
•
Pay close attention to any changes in mood, behavior, actions,
thoughts, or feelings, especially
sudden changes. This is very important when an antidepressant medicine
is started or when the
dose is changed.
•
Call your healthcare provider right away to report new or sudden
changes in mood, behavior,
thoughts, or feelings.
•
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare
provider between visits as needed, especially if you have concerns
about symptoms.
Call your healthcare provider right away if you have any of the
following symptoms or feelings,
especially if they are new, worse, or worr

Summary of Product characteristics

DULOXETINE- DULOXETINE HYDROCHLORIDE CAPSULE, DELAYED RELEASE
REMEDYREPACK INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
DULOXETINE DELAYED-
RELEASE CAPSULES SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING
INFORMATION FOR DULOXETINE
DELAYED-RELEASE CAPSULES.
DULOXETINE DELAYED-RELEASE CAPSULES, FOR ORAL USE
INITIAL U.S. APPROVAL: 2004
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
INCREASED RISK OF SUICIDAL THINKING AND BEHAVIOR IN CHILDREN,
ADOLESCENTS, AND YOUNG
ADULTS TAKING ANTIDEPRESSANTS ( 5.1)
MONITOR FOR WORSENING AND EMERGENCE OF SUICIDAL THOUGHTS AND BEHAVIORS
( 5.1)
INDICATIONS AND USAGE
Duloxetine delayed-release capsules are a serotonin and norepinephrine
reuptake inhibitor (SNRI)
indicated for the treatment of the following conditions:
Major depressive disorder (MDD) in adults ( 1)
Generalized anxiety disorder (GAD) in adults and pediatric patients 7
years of age and older ( 1)
Diabetic peripheral neuropathic pain (DPNP) in adults ( 1)
Fibromyalgia (FM) in adults and pediatric patients 13 years of age and
older ( 1)
Chronic musculoskeletal pain in adults ( 1)
DOSAGE AND ADMINISTRATION
Take duloxetine delayed-release capsules once daily, with or without
food. Swallow whole; do not crush,
chew, or open capsule ( 2.1)
INDICATION
STARTING DOSE
TARGET DOSE
MAXIMUM DOSE
MDD ( 2.2)
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
Geriatric
Pediatrics (7 to 17 years
of age)
60 mg/day
30 mg/day
30 mg/day
60 mg/day (once daily)
60 mg/day (once daily)
30 to 60 mg/day (once daily)
120 mg/day
120 mg/day
120 mg/day
DPNP ( 2.4)
60 mg/day
60 mg/day (once daily)
60 mg/day
FM ( 2.5)
Adults and Pediatrics (13
to 17 years of age)
30 mg/day
60 mg/day (once daily)
60 mg/day
Chronic Musculoskeletal
Pain ( 2.6)
30 mg/day
60 mg/day (once daily)
60 mg/day
Discontinuin