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Duloxetine Hydrochloride

FDA Drug Information • Also known as: Cymbalta, Duloxetine, Duloxetine Delayed-Release, Duloxetine Hydrochloride

Brand Names
Cymbalta, Duloxetine, Duloxetine Delayed-Release, Duloxetine Hydrochloride
Route
ORAL
Dosage Form
CAPSULE, DELAYED RELEASE PELLETS
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

BOXED WARNING WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions ( 5.1 )]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [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 children, adolescents, and young adults taking antidepressants ( 5.1 )
  • Monitor for worsening and emergence of suicidal thoughts and behaviors ( 5.1 )

    • Description

    11 DESCRIPTION Duloxetine delayed-release capsules, USP are a selective serotonin and norepinephrine reuptake inhibitor (SNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C 18 H 19 NOS

  • HCl, which corresponds to a molecular weight of 333.88. The structural formula is: Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water. Each capsule contains enteric-coated pellets of 20, 30, or 60 mg of duloxetine (equivalent to 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride, respectively). These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hypromellose phthalate, sodium lauryl sulfate, polyethylene glycol, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow. str

    • What Is Duloxetine Hydrochloride Used For?

    1 INDICATIONS & USAGE 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
  • Chronic musculoskeletal pain in adults 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

    2 DOSAGE & 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 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

  • Discontinuing duloxetine delayed-release capsules: Gradually reduce dosage to avoid discontinuation symptoms ( 2.8 , 5.7 ) 2.1 Important Administration Instructions Administer duloxetine delayed-release capsules orally (with or without meals) and swallow whole. Do not chew or crush, and do not open the delayed-release capsule and sprinkle its contents on food or mix with liquids because these actions might affect the enteric coating. If a dose of duloxetine delayed-release capsules 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 duloxetine delayed-release capsules at the same time. 2.2 Dosage for Treatment of Major Depressive Disorder in Adults The recommended starting dosage in adults with MDD is 40 mg/day (given as 20 mg twice daily) to 60 mg/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 duloxetine delayed-release capsules before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment. 2.3 Dosage 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 duloxetine delayed-release capsules 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 duloxetine 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/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. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dosage for such treatment....

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling:

  • Suicidal Thoughts and Behaviors in Children, 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 : decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc., at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical 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, one treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%,73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively. Most patients received duloxetine delayed-release capsules dosages of a total of 60 to 120 mg per day [see Clinical Studies (14)]. The data below do not include results of the trial that evaluated the efficacy of duloxetine delayed-release capsules for the treatment of GAD in patients ≥65 years old (Study GAD-5) [see Clinical Studies ( 14.3 )]; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population. Adverse Reactions Leading to Treatment Discontinuation in Adult Placebo-Controlled Trials Major Depressive Disorder Approximately 8.4% (319/3779) of 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 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 treated patients and at a rate of at least twice that of placebo-treated patients). Generalized Anxiety Disorder Approximately 13.7% (139/1018) of the...

    • Drug Interactions

    7 DRUG INTERACTIONS Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

  • Potent inhibitors of CYP1A2 should be avoided ( 7.1 ).
  • Potent inhibitors of CYP2D6 may increase duloxetine concentrations ( 7.2 ).
  • Duloxetine is a moderate inhibitor of CYP2D6 ( 7.9 ). 7.1 Inhibitors of CYP1A2 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. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions ( 5.12 )]. 7.2 Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions ( 5.12 )]. 7.3 Dual Inhibition of CYP1A2 and CYP2D6 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 C max. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUC τ,ss , C max,ss or t max , ss ) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see Warnings and Precautions ( 5.5 )]. 7.5 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. 7.6 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. 7.7 Drugs that...

    • Contraindications

    4 CONTRAINDICATIONS 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 are 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 )].

  • Concomitant use of an MAOI antidepressant with duloxetine delayed-release capsules is contraindicated
  • Use of duloxetine delayed-release capsules within 14 days of stopping an MAOI antidepressant is contraindicated.
  • In linezolid-or intravenous methylene blue-treated patients, initiation of duloxetine delayed-release capsules is contraindicated ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy 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/m2 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/m2 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....

    Overdosage

    10 OVERDOSAGE 10.1 Signs and Symptoms In postmarketing experience, fatal outcomes have been reported for acute duloxetine overdoses, primarily with mixed overdoses, but also with duloxetine only, including 1000 mg of duloxetine (approximately 8.3 times the maximum recommended dosage). Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence,coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. 10.2 Management of Overdose There is no specific antidote to a duloxetine overdosage, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose with duloxetine, treatment should consist of those general measures employed in the management of overdose with any drug, such as assuring an adequate airway, oxygenation, and ventilation and monitoring cardiac rhythm and vital signs. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Induction of emesis is not recommended. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease duloxetine AUC and Cmax by an average of one-third, although some patients had a limited effect of activated charcoal. Due to the large volume of distribution of duloxetine, forced diuresis,dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who overdose with duloxetine and tricyclic antidepressants. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation...

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Duloxetine delayed-release capsules USP, 20 mg are opaque green cap / opaque green body, size ‘4’ capsules containing, white to off white coloured pellets with “C84” on cap imprinted with black ink. Bottles of 60 NDC 33342-160-09 Bottles of 90 NDC 33342-160-10 Bottles of 1,000 NDC 33342-160-44 100 (10 x 10 Unit-dose Capsules) NDC 33342-160-12 Duloxetine delayed-release capsules USP, 30 mg are opaque blue cap / opaque white body, size ‘3’ capsules containing, white to off white coloured pellets with “C83” on cap imprinted with white ink. Bottles of 30 NDC 33342-161-07 Bottles of 90 NDC 33342-161-10 Bottles of 1,000 NDC 33342-161-44 100 (10 x 10 Unit-dose Capsules) NDC 33342-161-12 Duloxetine delayed-release capsules USP, 60 mg are opaque blue cap / opaque green body, size ‘1’ capsules containing, white to off white coloured pellets with “C81” on cap imprinted with white ink. Bottles of 30 NDC 33342-162-07 Bottles of 90 NDC 33342-162-10 Bottles of 1,000 NDC 33342-162-44 100 (10 x 10 Unit-dose Capsules) NDC 33342-162-12 16.2 Storage and Handling 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].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.