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duloxetine (Cymbalta, Yentreve, Drizalma Sprinkle)

Tradenames: Cymbalta, Yentreve. Generic approved Dec 2103. Indications: - depression* - urinary stress incontinence (Yentreve) - diabetic peripheral neuropathy [2] - chronic musculoskeletal pain [4], including - osteoarthritis* [14,15] - low back pain - fibromyalgia - chemotherapy-induced painful peripheral neuropathy (first line) [6] - generalized anxiety disorder [7] * on list of drugs to avoid for treatment of depression [9] - other antidepressants recommended [9] * no significant benefit for hip osteoarthritis or knee osteoarthritis Contraindications: 1) chronic liver disease or hepatic insufficiency 2) co-administration of monoamine oxidase inhibitors 3) uncontrolled narrow-angle glaucoma 4) renal insufficiency, eGFR < 30 mL/min Dosage: 1) 60 mg PO QD 2) taper to avoid withdrawal 3) maximum dose: 120 mg QD [12] Tabs: 20,30,60 mg Drizalma Sprinkle: - sprinkle formulation of delayed-release duloxetine capsules - 20, 30, 40, 60 mg Pharmacokinetics: 1) median 2 hours lag before absorption begins 2) maximal serum levels reached 6-10 hours after oral dosing 3) food does not affect availability but delays aborption 4) protein binding > 90%, to albumin & alpha-1 acid glycoprotein 5) volume of distribution 1640 L 4) metabolized by cyt P450 1A2 & cyt P340 2D6 5) elimination 1/2life 8-17 hours 6) no major differences seen in geriatric patients - elimination 1/2life 4 hours longer in elderly women Monitor: blood pressure Adverse effects: 1) similar to SSRIs & venlafaxine - SIADH 2) nausea, xerostomia, loss of appetite, constipation [4] 3) insomnia, fatigue, sexual dysfunction, dizziness, somnolence, 4) mydriasis, blurred vision (frequent), diplopia (infrequent) 5) hypertension, hyperhidrosis 6) serious adverse effects occur in < 1% of patients a) hepatic injury (including hepatitis & cholestatic jaundice) [3,4] b) allergic reactions: hives, rash, facial edema, anigoedema? c) pneumonia [4] d) depression, suicidal ideation [4] 7) may exacerbate restless legs syndrome (see venlafaxine) 8) may exacerbate periodic limb movment disorder (see venlafaxine) Drug interactions: 1) any drug that inhibits cyt P450 1A2 or cyt P450 2D6 may increase levels of duloxetine 2) any drug that induces cyt P450 1A2 or cyt P450 2D6 may decrease levels of duloxetine 3) duloxetine inhibits cyt P450 2D6 thus duloxetine may increase levels of drugs metabolized by cyt P450 2D6 4) may decrease metabolism of tricyclic antidepressants, thioridazine, propafenone Laboratory: - duloxetine in serum/plasma - duloxetine in urine Mechanism of action: 1) inhibits reuptake of serotonin & norepinephrine about equally 2) increases contractility of urethral sphincter 3) centrally-acting analgesic [16]

Interactions

drug interactions drug adverse effects (more general classes)

General

serotonin & norepinephrine reuptake inhibitor (SNRI, dual-acting reuptake inhibitor)

Properties

MISC-INFO: pregnancy-category C

Database Correlations

PUBCHEM correlations

References

  1. Prescriber's Letter 11(9): 2004 Comparison of Commonly Used Antidepressants Detail-Document#: 200901 (subscription needed) http://www.prescribersletter.com
  2. Prescriber's Letter 11(9): 2004 Duloxetine (Cymbalta) for Diabetic Peripheral Neuropathy Detail-Document#: 201004 (subscription needed) http://www.prescribersletter.com
  3. Medwatch http://www.fda.gov/medwatch/safety/2005/safety05.htm#Cymbalta - Prescriber's Letter 12(12): 2005 Liver function test scheduling Detail-Document#: 211210 (subscription needed) http://www.prescribersletter.com
  4. FDA News release, Nov. 4, 2010 FDA clears Cymbalta to treat chronic musculoskeletal pain http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm232708.htm
  5. Prescriber's Letter 17(12): 2010 Cymbalta (Duloxetine) for Chronic Pain Detail-Document#: 261202 (subscription needed) http://www.prescribersletter.com
  6. Smith EM et al Effect of Duloxetine on Pain, Function, and Quality of Life Among Patients With Chemotherapy-Induced Painful Peripheral Neuropathy. A Randomized Clinical Trial. JAMA. 2013;309(13):1359-1367 PMID: 23549581 http://jama.jamanetwork.com/article.aspx?articleid=1674238
  7. Deprecated Reference
  8. FDA News Release: Dec. 11, 2013 FDA approves first generic versions of antidepressant drug Cymbalta. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm378282.htm
  9. Therapeutics Letter #108. Therapeutics Initiative Drugs to Avoid. http://www.ti.ubc.ca/2018/01/04/108-drugs-avoid/
  10. A Pocket Guide to the 2019 Beer's Criteria. American Geriatrics Society.
  11. http://www.Cymbalta.com
  12. Drugc.com: Duloxetine https://www.drugs.com/ppa/duloxetine.html
  13. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115 PMID: 24385423 Review. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007115.pub3/full
  14. Sofat N, Harrison A, Russell M, et al. The effect of pregabalin or duloxetine on arthritis pain: a clinical and mechanistic study in people with hand osteoarthritis. J Pain Res. 2017;10:2437-2449 https://www.dovepress.com/the-effect-of-pregabalin-or-duloxetine-on-arthritis-pain-a-clinical-an-peer-reviewed-fulltext-article-JPR
  15. Uchio Y, Enomoto H, Alev L, et al. A randomized, double-blind, placebo-controlled phase III trial of duloxetine in Japanese patients with knee pain due to osteoarthritis. J Pain Res. 2018;11:809-821 https://www.dovepress.com/a-randomized-double-blind-placebo-controlled-phase-iii-trial-of-duloxe-peer-reviewed-fulltext-article-JPR
  16. Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  17. van den Driest JJ et al. No added value of duloxetine in patients with chronic pain due to hip or knee osteoarthritis: A cluster-randomized trial. Arthritis Rheumatol 2022 May; 74:818 PMID: 34989159 https://onlinelibrary.wiley.com/doi/10.1002/acr.24519 - Lenhard NK et al. Does screening for depressive symptoms help optimize duloxetine use in knee osteoarthritis patients with moderate pain? A cost-effectiveness analysis. Arthritis Rheumatol 2022 May; 74:776 PMID: 33253496 PMCID: PMC8164641 (available on 2023-05-01) https://onlinelibrary.wiley.com/doi/10.1002/acr.24519
  18. Highlights of Prescribing Information Cymbalta (duloxetine) delayed release capsules for oral use https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022516lbl.pdf