Description

Simple

A medication used to treat depression, anxiety, nerve pain, and incontinence.

Clinical

A serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence.

Overview

Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor.[label] It was originally discovered in 1993 and developed by Eli Lilly and Company as LY248686.[15] Duloxetine first received approval from the FDA in August, 2004 as Cymbalta for the treatment of Major Depressive Disorder.[20] It has since received approval for a variety of indications including the treatment of neuropathic pain, Generalized Anxiety disorder, osteoarthritis, and stress incontinence. Duloxetine continues to be investigated for the treatment of pain in cancer, surgery, and more.

Pharmacology

Indication

**Indicated** for:

1) Management of Major Depressive Disorder.[label]

2) Management of Generalized Anxiety Disorder.[label]

3) Management of diabetic peripheral neuropathy.[label]

4) Management of fibromyalgia.[label]

5) Management of chronic musculoskeletal pain.[label]

6) Managem... Read more

Pharmacodynamic

Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter.[ Read more

Mechanism of action

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake.[ Read more

Absorption

Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%.[ Read more

Protein binding

Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein.[label, Read more

Volume of distribution

Apparent Vd of 1620-1800 L.[label,7] Duloxetine cr... Read more

Clearance

There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h.[ Read more

Half life

Mean of 12 h with a range of 8-17.[label,7]

Route of elimination

About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites.[label] Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite.[label, Read more

Toxicity

**Overdose**

Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone.[label] Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and t... Read more

Adverse Effects

Contraindications

  • Route:
    • Oral
  • Dose Form:
    • Capsule, delayed release pellets
  • Recommended Actions:
    • Avoid use
  • Regions: EU
  • Patient Conditions:
      • Name: Uncontrolled Hypertension
      • Drugbank Id: DBCOND0043537
  • Route:
    • Oral
  • Dose Form:
    • Capsule, delayed release pellets
  • Recommended Actions:
    • Avoid use
  • Regions: Canada
  • Patient Conditions:
      • Name: Severe Renal Impairment
      • Drugbank Id: DBCOND0045819
      • Modification Of:
        • Base:
          • Name: Renal Impairment
          • Drugbank Id: DBCOND0031781
        • Severity:
          • Includes:
            • severe
  • Route:
    • Oral
  • Dose Form:
    • Capsule, delayed release pellets
  • Recommended Actions:
    • Avoid use
  • Regions: Canada
  • Patient Conditions:
      • Name: Uncontrolled narrow-angle glaucoma
      • Drugbank Id: DBCOND0107497
  • Route:
    • Oral
  • Dose Form:
    • Capsule, delayed release pellets
  • Recommended Actions:
    • Avoid use
  • Regions: Canada
  • Patient Conditions:
      • Name: Hepatic Impairment
      • Drugbank Id: DBCOND0031585
  • Route:
    • Oral
  • Dose Form:
    • Capsule, delayed release pellets
  • Recommended Actions:
    • Avoid use
  • Regions: Canada
  • With Drugs:
      • Name: Thioridazine
      • Drugbank Id: DB00679
  • Route:
    • Oral
  • Dose Form:
    • Capsule, delayed release pellets
  • Recommended Actions:
    • Avoid use
  • Regions: Canada
  • With Categories:
      • Name: Cytochrome P-450 CYP1A2 Inhibitors
      • Drugbank Id: DBCAT000402
      • Mesh Id: D065609
  • Route:
    • Oral
  • Dose Form:
    • Capsule, delayed release pellets
  • Recommended Actions:
    • discontinue
  • Sex Group: all
  • Regions: US
  • With Categories:
      • Name: Monoamine Oxidase Inhibitors
      • Drugbank Id: DBCAT001004
      • Mesh Id: D008996

Food Interactions

  • Avoid excessive or chronic alcohol consumption. Alcohol increases the risk of liver toxicity.
  • Take with or without food. Administration with food slightly alters absorption, but not to a clinically significant extent.

Interactions

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  • Paracetamol(acetaminophen)
  • Paxil(paroxetine)
  • Pamelor(nortriptyline)
  • Panadol(acetaminophen)
  • Patanol(olopatadine ophthalmic)
  • Pataday(olopatadine ophthalmic)
  • Parnate(tranylcypromine)
  • Pazeo(olopatadine ophthalmic)
(R)-warfarin
The serum concentration of (R)-warfarin can be increased when it is combined with Duloxetine.
(S)-Warfarin
The serum concentration of (S)-Warfarin can be increased when it is combined with Duloxetine.
1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine
The metabolism of Duloxetine can be decreased when combined with 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine.
2,4-thiazolidinedione
The risk or severity of hypoglycemia can be increased when Duloxetine is combined with 2,4-thiazolidinedione.
2,5-Dimethoxy-4-ethylamphetamine
The risk or severity of serotonin syndrome can be increased when Duloxetine is combined with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamine
The risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Duloxetine.
3,5-diiodothyropropionic acid
The therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Duloxetine.
3,5-Diiodotyrosine
The therapeutic efficacy of 3,5-Diiodotyrosine can be decreased when used in combination with Duloxetine.
4-Bromo-2,5-dimethoxyamphetamine
The risk or severity of adverse effects can be increased when Duloxetine is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-Bromo-2,5-dimethoxyphenethylamine
Duloxetine may increase the tachycardic activities of 4-Bromo-2,5-dimethoxyphenethylamine.
4-hydroxycoumarin
The risk or severity of hemorrhage can be increased when Duloxetine is combined with 4-hydroxycoumarin.
4-Methoxyamphetamine
The metabolism of 4-Methoxyamphetamine can be decreased when combined with Duloxetine.
5-methoxy-N,N-dimethyltryptamine
The metabolism of Duloxetine can be decreased when combined with 5-methoxy-N,N-dimethyltryptamine.
6-Deoxyerythronolide B
The metabolism of Duloxetine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanine
The metabolism of 6-O-benzylguanine can be decreased when combined with Duloxetine.
7-ethyl-10-hydroxycamptothecin
The metabolism of Duloxetine can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
7-Nitroindazole
The risk or severity of adverse effects can be increased when Duloxetine is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the serotonergic activities of Duloxetine.
8-azaguanine
The metabolism of 8-azaguanine can be decreased when combined with Duloxetine.
8-chlorotheophylline
The metabolism of 8-chlorotheophylline can be decreased when combined with Duloxetine.
20 References
  1. 1 . Turcotte JE, Debonnel G, de Montigny C, Hebert C, Blier P: Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology. 2001 May;24(5):511-21.PubMed: 11282251
  2. 2 . Anttila S, Leinonen E: Duloxetine Eli Lilly. Curr Opin Investig Drugs. 2002 Aug;3(8):1217-21.PubMed: 12211418
  3. 3 . Karpa KD, Cavanaugh JE, Lakoski JM: Duloxetine pharmacology: profile of a dual monoamine modulator. CNS Drug Rev. 2002 Winter;8(4):361-76.PubMed: 12481192
  4. 4 . van Groeningen CJ, Peters GJ, Pinedo HM: Lack of effectiveness of combined 5-fluorouracil and leucovorin in patients with 5-fluorouracil-resistant advanced colorectal cancer. Eur J Cancer Clin Oncol. 1989 Jan;25(1):45-9.PubMed: 2784100
  5. 5 . Jost W, Marsalek P: Duloxetine: mechanism of action at the lower urinary tract and Onuf's nucleus. Clin Auton Res. 2004 Aug;14(4):220-7.PubMed: 15316838
  6. 6 . Carter NJ, McCormack PL: Duloxetine: a review of its use in the treatment of generalized anxiety disorder. CNS Drugs. 2009;23(6):523-41. doi: 10.2165/00023210-200923060-00006.PubMed: 19480470
  7. 7 . Knadler MP, Lobo E, Chappell J, Bergstrom R: Duloxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet. 2011 May;50(5):281-94. doi: 10.2165/11539240-000000000-00000.PubMed: 21366359
  8. 8 . Hershman DL, Lacchetti C, Loprinzi CL: Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2014 Nov;10(6):e421-e424. doi: 10.1200/JOP.2014.001776.PubMed: 29424607
  9. 9 . de Groat WC, Yoshimura N: Pharmacology of the lower urinary tract. Annu Rev Pharmacol Toxicol. 2001;41:691-721. doi: 10.1146/annurev.pharmtox.41.1.691.PubMed: 11264473
  10. 10 . Thor KB, Kirby M, Viktrup L: Serotonin and noradrenaline involvement in urinary incontinence, depression and pain: scientific basis for overlapping clinical efficacy from a single drug, duloxetine. Int J Clin Pract. 2007 Aug;61(8):1349-55. doi: 10.1111/j.1742-1241.2007.01433.x. Epub 2007 Jun 30.PubMed: 17608681
  11. 11 . Basu M, Duckett J: The treatment of urinary incontinence with Duloxetine. J Obstet Gynaecol. 2008 Feb;28(2):166-9. doi: 10.1080/01443610801912931.PubMed: 18393011
  12. 12 . Millan MJ: Descending control of pain. Prog Neurobiol. 2002 Apr;66(6):355-474.PubMed: 12034378
  13. 13 . Bellingham GA, Peng PW: Duloxetine: a review of its pharmacology and use in chronic pain management. Reg Anesth Pain Med. 2010 May-Jun;35(3):294-303. doi: 10.1097/AAP.0b013e3181df2645.PubMed: 20921842
  14. 14 . Gupta S, Nihalani N, Masand P: Duloxetine: review of its pharmacology, and therapeutic use in depression and other psychiatric disorders. Ann Clin Psychiatry. 2007 Apr-Jun;19(2):125-32. doi: 10.1080/10401230701333319.PubMed: 17612852
  15. 15 . Wong DT, Bymaster FP, Mayle DA, Reid LR, Krushinski JH, Robertson DW: LY248686, a new inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology. 1993 Jan;8(1):23-33. doi: 10.1038/npp.1993.4.PubMed: 8424846
  16. 16 . David R. Sibley; Lisa A. Hazelwood; Susan G. Amara (2018). 13. In Goodman & Gilman's: The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education.
  17. 17 . Cymbalta Health Canada Monograph Link
  18. 18 . Yentreve EMA SmPC Link
  19. 19 . EAU Stress Urinary Incontinence Guidelines Link
  20. 20 . Original FDA Label Cymbalta Link