Brand Name:  CYMBALTA

Generic Name:  duloxetine hydrochloride

Manufacturer:  Eli Lilly and Company

Drug Class:  Duloxetine is a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SSNRI) type antidepressant.

Uses:

            Labeled: Duloxetine is indicated for the treatment of major depressive disorder (MDD), as well as management of diabetic peripheral neuropathic pain, as these conditions respond to treatment with both NE and 5-HT. ^1,3,4,16

Unlabeled: Duloxetine may be effective in treating stress urinary incontinence, and also in other pain associated with depression. Studies are under way.^{2,3,4,10,11,12}

Mechanism of Action: Duloxetine is a potent inhibitor of both 5-HT and NE reuptake, and a less potent inhibitor of dopamine reuptake.  Although its exact mechanism is not known, it is believed to be related to the potentiation of activity of these chemicals in the central nervous system (CNS).  Duloxetine has no monoamine oxidase inhibitor (MAO-I) activity. ^1-5

Pharmacokinetics: ^1-5

Metabolism is hepatic via CYP1A2 and 2D6, which form inactive metabolites.  Elimination is mainly through the urine (70%) and feces (20%).  Trace amounts (<1% of the dose) of unchanged duloxetine is excreted in the urine.

Selected Pharmacokinetic Data:

*Absolute data unavailable.  Figure is based on urinary excretion.¹⁷

Efficacy:

Duloxetine in the treatment of major depression disorder: a double-blinded clinical trial^.6

Study design: This study was an 8-week, multicenter double blind, placebo-controlled study, with parallel treatment groups.

Study description: This study’s purpose was to assess the effectiveness of duloxetine during 8 weeks of treatment.  The primary efficacy measure was the HAM-D-17 total score.

Results: Duloxetine was superior to placebo in change on the HAM-D-17 score.  Response and remission were reported at 64% and 56% respectively for duloxetine, as compared with 48% and 32% for placebo.  Duloxetine was well-tolerated, as 76% of patients reached the maximum dose, with insomnia and asthenia as the only statistically significant adverse events (p<0.05) reported more frequently than placebo.

Limitations: The study only used a small number of patients (173) assigned in a 2:2:1 ratio to duloxetine (N=70), placebo (N=70), and fluoxetine (N=33).  This only produced a power of 65%.  Additionally, Lilly funded this study, which may have added further bias.

Conclusion: Duloxetine is efficacious for the treatment of major depressive disorder, and is well tolerated and safe.

Duloxetine, 60mg once daily, for major depressive disorder (MDD): a randomized double-blind placebo-controlled trial.⁷

Study design: This study was a multicenter double blind, placebo-controlled parallel group study.

Study description: The purpose of this study was to determine the efficacy of a once daily dose of 60mg of duloxetine, as compared to placebo.  Efficacy measure was the HAM-D-17 score, and the Visual Pain Scale.

Results: Duloxetine was significantly superior (p<0.001) to placebo in reducing the HAM-D-17 scores.  The probability of remission in the duloxetine group was 44%, and was almost 3 times greater than the placebo group (16%).  Duloxetine treated patients had significantly greater improvement on all 5 of the assessed subfactors of the HAM-D-17 (anxiety, core, retardation, Maier, and sleep).  Nausea, dry mouth, and somnolence were the most common adverse effects.  17 duloxetine patients and 3 placebo patients withdrew due to adverse effects.

Limitations: This study was funded by Lilly and performed by its employees, which may introduce bias.  Patients were self-medicating, meaning dosages may have been missed or otherwise inaccurate. 

Conclusion: Duloxetine dosed at 60mg/day in a single dose is a well-tolerated and effective treatment for MDD and its associated painful physical symptoms.

Duloxetine in the long-term treatment of major depressive disorder (MDD).⁸

Study design: This study was an open-label, 52-week multinational clinical trial.

Study description: The purpose of this study was to determine the efficacy of duloxetine at various doses in long-term treatment.  The primary outcome of the study was to evaluate the safety of duloxetine, 40mg bid to 60mg bid, in patients with MDD.  Secondary outcomes evaluated long-term efficacy and patient quality of life.

Results: All dosages studied of duloxetine showed highly significant (p<0.001) improvements in all assessments, with improvements in the two scales rated at week 1 as 40.4% and 59.2%, and 50.8% and 75.6% in the 52^nd week.

Limitations: This trial was open-label, which can introduce bias.  The study was performed among outpatients, so it was relying upon their assurances that their medication regimen was followed.  Additionally, at the time of the study, all authors were employed by Lilly, who also funded the study, adding to the chance of bias.  Also, a majority of patients discontinued treatment for various reasons.

Conclusion: Duloxetine was found to be safe and well tolerated in the long-term treatment of MDD at a dose of 80-120mg/day.

Adverse Effects:

Adverse effects of duloxetine include:  Nausea (20%); xerostomia (15%); constipation (11%); insomnia (11%); dizziness (9%); fatigue (8%); decreased appetite (8%); diarrhea (8%); somnolence (7%); increased sweating (6%); vomiting (5%); blurred vision (4%); erectile dysfunction  (4%); anxiety (3%); tremors (3%); decreased libido (3%); abnormal orgasm (3%); delayed ejaculation (3%); hot flushes (2%); and decreased weight (2%).^1-4

Drug Interactions:

Monoamine oxidase inhibitors and linezolid:  serotonin syndrome (hyperpyrexia, hypertension, tachycardia, confusion, seizures, and death).

Thioridazine:  serum thioridazine concentrations may increase, causing malignant ventricular arrhythmias

Tricyclic antidepressants:  serum tricyclic antidepressant levels/effects may be increased.

Buspirone, meperidine, moclobemide, nefazodone, the SSRI’s, sibutramine, tramadol, trazadone, venlafaxine, and selegiline: may cause serotonin syndrome.

Sumatriptan and other serotonin agonists: may cause weakness, hyperreflexia, and incoordination.

CYP1A2 and CYP2D6 inhibitors: may increase the levels/effects of duloxetine.

CYP1A2 inducers: may decrease the levels/effects of duloxetine.

Ethanol: may increase CNS depression and hepatotoxic potential of duloxetine.

Valerian, St.John’s Wort, SAMe, kava kava, and gatu kola:  may increase CNS depression. ^1-4

Dosage/Administration:

            Usual dosage: 40-60mg orally every day. Dose may be divided into 20-30mg bid or given as a single dose.  Maximum dose is 60mg/day for treatment of depression.  Off-label use dosages include:  60-120mg/day for diabetic neuropathy, 60mg daily for chronic pain management; and 80mg daily for management of stress urinary incontinence.  Capsules should be swallowed whole.  Do not crush or break open cap.

            Geriatric Dose: Same as the adult dosing, no adjustment is required.

            Pediatric use:  Has not been established, and is not recommended.

            Renal/Hepatic impairment: Duloxetine is not recommended for use in patients with renal or hepatic impairment. ^1-4

Conclusion:

Duloxetine is both safe and effective in treating major depressive disorder in adults.  Duloxetine is known as a “dual inhibitor” which seems to offer higher efficacy in treating depression than either 5-HT or NE reuptake inhibitors alone.  Duloxetine is also showing promise in treating diabetic neuropathy, chronic pain syndromes, and stress urinary incontinence.  Study is currently under way in these areas, and may prove duloxetine to be a very versatile and effective multi-indication drug. ^1-15

REFERENCES:

1.                  Cymbalta (duloxetine) packaging insert, Eli Lilly and Company, August 2004

2.                  Fact Sheet for Cymbalta (duloxetine) drug representatives, Eli Lilly and Co.

3.                  Lexi-Comp; Lexi-Drugs for PDA, updated August 31, 2004

4.                  Clinical Pharmacology 2000, on-line version, access provided through SOLE

5.                  Sharma A, Goldberg M, Cerimele B, Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor.  J Clin Pharmacol 2000; Feb; 40(2) pp 161-167.

6.                  Goldstein D, Mallinckrodt C, et al, Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial.  J Clin Psychiatry 63:3 March 2002, pp 225-231.

7.                  Detke M, Lu Y, Goldstein D, et al, Duloxetine, 60mg once daily for major depressive disorder: a randomized double-blind placebo-controlled trial.  J Clin Psychiatry 63:4 April 2002, pp 308-315.

8.                  Raskin J, Goldstein D, Mallinckrodt C, et al, Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry 64:10 October 2003, pp 1237-1244.

9.                  Schatzberg A, Efficacy and tolerability of duloxetine, a novel dual reuptake inhibitor, in the treatment of major depressive disorder. J Clin Psychiatry 64(suppl 13) 2003, pp 30-37.

10.              van Kerrebroeck P, Duloxetine: an innovative approach for treating stress urinary incontinence. British Journal of Urology 94(suppl 1) 2004, pp 31-37.

11.              Millard RJ, Moore K, et al, Duloxetine vs. placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. British Journal of Urology 93:2004, pp 311-318.

12.              van Kerrebroeck P, Abrams P, et al, Duloxetine vs. placebo in the treatment of European and Canadian women with stress urinary incontinence.  British Journal of Obstetrics and Gynaecology 11:March 2004, pp 249-257.

13.              Goldstein DJ, Lu Y, Detke MJ, et al, Effects of duloxetine on painful physical symptoms associated with depression. Psychosomatics 2004: Jan-Feb; 45(1) pp 17-28.

14.              Goldstein D, Iyengar S, Mallinckrodt C, et al, Duloxetine: a potential new treatment for depressed patients with comorbid pain. Pain Med. 2002 Jun; 3(2) p 177.

15.              Briley M, New hope in the treatment of painful symptoms in depression. Curr Opin Investig Drugs. 2003 Jan;4(1) pp 42-45.

16.              FDA press release; New indication for Cymbalta (duloxetine) for neuropathic pain.  For immediate release, September 7, 2004.  www.fda.gov accessed 9/7/2004.

17.              MicroMedex Electronic Database; DrugDex (Cymbalta) [pharmacokinetics].  Accessed 9/7/2004.

By: Joe Grimes, Pharm D Candidate