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Yentreve (duloxetine)



Conclusion

Yentreve (duloxetine) is the first drug (a SNRI) in Denmark, indicated for the treatment of stress urinary incontinence (SUI) for women, when conservative therapy is inefficient.

 

There are four positive RCT’s demonstrating significant efficacy of duloxetine and placebo, in reducing the amount of incontinence episodes per week. Two of the trials show an absolute median reduction in incontinence episodes of 7 and 6 per week in the duloxetine treated, compared to 3 in the placebo treated. Approximately 75% of the duloxetine treated and app. 55% of the placebo treated experienced at least one adverse effect, the most common was nausea (app. 25%), which after one week resolved in 50%, and after four weeks 80%. It is recommended to evaluate adverse effects after 2-4 weeks of treatment.

 

Duloxetine is being developed for the treatment of major depressive disorder.

Yentreve was released for use the 13th of September 2004.


Background

Duloxetine is indicated for the treatment of women with moderate to severe stress incontinence. The recommended dose of duloxetine is 40mg BID, taken without concern to meals. After 2-4 weeks, patients should be evaluated for adverse effects, and adverse effects lasting more than 4 weeks; doses adjustment to 20mg BID is an option, though the efficacy for this dose is not well documented.

 

Duloxetine is considerable oxidised by CYP1A2 and the polymorphic CYP2D6. There is great pharmacokinetic variation between patients (generally 50-60%), due to sex, age, smoking status and the CYP2D6 metabolising status. T½ average is 12 h (8-17h).

 

Dose adjustments are not necessary in mild to moderate renal impairment. Duloxetine should not be administered to women with impaired liver function. Caution is advised for the geriatric. When discontinuing medication after one week of treatment or more, it’s recommended to gradually reduce consumption to avoid symptoms such as vertigo. There is no evidence concerning the pregnant, and is not indicated when breast-feeding.


Efficacy

One 12-week fase-2 RCT examined the efficacy and safety of duloxetine on 553 patients with SUI. Patients were randomised to 4 groups: placebo, duloxetine 10, 40 and 80mg/dy. Primary efficacy: incontinence episode frequency, IEF, per week. The median IEF was reduced by 41% for placebo, 54% for duloxetine 20mg/dy (not significant), 59% for duloxetine 40 mg/dy. (p=0,002), and 64% for 80mg/dy. (p<0,001).

 

Three fase-3 RCT’s of 12-weeks duration, in different geographical world regions, North America (NA)(2), South America, Europe, Australia and South Africa (SEAS)(3); and also Canada and Europe (CE)(4); randomised in all 1.635 women with SUI to either duloxetine 40 mg BID or placebo. Primary efficacy measures: IEF per week and the Incontinence Quality of Life Questionnaire, I-QOL. The change in IEF is registered as median, because a few patients were extreme outliers. All the results were statistically significant (p0,05). 

 

Placebo

Duloxetine 40mg BID

Efficacy

NA trial

n = 339

SEAS trial

n = 231

CE trial

n = 247

NA trial

n = 344

SEAS trial

n = 227

CE trial

n = 247

IEF/wk. B

E

D

19,0*

13,4

-3

-29%

14,7

7,0

no data

-40%

14,0

9,0

-3,0

-29%

18,2*

9,1

-7

-50%

14,0

6,0

no data

-54%

13,0

7,0

-6,0

-50%

I-QOL B

E

D

64,3

71,1

6,8

58,3

64,7

6,4

64,4

68,5

4,1§

62,0

73,1

11,1

58,9

69,2

10,3

66,6

72,2

5,5§

B: Baseline. E: Endpoint.
*: registered as average IEF per week.
§ : not significant.

 

The duloxetine treated had a minimum 50% median reduction in IEF’s per week, compared to 29-40% of the placebo treated. Specifically the SEAS trial had a considerable placebo effect, perhaps because fewer patients (9%) practised pelvic floor muscle training, compared to the NA and CE trials (17-19%). The considerable placebo effect makes the clinical efficacy assessment of duloxetine more difficult, but is a well-known phenomenon in incontinence trials, patients benefitting form clinical control at using a incontinence diary. The NA and SEAS trials had a significant better I-QOL score among the duloxetine-treated, compared to placebo. The CE trial showed no significant effect of duloxetine on I-QOL scores.


Adverse effects

The amount of patients with at least one adverse effect was 50-64% of the placebo and 74-81% of the duloxetine treated. In average 72% of the duloxetine, and 90% of the placebo treated, completed the trial period of 12 weeks. The most frequent adverse effects showed in the table.

 

duloxetine, range

n = 818

placebo, range

n = 817

Procent discontinuing the trials

n = 1635

Nausea

23-28%

2-6%

3-6%

Fatigue

10-15%

4-10%

<1-3%

Insomnia

13-14%

1-2%

1-2%

Dry mouth

12-19%

1-2%

0-<1

Constipation

10-14%

2-4%

0-<1

Of the patients suffering from nausea, the nausea resolved after one and four weeks in 40-60%, and 75-85%, respectively.


Interactions

Caution is advised administering duloxetine with centrally active drugs (incl. alcohol drugs) and with serotonergic drugs such as, SSRI’s, tricyclic antidepressives, venlafaxine, triptanes and tramadol.


Price

Prices for the 27th of September 2004 are used. Yentreve is not subsidised.

Drug

Package

Recommended daily dose

Price per recommended daily dose

Yentreve (duloxetin)

20 mg, 56 stk.

40 mg, 56 stk.

40 mg, 140 stk.

80 mg

34,80

17,40

16,90

More information can be found at the following web site.
http://www.produktresume.dk/docushare/dscgi/ds.py/View/Collection-96

 

References

  1. Norton PA, Zinner NR, Yalcin I, Bump R. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol 2002;187:40-8.
  2. Dmochowski RR, Miklos JR, Norton PA, Zinner NR, Yalcin I et al. J Urol 2003;170:1259-63.
  3. Millard RJ, Moore K, Rencken R, Yalcin I, Bump RC for the Duloxetine UI Study Group. Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. Br J Urol Int 2004;93:311-18.
  4. Van Kerrebroeck P, Abrams P, Lange R, Slack M, Wyndaele J-J et al. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. BJOG 2004;111:249-57.

 



Last modified:
October 12th 2004


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