The document compares Savella and Cymbalta for the treatment of fibromyalgia. Both drugs were shown to be effective in randomized controlled trials. Savella demonstrated significant improvements in pain and response rates compared to placebo in two large multicenter trials. Cymbalta also demonstrated efficacy in treating fibromyalgia. Overall, both drugs provide benefit for fibromyalgia patients but Savella may have a slightly lower cost and less severe side effects. The pharmacy and therapeutics committee will need to decide whether additional benefits of one drug outweighs the other for their formulary needs.

1. Savellavs. Cymbaltain the management ofFibromyalgia The pharmacy and Therapeutics Committee Munzur Morshed, Pharm D. candidate 2011Arnold & Marie Schwartz College of Pharmacy and Health Sciences of The Long Island UniversityThe International Drug Information Center July 09, 2010

2. What is Fibromyalgia? Chronic disorder affecting 5 million Americans A combination of neuropsychiatric and musculoskeletal disorder Pain and stiffness of the muscles Does not damage the joint or organs Female : Male-9:1

3. Symptoms

4. Etiology Stress and stress-related disorders PTSD IBS Depression Alteration of HPA axis secondary to stress-related disorders Low level of AM cortisol level and elevated level of evening Cortisol Development of widespread pain Disruption of dopamine related neurotransmission Dysfunction in serotonin metabolism Central Sensitization theory Decrease pain threshold due to increase sensitization of the brain to pain stimulus

5. Diagnosis

6. FDA approved management options

7. Comparisons of two management options

8. Savella Vs. Cymbalta

9. FDA and Non-FDA Indications Cymbalta savella

10. Doses

11. Doses- Cymbalta

12. Pharmacokinetics

13. Pharmacokinetics cont…

14. Warnings

15. Precautions

16. Adverse Drug Reactions- Savella

17. Adverse Drug Reactions- Cymbalta

18. Drug Interactions

19. Drug Interactions

20. Cost Comparisons

21. Cost Comparisons

22. Clinical Trial #1: Milnacipran for the Treatment of Fibromyalgia in Adults: A 15-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Clinical Trial Purpose To evaluate whether or not milnacipran(Savella) is efficacious and tolerable in treating patients with fibromyalgia and fibromyalgia pain

23. Clinical Trial #1: Milnacipran for the Treatment of Fibromyalgia in Adults: A 15-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Clinical Trial cont…. Methods Randomized, multicenter, double-blind, placebo-controlled, 3 arm, parallel-group design 86 centers throughout the United States from November 29,2004 to December 18,2006 1207 patients were randomized among three groups About 400 patients per group Group1- 100mg/d; Group2-200mg/d; group 3-placebo Doses were titrated in the 100mg dose group; No titration were performed in the 200mg dose group A four week washout period followed prior to start of the trial drug

24. Clinical Trial #1: Milnacipran for the Treatment of Fibromyalgia in Adults: A 15-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Clinical Trial cont…. Endpoints Primary Endpoint Fibromyalgia composite responder rate at week 15 The mean morning recall pain scores Rating of global impression of change due to tx. Change in physical function Fibromyalgia pain responder rate Secondary Endpoint Length of time or the time weighted average of the individual components of the composite responder rate

25. Clinical Trial #1: Milnacipran for the Treatment of Fibromyalgia in Adults: A 15-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Clinical Trial cont…. Results Response rate of the doses that were used had double the response rate of the placebo group milnacipran 100mg/d, P=0.002; milnacipran 200mg/d, P< 0.001 Greater improvement in pain score milnacipran 100mg/d,P= 0.001; milnacipran 200mg/d, P<0.001 Large number of patients had rated their status as a “very much improved or much improved” after 15 weeks milnacipran 100mg/d=48.3%; milnacipran 200mg/d= 51.0%; placebo= 32.9% For secondary endpoints- significant improvements in the time weighted averages of the weekly morning recall pain scores (P<0.001)

26. Clinical Trial #1: Milnacipran for the Treatment of Fibromyalgia in Adults: A 15-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Clinical Trial cont…. Conclusion Both doses of 100 and 200 mg/d of Savellasignificant improvements in FM and rate of response to pain Strong study- randomized, double-blind, multicenter, placebo-controlled trial Study had met power of 80% Weakness- funded by manufacturer + MD’s are employers of manufacturer

27. Clinical Trial #2: A European Multicenter Randomized Double-blind Placebo-controlled Monotherapy Clinical Trial of Milnacipran in Treatment of Fibromyalgia Purpose To confirm the efficacy and safety of milnacipran 200mg/d for the treatment of FM among European populations

28. Clinical Trial #2: A European Multicenter Randomized Double-blind Placebo-controlled Monotherapy Clinical Trial of Milnacipran in Treatment of Fibromyalgia cont… Methods Randomized, double-blind, placebo-controlled 89 outpt. clinical/research centers in 13 European countries 1406 patients screened; 884 randomized via 1:1 ratio among placebo and milnacipran group Similar baseline characteristics among both groups 4 week wash out period followed prior to initiation of therapy Doses were titrated over 4 weeks up to 200mg/d

29. Clinical Trial #2: A European Multicenter Randomized Double-blind Placebo-controlled Monotherapy Clinical Trial of Milnacipran in Treatment of Fibromyalgia cont… Endpoints Primary endpoints % of patient who had greater than 30% improvement from baseline in the pain visual analog scale(VAS) Rating’s of “very much or much improved” in the Patients Global Impression of Change(PGIC) scale Secondary endpoints Composite of endpoints that looked at the individual components of the primary endpoints Adverse event rates

30. Clinical Trial #2: A European Multicenter Randomized Double-blind Placebo-controlled Monotherapy Clinical Trial of Milnacipran in Treatment of Fibromyalgia cont… Results Primary Endpoints The number of patients that had a greater than 30% improvement in pain from baseline were much greater compared to the placebo group 38.6% vs. 30.0%, p=0.007, OR 1.48, 95% CI 1.41-2.60 Patients rating of “very much or much improved” was also significantly higher than the placebo group 33.3% vs. 20.6%; p< 0.0001, OR 1.92, 95% CI 1.41-2.60 Secondary Endpoints Improvements in the individual components of the VAS or the PGIC scores, found to be statistically significant in the treatment group compared to the placebo 93% of the ADR’s were mild to moderate among both groups

31. Clinical Trial #2: A European Multicenter Randomized Double-blind Placebo-controlled Monotherapy Clinical Trial of Milnacipran in Treatment of Fibromyalgia cont… Conclusion Milnacipran is safe and effective among patients in the European population Can correlate the result to American population due to the equivalence in efficacy and tolerability among both populations Strength randomized, double-blind, placebo controlled large sample size and longer time frame Weakness authors had received grant from the sponsor of the study some authors were employees of the sponsored group

32. Consideration for formulary- Savella

33. Weight of Balance-Savella

34. Consideration for formulary-Cymbalta

35. Weight of Balance-Cymbalta

37. Formulary Choice

38. Thank You!

39. References MICROMEDEX Healthcare Series: Micromedex, Greenwood Village, Colorado. Updated June 8th, 2010. Lexi-Comp Online (database online). Hudson, Oh; Lexi-Comp; 2010. Updated June 30th, 2010. Forest Pharmaceuticals. Savella (milnacipran).Forest Pharmaceuticals, 2010. Available at http://www.frx.com/products/savella.aspx. Accessed on July 02,2010 Savella (package insert) St. Louis, MO: Forest Pharmaceuticals, 2009. Cymbalta (package insert) Indianapolis, IN: Eli and Lilly and co. 2004. Branco JC, Zachrisson O, Perrot S, Mainguy Y. A European Multicenter Randomized Double-blind Placebo-controlled Monotherapy Clinical Trial of Milnacipran in Treatment of Fibromyalgia. The Journal of Rhematology, 2010; 37(4); 851-859. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the Treatment of Fibromyalgia in Adults: A 15-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Clinical Trial. Clin. Therap.2008;30(11); 1988-2004. Red Book ( database online).Montvale, NJ; Thompson Healthcare;2010. WebMD.Fibromyalgia,2o1o. Available at http://www.webmd.com/fibromyalgia/guide/fibromyalgia-overview-facts