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Application for Inclusion on WHO Model List of Essential Medicines

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Application for Inclusion on WHO Model List of Essential Medicines 20th Expert Committee on the Selection and Use of Essential Medicines Geneva, 2015 PROPOSAL FOR THE INCLUSION OF MISOPROSTOL IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES Submitted on behalf of: Gynuity Health Projects, NY, USA Dina Abbas, MPH Jill Durocher Beverly Winikoff, MD,MPH Program Associate Senior Program Associate President [email protected] [email protected] [email protected] Gynuity Health Projects 15 East 26th Street, Suite 801 New York, NY 10010 Tel: (1) 212-448-1230 Fax: (1) 212-448-1260 Table of Contents 1. Summary Statement of the proposal for inclusion, change or deletion ..................................3 2. Name of the focal point in WHO submitting or supporting the application ..........................5 3. Name of organization(s) consulted and/or supporting the application ...................................5 4. International Nonproprietary Name (INN, generic name) of the medicine............................5 5. Formulation proposed for inclusion; including adult and pediatric (if appropriate) ...............5 6. International availability – sources, of possible manufacturers and trade names ...................5 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group ..........................................................................................................................................6 8. Information support the public health relevance ...................................................................6 8.1 Disease Burden ..................................................................................................................6 8.2 Treatment of PPH ..............................................................................................................8 8.3 Assessment of Current Use ................................................................................................8 8.4 Target Population ..............................................................................................................9 9. Treatment details ...............................................................................................................10 9.1 Dosage regimen and duration ..........................................................................................10 9.2 Reference to Existing WHO and Other Clinical Guidelines .............................................10 10. Summary of comparative effectiveness in a variety of clinical settings ...........................12 10.1 Randomized controlled trials testing the effect of misoprostol to treat PPH..............14 11. Summary of comparative evidence on safety ..................................................................18 11.1 Side effects after misoprostol .........................................................................................18 11.2 Misoprostol and breastfeeding .......................................................................................24 11.3 Misoprostol and maternal mortality ...............................................................................24 12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group ...............................................................................25 12.1 Range of Costs for the Proposed Medicine.....................................................................25 12.2 Comparative Cost-Effectiveness ....................................................................................26 13. Summary of regulatory status of the medicine ................................................................27 14. Availability of pharmacopoeial standards .......................................................................28 15. Proposed text that could be included in a revised WHO Model Formulary ......................28 16. References ......................................................................................................................29 17. Appendix A – Partial List of Misoprostol (200 μg tablet formulation) Trade Names ......37 Page 1 of 39 List of Tables and Figures Table 1 Estimates of maternal mortality ratio, number of maternal deaths, and lifetime risk, by United Nations MDG region, 2013 (WHO 2014) ........................................................................7 Table 2 Distribution of deaths caused by hemorrhage by region (Say et al 2014) ........................8 Table 3 List of selected clinical guidelines on misoprostol for PPH treatment .......................... 11 Table 4 Misoprostol as an adjunct to standard uterotonics for treatment of PPH: a multicentre, double-blind randomised trial (Widmer et al, 2010)................................................................... 15 Table 5 Adjunct Misoprostol for treating PPH: a randomized controlled trial (Hofmeyr et al, 2004) ........................................................................................................................................ 16 Table 6 Misoprostol in the treatment of PPH in addition to routine management: a placebo randomised controlled trial (Walraven et al, 2004) .................................................................... 16 Table 7 Misoprostol in addition to routine treatment of PPH: A hospital-based randomized- controlled trial in Karachi, Pakistan (Zuberi et al, 2008) ............................................................ 17 Table 8 Case reports and observational studies on misoprostol for PPH treatment .................... 17 Table 9 Comparison of PPH treatment outcomes with 600 and 800 sublingual misoprostol in women receiving prophylactic oxytocin (León et al, 2012; Blum et al, 2010) ............................ 18 Table 10 Rates of shivering and fever following first-line PPH treatment with 800 μg regimen of sublingual misoprostol .......................................................................................................... 21 Table 11 Rates of shivering and fever following treatment with an adjunct dose of sublingual misoprostol (600 μg ) * ............................................................................................................. 22 Table 12 Comparison of reported side effects (by provider) among Ecuadorian women given PPH treatment with sublingual misoprostol (600μg and 800μg )^ ............................................. 23 Table 13 Supplier price information (USD) for 200 μg misoprostol tablets ............................... 26 Table 14 Buyer price information (USD) for 200 μg misoprostol tablets .................................. 26 Figure 1 Mean misoprostol plasma concentrations after sublingual administration of misoprostol (800 micrograms), and mean temperatures over time of 58 cases of high fever following treatment with 800 μg sublingual misoprostol in Quito, Ecuador (Durocher et al, 2010) ........... 22 Figure 2 Average temperature trends for cases with high fever following 600 μg (n=8) and 800μg (n=58) doses of misoprostol for PPH treatment (León et al 2012) .................................. 24 Page 2 of 39 1. Summary Statement of the proposal for inclusion, change or deletion The data presented in the following report show that misoprostol is a safe, effective, and low cost option to treat postpartum hemorrhage (PPH) attributable to uterine atony. Results from two large, multi-country studies on PPH treatment comparing the efficacy of misoprostol to intravenous oxytocin, the gold standard for PPH treatment, confirmed that misoprostol effectively controlled excessive bleeding postpartum for 9 out 10 women suffering a hemorrhage (Winikoff 2010; Blum 2010). A recent Cochrane review on the treatment of primary PPH concluded that while oxytocin infusion works better than misoprostol, misoprostol can be used in settings where refrigeration and infusions are not readily available (Mousa 2014). This is relevant as recent research on uterotonic access has shown that even when oxytocin is available, shortages of syringes, needles, and IV infusion sets limit its proper use (Bazant 2013). Further, in many settings the quality of oxytocin is compromised as oxytocic products are often stored at room temperature, although refrigeration is necessary. In one study, 89% of the tested oxytocin and ergometrine ampoules did not meet the specifications for the active ingredient (Stanton 2012). Recognizing the challenges of making oxytocics available in all settings, in January 2014, the European Medicines Agency approved the first misoprostol product (Hemoprostol) for the treatment of PPH. Hemoprostol contains the active ingredient misoprostol and is manufactured by Linepharma, France. Following an in-depth review of the evidence, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive scientific opinion of Hemoprostol for the treatment of PPH in accordance with Article 58 of Regulation (EC) No. 726/2004. The approved dose is 800µg (200µg x 4 tablets) to be taken sublingually for treatment of PPH due to uterine atony where intravenous oxytocin is not available. The regulatory authorities decided that, although less effective than oxytocin, Hemoprostol has been shown to be safe and of benefit in the treatment of women with PPH and concluded this benefit outweighs any side effects associated with the drug, including transient shivering and fever, which commonly occur following its postpartum administration. Because of oxytocin’s widespread availability within the European Union, Hemoprostol
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