Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes

Publication date: 2019

Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes A Summary of Information on Recommended Uses, Contraindications, and Supply Chain Considerations for Program Managers and Procurement Managers September 2019 Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes 1 ACKNOWLEDGEMENTS This document was developed by the United States Agency for International Development (USAID) with support from the Global Health Supply Chain - Procurement and Supply Management project and Boston Consulting Group (BCG), in collaboration with the Reproductive Health Supplies Coalition’s Maternal Health Supplies Caucus. Special thanks to the following stakeholders for their thought leadership and input: Kabir Ahmed, UNFPA Jane Briggs, MTaPS Program1, Management Sciences for Health Jill Durocher, Gynuity Health Projects Laura Frye, Gynuity Health Projects Meena Gandhi, DFID Kathleen Hill, Maternal and Child Survival Program2, Jhpiego Sharif Hossain, Population Council Jeffrey Jacobs, Merck for Mothers, an initiative of Merck & Co., Inc. (U.S.A) Bonnie Keith, PATH Ian Roberts, London School of Hygiene & Tropical Medicine Fiona Theunissen, Concept Foundation Ingrid van Elderen, Ferring Pharmaceuticals Hans Vemer, Concept Foundation Mariana Widmer, WHO 1. Medicines,Technologies, and Pharmaceutical Services Program, funded by USAID; 2. Funded by USAID Post-partum hemorrhage (PPH)—or excessive bleeding after childbirth—continues to be one of the major causes of maternal mortality in low- and middle-income countries, accounting for over a quarter of maternal deaths worldwide. WHO recommends the administration of a prophylactic uterotonic immediately after birth for every woman to help prevent PPH caused by uterine atony (non-contracted uterus). WHO also recommends treatment of PPH with a therapeutic uterotonic and intravenous tranexamic acid (TXA), supplemented by additional interventions based on the cause of the bleeding and the woman’s clinical status (e.g., removal of retained placenta, repair of laceration, blood transfusion, aortic compression, and surgical intervention if bleeding is not controlled.) Some medicines for prevention and treatment of PPH have been well-known for decades (i.e., oxytocin, ergometrine, and misoprostol) while others are more recent additions. In 2018, WHO updated its PPH treatment recommendations to include the administration of tranexamic acid (TXA) via intravenous route within 3 hours of birth in women with PPH (regardless of the underlying cause of PPH). Also, in 2018, WHO updated its PPH prevention guidelines to include the use of heat-stable carbetocin (HSC) and to provide expanded guidance on the selection of uterotonics for PPH prevention. Some of the uterotonic medicines (oxytocin and misoprostol) have other obstetric uses such as induction and augmentation of labor, while others are actually contraindicated for these uses and may cause harm if used inappropriately. With an expanding “toolkit” of uterotonic medicines and TXA to prevent and treat PPH and for other obstetric uses, program managers need clear information in one place on the indications, contraindications, safety profile, and health system requirements for individual medicines to help them make strategic decisions about which medicine to deploy at different levels of the health system based on their country context. With recent innovations and WHO recommendations, there are now more medication options to prevent and treat post-partum hemorrhage (PPH). However, there is still no single solution for preventing and managing PPH. Countries must determine the appropriate combination of uterotonics, tranexamic acid (TXA), and other life-saving PPH prevention and treatment interventions for use at community, primary, and referral levels. Additionally, these medicines have other important obstetric uses which must be considered. This brief highlights key characteristics and supply chain considerations for individual uterotonic medicines and TXA that will be used to help program and procurement managers determine the most appropriate combination of medicines for prevention and treatment of PPH and other obstetric indications at different levels of the health system. Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes 2 INTRODUCTION BACKGROUND Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes 3 RECOMMENDED AUDIENCE PURPOSE This brief is intended to serve as a summary of information on the suite of uterotonics and TXA that can be used for the prevention and treatment of post-partum hemorrhage and other obstetric uses. This brief provides background information for the needs of program managers, especially supply chain managers, by summarizing the recommended uses for the medicines currently available and proven effective for prevention or treatment of PPH, other obstetric uses, and the special characteristics of each. These recommended uses and characteristics are elements that may influence procurement and supply chain management decisions. This brief is part of a larger document to guide decision-making around procurement of the appropriate medicines. It is important to note that this brief is not a replacement for clinical guidelines or global recommendations. Furthermore, this brief should not be interpreted as a job aid for healthcare personnel for the provision of care. This information summary is intended for use by those making procurement decisions, including program managers, supply chain managers, and procurement managers for consultation as they consider future procurement and supply chain needs. Within this audience, sample roles include, but are not limited to, Family Health Division Chief, Maternal and Child Health Program Manager, Supply Chain Manager, Logistics Management Division Chief, Central Medical Store Manager, Hospital Purchasing Manager, and Procurement Officer in the Ministry of Health. Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes 4 KEY TERMS Antifibrinolytic agent: A type of drug that helps the blood clot. It prevents the breakdown of a protein called fibrin, which is the main protein in a blood clot. Antifibrinolytic agents may be used to help prevent or treat serious bleeding in patients Appropriately skilled health personnel: Refers to having health personnel (health providers) present that are skilled to administer IM and/or IV injections, as dictated by each medicine's recommended administration Coagulant: Agent used to promote the clotting of blood Cold chain: System of storing and transporting medicines at recommended temperatures (temperatures between 2 and 8 degrees Celsius) from the point of manufacture to the point of use Contraindications: Specific situation in which a drug, procedure, or surgery should not be used because it may be harmful to the patient Ergometrine: Refers to both ergometrine or methylergometrine, per WHO recommendations IV Infusion set: Consists of a pre-filled, sterile container (plastic bag) of fluids with an attachment that allows the fluid to flow one drop at a time; a long sterile tube with a clamp to regulate or stop the flow; and a connector to attach to the access device Prostaglandin: Any of a group of hormone-like fatty acids found throughout the body that affect blood pressure, metabolism, body temperature, and other important body processes Post-partum Hemorrhage: Excessive bleeding after childbirth Uterotonic: Agent used to induce contraction or greater tonicity of the uterus WHO prequalified products*: Finished pharmaceutical products and active pharmaceutical ingredients deemed by WHO to be safe, appropriate, and compliant with stringent quality standards. WHO ensures quality by assessing product dossiers on master files, inspecting manufacturing and clinical sites, and organizing quality control testing of products. *Note that there are many stringent regulatory authority (SRA) approved medicines available in LMIC markets, but this brief does not identify each medicine + ++ +++Low Medium High IM=IntramuscularNot recommended Contraindicated 1. Note: Use of ergometrine is contraindicated in women with hypertensive disorders. "Ergometrine" refers to ergometrine/methylergometrine 2 An agreement is in place to produce HSC at an affordable and sustainable subsidized price (comparable to UNFPA's price for oxytocin) for public sector in LMICs Recommended Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes Recommended Uses & Health System Factors Medicines proven effective for prevention or treatment of PPH and other obstetric purposes Oxytocin Misoprostol Heat-stable Carbetocin Ergometrine1 Tranexamic Acid Prevention of PPH Treatment of PPH Induction of Labor Augmentation of Labor Post-abortion Care Administration Route IV, IM Oral, Sublingual IV, IM IV, IM IV Cold Chain Requirement Yes No No Yes No Price per Unit + + +2 + ++ Skilled Healthcare Personnel Required Yes No Yes Yes Yes Contraindicated Contraindicated Contraindicated 5 Contraindicated SUMMARY OF RECOMMENDED USES AND HEALTH SYSTEM CONSIDERATIONS This following table summarizes the uses and health system requirements of individual uterotonic medicines and TXA. A selection of these medicines are proven to be effective for the prevention or treatment of PPH and other common obstetric indications. For greater detail on each medicine, including contraindications, characteristics, and safety considerations, please see pages 6-10 IV=Intravenous PRODUCT CHARACTERISTICS Presentation • 10 IU ampoule Administration • Intramuscularly or intravenously • For induction and augmentation of labor: IV infusion only Storage and Transport • Must be stored at 2 to 8 degrees Celsius Price per unit • UNFPA catalogue: USD 0.31 per ampoule Supplies required • Syringes, needles, and IV infusion set (for IV only) Availability • Currently 2 WHO prequalified products available HEALTH SYSTEM IMPLICATIONS RECOMMENDED USES AND DOSAGE Type of Health Facility • Should only be administered at health facilities where appropriately skilled health personnel are present Supply Chain • Should be procured in 10 IU ampoules, not 5 IU ampoules (minimize complexity and maximize efficiency, as unit costs are the same) • Requires functional cold chain and transport—from manufacturer to the point of entry and during distribution to, and storage at, health facilities • Care should be taken to procure quality-assured oxytocin (labelled for storage at 2 to 8 degrees Celsius), as there is high prevalence of poor quality in the public and private sector Administration & Safety Concerns • When oxytocin is used for PPH prevention, using oxytocin for PPH treatment may require an additional medicine to be administered to address bleeding Prevention of PPH In settings where multiple uterotonics are available and the quality of oxytocin can be guaranteed, the use of oxytocin is recommended for prevention of PPH  Recommended quantity per patient: 1 ampoule of 10 IU Treatment of PPH Intravenous oxytocin is the recommended uterotonic drug for the treatment of PPH Recommended quantity per patient: 2 ampoules of 10 IU Induction of labor If prostaglandins (e.g., misoprostol) are not available, intravenous oxytocin alone should be used for induction of labor  Recommended quantity per patient: 1 ampoule of 10 IU Augmentation of labor Use of IV oxytocin alone for treatment of delay in labor is recommended Recommended quantity per patient: 1 ampoule of 10 IU Inappropriate use can contribute to serious morbidities, including uterine rupture, fetal asphyxia or fetal demise Post-abortion care Not recommended Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes 6 OXYTOCIN Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes PRODUCT CHARACTERISTICS Presentation • 200 mcg oral tablets • 25 mcg oral or vaginal tablets Administration • Orally for PPH prevention; sublingually for PPH treatment • Orally / sublingually / vaginally for post-abortion care • Orally or vaginally for induction of labor Storage and Transport • Can be stored at room temperature at or below 25 degrees Celsius • Must be packaged in double aluminum blisters until used Price per unit • UNFPA catalogue: USD 0.25 per oral tablet of 200 mcg; no price listedin catalogue for 25 mcg presentation Supplies required • None Availability • Several WHO prequalified products available HEALTH SYSTEM IMPLICATIONS RECOMMENDED USES AND DOSAGE Type of Health Facility • Can be administered without the presence of skilled health personnel Supply Chain • Care should be taken to procure and keep misoprostol packaged in double aluminum blisters until use to reduce the risk of exposure to moisture. • Care should be taken to procure quality-assured misoprostol, as there is high prevalence of poor quality in the public and private sector Administration & Safety Concerns • The lack of availability of the 25 mcg presentation may cause providers to attempt to cut a 200 mcg tablet into the appropriate dose. This practice should be avoided as achieving a 25 mcg “piece” of a 200 mcg tablet is virtually impossible when done by hand Prevention of PPH In settings where skilled health personnel are not present to administer injectable uterotonics and oxytocin is unavailable or its quality cannot be guaranteed, misoprostol is recommended Recommended quantity per patient: 400 mcg or 600 mcg Treatment of PPH Recommended when oxytocin is not available, its quality cannot be guaranteed, or if bleeding does not respond to oxytocin  Recommended quantity per patient: 800 mcg Induction of labor Oral or vaginal misoprostol is recommended for induction of labor Recommended quantity per patient: 25 mcg Inappropriate use can contribute to serious morbidities Augmentation of labor Contraindicated - Inappropriate use can contribute to serious morbidities, including uterine rupture, fetal asphyxia or fetal demise Post-abortion care Recommended for post-abortion care Recommended quantity per patient: 400 mcg or 600 mcg 7 MISOPROSTOL Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes PRODUCT CHARACTERISTICS Presentation • 100 mcg in 1 ml ampoule Administration • Intramuscularly or intravenously Storage and Transport • Can be stored at temperatures at or below 30 degrees Celsius Price per unit • • Current market price ranges from approximately USD 13 to 25 WHO, Merck for Mothers and Ferring Pharmaceuticals have signed an agreement to make the product available at an affordable and sustainable subsidized price of USD 0.31 +/- 10% per ampoule (comparable to the current UNFPA price of oxytocin of USD 0.31 per unit) for the public sector of low & lower-middle income countries Supplies required • Syringes, needles, IV infusion set (for IV only) Availability • Currently no WHO prequalified product available HEALTH SYSTEM IMPLICATIONS HEAT-STABLE CARBETOCIN RECOMMENDED USES AND DOSAGE Type of Health Facility • Should only be administered at health facilities where appropriately skilled health personnel are present. Supply Chain • Availability of investigational HSC is subject to regulatory review and approval inrelevant countries. Administration & Safety Concerns • Since the use of HSC for prevention of post-partum hemorrhage is a new recommendation, the product will need to go through the process of introduction and scale-up in the health system Prevention of PPH Recommended when cost is comparable to other effective uterotonics in settings where oxytocin is unavailable or its quality cannot be guaranteed  Recommended quantity per patient: 100 mcg Treatment of PPH Not recommended Induction of labor Not recommended Augmentation of labor Contraindicated - Inappropriate use can contribute to serious morbidities, including uterine rupture, fetal asphyxia or fetal demise Post-abortion care Not recommended 8 Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes PRODUCT CHARACTERISTICS Presentation • Ergometrine maleate 200 mcg/ml injection in 1ml ampoule • Methylergometrine maleate 200 mcg/ml injection in 1 ml ampoule Administration • Intramuscularly or intravenously Storage and Transport • Must be stored at 2 to 8 degrees Celsius and kept away from light Price per unit • UNFPA catalogue: USD 0.219 per ampoule Supplies required • Syringes, needles, and IV infusion set (for IV only) Availability • Currently no WHO prequalified products available HEALTH SYSTEM IMPLICATIONS ERGOMETRINE1 RECOMMENDED USES AND DOSAGE Type of Health Facility • Should only be administered at health facilities where appropriately skilled health personnel are present and where women's blood pressure can be monitored Supply Chain • Requires a functional cold chain—from the manufacturer to the point of entry and during distribution to, and storage at, health facilities. • Critical that the medicine is protected from light—ergometrine is more sensitive to heat and light than oxytocin • Care should be taken to procure quality-assured ergometrine, as there is high prevalence of poor quality in the public and private sector Administration & Safety Concerns • Use of ergometrine is contraindicated in women with hypertensive disorders, elevated BP or in settings where BP cannot be monitored accurately • Other options may have a better side effect profile Prevention of PPH Recommended in contexts where quality oxytocin cannot be guaranteed and where hypertensive disorders can be safely excluded before use  Recommended quantity per patient: 200 mcg Treatment of PPH Recommended when oxytocin is not available or when bleeding does not respond to oxytocin and a hypertensive disorder can be safely excluded prior to use  Recommended quantity per patient: 200 mcg Induction of labor Contraindicated - Inappropriate use can contribute to serious morbidities, including uterine rupture, fetal asphyxia or fetal demise Augmentation of labor Contraindicated - Inappropriate use can contribute to serious morbidities, including uterine rupture, fetal asphyxia or fetal demise Post-abortion care Not recommended 9 1. "Ergometrine" refers to ergometrine / methylergometrine Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes 10 PRODUCT CHARACTERISTICS Presentation • 1g in 1 ampoule of 10 ml Administration • Intravenously, in complement with uterotonics Storage and Transport • Heat stable with no special storage requirements Price per unit • No price listed in UNFPA catalogue; USD 0.90 per ampoule per USAIDwholesale price Supplies required • IV infusion set, syringes and needles Availability • Currently no WHO prequalified products available HEALTH SYSTEM IMPLICATIONS TRANEXAMIC ACID RECOMMENDED USES AND DOSAGE Type of Health Facility • Should only be available at health facilities where appropriately skilled health personnel are present Supply Chain • TXA is available on many countries’ essential medicine list (EML), with trauma as the clinical indication; Countries should update EML to specify PPH treatment as one of the indications for administration of IV TXA Administration & Safety Concerns • TXA complements uterotonics—it is not a substitute • TXA is not a uterotonic—it is a coagulant and antifibrinolytic agent Prevention of PPH Not recommended Treatment of PPH Early use of IV TXA (within 3 hours of birth) in addition to standard care with uterotonics is recommended for women with clinically diagnosed PPH following vaginal birth or caesarean section  Recommended quantity per patient: 1g Induction of labor Not recommended Augmentation of labor Not recommended Post-abortion care Not recommended Uses of Medicines for Prevention and Treatment of Post-partum Hemorrhage and Other Obstetric Purposes 11 REFERENCES Global Causes of Maternal Death: A WHO Systematic Analysis. Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels JD, et al. Lancet Global Health. 2014;2(6): e323-e333. WHO recommendations: uterotonics for the prevention of postpartum haemorrhage. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO.WHO http://apps.who.int/iris/bitstream/handle/10665/277276/9789241550420- eng.pdf?ua=1&ua=1 WHO recommendations for induction of labour. 2011. http://apps.who.int/iris/bitstream/ handle/10665/44531/9789241501156_eng.pdf?sequence=1 WHO recommendations for augmentation of labour. 2014. http://apps.who.int/iris/bitstream/ handle/10665/112825/9789241507363_eng.pdf?sequence=1 International Medical Products Price Guide. Management Sciences for Health. 2016 http://mshpriceguide.org/en/home/ UNFPA Procurement Services Product Catalogue. Accessed 11/11/18https://www.unfpaprocurement.org/catalog?id=OXYTOCIN _10IU/ML Torloni MR, Gomes Freitas C, Kartoglu UH, Metin Gülmezoglu A, Widmer M. Quality of oxytocin available in low- and middle- income countries: a systematic review of the literature. BJOG Int J Obstet Gynaecol. 2016;123(13):2076-2086. doi:10.1111/1471-0528.13998 Hogerzeil, H; Godfrey, P. Instability of (methyl)ergometrine in tropical climates: an overview. European Journal of Obstetrics & Gynecology and Reproductive Biology 69 (1996) 25 29. International Medical Products Price Guide. Management Sciences for Health. 2016 http://mshpriceguide.org/en/home/ WHO Essential Medicines List 2017. http://apps.who.int/iris/bitstream/handle/10665/273826/EML-20-eng.pdf?ua=1 WHO: Safe abortion: technical and policy guidance for health systems. 2012 https://www.who.int/reproductivehealth/publications/unsafe_abortion/978924154843 4/en/ UNFPA Procurement Services Product Catalogue. Accessed 11/11/18 https://www.unfpaprocurement.org/catalog? id=MISOPROSTOL_200MG Widmer M, et al. Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth. N Engl J Med 2018; 379:743-752. Updated WHO Recommendation on Tranexamic Acid for the Treatment of Postpartum Haemorrhage. October 2017. http://apps.who.int/iris/bitstreamhttp://apps.who.int/iris/bitstream/handle/10665/259379/WHO-RHR-17.21- eng.pdf?sequence=1/ handle/10665/259379/WHO-RHR-17.21-eng.pdf?sequence=1 WHO Drug Information Vol. 30, No. 1, 2016, Quality of misoprostol. https://www.who.int/medicines/publications/druginformation/WHO_DI_30- 1_Quality.pdf USAID Global Health Supply Chain Program. Guidelines: Buy Quality Oxytocin, Keep it Cold. https://www.ghsupplychain.org/resource/buy-quality-oxytocin-keep-it-cold Slide Number 1 With recent innovations and WHO recommendations, there are now more medication options to prevent and treat post-partum hemorrhage (PPH). However, there is still no single solution for preventing and managing PPH. Countries must determine the appropriate combination of uterotonics, tranexamic acid (TXA), and other life-saving PPH prevention and treatment interventions for use at community, primary, and referral levels. Additionally, these medicines have other important obstetric uses which must�be considered. Slide Number 3 Slide Number 4 Slide Number 5 Slide Number 6 Slide Number 7 Slide Number 8 Slide Number 9 Slide Number 10 Slide Number 11 Blank Page

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