CHAPTER 7 USE of ANTIHAEMORRHAGIC MEDICINES Malaysian Statistics on Medicines 2006

CHAPTER 7 USE OF ANTIHAEMORRHAGIC MEDICINES Malaysian Statistics on Medicines 2006

Edited by: Lim YS 1, Goh AS2

1. Kuala Lumpur Hospital, 2. Pulau Pinang Hospital

Concerns for the safety of blood transfusions are partly the cause for the development of a range of interventions to minimise blood loss during major surgeries. One of the interventions is the widespread use of anti-fibrinolytic agents especially in cardiac surgeries where they are found to reduce blood lossand decrease the need for red cell transfusions.

Tranexamic acid is a synthetic derivative which exerts its anti-fibrinolytic effect through reversible blockade of lysine binding sites on plasminogen molecules. It was the most commonly prescribed anti-haemorrhagic agent in 2006 (0.068DDD/1000 population/day). Tranexamic acid is effective in reducing postoperative blood loss in patients undergoing cardiac surgeries with statistically significant reductions in transfusion requirements. In comparison, the usage of aprotinin was rather low (<0.0006DDD/1000 population/day) and was mainly used therapeutically in open heart surgeries and cardiopulmonary bypass surgeries. Interestingly the usage of aprotinin was more than 6 times higher in the private institutions reflecting that a higher number of cardiac surgeries were being done in the private sector. Aprotinin is a proteinase inhibitor from bovine organs and can only be given intravenously. The loading dose of aprotinin is 15,000 to 20,000 kallikrein inhibitory units (kiu)/kg body weight as short intravenous infusions followed by 50,000 kiu/hour by continuous infusion. On the other hand, tranexamic acid can be given orally since it is readily absorbed from gastrointestinal tract and excreted in its active form in the urine. With short plasma half-life of 80 minutes, tranexamic acid side effects are transient mainly manifesting as nausea or diarrhoea.

The main indications for tranexamic acid are to prevent excessive bleeding after prostatic surgery, liver transplant, tonsillectomy, cervical conisation, primary and intrauterine device-induced menorrhagia, from gastric and intestinal sites, from epistaxis and ocular trauma, after tooth extraction in haemophilia and hereditary angioneurotic edema. It is also used in controlling bleeding in pregnancy. Tranexamic acid could be administered intravenously at a dose of 0.5–1g (10-15mg/kg body weight) two to three times a day or administered orally at 1-1.5 g three to four times daily. In renal insufficiency, this dose needs to be reduced. Tranexamic acid was reported to be more effective than mefenamic acid and norethisterone but less effective than intrauterine administration of levonorgestrel in reduction of menstrual blood loss in clinical trials. However the high incidence of amenorrhoea and adverse events such as intermenstrual bleeding reported with some hormonal therapy may be unacceptable to patients in which case tranexamic acid would be particularly useful. Hence tranexamic acid remains as the first line therapy for initial management of idiopathic menorrhagia for three to four days cycle over two to three cycles to reduce menstrual blood loss.

Factor VIII and IX concentrates are used to treat bleeding episodes in haemophilia A and haemophilia B respectively. In Malaysia, patients are given factor concentrates as “on-demand therapy” without charge in government hospitals. Furthermore haemophilia is a congenital disorder so the patients are not eligible for insurance coverage. Hence, most hemophiliacs seek treatment in government hospitals and the usage of factor concentrates is very low in the private sector.

Recombinant factor VIIa or Eptacog alfa (activated) has been licensed for treatment of haemophilia A and B with inhibitors in Europe since 1996 and in North America since 1999. Overall 1.5 million doses had been administered. It is indicated as an intravenous haemostatic agent in hemophilia patients with inhibitors to coagulation factors VIII and IX. On-demand therapy with Eptacog alfa was effective in controlling episodes of mild to moderate bleeding. Prophylactic treatment was also effective in maintaining haemostasis in haemophiliacs undergoing orthopaedic surgeries and it is reported that the acquisition costs of Eptacog alfa are offset by cost savings resulting from the reduction in the episodes of joint-related bleeds. The data had shown that Eptacog alfa (activated) was as sparingly used in the private as in the government sector.

21 CHAPTER 7 Malaysian Statistics on Medicines 2006 USE OF ANTIHAEMORRHAGIC MEDICINES

There was no data available for the use of Vitamin K or phytomenadione as a haemostatic agent even though our Malaysian hospitals do administer the vitamin intramuscularly for prophylactic use in haemorrhagic disease of the newborn. In life threatening bleeding, Vitamin K may be used therapeutically by the intravenous route together with fresh frozen plasma or factor concentrates.

Table 7.1: Use of Antihaemorrhagics in DDD/1000 population/day 2006 ATC Drug Class 2006 B02 ANTI HAEMORRHAGICS 0.0713

Table 7.2: Use of Antianaemics by Drug Class, in DDD/1000 population/day 2006 ATC Drug Class 2006 B02A ANTIFIBRINOLYTICS 0.0695 B02A A Amino acids 0.0688 B02A B Proteinase inhibitors 0.0006 B02B VITAMIN K AND OTHER HEMOSTATICS 0.0018 B02B A Vitamin K - B02B D Blood coagulation factors 0.0018

Table 7.3: Use of Antihaemorrhagics by Drug Class and Agents, in DDD/1000 population/day 2006 ATC Drug Class and Agents 2006 B02A A Amino acids B02A A02 Tranexamic acid Public 0.0524 Private 0.0165 Total 0.0688 B02A B Proteinase inhibitors B02A B01 Aprotinin Public <0.0001 Private 0.0006 Total 0.0006 B02B A Vitamin K B02B A01 Phytomenadione Public - Private - Total - B02B D Blood coagulation factors B02B D02 Coagulation factor VIII Public 0.0007 Private <0.0001 Total 0.0007 B02B D04 Coagulation factor IX Public 0.0011 Private - Total 0.0011 B02B D08 Eptacog alfa (activated) Public <0.0001 Private <0.0001 Total <0.0001

References: 1. Srivasta A, Chuansumrit A, Chandy M, Duraisamy G, Karagus C. Management of haemophilia in the developing world. Hemophilia 1998 Jul; 4(4):474-80. 2. Srivasta A, You SK, Ayob Y, Chuansumrit A, de Bosch N, Perez Bianco R, Ala F Hemophilia treatment in developing countries: products and protocols. Semin. Thromb. Hemost. 2005 Nov; 31(5): 495-500. 3. Stonebraker JS, Amand RE, Nagle AJ; A country-by-country comparison of FVIII concentrate consumption and economic capacity for the global hemophilia community Hemophilia Vol 9 (3) May 2003; 245-250(6).

22 CHAPTER 7 USE OF ANTIHAEMORRHAGIC MEDICINES Malaysian Statistics on Medicines 2006

4. Panicker J et al; The overall effectiveness of prophylaxis in severe haemophilia Haemophilia Vol 9, No. 3 May 2003 : 272-278. 5. Lyseng-Williamson KA, Plosker GL Recombinant factor VIIa (Eptacog alfa) a pharmacoeconomic review of its use in haemophilia in patients with inhibitors to clotting factors VIII and IX. Pharmacoeconomics 2007 : 25 (12) pgs 1007-29. 6. Puckett RM, Offringa M, Department of Paediatrics, Amsterdam. Prophylactic Vitamin K for Vitamin K deficiency bleeding in neonates. Cochrane Database Systematic Review 2000; (4): CD 002776.