HAEMOPHILIA CHEMO 2023 BERIATE®️.pptx

hemophilia slide

1. DR.dr.Tutik Harjianti.SpPD.KHOM.FINASIM SubDiv. of Hematology & Medical Oncology Dept.of Internal Medicine, Medical Faculty , Hasanuddin University Agust 2020 ETIOLOGY, DIAGNOSIS AND THERAPY OF HEMO PH ILIA

2. Blood Coagulation Disorder Abnormal bleeding can result from disorders of the coagulation system, of platelets, or of blood vessels. Disorders of coagulation can be acquired or hereditary. Hemophilia is an example of an inherited bleeding disorder caused by abnormal genes on the X chromosome, mostly affecting males. Goodman DM, JAMA, October 10, 2012— Vol 308, No. 14

3. Haemophilia There are 2 types of common hemophilia, resulting from missing coagulation factors: Peyvandi , Seminar, Volume 388, ISSUE 10040, P187-197, July 09, 2016

4. Haemophilia Inheritance Pattern Haemophilia is one of X-linked reccesive blood disorder that affect males only, females act as carriers. Adapted from https://www.cdc.gov/ncbddd/hemophilia/course/Hemophilia_Patterns_v3.pdf

5. Clinical Manifestation and Diagnosis Mainly discovered in early childhood or infancy Bleeding into muscle Deep bruise after receiving shots Prolonged bleeding after male child is circumcised Prolonged bleeding after umbilical cord is cut WFH 2012, Guidelines for the management of hemophilia Sites and severity of bleeding

6. Clinical Manifestation and Diagnosis Lab test result confirm possible coagulation disorder, but factor and specific assay needed to characterized specific cause of the disorder. Peyvandi , Seminar, Volume 388, ISSUE 10040, P187-197, July 09, 2016 Specific assay: aPTT mixing test (1:1) Factor assay (FVIII/FIX:C activity) Inhibitor test (Bethesda assay) Lupus anticoagulant/anti- phospolipid antibodies

7. Hemophilia A Classification Distribution Clotting factor activity Bleeding episodes Severe hemophilia 50% <1% (less than 1 IU/ dL ) Spontaneous bleeding into joints or muscles, predominantly in the absence of identifiable hemostatic challenge Moderate hemophilia 10% 1-5% (1-5 IU/ dL ) Occasional spontaneous bleeding; prolonged bleeding with minor trauma or surgery Mild hemophilia 30-40% 5-40% (5-40 IU/ dL ) Severe bleeding with major trauma or surgery. Spontaneous bleeding is rare. WFH 2012, Guidelines for the management of hemophilia

8. Treatment National Hemofilia Foundation, 2012

9. On Demand vs Prophylaxis Therapy WFH 2012, Guidelines for the management of hemophilia Protocol Definition Episodic (“on demand) treatment Treatment given at the time of clinically evident bleeding Continous prophylaxis Primary prophylaxis Regular continuous* treatment initiated in the absence of documented osteochondral joint disease , determined by physical examination and/or imaging studies, and started before the second clinically evident large joint bleed and age 3 years **. Secondary prophylaxis Regular continuous* treatment started after 2 or more bleed into large joints ** and before the onset of joint disease documented by physical examination and imaging studies. Tertiary prophylaxis Regular continuous* treatment started after the onset of joint disease documented by physical examination and plain radiographs of the affected joints. Intermittent (“periodic”) prophylaxis Treatment given to prevent bleeding for period not exceeding 45 weeks in a year. * Continous is defined as the intent of treating for 52 weeks/year and receiving a minimum of an a priori defined frequency of infusions for at least 45 weeks (85%) of the year under consideration. **large joints = ankles, knees, hips, elbows, and shoulders

10. On Demand vs Prophylaxis Therapy WFH 2012, Guidelines for the management of hemophilia Prophylaxis is the treatment by intravenous injection of factor concentrate in order to prevent anticipated bleeding . Prophylaxis prevents bleeding and joint destruction and should be the goal of therapy to preserve normal musculoskeletal function . Prophylactic replacement of clotting factor has been shown to be useful even when factor levels are not maintained above 1 IU/dl at all times.

11. Clotting Factor Concentrate WFH 2012, Guidelines for the management of hemophilia

12. Purity of concentrates refers to the percentage of the desired ingredient (e.g. FVIII), relative to other ingredients present. Concentrates of lower purity may give rise to allergic reactions and thromboembolic events. PARAMETER BERIATE Product X Product Y MARKETER DEXA MEDICA: CSL BEHRING XX YY KEMURNIAN 400 IU/mg protein 9 - 22 IU/mg protein 100 IU/mg protein Purity of products There is no universally agreed classification of products based on purity, but in general the classification as follows: Low purity  less than 10 IU/mg proteins Intermediate purity  10-100 IU/mg proteins High purity  100-1000 IU/mg proteins Very High Purity  more than 1000 IU/mg proteins WFH 2012, Guidelines for the management of hemophilia

13. Plasma Control Donation tested Decrease virus potential through NAT/PCR Virus validation studies Prion evaluation studies Manufacturing Process of Beriate®P Beriate®P. Data on file Viral innactivation - Safety

14. Result in long-term clinical studies for virus safety monitoring No proven case of virus transmission with the use of over 300 mil IU of Beriate®P in 20 years Beriate®P. Data on file Viral innactivation - Safety

15. Beriate ® P in the treatment of patients with haemophilia A: Results of a long term pharmacovigilance study Robert Klamroth , Susanne Holzhauer , Rainer Zimmermann, Christine Heller Of a total of 1,311 bleeding episodes, a median of one Beriate ® P infusion was used per bleed. In most cases, one infusion was sufficient to treat the bleed (661 bleeds). R. Klamroth et al. / Thrombosis Research (2013)

16. Prospective study of continuous infusion with Beriate ® P in patients with severe haemophilia A undergoing surgery – a subgroup analysis Günter Auerswald , Andrea Bade, Julia Johne , Kirstin Haubold , David Overberg, Sylvia Masurat , Carolin Moorthi Auerswald et al. / Thrombosis Research (2013) Introduction: Inhibitor development in severe haemophilia A patients is currently the most serious complication of factor VIII (FVIII) treatment. Although continuous infusion (CI) of FVIII concentrate during surgical procedures in haemophilia A patients has been shown to be beneficial, some publications suggest that CI increases the risk of inhibitor generation. We conducted a prospective subgroup analysis to investigate if CI of the high-purity, pasteurized, plasma-derived FVIII concentrate Beriate®P during surgery increases the risk of inhibitor formation. Inclusion criteria Hemophilia A (FVIII<1%) Age < 50 y.o No previous history of inhibitors Documented HAV, HBV, HCV, HIV status Scheduled for minor/major surgical procedure Exclusion criteria Contraindicated to Beriate P Hypersensitive to Beriate P Thrombophilia Confirmed/suspected pregnancy

17. Prospective study of continuous infusion with Beriate ® P in patients with severe haemophilia A undergoing surgery – a subgroup analysis Günter Auerswald , Andrea Bade, Julia Johne , Kirstin Haubold , David Overberg, Sylvia Masurat , Carolin Moorthi Auerswald et al. / Thrombosis Research (2013)

18. Prospective study of continuous infusion with Beriate ® P in patients with severe haemophilia A undergoing surgery – a subgroup analysis Günter Auerswald , Andrea Bade, Julia Johne , Kirstin Haubold , David Overberg, Sylvia Masurat , Carolin Moorthi Auerswald et al. / Thrombosis Research (2013) In summary, in our study, Beriate®P was found to have an excellent efficacy and safety profile when used as a continuous infusion during surgery. Haemostasis was achieved in all patients, wound healing was uncomplicated, no re-surgeries were required, no virus transmissions or thromboses occurred, and no inhibitor generation was observed.

19. A comparison between prophylaxis and on demand treatment for severe haemophilia Khoriaty 2005, Clin. Lab. Haem.27, 320–323 CONCLUSIONS Prophylaxis reduces the risk of arthropathies, the number of future hospital visits and orthopaedic surgeries, and is thus the optimal modality of treatment for patients with severe haemophilia . Background Patients with severe haemophilia can be treated for bleeding either prophylactically or on demand. Each treatment modality has advantages and disadvantages from both a medical and economic point of view. This study aims to find which modality requires more units of clotting factors per body weight per year and to compare the number of bleeds between the two. p=0.0021

20. Product Information

21. Composition One vial contains nominally: 250/500 IU human coagulation factor VIII (FVIII). After reconstitution with 2.5/5 ml Beriate 250/500 contains 100 IU/ml factor VIII. The potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The mean specific activity of Beriate is approximately 400 IU/mg protein. Excipient with known effect: Sodium approximately 100 mmol /l (2.3 mg/ml). Beriate ®P. Package Insert. 2018

22. Pharmacokinetic parameter Parameter Value Mean half life 12 h (5-22h) Increase in FVIII:C after 1 IU FVIII/ kgBB (incremental recovery) 2% (1.5-3%) Mean residence time 17h ± 5.5h Mean area under the data completed by extrapolation (AUDC) 0.4 ± 0.2 h x kg/mL Mean clearance 3 mL/h/kg Mean specific activity* 270 IU/mg protein Beriate ®P. Package Insert. 2018 *Specific activity= quantity of active protein per mg of total protein of factor VIII concentrate

23. Indication Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). Contraindication Beriate P is contraindicated for patient with known hypersensitivity to the active substance or to any of the excipients. Beriate ®P. Package Insert. 2018

24. Dosage and Administration Treatment Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia . The dosage and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient’s clinical condition. . Required units = body weight [kg] x desired factor VIII rise [% or IU/dl] x 0.5 Beriate ®P. Package Insert. 2018

25. Dosage and Administration Degree of haemorrhage /Type of surgical procedure Factor VIII level required (% or IU/dl) Frequency of doses (hours)/Duration of therapy (days) Haemorrhage Early haemarthrosis , muscle bleeding or oral bleeding 20-40 Repeat infusion every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing achieved. More extensive haemarthrosis , muscle bleeding or haematoma 30-60 Repeat infusion every 12 to 24 hours for 3 to 4 days or more until pain and acute disability are resolved. Life-threatening haemorrhages 60-100 Repeat infusion every 8 to 24 hours until threat is resolved. Surgery Minor including tooth extraction 30-60 Every 24 hours, at least 1 day, until healing is achieved. Major 80-100 (pre-and postoperative) Repeat infusion every 8 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/ dL ). Beriate ®P. Package Insert. 2018

26. Dosage and Administration Prophylaxis For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary. Administration The preparation should be warmed to room or body temperature before administration. Inject or infuse slowly intravenously at a rate which the patient finds comfortable. The injection or infusion rate should not exceed 2 ml per minute. Beriate ®P. Package Insert. 2018

27. Dosage and Administration-Reconstitution Beriate ®P. Package Insert. 2018 6 7 Open the Mix2Vial package by peeling off the lid. Do not remove the Mix2Vial from the blister package. Place the solvent vial on an even, clean surface, and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial Package Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial Set and push the spike of transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew counterclockwise the set carefully into two pieces. Discard the solvent vial with the blue Mix2vial attached. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vials’s Luer Lock fitting by screwing clockwise. Inject air to the product vial.