ASH Clinical News July 2017 V2 - Page 29

CLINICAL NEWS

“ We were surprised to find differences in variables related to response between [ pomalidomide and placebo ].”

— AYALEW TEFFERI , MD
of transfusion-independence response criteria that were more stringent than recent criteria published by the International Working Group for MPN Research and Treatment . “ The criteria we used do not reflect the clinical benefit physicians expect , wherein a > 50 percent reduction in RBC transfusion
intensity may be considered beneficial depending on the baseline intensity ,” the authors wrote . “ Consequently , the strength of our conclusion of no efficacy should be downgraded according to the [ Grading of Recommendations Assessment , Development and Evaluation ] criteria .” ●
REFERENCE
Tefferi A , Al-Ali HK , Barosi G , et al . A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence . Leukemia . 2017 ; 31:896-902 .
( including neutralizing antibody ) positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , comparison of the incidence of antibodies to Kogenate FS with the incidence of antibodies to other products may be misleading .
6.2 Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure . The following adverse reaction has been identified during post approval use of Kogenate FS :
Sensory System – Dysgeusia Immunogenicity – Postmarketing Registries Data from the Research of Determinants of Inhibitor Development ( RODIN ) study 7 , French National Registry ( FranceCoag ) 8 and United Kingdom Haemophilia Centre Doctors ’ Organisation ( UKHCDO ) 9 registry reported an inhibitor development rate in PUPs for Kogenate FS of 38 %, 50 % and 35 %, respectively , which is comparable to previously-reported inhibitor rates 10 for FVIII products . These registry studies show a trend towards an increased risk of inhibitor development in PUPs , as compared to the reference rFVIII product . A survey of Canadian hemophilia centers 11 ( 2005 to 2012 ) and available data from the European Haemophilia Safety Surveillance ( EUHASS ) 12 registry from 2009 to 2013 , reported an inhibitor development rate in PUPs for Kogenate FS of 42 % and 31 %, respectively , with no statistically significant differences observed across FVIII products .
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C . Animal reproduction studies have not been conducted with Kogenate FS . It is also not known whether Kogenate FS can cause fetal harm when administered to a pregnant woman or affect reproductive capacity . Kogenate FS should be given to a pregnant woman only if clearly needed .
8.2 Labor and Delivery There is no information available on the effect of factor VIII replacement therapy on labor and delivery . Kogenate FS should be used only if clinically needed .
8.3 Nursing Mothers It is not known whether this drug is excreted into human milk . Because many drugs are excreted into human milk , caution should be exercised if Kogenate FS is administered to a nursing woman .
8.4 Pediatric Use Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients . Children , in comparison to adults , present higher factor VIII clearance values and , thus , lower half-life and recovery of factor VIII . This may be due to differences in body composition . 13 Account for this difference in clearance when dosing or following factor VIII levels in the pediatric population [ see Clinical Pharmacology ( 12.3 )].
Routine prophylactic treatment in children ages 0 – 2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage . This data can be extrapolated to ages > 2.5 – 16 years for children who have no existing joint damage [ see Clinical Studies ( 14 )].
8.5 Geriatric Use Clinical studies with Kogenate FS did not include patients aged 65 and over . Dose selection for an elderly patient should be individualized .
15 REFERENCES
1 . White GC , Rosendaal F , Aledort LM , Lusher JM , Rothschild C , Ingerslev J , for the Factor VIII and Factor IX Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis . Definitions in hemophilia . Thromb Haemost 85:560-75 , 2001 .
2 . Abildgaard CF , Simone JV , Corrigan JJ , et al : Treatment of hemophilia with glycine-precipitated Factor VIII . N Engl J Med 275 ( 9 ): 471 – 5 , 1966 .
3 . Schwartz RS , Abildgaard CF , Aledort LM , et al : Human recombinant DNAderived antihemophilic factor ( factor VIII ) in the treatment of hemophilia A . Recombinant Factor VIII Study Group . N Engl J Med 323 ( 26 ): 1800-5 , 1990 .
4 . White GC 2nd , Courter S , Bray GL , et al : A multicenter study of recombinant factor VIII ( Recombinate ) in previously treated patients with hemophilia A . The Recombinate Previously Treated Patient Study Group . Thromb Haemost 77 ( 4 ): 660-667 , 1997 .
5 . Manco-Johnson MJ , Abshire TC , Shapiro AD , Riske B , Hacker MR , Kilcoyne R , et al . Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia . N Engl J Med 2007 ; 357 ( 6 ): 535-44 .
6 . Kasper CK : Complications of hemophilia A treatment : factor VIII inhibitors . Ann NY Acad Sci 614:97-105 , 1991 .
7 . Gouw SC , van den Berg HM , et al : Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A : the RODIN study . Blood 121 ( 20 ): 4046-4055 , 2013 .
8 . Calvez T , Chambost H , et al : Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A . Blood 124 ( 23 ): 3398-3408 , 2014 .
9 . Collins PW , Palmer BP , et al : Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A , 2000-2011 . Blood 124 ( 23 ): 3389-3397 , 2014 .
10 . Franchini M , Coppola A , et al : Systematic Review of the Role of FVIII Concentrates in Inhibitor Development in Previously Untreated Patients with Severe Hemophilia A : A 2013 Update . Semin Throm Hemost ( 39 ): 752-766 , 2013 .
11 . Vezina C , Carcao M , et al : Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010 . Haemophilia 20 ( 6 ): 771-776 , 2014 .
12 . Fisher K , Lassila , R , et al . Inhibitor development in haemophilia according to concentrate : Four-year results from the European HAemophilia Safety Surveillance ( EUHASS ) project . Thromb Haemost 113.4 , 2015 .
13 . Barnes C , Lillicrap D , Pazmino-Canizares J , et al : Pharmacokinetics of recombinant factor VIII ( Kogenate-FS ® ) in children and causes of interpatient pharmacokinetic variability . Haemophilia 12 ( Suppl . 4 ): 40-49 , 2006 .
14 . Lawn RM , Vehar GA : The molecular genetics of hemophilia . Sci Am 254 ( 3 ): 48 – 54 , 1986 .
15 . Stenland CJ , et al : Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma . Transfusion 42 ( 11 ): 1497-500 , 2002 .
16 . Lee DC , Miller JL , Petteway SR : Pathogen safety of manufacturing processes for biological products : special emphasis on KOGENATE ® Bayer . Haemophilia 8 ( Suppl . 2 ): 6-9 , 2002 .
17 . Lee DC , Stenland CJ , Miller JL , et al : A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins . Transfusion 41 ( 4 ): 449-55 , 2001 .
18 . Cai K , Miller JL , Stenland CJ , et al : Solvent-dependent precipitation of prion protein . Biochim Biophys Acta 1597 ( 1 ): 28-35 , 2002 .
19 . Trejo SR , Hotta JA , Lebing W , et al : Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process . Vox Sang 84 ( 3 ): 176-87 , 2003 .
20 . Nuss R , Kilcoyne RF , Geraghty S , et al : MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage . Haemophilia 6:162-169 , 2000 .
21 . Pettersson H , Ahlberg A , Nilsson IM : A radiologic classification of hemophilia arthropathy . Clin Orthop Relat Res 149:153-159 , 1980 .
17 PATIENT COUNSELING INFORMATION
• Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ).
• Advise patients to report any adverse reactions or problems following Kogenate FS administration to their physician or healthcare provider .
• Allergic-type hypersensitivity reactions have been reported with Kogenate FS . Warn patients of the early signs of hypersensitivity reactions [ including hives ( rash with itching ), generalized urticaria , tightness of the chest , wheezing , hypotension ] and anaphylaxis . Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen .
• Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A . Advise patients to contact their physician or treatment center for further treatment and / or assessment , if they experience a lack of clinical response to factor VIII replacement therapy , as this may be a manifestation of an inhibitor .
• Advise patients to consult with their healthcare provider prior to travel . While traveling advise patients to bring an adequate supply of Kogenate FS based on their current regimen of treatment .
Bayer HealthCare LLC Whippany , NJ 07981 USA
U . S . License No . 8 ( License Holder : Bayer Corporation )
http :// www . kogenatefs . com / 6709904BS

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ASH Clinical News 27
“We were surprised to find differences in variables related to response between [pomalidomide and placebo].” —AYALEW TEFFERI, MD 15” of transfusion-independence response criteria that were more stringent than recent criteria published by the International Working Group for MPN Research and Treatment. “The criteria we used do not reflect the clinical benefit physicians expect, wherein a >50 percent reduction in RBC transfusion intensity may be considered beneficial depending on the baseline intensity,” the authors wrote. “Consequently, the strength of our conclusion of no efficacy should be downgraded according to the [Grading of Recommendations Assessment, Development and Evaluation] criteria.” ● REFERENCE Tefferi A, Al-Ali HK, Barosi G, et al. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2017;31:896-902. 4.75” (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kogenate FS with the incidence of antibodies to other products may be misleading. 6.2 Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reaction has been identified during post approval use of Kogenate FS: Sensory System – Dysgeusia Immunogenicity – Postmarketing Registries Data from the Research of Determinants of Inhibitor Development (RODIN) study 7 , French National Registry (FranceCoag) 8 and United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) 9 registry reported an inhibitor development rate in PUPs for Kogenate FS of 38%, 50% and 35%, respectively, which is comparable to previously-reported inhibitor rates 10 for FVIII products. These registry studies show a trend towards an increased risk of inhibitor development in PUPs, as compared to the reference rFVIII product. 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