ASH Clinical News December 2016 | Page 39

identified during post approval use of NovoSeven ® . Because these 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 .
Table : Post Marketing Experience
MedDRA System Preferred Term Organ Class
Immune system disorders
Vascular disorders
Hypersensitivity ( including anaphylactic shock , flushing , urticaria , rash , angioedema )
Thromboembolic events ( including hepatic artery thrombosis , myocardial infarction , cerebral infarction , intestinal infarction , intracardiac thrombus , peripheral ischemia , portal vein thrombosis , myocardial ischemia , renal artery thrombosis )
DRUG INTERACTIONS : Avoid simultaneous use of activated prothrombin complex concentrates or prothrombin complex concentrates . The risk of a potential interaction between NovoSeven ® RT and coagulation factor concentrates has not been adequately evaluated in preclinical or clinical studies . Do not mix NovoSeven ® RT with infusion solutions . Thrombosis may occur if NovoSeven ® RT is administered concomitantly with Coagulation Factor XIII .
USE IN SPECIFIC POPULATIONS : Pregnancy : Risk Summary : There are no adequate and well-controlled studies using NovoSeven ® RT in pregnant women to determine whether there is a drug-associated risk . Treatment of rats and rabbits with NovoSeven ® in reproduction studies has been associated with mortality at doses up to 6 mg per kg body weight and 5 mg per kg body weight respectively . At 6 mg per kg body weight in rats , the abortion rate was 0 out of 25 litters ; in rabbits at 5 mg per kg body weight , the abortion rate was 2 out of 25 litters . Twenty-three out of 25 female rats given 6 mg per kg body weight of NovoSeven ® gave birth successfully , however , two of the 23 litters died during the early period of lactation . No evidence of teratogenicity was observed after dosing with NovoSeven ® . In the U . S . general population , the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively . Lactation : Risk Summary : There is no information regarding the presence of NovoSeven ® RT in human milk , the effect on the breastfed infant , and the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for NovoSeven ® RT and any potential adverse effects on the breastfed infant from NovoSeven ® RT or from the underlying maternal condition . Pediatric Use : Clinical trials enrolling pediatric patients were conducted with dosing determined according to body weight and not according to age . Hemophilia A or B with Inhibitors : During the investigational phase of product development NovoSeven ® was used in 16 children aged 0 to < 2 years for 151 bleeding episodes , 27 children aged 2 to < 6 years for 140 bleeding episodes , 43 children aged 6 to < 12 for 375 bleeding episodes and 30 children aged 12 to 16 years for 446 bleeding episodes . In a double-blind , randomized comparison trial of two dose levels of NovoSeven ® in the treatment of joint , muscle and mucocutaneous hemorrhages in hemophilia A and B patients with and without inhibitors 20 children aged 0 to < 12 and 8 children aged 12 to 16 were treated with NovoSeven ® in doses of 35 or 70 micrograms per kg dose . Treatment was assessed as effective ( definite relief of pain / tenderness as reported by the patient and / or a measurable decrease of the size of the hemorrhage and / or arrest of bleeding within 8 hours [ rated as excellent = 51 %], within 8-14 hours [ rated as effective = 18 %] or after 14 hours [ rated as partially effective = 25 %]) in 94 % of the patients . NovoSeven ® was used in two trials in surgery . In a dose comparison 22 children aged 0 to 16 years were treated with NovoSeven ® . Effective intraoperative hemostasis ( defined as bleeding that had stopped completely or had decreased substantially [ rated as effective = 86 %] or bleeding that was reduced but continued [ rated as partially effective = 9 %]) was achieved in 21 / 22 ( 95 %) patients . Effective hemostasis was achieved in 10 / 10 ( 100 %) patients in the 90 mcg / kg dose group and 10 / 12 ( 83 %) in the 35 mcg / kg dose group at 48 hours ; effective hemostasis was achieved in 10 / 10 ( 100 %) in the 90 mcg / kg dose group and 9 / 12 ( 75 %) in the 35 mcg / kg dose group at 5 days . In the surgery trial comparing bolus ( BI ) and continuous infusion ( CI ) 6 children aged 10 to 15 years participated , 3 in each group . Both regimens were 100 % effective ( defined as bleeding has stopped completely , or decreased substantially ) intra-operatively , through the first 24 hours and at day 5 . At the end of the study period ( Postoperative day 10 or discontinuation of therapy ) hemostasis in two patients in the BI group was rated effective and hemostasis in one patient was rated as ineffective ( defined as bleeding is the same or has worsened ). Hemostasis in all three patients in the CI group was rated as effective . Adverse drug reactions in pediatric patients were similar to those previously reported in clinical trials with NovoSeven ® , including one thrombotic event in a 4 year old with internal jugular vein thrombosis after porta-cath placement which resolved . Congenital Factor VII deficiency : In published literature , compassionate use trials and registries on use of NovoSeven ® in congenital Factor VII deficiency , NovoSeven ® was used in 24 children aged 0 to < 12 years and 7 children aged 12 to 16 years for 38 bleeding episodes , 16 surgeries and 8 prophylaxis regimens . Treatment was effective in 95 % of bleeding episodes ( 5 % not rated ) and 100 % of surgeries . No thrombotic events were reported . A seven-month old exposed to NovoSeven ® and various plasma products developed antibodies against FVII and rFVIIa [ see Adverse Reactions and Overdosage ]. Glanzmann ’ s
Thrombasthenia : In the Glanzmann ’ s Thrombasthenia Registry , NovoSeven ® was used in 43 children aged 0 to 12 years for 157 bleeding episodes and in 15 children aged 0 to 12 years for 19 surgical procedures . NovoSeven ® was also used in 8 children aged > 12 to 16 years for 17 bleeding episodes and in 3 children aged > 12 to 16 years for 3 surgical procedures . Efficacy of regimens including NovoSeven ® was evaluated by independent adjudicators as 93.6 % and 100 % for bleeding episodes in children aged 0 to 12 years and > 12 to 16 years , respectively . Efficacy in surgical procedures was evaluated as 100 % for all surgical procedures in children aged 0 to 16 years . No adverse reactions were reported in Glanzmann ’ s thrombasthenia children . Geriatric Use : Clinical studies of NovoSeven ® RT in congenital factor deficiencies and Glanzmann ’ s thrombasthenia did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects .
OVERDOSAGE : Dose limiting toxicities of NovoSeven ® RT have not been investigated in clinical trials . The following are examples of accidental overdose . One newborn female with congenital factor VII deficiency was administered an overdose of NovoSeven ® ( single dose : 800 micrograms per kg body weight ). Following additional administration of NovoSeven ® and various plasma products , antibodies against rFVIIa were detected , but no thrombotic complications were reported . One Factor VII deficient male ( 83 years of age , 111.1 kg ) received two doses of 324 micrograms per kg body weight ( 10-20 times the recommended dose ) and experienced a thrombotic event ( occipital stroke ). One hemophilia B patient ( 16 years of age , 68 kg ) received a single dose of 352 micrograms per kg body weight and one hemophilia A patient ( 2 years of age , 14.6 kg ) received doses ranging from 246 micrograms per kg body weight to 986 micrograms per kg body weight on five consecutive days . There were no reported complications in either case .
More detailed information is available upon request .
For information contact : Novo Nordisk Inc . 800 Scudders Mill Road Plainsboro , NJ 08536 , USA 1-877-NOVO-777 www . NovoSevenRT . com
Manufactured by : Novo Nordisk A / S 2880 Bagsvaerd , Denmark License Number : 1261
Novo Nordisk ® is a registered trademark of Novo Nordisk A / S . NovoSeven ® is a registered trademark of Novo Nordisk Health Care AG .
© 2016 Novo Nordisk USA16HDM01503 3 / 16