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the Perelman School of Medicine at the University of Pennsylvania , noted that the results of the trial suggest that it would be “ helpful to evaluate the effect of reduced doses of rivaroxaban within six months after an episode of VTE .” 2

“ Clinicians now have good-quality evidence to support the use of long-term , reduced-intensity anticoagulation therapy with rivaroxaban after an initial treatment course at usual therapeutic doses ,” the authors wrote . “ The favorable safety and efficacy profile of reduced-intensity rivaroxaban may lead to questions about how patients with provoked VTE should be treated .”

REFERENCES

1 . Weitz JI , Lensing AWA , Prins MH , et al . Rivaroxaban or aspirin for extended treatment of venous thromboembolism . N Engl J Med . 2017 ; 376:1211-22 .

2 . Crowther MA and Cuker A . Reduced-intensity rivaroxaban for the prevention of recurrent venous thromboembolism . N Engl J Med . 2017 ; 376:1279-80

The systemic inflammation that characterizes aplastic anemia ( AA ) may also contribute to a greater risk of venous thromboembolism ( VTE ), giving patients with AA a 2.6-fold higher risk of developing deep vein thrombosis ( DVT ) or pulmonary embolism ( PE ) compared with patients without AA , according to a study conducted in Taiwan and published in Thrombosis Research .

KOGENATE FS ( Antihemophilic Factor [ Recombinant ], Formulated with Sucrose ) For Intravenous Use , Lyophilized Powder for Reconstitution with Vial Adapter Initial U . S . Approval : 1993

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Kogenate ® FS is a recombinant antihemophilic factor indicated for :

• On-demand treatment and control of bleeding episodes in adults and children with hemophilia A .

• Perioperative management of bleeding in adults and children with hemophilia A .

• Routine prophylaxis to reduce the frequency of bleeding episodes in children with hemophilia A and to reduce the risk of joint damage in children without pre-existing joint damage .

• Routine prophylaxis to reduce the frequency of bleeding episodes in adults with hemophilia A .

Kogenate FS is not indicated for the treatment of von Willebrand disease .

4 CONTRAINDICATIONS Kogenate FS is contraindicated in patients who have life-threatening hypersensitivity reactions , including anaphylaxis to mouse or hamster protein or other constituents of the product ( sucrose , glycine , histidine , sodium , calcium chloride , polysorbate 80 , imidazole , tri-n-butyl phosphate , and copper ).

5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions , including anaphylaxis have been reported with Kogenate FS . Reported symptoms included facial swelling , flushing , hives , decrease in blood pressure , nausea , rash , restlessness , shortness of breath , tachycardia , tightness of the chest , tingling , urticaria , and vomiting .

Kogenate FS contains trace amounts of mouse immunoglobulin G ( MuIgG ) and hamster ( BHK ) proteins [ see Description ( 11 )]. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins .

Discontinue Kogenate FS if symptoms occur and seek immediate emergency treatment .

5.2 Neutralizing Antibodies

Neutralizing antibodies ( inhibitors ) have been reported following administration of Kogenate FS , predominantly in previously untreated patients ( PUPs ) [ see Adverse Reactions ( 6 )]. Carefully monitor patients for the development of factor VIII inhibitors , using appropriate clinical observations and laboratory tests . 6 If expected plasma factor VIII activity levels are not attained , or if bleeding is not controlled with an expected dose , perform an assay that measures factor VIII inhibitor concentration [ see Warnings and Precautions ( 5.4 )].

5.3 Cardiovascular Risk Factors Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with factor VIII .

5.4 Monitoring Laboratory Tests

• Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained , when clinically indicated [ see Dosage and Administration ( 2 )].

• Monitor for development of factor VIII inhibitors . Perform assay to determine if factor VIII inhibitor is present . If expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Kogenate FS , use Bethesda Units ( BU ) to titer inhibitors .

If the inhibitor is less than 10 BU per mL , the administration of additional Kogenate FS concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response . If inhibitor titers are above 10 BU per mL , adequate hemostasis may not be achieved . The inhibitor titer may rise following Kogenate FS infusion as a result of an anamnestic response to factor VIII . The on-demand treatment and control of bleeding in such patients requires the use of alternative therapeutic approaches and agents .

6 ADVERSE REACTIONS Serious adverse reactions seen with Kogenate FS are systemic hypersensitivity reactions , including bronchospastic reactions and / or hypotension and anaphylaxis , and the development of high-titer inhibitors necessitating alternative treatments to factor VIII .

The most common adverse reactions ( ≥ 4 %) observed in clinical trials were inhibitor formation in previously untreated patients ( PUPs ) and minimally treated patients ( MTPs ), skin-related hypersensitivity reactions ( e . g ., rash , pruritus ), infusion site reactions ( e . g ., inflammation , pain ), and central venous access device ( CVAD ) associated infections .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse

Blood and Lymphatic System Disorders

Factor VIII inhibition ( neutralizing antibodies ) Infusion site reactions

9 ( 15 %) †

General Disorders and

4 ( 7 %)

Administration Site Conditions SOC = System Organ Class

† Denominator for de novo inhibitors is N = 60 , since one patient had a preexisting inhibitor .

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Minimally Treated Patients ( MTPs ) in the Joint Outcome Study In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years , 46 of the 65 randomized patients experienced adverse events over the study duration .

Table 5 Adverse Reactions in Minimally Treated Patients in the Joint Outcome Study ( Age Range 0 – 6 years )

Surgical and Medical Procedures

Infections and Infestations

General Disorders and Administration Site Conditions

Enhanced Episodic Arm N = 33 AR (%)

SOC = System Organ Class ‡ Three patients from the enhanced episodic arm had catheter removal .

Immunogenicity In clinical studies with 73 PTPs ( defined as having more than 100 exposure days ), one patient had a pre-existing inhibitor . In the other 72 patients , followed over 4 years , no de novo inhibitors were observed .

In clinical studies with pediatric PUPs and MTPs , inhibitor development was observed in 9 out of 60 patients ( 15 %), 6 were high titer 1 (> 5 BU ) and 3 were low-titer inhibitors . Inhibitors were detected at a median number of 7 exposure days ( range 2 to 16 exposure days ).

In the Joint Outcome Study with Kogenate FS , 5 de novo inhibitor development was observed in 8 of 64 patients with negative baseline values ( 12.5 %), 2 patients developed high titer 1 (> 5 BU ) and were withdrawn from the study . Six patients developed low-titer inhibitors . Inhibitors were detected at a median number of 44 exposure days ( range 5 to 151 exposure days ).

Inhibitor data in PUPs have been collected in several postmarketing registries [ see Postmarketing Experience ( 6.2 )].

The detection of antibody formation is dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody