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versus 24.0 months ( range = 16.5-33.3 months ; hazard ratio [ HR ] = 0.98 ; 95 % CI 0.85-1.14 ; p value for non-inferiority = 0.010 ).
In a post hoc analysis at 15 months , the time to first skeletal-related event favored denosumab over ZA ( HR = 0.66 ; 95 % CI 0.44-0.98 ; p = 0.039 ). Secondary analyses also found that the rate of PFS after 42 months was higher in the denosumab group ( HR for PFS = 0.82 [ 95 %
CI 0.68-0.99 ; p = 0.036 ], while OS was not , with HR = 0.90 [ 95 % CI 0.70-1.16 ; p = 0.41 ]).
A total of 852 patients assigned to ZA and 850 patients assigned to denosumab who had received at least one dose of the investigational drug were subsequently included in the safety analysis . The most frequently reported grade ≥3 treatmentemergent AEs in the denosumab and ZA groups were as follows :
ADYNOVATE [ Antihemophilic Factor ( Recombinant )]
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Lyophilized Powder for Reconstitution for Intravenous Injection BRIEF SUMMARY : Consult the Full Prescribing Information for complete product information .
• neutropenia : 15 % vs . 15 %
• thrombocytopenia : 14 % vs . 12 %
• anemia : 12 % vs . 10 %
• febrile neutropenia : 11 % vs . 10 %
• pneumonia : 8 % vs . 8 %
Similar rates of osteonecrosis of the jaw were reported in patients assigned to denosumab and ZA ( 4 % vs . 3 %, respectively ; p = 0.147 ). While more patients in the denosumab group reported hypocalcemia ( 17 % vs . 12 %), a greater proportion of patients assigned to ZA experienced renal toxicity ( 17 % vs . 10 %, respectively ; p values not reported ). “ This difference is of particular importance because MMrelated renal injury is frequent and occurs progressively during disease progression , with a known association between increased renal dysfunction and decreased treatment options , quality of life , and survival ,” the authors noted , adding that these results “ support denosumab as an additional option to the standard of care for patients with MM .”
CONTRAINDICATIONS
ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE , to the parent molecule ( ADVATE ), mouse or hamster protein , or excipients of ADYNOVATE ( e . g . Tris , mannitol , trehalose , glutathione , and / or polysorbate 80 ).
WARNINGS and PRECAUTIONS
Hypersensitivity Reactions Hypersensitivity reactions are possible with ADYNOVATE . Allergic-type hypersensitivity reactions , including anaphylaxis , have been reported with other recombinant antihemophilic factor VIII products , including the parent molecule , ADVATE . Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema , chest tightness , dyspnea , wheezing , urticaria , and pruritus . Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur .
Neutralizing Antibodies Formation of neutralizing antibodies ( inhibitors ) to factor VIII can occur following administration of ADYNOVATE . Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests . Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected , or if bleeding is not controlled with expected dose .
Monitoring Laboratory Tests
• Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained .
• Monitor for the development of factor VIII inhibitors . Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present . If
USE IN SPECIFIC POPULATIONS expected factor VIII activity plasma levels are not attained , or if bleeding is not controlled with the expected dose of ADYNOVATE , use Bethesda Units ( BU ) to determine inhibitor levels .
ADVERSE REACTIONS
The most common adverse reactions ( ≥1 % of subjects ) reported in the clinical studies were headache and nausea .
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice .
The safety of ADYNOVATE was evaluated in 237 previously treated patients ( PTPs ) and 6 previously untreated patients ( PUPs ) with severe hemophilia A ( factor VIII less than 1 % of normal ), who received at least one dose of ADYNOVATE in 3 completed multi-center , prospective , open label clinical studies and 4 ongoing clinical studies . The median duration of participation per subject was 401 ( min-max : 3-1034 ) days and the median number of exposure days to ADYNOVATE per subject was 111 ( min-max : 1-322 ). Following are the adverse reactions reported during clinical studies .
Adverse reactions reported for ADYNOVATE as shown by Percent of Subjects , Number of subjects (%, n ) ( N = 243 ) and Rate of AEs per 100 infusions ( N = 30865 ). Reported adverse reactions are listed by MedDRA System Organ Class followed by MedDRA Preferred Term . Gastrointestinal Disorders : Diarrhea ( 0.4 %, n = 1 ) ( 0.003 rate of AE ), Nausea ( 0.8 %, n = 2 ) ( 0.006 rate of AE ); Immune System Disorder : Hypersensitivity a ( 0.4 %, n = 1 ) ( 0.003 rate of AE ); Nervous System Disorders : Headache ( 2.1 %, n = 5 ) ( 0.026 rate of AE ); Skin and Subcutaneous Tissue Disorders , Rash ( 0.4 %, n = 1 ) ( 0.003 rate of AE ); and Vascular Disorders : Flushing ( 0.4 %, n = 1 ) ( 0.003 rate of AE ).
a
The event of hypersensitivity was a mild transient non-serious rash , occurring in one 2-year old patient who had developed a previous rash while on ADYNOVATE .
Immunogenicity The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 3 completed and 4 ongoing clinical trials . Subjects consisted of adolescent and adult ( n = 148 with ≥150 prior EDs ) and pediatric PTPs [(< 6 years of age with ≥50 prior EDs ( n = 32 ), ≥6 years of age with ≥150 prior EDs ( n = 57 )], and pediatric PUPs ( n = 6 ). In 191 adult and pediatric PTPs who were treated for at least 50 exposure days with
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ADYNOVATE , the factor VIII inhibitor frequency was 0 ( 95 % CI of 0 to 0.019 ). Shire Lexington , MA 02421 USA Printed in USA Issued 11 / 2016 S40815 06 / 18
One PUP subject from an ongoing study , who received at least one infusion of ADYNOVATE , developed neutralizing antibodies to factor VIII .
Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII , PEGylated ( PEG ) -factor VIII , PEG and Chinese hamster ovary ( CHO ) protein using validated ELISA assays . The majority of subjects ( 238 / 243 ) with at least one infusion of ADYNOVATE did not develop a persistent binding antibody response to any of these antigens . Twenty-eight subjects in total showed pre-existing antibodies to factor VIII ( n = 3 ), PEG-factor VIII ( n = 25 ) and / or PEG ( n = 3 ) prior to the first exposure to ADYNOVATE . Thirteen subjects who tested negative at screening developed transient antibodies against factor VIII ( n = 6 ), PEG-FVIII ( n = 8 ) at one or two consecutive study visits . Antibodies were transient and not detectable at subsequent visits . Five subjects showed positive results for binding antibodies at study completion or at the time of data cutoff . Binding antibodies that were detected prior to exposure to ADYNOVATE , that transiently developed during the trial or were still detectable at study completion or data cutoff could not be correlated to any impaired treatment efficacy or altered PK parameters . There was no causal relationship between observed adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out based on available data . No subject had pre-existing or treatment-emergent antibodies to CHO protein .
The detection of antibodies that are reactive to factor VIII is highly dependent on many factors , including : the sensitivity and specificity of the assay , sample handling , timing of sample collection , concomitant medications and underlying disease . For these reasons , comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading .
Pregnancy : Risk Summary There are no data with ADYNOVATE use in pregnant women to inform a drug-associated risk . Animal reproduction studies have not been conducted with ADYNOVATE . It is unknown whether ADYNOVATE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity . ADYNOVATE should be given to a pregnant woman only if clearly needed . 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 ADYNOVATE in human milk , the effect on the breastfed infant , or the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for ADYNOVATE and any potential adverse effects on the breastfed infant from ADYNOVATE or from the underlying maternal condition .
Pediatric Use Safety and efficacy studies have been performed in 91 previously treated , pediatric patients age 1 year to < 18 years who received at least one dose of ADYNOVATE as part of routine prophylaxis , on-demand treatment of bleeding episodes , or perioperative management . Adolescent subjects age 12 to < 18 ( n = 25 ) were enrolled in the adult and adolescent safety and efficacy trial , and subjects < 12 years of age ( n = 66 ) were enrolled in a pediatric trial . The safety and efficacy of ADYNOVATE in routine prophylaxis and the treatment of bleeding episodes were comparable between children and adults . Pharmacokinetic studies in children (< 12 years ) have demonstrated higher clearance , a shorter half-life and lower incremental recovery of factor VIII compared to adults . Because clearance ( based on per kg body weight ) has been demonstrated to be higher in children (< 12 years ), dose adjustment or more frequent dosing based on per kg body weight may be needed in this population .
Geriatric Use Clinical studies of ADYNOVATE did not include subjects aged 65 and over .
© 2018 Shire US Inc ., Lexington , MA 02421 . All rights reserved . 1-800-828-2088 . SHIRE and the Shire Logo are registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates .
ADYNOVATE and ADVATE are registered trademarks of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc .
“ I certainly believe these data will impact clinical care , specifically in patients with [ myeloma and ] renal impairment .”
— NOOPUR RAJE , MD
Limitations of the analysis include a lack of response data , as well as the exclusion of patients with creatinine clearance of < 30 mL / min , which potentially limits the generalizability of the findings .
According to Dr . Raje , future trials are needed with longer follow-up periods to determine the full advantage of denosumab for preventing skeletal events in MM . “ I would like to see the use of denosumab in patients with creatinine clearance of < 30 mL / min , which is being investigated in an ongoing trial ,” she noted . “ In addition , there may be a need to study the impact of less-frequent dosing of denosumab , such as every three months , in this patient population .”
The authors reported financial relationships with Amgen , which sponsored this trial .
REFERENCE
Raje N , Terpos E , Willenbacher W , et al . Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma : an international , double-blind , double-dummy , randomised , controlled , phase 3 study . Lancet Oncol . 2018 ; 19:370-81 .
August 2018