CLINICAL NEWS percent , ranging from 3.1 to 65.6 percent . Among the 14 prospective studies , the pooled prevalence of concomitant DVT was 24 percent ( 95 % CI 18.9-30 ; p < 0.001 ), while the seven retrospective studies had a pooled prevalence of 10 percent ( 95 % CI 5.6-17.2 ; p < 0.001 ).
Among the 11 studies examining PE , the pooled prevalence of concomitant PE at SVT diagnosis was 6.9 percent ,
Brief Summary ( cont ’ d )
Table 5 : Thrombocytopenia and Neutropenia ( pooled adverse event and laboratory data )
NINLARO + Lenalidomide and Dexamethasone N = 360 ranging from 0.9 to 33 percent . Among the nine prospective studies , the pooled prevalence of concomitant PE was 8.2 percent ( 95 % CI 4.3-14.9 ; p < 0.001 ), while the two retrospective studies had a pooled prevalence of 3.6 percent ( 95 % CI 2-6.4 ; p = 0.347 ).
The researchers observed that the following risk factors were associated with SVT and concomitant DVT / PE :
Placebo + Lenalidomide and Dexamethasone N = 360
N (%) N (%)
Any Grade Grade 3-4 Any Grade Grade 3-4 Thrombocytopenia 281 ( 78 ) 93 ( 26 ) 196 ( 54 ) 39 ( 11 ) Neutropenia 240 ( 67 ) 93 ( 26 ) 239 ( 66 ) 107 ( 30 )
Eye Disorders
Eye disorders were reported with many different preferred terms but in aggregate , the frequency was 26 % in patients in the NINLARO regimen and 16 % of patients in the placebo regimen . The most common adverse reactions were blurred vision ( 6 % in the NINLARO regimen and 3 % in the placebo regimen ), dry eye ( 5 % in the NINLARO regimen and 1 % in the placebo regimen ), and conjunctivitis ( 6 % in the NINLARO regimen and 1 % in the placebo regimen ). Grade 3 adverse reactions were reported in 2 % of patients in the NINLARO regimen and 1 % in the placebo regimen .
The following serious adverse reactions have each been reported at a frequency of < 1 %: acute febrile neutrophilic dermatosis ( Sweet ’ s syndrome ), Stevens-Johnson syndrome , transverse myelitis , posterior reversible encephalopathy syndrome , tumor lysis syndrome , and thrombotic thrombocytopenic purpura .
7 DRUG INTERACTIONS
7.1 Strong CYP3A Inducers : Avoid concomitant administration of NINLARO with strong CYP3A inducers ( such as rifampin , phenytoin , carbamazepine , and St . John ’ s Wort )
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy : Women should avoid becoming pregnant while being treated with NINLARO .
Risk Summary : NINLARO can cause fetal harm when administered to a pregnant woman . There are no human data available regarding the potential effect of NINLARO on pregnancy or development of the embryo or fetus . Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose . Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO . In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively . Animal Data : In an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal variations / abnormalities ( caudal vertebrae , number of lumbar vertebrae , and full supernumerary ribs ) at doses that were also maternally toxic ( ≥ 0.3 mg / kg ). Exposures in the rabbit at 0.3 mg / kg were 1.9 times the clinical time averaged exposures at the recommended dose of 4 mg . In a rat dose range-finding embryo-fetal development study , at doses that were maternally toxic , there were decreases in fetal weights , a trend towards decreased fetal viability , and increased post-implantation losses at 0.6 mg / kg . Exposures in rats at the dose of 0.6 mg / kg was 2.5 times the clinical time averaged exposures at the recommended dose of 4 mg .
8.2 Lactation : It is not known whether NINLARO or its metabolites are present in human milk . Many drugs are present in human milk and as a result , there could be a potential for adverse events in nursing infants . Advise women to discontinue nursing .
8.3 Females and Males of Reproductive Potential : Contraception - Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment . Infertility - Fertility studies were not conducted with NINLARO ; however there were no effects on reproductive organs in either males or females in nonclinical studies in rats and dogs
8.4 Pediatric Use : Safety and effectiveness have not been established in pediatric patients .
8.5 Geriatric Use : Of the total number of subjects in clinical studies of NINLARO , 55 % were 65 and over , while 17 % were 75 and over . No overall differences in safety or effectiveness were observed between these subjects and younger subjects , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out .
8.6 Hepatic Impairment : In patients with moderate or severe hepatic impairment , the mean AUC increased by 20 % when compared to patients with normal hepatic function . Reduce the starting dose of NINLARO in patients with moderate or severe hepatic impairment .
• Age
• Obesity
• Active cancer
• Previous thromboembolic events
• Pregnancy
8.7 Renal Impairment : In patients with severe renal impairment or ESRD requiring dialysis , the mean AUC increased by 39 % when compared to patients with normal renal function . Reduce the starting dose of NINLARO in patients with severe renal impairment or ESRD requiring dialysis . NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis .
10 OVERDOSAGE : There is no known specific antidote for NINLARO overdose . In the event of an overdose , monitor the patient for adverse reactions and provide appropriate supportive care .
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling ( Patient Information ).
Dosing Instructions
• Instruct patients to take NINLARO exactly as prescribed .
• Advise patients to take NINLARO once a week on the same day and at approximately the same time for the first three weeks of a four week cycle .
• Advise patients to take NINLARO at least one hour before or at least two hours after food .
• Advise patients that NINLARO and dexamethasone should not be taken at the same time , because dexamethasone should be taken with food and NINLARO should not be taken with food .
• Advise patients to swallow the capsule whole with water . The capsule should not be crushed , chewed or opened .
• Advise patients that direct contact with the capsule contents should be avoided . In case of capsule breakage , avoid direct contact of capsule contents with the skin or eyes . If contact occurs with the skin , wash thoroughly with soap and water . If contact occurs with the eyes , flush thoroughly with water .
• If a patient misses a dose , advise them to take the missed dose as long as the next scheduled dose is ≥ 72 hours away . Advise patients not to take a missed dose if it is within 72 hours of their next scheduled dose .
• If a patient vomits after taking a dose , advise them not to repeat the dose but resume dosing at the time of the next scheduled dose .
• Advise patients to store capsules in original packaging , and not to remove the capsule from the packaging until just prior to taking NINLARO .
Thrombocytopenia : Advise patients that they may experience low platelet counts ( thrombocytopenia ). Signs of thrombocytopenia may include bleeding and easy bruising .
Gastrointestinal Toxicities : Advise patients they may experience diarrhea , constipation , nausea and vomiting and to contact their physician if these adverse reactions persist .
Peripheral Neuropathy : Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling , numbness , pain , a burning feeling in the feet or hands , or weakness in the arms or legs .
Peripheral Edema : Advise patients to contact their physicians if they experience unusual swelling of their extremities or weight gain due to swelling .
Cutaneous Reactions : Advise patients to contact their physicians if they experience new or worsening rash .
Hepatotoxicity : Advise patients to contact their physicians if they experience jaundice or right upper quadrant abdominal pain .
Pregnancy : Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO and for 90 days following the final dose . Advise patients to contact their physicians immediately if they or their female partner become pregnant during treatment or within 90 days of the final dose .
Concomitant Medications : Advise patients to speak with their physicians about any other medication they are currently taking and before starting any new medications .
Please see full Prescribing Information for NINLARO at NINLARO-hcp . com .
NINLARO is a registered trademark of Millennium Pharmaceuticals , Inc . Millennium Pharmaceuticals , Inc . is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited .
© 2016 Millennium Pharmaceuticals , Inc . 20160209 v2 USO / IXA / 15 / 0123 ( 2 )
• Use of oral contraceptives
• Hormone replacement therapy
• Recent surgery
• Autoimmune diseases
A meta-regression analysis showed that female patients , those who had experienced recent trauma , and pregnant women had a lower prevalence of concomitant DVT / PE at the time of SVT diagnosis , while increasing age was a predictor of DVT / PE in SVT patients .
“ Interestingly , when we specifically analyzed data from studies enrolling outpatients , female gender and recent trauma were confirmed as negative predictors of concomitant involvement of the deep venous system at the time of SVT diagnosis ( p < 0.001 ),” the authors noted .
Dr . Di Minno and authors proposed several possible explanations for the co-existence of SVT and DVT / PE , including the migration of the SVT toward the deep venous system , via the saphenofemoral junction ( SFJ ), the saphenopopliteal junction , or a perforating vein . Involvement of the SFJ was reported by 17.5 percent of SVT patients , suggesting it has a direct effect on the prevalence of deep venous system involvement .
Limitations of the analysis include the heterogeneity among the studies and the differences in the prevalence of concomitant risk factors for VTE among different study populations . In addition , the prevalence of DVT in this analysis was slightly lower than what previous large studies have found . There is also a risk of publication bias with this type of meta-analysis .
“ The results of our large metaanalysis suggest that the prevalence of concomitant DVT and PE in patients presenting with SVT is not negligible ,” the authors concluded . “ Screening for a major thromboembolic event might be worthwhile in some ‘ high-risk ’ SVT patients , to allow adequate anticoagulant treatment to be planned .” Further studies are needed to confirm these findings and to identify clinical and demographic predictors of the presence of DVT / PE in SVT patients , they added .
REFERENCE
Di Minno MND , Ambrosino P , Ambrosini F , et al . Prevalence of deep vein thrombosis and pulmonary embolism in patients with superficial vein thrombosis : a systematic review and metaanalysis . J Thromb Haemost . 2016 ; 14:964-72 .
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