ASH Clinical News November 2016 | Page 48

Literature Scan

REFERENCE : 1 . Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology ( NCCN Guidelines ®) for Multiple Myeloma V . 3.2016 . © National Comprehensive Cancer Network , Inc 2016 . All rights reserved . Accessed April 5 , 2016 . To view the most recent and complete version of the guideline , go online to NCCN . org . NATIONAL COMPREHENSIVE CANCER NETWORK ®, NCCN ®, NCCN GUIDELINES ®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network , Inc .

BRIEF SUMMARY OF PRESCRIBING INFORMATION NINLARO ( ixazomib ) capsules , for oral use

1 INDICATION

NINLARO ( ixazomib ) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy .

5 WARNINGS AND PRECAUTIONS

5.1 Thrombocytopenia : Thrombocytopenia has been reported with NINLARO with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle . Three percent of patients in the NINLARO regimen and 1 % of patients in the placebo regimen had a platelet count ≤ 10,000 / mm 3 during treatment . Less than 1 % of patients in both regimens had a platelet count ≤ 5000 / mm 3 during treatment . Discontinuations due to thrombocytopenia were similar in both regimens (< 1 % of patients in the NINLARO regimen and 2 % of patients in the placebo regimen discontinued one or more of the three drugs ). The rate of platelet transfusions was 6 % in the NINLARO regimen and 5 % in the placebo regimen .

Monitor platelet counts at least monthly during treatment with NINLARO . Consider more frequent monitoring during the first three cycles . Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines .

5.2 Gastrointestinal Toxicities : Diarrhea , constipation , nausea , and vomiting , have been reported with NINLARO , occasionally requiring use of antidiarrheal and antiemetic medications , and supportive care . Diarrhea was reported in 42 % of patients in the NINLARO regimen and 36 % in the placebo regimen , constipation in 34 % and 25 %, respectively , nausea in 26 % and 21 %, respectively , and vomiting in 22 % and 11 %, respectively . Diarrhea resulted in discontinuation of one or more of the three drugs in 1 % of patients in the NINLARO regimen and < 1 % of patients in the placebo regimen . Adjust dosing for Grade 3 or 4 symptoms .

5.3 Peripheral Neuropathy : The majority of peripheral neuropathy adverse reactions were Grade 1 ( 18 % in the NINLARO regimen and 14 % in the placebo regimen ) and Grade 2 ( 8 % in the NINLARO regimen and 5 % in the placebo regimen ). Grade 3 adverse reactions of peripheral neuropathy were reported at 2 % in both regimens ; there were no Grade 4 or serious adverse reactions .

The most commonly reported reaction was peripheral sensory neuropathy ( 19 % and 14 % in the NINLARO and placebo regimen , respectively ). Peripheral motor neuropathy was not commonly reported in either regimen (< 1 %). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1 % of patients in both regimens . Patients should be monitored for symptoms of neuropathy . Patients experiencing new or worsening peripheral neuropathy may require dose modification .

5.4 Peripheral Edema : Peripheral edema was reported in 25 % and 18 % of patients in the NINLARO and placebo regimens , respectively . The majority of peripheral edema adverse reactions were Grade 1 ( 16 % in the NINLARO regimen and 13 % in the placebo regimen ) and Grade 2 ( 7 % in the NINLARO regimen and 4 % in the placebo regimen ).

Grade 3 peripheral edema was reported in 2 % and 1 % of patients in the NINLARO and placebo regimens , respectively . There was no Grade 4 peripheral edema reported . There were no discontinuations reported due to peripheral edema . Evaluate for underlying causes and provide supportive care , as necessary . Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms .

5.5 Cutaneous Reactions : Rash was reported in 19 % of patients in the NINLARO regimen and 11 % of patients in the placebo regimen . The majority of the rash adverse reactions were Grade 1 ( 10 % in the NINLARO regimen and 7 % in the placebo regimen ) or Grade 2 ( 6 % in the NINLARO regimen and 3 % in the placebo regimen ). Grade 3 rash was reported in 3 % of patients in the NINLARO regimen and 1 % of patients in the placebo regimen . There were no Grade 4 or serious adverse reactions of rash reported . The most common type of rash reported in both regimens included maculo-papular and macular rash . Rash resulted in discontinuation of one or more of the three drugs in < 1 % of patients in both regimens . Manage rash with supportive care or with dose modification if Grade 2 or higher .

5.6 Hepatotoxicity : Drug-induced liver injury , hepatocellular injury , hepatic steatosis , hepatitis cholestatic and hepatotoxicity have each been reported in < 1 % of patients treated with NINLARO . Events of liver impairment have been reported ( 6 % in the NINLARO regimen and 5 % in the placebo regimen ). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms .

5.7 Embryo-Fetal Toxicity : NINLARO can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animals . There are no adequate and well-controlled studies in pregnant women using NINLARO . 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 .

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with NINLARO . If NINLARO is used during pregnancy or if the patient becomes pregnant while taking NINLARO , the patient should be apprised of the potential hazard to the fetus . Advise females of reproductive potential that they must use effective contraception during treatment with NINLARO and for 90 days following the final dose .

6 ADVERSE REACTIONS

The following adverse reactions are described in detail in other sections of the prescribing information :

• Thrombocytopenia [ see Warnings and Precautions ( 5.1 )]

• Gastrointestinal Toxicities [ see Warnings and Precautions ( 5.2 )]

• Peripheral Neuropathy [ see Warnings and Precautions ( 5.3 )]

• Peripheral Edema [ see Warnings and Precautions ( 5.4 )]

• Cutaneous Reactions [ see Warnings and Precautions ( 5.5 )]

• Hepatotoxicity [ see Warnings and Precautions ( 5.6 )] 6.1 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 the clinical trials of another drug and may not reflect the rates observed in practice .

The safety population from the randomized , double-blind , placebo-controlled clinical study included 720 patients with relapsed and / or refractory multiple myeloma , who received NINLARO in combination with lenalidomide and dexamethasone ( NINLARO regimen ; N = 360 ) or placebo in combination with lenalidomide and dexamethasone ( placebo regimen ; N = 360 ).

The most frequently reported adverse reactions ( ≥ 20 %) in the NINLARO regimen and greater than the placebo regimen were diarrhea , constipation , thrombocytopenia , peripheral neuropathy , nausea , peripheral edema , vomiting , and back pain . Serious adverse reactions reported in ≥ 2 % of patients included thrombocytopenia ( 2 %) and diarrhea ( 2 %). For each adverse reaction , one or more of the three drugs was discontinued in ≤ 1 % of patients in the NINLARO regimen .

Table 4 : Non-Hematologic Adverse Reactions Occurring in ≥ 5 % of Patients with a ≥ 5 % Difference Between the NINLARO Regimen and the Placebo Regimen ( All Grades , Grade 3 and Grade 4 )

System Organ Class / Preferred Term

Infections and infestations Upper respiratory tract infection

NINLARO + Lenalidomide and Dexamethasone N = 360

All

Placebo + Lenalidomide and Dexamethasone N = 360

N (%) N (%)

Grade 3

Grade 4

All

Grade 3

Grade 4

69 ( 19 ) 1 (< 1 ) 0 52 ( 14 ) 2 (< 1 ) 0

Gastrointestinal disorders Diarrhea Constipation Nausea Vomiting

151 ( 42 ) 122 ( 34 ) 92 ( 26 ) 79 ( 22 )

22 ( 6 ) 1 (< 1 ) 6 ( 2 ) 4 ( 1 )

0 0 0 0

130 ( 36 ) 90 ( 25 ) 74 ( 21 ) 38 ( 11 )

8 ( 2 )

1 (< 1 ) 0 2 (< 1 )

Note : Adverse reactions included as preferred terms are based on MedDRA version 16.0 . * Represents a pooling of preferred terms

0 0 0 0

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