ninlaro

Important safety information

Thrombocytopenia : Monitor platelet counts at least monthly during treatment and adjust dosing, as needed. ( 2.2 , 5.1 ) Gastrointestinal Toxicities : Adjust dosing for severe diarrhea, constipation, nausea, and vomiting, as needed. ( 2.2 , 5.2 ) Peripheral Neuropathy : Monitor patients for symptoms of peripheral neuropathy and adjust dosing, as needed. ( 2.2 , 5.3 ) Peripheral Edema : Monitor for fluid retention. Investigate for underlying causes, when appropriate. Adjust dosing, as needed. ( 2.2 , 5.4 ) Cutaneous Reactions : Monitor patients for rash and adjust dosing, as needed. ( 2.2 , 5.5 ) Thrombotic Microangiopathy : Monitor for signs and symptoms. Discontinue NINLARO if suspected. ( 5.6 ) Hepatotoxicity : Monitor hepatic enzymes during treatment. ( 5.7 ) Embryo-Fetal Toxicity : NINLARO can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective non-hormonal contraception. ( 5.8 , 8.1 , 8.3 ) Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting : Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials. ( 5.9 ) 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 [see Adverse Reactions (6.1) ] . Grade 3 thrombocytopenia was reported in 17% of patients in the NINLARO regimen and Grade 4 thrombocytopenia was reported in 13% in the NINLARO regimen. The rate of platelet transfusions was 10% in the NINLARO regimen and 7% 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 [see Dosage and Administration (2.2) ] 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 52% of patients in the NINLARO regimen and 43% in the placebo regimen, constipation in 35% and 28%, respectively, nausea in 32% and 23%, respectively, and vomiting in 26% and 13%, respectively. Diarrhea resulted in discontinuation of one or more of the three drugs in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen [see Adverse Reactions (6.1) ] . Adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2) ] . 5.3 Peripheral Neuropathy The majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the NINLARO regimen and 16% in the placebo regimen) and Grade 2 (11% in the NINLARO regimen and 6% in the placebo regimen) [see Adverse Reactions (6.1) ] . Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens. The most commonly reported reaction was peripheral sensory neuropathy (24% and 17% 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 4% of patients in the NINLARO regimen and <1% of patients in the placebo regimen. Patients should be monitored for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification [see Dosage and Administration (2.2) ] . 5.4 Peripheral Edema Peripheral edema was reported in 27% and 21% of patients in the NINLARO and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (17% in the NINLARO regimen and 14% in the placebo regimen) and Grade 2 (7% in the NINLARO regimen and 6% in the placebo regimen). Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively [see Adverse Reactions (6.1) ] . Peripheral edema resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. 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 [see Dosage and Administration (2.2) ] . 5.5 Cutaneous Reactions Rash was reported in 27% of patients in the NINLARO regimen and 16% of patients in the placebo regimen. The majority of the rash adverse reactions were Grade 1 (15% in the NINLARO regimen and 9% in the placebo regimen) or Grade 2 (9% in the NINLARO regimen and 4% in the placebo regimen) [see Adverse Reactions (6.1) ] . Grade 3 rash was reported in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Serious adverse reactions of rash were reported in <1% of patients in the NINLARO regimen. 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 [see Dosage and Administration (2.2) ] . Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatal cases, have been reported with NINLARO [see Adverse Reactions (6.1 , 6.2 )] . If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue NINLARO and manage as clinically indicated. 5.6 Thrombotic Microangiopathy Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO [see Adverse Reactions (6.1) ] . Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known. 5.7 Hepatotoxicity Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients treated with NINLARO [see Adverse Reactions (6.1) ] . Hepatotoxicity has been reported (10% in the NINLARO regimen and 9% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2) ] . 5.8 Embryo-Fetal Toxicity NINLARO can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animal studies. 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the last dose [see Drug Interactions (7.1) and Use in Specific Populations (8.1 , 8.3) ] . 5.9 Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting In two prospective randomized clinical trials in multiple myeloma in the maintenance setting, treatment with NINLARO resulted in increased deaths. Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials [see Clinical Studies (14.2) ] .