Ninlaro Special Precautions

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/mm³ during treatment. Less than 1% of patients in both regimens had a platelet count ≤ 5000/mm³ 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 [see Dosage & Administration] and platelet transfusions as per standard medical guidelines.
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 [see Dosage & Administration].
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 [see Dosage & Administration].
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 [see Dosage & Administration].
Cutaneous Reactions: Rash has been reported with Ninlaro (see Adverse Reactions). Rash should be managed with supportive care or with dose modification if Grade 2 or higher (see Adverse Reactions). Stevens-Johnson syndrome has also been reported with ixazomib (see Adverse Reactions). If Stevens-Johnson syndrome occurs, discontinue ixazomib.
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. 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.
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 [see Dosage & Administration].
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. Women using hormonal contraceptives should also use a barrier method of contraception [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation and Pharmacology: Toxicology: Nonclinical Toxicology under Actions].
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 [see Dosage & Administration, Pharmacology under Actions].
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 [see Dosage & Administration, Pharmacology under Actions].
Use in Children: Safety and effectiveness have not been established in pediatric patients.
Use in the Elderly: 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.