ADVERSE REACTIONS SECTION.

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)] Thrombotic Microangiopathy [see Warnings and Precautions (5.6)] Hepatotoxicity [see Warnings and Precautions (5.7)] 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)] Thrombotic Microangiopathy [see Warnings and Precautions (5.6)] Hepatotoxicity [see Warnings and Precautions (5.7)] The most common adverse reactions (>= 20%) are diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-617-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 summarizes the adverse reactions occurring in at least 5% of patients with at least 5% difference between the NINLARO regimen and the placebo regimen.Table 4: Non-Hematologic Adverse Reactions Occurring in >= 5% of Patients with >= 5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade and Grade 4)System Organ Class /Preferred TermNINLARO Lenalidomide and DexamethasoneN=360Placebo Lenalidomide and DexamethasoneN=360N (%)N (%)AllGrade 3Grade 4AllGrade 3Grade 4Note: Adverse reactions included as preferred terms are based on MedDRA version 16.0.Infections and infestations Upper respiratory tract infection69 (19)1 (< 1)052 (14)2 (< 1)0Nervous system disorders Peripheral neuropathiesRepresents pooling of preferred terms 100 (28)7 (2)077 (21)7 (2)0Gastrointestinal disorders Diarrhea151 (42)22 (6)0130 (36)8 (2)0 Constipation122 (34)1 (< 1)090 (25)1 (< 1)0 Nausea92 (26)6 (2)074 (21)00 Vomiting79 (22)4 (1)038 (11)2 (< 1)0Skin and subcutaneous tissue disorders Rash 68 (19)9 (3)038 (11)5 (1)0Musculoskeletal and connective tissue disorders Back pain74 (21)2 (< 1)057 (16)9 (3)0General disorders and administration site conditions Edema peripheral91 (25)8 (2)066 (18)4 (1)0Table represents pooled information from adverse event and laboratory data.Table 5: Thrombocytopenia and NeutropeniaNINLARO Lenalidomide and DexamethasoneN=360Placebo Lenalidomide and DexamethasoneN=360N (%)N (%)Any GradeGrade 3-4Any GradeGrade 3-4Thrombocytopenia281 (78)93 (26)196 (54)39 (11)Neutropenia240 (67)93 (26)239 (66)107 (30). Herpes ZosterHerpes zoster was reported in 4% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Antiviral prophylaxis was allowed at the healthcare providers discretion. Patients treated in the NINLARO regimen who received antiviral prophylaxis had lower incidence (< 1%) of herpes zoster infection compared to patients who did not receive prophylaxis (6%).. Eye DisordersEye 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 adverse reactions were reported in 2% of patients in the NINLARO regimen and 1% in the placebo regimen.. Adverse Reactions Reported Outside of the Randomized Controlled TrialThe following serious adverse reactions have each been reported at frequency of 1%: acute febrile neutrophilic dermatosis (Sweets syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ixazomib is reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta subunit of the 20S proteasome.Ixazomib induced apoptosis of multiple myeloma cell lines in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in mouse multiple myeloma tumor xenograft model.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyNINLARO did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients.. 12.3 Pharmacokinetics. AbsorptionAfter oral administration, the median time to achieve peak ixazomib plasma concentrations was one hour. The mean absolute oral bioavailability was 58%, based on population PK analysis. Ixazomib AUC increases in dose proportional manner over dose range of 0.2 to 10.6 mg.A food effect study conducted in patients with single mg dose of ixazomib showed that high-fat meal decreased ixazomib AUC by 28% and Cmax by 69% [see Dosage and Administration (2.1)].. DistributionIxazomib is 99% bound to plasma proteins and distributes into red blood cells with blood-to-plasma ratio of 10. The steady-state volume of distribution is 543 L.. EliminationBased on population PK analysis, systemic clearance was approximately 1.9 L/hr with inter-individual variability of 44%. The terminal half-life (t1/2) of ixazomib was 9.5 days. Following weekly oral dosing, the accumulation ratio was determined to be 2-fold.. MetabolismAfter oral administration of radiolabeled dose, ixazomib represented 70% of total drug-related material in plasma. Metabolism by multiple CYP enzymes and non-CYP proteins is expected to be the major clearance mechanism for ixazomib. At clinically relevant ixazomib concentrations, in vitro studies using human cDNA-expressed cytochrome P450 isozymes showed that no specific CYP isozyme predominantly contributes to ixazomib metabolism. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).. ExcretionAfter administration of single oral dose of 14C-ixazomib to patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for 3.5% of the administered dose recovered in urine.. Specific PopulationsThere was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m2), or race on the clearance of ixazomib based on population PK analysis.. Patients with Hepatic ImpairmentThe PK of ixazomib was similar in patients with normal hepatic function and in patients with mild hepatic impairment (total bilirubin <= ULN and AST ULN or total bilirubin 1-1.5 ULN and any AST) based on population PK analysis.The PK of ixazomib was characterized in patients with normal hepatic function at mg (N=12), moderate hepatic impairment at 2.3 mg (total bilirubin 1.5-3 ULN, N=13) or severe hepatic impairment at 1.5 mg (total bilirubin 3 ULN, N=18). Dose-normalized mean AUC was 20% higher in patients with moderate or severe hepatic impairment as compared to patients with normal hepatic function [see Dosage and Administration (2.3)].. Patients with Renal ImpairmentThe PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance >= 30 mL/min) based on population PK analysis.The PK of ixazomib was characterized at dose of mg in patients with normal renal function (creatinine clearance >= 90 mL/min, N=18), severe renal impairment (creatinine clearance 30 mL/min, N=14), or ESRD requiring dialysis (N=6). Mean AUC was 39% higher in patients with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal function. Pre- and post-dialyzer concentrations of ixazomib measured during the hemodialysis session were similar, suggesting that ixazomib is not dialyzable [see Dosage and Administration (2.4)].. Drug Interaction Studies. Effect of Other Drugs on NINLARO. Strong CYP3A InducersCo-administration of NINLARO with rifampin decreased ixazomib Cmax by 54% and AUC by 74% [see Drug Interactions (7.1)].. Strong CYP3A InhibitorsCo-administration of NINLARO with clarithromycin did not result in clinically meaningful change in the systemic exposure of ixazomib.. Strong CYP1A2 InhibitorsCo-administration of NINLARO with strong CYP1A2 inhibitors did not result in clinically meaningful change in the systemic exposure of ixazomib based on population PK analysis.. Effect of NINLARO on Other DrugsIxazomib is neither reversible nor time-dependent inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Ixazomib did not induce CYP1A2, CYP2B6, and CYP3A4/5 activity or corresponding immunoreactive protein levels. NINLARO is not expected to produce drug-drug interactions via CYP inhibition or induction.. Transporter-Based InteractionsIxazomib is low affinity substrate of P-gp. Ixazomib is not substrate of BCRP, MRP2 or hepatic OATPs. Ixazomib is not an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K. NINLARO is not expected to cause transporter-mediated drug-drug interactions.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy and safety of NINLARO in combination with lenalidomide and dexamethasone was evaluated in randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy. Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the study.A total of 722 patients were randomized in 1:1 ratio to receive either the combination of NINLARO, lenalidomide and dexamethasone (N=360; NINLARO regimen) or the combination of placebo, lenalidomide and dexamethasone (N=362; placebo regimen) until disease progression or unacceptable toxicity. Randomization was stratified according to number of prior lines of therapy (1 versus or 3), myeloma International Staging System (ISS) (stage or II versus III), and previous therapy with proteasome inhibitor (exposed or naive). Twenty three percent (N=166) of the patients had light chain disease and 12% (N=87) of patients had free light chain-measurable only disease.Thromboprophylaxis was recommended for all patients in both treatment groups according to the lenalidomide prescribing information. Antiemetics were used in 19% of patients in the NINLARO regimen and 12% of patients in the placebo regimen; antivirals in 64% and 60%, respectively, and antihistamines in 27% and 19%, respectively. These medications were given to patients at the healthcare providers discretion as prophylaxis and/or management of symptoms.Patients received NINLARO mg or placebo on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of 28-day cycle. Patients with renal impairment received starting dose of lenalidomide according to its prescribing information. Treatment continued until disease progression or unacceptable toxicities.Table summarizes the baseline patient and disease characteristics in the study. The baseline demographics and disease characteristics were balanced and comparable between the study regimens.Table 6: Baseline Patient and Disease CharacteristicsNINLARO Lenalidomide and Dexamethasone(N 360)Placebo Lenalidomide and Dexamethasone(N 362)Patient CharacteristicsMedian age in years (range)66 (38, 91)66 (30, 89)Gender (%) Male/ Female58/4256/44Age Group (% [< 65/ >= 65 years])41/5943/57Race (%) White310 (86)301 (83) Black7 (2)6 (2) Asian30 (8)34 (9) Other or Not Specified13 (4)21 (6)ECOG performance status, (%) or 1336 (93)334 (92) 218 (5)24 (7) Missing6 (2)4 (1)Creatinine clearance, (%) 30 mL/min5 (1)5 (1) 30-59 mL/min74 (21)95 (26) >= 60 mL/min281 (78)261 (72)Disease CharacteristicsMyeloma ISS stage, (%) Stage or II315 (87)320 (88) Stage III45 (13)42 (12)Prior line therapies (%) Median (range)1 (1, 3)1 (1,3) 1224 (62)217 (60) or 3136 (38)145 (40)Status at Baseline (%) Relapsed276 (77)280 (77) RefractoryPrimary refractory, defined as best response of stable disease or disease progression on all prior lines of therapy, was documented in 7% and 6% of patients in the NINLARO regimen and placebo regimens, respectively. 42 (12)40 (11) Relapsed and Refractory41 (11)42 (12)Type of Prior Therapy (%) Bortezomib containing248 (69)250 (69) Carfilzomib containing1 (<1)4 (1) Thalidomide containing157 (44)170 (47) Lenalidomide containing44 (12)44 (12) Melphalan containing293 (81)291 (80) Stem cell transplantation212 (59)199 (55)High risk (deletion (del) 17, t(4:14) and/or t(14:16)75 (21)62 (17) deletion del (17)36 (10)33 (9)The efficacy of NINLARO was evaluated by progression-free survival (PFS) according to the 2011 International Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by blinded independent review committee (IRC) based on central lab results. Response was assessed every four weeks until disease progression.The approval of NINLARO was based upon statistically significant improvement in PFS of the NINLARO regimen compared to the placebo regimen. PFS results are summarized in Table and shown in Figure 1.Table 7: Progression-Free Survival and Response RateNINLARO Lenalidomide and Dexamethasone(N 360)Placebo Lenalidomide and Dexamethasone(N 362)NE: Not evaluable.Progression-free SurvivalPFS Events, (%)129 (36)157 (43)Median (months)(95% CI)20.6(17.0, NE)14.7(12.9, 17.6)Hazard RatioHazard ratio is based on stratified Coxs proportional hazard regression model. hazard ratio less than indicates an advantage for the NINLARO regimen. (95% CI)0.74(0.59, 0.94)p-valueP-value is based on the stratified log-rank test. 0.012Response RateOverall Response Rate, (%)282 (78)259 (72) Complete Response42 (12)24 (7) Very Good Partial Response131 (36)117 (32) Partial Response109 (30)118 (33)The median time to response was 1.1 months in the NINLARO regimen and 1.9 months in the placebo regimen. The median duration of response was 20.5 months in the NINLARO regimen and 15 months in the placebo regimen for responders in the response evaluable population.Figure 1: Kaplan-Meier Plot of Progression-Free SurvivalA non-inferential PFS analysis was conducted at median follow up of 23 months with 372 PFS events. Hazard ratio of PFS was 0.82 (95% confidence interval [0.67, 1.0]) for NINLARO regimen versus placebo regimen, and estimated median PFS was 20 months in the NINLARO regimen and 15.9 months in the placebo regimen. At the same time, planned interim OS analysis was conducted with 35% of the required number of deaths for final OS analysis; there were 81 deaths in the NINLARO regimen and 90 deaths in the placebo regimen. An OS benefit was not demonstrated.. Figure 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended starting dose of mg taken orally on Days 1, 8, and 15 of 28-day cycle. (2.1)Dose should be taken at least one hour before or at least two hours after food. (2.1). Recommended starting dose of mg taken orally on Days 1, 8, and 15 of 28-day cycle. (2.1). Dose should be taken at least one hour before or at least two hours after food. (2.1). 2.1 Dosing and Administration Guidelines. NINLARO in combination with lenalidomide and dexamethasoneThe recommended starting dose of NINLARO is mg administered orally once week on Days 1, 8, and 15 of 28-day treatment cycle.The recommended starting dose of lenalidomide is 25 mg administered daily on Days through 21 of 28-day treatment cycle.The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of 28-day treatment cycle.Table 1: Dosing Schedule for NINLARO taken with Lenalidomide and Dexamethasone Take medicine28-Day Cycle (a 4-week cycle)Week 1Week 2Week 3Week 4Day 1Days 2-7Day 8Days 9-14Day 15Days 16-21Day 22Days 23-28NINLAROLenalidomide Daily Daily DailyDexamethasoneFor additional information regarding lenalidomide and dexamethasone, refer to their prescribing information.NINLARO should be taken once week on the same day and at approximately the same time for the first three weeks of four week cycle. The importance of carefully following all dosage instructions should be discussed with patients starting treatment. Instruct patients to take the recommended dosage as directed, because overdosage has led to deaths [see Overdosage (10)]. NINLARO should be taken at least one hour before or at least two hours after food [see Clinical Pharmacology (12.3)]. The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened [see How Supplied/Storage and Handling (16.3)].If NINLARO dose is delayed or missed, the dose should be taken only if the next scheduled dose is >= 72 hours away. missed dose should not be taken within 72 hours of the next scheduled dose. double dose should not be taken to make up for the missed dose.If vomiting occurs after taking dose, the patient should not repeat the dose. The patient should resume dosing at the time of the next scheduled dose.Prior to initiating new cycle of therapy:Absolute neutrophil count should be at least 1,000/mm3 Platelet count should be at least 75,000/mm3 Non-hematologic toxicities should, at the healthcare providers discretion, generally be recovered to patients baseline condition or Grade or lowerTreatment should be continued until disease progression or unacceptable toxicity. Absolute neutrophil count should be at least 1,000/mm3 Platelet count should be at least 75,000/mm3 Non-hematologic toxicities should, at the healthcare providers discretion, generally be recovered to patients baseline condition or Grade or lower. Concomitant MedicationsConsider antiviral prophylaxis in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation [see Adverse Reactions (6.1)].. 2.2 Dose Modification Guidelines. The NINLARO dose reduction steps are presented in Table and the dose modification guidelines are provided in Table 3.Table 2: NINLARO Dose Reductions due to Adverse ReactionsRecommended starting doseRecommended starting dose of mg in patients with moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease requiring dialysis [see Dosage and Administration (2.3, 2.4)]. First reduction toSecond reduction toDiscontinue mg mg 2.3 mgAn alternating dose modification approach is recommended for NINLARO and lenalidomide for thrombocytopenia, neutropenia, and rash as described in Table 3. Refer to the lenalidomide prescribing information if dose reduction is needed for lenalidomide.Table 3: Dose Modifications Guidelines for NINLARO in Combination with Lenalidomide and DexamethasoneHematological ToxicitiesRecommended ActionsThrombocytopenia (Platelet Count)Platelet count less than 30,000/mm3 Withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm3.Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose.If platelet count falls to less than 30,000/mm3 again, withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm3.Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.For additional occurrences, alternate dose modification of lenalidomide and NINLARO Neutropenia (Absolute Neutrophil Count)Absolute neutrophil count less than 500/mm3 Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3. Consider adding G-CSF as per clinical guidelines.Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose.If absolute neutrophil count falls to less than 500/mm3 again, withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3.Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose. Non-Hematological ToxicitiesRecommended ActionsRashGradeGrading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03 or 3Withhold lenalidomide until rash recovers to Grade or lower.Following recovery, resume lenalidomide at the next lower dose according to its prescribing information.If Grade or rash occurs again, withhold NINLARO and lenalidomide until rash recovers to Grade or lower.Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose. Grade 4Discontinue treatment regimen.Peripheral NeuropathyGrade Peripheral Neuropathy with Pain or Grade Peripheral NeuropathyWithhold NINLARO until peripheral neuropathy recovers to Grade or lower without pain or patients baseline.Following recovery, resume NINLARO at its most recent dose.Grade Peripheral Neuropathy with Pain or Grade Peripheral NeuropathyWithhold NINLARO. Toxicities should, at the healthcare providers discretion, generally recover to patients baseline condition or Grade or lower prior to resuming NINLARO.Following recovery, resume NINLARO at the next lower dose.Grade Peripheral NeuropathyDiscontinue treatment regimen.Other Non-Hematological ToxicitiesOther Grade or Non-Hematological ToxicitiesWithhold NINLARO. Toxicities should, at the healthcare providers discretion, generally recover to patients baseline condition or Grade or lower prior to resuming NINLARO.If attributable to NINLARO, resume NINLARO at the next lower dose following recovery.. Withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm3.. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose.. If platelet count falls to less than 30,000/mm3 again, withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm3.. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.For additional occurrences, alternate dose modification of lenalidomide and NINLARO Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3. Consider adding G-CSF as per clinical guidelines.. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose.. If absolute neutrophil count falls to less than 500/mm3 again, withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3.. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose. Withhold lenalidomide until rash recovers to Grade or lower.. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information.. If Grade or rash occurs again, withhold NINLARO and lenalidomide until rash recovers to Grade or lower.. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose. Withhold NINLARO until peripheral neuropathy recovers to Grade or lower without pain or patients baseline.. Following recovery, resume NINLARO at its most recent dose.. Withhold NINLARO. Toxicities should, at the healthcare providers discretion, generally recover to patients baseline condition or Grade or lower prior to resuming NINLARO.. Following recovery, resume NINLARO at the next lower dose.. Withhold NINLARO. Toxicities should, at the healthcare providers discretion, generally recover to patients baseline condition or Grade or lower prior to resuming NINLARO.. If attributable to NINLARO, resume NINLARO at the next lower dose following recovery.. 2.3 Dosage in Patients with Hepatic Impairment. Reduce the starting dose of NINLARO to mg in patients with moderate (total bilirubin greater than 1.5-3 ULN) or severe (total bilirubin greater than x ULN) hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 2.4 Dosage in Patients with Renal Impairment. Reduce the starting dose of NINLARO to mg in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.

INFORMATION FOR PATIENTS SECTION.

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 week on the same day and at approximately the same time for the first three weeks of four week cycle. The importance of carefully following all dosage instructions should be discussed with patients starting treatment. Advise patients to take the recommended dosage as directed, because overdosage has led to deaths [see Overdosage (10)]. 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 patient misses dose, advise them to take the missed dose as long as the next scheduled dose is >= 72 hours away. Advise patients not to take missed dose if it is within 72 hours of their next scheduled dose.If patient vomits after taking 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.[see Dosage and Administration (2.1)]. Instruct patients to take NINLARO exactly as prescribed.. Advise patients to take NINLARO once week on the same day and at approximately the same time for the first three weeks of four week cycle. The importance of carefully following all dosage instructions should be discussed with patients starting treatment. Advise patients to take the recommended dosage as directed, because overdosage has led to deaths [see Overdosage (10)]. 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 patient misses dose, advise them to take the missed dose as long as the next scheduled dose is >= 72 hours away. Advise patients not to take missed dose if it is within 72 hours of their next scheduled dose.. If patient vomits after taking 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.. ThrombocytopeniaAdvise patients that they may experience low platelet counts (thrombocytopenia). Signs of thrombocytopenia may include bleeding and easy bruising. [see Warnings and Precautions (5.1)].. Gastrointestinal ToxicitiesAdvise patients they may experience diarrhea, constipation, nausea and vomiting and to contact their healthcare providers if these adverse reactions persist. [see Warnings and Precautions (5.2)].. Peripheral NeuropathyAdvise patients to contact their healthcare providers if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, burning feeling in the feet or hands, or weakness in the arms or legs. [see Warnings and Precautions (5.3)].. Peripheral EdemaAdvise patients to contact their healthcare providers if they experience unusual swelling of their extremities or weight gain due to swelling [see Warnings and Precautions (5.4)].. Cutaneous ReactionsAdvise patients to contact their healthcare providers if they experience new or worsening rash [see Warnings and Precautions (5.5)].. Thrombotic MicroangiopathyAdvise patients to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur [see Warnings and Precautions (5.6)].. HepatotoxicityAdvise patients to contact their healthcare providers if they experience jaundice or right upper quadrant abdominal pain [see Warnings and Precautions (5.7)].. Other Adverse ReactionsAdvise patients to contact their healthcare providers if they experience signs and symptoms of acute febrile neutrophilic dermatosis (Sweets syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura [see Adverse Reactions (6.1)].. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the final dose. Advise women using hormonal contraceptives to also use barrier method of contraception [see Use in Specific Populations (8.1)].Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the final dose [see Use in Specific Populations (8.1)].. LactationAdvise women not to breastfeed during treatment with NINLARO and for 90 days after the final dose [see Use in Specific Populations (8.2)]. Concomitant MedicationsAdvise patients to speak with their healthcare providers about any other medication they are currently taking and before starting any new medications.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter oral administration, the median time to achieve peak ixazomib plasma concentrations was one hour. The mean absolute oral bioavailability was 58%, based on population PK analysis. Ixazomib AUC increases in dose proportional manner over dose range of 0.2 to 10.6 mg.A food effect study conducted in patients with single mg dose of ixazomib showed that high-fat meal decreased ixazomib AUC by 28% and Cmax by 69% [see Dosage and Administration (2.1)].. DistributionIxazomib is 99% bound to plasma proteins and distributes into red blood cells with blood-to-plasma ratio of 10. The steady-state volume of distribution is 543 L.. EliminationBased on population PK analysis, systemic clearance was approximately 1.9 L/hr with inter-individual variability of 44%. The terminal half-life (t1/2) of ixazomib was 9.5 days. Following weekly oral dosing, the accumulation ratio was determined to be 2-fold.. MetabolismAfter oral administration of radiolabeled dose, ixazomib represented 70% of total drug-related material in plasma. Metabolism by multiple CYP enzymes and non-CYP proteins is expected to be the major clearance mechanism for ixazomib. At clinically relevant ixazomib concentrations, in vitro studies using human cDNA-expressed cytochrome P450 isozymes showed that no specific CYP isozyme predominantly contributes to ixazomib metabolism. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).. ExcretionAfter administration of single oral dose of 14C-ixazomib to patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for 3.5% of the administered dose recovered in urine.. Specific PopulationsThere was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m2), or race on the clearance of ixazomib based on population PK analysis.. Patients with Hepatic ImpairmentThe PK of ixazomib was similar in patients with normal hepatic function and in patients with mild hepatic impairment (total bilirubin <= ULN and AST ULN or total bilirubin 1-1.5 ULN and any AST) based on population PK analysis.The PK of ixazomib was characterized in patients with normal hepatic function at mg (N=12), moderate hepatic impairment at 2.3 mg (total bilirubin 1.5-3 ULN, N=13) or severe hepatic impairment at 1.5 mg (total bilirubin 3 ULN, N=18). Dose-normalized mean AUC was 20% higher in patients with moderate or severe hepatic impairment as compared to patients with normal hepatic function [see Dosage and Administration (2.3)].. Patients with Renal ImpairmentThe PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance >= 30 mL/min) based on population PK analysis.The PK of ixazomib was characterized at dose of mg in patients with normal renal function (creatinine clearance >= 90 mL/min, N=18), severe renal impairment (creatinine clearance 30 mL/min, N=14), or ESRD requiring dialysis (N=6). Mean AUC was 39% higher in patients with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal function. Pre- and post-dialyzer concentrations of ixazomib measured during the hemodialysis session were similar, suggesting that ixazomib is not dialyzable [see Dosage and Administration (2.4)].. Drug Interaction Studies. Effect of Other Drugs on NINLARO. Strong CYP3A InducersCo-administration of NINLARO with rifampin decreased ixazomib Cmax by 54% and AUC by 74% [see Drug Interactions (7.1)].. Strong CYP3A InhibitorsCo-administration of NINLARO with clarithromycin did not result in clinically meaningful change in the systemic exposure of ixazomib.. Strong CYP1A2 InhibitorsCo-administration of NINLARO with strong CYP1A2 inhibitors did not result in clinically meaningful change in the systemic exposure of ixazomib based on population PK analysis.. Effect of NINLARO on Other DrugsIxazomib is neither reversible nor time-dependent inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Ixazomib did not induce CYP1A2, CYP2B6, and CYP3A4/5 activity or corresponding immunoreactive protein levels. NINLARO is not expected to produce drug-drug interactions via CYP inhibition or induction.. Transporter-Based InteractionsIxazomib is low affinity substrate of P-gp. Ixazomib is not substrate of BCRP, MRP2 or hepatic OATPs. Ixazomib is not an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K. NINLARO is not expected to cause transporter-mediated drug-drug interactions.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.IXB349 R6 Revised: January 2022 PATIENT INFORMATIONNINLARO(R) (nin-LAR-oh)(ixazomib)capsulesNINLARO is used with two other prescription medicines called REVLIMID(R) (lenalidomide) and dexamethasone. Read the Medication Guide that comes with REVLIMID(R) (lenalidomide). You can ask your healthcare provider or pharmacist for information about dexamethasone.What is NINLARONINLARO is prescription medicine used to treat multiple myeloma in combination with the medicines REVLIMID(R) (lenalidomide) and dexamethasone, in people who have received at least one prior treatment for their multiple myeloma.It is not known if NINLARO is safe and effective in children.Before taking NINLARO, tell your healthcare provider about all of your medical conditions, including if you:have liver problemshave kidney problems or are on dialysisare pregnant or plan to become pregnant. NINLARO can harm your unborn baby. Females who are able to become pregnant: Avoid becoming pregnant during treatment with NINLARO.Your healthcare provider will do pregnancy test before you start treatment with NINLARO.You should use effective non-hormonal birth control during treatment and for 90 days after your final dose of NINLARO. If using hormonal contraceptives (for example, birth control pills), you should also use an additional barrier method of contraception (for example, diaphragm or condom). Talk to your healthcare provider about birth control methods that may be right for you during this time.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with NINLARO. Males with female partners who are able to become pregnant: You should use effective birth control during treatment and for 90 days after your final dose of NINLARO.Tell your healthcare provider right away if your partner becomes pregnant or thinks she may be pregnant while you are being treated with NINLARO. are breastfeeding or plan to breastfeed. It is not known if NINLARO passes into breast milk, if it affects an infant who is breastfed, or breast milk production. Do not breastfeed during treatment with NINLARO and for 90 days after your final dose of NINLARO. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before starting any new medicines during treatment with NINLARO.How should take NINLARO Take NINLARO exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking NINLARO without talking to your healthcare provider first.NINLARO is taken in cycles. Each cycle lasts weeks (28 days). The usual dose of NINLARO is capsule taken time each week, on the same day of the week for the first weeks of each cycle.Take each dose of NINLARO at about the same time of day.Take REVLIMID (lenalidomide) and dexamethasone exactly as your healthcare provider tells you to.Your healthcare provider will do blood tests during treatment with NINLARO to check for side effects.Your healthcare provider may change your dose or stop NINLARO, REVLIMID (lenalidomide), or dexamethasone if you have side effects. Take NINLARO at least hour before or at least hours after food.On the days that you take both NINLARO and dexamethasone, do not take NINLARO and dexamethasone at the same time. Take dexamethasone with food. Swallow NINLARO capsules whole with water. Do not crush, chew or open the capsule.Avoid direct contact with the capsule contents. If you accidentally get powder from the NINLARO capsule on your skin, wash the area well with soap and water. If you accidentally get powder from the NINLARO capsule in your eyes, flush your eyes well with water.If you miss dose of NINLARO, or if you are late taking dose, take the dose as long as the next scheduled dose is more than days (72 hours) away. Do not take missed dose of NINLARO if it is within days (72 hours) of your next scheduled dose.If you vomit after taking dose of NINLARO, do not repeat the dose. Take your next dose of NINLARO on the next scheduled day and time.Your healthcare provider may prescribe medicine to take with NINLARO to decrease the risk of the chicken pox virus (herpes zoster) coming back (reactivation).Taking too much NINLARO (overdose) can cause serious side effects, including death. If you take more NINLARO than instructed by your healthcare provider, call your healthcare provider right away or go to the nearest hospital emergency room right away. Take your medicine pack with you.What are the possible side effects of NINLARONINLARO may cause serious side effects, including:Low platelet counts (thrombocytopenia). Low platelet counts are common with NINLARO, and can sometimes be serious. You may need platelet transfusions if your counts are too low. Tell your healthcare provider if you have any signs of low platelet counts, including bleeding and easy bruising.Stomach and intestinal (gastrointestinal) problems. Diarrhea, constipation, nausea, and vomiting are common with NINLARO, and can sometimes be severe. Call your healthcare provider if you get any of these symptoms and they do not go away during treatment with NINLARO. Your healthcare provider may prescribe medicine to help treat your symptoms.Nerve problems. Nerve problems are common with NINLARO and may also be severe. Tell your healthcare provider if you get any new or worsening symptoms, including:tinglingnumbnesspaina burning feeling in your feet or handsweakness in your arms or legsSwelling. Swelling is common with NINLARO and can sometimes be severe. Tell your healthcare provider if you develop swelling in your arms, hands, legs, ankles, or feet, or if you gain weight from swelling.Skin reactions. Tell your healthcare provider if you get new or worsening rash.Thrombotic microangiopathy (TMA). This is condition involving blood clots and injury to small blood vessels that may cause harm to your kidneys, brain, and other organs, and may lead to death. Get medical help right away if you get any of the following signs or symptoms during treatment with NINLARO:feverbruisingnose bleedstirednessdecreased urinationLiver problems. Tell your healthcare provider if you get these signs of liver problem: yellowing of your skin or the whites of your eyespain in your right upper stomach-areaOther common side effects have occurred. Tell your healthcare provider if you get new or worsening signs or symptoms of the following:back painskin rash and pain (shingles) as result of reactivation of the chicken pox virus (herpes zoster)lowered white blood cells called neutrophils (neutropenia) that may increase the risk of infectionvision conditions including blurred vision, dry eye and pink eye (conjunctivitis)These are not all the possible side effects of NINLARO. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store NINLARO Store NINLARO at room temperature. Do not store above 86F (30C).Do not freeze NINLARO.Store NINLARO capsules in the original packaging until just before each use.Ask your pharmacist or healthcare provider about how to dispose of (throw away) unused NINLARO.Keep NINLARO and all medicines out of the reach of children.General information about the safe and effective use of NINLARO. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use NINLARO for condition for which it was not prescribed. Do not give NINLARO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NINLARO that is written for healthcare professionals.What are the ingredients in NINLARO Active ingredient: ixazomibInactive ingredients: microcrystalline cellulose, magnesium stearate, and talcCapsule shells: gelatin and titanium dioxide. The mg capsule shell contains red and yellow iron oxide. The mg capsule shell contains black iron oxide. The 2.3 mg capsule shell contains red iron oxide. The printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide.Distributed by: Takeda Pharmaceuticals America, Inc., Lexington, MA 02421NINLARO(R) is registered trademark of Takeda Pharmaceuticals U.S.A., Inc.All other trademarks are the property of their respective owners.(C)2022 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved.For more information, you may also go to www.NINLARO.com or call 1-844-617-6468.. have liver problems. have kidney problems or are on dialysis. are pregnant or plan to become pregnant. NINLARO can harm your unborn baby. Females who are able to become pregnant: Avoid becoming pregnant during treatment with NINLARO.Your healthcare provider will do pregnancy test before you start treatment with NINLARO.You should use effective non-hormonal birth control during treatment and for 90 days after your final dose of NINLARO. If using hormonal contraceptives (for example, birth control pills), you should also use an additional barrier method of contraception (for example, diaphragm or condom). Talk to your healthcare provider about birth control methods that may be right for you during this time.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with NINLARO. Males with female partners who are able to become pregnant: You should use effective birth control during treatment and for 90 days after your final dose of NINLARO.Tell your healthcare provider right away if your partner becomes pregnant or thinks she may be pregnant while you are being treated with NINLARO. Avoid becoming pregnant during treatment with NINLARO.. Your healthcare provider will do pregnancy test before you start treatment with NINLARO.. You should use effective non-hormonal birth control during treatment and for 90 days after your final dose of NINLARO. If using hormonal contraceptives (for example, birth control pills), you should also use an additional barrier method of contraception (for example, diaphragm or condom). Talk to your healthcare provider about birth control methods that may be right for you during this time.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with NINLARO.. You should use effective birth control during treatment and for 90 days after your final dose of NINLARO.. Tell your healthcare provider right away if your partner becomes pregnant or thinks she may be pregnant while you are being treated with NINLARO.. are breastfeeding or plan to breastfeed. It is not known if NINLARO passes into breast milk, if it affects an infant who is breastfed, or breast milk production. Do not breastfeed during treatment with NINLARO and for 90 days after your final dose of NINLARO. Take NINLARO exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking NINLARO without talking to your healthcare provider first.. NINLARO is taken in cycles. Each cycle lasts weeks (28 days). The usual dose of NINLARO is capsule taken time each week, on the same day of the week for the first weeks of each cycle.Take each dose of NINLARO at about the same time of day.Take REVLIMID (lenalidomide) and dexamethasone exactly as your healthcare provider tells you to.Your healthcare provider will do blood tests during treatment with NINLARO to check for side effects.Your healthcare provider may change your dose or stop NINLARO, REVLIMID (lenalidomide), or dexamethasone if you have side effects. The usual dose of NINLARO is capsule taken time each week, on the same day of the week for the first weeks of each cycle.. Take each dose of NINLARO at about the same time of day.. Take REVLIMID (lenalidomide) and dexamethasone exactly as your healthcare provider tells you to.. Your healthcare provider will do blood tests during treatment with NINLARO to check for side effects.. Your healthcare provider may change your dose or stop NINLARO, REVLIMID (lenalidomide), or dexamethasone if you have side effects.. Take NINLARO at least hour before or at least hours after food.. On the days that you take both NINLARO and dexamethasone, do not take NINLARO and dexamethasone at the same time. Take dexamethasone with food. Swallow NINLARO capsules whole with water. Do not crush, chew or open the capsule.. Avoid direct contact with the capsule contents. If you accidentally get powder from the NINLARO capsule on your skin, wash the area well with soap and water. If you accidentally get powder from the NINLARO capsule in your eyes, flush your eyes well with water.. If you miss dose of NINLARO, or if you are late taking dose, take the dose as long as the next scheduled dose is more than days (72 hours) away. Do not take missed dose of NINLARO if it is within days (72 hours) of your next scheduled dose.. If you vomit after taking dose of NINLARO, do not repeat the dose. Take your next dose of NINLARO on the next scheduled day and time.. Your healthcare provider may prescribe medicine to take with NINLARO to decrease the risk of the chicken pox virus (herpes zoster) coming back (reactivation).. Taking too much NINLARO (overdose) can cause serious side effects, including death. If you take more NINLARO than instructed by your healthcare provider, call your healthcare provider right away or go to the nearest hospital emergency room right away. Take your medicine pack with you.. Low platelet counts (thrombocytopenia). Low platelet counts are common with NINLARO, and can sometimes be serious. You may need platelet transfusions if your counts are too low. Tell your healthcare provider if you have any signs of low platelet counts, including bleeding and easy bruising.. Stomach and intestinal (gastrointestinal) problems. Diarrhea, constipation, nausea, and vomiting are common with NINLARO, and can sometimes be severe. Call your healthcare provider if you get any of these symptoms and they do not go away during treatment with NINLARO. Your healthcare provider may prescribe medicine to help treat your symptoms.. Nerve problems. Nerve problems are common with NINLARO and may also be severe. Tell your healthcare provider if you get any new or worsening symptoms, including:. tingling. numbness. pain. burning feeling in your feet or hands. weakness in your arms or legs. Swelling. Swelling is common with NINLARO and can sometimes be severe. Tell your healthcare provider if you develop swelling in your arms, hands, legs, ankles, or feet, or if you gain weight from swelling.. Skin reactions. Tell your healthcare provider if you get new or worsening rash.. Thrombotic microangiopathy (TMA). This is condition involving blood clots and injury to small blood vessels that may cause harm to your kidneys, brain, and other organs, and may lead to death. Get medical help right away if you get any of the following signs or symptoms during treatment with NINLARO:. fever. bruising. nose bleeds. tiredness. decreased urination. Liver problems. Tell your healthcare provider if you get these signs of liver problem: yellowing of your skin or the whites of your eyespain in your right upper stomach-area. yellowing of your skin or the whites of your eyes. pain in your right upper stomach-area. back pain. skin rash and pain (shingles) as result of reactivation of the chicken pox virus (herpes zoster). lowered white blood cells called neutrophils (neutropenia) that may increase the risk of infection. vision conditions including blurred vision, dry eye and pink eye (conjunctivitis). Store NINLARO at room temperature. Do not store above 86F (30C).. Do not freeze NINLARO.. Store NINLARO capsules in the original packaging until just before each use.. Ask your pharmacist or healthcare provider about how to dispose of (throw away) unused NINLARO.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Hepatic Impairment: Reduce the NINLARO starting dose to mg in patients with moderate or severe hepatic impairment. (2.3, 8.6)Renal Impairment: Reduce the NINLARO starting dose to mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. (2.4, 8.7)Lactation: Advise not to breastfeed. (8.2). Hepatic Impairment: Reduce the NINLARO starting dose to mg in patients with moderate or severe hepatic impairment. (2.3, 8.6). Renal Impairment: Reduce the NINLARO starting dose to mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. (2.4, 8.7). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)] and data from animal reproduction studies, NINLARO can cause fetal harm when administered to pregnant woman. There are no available data on NINLARO use in pregnant women to evaluate drug-associated risk. 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 (see Data). Advise pregnant women of the potential risk to fetus.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.. Data. Animal DataIn an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal variations/abnormalities (fused 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 mg. In rat dose range-finding embryo-fetal development study, at doses that were maternally toxic, there were decreases in fetal weights, 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 mg.. 8.2 Lactation. Risk SummaryThere are no data on the presence of ixazomib or its metabolites in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Because of the potential for serious adverse reactions from NINLARO in breastfed infant, advise women not to breastfeed during treatment with NINLARO and for 90 days after the last dose.. 8.3 Females and Males of Reproductive Potential. NINLARO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating NINLARO.. Contraception. FemalesAdvise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days after the final dose. Dexamethasone is known to be weak to moderate inducer of CYP3A4 as well as other enzymes and transporters. Because NINLARO is administered with dexamethasone, the risk for reduced efficacy of contraceptives needs to be considered [see Drug Interactions (7.1)].. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days after the final dose.. 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 [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].. 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 [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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 fetus and to use effective non-hormonal contraception. (5.8, 8.1, 8.3). 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 fetus and to use effective non-hormonal contraception. (5.8, 8.1, 8.3). 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 platelet count <= 10,000/mm3 during treatment. Less than 1% of patients in both regimens had 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 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 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 or symptoms [see Dosage and Administration (2.2)]. 5.3 Peripheral Neuropathy. The majority of peripheral neuropathy adverse reactions were Grade (18% in the NINLARO regimen and 14% in the placebo regimen) and Grade (8% in the NINLARO regimen and 5% in the placebo regimen). Grade adverse reactions of peripheral neuropathy were reported at 2% in both regimens; there were no Grade 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 and Administration (2.2)]. 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 (16% in the NINLARO regimen and 13% in the placebo regimen) and Grade (7% in the NINLARO regimen and 4% in the placebo regimen).Grade peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively. There was no Grade 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 or symptoms [see Dosage and Administration (2.2)]. 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 (10% in the NINLARO regimen and 7% in the placebo regimen) or Grade (6% in the NINLARO regimen and 3% in the placebo regimen). Grade rash was reported in 3% of patients in the NINLARO regimen and 1% of patients in the placebo regimen. There were no Grade 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 or higher [see Dosage and Administration (2.2)]. 5.6Thrombotic 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.. 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. 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 or symptoms [see Dosage and Administration (2.2)]. 5.8 Embryo-Fetal Toxicity. NINLARO can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the final dose [see Drug Interactions (7.1) and Use in Specific Populations (8.1, 8.3)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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=361) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=359).The most frequently reported adverse reactions (>= 20% with difference of >=5% compared to placebo) in the NINLARO regimen were thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis. Serious adverse reactions reported in >= 2% of patients in the NINLARO regimen included diarrhea (3%), thrombocytopenia (2%) and bronchitis (2%). One or more of the three drugs was permanently discontinued in 4% of patients reporting peripheral neuropathy, 3% of patients reporting diarrhea and 2% of patients reporting thrombocytopenia. Permanent discontinuation of NINLARO due to an adverse reaction occurred in 10% of patients. Table summarizes the non-hematologic adverse reactions occurring in at least 5% of patients with at least 5% difference between the NINLARO regimen and the placebo regimen.Table 4: Non-Hematologic Adverse Reactions Occurring in >= 5% of Patients with >= 5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade and Grade 4)System Organ Class /Preferred TermNINLARO Lenalidomide and DexamethasoneN=361Placebo Lenalidomide and DexamethasoneN=359%%All GradesGrade 3Grade 4All GradesGrade 3Grade 4Note: Adverse reactions included as preferred terms are based on MedDRA version 23.0.Gastrointestinal disorders Diarrhea521004330 Constipation35< 1028< 10 Nausea32202300 Vomiting261013<10Nervous system disorders Peripheral neuropathiesRepresents pooling of preferred terms 32202420Musculoskeletal and connective tissue disorders Back painAt the time of the final analysis, these adverse reactions no longer met the criterion for >= 5% difference between the NINLARO regimen and the placebo regimen. 27<102430Infections and infestations Upper respiratory tract infection 27102310 Bronchitis2220172<1Skin and subcutaneous tissue disorders Rash 27301620General disorders and administration site conditions Edema peripheral27202110Table represents pooled information from adverse event and laboratory data.Table 5: Thrombocytopenia and NeutropeniaNINLARO Lenalidomide and DexamethasoneN=361Placebo Lenalidomide and DexamethasoneN=359%%Any GradeGrade 3-4Any GradeGrade 3-4Thrombocytopenia85306714Neutropenia74347037. Herpes ZosterHerpes zoster was reported in 6% of patients in the NINLARO regimen and 3% of patients in the placebo regimen. Antiviral prophylaxis was allowed at the healthcare providers discretion. Patients treated in the NINLARO regimen who received antiviral prophylaxis had lower incidence (1%) of herpes zoster infection compared to patients who did not receive prophylaxis (10%).. Eye DisordersEye disorders were reported with many different preferred terms but in aggregate, the frequency was 38% in patients in the NINLARO regimen. The most common adverse reactions of the eyes were cataract (15%), conjunctivitis (9%), blurred vision (7%), and dry eye (6%).. Other Clinical Trials ExperienceThe following serious adverse reactions have each been reported at frequency of 1% in patients treated with NINLARO: acute febrile neutrophilic dermatosis (Sweets syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.