NINLARO- ixazomib_capsule

Ixazomib is a reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 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 a mouse multiple myeloma tumor xenograft model. Cardiac Electrophysiology NINLARO did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients. Absorption After 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 a dose proportional manner over a dose range of 0. A food effect study conducted in patients with a single 4 mg dose of ixazomib showed that a high-fat meal decreased ixazomib AUC by 28% and C max [see Dosage and Administration (2. 1) Distribution Ixazomib is 99% bound to plasma proteins and distributes into red blood cells with a blood-to-plasma ratio of 10. The steady-state volume of distribution is 543 L. Elimination Based on a population PK analysis, systemic clearance was approximately 1. 9 L/hr with inter-individual variability of 44%. The terminal half-life (t 1/2 Metabolism After oral administration of a 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%). Excretion After administration of a single oral dose of 14 Specific Populations There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1. 7 m 2 Patients with Hepatic Impairment The 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 4 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 Impairment The 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 a dose of 3 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 Inducers Coadministration of NINLARO with rifampin decreased ixazomib C max [see Drug Interactions (7. 1) Strong CYP3A Inhibitors Coadministration of NINLARO with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib. Strong CYP1A2 Inhibitors Coadministration of NINLARO with strong CYP1A2 inhibitors did not result in a clinically meaningful change in the systemic exposure of ixazomib based on a population PK analysis. Effect of NINLARO on Other Drugs Ixazomib is neither a reversible nor a 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 Interactions Ixazomib is a low affinity substrate of P-gp. Ixazomib is not a 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.

NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. ( 1 Limitations of Use 1 Limitations of Use [see Warnings and Precautions (5. 9) Clinical Studies (14.

Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15 of a 28-day cycle. 1 Dose should be taken at least one hour before or at least two hours after food. 1 NINLARO in combination with lenalidomide and dexamethasone The recommended starting dose of NINLARO is 4 mg administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle. The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 through 21 of a 28-day treatment cycle. The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle. Table 1: Dosing Schedule for NINLARO taken with Lenalidomide and Dexamethasone ✔ Take medicine 28-Day Cycle (a 4-week cycle) Week 1 Week 2 Week 3 Week 4 Day 1 Days 2-7 Day 8 Days 9-14 Day 15 Days 16-21 Day 22 Days 23-28 NINLARO ✔ ✔ ✔ Lenalidomide ✔ ✔ Daily ✔ ✔ Daily ✔ ✔ Daily Dexamethasone ✔ ✔ ✔ ✔ For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information. NINLARO should be taken once a week on the same day and at approximately the same time for the first three weeks of a 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) [see How Supplied/Storage and Handling (16) If a NINLARO dose is delayed or missed, the dose should be taken only if the next scheduled dose is >=72 hours away. A missed dose should not be taken within 72 hours of the next scheduled dose. A double dose should not be taken to make up for the missed dose. If vomiting occurs after taking a dose, the patient should not repeat the dose. The patient should resume dosing at the time of the next scheduled dose. Prior to initiating a new cycle of therapy: Absolute neutrophil count should be at least 1,000/mm 3 Platelet count should be at least 75,000/mm 3 Non-hematologic toxicities should, at the healthcare provider's discretion, generally be recovered to patient's baseline condition or Grade 1 or lower Treatment should be continued until disease progression or unacceptable toxicity. Concomitant Medications Consider antiviral prophylaxis in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation [see Adverse Reactions (6. 1) The NINLARO dose reduction steps are presented in Table 2 and the dosage modification guidelines are provided in Table 3. Table 2: NINLARO Dose Reductions due to Adverse Reactions Recommended starting dose Recommended starting dose of 3 mg in patients with moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease requiring dialysis [see Dosage and Administration (2. 4) First reduction to Second reduction to Discontinue 4 mg 3 mg 2. 3 mg An 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: Dosage Modifications Guidelines for NINLARO in Combination with Lenalidomide and Dexamethasone Hematological Toxicities Recommended Actions Thrombocytopenia (Platelet Count) Platelet count less than 30,000/mm 3 Withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm 3 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/mm 3 3 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/mm 3 Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm 3 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/mm 3 3 Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose. Non-Hematological Toxicities Recommended Actions Rash Grade Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4. 03 Withhold lenalidomide until rash recovers to Grade 1 or lower. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information. If Grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to Grade 1 or lower. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose. Grade 4 Discontinue treatment regimen. Peripheral Neuropathy Grade 1 Peripheral Neuropathy with Pain or Grade 2 Peripheral Neuropathy Withhold NINLARO until peripheral neuropathy recovers to Grade 1 or lower without pain or patient's baseline. Following recovery, resume NINLARO at its most recent dose. Grade 2 Peripheral Neuropathy with Pain or Grade 3 Peripheral Neuropathy Withhold NINLARO. Toxicities should, at the healthcare provider's discretion, generally recover to patient's baseline condition or Grade 1 or lower prior to resuming NINLARO. Following recovery, resume NINLARO at the next lower dose. Grade 4 Peripheral Neuropathy Discontinue treatment regimen. Other Non-Hematological Toxicities Other Grade 3 or 4 Non-Hematological Toxicities Withhold NINLARO. If attributable to NINLARO, resume NINLARO at the next lower dose following recovery. Reduce the starting dose of NINLARO to 3 mg in patients with moderate (total bilirubin greater than 1. 5-3 × ULN) or severe (total bilirubin greater than 3 × ULN) hepatic impairment [see Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) Reduce the starting dose of NINLARO to 3 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) Clinical Pharmacology (12. 3) Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.

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) The most common adverse reactions (>=20%) are thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis. 1 To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-617-6468 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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=361) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=359). The most frequently reported adverse reactions (>=20% with a 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 4 summarizes the non-hematologic adverse reactions occurring in at least 5% of patients with at least a 5% difference between the NINLARO regimen and the placebo 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 / NINLARO + Lenalidomide and Dexamethasone Placebo + Lenalidomide and Dexamethasone % % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Note: Adverse reactions included as preferred terms are based on MedDRA version 23. Gastrointestinal disorders Diarrhea 52 10 0 43 3 0 Constipation 35 <1 0 28 <1 0 Nausea 32 2 0 23 0 0 Vomiting 26 1 0 13 <1 0 Nervous system disorders Peripheral neuropathies Represents a pooling of preferred terms 32 2 0 24 2 0 Musculoskeletal and connective tissue disorders Back pain At the time of the final analysis, these adverse reactions no longer met the criterion for a >=5% difference between the NINLARO regimen and the placebo regimen. 27 <1 0 24 3 0 Infections and infestations Upper respiratory tract infection 27 1 0 23 1 0 Bronchitis 22 2 0 17 2 <1 Skin and subcutaneous tissue disorders Rash 27 3 0 16 2 0 General disorders and administration site conditions Edema peripheral 27 2 0 21 1 0 Table 5 represents pooled information from adverse event and laboratory data. Table 5: Thrombocytopenia and Neutropenia NINLARO + Lenalidomide and Dexamethasone Placebo + Lenalidomide and Dexamethasone % % Any Grade Grade 3-4 Any Grade Grade 3-4 Thrombocytopenia 85 30 67 14 Neutropenia 74 34 70 37 Herpes Zoster Herpes 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 provider's discretion. Patients treated in the NINLARO regimen who received antiviral prophylaxis had a lower incidence (1%) of herpes zoster infection compared to patients who did not receive prophylaxis (10%). Eye Disorders Eye 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 Experience The following serious adverse reactions have each been reported at a frequency of <1% in patients treated with NINLARO: acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura. The following adverse reactions have been identified during post-approval use of NINLARO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Angioedema Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis.

Hepatic Impairment 2. 6 Renal Impairment 2. 7 Lactation 8. 2 Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12. 1) (see Data In the U. 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 Data In 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. Exposures in the rabbit at 0. 3 mg/kg were 1. 9 times the clinical time averaged exposures at the recommended dose of 4 mg. In a rat dose range-finding embryo-fetal development study, at doses that were maternally toxic, there were decreases in fetal weights, a trend towards decreased fetal viability, and increased post-implantation losses at 0. Exposures in rats at the dose of 0. 6 mg/kg was 2. 5 times the clinical time averaged exposures at the recommended dose of 4 mg. Risk Summary There 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 a breastfed infant, advise women not to breastfeed during treatment with NINLARO and for 90 days after the last dose. NINLARO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8. 1) Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating NINLARO. Contraception Females Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days after the last dose. Dexamethasone is known to be a 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) Males Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days after the last dose. Safety and effectiveness of NINLARO have not been established in pediatric patients. 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. 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) 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.

Strong CYP3A inducers 7. 3 Avoid concomitant administration of NINLARO with strong CYP3A inducers (such as rifampin, phenytoin, carbamazepine, and St. John's Wort) [see Clinical Pharmacology (12.

OVERDOSAGE
Overdosage, including fatal overdosage, has been reported in patients taking NINLARO. Manifestations of overdosage include adverse reactions reported at the recommended dosage [see Dosage and Administration (2.1) Adverse Reactions (6.1) In the event of an overdosage, monitor for adverse reactions and provide appropriate supportive care. NINLARO is not dialyzable.
NONCLINICAL TOXICOLOGY
Ixazomib was not mutagenic in a bacterial reverse mutation assay (Ames assay). Ixazomib was considered positive in an in vitro clastogenicity test in human peripheral blood lymphocytes. However, in vivo, ixazomib was not clastogenic in a bone marrow micronucleus assay in mice and was negative in an in vivo comet assay in mice, as assessed in the stomach and liver. No carcinogenicity studies have been performed with ixazomib. Developmental toxicity studies in rats and rabbits did not show direct embryo-fetal toxicity below maternally toxic doses of ixazomib. Studies of fertility and early embryonic development and pre- and postnatal toxicology were not conducted with ixazomib, but evaluation of reproductive tissues was conducted in the general toxicity studies. There were no effects due to ixazomib treatment on male or female reproductive organs in studies up to 6-months duration in rats and up to 9-months duration in dogs.
CLINICAL STUDIES
The efficacy and safety of NINLARO in combination with lenalidomide and dexamethasone was evaluated in a 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 a 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 2 or 3), myeloma International Staging System (ISS) (stage I or II versus III), and previous therapy with a proteasome inhibitor (exposed or naïve). 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 provider''s discretion as prophylaxis and/or management of symptoms. Patients received NINLARO 4 mg or placebo on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle. Patients with renal impairment received a starting dose of lenalidomide according to its prescribing information. Treatment continued until disease progression or unacceptable toxicities. Table 6 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 Characteristics NINLARO + Lenalidomide and Dexamethasone Placebo + Lenalidomide and Dexamethasone Patient Characteristics Median age in years (range) 66 (38, 91) 66 (30, 89) Gender (%) Male/ Female 58/42 56/44 Age Group (% [<65/ >=65 years]) 41/59 43/57 Race n (%) White 310 (86) 301 (83) Black 7 (2) 6 (2) Asian 30 (8) 34 (9) Other or Not Specified 13 (4) 21 (6) ECOG performance status, n (%) 0 or 1 336 (93) 334 (92) 2 18 (5) 24 (7) Missing 6 (2) 4 (1) Creatinine clearance, n (%) <30 mL/min 5 (1) 5 (1) 30-59 mL/min 74 (21) 95 (26) >=60 mL/min 281 (78) 261 (72) Disease Characteristics Myeloma ISS stage, n (%) Stage I or II 315 (87) 320 (88) Stage III 45 (13) 42 (12) Prior line therapies n (%) Median (range) 1 (1, 3) 1 (1,3) 1 224 (62) 217 (60) 2 or 3 136 (38) 145 (40) Status at Baseline n (%) Relapsed 276 (77) 280 (77) Refractory Primary 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 Refractory 41 (11) 42 (12) Type of Prior Therapy n (%) Bortezomib containing 248 (69) 250 (69) Carfilzomib containing 1 (<1) 4 (1) Thalidomide containing 157 (44) 170 (47) Lenalidomide containing 44 (12) 44 (12) Melphalan containing 293 (81) 291 (80) Stem cell transplantation 212 (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 a 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 a statistically significant improvement in PFS of the NINLARO regimen compared to the placebo regimen. PFS results are summarized in Table 7 and shown in Figure 1. Table 7: Progression-Free Survival and Response Rate NINLARO + Lenalidomide and Dexamethasone Placebo + Lenalidomide and Dexamethasone NE: Not evaluable. Progression-free Survival PFS Events, n (%) 129 (36) 157 (43) Median (months) 20. 7 Hazard Ratio Hazard ratio is based on a stratified Cox''s proportional hazard regression model. A hazard ratio less than 1 indicates an advantage for the NINLARO regimen. 74 p-value P-value is based on the stratified log-rank test. 012 Response Rate Overall Response Rate, n (%) 282 (78) 259 (72) Complete Response 42 (12) 24 (7) Very Good Partial Response 131 (36) 117 (32) Partial Response 109 (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 Survival A non-inferential PFS analysis was conducted at a median follow up of 23 months with 372 PFS events. Hazard ratio of PFS was 0. 82 (95% confidence interval [0. 0]) for NINLARO regimen versus placebo regimen, and estimated median PFS was 20 months in the NINLARO regimen and 15. At the final analysis for OS at a median duration of follow up of approximately 85 months, median OS in the ITT population was 53. 6 months for patients in the NINLARO regimen and 51. 6 months for patients in the placebo regimen (HR = 0. 94 [95% CI: 0. Figure 1 In C16019 (NCT02181413), newly diagnosed multiple myeloma patients who underwent autologous stem cell transplantation, continued on maintenance therapy for 24 months. There were 27% (105/395) deaths in the NINLARO arm compared with 26% (69/261) in the placebo arm. The hazard ratio for overall survival was 1. 008 (95% CI: 0. In C16021 (NCT02312258), newly diagnosed multiple myeloma patients, not treated with a stem cell transplant who achieved a partial response or better, continued on maintenance therapy for 24 months. There were 30% (127/425) deaths in the NINLARO arm compared with 27% (76/281) in the placebo arm. 136 (95% CI: 0. NINLARO is not recommended for use in the maintenance setting for multiple myeloma outside of controlled clinical trials [see Indications and Usage (1) Warnings and Precautions (5. 9) Lack of efficacy in patients with newly diagnosed multiple myeloma was determined in a prospective randomized clinical trial. In C16014 (NCT01850524), in newly diagnosed multiple myeloma patients, the study did not meet the prespecified primary endpoint for PFS. There were 136 (39%) deaths in the NINLARO, lenalidomide, and dexamethasone arm compared to 148 (42%) in the lenalidomide and dexamethasone arm. The hazard ratio for overall survival was 0. 998 (95% CI: 0. NINLARO is not recommended for use in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma outside of controlled clinical trials [see Indications and Usage (1).
REFERENCES
OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Takeda Pharmaceuticals America, Inc.

NINLARO- ixazomib_capsule Product manual source documgent