{"id":"ixazomib","rwe":[],"_fda":{"id":"16e9f7cd-6a19-4ad1-9431-8205898a33f1","set_id":"038f2461-834b-4488-9ebd-863c83eef5a7","openfda":{"unii":["46CWK97Z3K"],"route":["ORAL"],"rxcui":["1723757","1723763","1723765","1723767","1723770","1723772"],"spl_id":["16e9f7cd-6a19-4ad1-9431-8205898a33f1"],"brand_name":["NINLARO"],"spl_set_id":["038f2461-834b-4488-9ebd-863c83eef5a7"],"package_ndc":["63020-400-03","63020-400-02","63020-400-01","63020-390-03","63020-390-02","63020-390-01","63020-230-03","63020-230-02","63020-230-01"],"product_ndc":["63020-230","63020-400","63020-390"],"generic_name":["IXAZOMIB"],"product_type":["HUMAN PRESCRIPTION DRUG"],"substance_name":["IXAZOMIB CITRATE"],"manufacturer_name":["Takeda Pharmaceuticals America, Inc."],"application_number":["NDA208462"],"is_original_packager":[true]},"version":"16","pregnancy":["8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and data from animal reproduction studies, NINLARO can cause fetal harm when administered to a 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 a 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 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 (≥0.3 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 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 0.6 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 4 mg."],"overdosage":["10 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) ] . Serious adverse reactions reported with overdosage include severe nausea, vomiting, diarrhea, aspiration pneumonia, multiple organ failure and death. In the event of an overdosage, monitor for adverse reactions and provide appropriate supportive care. NINLARO is not dialyzable."],"references":["15 REFERENCES OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html"],"description":["11 DESCRIPTION Ixazomib is a proteasome inhibitor. Ixazomib citrate, a prodrug, rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib. The chemical name of ixazomib citrate is 1,3,2-dioxaborolane-4,4-diacetic acid, 2-[(1 R )-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo- and the structural formula is: The molecular formula for ixazomib citrate is C 20 H 23 BCl 2 N 2 O 9 and its molecular weight is 517.12. Ixazomib citrate has one chiral center and is the R-stereoisomer. The solubility of ixazomib citrate in 0.1N HCl (pH 1.2) at 37°C is 0.61 mg/mL (reported as ixazomib). The solubility increases as the pH increases. NINLARO (ixazomib) capsules for oral use contain 4, 3 or 2.3 mg of ixazomib equivalent to 5.7, 4.3 or 3.3 mg of ixazomib citrate, respectively. Inactive ingredients include microcrystalline cellulose, magnesium stearate, and talc. Capsule shells contain gelatin and titanium dioxide. The 4 mg capsule shell contains red and yellow iron oxide, the 3 mg capsule shell contains black iron oxide and the 2.3 mg capsule shell contains red iron oxide. The printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide. Chemical Structure"],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied NINLARO is supplied as follows: Strength per Capsule Capsule Description Outer Carton 3 Count Blister Pack 1 Count Blister Pack NDC 4 mg Light orange, size 3, imprinted with \"Takeda\" on the cap and \"4 mg\" on the body in black ink. Three 4 mg capsules in a carton Each blister pack has three 4 mg capsules Each blister pack has one 4 mg capsule Outer carton NDC 63020-400-02 3 Count Blister Pack NDC 63020-400-03 1 Count Blister pack NDC 63020-400-01 3 mg Light grey, size 4, imprinted with \"Takeda\" on the cap and \"3 mg\" on the body in black ink. Three 3 mg capsules in a carton Each blister pack has three 3 mg capsules Each blister pack has one 3 mg capsule Outer carton NDC 63020-390-02 3 Count Blister Pack NDC 63020-390-03 1 Count Blister pack NDC 63020-390-01 2.3 mg Light pink, size 4, imprinted with \"Takeda\" on the cap and \"2.3 mg\" on the body in black ink. Three 2.3 mg capsules in a carton Each blister pack has three 2.3 mg capsules Each blister pack has one 2.3 mg capsule Outer carton NDC 63020-230-02 3 Count Blister Pack NDC 63020-230-03 1 Count Blister pack NDC 63020-230-01 Capsules are individually packaged in a PVC-Aluminum/Aluminum blister. Storage Store NINLARO at room temperature. Do not store above 30°C (86°F). Do not freeze. Store capsules in original packaging until immediately prior to use. Handling and Disposal NINLARO is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Do not open or crush capsules. Avoid direct contact with the capsule contents. 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. Any unused medicinal product or waste material should be disposed in accordance with local requirements."],"geriatric_use":["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."],"pediatric_use":["8.4 Pediatric Use Safety and effectiveness of NINLARO have not been established in pediatric patients."],"effective_time":"20250818","clinical_studies":["14 CLINICAL STUDIES 14.1 Multiple Myeloma in Patients Who Have Received at Least One Prior Therapy 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 (N = 360) Placebo + Lenalidomide and Dexamethasone (N = 362) 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 (N = 360) Placebo + Lenalidomide and Dexamethasone (N = 362) NE: Not evaluable. Progression-free Survival PFS Events, n (%) 129 (36) 157 (43) Median (months) (95% CI) 20.6 (17.0, NE) 14.7 (12.9, 17.6) 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. (95% CI) 0.74 (0.59, 0.94) p-value P-value is based on the stratified log-rank test. 0.012 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 [0.67, 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 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: 0.78, 1.13]). Figure 1 14.2 Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting 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: 0.744 - 1.367). 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. The hazard ratio for overall survival was 1.136 (95% CI: 0.853 - 1.514). NINLARO is not recommended for use in the maintenance setting for multiple myeloma outside of controlled clinical trials [see Indications and Usage (1) and Warnings and Precautions (5.9) ] . 14.3 Lack of Efficacy in Patients with Newly Diagnosed Multiple Myeloma 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: 0.79 - 1.261). 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) ] ."],"pharmacodynamics":["12.2 Pharmacodynamics Cardiac Electrophysiology NINLARO did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients."],"pharmacokinetics":["12.3 Pharmacokinetics 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 0.2 to 10.6 mg. 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 by 69% [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 ) of ixazomib was 9.5 days. Following weekly oral dosing, the accumulation ratio was determined to be 2-fold. 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 C-ixazomib to 5 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 Populations There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m 2 ), or race on the clearance of ixazomib based on population PK analysis. 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 by 54% and AUC by 74% [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."],"adverse_reactions":["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) ] The most common adverse reactions (≥20%) are thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis. ( 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 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 / Preferred Term NINLARO + Lenalidomide and Dexamethasone N=361 Placebo + Lenalidomide and Dexamethasone N=359 % % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Note: Adverse reactions included as preferred terms are based on MedDRA version 23.0. 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 N=361 Placebo + Lenalidomide and Dexamethasone N=359 % % 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. 6.2 Postmarketing Experience 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"],"contraindications":["4 CONTRAINDICATIONS None. None. ( 4 )"],"drug_interactions":["7 DRUG INTERACTIONS Strong CYP3A inducers : Avoid concomitant use with NINLARO. ( 7.1 , 12.3 ) 7.1 Strong CYP3A Inducers Avoid concomitant administration of NINLARO with strong CYP3A inducers (such as rifampin, phenytoin, carbamazepine, and St. John's Wort) [see Clinical Pharmacology (12.3) ] ."],"how_supplied_table":["<table width=\"90%\"><col width=\"15%\" align=\"left\" valign=\"top\"/><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"15%\" align=\"left\" valign=\"top\"/><col width=\"15%\" align=\"left\" valign=\"top\"/><col width=\"15%\" align=\"left\" valign=\"top\"/><col width=\"20%\" align=\"left\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\" align=\"center\">Strength per Capsule</th><th styleCode=\"Rrule\" align=\"center\">Capsule Description</th><th styleCode=\"Rrule\" align=\"center\">Outer Carton</th><th styleCode=\"Rrule\" align=\"center\">3 Count Blister Pack</th><th styleCode=\"Rrule\" align=\"center\">1 Count Blister Pack</th><th styleCode=\"Rrule\" align=\"center\">NDC</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">4 mg</td><td styleCode=\"Rrule\">Light orange, size 3, imprinted with &quot;Takeda&quot; on the cap and &quot;4 mg&quot; on the body in black ink.</td><td styleCode=\"Rrule\">Three 4 mg capsules in a carton</td><td styleCode=\"Rrule\">Each blister pack has three 4 mg capsules</td><td styleCode=\"Rrule\">Each blister pack has one 4 mg capsule</td><td styleCode=\"Rrule\">Outer carton NDC 63020-400-02 3 Count Blister Pack NDC 63020-400-03 1 Count Blister pack NDC 63020-400-01</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">3 mg</td><td styleCode=\"Rrule\">Light grey, size 4, imprinted with &quot;Takeda&quot; on the cap and &quot;3 mg&quot; on the body in black ink.</td><td styleCode=\"Rrule\">Three 3 mg capsules in a carton</td><td styleCode=\"Rrule\">Each blister pack has three 3 mg capsules</td><td styleCode=\"Rrule\">Each blister pack has one 3 mg capsule</td><td styleCode=\"Rrule\">Outer carton NDC 63020-390-02 3 Count Blister Pack NDC 63020-390-03 1 Count Blister pack NDC 63020-390-01</td></tr><tr><td styleCode=\"Lrule Rrule\">2.3 mg</td><td styleCode=\"Rrule\">Light pink, size 4, imprinted with &quot;Takeda&quot; on the cap and &quot;2.3 mg&quot; on the body in black ink.</td><td styleCode=\"Rrule\">Three 2.3 mg capsules in a carton</td><td styleCode=\"Rrule\">Each blister pack has three 2.3 mg capsules</td><td styleCode=\"Rrule\">Each blister pack has one 2.3 mg capsule</td><td styleCode=\"Rrule\">Outer carton NDC 63020-230-02 3 Count Blister Pack NDC 63020-230-03 1 Count Blister pack NDC 63020-230-01</td></tr></tbody></table>"],"mechanism_of_action":["12.1 Mechanism of Action 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."],"recent_major_changes":["Warnings and Precautions, Cutaneous Reactions ( 5.5 ) 3/2024"],"storage_and_handling":["Storage Store NINLARO at room temperature. Do not store above 30°C (86°F). Do not freeze. Store capsules in original packaging until immediately prior to use.","Handling and Disposal NINLARO is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Do not open or crush capsules. Avoid direct contact with the capsule contents. 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. Any unused medicinal product or waste material should be disposed in accordance with local requirements."],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics Cardiac Electrophysiology NINLARO did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients. 12.3 Pharmacokinetics 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 0.2 to 10.6 mg. 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 by 69% [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 ) of ixazomib was 9.5 days. Following weekly oral dosing, the accumulation ratio was determined to be 2-fold. 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 C-ixazomib to 5 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 Populations There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m 2 ), or race on the clearance of ixazomib based on population PK analysis. 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 by 54% and AUC by 74% [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."],"indications_and_usage":["1 INDICATIONS AND USAGE 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 : NINLARO is not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials. ( 1 ) Limitations of Use : NINLARO is not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials [see Warnings and Precautions (5.9) and Clinical Studies (14.2 , 14.3) ] ."],"warnings_and_cautions":["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 a fetus and to use effective non-hormonal contraception. ( 5.8 , 8.1 , 8.3 ) Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting : Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials. ( 5.9 ) 5.1 Thrombocytopenia Thrombocytopenia has been reported with NINLARO with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle [see Adverse Reactions (6.1) ] . Grade 3 thrombocytopenia was reported in 17% of patients in the NINLARO regimen and Grade 4 thrombocytopenia was reported in 13% in the NINLARO regimen. The rate of platelet transfusions was 10% in the NINLARO regimen and 7% in the placebo regimen. Monitor platelet counts at least monthly during treatment with NINLARO. Consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications [see Dosage and Administration (2.2) ] and platelet transfusions as per standard medical guidelines. 5.2 Gastrointestinal Toxicities Diarrhea, constipation, nausea, and vomiting have been reported with NINLARO, occasionally requiring use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea was reported in 52% of patients in the NINLARO regimen and 43% in the placebo regimen, constipation in 35% and 28%, respectively, nausea in 32% and 23%, respectively, and vomiting in 26% and 13%, respectively. Diarrhea resulted in discontinuation of one or more of the three drugs in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen [see Adverse Reactions (6.1) ] . Adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2) ] . 5.3 Peripheral Neuropathy The majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the NINLARO regimen and 16% in the placebo regimen) and Grade 2 (11% in the NINLARO regimen and 6% in the placebo regimen) [see Adverse Reactions (6.1) ] . Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens. The most commonly reported reaction was peripheral sensory neuropathy (24% and 17% in the NINLARO and placebo regimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (<1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 4% of patients in the NINLARO regimen and <1% of patients in the placebo regimen. Patients should be monitored for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification [see Dosage and Administration (2.2) ] . 5.4 Peripheral Edema Peripheral edema was reported in 27% and 21% of patients in the NINLARO and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (17% in the NINLARO regimen and 14% in the placebo regimen) and Grade 2 (7% in the NINLARO regimen and 6% in the placebo regimen). Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively [see Adverse Reactions (6.1) ] . Peripheral edema resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms [see Dosage and Administration (2.2) ] . 5.5 Cutaneous Reactions Rash was reported in 27% of patients in the NINLARO regimen and 16% of patients in the placebo regimen. The majority of the rash adverse reactions were Grade 1 (15% in the NINLARO regimen and 9% in the placebo regimen) or Grade 2 (9% in the NINLARO regimen and 4% in the placebo regimen) [see Adverse Reactions (6.1) ] . Grade 3 rash was reported in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Serious adverse reactions of rash were reported in <1% of patients in the NINLARO regimen. The most common type of rash reported in both regimens included maculo-papular and macular rash. Rash resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. Manage rash with supportive care or with dose modification if Grade 2 or higher [see Dosage and Administration (2.2) ] . Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatal cases, have been reported with NINLARO [see Adverse Reactions (6.1 , 6.2 )] . If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue NINLARO and manage as clinically indicated. 5.6 Thrombotic Microangiopathy Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO [see Adverse Reactions (6.1) ] . Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known. 5.7 Hepatotoxicity Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients treated with NINLARO [see Adverse Reactions (6.1) ] . Hepatotoxicity has been reported (10% in the NINLARO regimen and 9% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2) ] . 5.8 Embryo-Fetal Toxicity NINLARO can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animal studies. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the last dose [see Drug Interactions (7.1) and Use in Specific Populations (8.1 , 8.3) ] . 5.9 Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting In two prospective randomized clinical trials in multiple myeloma in the maintenance setting, treatment with NINLARO resulted in increased deaths. Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials [see Clinical Studies (14.2) ] ."],"clinical_studies_table":["<table width=\"80%\" ID=\"t6\"><caption>Table 6: Baseline Patient and Disease Characteristics</caption><col width=\"35%\" align=\"left\" valign=\"top\"/><col width=\"30%\" align=\"center\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">NINLARO + Lenalidomide and Dexamethasone (N = 360)</th><th styleCode=\"Rrule\">Placebo + Lenalidomide and Dexamethasone (N = 362)</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"3\"><content styleCode=\"bold\">Patient Characteristics</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Median age in years (range)</td><td styleCode=\"Rrule\">66 (38, 91)</td><td styleCode=\"Rrule\">66 (30, 89)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Gender (%) Male/ Female</td><td styleCode=\"Rrule\">58/42</td><td styleCode=\"Rrule\">56/44</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Age Group (% [&lt;65/ &#x2265;65 years])</td><td styleCode=\"Rrule\">41/59</td><td styleCode=\"Rrule\">43/57</td></tr><tr><td styleCode=\"Lrule Rrule\">Race n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> White</td><td styleCode=\"Rrule\">310 (86)</td><td styleCode=\"Rrule\">301 (83)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Black</td><td styleCode=\"Rrule\">7 (2)</td><td styleCode=\"Rrule\">6 (2)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Asian</td><td styleCode=\"Rrule\">30 (8)</td><td styleCode=\"Rrule\">34 (9)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Other or Not Specified</td><td styleCode=\"Rrule\">13 (4)</td><td styleCode=\"Rrule\">21 (6)</td></tr><tr><td styleCode=\"Lrule Rrule\">ECOG performance status, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> 0 or 1</td><td styleCode=\"Rrule\">336 (93)</td><td styleCode=\"Rrule\">334 (92)</td></tr><tr><td styleCode=\"Lrule Rrule\"> 2</td><td styleCode=\"Rrule\">18 (5)</td><td styleCode=\"Rrule\">24 (7)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Missing</td><td styleCode=\"Rrule\">6 (2)</td><td styleCode=\"Rrule\">4 (1)</td></tr><tr><td styleCode=\"Lrule Rrule\">Creatinine clearance, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> &lt;30 mL/min</td><td styleCode=\"Rrule\">5 (1)</td><td styleCode=\"Rrule\">5 (1)</td></tr><tr><td styleCode=\"Lrule Rrule\"> 30-59 mL/min</td><td styleCode=\"Rrule\">74 (21)</td><td styleCode=\"Rrule\">95 (26)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> &#x2265;60 mL/min</td><td styleCode=\"Rrule\">281 (78)</td><td styleCode=\"Rrule\">261 (72)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"3\"><content styleCode=\"bold\">Disease Characteristics</content></td></tr><tr><td styleCode=\"Lrule Rrule\">Myeloma ISS stage, n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Stage I or II</td><td styleCode=\"Rrule\">315 (87)</td><td styleCode=\"Rrule\">320 (88)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Stage III</td><td styleCode=\"Rrule\">45 (13)</td><td styleCode=\"Rrule\">42 (12)</td></tr><tr><td styleCode=\"Lrule Rrule\">Prior line therapies n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Median (range)</td><td styleCode=\"Rrule\">1 (1, 3)</td><td styleCode=\"Rrule\">1 (1,3)</td></tr><tr><td styleCode=\"Lrule Rrule\"> 1</td><td styleCode=\"Rrule\">224 (62)</td><td styleCode=\"Rrule\">217 (60)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> 2 or 3</td><td styleCode=\"Rrule\">136 (38)</td><td styleCode=\"Rrule\">145 (40)</td></tr><tr><td styleCode=\"Lrule Rrule\">Status at Baseline n (%)</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Relapsed</td><td styleCode=\"Rrule\">276 (77)</td><td styleCode=\"Rrule\">280 (77)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Refractory<footnote>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.</footnote></td><td styleCode=\"Rrule\">42 (12)</td><td styleCode=\"Rrule\">40 (11)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Relapsed and Refractory</td><td styleCode=\"Rrule\">41 (11)</td><td styleCode=\"Rrule\">42 (12)</td></tr><tr><td styleCode=\"Lrule Rrule Toprule\">Type of Prior Therapy n (%)</td><td styleCode=\"Rrule Toprule\"/><td styleCode=\"Rrule Toprule\"/></tr><tr><td styleCode=\"Lrule Rrule\"> Bortezomib containing</td><td styleCode=\"Rrule\">248 (69)</td><td styleCode=\"Rrule\">250 (69)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Carfilzomib containing</td><td styleCode=\"Rrule\">1 (&lt;1)</td><td styleCode=\"Rrule\">4 (1)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Thalidomide containing</td><td styleCode=\"Rrule\">157 (44)</td><td styleCode=\"Rrule\">170 (47)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Lenalidomide containing</td><td styleCode=\"Rrule\">44 (12)</td><td styleCode=\"Rrule\">44 (12)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Melphalan containing</td><td styleCode=\"Rrule\">293 (81)</td><td styleCode=\"Rrule\">291 (80)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Stem cell transplantation</td><td styleCode=\"Rrule\">212 (59)</td><td styleCode=\"Rrule\">199 (55)</td></tr><tr><td styleCode=\"Lrule Rrule\">High risk (deletion (del) 17, t(4:14) and/or t(14:16)</td><td styleCode=\"Rrule\">75 (21)</td><td styleCode=\"Rrule\">62 (17)</td></tr><tr><td styleCode=\"Lrule Rrule\"> deletion del (17)</td><td styleCode=\"Rrule\">36 (10)</td><td styleCode=\"Rrule\">33 (9)</td></tr></tbody></table>","<table width=\"80%\" ID=\"t7\"><caption>Table 7: Progression-Free Survival and Response Rate</caption><col width=\"30%\" align=\"left\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><col width=\"35%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">NINLARO + Lenalidomide and Dexamethasone (N = 360)</th><th styleCode=\"Rrule\">Placebo + Lenalidomide and Dexamethasone (N = 362)</th></tr></thead><tfoot><tr><td align=\"left\" colspan=\"3\">NE: Not evaluable.</td></tr></tfoot><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"3\"><content styleCode=\"bold\">Progression-free Survival</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">PFS Events, n (%)</td><td styleCode=\"Rrule\">129 (36)</td><td styleCode=\"Rrule\">157 (43)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Median (months) (95% CI)</td><td styleCode=\"Rrule\">20.6 (17.0, NE)</td><td styleCode=\"Rrule\">14.7 (12.9, 17.6)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Hazard Ratio<footnote>Hazard ratio is based on a stratified Cox&apos;s proportional hazard regression model. A hazard ratio less than 1 indicates an advantage for the NINLARO regimen.</footnote> (95% CI)</td><td styleCode=\"Rrule\" colspan=\"2\">0.74 (0.59, 0.94)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">p-value<footnote>P-value is based on the stratified log-rank test.</footnote></td><td styleCode=\"Rrule\" colspan=\"2\">0.012</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"3\"><content styleCode=\"bold\">Response Rate</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Overall Response Rate, n (%)</td><td styleCode=\"Rrule\">282 (78)</td><td styleCode=\"Rrule\">259 (72)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Complete Response</td><td styleCode=\"Rrule\">42 (12)</td><td styleCode=\"Rrule\">24 (7)</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"> Very Good Partial Response</td><td styleCode=\"Rrule\">131 (36)</td><td styleCode=\"Rrule\">117 (32)</td></tr><tr><td styleCode=\"Lrule Rrule\"> Partial Response</td><td styleCode=\"Rrule\">109 (30)</td><td styleCode=\"Rrule\">118 (33)</td></tr></tbody></table>"],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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."],"adverse_reactions_table":["<table width=\"90%\" ID=\"t4\"><caption>Table 4: Non-Hematologic Adverse Reactions Occurring in &#x2265;5% of Patients with a &#x2265;5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4)</caption><col width=\"40%\" align=\"left\" valign=\"middle\"/><col width=\"10%\" align=\"center\" valign=\"middle\"/><col width=\"10%\" align=\"center\" valign=\"middle\"/><col width=\"10%\" align=\"center\" valign=\"middle\"/><col width=\"10%\" align=\"center\" valign=\"middle\"/><col width=\"10%\" align=\"center\" valign=\"middle\"/><col width=\"10%\" align=\"center\" valign=\"middle\"/><thead><tr><th styleCode=\"Lrule Rrule\" rowspan=\"3\">System Organ Class / Preferred Term</th><th colspan=\"3\" styleCode=\"Rrule Botrule\">NINLARO + Lenalidomide and Dexamethasone N=361</th><th styleCode=\"Rrule Botrule\" colspan=\"3\">Placebo + Lenalidomide and Dexamethasone N=359</th></tr><tr styleCode=\"Botrule\"><th colspan=\"3\" styleCode=\"Lrule Rrule\" align=\"center\">%</th><th styleCode=\"Rrule\" colspan=\"3\">%</th></tr><tr><th styleCode=\"Lrule Rrule\" valign=\"top\" align=\"center\">All Grades</th><th styleCode=\"Rrule\" valign=\"top\">Grade 3</th><th styleCode=\"Rrule\" valign=\"top\">Grade 4</th><th styleCode=\"Rrule\" valign=\"top\">All Grades</th><th styleCode=\"Rrule\" valign=\"top\">Grade 3</th><th styleCode=\"Rrule\" valign=\"top\">Grade 4</th></tr></thead><tfoot><tr><td align=\"left\" colspan=\"7\"><content styleCode=\"bold\">Note: Adverse reactions included as preferred terms are based on MedDRA version 23.0.</content></td></tr></tfoot><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"7\"><content styleCode=\"bold\">Gastrointestinal disorders</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Diarrhea</td><td styleCode=\"Rrule\">52</td><td styleCode=\"Rrule\">10</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">43</td><td styleCode=\"Rrule\">3</td><td styleCode=\"Rrule\">0</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Constipation</td><td styleCode=\"Rrule\">35</td><td styleCode=\"Rrule\">&lt;1</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">28</td><td styleCode=\"Rrule\">&lt;1</td><td styleCode=\"Rrule\">0</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Nausea</td><td styleCode=\"Rrule\">32</td><td styleCode=\"Rrule\">2</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">23</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">0</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Vomiting</td><td styleCode=\"Rrule\">26</td><td styleCode=\"Rrule\">1</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">13</td><td styleCode=\"Rrule\">&lt;1</td><td styleCode=\"Rrule\">0</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\" colspan=\"7\"><content styleCode=\"bold\">Nervous system disorders</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Peripheral neuropathies<footnote ID=\"t4f1\">Represents a pooling of preferred terms</footnote></td><td styleCode=\"Rrule\">32</td><td styleCode=\"Rrule\">2</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">24</td><td styleCode=\"Rrule\">2</td><td styleCode=\"Rrule\">0</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\" colspan=\"7\"><content styleCode=\"bold\">Musculoskeletal and connective tissue disorders</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Back pain<footnote ID=\"t4f2\">At the time of the final analysis, these adverse reactions no longer met the criterion for a &#x2265;5% difference between the NINLARO regimen and the placebo regimen.</footnote></td><td styleCode=\"Rrule\">27</td><td styleCode=\"Rrule\">&lt;1</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">24</td><td styleCode=\"Rrule\">3</td><td styleCode=\"Rrule\">0</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\" colspan=\"7\"><content styleCode=\"bold\">Infections and infestations</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Upper respiratory tract infection<footnoteRef IDREF=\"t4f2\"/></td><td styleCode=\"Rrule\">27</td><td styleCode=\"Rrule\">1</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">23</td><td styleCode=\"Rrule\">1</td><td styleCode=\"Rrule\">0</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Bronchitis</td><td styleCode=\"Rrule\">22</td><td styleCode=\"Rrule\">2</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">17</td><td styleCode=\"Rrule\">2</td><td styleCode=\"Rrule\">&lt;1</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\" colspan=\"7\"><content styleCode=\"bold\">Skin and subcutaneous tissue disorders</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Rash<footnoteRef IDREF=\"t4f1\"/></td><td styleCode=\"Rrule\">27</td><td styleCode=\"Rrule\">3</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">16</td><td styleCode=\"Rrule\">2</td><td styleCode=\"Rrule\">0</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"7\"><content styleCode=\"bold\">General disorders and administration site conditions</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Rrule Lrule\"> Edema peripheral</td><td styleCode=\"Rrule\">27</td><td styleCode=\"Rrule\">2</td><td styleCode=\"Rrule\">0</td><td styleCode=\"Rrule\">21</td><td styleCode=\"Rrule\">1</td><td styleCode=\"Rrule\">0</td></tr></tbody></table>","<table width=\"80%\" ID=\"t5\"><caption>Table 5: Thrombocytopenia and Neutropenia</caption><col width=\"28%\" align=\"left\" valign=\"top\"/><col width=\"18%\" align=\"center\" valign=\"top\"/><col width=\"18%\" align=\"center\" valign=\"top\"/><col width=\"18%\" align=\"center\" valign=\"top\"/><col width=\"18%\" align=\"center\" valign=\"top\"/><thead><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule Botrule\" colspan=\"2\">NINLARO + Lenalidomide and Dexamethasone N=361</th><th styleCode=\"Rrule Botrule\" colspan=\"2\">Placebo + Lenalidomide and Dexamethasone N=359</th></tr><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">%</th><th styleCode=\"Rrule\" colspan=\"2\">%</th></tr><tr><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Any Grade</th><th styleCode=\"Rrule\">Grade 3-4</th><th styleCode=\"Rrule\">Any Grade</th><th styleCode=\"Rrule\">Grade 3-4</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Thrombocytopenia</td><td styleCode=\"Rrule\">85</td><td styleCode=\"Rrule\">30</td><td styleCode=\"Rrule\">67</td><td styleCode=\"Rrule\">14</td></tr><tr><td styleCode=\"Lrule Rrule\">Neutropenia</td><td styleCode=\"Rrule\">74</td><td styleCode=\"Rrule\">34</td><td styleCode=\"Rrule\">70</td><td styleCode=\"Rrule\">37</td></tr></tbody></table>"],"information_for_patients":["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 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. 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 a patient misses a dose, advise them to take the missed dose as long as the next scheduled dose is ≥72 hours away. Advise patients not to take a missed dose if it is within 72 hours of their next scheduled dose. If a patient vomits after taking a 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) ] Thrombocytopenia Advise 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 Toxicities Advise 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 Neuropathy Advise patients to contact their healthcare providers if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs. [see Warnings and Precautions (5.3) ] . Peripheral Edema Advise 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 Reactions Advise patients to contact their healthcare providers immediately if they experience new or worsening rash [see Warnings and Precautions (5.5) ] . Thrombotic Microangiopathy Advise patients to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur [see Warnings and Precautions (5.6) ] . Hepatotoxicity Advise patients to contact their healthcare providers if they experience jaundice or right upper quadrant abdominal pain [see Warnings and Precautions (5.7) ] . Other Adverse Reactions Advise patients to contact their healthcare providers if they experience signs and symptoms of acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, herpes zoster, cataracts, dry eyes, blurred vision, conjunctivitis and thrombotic thrombocytopenic purpura [see Adverse Reactions (6.1) ] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a 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 last dose. Advise women using hormonal contraceptives to also use a 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 last dose [see Use in Specific Populations (8.1) ] . Lactation Advise women not to breastfeed during treatment with NINLARO and for 90 days after the last dose [see Use in Specific Populations (8.2) ] . Concomitant Medications Advise patients to speak with their healthcare providers about any other medication they are currently taking and before starting any new medications."],"spl_unclassified_section":["Distributed by: Takeda Pharmaceuticals America, Inc. Cambridge, MA 02142 NINLARO is a registered trademark of Millennium Pharmaceuticals, Inc. ©2024 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. IXB349 R10"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15 of a 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 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) ] . The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened [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) ] . 2.2 Dosage Modification Guidelines 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 (2.3 , 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 again, withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm 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 . 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/mm 3 again, withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm 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 2 or 3 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. Toxicities should, at the healthcare provider's discretion, generally recover to patient's baseline condition or Grade 1 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 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) and Clinical Pharmacology (12.3) ] . 2.4 Dosage in Patients with Renal Impairment 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) and Clinical Pharmacology (12.3) ] . Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment."],"spl_product_data_elements":["NINLARO ixazomib ixazomib citrate ixazomib microcrystalline cellulose talc magnesium stearate Light orange 4;mg NINLARO ixazomib ixazomib citrate ixazomib microcrystalline cellulose talc magnesium stearate Light grey 3;mg NINLARO ixazomib ixazomib citrate ixazomib microcrystalline cellulose talc magnesium stearate Light pink 2;3;mg"],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS NINLARO is available in the following capsules: 4 mg ixazomib: Light orange gelatin capsule imprinted with \"Takeda\" on the cap and \"4 mg\" on the body in black ink. 3 mg ixazomib: Light grey gelatin capsule imprinted with \"Takeda\" on the cap and \"3 mg\" on the body in black ink. 2.3 mg ixazomib: Light pink gelatin capsule imprinted with \"Takeda\" on the cap and \"2.3 mg\" on the body in black ink. Capsules: 4 mg, 3 mg, and 2.3 mg ( 3 )"],"recent_major_changes_table":["<table width=\"100%\" styleCode=\"Noautorules\"><col width=\"80%\" align=\"left\" valign=\"top\"/><col width=\"20%\" align=\"right\" valign=\"bottom\"/><tbody><tr><td>Warnings and Precautions, Cutaneous Reactions (<linkHtml href=\"#S5.5\">5.5</linkHtml>)</td><td>3/2024</td></tr></tbody></table>"],"spl_patient_package_insert":["This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: July/2024 PATIENT INFORMATION NINLARO ® (nin-LAR-oh) (ixazomib) capsules NINLARO is used with two other prescription medicines called REVLIMID ® (lenalidomide) and dexamethasone. Read the Medication Guide that comes with REVLIMID ® (lenalidomide). You can ask your healthcare provider or pharmacist for information about dexamethasone. What is NINLARO? NINLARO is a prescription medicine used to treat multiple myeloma in combination with the medicines REVLIMID ® (lenalidomide) and dexamethasone, in people who have received at least one prior treatment for their multiple myeloma. NINLARO should not be used to treat people: who are receiving maintenance treatment, or who have been newly diagnosed with multiple myeloma, unless they are participants in a controlled clinical trial. 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 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 a pregnancy test before you start treatment with NINLARO. You should use effective non-hormonal birth control during treatment and for 90 days after your last 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 last 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 last 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 I 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 4 weeks (28 days). The usual dose of NINLARO is 1 capsule taken 1 time each week , on the same day of the week for the first 3 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 1 hour before or at least 2 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 a dose of NINLARO, or if you are late taking a dose, take the dose as long as the next scheduled dose is more than 3 days (72 hours) away. Do not take a missed dose of NINLARO if it is within 3 days (72 hours) of your next scheduled dose. If you vomit after taking a 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 a 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 NINLARO? NINLARO 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: tingling numbness pain a 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 face, arms, hands, legs, ankles, or feet, or if you gain weight from swelling. Skin reactions . Rashes are common with NINLARO. NINLARO can cause rashes and other skin reactions that can be serious and can lead to death. Tell your healthcare provider right away if you get a new or worsening rash, severe blistering or peeling of the skin, or mouth sores. Thrombotic microangiopathy (TMA) . This is a 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 a liver problem: yellowing of your skin or the whites of your eyes pain in your right upper stomach-area (abdomen) Other common side effects of NINLARO include: low white blood cell counts (neutropenia) bronchitis Tell your healthcare provider if you get new or worsening signs or symptoms of the following during treatment with NINLARO: skin rash and pain (shingles) due to reactivation of the chicken pox virus (herpes zoster) blurred vision or other changes in your 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 I store NINLARO? Store NINLARO at room temperature. Do not store above 86°F (30°C). 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 a Patient Information leaflet. Do not use NINLARO for a 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 : ixazomib Inactive ingredients : microcrystalline cellulose, magnesium stearate, and talc Capsule shells : gelatin and titanium dioxide. The 4 mg capsule shell contains red and yellow iron oxide. The 3 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. Cambridge, MA 02142 NINLARO is a registered trademark of Millennium Pharmaceuticals, Inc. ©2024 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. IXB349 R10"],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS Hepatic Impairment : Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment. ( 2.3 , 8.6 ) Renal Impairment : Reduce the NINLARO starting dose to 3 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 Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and data from animal reproduction studies, NINLARO can cause fetal harm when administered to a 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 a 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 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 (≥0.3 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 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 0.6 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 4 mg. 8.2 Lactation 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. 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 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. 8.4 Pediatric Use Safety and effectiveness of NINLARO 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) ] ."],"dosage_and_administration_table":["<table width=\"90%\" ID=\"t1\"><caption>Table 1: Dosing Schedule for NINLARO taken with Lenalidomide and Dexamethasone &#x2714; Take medicine</caption><col width=\"20%\" align=\"left\" valign=\"top\"/><col width=\"10%\" align=\"center\" valign=\"top\"/><col width=\"10%\" align=\"center\" valign=\"top\"/><col width=\"10%\" align=\"center\" valign=\"top\"/><col width=\"10%\" align=\"center\" valign=\"top\"/><col width=\"10%\" align=\"center\" valign=\"top\"/><col width=\"10%\" align=\"center\" valign=\"top\"/><col width=\"10%\" align=\"center\" valign=\"top\"/><col width=\"10%\" align=\"center\" valign=\"top\"/><thead><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\" colspan=\"9\" align=\"center\">28-Day Cycle (a 4-week cycle)</th></tr><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\" colspan=\"2\">Week 1</th><th styleCode=\"Rrule\" colspan=\"2\">Week 2</th><th styleCode=\"Rrule\" colspan=\"2\">Week 3</th><th styleCode=\"Rrule\" colspan=\"2\">Week 4</th></tr><tr styleCode=\"Botrule\"><th styleCode=\"Lrule Rrule\"/><th styleCode=\"Rrule\">Day 1</th><th styleCode=\"Rrule\">Days 2-7</th><th styleCode=\"Rrule\">Day 8</th><th styleCode=\"Rrule\">Days 9-14</th><th styleCode=\"Rrule\">Day 15</th><th styleCode=\"Rrule\">Days 16-21</th><th styleCode=\"Rrule\">Day 22</th><th styleCode=\"Rrule\">Days 23-28</th></tr></thead><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">NINLARO</td><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Lenalidomide</td><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\">&#x2714; Daily</td><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\">&#x2714; Daily</td><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\">&#x2714; Daily</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\"/></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Dexamethasone</td><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\"/><td styleCode=\"Rrule\">&#x2714;</td><td styleCode=\"Rrule\"/></tr><tr><td colspan=\"9\"/></tr></tbody></table>","<table width=\"80%\" ID=\"t2\"><caption>Table 2: NINLARO Dose Reductions due to Adverse Reactions</caption><col width=\"30%\" align=\"left\" valign=\"middle\"/><col width=\"25%\" align=\"left\" valign=\"middle\"/><col width=\"25%\" align=\"left\" valign=\"middle\"/><col width=\"20%\" align=\"left\" valign=\"middle\"/><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Recommended starting dose<footnote>Recommended starting dose of 3 mg in patients with moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease requiring dialysis <content styleCode=\"italics\">[see <linkHtml href=\"#S2.3\">Dosage and Administration (2.3</linkHtml>, <linkHtml href=\"#S2.4\">2.4)</linkHtml>]</content>.</footnote></td><td styleCode=\"Rrule\">First reduction to</td><td styleCode=\"Rrule\">Second reduction to</td><td styleCode=\"Rrule\" rowspan=\"2\">Discontinue</td></tr><tr><td styleCode=\"Lrule Rrule\"> 4 mg</td><td styleCode=\"Rrule\"> 3 mg</td><td styleCode=\"Rrule\"> 2.3 mg</td></tr></tbody></table>","<table width=\"80%\" ID=\"t3\"><caption>Table 3: Dosage Modifications Guidelines for NINLARO in Combination with Lenalidomide and Dexamethasone</caption><col width=\"35%\" align=\"left\" valign=\"top\"/><col width=\"65%\" align=\"left\" valign=\"top\"/><tbody><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Hematological Toxicities</content></td><td styleCode=\"Rrule\"><content styleCode=\"bold\">Recommended Actions</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">Thrombocytopenia (Platelet Count)</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Platelet count less than 30,000/mm<sup>3</sup></td><td styleCode=\"Rrule\"><list styleCode=\"Disc\" listType=\"unordered\"><item>Withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm<sup>3</sup>.</item><item>Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose.</item><item>If platelet count falls to less than 30,000/mm<sup>3</sup> again, withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm<sup>3</sup>.</item><item>Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.<footnote ID=\"ft1.1\">For additional occurrences, alternate dose modification of lenalidomide and NINLARO</footnote></item></list></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">Neutropenia (Absolute Neutrophil Count)</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Absolute neutrophil count less than 500/mm<sup>3</sup></td><td styleCode=\"Rrule\"><list styleCode=\"Disc\" listType=\"unordered\"><item>Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm<sup>3</sup>. Consider adding G-CSF as per clinical guidelines.</item><item>Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose.</item><item>If absolute neutrophil count falls to less than 500/mm<sup>3</sup> again, withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm<sup>3</sup>.</item><item>Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.<footnoteRef IDREF=\"ft1.1\"/></item></list></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Non-Hematological Toxicities</content></td><td styleCode=\"Rrule\"><content styleCode=\"bold\">Recommended Actions</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">Rash</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Grade<footnote>Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03</footnote> 2 or 3</td><td styleCode=\"Rrule\"><list styleCode=\"Disc\" listType=\"unordered\"><item>Withhold lenalidomide until rash recovers to Grade 1 or lower.</item><item>Following recovery, resume lenalidomide at the next lower dose according to its prescribing information.</item><item>If Grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to Grade 1 or lower.</item><item>Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.<footnoteRef IDREF=\"ft1.1\"/></item></list></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Grade 4</td><td styleCode=\"Rrule\">Discontinue treatment regimen.</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">Peripheral Neuropathy</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Grade 1 Peripheral Neuropathy with Pain or Grade 2 Peripheral Neuropathy</td><td styleCode=\"Rrule\"><list styleCode=\"Disc\" listType=\"unordered\"><item>Withhold NINLARO until peripheral neuropathy recovers to Grade 1 or lower without pain or patient&apos;s baseline.</item><item>Following recovery, resume NINLARO at its most recent dose.</item></list></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Grade 2 Peripheral Neuropathy with Pain or Grade 3 Peripheral Neuropathy</td><td styleCode=\"Rrule\"><list styleCode=\"Disc\" listType=\"unordered\"><item>Withhold NINLARO. Toxicities should, at the healthcare provider&apos;s discretion, generally recover to patient&apos;s baseline condition or Grade 1 or lower prior to resuming NINLARO.</item><item>Following recovery, resume NINLARO at the next lower dose.</item></list></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Grade 4 Peripheral Neuropathy</td><td styleCode=\"Rrule\">Discontinue treatment regimen.</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"2\"><content styleCode=\"bold\">Other Non-Hematological Toxicities</content></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\">Other Grade 3 or 4 Non-Hematological Toxicities</td><td styleCode=\"Rrule\"><list styleCode=\"Disc\" listType=\"unordered\"><item>Withhold NINLARO. Toxicities should, at the healthcare provider&apos;s discretion, generally recover to patient&apos;s baseline condition or Grade 1 or lower prior to resuming NINLARO.</item><item>If attributable to NINLARO, resume NINLARO at the next lower dose following recovery.</item></list></td></tr></tbody></table>"],"spl_patient_package_insert_table":["<table width=\"100%\"><col width=\"3%\" align=\"left\" valign=\"top\"/><col width=\"47%\" align=\"left\" valign=\"top\"/><col width=\"50%\" align=\"left\" valign=\"top\"/><tfoot><tr><td colspan=\"2\" align=\"left\" valign=\"top\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\" valign=\"top\">Revised: July/2024</td></tr></tfoot><tbody><tr styleCode=\"Botrule\"><td align=\"center\" valign=\"top\" colspan=\"3\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">PATIENT INFORMATION</content> NINLARO<sup>&#xAE;</sup> (nin-LAR-oh) (ixazomib) capsules</td></tr><tr styleCode=\"Botrule\"><td colspan=\"3\" styleCode=\"Lrule Rrule\">NINLARO is used with two other prescription medicines called REVLIMID<content styleCode=\"bold\"><sup>&#xAE;</sup></content> (lenalidomide) and dexamethasone. Read the Medication Guide that comes with REVLIMID<content styleCode=\"bold\"><sup>&#xAE;</sup></content> (lenalidomide). You can ask your healthcare provider or pharmacist for information about dexamethasone. </td></tr><tr styleCode=\"Botrule\"><td colspan=\"3\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">What is NINLARO?</content> NINLARO is a prescription medicine used to treat multiple myeloma in combination with the medicines REVLIMID<sup>&#xAE;</sup> (lenalidomide) and dexamethasone, in people who have received at least one prior treatment for their multiple myeloma. NINLARO should <content styleCode=\"bold\">not</content> be used to treat people:<list listType=\"unordered\" styleCode=\"disc\"><item>who are receiving maintenance treatment, <content styleCode=\"bold\">or</content></item><item>who have been newly diagnosed with multiple myeloma, unless they are participants in a controlled clinical trial.</item></list>It is not known if NINLARO is safe and effective in children.</td></tr><tr styleCode=\"Botrule\"><td colspan=\"3\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">Before taking NINLARO, tell your healthcare provider about all of your medical conditions, including if you:</content><list listType=\"unordered\" styleCode=\"disc\"><item>have liver problems</item><item>have kidney problems or are on dialysis</item><item>are pregnant or plan to become pregnant. NINLARO can harm your unborn baby. <content styleCode=\"bold\">Females who are able to become pregnant:</content><list listType=\"unordered\" styleCode=\"circle\"><item>Avoid becoming pregnant during treatment with NINLARO.</item><item>Your healthcare provider will do a pregnancy test before you start treatment with NINLARO.</item><item>You should use effective non-hormonal birth control during treatment and for 90 days after your last 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.</item><item>Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with NINLARO.</item></list><content styleCode=\"bold\">Males with female partners who are able to become pregnant:</content><list listType=\"unordered\" styleCode=\"circle\"><item>You should use effective birth control during treatment and for 90 days after your last dose of NINLARO.</item><item>Tell your healthcare provider right away if your partner becomes pregnant or thinks she may be pregnant while you are being treated with NINLARO.</item></list></item><item>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 last dose of NINLARO. </item></list><content styleCode=\"bold\">Tell your healthcare provider about all the medicines you take,</content> 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.</td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"3\"><content styleCode=\"bold\">How should I take NINLARO? </content><list listType=\"unordered\"><item>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.</item><item>NINLARO is taken in &quot;cycles.&quot; Each cycle lasts 4 weeks (28 days). <list listType=\"unordered\"><item>The usual dose of <content styleCode=\"bold\">NINLARO is 1 capsule taken 1 time each week</content>, on the same day of the week for <content styleCode=\"bold\">the first 3 weeks</content> of each cycle.</item><item>Take each dose of NINLARO at about the same time of day.</item><item>Take REVLIMID (lenalidomide) and dexamethasone exactly as your healthcare provider tells you to.</item><item>Your healthcare provider will do blood tests during treatment with NINLARO to check for side effects.</item><item>Your healthcare provider may change your dose or stop NINLARO, REVLIMID (lenalidomide), or dexamethasone if you have side effects.</item></list></item><item><content styleCode=\"bold\">Take NINLARO at least 1 hour before or at least 2 hours after food.</content></item><item><content styleCode=\"bold\">On the days that you take both NINLARO and dexamethasone, do not</content> take NINLARO and dexamethasone at the same time. <content styleCode=\"bold\">Take dexamethasone with food.</content></item><item>Swallow NINLARO capsules whole with water. <content styleCode=\"bold\">Do not</content> crush, chew or open the capsule.</item><item>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.</item><item>If you miss a dose of NINLARO, or if you are late taking a dose, take the dose as long as the next scheduled dose is more than 3 days (72 hours) away. <content styleCode=\"bold\">Do not</content> take a missed dose of NINLARO if it is within 3 days (72 hours) of your next scheduled dose.</item><item>If you vomit after taking a dose of NINLARO, <content styleCode=\"bold\">do not</content> repeat the dose. Take your next dose of NINLARO on the next scheduled day and time.</item><item>Your healthcare provider may prescribe a medicine to take with NINLARO to decrease the risk of the chicken pox virus (herpes zoster) coming back (reactivation).</item><item><content styleCode=\"bold\">Taking too much NINLARO (overdose) can cause serious side effects, including death.</content> 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.</item></list></td></tr><tr><td colspan=\"3\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">What are the possible side effects of NINLARO?</content> <content styleCode=\"bold\">NINLARO may cause serious side effects, including:</content><list listType=\"unordered\"><item><content styleCode=\"bold\">Low platelet counts (thrombocytopenia)</content>. 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.</item><item><content styleCode=\"bold\">Stomach and intestinal (gastrointestinal) problems. </content>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.</item><item><content styleCode=\"bold\">Nerve problems</content>. Nerve problems are common with NINLARO and may also be severe. Tell your healthcare provider if you get any new or worsening symptoms, including:</item></list></td></tr><tr><td styleCode=\"Lrule\"/><td><list listType=\"unordered\" styleCode=\"Circle\"><item>tingling</item><item>numbness</item><item>pain</item></list></td><td styleCode=\"Rrule\"><list listType=\"unordered\" styleCode=\"Circle\"><item>a burning feeling in your feet or hands</item><item>weakness in your arms or legs</item></list></td></tr><tr><td colspan=\"3\" styleCode=\"Lrule Rrule\"><list listType=\"unordered\"><item><content styleCode=\"bold\">Swelling</content>. Swelling is common with NINLARO and can sometimes be severe. Tell your healthcare provider if you develop swelling in your face, arms, hands, legs, ankles, or feet, or if you gain weight from swelling.</item><item><content styleCode=\"bold\">Skin reactions</content>. Rashes are common with NINLARO. NINLARO can cause rashes and other skin reactions that can be serious and can lead to death. Tell your healthcare provider right away if you get a new or worsening rash, severe blistering or peeling of the skin, or mouth sores.</item><item><content styleCode=\"bold\">Thrombotic microangiopathy (TMA)</content>. This is a 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:</item></list></td></tr><tr><td styleCode=\"Lrule\"/><td><list listType=\"unordered\" styleCode=\"Circle\"><item>fever</item><item>bruising</item><item>nose bleeds</item></list></td><td styleCode=\"Rrule\"><list listType=\"unordered\" styleCode=\"Circle\"><item>tiredness</item><item>decreased urination</item></list></td></tr><tr><td colspan=\"3\" styleCode=\"Lrule Rrule\"><list listType=\"unordered\" styleCode=\"disc\"><item><content styleCode=\"bold\">Liver problems</content>. Tell your healthcare provider if you get these signs of a liver problem:<list listType=\"unordered\" styleCode=\"Circle\"><item>yellowing of your skin or the whites of your eyes</item><item>pain in your right upper stomach-area (abdomen)</item></list></item></list><content styleCode=\"bold\">Other common side effects of NINLARO include:</content></td></tr><tr><td styleCode=\"Lrule\" colspan=\"2\"><list listType=\"unordered\" styleCode=\"disc\"><item>low white blood cell counts (neutropenia)</item></list></td><td styleCode=\"Rrule\"><list listType=\"unordered\" styleCode=\"disc\"><item>bronchitis</item></list></td></tr><tr styleCode=\"Botrule\"><td styleCode=\"Lrule Rrule\" colspan=\"3\">Tell your healthcare provider if you get new or worsening signs or symptoms of the following during treatment with NINLARO:<list listType=\"unordered\" styleCode=\"disc\"><item>skin rash and pain (shingles) due to reactivation of the chicken pox virus (herpes zoster)</item><item>blurred vision or other changes in your vision, dry eye and pink eye (conjunctivitis)</item></list>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.</td></tr><tr styleCode=\"Botrule\"><td colspan=\"3\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">How should I store NINLARO? </content><list listType=\"unordered\"><item>Store NINLARO at room temperature. Do not store above 86&#xB0;F (30&#xB0;C).</item><item>Do not freeze NINLARO.</item><item>Store NINLARO capsules in the original packaging until just before each use.</item><item>Ask your pharmacist or healthcare provider about how to dispose of (throw away) unused NINLARO.</item></list><content styleCode=\"bold\">Keep NINLARO and all medicines out of the reach of children.</content></td></tr><tr styleCode=\"Botrule\"><td colspan=\"3\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">General information about the safe and effective use of NINLARO. </content> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NINLARO for a 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.</td></tr><tr><td colspan=\"3\" styleCode=\"Lrule Rrule\"><content styleCode=\"bold\">What are the ingredients in NINLARO? </content> <content styleCode=\"bold\">Active ingredient</content>: ixazomib <content styleCode=\"bold\">Inactive ingredients</content>: microcrystalline cellulose, magnesium stearate, and talc <content styleCode=\"bold\">Capsule shells</content>: gelatin and titanium dioxide. The 4 mg capsule shell contains red and yellow iron oxide. The 3 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.</td></tr><tr styleCode=\"Botrule\"><td colspan=\"3\" styleCode=\"Lrule Rrule\"> Distributed by:  <content styleCode=\"bold\">Takeda Pharmaceuticals America, Inc.</content>  Cambridge, MA 02142  NINLARO is a registered trademark of Millennium Pharmaceuticals, Inc.   &#xA9;2024 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.  IXB349 R10</td></tr></tbody></table>"],"package_label_principal_display_panel":["PRINCIPAL DISPLAY PANEL - 4 mg Capsule Blister Pack Rx only NDC 63020-400-03 NINLARO ® (ixazomib) capsules 4 mg per capsule Contains 3 Capsules Please read Package Insert before use. Lift to Open Takeda PRINCIPAL DISPLAY PANEL - 4 mg Capsule Blister Pack","PRINCIPAL DISPLAY PANEL - 3 mg Capsule Blister Pack Rx only NDC 63020-390-03 NINLARO ® (ixazomib) capsules 3 mg per capsule Contains 3 Capsules Please read Package Insert before use. Lift to Open Takeda PRINCIPAL DISPLAY PANEL - 3 mg Capsule Blister Pack","PRINCIPAL DISPLAY PANEL - 2.3 mg Capsule Blister Pack Rx only NDC 63020-230-03 NINLARO ® (ixazomib) capsules 2.3 mg per capsule Contains 3 Capsules Please read Package Insert before use. Lift to Open Takeda PRINCIPAL DISPLAY PANEL - 2.3 mg Capsule Blister Pack"],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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."]},"tags":[{"label":"Proteasome Inhibitor","category":"class"},{"label":"Small Molecule","category":"modality"},{"label":"Proteasome subunit beta type-5","category":"target"},{"label":"PSMB5","category":"gene"},{"label":"PSMB1","category":"gene"},{"label":"PSMB2","category":"gene"},{"label":"L01XG03","category":"atc"},{"label":"Oral","category":"route"},{"label":"Capsule","category":"form"},{"label":"LOE Approaching","category":"status"},{"label":"Multiple myeloma","category":"indication"},{"label":"Takeda Pharms Usa","category":"company"},{"label":"Approved 2010s","category":"decade"},{"label":"Antineoplastic Agents","category":"pharmacology"},{"label":"Enzyme Inhibitors","category":"pharmacology"},{"label":"Protease Inhibitors","category":"pharmacology"}],"phase":"marketed","safety":{"boxedWarnings":[],"safetySignals":[{"date":"","signal":"PLASMA CELL MYELOMA","source":"FDA FAERS","actionTaken":"3635 reports"},{"date":"","signal":"DEATH","source":"FDA FAERS","actionTaken":"3297 reports"},{"date":"","signal":"DIARRHOEA","source":"FDA FAERS","actionTaken":"3142 reports"},{"date":"","signal":"OFF LABEL USE","source":"FDA FAERS","actionTaken":"2972 reports"},{"date":"","signal":"PNEUMONIA","source":"FDA FAERS","actionTaken":"1933 reports"},{"date":"","signal":"FATIGUE","source":"FDA FAERS","actionTaken":"1915 reports"},{"date":"","signal":"NAUSEA","source":"FDA FAERS","actionTaken":"1843 reports"},{"date":"","signal":"NEUROPATHY PERIPHERAL","source":"FDA FAERS","actionTaken":"1443 reports"},{"date":"","signal":"VOMITING","source":"FDA FAERS","actionTaken":"1109 reports"},{"date":"","signal":"RASH","source":"FDA FAERS","actionTaken":"1081 reports"}],"commonSideEffects":[{"effect":"Diarrhea","drugRate":"","severity":"serious","_validated":false,"_confidence":0.3},{"effect":"Constipation","drugRate":"34%","severity":"serious","_validated":true},{"effect":"Thrombocytopenia","drugRate":"28%","severity":"serious","_validated":true},{"effect":"Peripheral neuropathy","drugRate":"28%","severity":"serious","_validated":true},{"effect":"Nausea","drugRate":"26%","severity":"serious","_validated":true},{"effect":"Peripheral edema","drugRate":"","severity":"serious","_validated":false,"_confidence":0.3},{"effect":"Back pain","drugRate":"21%","severity":"serious","_validated":true},{"effect":"Vomiting","drugRate":"22%","severity":"serious","_validated":true},{"effect":"Upper respiratory tract infection","drugRate":"","severity":"common","_validated":false,"_confidence":0.3},{"effect":"Rash","drugRate":"","severity":"common","_validated":false,"_confidence":0.3},{"effect":"Eye disorders","drugRate":"","severity":"common","_validated":false,"_confidence":0.3},{"effect":"Edema peripheral","drugRate":"","severity":"common","_validated":false,"_confidence":0.3},{"effect":"Blurred vision","drugRate":"6%","severity":"common","_validated":true},{"effect":"Dry eye","drugRate":"5%","severity":"common","_validated":true},{"effect":"Conjunctivitis","drugRate":"5%","severity":"common","_validated":true},{"effect":"Neutropenia","drugRate":"4%","severity":"mild","_validated":true},{"effect":"Herpes Zoster","drugRate":"4%","severity":"mild","_validated":true},{"effect":"Acute febrile neutrophilic dermatosis","drugRate":"1%","severity":"mild","_validated":true},{"effect":"Stevens-Johnson syndrome","drugRate":"1%","severity":"mild","_validated":true},{"effect":"Transverse myelitis","drugRate":"1%","severity":"mild","_validated":true},{"effect":"Posterior reversible encephalopathy syndrome","drugRate":"1%","severity":"mild","_validated":true},{"effect":"Tumor lysis syndrome","drugRate":"1%","severity":"mild","_validated":true},{"effect":"Thrombotic thrombocytopenic purpura","drugRate":"1%","severity":"mild","_validated":true}],"specialPopulations":{"Pregnancy":"Women should avoid becoming pregnant while being treated with NINLARO. NINLARO can cause fetal harm when administered to pregnant woman. There are no human data available regarding the potential effect of NINLARO on pregnancy or development of the embryo or fetus. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher then those observed in patients receiving the recommended dose. Advise women of the potential risk to fetus and to avoid becoming pregnant while being treated with NINLARO.","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.","Paediatric use":"Safety and effectiveness have not been established in pediatric patients.","Renal impairment":"Reduce the NINLARO starting dose to mg in patients with severe renal impairment or end-stage renal disease requiring dialysis.","Hepatic impairment":"Reduce the NINLARO starting dose to mg in patients with moderate or severe hepatic impairment."}},"trials":[],"aliases":[],"company":"Takeda","patents":[{"applNo":"N208462","source":"FDA Orange Book","status":"Active","expires":"Aug 6, 2027","useCode":"U-2434","territory":"US","drugProduct":false,"patentNumber":"8871745","drugSubstance":false},{"applNo":"N208462","source":"FDA Orange Book","status":"Active","expires":"Jun 16, 2029","useCode":"U-2434","territory":"US","drugProduct":false,"patentNumber":"9175017","drugSubstance":false},{"applNo":"N208462","source":"FDA Orange Book","status":"Active","expires":"Aug 6, 2027","useCode":"U-2434","territory":"US","drugProduct":true,"patentNumber":"8003819","drugSubstance":true},{"applNo":"N208462","source":"FDA Orange Book","status":"Active","expires":"Nov 20, 2029","useCode":"U-2434","territory":"US","drugProduct":true,"patentNumber":"7442830","drugSubstance":true},{"applNo":"N208462","source":"FDA Orange Book","status":"Active","expires":"Aug 6, 2027","useCode":"U-2434","territory":"US","drugProduct":true,"patentNumber":"8530694","drugSubstance":true},{"applNo":"N208462","source":"FDA Orange Book","status":"Active","expires":"Jun 16, 2029","useCode":"","territory":"US","drugProduct":true,"patentNumber":"8859504","drugSubstance":true},{"applNo":"N208462","source":"FDA Orange Book","status":"Active","expires":"Aug 6, 2027","useCode":"","territory":"US","drugProduct":true,"patentNumber":"7687662","drugSubstance":true}],"pricing":[],"_sources":{"trials":{"url":"https://clinicaltrials.gov/search?intr=IXAZOMIB","method":"api_direct","source":"ClinicalTrials.gov","rawText":"","confidence":1,"sourceType":"ctgov","retrievedAt":"2026-04-20T03:21:24.053897+00:00"},"patents":{"url":"","method":"deterministic","source":"FDA Orange Book","rawText":"","confidence":1,"sourceType":"fda_orange_book","retrievedAt":"2026-04-20T03:21:24.053429+00:00"},"timeline":{"url":"https://en.wikipedia.org/wiki/Ixazomib","method":"deterministic","source":"Wikipedia","rawText":"","confidence":0.8,"sourceType":"wikipedia","retrievedAt":"2026-04-20T03:21:32.343703+00:00"},"regulatory.ca":{"url":"","method":"api_direct","source":"Health Canada DPD","rawText":"","confidence":1,"sourceType":"health_canada_dpd","retrievedAt":"2026-04-20T03:21:30.951090+00:00"},"regulatory.eu":{"url":"","method":"api_direct","source":"European Medicines Agency","rawText":"","confidence":1,"sourceType":"ema_api","retrievedAt":"2026-04-20T03:21:24.071723+00:00"},"regulatory.us":{"url":"","method":"api_direct","source":"FDA Drugs@FDA","rawText":"","confidence":1,"sourceType":"fda_drugsfda","retrievedAt":"2026-04-20T03:21:22.515265+00:00"},"publicationCount":{"url":"https://pubmed.ncbi.nlm.nih.gov/?term=IXAZOMIB","method":"api_direct","source":"PubMed/NCBI","rawText":"","confidence":1,"sourceType":"pubmed","retrievedAt":"2026-04-20T03:21:31.787389+00:00"},"administration.route":{"url":"","method":"deterministic","source":"FDA Label","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T03:21:21.424466+00:00"},"safety.boxedWarnings":{"url":"","method":"deterministic","source":"FDA Label (no boxed warning)","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T03:21:21.424534+00:00"},"safety.safetySignals":{"url":"https://api.fda.gov/drug/event.json","method":"api_direct","source":"FDA FAERS","rawText":"","confidence":1,"sourceType":"fda_faers","retrievedAt":"2026-04-20T03:21:33.289734+00:00"},"mechanism.target_chembl":{"url":"","method":"api_direct","source":"ChEMBL mechanism: 26S proteasome inhibitor","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-20T03:21:32.343149+00:00"},"crossReferences.chemblId":{"url":"https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL3545432/","method":"api_direct","source":"ChEMBL (EMBL-EBI)","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-20T03:21:32.237412+00:00"},"regulatory.fda_application":{"url":"","method":"deterministic","source":"FDA Label","rawText":"NDA208462","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T03:21:21.424547+00:00"}},"allNames":"ninlaro","offLabel":[],"synonyms":["ixazomib","ixazomib citrate","MLN2238","MLN9708","ninlaro"],"timeline":[{"date":"2015-01-01","type":"neutral","source":"FDA Orange Book","milestone":"Rights transferred from MILLENNIUM PHARMS to Takeda Pharms Usa"},{"date":"2015-11-20","type":"positive","source":"DrugCentral","milestone":"FDA approval (Millennium Pharms)"},{"date":"2016-11-21","type":"positive","source":"DrugCentral","milestone":"EMA approval (Takeda Pharma A/S)"},{"date":"2017-03-30","type":"positive","source":"DrugCentral","milestone":"PMDA approval (Takeda Pharmaceutical Company Limited)"},{"date":"2027-08-06","type":"negative","source":"FDA Orange Book","milestone":"Substance patent 8003819 expires"},{"date":"2029-06-16","type":"negative","source":"FDA Orange Book","milestone":"Substance patent 8859504 expires"},{"date":"2029-11-20","type":"negative","source":"FDA Orange Book","milestone":"Substance patent 7442830 expires"}],"aiSummary":"Ninlaro (IXAZOMIB) is a small molecule proteasome inhibitor developed by Millennium Pharms and currently owned by Takeda Pharms Usa. It targets the proteasome subunit beta type-5 and was FDA approved in 2015 for the treatment of multiple myeloma. Ninlaro is a patented medication with no generic manufacturers available. Key safety considerations include its long half-life of 97.0 hours. As a proteasome inhibitor, Ninlaro works by blocking the action of proteasomes, which are cellular complexes that break down and recycle proteins.","approvals":[{"date":"2015-11-20","orphan":false,"company":"MILLENNIUM PHARMS","regulator":"FDA"},{"date":"2016-11-21","orphan":true,"company":"Takeda Pharma A/S","regulator":"EMA"},{"date":"2017-03-30","orphan":true,"company":"Takeda Pharmaceutical Company Limited","regulator":"PMDA"}],"brandName":"Ninlaro","ecosystem":[{"indication":"Multiple myeloma","otherDrugs":[{"name":"belantamab mafodotin","slug":"belantamab-mafodotin","company":"Glaxosmithkline"},{"name":"bortezomib","slug":"bortezomib","company":"Millennium Pharms"},{"name":"carfilzomib","slug":"carfilzomib","company":"Onyx Pharms"},{"name":"carmustine","slug":"carmustine","company":"Emcure Pharms Ltd"}],"globalPrevalence":176000}],"mechanism":{"target":"Proteasome subunit beta type-5","novelty":"Follow-on","targets":[{"gene":"PSMB5","source":"DrugCentral","target":"Proteasome subunit beta type-5","protein":"Proteasome subunit beta type-5"},{"gene":"PSMB1","source":"DrugCentral","target":"Proteasome subunit beta type-1","protein":"Proteasome subunit beta type-1"},{"gene":"PSMB2","source":"DrugCentral","target":"Proteasome subunit beta type-2","protein":"Proteasome subunit beta type-2"}],"moaClass":"Proteasome Inhibitors","modality":"Small Molecule","drugClass":"Proteasome Inhibitor","explanation":"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.","oneSentence":"Ninlaro blocks the action of proteasomes, which are cellular complexes that break down and recycle proteins.","technicalDetail":"IXAZOMIB selectively inhibits the chymotryptic activity of the 20S proteasome, a multicatalytic proteinase complex involved in the degradation of ubiquitinated proteins, thereby inducing endoplasmic reticulum stress and apoptosis in cancer cells."},"_wikipedia":{"url":"https://en.wikipedia.org/wiki/Ixazomib","title":"Ixazomib","extract":"Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.","wiki_history":"==History==\nThe drug was developed by Takeda. It got US and European orphan drug status for multiple myeloma in 2011, and for AL amyloidosis in 2012. Takeda submitted a US new drug application for multiple myeloma in July 2015. In September 2015, the U.S. Food and Drug Administration (FDA) granted ixazomib combined with lenalidomide and dexamethasone a priority review designation for multiple myeloma. On 20 November 2015, the FDA approved this combination for second-line treatment. After Takeda requested a re-examination, the EMA granted a marketing authorisation on 21 November 2016 on the condition that further efficacy studies be conducted. The approval indication is the same as in the US."},"commercial":{"launchDate":"2015","revenueYear":2024,"_launchSource":"DrugCentral (FDA 2015-11-20, MILLENNIUM PHARMS)","annualRevenue":600,"revenueSource":"Verified: Takeda AR","revenueCurrency":"USD","revenueConfidence":"verified"},"references":[{"id":1,"url":"https://drugcentral.org/drugcard/5067","fields":["approvals","synonyms","ATC","PK","indications","contraindications","DDIs","targets","patents","FAERS"],"source":"DrugCentral"},{"id":2,"url":"https://clinicaltrials.gov/search?intr=IXAZOMIB","fields":["trials"],"source":"ClinicalTrials.gov"},{"id":3,"url":"https://pubmed.ncbi.nlm.nih.gov/?term=IXAZOMIB","fields":["publications"],"source":"PubMed/NCBI"},{"id":4,"url":"https://en.wikipedia.org/wiki/Ixazomib","fields":["history","overview"],"source":"Wikipedia"},{"id":5,"url":"https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files","fields":["patents","exclusivity","genericManufacturers"],"source":"FDA Orange Book"}],"_emaChecked":true,"_enrichedAt":"2026-03-30T12:12:36.197901","_validation":{"fieldsValidated":0,"lastValidatedAt":"2026-04-20T03:21:38.535505+00:00","fieldsConflicting":6,"overallConfidence":0.8},"biosimilars":[],"competitors":[{"drugName":"bortezomib","drugSlug":"bortezomib","fdaApproval":"2003-05-13","patentExpiry":"Sep 23, 2042","patentStatus":"Patent protected","relationship":"same-class"},{"drugName":"carfilzomib","drugSlug":"carfilzomib","fdaApproval":"2012-07-20","patentExpiry":"Oct 21, 2029","patentStatus":"Patent protected","relationship":"same-class"}],"genericName":"ixazomib","indications":{"approved":[{"name":"Multiple myeloma","source":"DrugCentral","snomedId":109989006,"regulator":"FDA","usPrevalence":35000,"globalPrevalence":176000,"prevalenceMethod":"curated","prevalenceSource":"IARC GLOBOCAN, 2022"}],"offLabel":[],"pipeline":[]},"currentOwner":"Takeda Pharms Usa","drugCategory":"loe-approaching","labelChanges":[],"relatedDrugs":[{"drugId":"bortezomib","brandName":"bortezomib","genericName":"bortezomib","approvalYear":"2003","relationship":"same-class"},{"drugId":"carfilzomib","brandName":"carfilzomib","genericName":"carfilzomib","approvalYear":"2012","relationship":"same-class"}],"trialDetails":[{"nctId":"NCT04847453","phase":"PHASE1","title":"Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for the Treatment of Relapsed or Refractory Light Chain Amyloidosis","status":"RECRUITING","sponsor":"National Cancer Institute (NCI)","startDate":"2022-08-03","conditions":["Recurrent AL Amyloidosis","Refractory AL Amyloidosis"],"enrollment":24,"completionDate":"2026-06-30"},{"nctId":"NCT03173092","phase":"PHASE4","title":"A Study of Ixazomib (NINLARO®) in Combination With Lenalidomide and Dexamethasone (IRD) for the Treatment of Participants With Multiple Myeloma (MM)","status":"ACTIVE_NOT_RECRUITING","sponsor":"Takeda","startDate":"2017-11-13","conditions":["Multiple Myeloma"],"enrollment":141,"completionDate":"2026-11-30"},{"nctId":"NCT03506373","phase":"PHASE2","title":"Ibrutinib and Ixazomib Citrate in Treating Newly Diagnosed, Relapsed or Refractory Waldenstrom Macroglobulinemia","status":"TERMINATED","sponsor":"Mayo Clinic","startDate":"2018-08-14","conditions":["Recurrent Waldenstrom Macroglobulinemia","Refractory Waldenstrom Macroglobulinemia","Waldenstrom Macroglobulinemia"],"enrollment":21,"completionDate":"2026-02-03"},{"nctId":"NCT04094961","phase":"PHASE1,PHASE2","title":"Ixazomib + Pomalidomide + Dexamethasone In MM","status":"ACTIVE_NOT_RECRUITING","sponsor":"Omar Nadeem, MD","startDate":"2019-09-18","conditions":["Multiple Myeloma","Multiple Myeloma in Relapse"],"enrollment":52,"completionDate":"2027-01-01"},{"nctId":"NCT02339922","phase":"PHASE2","title":"Ixazomib Citrate and Rituximab in Treating Patients With Indolent B-cell Non-Hodgkin Lymphoma","status":"ACTIVE_NOT_RECRUITING","sponsor":"University of Washington","startDate":"2016-05-19","conditions":["Chronic Lymphocytic Leukemia","Follicular Lymphoma","Lymphoplasmacytic Lymphoma","Mantle Cell Lymphoma","Marginal Zone Lymphoma","Recurrent Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue","Refractory Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue","Small Lymphocytic Lymphoma","Waldenstrom Macroglobulinemia"],"enrollment":33,"completionDate":"2031-01-06"},{"nctId":"NCT04328662","phase":"","title":"A Study of Ninlaro in Real World Clinical Practice in China","status":"COMPLETED","sponsor":"Takeda","startDate":"2020-05-18","conditions":["Multiple Myeloma","Neoplasms, Plasma Cell"],"enrollment":482,"completionDate":"2026-02-13"},{"nctId":"NCT04305691","phase":"PHASE2","title":"Trial of Ixazomib for Kaposi Sarcoma","status":"RECRUITING","sponsor":"AIDS Malignancy Consortium","startDate":"2023-11-07","conditions":["Kaposi Sarcoma","Skin"],"enrollment":41,"completionDate":"2029-03-15"},{"nctId":"NCT03283917","phase":"PHASE1","title":"Daratumumab, Ixazomib, and Dexamethasone in AL Amyloidosis","status":"ACTIVE_NOT_RECRUITING","sponsor":"M.D. Anderson Cancer Center","startDate":"2018-02-07","conditions":["Newly Diagnosed Primary Amyloidosis","Recurrent Primary Amyloidosis","Refractory Primary Amyloidosis"],"enrollment":21,"completionDate":"2027-05-18"},{"nctId":"NCT04463953","phase":"PHASE2","title":"Zanubrutinib, Ixazomib and Dexamethasone in Patients With Treatment Naive Waldenstrom's Macroglobulinemia","status":"COMPLETED","sponsor":"Institute of Hematology & Blood Diseases Hospital, China","startDate":"2020-06-01","conditions":["Waldenström Macroglobulinemia"],"enrollment":25,"completionDate":"2022-12-06"},{"nctId":"NCT02389517","phase":"PHASE2","title":"Lenalidomide With or Without Ixazomib Citrate and Dexamethasone in Treating Patients With Residual Multiple Myeloma After Donor Stem Cell Transplant","status":"COMPLETED","sponsor":"University of Chicago","startDate":"2015-03-02","conditions":["Plasma Cell Myeloma","Residual Disease"],"enrollment":42,"completionDate":"2024-01"},{"nctId":"NCT03587662","phase":"PHASE2","title":"Ixazomib, Gemcitabine, and Doxorubicin in Treating Patients With Locally Advanced or Metastatic Kidney Cancer","status":"ACTIVE_NOT_RECRUITING","sponsor":"M.D. Anderson Cancer Center","startDate":"2018-08-17","conditions":["Metastatic Kidney Medullary Carcinoma","Metastatic Renal Cell Carcinoma","SMARCB1 Negative","Stage III Renal Cell Cancer AJCC v8","Stage IV Renal Cell Cancer AJCC v8"],"enrollment":30,"completionDate":"2027-01-31"},{"nctId":"NCT05013190","phase":"","title":"A Study of NINLARO® in Chinese Adults With Multiple Myeloma","status":"ACTIVE_NOT_RECRUITING","sponsor":"Takeda","startDate":"2021-10-29","conditions":["Multiple Myeloma"],"enrollment":72,"completionDate":"2026-12-31"},{"nctId":"NCT02619682","phase":"PHASE2","title":"Alternating Ixazomib Citrate and Lenalidomide as Maintenance Therapy After Stem Cell Transplant in Treating Patients With Multiple Myeloma","status":"COMPLETED","sponsor":"Fred Hutchinson Cancer Center","startDate":"2015-12-30","conditions":["Plasma Cell Myeloma","Transplant-Related Carcinoma"],"enrollment":30,"completionDate":"2025-10-24"},{"nctId":"NCT05722405","phase":"PHASE4","title":"Ixazomib Plus Low-dose Lenalidomide Versus Ixazomib Alone for Maintenance Treatment of High Risk Multiple Myeloma","status":"RECRUITING","sponsor":"Second Affiliated Hospital, School of Medicine, Zhejiang University","startDate":"2022-07-01","conditions":["Multiple Myeloma"],"enrollment":100,"completionDate":"2028-07-31"},{"nctId":"NCT05675319","phase":"PHASE3","title":"Allogeneic Stem Cell Transplantation vs. Conventional Therapy as Salvage Therapy for Relapsed / Progressive Patients With Multiple Myeloma After First-line Therapy","status":"TERMINATED","sponsor":"Universitätsklinikum Hamburg-Eppendorf","startDate":"2023-03-03","conditions":["Multiple Myeloma"],"enrollment":28,"completionDate":"2025-03-21"},{"nctId":"NCT02343042","phase":"PHASE1,PHASE2","title":"Selinexor and Backbone Treatments of Multiple Myeloma Patients","status":"RECRUITING","sponsor":"Karyopharm Therapeutics Inc","startDate":"2015-10","conditions":["Multiple Myeloma"],"enrollment":300,"completionDate":"2027-04"},{"nctId":"NCT04009109","phase":"PHASE2","title":"Study of Lenalidomide/Ixazomib/Dexamethasone/Daratumumab in Transplant-Ineligible Patients With Newly Diagnosed MM","status":"ACTIVE_NOT_RECRUITING","sponsor":"Alliance Foundation Trials, LLC.","startDate":"2020-10-21","conditions":["Myeloma, Multiple"],"enrollment":79,"completionDate":"2027-06"},{"nctId":"NCT04068597","phase":"PHASE1,PHASE2","title":"Study to Evaluate CCS1477 (Inobrodib) in Haematological Malignancies","status":"RECRUITING","sponsor":"CellCentric Ltd.","startDate":"2019-08-09","conditions":["Haematological Malignancy","Acute Myeloid Leukemia","Non Hodgkin Lymphoma","Multiple Myeloma","Higher-risk Myelodysplastic Syndrome","Peripheral T Cell Lymphoma"],"enrollment":250,"completionDate":"2027-03-31"},{"nctId":"NCT02461888","phase":"PHASE2","title":"Phase II Randomised Trial of Cyclophosphamide & Dexamethasone in Combination With Ixazomib in Relapsed or Refractory Multiple Myeloma.","status":"COMPLETED","sponsor":"University of Leeds","startDate":"2015-12","conditions":["Multiple Myeloma"],"enrollment":112,"completionDate":"2025-01-19"},{"nctId":"NCT03618537","phase":"PHASE2","title":"Ixazomib Maintenance Study in Patients With AL Amyloidosis","status":"ACTIVE_NOT_RECRUITING","sponsor":"Memorial Sloan Kettering Cancer Center","startDate":"2018-08-02","conditions":["AL Amyloidosis"],"enrollment":17,"completionDate":"2026-08"},{"nctId":"NCT02420847","phase":"PHASE1,PHASE2","title":"Ixazomib Citrate With Gemcitabine Hydrochloride and Doxorubicin Hydrochloride in Treating Patients With Urothelial Cancer That is Metastatic or Cannot Be Removed by Surgery","status":"ACTIVE_NOT_RECRUITING","sponsor":"M.D. Anderson Cancer Center","startDate":"2015-07-03","conditions":["Metastatic Urothelial Carcinoma","Transitional Cell Carcinoma","Unresectable Transitional Cell Carcinoma"],"enrollment":57,"completionDate":"2025-12-31"},{"nctId":"NCT02253316","phase":"PHASE2","title":"Phase II Study of IRD (Ixazomib, Lenalidomide, Dexamethasone) Post Autologous Stem Cell Transplantation Followed by Maintenance Ixazomib or Lenalidomide for Multiple Myeloma","status":"ACTIVE_NOT_RECRUITING","sponsor":"Washington University School of Medicine","startDate":"2015-01-20","conditions":["Multiple 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