NINLARO

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 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.

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.

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.

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.

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% .

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.

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%).

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.

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.

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.

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.

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.

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).

AUC was 39% higher in patients with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal function.

• and post-dialyzer concentrations of ixazomib measured during the hemodialysis session were similar, suggesting that ixazomib is not dialyzable.

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% .

CYP3A Inhibitors Coadministration of NINLARO with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib.

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.

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.

The following adverse reactions are described in detail in other sections of the prescribing information: Thrombocytopenia Gastrointestinal Toxicities Peripheral Neuropathy Peripheral Edema Cutaneous Reactions Thrombotic Microangiopathy Hepatotoxicity The most common adverse reactions (≥20%) are thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis.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 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%).

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%).

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.

Overdosage, including fatal overdosage, has been reported in patients taking NINLARO.

Manifestations of overdosage include adverse reactions reported at the recommended dosage.

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.

Recommended starting dose of 4 mg taken orally on Days 1, 8, and of a 28-day cycle.

Dose should be taken at least one hour before or at least two hours after food. 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 of a 28-day treatment cycle.

The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 through of a 28-day treatment cycle.

The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 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.

NINLARO should be taken at least one hour before or at least two hours after food.

The whole capsule should be swallowed with water.

The capsule should not be crushed, chewed or opened.

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.

Consider antiviral prophylaxis in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation. 2.2 Dosage Modification Guidelines The NINLARO dose reduction steps are presented in Table 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.

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.

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.

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.

Grade 4 Discontinue treatment regimen.

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.

Grade 3 or 4 Non-Hematological Toxicities Withhold 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. 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.

Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.

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.

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.

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.

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.

Based on its mechanism of action 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.

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.

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.

Safety and effectiveness of

NINLARO have not been established in pediatric patients.

Of the total number of subjects in clinical studies of NINLARO, 55% were and over, while 17% were 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.