NINLARO

Ixazomib is a reversible proteasome inhibitor.

Because it is a modified peptide boronic acid with one chiral center, 4 it is considered a boronate proteasome inhibitor.

More than 99% of the drug compound is the R-enantiomer.

Ixazomib was approved by the FDA on November 20, 2015, making it the first oral proteasome inhibitor approved in the US.

It was later approved by Health Canada on August and by the EMA on November 21, 2016.

It was also investigated in other hematological malignancies as well as other conditions, such as systemic light chain (AL) amyloidosis, graft-versus-host disease, and lupus nephritis.

Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. 5, 6,

Ixazomib exerts antimyeloma effects with time-dependent reversible proteasome inhibition.

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 antitumour activity in a mouse multiple myeloma tumour xenograft model.

Studies show that ixazomib exhibits an antiangiogenic activity and blocks osteoclastogenesis and osteoclast reabsorption.

Upon oral administration, ixazomib is rapidly absorbed with a T max of one hour.

Based on population pharmacokinetic (PK) analysis, the mean absolute oral bioavailability was 58%.

Ixazomib area under the curve (AUC) increases in a dose-proportional manner over a dose range of 0.2-10.6 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%.

The steady-state volume of distribution is 543 L.

After the oral administration of a radiolabeled dose, ixazomib represented 70% of total drug-related material in plasma.

Ixazomib undergoes both

• and non-CYP-mediated metabolism, which is reported to be the major drug clearance mechanism.

The major biotransformation pathways include hydrolysis, deboronation, and N-dealkylation, with drug metabolites not expected to retain pharmacological activity.

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%).

Hover over products below to view reaction partners Ixazomib Ixazomib M6 metabolite Ixazomib M3 metabolite Ixazomib M1 metabolite Ixazomib M2 metabolite Ixazomib M1 metabolite Ixazomib M5 metabolite Ixazomib M6 metabolite Ixazomib M2 metabolite.

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.

Following weekly oral dosing, the accumulation ratio was determined to be two-fold.

The terminal half-life (t1/2) of ixazomib was 9.5 days based on a population PK analysis.

Based on a population

PK analysis, systemic clearance was approximately 1.9 L/hr with inter-individual variability of 44%.

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

Manifestations of overdosage include adverse reactions reported at the recommended dosage, including severe nausea, vomiting, diarrhea, aspiration pneumonia, multiple organ failure and death.

There is no known specific antidote for ixazomib overdose and ixazomib is not dialyzable.

In the event of an overdose, monitor the patient closely for adverse reactions and provide appropriate supportive care. 5, 6.

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.