Ninlaro

Ninlaro

ixazomib

Manufacturer:

Takeda

Distributor:

DKSH
Full Prescribing Info
Contents
Ixazomib.
Description
Each NINLARO capsule contains 5.7 mg, 4.3 mg of ixazomib citrate which is equivalent to 4 mg, 3 mg, respectively, of ixazomib.
Proper name: Ixazomib citrate.
Chemical name: 1,3,2-dioxaborolane-4,4-diacetic acid, 2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-.
Molecular formula and molecular mass: C20H23BCl2N2O9; 517.12.
Physicochemical properties: Ixazomib citrate has one chiral center and has been unambiguously determined to be 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.
Excipients/Inactive Ingredients: Inactive ingredients: microcrystalline cellulose, magnesium stearate, and talc. In addition, the capsule shell contains the following inactive ingredients: gelatin, titanium dioxide, red and yellow oxide (4 mg), black oxide (3 mg). The printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: NINLARO (ixazomib) is an antineoplastic agent for oral use. Ixazomib citrate, a prodrug, is the drug substance that rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib.
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 several tumor cell types in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in various tumor xenograft models, including models of multiple myeloma.
In vitro, ixazomib inhibited proliferation of multiple myeloma cells co-cultured with bone marrow stromal cells. Ixazomib demonstrated an anti-angiogenic effect in an in vitro capillary tube formation assay.
Cardiac Electrophysiology: NINLARO does not prolong the QTc interval at clinically relevant exposures based on the results of a pharmacokinetic-pharmacodynamic analysis of data from 245 patients. There was no discernible relationship between ixazomib concentration and the RR interval.
Clinical Studies: Study C16010: Study demographics and trial design: The efficacy and safety of NINLARO in combination with lenalidomide and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter Phase 3 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 at any line were excluded from the study. For the purposes of this study, refractory disease was defined as disease progression on treatment or progression within 60 days after the last dose of lenalidomide or a proteasome inhibitor.
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 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). Patients enrolled in the trial had multiple myeloma that was measurable by paraprotein in the serum, urine, or via free light chain measurements.
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. Some patients with renal impairment received a reduced starting dose of lenalidomide. Treatment continued until disease progression or unacceptable toxicities.
Table 1 summarizes the baseline patient and disease characteristics in the study. The baseline demographics and disease characteristics were balanced and comparable between the study regimens. (See Table 1.)

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The primary endpoint was 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. Confirmation of progressive disease was required. Progression and disease response were assessed every four weeks until disease progression. Overall survival (OS) and OS in patients harboring del(17) were key secondary endpoints. Other secondary endpoints included determination of overall response rate; duration of response; time to response; PFS in high-risk populations according to cytogenetics; and comparison of change in global health status, functioning, and symptoms measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and Multiple Myeloma Module (MY-20).
There were two analyses for PFS and four planned for OS. The test for PFS was statistically significant at the first analysis thus it became the only analysis for statistical testing purposes. As a result, the study continued in a double-blind fashion with a non-inferential second analysis of PFS. Two interim analyses of overall survival have been conducted to date. If the test for OS was statistically significant, the key secondary endpoint of OS in patients harboring del(17) was to be assessed. All other analyses (except primary and key secondary endpoints) were conducted without adjustments for multiplicity.
Study results: At the first analysis for PFS (median follow up of 14.7 months and median number of cycles of 13), the NINLARO regimen demonstrated a statistically significant improvement in median PFS of approximately 6 months when compared to the placebo regimen in the intent-to-treat (ITT) population. PFS results are summarized in Table 2. (See Table 2 and Figure 1.)

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A non-inferential second 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 the NINLARO regimen versus the placebo regimen, and estimated median PFS was 20 months in the NINLARO regimen and 15.9 months in the placebo regimen. At the same time, a planned interim OS analysis was conducted with 35% of the required number of deaths for final OS analysis; there were 81 deaths in the NINLARO regimen and 90 deaths in the placebo regimen. An OS benefit was not demonstrated.
A pre-specified subgroup analysis for PFS was conducted in patients whose myeloma harbored high risk cytogenetic abnormalities, which included: del(17); translocation of chromosomes 4 and 14 (t[4:14]); and/or translocation of chromosomes 14 and 16 (t[14:16]. The hazard ratio was 0.54, with a nominal p-value=0.02. Median PFS was 21.4 months in the NINLARO regimen compared to 9.7 months in the placebo regimen.
Improvement in PFS with the addition of NINLARO to lenalidomide, and dexamethasone was observed across subgroup populations, including those defined by stratification factors, cytogenetics (high risk or standard risk), and thalidomide refractoriness (yes or no); (see Figure 2 as follows).

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The improvement in PFS in the NINLARO regimen was supported by improvements in overall response rate. Response rates are summarized in Table 3. (See Table 3.)

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In the Phase 3 study, the addition of NINLARO to lenalidomide and dexamethasone did not appear to have a negative impact on patient-reported outcomes. Quality of life was maintained during treatment and was similar in both regimens. There was a trend for better physical functioning, emotional functioning, and fatigue scores for the NINLARO regimen compared with the placebo regimen, while diarrhea appeared to worsen in the NINLARO regimen in later cycles.
Pharmacokinetics: Absorption: After oral administration, peak plasma concentrations of ixazomib were achieved at approximately one hour after dosing. The mean absolute oral bioavailability is 58% based on a population PK analysis. Ixazomib AUC increases in a dose proportional manner over a dose range of 0.2 - 10.6 mg. The Cmax and AUC0-168h in plasma and whole blood following once weekly oral administration of ixazomib 4 mg on Days 1, 8, and 15 in patients are shown in Table 4 as follows.
Administration with a high-fat meal decreased ixazomib AUC0-216h by 28% and Cmax by 69% compared with administration after an overnight fast. In addition, administration with food delayed the time to the peak plasma concentration (Tmax) from 1 hour to 4 hours. (See Table 4.)

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Distribution: Ixazomib is 99% bound to plasma proteins, primarily to serum albumin. Ixazomib distributes into red blood cells with a blood-to-plasma AUC ratio of 10 (see Table 4, previously). The steady-state volume of distribution is 543 L based on a population PK analysis.
Metabolism: After oral administration of a single radiolabeled dose of 4.1 mg to 5 patients with advanced cancer, 70% of total drug-related material in plasma was accounted for by ixazomib. 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 indicate that no specific CYP isozyme predominantly contributes to ixazomib metabolism and non-CYP proteins contribute to overall metabolism. At concentrations exceeding those observed clinically, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 2B6 (16.0%), 2C8 (6.0%), 2D6 (4.8%), 2C19 (4.8%) and 2C9 (< 1%).
Excretion and Elimination: Elimination: Ixazomib exhibits a multi-exponential disposition profile. Based on a population PK analysis, systemic clearance (CL) was approximately 1.86 L/h with inter-individual variability of 44%. The terminal half-life (t1/2) of ixazomib was 9.5 days. Approximately 2-fold accumulation in AUC was observed with weekly oral dosing on Day 15.
Excretion: After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces over 35 days post dose. Unchanged ixazomib accounted for < 3.5% of the administered dose recovered in urine.
Special Populations: Age, Gender, Race: There was no clinically meaningful effect of age (23-91 years), sex, body surface area (1.2-2.7 m2), or race on the clearance of ixazomib based on the results of a population PK analysis. Mean AUC0-∞ was 35% higher in Asian patients than White patients.
Impaired Hepatic Function: The PK of ixazomib is 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 x ULN and any AST) based on the results of a 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 x ULN, N=10) or severe hepatic impairment at 1.5 mg (total bilirubin > 3 x ULN, N=11). Dose-normalized mean AUC was 20% higher in patients with moderate or severe hepatic impairment as compared to patients with normal hepatic function.
Impaired Renal Function: The PK of ixazomib is similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min) based on the results of a 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=15), severe renal impairment (creatinine clearance < 30 mL/min, N=10), 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.
Toxicology: Nonclinical Safety Data: Carcinogenesis and Mutagenesis: Ixazomib was not mutagenic in a bacterial reverse mutation assay (Ames assay) nor was it clastogenic in a bone marrow micronucleus assay in mice. Ixazomib was considered positive in an in vitro clastogenicity test in human peripheral blood lymphocytes. However, ixazomib was negative for inducing DNA damage in the glandular stomach and liver in an in vivo comet assay in mice. Therefore, the weight of evidence supports that ixazomib does not present a genotoxic risk. No carcinogenicity studies have been performed with ixazomib.
Reproductive and Developmental Toxicity: Developmental toxicity studies in rats and rabbits did not show direct embryo-fetal toxicity below maternally toxic doses of ixazomib. In pregnant rat (0.6 mg/kg; AUC0-72h=1081 ng hr/mL) and rabbit (1.0 mg/kg; AUC0-72h=1340 ng hr/mL) dose range-finding studies, there were decreases in fetal weights, a trend towards decreased fetal viability, and/or increased post-implantation losses; however, these findings were not clearly reproduced in definitive studies, and were only observed at maternally toxic doses (0.6 mg/kg in rats, ≥0.25 mg/kg in rabbits) that caused decreased body weight and/or food consumption. In the definitive rabbit study, increases in fetal skeletal variations/abnormalities (caudal vertebrae, number of lumbar vertebrae and full supernumerary ribs) were observed at doses ≥ 0.3 mg/kg (AUC0-72h=792 ng hr/mL), which were also associated with maternal toxicity. A dose of 0.1 mg/kg (AUC0-72h=497 ng hr/mL) did not result in maternal toxicity or cause embryo-fetal effects.
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.
Animal Toxicology: In multi-cycle general toxicity studies conducted in rats and dogs, the principal target organs included the gastrointestinal (GI) tract, lymphoid tissues, and the nervous system.
GI findings included emesis and/or diarrhea increases in leukocyte parameters and microscopic changes (inflammation, epithelial hyperplasia, neutrophilic infiltration, single cell necrosis, congestion, hemorrhage, and/or erosion/ulceration). GI effects were observed at doses ≥0.2 mg/kg in rats (≥0.45 times human exposure based on plasma AUC0-168h in the 6-month rat study) and at ≥0.1 mg/kg in dogs (≥1.8 times human exposure based on plasma AUC0-168h in the 9-month dog study).
Lymphoid system toxicity was characterized by lymphoid depletion/necrosis (including bone marrow), neutrophilic infiltration, and single cell necrosis at doses ≥0.2 mg/kg in rats (≥0.45 times human exposure based on plasma AUC0-168h) and at doses ≥0.1 mg/kg in dogs (≥1.8 times human exposure based on plasma AUC0-168h).
Nervous system effects were primarily seen in dogs at oral doses ≥ 0.1 mg/kg (AUC0-168h=1940 ng hr/mL) and included microscopic findings of minimal to mild neuronal degeneration of the sympathetic, dorsal root, peripheral autonomic (salivary gland), and end organ ganglia, and minimal secondary axonal/nerve fiber degeneration of the peripheral nerves and ascending tracts in the dorsal columns of the spinal cord. In the 9-month study (10 cycles) in dogs where the dosing regimen mimics the clinical regimen (28-day cycle), microscopic neuronal effects were generally minimal in nature at 0.2 mg/kg (AUC0-168h= 3900 ng hr/mL; 3.6 times human exposure).
The majority of target organ findings demonstrated partial to full recovery following discontinuation of treatment, with the exception of neuronal findings in the lumbar dorsal root ganglion and dorsal column. The absence of ongoing neuronal degeneration in the peripheral ganglia and presence of only secondary degenerative changes in the nerve fibers and axons is consistent with lack of persistent toxicity.
In tissue distribution studies in rats, ixazomib did not result in excessive individual tissue exposure. The levels in the brain and spinal cord, in addition to the eye lens, had the lowest levels.
Based on the hERG assay, ixazomib weakly inhibits the potassium ion channel. The safety pharmacology study in conscious dogs demonstrated no effects of ixazomib on cardiovascular function at the highest dose tested (0.3 mg/kg).
Indications/Uses
NINLARO [ixazomib (as ixazomib citrate)] in combination with lenalidomide and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
Dosage/Direction for Use
Recommended Dose and Dosage Adjustment: NINLARO in combination with lenalidomide and dexamethasone: The recommended starting dose of NINLARO is 4 mg (one capsule) 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. (See Table 5.)

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For additional information regarding lenalidomide and dexamethasone, refer to their respective product information.
Prior to initiating a new cycle of therapy: Absolute neutrophil count should be ≥ 1,000/mm3; Platelet count should be ≥ 75,000/mm3; Non-hematologic toxicities should, at the physician's discretion, generally be recovered to patient's baseline condition or ≤ Grade 1.
Treatment should be continued until disease progression or unacceptable toxicity.
Delayed or Missed Doses: In the event that 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 a missed dose.
If a patient vomits after taking a dose, the patient should not repeat the dose but should resume dosing at the time of the next scheduled dose.
Dose Modifications: The NINLARO dose reduction steps in combination with lenalidomide and dexamethasone are presented in Table 6 and the dose modification guidelines are provided in Table 7. (See Table 6.)

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An alternating dose modification approach is recommended for NINLARO and lenalidomide for overlapping toxicities of thrombocytopenia, neutropenia, and rash as described in Table 7. Refer to the lenalidomide product information for dose modification guidelines if dose modification is needed for lenalidomide. (See Table 7.)

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Concomitant Medicinal Products: Antiviral prophylaxis should be considered in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation. 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 (6%).
Special Patient Populations: Geriatrics (≥ 65 years of age): No dose adjustment of NINLARO is required for patients over 65 years of age based on the results of a population PK analysis.
In studies of NINLARO, there were no clinically significant differences in safety and efficacy between patients less than 65 years of age and patients 65 years of age or older.
Pediatric Patients (< 18 years of age): The safety and efficacy of NINLARO in children below 18 years of age have not been established.
Hepatic Impairment: No dose adjustment of NINLARO is required for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1-1.5 x ULN and any AST) based on the results of a population pharmacokinetic (PK) analysis. A lower starting dose of 3 mg is recommended for patients with moderate (total bilirubin > 1.5-3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment based on the results of a PK study (see Pharmacology: Pharmacokinetics under Actions).
Renal Impairment: No dose adjustment of NINLARO is required for patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min) based on the results of a population PK analysis. A lower starting dose of 3 mg is recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease (ESRD) requiring dialysis based on the results of a PK study. NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis (see Pharmacology: Pharmacokinetics under Actions).
Refer to the lenalidomide product information for dosing recommendations in patients with renal impairment.
Method of Administration: 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. NINLARO should be taken at least one hour before or at least two hours after food (see Pharmacology: Pharmacokinetics under Actions). The capsule should be swallowed whole with water. The capsule should not be crushed, chewed or opened. Direct contact with capsule contents should be avoided as NINLARO may be harmful by inhalation, ingestion, or skin absorption (see Instructions for Use/Handling under Cautions for Usage).
Overdosage
Overdose has been reported in patients taking NINLARO. Symptoms of overdose are generally consistent with the known risks of NINLARO (see Adverse Reactions). Reports of accidental overdose have been associated with adverse events: syncope, polyneuropathy, neuralgia, convulsion, AST increased, peripheral neuropathy, hypotension, severe nausea, aspiration pneumonia, multiple organ failure and death.
There is no known specific antidote for ixazomib overdose. In the event of an overdose, monitor the patient closely for adverse reactions (see Adverse Reactions) and provide appropriate supportive care.
Health care providers should instruct patients and care givers that only one dose of NINLARO should be taken at a time, and only at the prescribed interval (one capsule, once a week, on days 1, 8, and 15 of every 28-day cycle). The importance of carefully following all dosage instructions should be discussed with patients starting treatment.
Contraindications
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Excipients/Inactive Ingredients under Description.
Special Precautions
NINLARO should be prescribed and supervised by a qualified physician experienced in the use of anticancer agents.
Peripheral Edema: Peripheral edema has been reported with NINLARO (see Adverse Reactions). Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively. There were no Grade 4 or 5 events reported. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing for Grade 3 or 4 symptoms (see Dosage & Administration).
Gastrointestinal Toxicities: Diarrhea, vomiting, nausea and constipation have been reported with NINLARO (see Adverse Reactions). Medical management included dose modification, use of antidiarrheal and antiemetic medications, and supportive care. Adjust dosing for Grade 3 or 4 symptoms (see Dosage & Administration).
Thrombocytopenia: Thrombocytopenia has been reported with NINLARO (see Adverse Reactions) 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. Thrombocytopenia (combined preferred terms of thrombocytopenia and platelet count decreased) was reported as an adverse event in 28% of patients in the NINLARO regimen and 14% in the placebo regimen. The difference in frequency was across all grades, including Grade 3 and Grade 4 thrombocytopenia (13% and 5% of patients in the NINLARO and placebo regimens, respectively). Three percent of patients in the NINLARO regimen and 1% of patients in the placebo regimen had a platelet count ≤ 10,000/mm3 during treatment. Thrombocytopenia did not result in an increase in hemorrhagic events or platelet transfusions.
Platelet counts should be monitored at least monthly during NINLARO treatment. More frequent monitoring should be considered during the first three cycles. Thrombocytopenia should be managed with dose modifications (see Dosage & Administration) and platelet transfusions as per standard medical guidelines.
Hepatic: Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in < 1% of patients treated with NINLARO. Events of liver impairment have been reported (6% in the NINLARO regimen and 5% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms (see Dosage & Administration).
Herpes Zoster: Herpes zoster was reported in 4% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Antiviral prophylaxis was allowed at the physician'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 (6%). Antiviral prophylaxis should be considered in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation.
Peripheral neuropathy: Peripheral neuropathies have been reported with NINLARO (see Adverse Reactions). The majority of peripheral neuropathy adverse reactions were Grade 1 (18% and 14% in the NINLARO and placebo regimen, respectively) and Grade 2 (8% and 5% in the NINLARO and placebo regimen, respectively). Grade 3 peripheral neuropathy was reported at 2% in both regimens; there were no Grade 4 adverse reactions. The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). The overall incidence of peripheral neuropathy specifically with pain was 3% in the NINLARO regimen and 2% 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 & Administration).
Skin: Rash (representing a pooling of preferred terms) has been reported as an adverse event associated with NINLARO. Grade 3 rash was reported in 3% of patients in the NINLARO regimen compared to 1% of patients in the placebo regimen, and there were no Grade 4 adverse events of rash across the Phase 3 study. The most common type of rash reported in both regimens included maculo-papular and macular rash. Across the NINLARO development program, serious cutaneous adverse events have been reported (see Adverse Reactions).
Rash should be managed with dose modification/discontinuation if Grade 2 or higher, and supportive care (see Dosage & Administration).
Monitoring and Laboratory Tests: Platelet counts should be monitored at least monthly during NINLARO treatment. More frequent monitoring should be considered during the first three cycles.
Monitor hepatic enzymes regularly when NINLARO is administered in combination with lenalidomide and dexamethasone.
Thrombotic Microangiopathy: Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/haemolytic uremic syndrome (TTP/HUS), have been reported in the postmarketing setting in patients who received NINLARO. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known.
Effects on Ability to Drive and Use Machines: There are no data on the effect of ixazomib on the ability to drive or operate machinery. Fatigue and dizziness have been observed in clinical trials. Patients should be advised not to drive or operate machines if they experience any of these symptoms.
Use in Pregnancy: NINLARO can cause fetal harm when administered to a 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 plasma exposures that were slightly higher than those observed in patients receiving the recommended dose (see Pharmacology: Toxicology: Nonclinical safety data under Actions).
Advise women of the potential risk to a fetus. Women should not become pregnant while being treated with NINLARO.
Male and female patients of child-bearing potential must use two effective contraceptive measures during and for 90 days following treatment. Since some oral contraceptive products may interact with dexamethasone, and NINLARO is administered with dexamethasone, the risk for reduced efficacy of oral contraceptives needs to be considered. Women using oral hormonal contraceptives should also use a barrier method of contraception.
Use In Pregnancy & Lactation
Pregnancy: NINLARO can cause fetal harm when administered to a 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 plasma exposures that were slightly higher than those observed in patients receiving the recommended dose (see Pharmacology: Toxicology: Nonclinical safety data under Actions).
Advise women of the potential risk to a fetus. Women should not become pregnant while being treated with NINLARO.
Male and female patients of child-bearing potential must use two effective contraceptive measures during and for 90 days following treatment. Since some oral contraceptive products may interact with dexamethasone, and NINLARO is administered with dexamethasone, the risk for reduced efficacy of oral contraceptives needs to be considered. Women using oral hormonal contraceptives should also use a barrier method of contraception.
Lactation: It is not known whether ixazomib/metabolites are excreted in human milk. Many drugs are excreted in human milk and as a result, there could be a potential for adverse events in nursing infants. Advise women to discontinue nursing.
Fertility: Fertility studies were not conducted with NINLARO. There were no effects in reproductive organs in either males or females in nonclinical studies in rats and dogs (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions).
Adverse Reactions
The safety profile of ixazomib is based on all available clinical trial data and post-marketing experience to date.
Adverse Drug Reaction Overview: Safety data was primarily from the Phase 3 clinical study in patients with relapsed and/or refractory multiple myeloma. The most frequently reported NINLARO adverse drug reactions (≥ 20%) were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain. Serious adverse drug reactions reported in ≥ 2% of patients in the NINLARO regimen included thrombocytopenia (2%) and diarrhea (2%).
In the Phase 3 study, the median dose intensity for NINLARO and placebo was high and similar in the NINLARO and placebo regimens: 97.4% and 98.2%, respectively. Dose modifications in both regimens were more common in the first 6 cycles and decreased in frequency over time. Dose modifications included a dose reduction, a cycle delay or dosing delay within a cycle, dose being held, dose missed, or treatment discontinuation. Eighty percent of patients in the NINLARO regimen continued treatment at the starting dose of NINLARO without dose reduction. Further, the median dose intensity was high and similar in both the NINLARO and placebo regimens for lenalidomide: 93.8% and 95.6%, respectively, and for dexamethasone, 92.8% and 95.0%, respectively.
For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen. The rates of discontinuation of the full study drug regimen due to a treatment-emergent adverse event were 13% in the NINLARO regimen and 11% in the placebo regimen.
Across the NINLARO development program, the following serious cutaneous adverse events were reported: erythema multiforme, acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalised exanthematous pustulosis and cutaneous vasculitis
Across the NINLARO development program, the following serious adverse events for which causality has not been established were rarely reported: transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety population from the Phase 3, randomized, double-blind, placebo-controlled clinical study included 720 patients with relapsed and/or refractory multiple myeloma, who received NINLARO in combination with lenalidomide and dexamethasone (NINLARO regimen; N=360) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=360). In the NINLARO and placebo regimens, the median treatment duration was 341 days and 334 days, respectively.
Adverse events of any type were reported with similar frequency between the NINLARO and placebo regimens (98% and 99%, respectively). In all patients, the worst toxicity grade was most often Grade 3 (49% NINLARO regimen and 43% placebo regimen). The frequency of Grade 4 (15% and 14%, respectively) and Grade 5 (4% and 5%, respectively) adverse events was similar between the regimens.
Table 8 summarizes the adverse events, regardless of causality, occurring in ≥ 10% of patients in either the NINLARO regimen or the placebo regimen. (See Table 8.)

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Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 26% in patients in the NINLARO regimen and 16% of patients in the placebo regimen. The most common adverse reactions were blurred vision (6% in the NINLARO regimen and 3% in the placebo regimen), dry eye (5% in the NINLARO regimen and 1% in the placebo regimen), and conjunctivitis (6% in the NINLARO regimen and 1% in the placebo regimen). Grade 3 adverse reactions were reported in 2% of patients in the NINLARO regimen and 1% in the placebo regimen.
Postmarketing: Clinically significant adverse drug reactions are listed here if they have not been previously reported.
Blood and lymphatic system disorders: thrombotic microangiopathy.
Drug Interactions
Overview: At clinically relevant ixazomib concentrations, in vitro studies indicate that no specific CYP isozyme predominantly contributes to ixazomib metabolism and non-CYP proteins contribute to overall metabolism. At concentrations exceeding those observed clinically, ixazomib was metabolized in vitro by multiple CYP isoforms (see Pharmacology under Actions). Co-administration of NINLARO with strong CYP3A inducers is not recommended. The potential for ixazomib to produce clinically relevant drug-drug interactions via CYP isozyme induction or inhibition is low. Ixazomib is unlikely to cause or be susceptible to drug-drug interactions with substrates or inhibitors of clinically relevant drug transporters.
Drug-Drug Interactions: Effect of Other Drugs on NINLARO: Strong CYP3A Inducers: Co-administration of NINLARO with rifampin decreased ixazomib Cmax by 54% and AUC by 74%. Co-administration of strong CYP3A inducers (such as rifampin, phenytoin, carbamazepine, and St. John's wort) with NINLARO is not recommended.
Strong CYP3A Inhibitors: Co-administration of NINLARO with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib. Ixazomib Cmax was decreased by 4% and AUC was increased by 11%. No dose modification is required for NINLARO with co-administration of strong CYP3A inhibitors.
Strong CYP1A2 Inhibitors: Co-administration of NINLARO with strong CYP1A2 inhibitors did not result in a clinically meaningful change in the systemic exposure of ixazomib based on the results of a population PK analysis. No dose modification is required for NINLARO with co-administration of strong CYP1A2 inhibitors.
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 and 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.
Drug-Food Interactions: Administration of NINLARO with a high-fat meal decreased ixazomib AUC0-216h by 28% and Cmax by 69%, and delayed the time to the peak plasma concentration (Tmax) from 1 hour to 4 hours, compared with administration after an overnight fast. Therefore, NINLARO should be taken at least one hour before or at least two hours after food.
Drug-Herb Interactions: Interactions with herbal products have not been established. Co-administration of St. John's wort (a strong CYP3A inducer) with NINLARO should be avoided.
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established.
Drug-Lifestyle Interactions: No studies on the effects on the ability to drive or use machines have been performed.
Caution For Usage
Incompatibilities: Not applicable.
Instructions for Use/Handling: NINLARO is cytotoxic. Capsules should not be opened or crushed. Direct contact with the capsule contents should be avoided. In case of capsule breakage, avoid raising dust and wear gloves and protective clothing during clean-up. If contact occurs, wash thoroughly with soap and water.
Any unused medicinal product or waste material should be disposed in accordance with local requirements.
Storage
Do not store above 30°C. Do not freeze.
Store capsules in original packaging until immediately prior to use.
ATC Classification
L01XG03 - ixazomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.
Presentation/Packing
Cap 3 mg (light grey, marked "Takeda" on the cap and "3 mg" on the body with black ink) x 3's. 4 mg (light orange, marked "Takeda" on the cap and "4 mg" on the body with black ink) x 3's.
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