Ninlaro

Ixazomib citrate.

Ninlaro is available in the following capsule strengths: 2.3 mg: Ninlaro 2.3 mg hard capsules contain 2.3 mg of ixazomib equivalent to 3.3 mg of ixazomib citrate.
3 mg: Ninlaro 3 mg hard capsules contain 3 mg of ixazomib equivalent to 4.3 mg of ixazomib citrate.
4 mg: Ninlaro 4 mg hard capsules contain 4 mg of ixazomib equivalent to 5.7 mg of ixazomib citrate.
Ninlaro is supplied as immediate release hard gelatin capsule and are distinguished both by color and dose specific imprinted markings on the body.
Excipients/Inactive Ingredients: microcrystalline cellulose, talc and magnesium stearate.

Pharmacology: 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.
Pharmacodynamics: Cardiac Electrophysiology: Ninlaro did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients.
CLINICAL STUDIES: TOURMALINE-MM1: 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 physician'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 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 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 2 and shown in the figure. (See Table 2.)

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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. (See figure.)

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A second, non-inferential, PFS analysis was conducted with a median follow up of 23 months. At this analysis, estimated median PFS was 20 months in the ixazomib regimen and 15.9 months in the placebo regimen (HR=0.82 [95% CI (0.67, 1.0)]) in the ITT population. For patients with one prior therapy, the median PFS was 18.7 months in the ixazomib regimen and 17.6 months in the placebo regimen (HR = 0.99). For patients with 2 or 3 prior therapies, PFS was 22.0 months in the ixazomib regimen and 13.0 months in the placebo regimen (HR = 0.62).
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 ixazomib regimen and 51.6 months for patients in the placebo regimen (HR = 0.94 [95% CI: 0.78, 1.13; p=0.495]). For patients with one prior therapy, the median OS was 54.3 months in the ixazomib regimen and 58.3 months in the placebo regimen (HR = 1.02 [95% CI: 0.80, 1.29]). For patients with 2 or 3 prior therapies, the median OS was 53.0 months in the ixazomib regimen and 43.0 months in the placebo regimen (HR = 0.85 [95% CI: 0.64, 1.11]).
A randomised, double blind, placebo controlled Phase 3 study was conducted in China (N=115) with a similar study design and eligibility criteria. Many of the patients enrolled in the study had advanced disease with Durie Salmon Stage III (69%) at initial diagnosis and a treatment history of receiving at least 2 prior therapies (60%) and being thalidomide refractory (63%). At the primary analysis (median follow up of 8 months and a median of 6 cycles), the median PFS was 6.7 months in the ixazomib regimen compared to 4 months in the placebo regimen (p value=0.035, HR=0.60). At the final analysis for OS at a median follow up of 19.8 months, OS was improved for patients treated in the ixazomib regimen compared with placebo [p value=0.0014, HR=0.42, 95% CI: 0.242, 0.726]).
As multiple myeloma is a heterogeneous disease, benefit may vary across subgroups in the Phase 3 study (C16010) (see Figure 2). (See Figure 2.)

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In the Phase 3 study (C16010), 10 patients (5 in each treatment regimen) had severe renal impairment at baseline. Of the 5 patients in the ixazomib regimen, one patient had a confirmed partial response and 3 confirmed stable disease (however 2 were unconfirmed partial response and 1 was an unconfirmed very good partial response). Of the 5 patients in the placebo regimen, 2 had a confirmed very good partial response.
Quality of life as assessed by global health scores (EORTC QLQ-C30 and MY-20) was maintained during treatment and was similar in both treatment regimens in the Phase 3 study (C16010).
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 & Administration].
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.
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%).
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.
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. Unchanged ixazomib accounted for < 3.5% of the administered dose recovered in urine.
Special Populations: Age, Sex, Race: There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m²), or race on the clearance of ixazomib based on population PK analysis.
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 x 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 x ULN, N=13) or severe hepatic impairment at 1.5 mg (total bilirubin > 3 x 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 & Administration].
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 & Administration].
Drug Interactions: Effect of Other Drugs on Ninlaro: Strong CYP3A Inducers: Co-administration of Ninlaro with rifampin decreased ixazomib C_max by 54% and AUC by 74% [see Interactions].
Strong CYP3A Inhibitors: Co-administration of Ninlaro with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib.
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 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 immune-reactive 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.
Toxicology: Nonclinical Toxicology: 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 post-natal 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.

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.

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. (See Table 3.)

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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. Ninlaro should be taken at least one hour before or at least two hours after food [see Pharmacology under Actions]. 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/mm³; Platelet count should be at least 75,000/mm³; Non-hematologic toxicities should, at the physician'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.
Dose Modification Guidelines: The Ninlaro dose reduction steps are presented in Table 4 and the dose modification guidelines are provided in Table 5. (See Table 4.)

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An alternating dose modification approach is recommended for Ninlaro and lenalidomide for thrombocytopenia, neutropenia, and rash as described in Table 5. Refer to the lenalidomide prescribing information if dose reduction is needed for lenalidomide. (See Table 5.)

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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 x ULN) or severe (total bilirubin greater than 3 x ULN) hepatic impairment [see Hepatic Impairment under Precautions and Pharmacology under Actions].
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 Renal Impairment under Precautions and Pharmacology under Actions].
Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.

Overdose has been reported in patients taking Ninlaro. Symptoms of overdose are generally consistent with the known risks of Ninlaro (see Adverse Reactions). Overdose of 12 mg (taken at one time) has resulted in serious adverse events, such as severe nausea, aspiration pneumonia, multiple organ failure and death. There is no known specific antidote for Ninlaro overdose. In the event of an overdose, monitor the patient closely for adverse reactions and provide appropriate supportive care. Ixazomib is not dialyzable (see Pharmacology: Pharmacokinetics under Actions).
Overdoses were most common in patients starting treatment with Ninlaro. 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 overdose has led to deaths.

Hypersensitivity to the active substance or to any of the excipients listed. As Ninlaro is administered in combination with lenalidomide and dexamethasone, refer to the SmPC for these medicinal products for additional special warnings and precautions for use.

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.
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. Less than 1% of patients in both regimens had a platelet count ≤ 5000/mm³ during treatment. Discontinuations due to thrombocytopenia were similar in both regimens (< 1% of patients in the Ninlaro regimen and 2% of patients in the placebo regimen discontinued one or more of the three drugs). The rate of platelet transfusions was 6% in the Ninlaro regimen and 5% 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 & Administration] and platelet transfusions as per standard medical guidelines.
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 42% of patients in the Ninlaro regimen and 36% in the placebo regimen, constipation in 34% and 25%, respectively, nausea in 26% and 21%, respectively, and vomiting in 22% and 11%, respectively. Diarrhea resulted in discontinuation of one or more of the three drugs in 1% of patients in the Ninlaro regimen and < 1% of patients in the placebo regimen. Adjust dosing for Grade 3 or 4 symptoms [see Dosage & Administration].
Peripheral Neuropathy: The majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the Ninlaro regimen and 14% in the placebo regimen) and Grade 2 (8% in the Ninlaro regimen and 5% in the placebo regimen). Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens; there were no Grade 4 or serious 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%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1% of patients in both regimens. Patients should be monitored for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification [see Dosage & Administration].
Peripheral Edema: Peripheral edema was reported in 25% and 18% of patients in the Ninlaro and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (16% in the Ninlaro regimen and 13% in the placebo regimen) and Grade 2 (7% in the Ninlaro regimen and 4% in the placebo regimen).
Grade 3 peripheral edema was reported in 2% and 1% of patients in the Ninlaro and placebo regimens, respectively. There was no Grade 4 peripheral edema reported. There were no discontinuations reported due to peripheral edema. 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 & Administration].
Cutaneous Reactions: Rash has been reported with Ninlaro (see Adverse Reactions). Rash should be managed with supportive care or with dose modification if Grade 2 or higher (see Adverse Reactions). Stevens-Johnson syndrome has also been reported with ixazomib (see Adverse Reactions). If Stevens-Johnson syndrome occurs, discontinue ixazomib.
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. 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.
Hepatotoxicity: 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].
Embryo-Fetal Toxicity: Ninlaro can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using Ninlaro. 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.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Ninlaro. If Ninlaro is used during pregnancy or if the patient becomes pregnant while taking Ninlaro, the patient should be apprised of the potential hazard to the fetus. Advise females of reproductive potential that they must use effective contraception during treatment with Ninlaro and for 90 days following the final dose. Women using hormonal contraceptives should also use a barrier method of contraception [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation and Pharmacology: Toxicology: Nonclinical Toxicology under Actions].
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 & Administration, Pharmacology under Actions].
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 & Administration, Pharmacology under Actions].
Use in Children: Safety and effectiveness have not been established in pediatric patients.
Use in the Elderly: 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.

Pregnancy: Risk Summary: Based on its mechanism of action and data from animal reproduction studies, Ninlaro can cause fetal harm when administered to a pregnant woman [see Pharmacology under Actions]. 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 a fetus and to avoid becoming pregnant while being treated with Ninlaro.
Lactation: Risk Summary: No data are available regarding the presence of Ninlaro 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 the potential for serious adverse reactions from Ninlaro in breastfed infants is unknown, advise nursing women not to breastfeed during treatment with Ninlaro and for 90 days after the last dose.
Females and Males of Reproductive Potential: Contraception: Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment. 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. Advise women using hormonal contraceptives to also use a barrier method of contraception.

As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPC for these medicinal products for additional undesirable effects.
Summary of the safety profile: The safety profile of NINLARO is based on available clinical trial data and post-marketing experience to date. Frequencies of adverse reactions described as follows and in Table 6 have been determined based on data generated from clinical studies.
Unless otherwise noted, the data presented as follows is the pooled safety data from the pivotal, Phase 3, global C16010 study (n=720) and the double-blind, placebo-controlled C16010 China Continuation Study (n=115). The most frequently reported adverse reactions (≥ 20%) across 418 patients treated within the ixazomib regimen and 417 patients within the placebo regimen were diarrhoea (47% vs. 38%), thrombocytopenia (41% vs. 24%), neutropenia (37% vs. 36%), constipation (31% vs. 24%), upper respiratory tract infection (28% vs. 24%), peripheral neuropathy (28% vs. 22%), nausea (28% vs. 20%), back pain (25% vs. 21%), rash (25% vs. 15%), peripheral oedema (24% vs. 19%), vomiting (23% vs. 12%) and bronchitis (20% vs. 15%). Serious adverse reactions reported in ≥ 2% of patients included diarrhoea (3%), thrombocytopenia (2%) and bronchitis (2%).
Tabulated list of adverse reactions: The following convention is used for the classification of the frequency of an adverse drug reaction (ADR): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 6.)

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Description of selected adverse reactions: Discontinuations: For each adverse reaction, one or more of the three medicinal products was discontinued in ≤ 3% of patients in the ixazomib regimen.
Thrombocytopenia: Two percent of patients in both the ixazomib regimen and the placebo regimen had a platelet count ≤ 10,000/mm³ during treatment. Less than 1% of patients in both regimens had a platelet count ≤ 5,000/mm³ during treatment. Thrombocytopenia resulted in discontinuation of one or more of the three medicinal products in 2% of patients in the ixazomib regimen and 3% of patients in the placebo regimen. Thrombocytopenia did not result in an increase in haemorrhagic events or platelet transfusions.
Gastrointestinal toxicities: Diarrhoea resulted in discontinuation of one or more of the three medicinal products in 2% of patients in the ixazomib regimen and 1% of patients in the placebo regimen.
Rash: Rash occurred in 25% of patients in the ixazomib regimen compared to 15% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Grade 3 rash was reported in 3% of patients in the ixazomib regimen compared to 2% of patients in the placebo regimen. Rash resulted in discontinuation of one or more of the three medicinal products in < 1% of patients in both regimens.
Peripheral neuropathy: Peripheral neuropathy occurred in 28% of patients in the ixazomib regimen compared to 22% of patients in the placebo regimen. Grade 3 adverse reactions of peripheral neuropathy were reported in 2% of patients in the ixazomib regimen compared to 1% in the placebo regimen. The most commonly reported reaction was peripheral sensory neuropathy (21% and 15% in the ixazomib 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 medicinal products in 3% of patients in the ixazomib regimen compared to < 1% of patients in the placebo regimen.
Eye disorders: Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 34% in patients in the ixazomib regimen and 28% of patients in the placebo regimen. The most common adverse reactions were blurred vision (6% in the ixazomib regimen and 5% in the placebo regimen), dry eye (6% in the ixazomib regimen and 1% in the placebo regimen), conjunctivitis (8% in the ixazomib regimen and 2% in the placebo regimen) and cataract (13% in the ixazomib regimen and 17% in the placebo regimen). Grade 3 adverse reactions were reported in 6% of patients in the ixazomib regimen and 8% of patients in the placebo regimen.
Other adverse reactions: In the pooled dataset from the pivotal, Phase 3, global C16010 study (n=720) and the double-blind, placebo-controlled, C16010 China Continuation Study (n=115), the following adverse reactions occurred with a similar rate between the ixazomib and placebo regimens: fatigue (28% vs. 26%), decreased appetite (13% vs. 11%), hypotension (5% vs. 4%), heart failure^† (5% each), arrhythmia^† (17% vs. 16%), and liver impairment including enzyme changes^† (11% vs. 9%).
The frequency of severe (Grade 3-4) events of hypokalaemia was higher in the ixazomib regimen (7%) than the placebo regimen (2%).
Fungal and viral pneumonia resulting in fatal outcome were rarely reported in patients given the ixazomib, lenalidomide and dexamethasone combination.
^† Standardised MedDRA Queries (SMQs)
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Strong CYP3A Inducers: Avoid concomitant administration of Ninlaro with strong CYP3A inducers (such as rifampin, phenytoin, carbamazepine, and St. John's Wort) [see Pharmacology under Actions].
Strong CYP3A Inhibitors: Co-administration of Ninlaro with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib.
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 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 immune-reactive 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.
Oral contraceptives: When NINLARO is administered together with dexamethasone, which is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy of oral contraceptives needs to be considered. Women using hormonal contraceptives should additionally use a barrier method of contraception.

Handling And Disposal: Ninlaro is a cytotoxic drug. Follow applicable special handling and disposal procedures. 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.

Do not store above 30°C. Do not freeze.
Store capsules in original packaging until immediately prior to use.
Shelf life: 3 years.

Targeted Cancer Therapy

L01XG03 - ixazomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.

B