Approval Date
Ixazomib Citrate Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Ixazomib Citrate Capsules
Trade name: Enrei®
English name: Ixazomib Citrate Capsules
Hanyu Pinyin: Juyuansuan Yishazuomi Jiaonang
Ingredients
The main ingredient of this product: Ixazomib Citrate
2.3mg: each capsule contains 3.3 mg of Ixazomib Citrate, equivalent to 2.3 mg of Ixazomib
3mg: each capsule contains 4.3 mg of Ixazomib citrate, equivalent to 3 mg of Ixazomib
4mg: each capsule contains 5.7 mg of Ixazomib citrate, equivalent to 4 mg of Ixazomib
Chemical Name.
2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diacetic acid
Chemical structure formula.
Molecular formula: C20H23BCl2N2O9
Molecular weight: 517.12
Properties
This product is light pink capsule (2.3mg), light gray capsule (3mg) or light orange (4mg) capsule, the capsule shell is printed with the logo “” and specifications, the contents are white powder.
Indications】
Used in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one previous treatment.
Specification
According to C14H19BCl2N2O4, (1) 2.3mg, (2) 3mg, (3) 4mg
Dosage]
This product should be started under the supervision of a physician with experience in the treatment of multiple myeloma, and the treatment should be monitored.
Dosage
Recommended starting dose of lenalidomide: 4 mg orally once weekly on days 1, 8 and 15 of a 28-day treatment cycle.
Recommended starting dose of lenalidomide: 25 mg administered once daily on days 1-21 of a 28-day treatment cycle.
Recommended starting dose of dexamethasone: 40 mg per dose administered on days 1, 8, 15 and 22 of a 28-day treatment cycle.
Dosing regimen: Ixazomib in combination with lenalidomide and dexamethasone
For more information on lenalidomide and dexamethasone, please refer to the drug inserts for lenalidomide and dexamethasone.
Dosage
The route of administration of this product is oral.
Patients should take this product at approximately the same time on days 1, 8 and 15 of each treatment cycle, at least 1 hour before or at least 2 hours after a meal (see [Pharmacokinetics]). The entire capsule should be taken with water. Do not crush, chew, or open the capsule (see [Precautions]).
Prior to starting a new treatment cycle.
Absolute neutrophil count should be ≥1000/mm3
Platelet count should be ≥ 75, 000/mm3
Non-hematologic toxicity should generally return to the patient’s baseline status or ≤ grade 1, as determined by the physician
Treatment should continue until disease progression or unacceptable toxicity occurs. Because of the limited data related to tolerability and toxicity after 24 cycles, coadministration of therapy requiring longer than 24 cycles should be based on the results of individual patient benefit risk assessment. (See [Pharmacology and Toxicology])
Delayed or missed doses
If a dose of this product is delayed or missed, the missed dose should be made up only if it is ≥72 hours before the next scheduled dose. The missed dose should not be made up within 72 hours of the next scheduled dose. Do not take a double dose to make up for a missed dose.
If a patient vomits after a dose, the dose should not be repeated but should be resumed at the next scheduled dose.
Dose Adjustment
Table 1 lists the steps for reducing the dose of this product and Table 2 provides guidelines for dose adjustment.
Table 1: Ixazomib Dose Reduction Steps
Recommended starting dose * First dose reduction to second dose reduction to discontinuation 4 mg 3 mg 2.3 mg * Dose reduction to 3 mg is recommended in patients with moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease (ESRD) requiring dialysis.
For overlapping toxicity of isazolomib and lenalidomide thrombocytopenia, neutropenia, and rash, alternate dose adjustments of isazolomib and lenalidomide are recommended. For these toxicities, the first step in dose adjustment is to discontinue/reduce the lenalidomide dose. For dose reduction steps for these toxicities, see the lenalidomide drug insert.
Table 2: Dose Adjustment Guidelines for Ixazomib in Combination with Lenalidomide and Dexamethasone
Recommended Measures for Hematologic Toxicity Thrombocytopenia (platelet count) Platelet count <30, 000/mm3 Discontinue Ixazomib and lenalidomide until platelet count ≥30, 000/mm3.
After recovery, reintroduce lenalidomide at the next lower dose according to its drug instructions and reintroduce rizazomib at the most recently used dose.
If the platelet count falls again to <30, 000/mm3, discontinue rizazomib and lenalidomide until the platelet count is ≥30, 000/mm3.
After recovery, reintroduce Ixazomib at the next lower dose and lenalidomide at the most recently used dose. *Neutropenia (absolute neutrophil count) Absolute neutrophil count < 500/mm3 Discontinue isazomib and lenalidomide until absolute neutrophil count ≥ 500/mm3. Consider adding G-CSF per clinical guidelines.
After recovery, reintroduce lenalidomide at the next lower dose according to their prescribing information and reintroduce rizazomib at the most recently used dose.
If the absolute neutrophil count drops again to <500/mm3, discontinue izatzomib and lenalidomide until the absolute neutrophil count is ≥500/mm3.
After recovery, reintroduce isazomib at the next lower dose and lenalidomide at the most recently used dose. *Non-hematologic toxicity recommended measures rash grade 2 or 3† Discontinue lenalidomide until rash returns to ≤ grade 1.
After recovery, reinitiate lenalidomide at the next lower dose according to its drug instructions.
If Grade 2 or 3 rash reappears, discontinue rizazomib and lenalidomide until rash returns to ≤ Grade 1.
After recovery, reintroduce rizazomib at the next lower dose and lenalidomide at the most recently used dose. *Grade 4 discontinuation of treatment regimen. Peripheral neuropathy Grade 1 peripheral neuropathy with pain or Grade 2 peripheral neuropathy Discontinue rizazomib until recovery of peripheral neuropathy to ≤ Grade 1 without pain, or to the patient’s baseline level.
After recovery, reintroduce Ixazomib at the most recently used dose. discontinue Ixazomib for grade 2 peripheral neuropathy with pain or grade 3 peripheral neuropathy. At the physician’s discretion, toxicity should generally return to the patient’s baseline status or ≤ grade 1 before resuming izazomib.
After recovery, the next lower dose of Ixazomib is reintroduced. grade 4 peripheral neuropathy is discontinued from the treatment regimen. Other non-hematologic toxicity Other Grade 3 or Grade 4 non-hematologic toxicity Discontinue Ixazomib. At the physician’s discretion, toxicity should generally return to the patient’s baseline status or ≤ Grade 1 before reintroduction of Ixazomib.
If caused by rizazomib, after recovery, reintroduce rizazomib at the next lower dose. *If reoccurrence occurs, alternate dose adjustment of lenalidomide and rizazomib.
†Grade according to the National Cancer Institute Common Terminology Criteria (CTCAE) version 4.03.
Concomitant Dosing
Prophylaxis with antiviral agents should be considered in patients receiving this product to reduce the risk of herpes zoster virus reactivation. In the Ixazomib study, the incidence of herpes zoster infection was lower in patients receiving antiviral drug prophylaxis than in those who did not receive prophylaxis.
In patients treated with this product in combination with lenalidomide and dexamethasone, it is recommended that thromboprophylaxis should be administered based on an assessment of the patient’s underlying risk and clinical status.
If a combination of other drugs is required, please refer to the current version of the Drug Guide for lenalidomide and dexamethasone.
Special Patient Populations
Geriatric patients
In patients older than 65 years of age, no dose adjustment of this product is required.
Discontinuation of therapy was reported in 13 patients (28%) in the Ixazomib regimen group and in 10 patients (16%) in the placebo regimen group in patients older than 75 years of age. Among patients older than 75 years, 10 patients (21%) in the isazomib treatment regimen group and 9 patients (15%) in the placebo treatment regimen group developed cardiac arrhythmias.
Liver damage
In 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 AST at any level), no adjustment of the dose of this product is required. For patients with moderate (total bilirubin > 1.5-3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment, a dose reduction to 3 mg is recommended. (See [Pharmacokinetics])
Renal impairment
In patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min), no dose adjustment of this product is required. For patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (ESRD) requiring dialysis, a dose reduction to 3 mg is recommended. isazolomib is not cleared by dialysis and therefore can be administered without regard to the duration of dialysis (see [Pharmacokinetics]).
For dosing recommendations for lenalidomide in patients with renal impairment, please refer to its drug insert.
Pediatric Patients
The safety and efficacy of this product in pediatric patients less than 18 years of age have not been established. No data are available to support this.
Adverse Reactions]
Since this product is administered in combination with lenalidomide and dexamethasone, for additional information on adverse reactions, please refer to the drug inserts for lenalidomide and dexamethasone.
1. Summary of adverse reactions in the Global C16010 Study
The Global C16010 Study is a randomized, double-blind, placebo-controlled clinical study of a safety population of 720 patients with relapsed and/or refractory multiple myeloma treated with either rizazomib in combination with lenalidomide and dexamethasone (rizazomib regimen group; N=360) or placebo in combination with lenalidomide and dexamethasone (placebo regimen group; N=360).
The most frequently reported (≥20%) and more frequent adverse reactions in the isazomib regimen group than in the placebo regimen group were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain. serious adverse reactions reported in 2% and more of patients included thrombocytopenia (2%) and diarrhea (2%).
Table 3: Adverse reactions with an incidence of ≥ 5% in patients treated with rizazomib in combination with lenalidomide and dexamethasone in the global C16010 study and with a difference of ≥ 5% between the two groups (all grades, grades 3 and 4)
Systemic organ classification/preferred term Ixazomib + lenalidomide + dexamethasone
N=360 Placebo + lenalidomide + dexamethasone
N=360 N (%) N (%) All grades 3 grade 4 All grades 3 grade 4 Infections and infectious diseases Upper respiratory tract infections 69 (19) 1 (< 1) 0 52 (14) 2 (< 1) 0 Blood and lymphatic system disorders Thrombocytopenia #281 (78) 93 (26) 196 (54) 39 (11) Neutropenia #240 (67) 93 (26) 239 (66) 107 (30) Neurological disorders Peripheral neuropathy* 100 (28) 7 (2) 0 77 (21) 7 (2) 0 Gastrointestinal disorders Diarrhea 151 (42) 22 (6) 0 130 (36) 8 (2) 0 Constipation 122 (34) 1 (< 1) 0 90 (25) 1 (< 1) 0 Nausea 92 (26) 6 (2) 0 74 (21) 0 0 Vomiting 79 (22) 4 (1) 0 38 (11) 2 (< 1) 0 Skin and subcutaneous tissue disorders Rash* 68 (19) 9 (3) 0 38 (11) 5 (1) 0 Skeletal muscle and connective tissue disorders Back pain 74 (21) 2 (< 1) 0 57 (16) 9 (3) 0 General condition and manifestations at the site of drug administration Peripheral edema 91 (25) 8 (2) 0 66 (18) 4 (1) 0 Note: Preferred terms included in adverse reactions are based on MedDRA version 16.0.
*Represents summary of preferred terms.
# is summary information of reported adverse events and laboratory data
2. Summary of adverse reactions in the C16010 China Extension Study
The C16010 China Extension Study is a randomized, double-blind, placebo-controlled clinical study of a safety population of 115 patients with relapsed and/or refractory multiple myeloma treated with either rizazomib in combination with lenalidomide and dexamethasone (rizazomib regimen group; N=57) or placebo in combination with lenalidomide and dexamethasone (placebo regimen group; N=58).
Adverse reactions most frequently reported (≥20%) and more frequently than in the placebo arm were thrombocytopenia, neutropenia, upper respiratory tract infections, leukopenia, and herpes zoster. serious adverse reactions reported in 2% or more of patients included pneumonia (12% in the isazomib arm and 7% in the placebo arm), herpes zoster (4%), bronchitis (4%), bronchiectasis (4%), and dexamethasone. bronchitis (4%), thrombocytopenia (4%), hypokalemia (7%), neutropenia (2%), peripheral edema (2%), and diarrhea (2%).
Table 4: Adverse reactions (all grades, grades 3 and 4) with an incidence of ≥ 5% and a difference of ≥ 5% between the two groups in patients treated with ixazomib in combination with lenalidomide and dexamethasone in the C16010 Chinese extension study
Systemic organ classification/preferred term Ixazomib + lenalidomide + dexamethasone
N=57 Placebo + lenalidomide + dexamethasone
N=58 N (%) N (%) All grades 3 grade 4 All grades 3 grade 4 Blood and lymphatic system disorders Thrombocytopenia #51 (89) 11 (19) 4 (7) 49 (84) 10 (17) 7 (12) Neutropenia #37 (65) 14 (25) 3 (5) 44 (76) 13 (22) 2 (3) Leukopenia 17 (30) 5 (9 ) 0 10 (17) 1 (2) 0 Lymphopenia* 16 (29) 5 (9) 1 (2) 7 (12) 3 (5) 1 (2) Infections and infectious diseases Upper respiratory tract infections 19 (33) 3 (5) 0 14 (24) 1 (2) 0 Herpes zoster 12 (21) 4 (7) 0 2 (3) 0 0 Bronchiectasis 5 (9) 0 0 2 (3) 1 (2) 0 Gastrointestinal disorders Diarrhea 10 (18) 1 (2) 0 4 (7) 0 0 0 Nausea5 (9) 0 0 2 (3) 0 0 0 Vomiting5 (9) 0 0 0 2 (3) 0 0 0 Epigastric pain4 (7) 0 0 0 0 0 0 0 0 Metabolic and nutritional disorders Hypokalemia*10 (17) 4 (7) 1 (2) 2 (3) 0 0 0 Liver and biliary disorders Elevated ALT7 (12) 1 (2) 0 3 (5) 0 0 0 Skeletal muscle and connective tissue disorders Arthralgia3 (5) 0 0 0 0 0 0 0 Note: Preferred terms included in adverse reactions are based on MedDRA version 16.0.
*Represents a summary of preferred terms.
# is summary information for reported adverse events and laboratory data
3. Specific Adverse Reaction Descriptions
Unless otherwise noted, the following adverse reaction information is derived from the pooled safety data from the global C16010 study and the C16010 China extension study.
Discontinuation
In the isazolomib regimen group, ≤1% of patients discontinued at least 1 of the 3 drugs due to various adverse reactions.
Thrombocytopenia
In both regimen groups, <1% of patients had a platelet count ≤5, 000/mm3 during treatment. <1% of patients on the isazomib regimen discontinued at least 1 of the 3 drugs due to thrombocytopenia. at least 1 of the 3 drugs, compared with 1% of patients receiving the placebo regimen. The above thrombocytopenic events did not result in bleeding events or increased platelet transfusions.
Gastrointestinal toxicity
Discontinuation of at least 1 of the 3 drugs due to diarrhea in 1% of patients receiving the isazomib regimen compared to <1% of patients receiving the placebo regimen.
Skin rash
Rash was reported in 18% of patients in the isazomib regimen group and 10% of patients in the placebo regimen group. The most commonly reported types of rash in both regimens were maculopapular rash and erythematous rash. Grade 3 rash was reported in 2% of patients in the isazolomib regimen group and 1% of patients in the placebo regimen group. At least 1 of the 3 drugs was discontinued for rash in <1% of patients in both regimens.
Peripheral neuropathy
Peripheral neuropathy was reported in 25% of patients in the isazolomib regimen group and 20% of patients in the placebo regimen group. Grade 3 peripheral neuropathy was reported as an adverse reaction in 2% of patients in both regimens. The most frequently reported reaction was peripheral sensory neuropathy (16% and 12% in the Ixazomib and placebo treatment regimens, respectively). Peripheral motor neuropathy was infrequently reported in both regimens (<1%). At least 1 of the 3 drugs was discontinued for peripheral neuropathy in 1% of patients in the isazomib regimen group and in <1% of patients in the placebo regimen group.
Ocular disease
Ocular disease was reported under many different preferred terms, but was summarized as occurring in 24% of patients in the group receiving the isazolomib regimen and 15% of patients receiving the placebo regimen. The most common adverse reactions were blurred vision (5% in the isazomib treatment regimen group and 4% in the placebo treatment regimen group), dry eye (4% in the isazomib treatment regimen group and 1% in the placebo treatment regimen group), and
conjunctivitis (5% in the isazolomib group versus 1% in the placebo group) and cataract (4% in the isazolomib group versus 5% in the placebo group). Grade 3 adverse reactions were reported in 2% of patients in both regimen groups.
Herpes zoster
In the global C16010 study, the occurrence of herpes zoster was reported in 4% of patients in the isazomib regimen and 2% of patients in the placebo regimen. In the C16010 China extension study, the occurrence of herpes zoster was reported in 21% of patients in the isazomib regimen and 3% of patients in the placebo regimen. Patients may be treated with antiviral prophylaxis at the discretion of their physician. In the global C16010 study, the incidence of herpes zoster infection was lower in patients in the isazomib regimen group who received antiviral prophylaxis (<1%) compared with those who did not receive antiviral prophylaxis (6%). In the C16010 Chinese continuation study, the incidence of herpes zoster infection was also lower in patients in the isazomib regimen group who received antiviral prophylaxis (9%) compared with patients who did not receive antiviral prophylaxis (24%).
Other Adverse Reactions
The following serious adverse reactions were reported rarely, except in the Phase III study: acute febrile neutrophilic dermatosis (Sweet syndrome), Stevens-Johnson syndrome, transverse myelitis, reversible posterior encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.
In the pooled data sets from the pivotal phase III global C16010 study (n = 720) and the double-blind placebo-controlled C16010 Chinese continuation study (n = 115), the incidence of the following adverse reactions was similar in the isazomib and placebo regimen groups: fatigue (26% vs. 24%), decreased appetite (12% vs. 9%), hypotension (both 4%), and heart failure (both 3%), tardive dyskinesia† (12% vs. 11%) and liver damage, including liver enzyme changes† (8% vs. 6%).
The frequency of moderately severe (grade 3-4) event hyperkalemia was higher in the isazomib treatment regimen group (5%) than in the placebo treatment regimen group (<1%).
Fungal pneumonia and viral pneumonia leading to fatal outcomes were reported rarely in patients receiving the combination of ixazomib, lenalidomide, and dexamethasone.
“†”Standardized MedDRA Query (SMQ)
[Contraindications
Hypersensitivity to the active ingredient or any of the excipients of this product.
Since this product is co-administered with lenalidomide and dexamethasone, please refer to the drug insert for lenalidomide and dexamethasone for additional information regarding contraindications.
[Precautions].
Since this product is co-administered with lenalidomide and dexamethasone, for additional information on precautions, please refer to the Drug Guide for lenalidomide and dexamethasone.
Thrombocytopenia
Thrombocytopenia may occur with treatment with this product and is generally characterized by a decrease in platelets to a minimum value between days 14-21 of each 28-day treatment cycle and a return to baseline levels at the start of the next cycle (see [ADVERSE REACTIONS]).
Platelet counts should be monitored at least monthly during treatment with this product. During the first 3 cycles, additional monitoring frequency should be considered according to the lenalidomide drug insert. Thrombocytopenia can be managed by dose adjustment and platelet transfusion in accordance with standard medical guidelines (see [DOSAGE AND ADMINISTRATION]).
Gastrointestinal Toxicity
Diarrhea, constipation, nausea, and vomiting are possible while receiving this product and occasionally require antiemetic and antidiarrheal medications and supportive therapy (see [ADVERSE REACTIONS]). The dose should be adjusted for severe (grade 3-4) symptoms (see [Dosage]). If severe gastrointestinal events occur, monitoring of serum potassium levels is recommended.
Peripheral Neuropathy
Peripheral neuropathy is possible with treatment with this product (see [ADVERSE REACTIONS]). Patients should be monitored for signs of peripheral neuropathy. Patients may require dose adjustment in the event of new or worsening peripheral neuropathy (see [DOSAGE AND ADMINISTRATION]).
Peripheral edema
Peripheral edema is possible with treatment with this product (see [ADVERSE REACTIONS]). Evaluate the patient for the underlying cause and provide supportive therapy as needed. Adjust the dose of dexamethasone or isazomib administered at the onset of Grade 3 or 4 symptoms according to prescribing information (see [DOSAGE AND ADMINISTRATION]).
Skin reactions
There is a possibility of skin rash when receiving this product (see [ADVERSE REACTIONS]). Treat grade 2 or higher rash with supportive therapy or dose adjustment (see [DOSAGE AND ADMINISTRATION]).
Hepatotoxicity
Drug-induced liver injury, hepatocellular injury, hepatic steatosis, cholestatic hepatitis, and hepatotoxicity have been reported in patients treated with this product, none of which are common (see [ADVERSE REACTIONS]). Monitor liver enzymes regularly and make dose adjustments for grade 3 or 4 symptoms (see [DOSAGE AND ADMINISTRATION]).
Pregnancy
Pregnancy should be avoided in female patients receiving this product. If this product is used during pregnancy or if pregnancy occurs while the patient is using this product, the patient should be informed of the potential risks to the fetus.
Women of childbearing potential must use highly effective contraception while taking this product and for 90 days after stopping treatment (see Drug Interactions], [Use in Pregnant and Lactating Women]). Women using hormonal contraception also need to use barrier contraception.
Reversible posterior encephalopathy syndrome
Reversible posterior encephalopathy syndrome (PRES), a rare reversible neurological disorder that may manifest as seizures, hypertension, headache, altered consciousness, and visual disturbances, has been reported in patients treated with this drug. The diagnosis is confirmed by brain imaging, preferably magnetic resonance imaging. Patients presenting with PRES need to discontinue this product.
CYP3A potent inducer
Potent inducers reduce the efficacy of this product and therefore co-administration with CYP3A potent inducers such as, carbamazepine, phenytoin, rifampin, and St. John’s Wort (Hypericum) should be avoided (see [Drug Interactions], [Pharmacokinetics]). If co-administration with CYP3A potent inducers is necessary, close monitoring of the patient’s disease control is required.
Cardiac electrophysiology
Based on the results of a pharmacokinetic-pharmacodynamic analysis of data from 245 patients, isazolomib did not prolong the QTc interval during clinically relevant exposures. Based on model analysis, the estimated mean change in QTcF from baseline was 0.07 msec (90% CI; -0.22, 0.36) at a 4 mg dose. There was no significant relationship between isazomib concentration and RR interval, suggesting that the effect of isazomib on heart rate was not clinically significant.
Effects on the ability to drive a vehicle and operate machinery
The effects of this product on the ability to drive a vehicle and operate machinery were minimal. Symptoms of fatigue and dizziness have been observed in clinical trials. If patients experience these symptoms, it is recommended that they not drive vehicles or operate machinery.
Special Precautions for Disposal and Other Handling
This product is a cytotoxic drug. Remove the capsule when about to take it. Do not open or crush the capsule. Direct contact with the contents of the capsule should be avoided. If the capsule is broken, avoid raising dust during cleaning. In case of contact with skin, wash thoroughly with soap and water.
Any unused medication or waste should be disposed of in accordance with local requirements.
[For Pregnant and Lactating Women].
Since this product is administered in combination with lenalidomide and dexamethasone, for additional information on fertility, pregnancy and breast-feeding, please refer to the drug insert for lenalidomide and dexamethasone.
Contraception for women of childbearing potential/men and women
Male and female patients of childbearing potential must use effective contraception during treatment and for 90 days after treatment. This product is not recommended for women of childbearing potential who are not using contraception.
When this product is co-administered with dexamethasone, a known weak to moderate inducer of CYP3A4, other enzymes and transporter proteins, the risk of reduced efficacy of oral contraceptives needs to be considered. Therefore, women using oral hormonal contraceptives also need to use barrier contraception.
Pregnancy
The use of this product is not recommended for female patients during pregnancy because of the potential for fetal harm. Therefore, female patients being treated with this product should avoid pregnancy.
There are no data on the use of Ixazomib in pregnant women. Reproductive toxicity has been demonstrated in animal studies (see [Pharmacologic Toxicology]).
This product is administered in combination with lenalidomide, which is structurally related to thalidomide. Thalidomide is a human teratogenic active substance that causes serious life-threatening birth defects. Lenalidomide is expected to have teratogenic effects in humans if used during pregnancy. All patients must meet the conditions of the Lenalidomide Pregnancy Prevention Program unless there is reliable evidence that the patient is not fertile. Please refer to the current version of the Lenalidomide Drug Formulary.
Lactation
It is uncertain whether rizazomib or its metabolites are secreted through human milk. Animal data are also not available. Risks to the newborn and infant cannot be excluded and therefore breast-feeding should be discontinued.
Ixazomib will be administered in combination with lenalidomide and patients should discontinue breast-feeding due to the use of lenalidomide.
Fertility
Fertility studies have not been performed on Ixazomib (see [Pharmacology and Toxicology]).
[Pediatric Use].
The safety and efficacy of this product in pediatric patients less than 18 years of age have not been determined. No data are available to support this.
Geriatric Use]
In patients older than 65 years of age, no dose adjustment of this product is necessary.
In patients older than 75 years, discontinuation of therapy was reported in 13 patients (28%) in the Ixazomib regimen group and 10 patients (16%) in the placebo regimen group. Among patients older than 75 years, 10 patients (21%) in the Ixazomib regimen group and 9 patients (15%) in the placebo regimen group developed cardiac arrhythmias.
[Drug Interactions].
Pharmacokinetic interactions.
CYP inhibitors
The combination of ixazomib with clarithromycin, a potent inhibitor of CYP3A, did not result in clinically meaningful changes in systemic exposure to ixazomib. Ixazomib Cmax decreased by 4% and AUC increased by 11%. Therefore, no dose adjustment was required for the co-administration of isazomib and a potent CYP3A inhibitor.
Based on the results of a population PK analysis, the coadministration of izatzomib with a potent CYP1A2 inhibitor did not result in clinically meaningful changes in systemic exposure to izatzomib. Therefore, no dose adjustment is required for the co-administration of isazomib and CYP1A2 potent inhibitors.
CYP inducers
Co-administration of izazomib with rifampicin resulted in a 54% decrease in Cmax and a 74% decrease in AUC for izazomib. Therefore, co-administration of Ixazomib with CYP3A potent inducers is not recommended (see [Precautions]).
Effects of Ixazomib 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 does not induce CYP1A2, CYP2B6 and CYP3A4/5 activity or corresponding immunoreactive protein levels. No drug interactions are expected to occur with Ixazomib through CYP induction or inhibition.
Transporter protein-based interactions
Ixazomib is a low-affinity substrate for P-gp. Ixazomib is not a substrate for BCRP, MRP2, or hepatic OATP. Ixazomib is not an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1 or MATE2-K. Ixazomib is not expected to produce transporter protein-mediated drug-drug interactions.
Oral contraceptives.
The risk of reduced efficacy of oral contraceptives needs to be considered when isazomib is co-administered with dexamethasone, a known weak to moderate inducer of CYP3A4, other enzymes and transporter proteins. Women who use hormonal contraception also need to use barrier contraception.
Drug overdose]
There is no known specific antidote for isazolomib overdose. Although clinical data are limited, doses ≤12 mg have been reported in randomized controlled trials. If an overdose occurs, patients should be monitored for adverse reactions (see [Adverse Reactions]) and provided with appropriate supportive therapy.
[Clinical Trials].
The efficacy and safety of isazomib in combination with lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma who had received at least one prior therapy was evaluated in an international, randomized, double-blind, placebo-controlled, multicenter, phase III superiority study (C16010). A total of 722 patients (intent-to-treat [ITT] population) were randomly assigned in a 1:1 ratio to receive either rizazomib in combination with lenalidomide and dexamethasone (N=360; rizazomib regimen group) or placebo in combination with lenalidomide and dexamethasone (N=362; placebo regimen group) until disease progression or intolerable toxicity developed. The trial enrolled patients with primary refractory, relapsed after prior treatment, or refractory to any prior treatment who had relapsed multiple myeloma. Patients with a change in treatment regimen prior to disease progression and those with controlled cardiovascular abnormalities may also be enrolled. Patients resistant to lenalidomide or proteasome inhibitors and those who have received more than 3 lines of prior therapy are excluded from this phase III study. For the purposes of this study, refractory, i.e., drug-resistant, was defined as disease progression on therapy or progression within 60 days of the last dose of lenalidomide or proteasome inhibitors. Due to the limited data on such patients resistant to lenalidomide or proteasome inhibitors, a careful risk-benefit assessment is recommended prior to initiating treatment with isazolomib.
Thromboprophylaxis according to the lenalidomide drug insert is recommended for all patients in both treatment groups. Concomitant medications, such as antiemetics, antivirals, and antihistamines, are given to patients at the discretion of their physician for symptom prevention and/or treatment.
During the 28-day cycle, patients receive oral izatzomib 4 mg or placebo on days 1, 8 and 15, oral lenalidomide (25 mg) on days 1-21, and oral dexamethasone (40 mg) on days 1, 8, 15 and 22. Adjust starting dose according to lenalidomide drug instructions in patients with renal impairment. Treatment was continued until disease progression or intolerable toxicity developed.
Baseline demographics and disease characteristics were balanced and comparable between the two treatment regimen groups. The median age was 66 years, with a range of 38-91 years; 58% of patients were older than 65 years. 57% of patients were male. The study population was 85% white, 9% Asian, and 2% black. Ninety-three percent of patients had an ECOG physical status score of 0-1, and 12% had a stage III ISS stage at baseline (N=90). 25% of patients had creatinine clearance <60 mL/min. 23% of patients were light chain type, and 12% had measurable lesions of only free light chain. 19% were at high risk for cytogenetic abnormalities (del[17], t[4; 14] , t[14; 16]) (N=137), 10% had del(17) abnormalities (N=69) and 34% had 1q amplification (1q21) (N=247). Patients had received 1-3 lines of prior therapy (median value 1) and prior therapy included bortezomib (69%), carfilzomib (<1%), thalidomide (45%), lenalidomide (12%), and melphalan (81%). 57% of patients had received prior stem cell transplantation. 77% of patients relapsed after prior therapy and 11% were previously refractory. Primary refractory accounted for 6% of patients and was defined as best outcome for all prior therapies as disease stabilization or disease progression.
Disease assessment was performed by a blinded independent review committee (IRC) based on central laboratory results according to the 2011 International Myeloma Working Group (IMWG) Consensus Harmonized Efficacy Criteria, with the primary endpoint of progression-free survival (PFS). Disease status was assessed every 4 weeks until disease progression. At the time of the primary analysis (median follow-up of up to 14.7 months and median number of treatment cycles of 13), there was a statistically significant difference in PFS between treatment groups.The PFS results are summarized in Table 5 and Figure 1.The improvement in PFS is supported by the improved overall remission rate in the isazomib treatment regimen group.
Table 5: Progression-free survival and remission outcomes in patients with multiple myeloma treated with isazomib or placebo in combination with lenalidomide and dexamethasone (intention-to-treat population)
Ixazomib + lenalidomide and dexamethasone (N = 360) Placebo + lenalidomide and dexamethasone (N = 362) Progression-free survival events, n (%) 129 (36) 157 (43) Median (months) 20.6 14.7 P value*0.012 Risk ratio† (95% CI) 0.74 (0.59, 0.94) Overall remission rate‡, n (%) 282 (78.3) 259 (71.5) Remission category, n (%) Complete remission 42 (11.7) 24 (6.6) Very good partial remission 131 (36.4) 117 (32.3) Partial remission 109 (30.3) 118 (32.6) Time to remission (months) median 1.1 1.9 Duration of remission§ (months) median 20.5 15.0 * P values are based on a stratified log-rank test.
† Risk ratios were derived from a stratified Cox proportional risk regression model. Risk ratios less than 1 indicate an advantage of the isazomib treatment regimen.
‡ORR (overall remission rate) = CR (complete remission) + VGPR (very good partial remission) + PR (partial remission)
§Relievers in the efficacy-based evaluable population
Figure 1: Kaplan-Meier curves for progression-free survival in the intention-to-treat population
In a planned (at median follow-up month 23) interim analysis of overall survival (OS), deaths accounted for 35% of the deaths required for final OS analysis in the ITT population; there were 81 deaths in the isazomib regimen and 90 deaths in the placebo regimen. median overall survival was not achieved for either of the 2 treatment regimens. In the ITT population, the median PFS estimated in this analysis was 20 months in the isazomib regimen group and 15.9 months in the placebo regimen group (HR = 0.82 [95% CI (0.67, 1.0)]).
A randomized, double-blind, placebo-controlled phase III study was conducted in China (N = 115) using a similar study design and inclusion criteria. Many of the patients enrolled in the study had advanced disease at initial diagnosis, Duria-Salmon stage III (69%), and 60% had received at least 2 lines of prior therapy, with 63% being thalidomide resistant. In the primary analysis (median follow-up 8 months and median treatment 6 cycles), median PFS was 6.7 months in the isazomib regimen group and 4 months in the placebo regimen group (p value = 0.035, HR = 0.60).
For the final analysis of OS at a median follow-up of 19.8 months
median OS was improved by 10 months (25.8 months for patients in the isazomib treatment regimen group and 15.8 months for patients in the placebo treatment regimen group [p-value = 0.0014, HR = 0.42,95% CI: 0.242,0.726]).
Since multiple myeloma is a heterogeneous disease, the treatment benefit may differ between patient subgroups in the phase III study (C16010) (see Figure 2).
Figure 2: Forest plot of progression-free survival in subgroups
Event; N/Median survival (months) Variable Subgroup Placebo treatment regimen Ixazomib treatment regimen HR 95% CI All subjects All (n=722) Age classification <=65 (n=344)
>65-75 (n=270)
>75 (n=108) Cytogenetic risk High risk (n=137) 1Q amplification (n=249) Standard risk (n=415) ISS stage I or II at screening (n=632)
Ill (n=90) Prior treatment1 (n=425)
2 or 3 (n=297) Relapsed or refractory relapse (n=556) Refractory (n=82) Reference and relative values (n=83) Proteasome inhibitor exposure (n=503) Untreated (n=219) Prior IMID treatment exposure (n=397) Untreated (n=325) ECOG physical status 0 or 1 (n=670)
2 (n=42) Baseline CrCI group <50 mL/min (n=92) >=50 mL/min (n=629) Favorable Ixazomib regimen in favor of placebo regimen
In the phase III study (C16010), 10 patients (5 in each treatment regimen group) had severe renal impairment at baseline. Of the 5 patients in the isazolomib regimen group, 1 patient achieved confirmed partial remission and 3 achieved confirmed stable disease (but 2 were in unconfirmed partial remission and 1 was in unconfirmed very good partial remission). Of the 5 patients in the placebo regimen group, 2 achieved confirmed very good partial remission.
In the phase III study (C16010), patients’ quality of life as assessed by the overall health score (EORTC QLQ-C30 and MY-20) remained unchanged during treatment and was similar in both treatment regimens.
Pharmacology and Toxicology]
Pharmacological effects
Ixazomib is a reversible proteasome inhibitor that preferentially binds the β5 subunit of the 20S proteasome and inhibits its chymotrypsin-like activity. It induces apoptosis in multiple myeloma cell lines in vitro and has cytotoxic effects on myeloma cells from patients who relapsed after treatment with various drugs such as bortezomib, lenalidomide and dexamethasone, and the combination of izarazomib and lenalidomide has synergistic cytotoxic effects on multiple myeloma cell lines. Ixazomib has in vivo antitumor activity in a mouse multiple myeloma xenograft model.
Toxicological studies
Genotoxicity
The results of the Ames test for izatzomib, the comet test in the stomach and liver of mice in vivo, and the bone marrow micronucleus test in mice were negative, and the results of the chromosomal aberration test in human peripheral blood lymphocytes were positive.
Reproductive toxicity
Fertility and early embryonic development studies as well as perinatal toxicity studies were not performed with isazomib, but the reproductive system was evaluated in general toxicology studies. Ixazomib did not produce significant effects on male and female reproductive organs in a 6-month-long test in rats and a 9-month-long test in dogs.
In the rabbit embryo-fetal developmental toxicity test, an increased incidence of skeletal abnormalities/deformities (fused caudal vertebrae, abnormal number of lumbar vertebrae, multiple ribs) was seen with isazomib at maternal toxic doses (≥0.3 mg/kg, 1.9 times the average exposure of the clinically recommended dose of 4 mg/kg). In the rat embryo-fetus developmental toxicity exploratory study, a trend toward reduced fetal weight and fetal survival was seen at maternal toxicity doses and increased post-embryo loss was seen at 0.6 mg/kg (2.5 times the average exposure of the clinically recommended dose of 4 mg/kg). In both rat and rabbit embryo-fetal developmental toxicity assays, no direct embryo-fetal toxicity was seen with isazomib at doses below maternal toxicity.
Carcinogenicity
No carcinogenicity studies have been conducted.
Pharmacokinetics
Absorption
Ixazomib plasma concentration peaks approximately 1 hour after oral administration. The mean absolute oral bioavailability was 58%. In the dose range of 0.2-10.6 mg, isazomib AUC increases in a proportional manner to the dose.
Concomitant high-fat diet reduced isazomib AUC by 28% compared to administration after overnight fasting (see [DOSAGE]).
Distribution
Ixazomib is 99% bound to plasma proteins and distributed to red blood cells with an AUC ratio of 10 in blood and plasma. steady-state volume of distribution is 543 L.
Biotransformation
Following oral administration of a radiolabeled dose, izatzomib accounted for 70% of all drug-related substances in plasma. Both metabolism by multiple CYP enzymes and metabolism by non-CYP proteins are expected to be the major clearance mechanisms for isazomib. At clinically relevant concentrations of rizazomib, in vitro studies using human cDNA-expressed cytochrome P450 isozymes showed that non-specific CYP isozymes play a major role in rizazomib metabolism and non-CYP proteins promote overall metabolism. At concentrations above those observed clinically, isazomib is 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%), respectively.
Elimination
Ixazomib showed a multiphase elimination profile. Based on a population PK analysis, systemic clearance (CL) was approximately 1.86 L/hr, with 44% interindividual variation. The terminal half-life (t1/2) of Ixazomib is 9.5 days. With weekly oral administration, an accumulation of AUC up to approximately 2-fold was observed on day 15.
Excretion
In 5 patients with advanced cancer, after a single oral administration of 14C-isazomib, 62% of the radioactive component was excreted via urine and 22% via feces. Urinary recovery of the prototype drug of isazomib accounted for <3.5% of the administered dose.
Special Populations
Liver damage
According to the results of the population PK analysis, the PK of isazomib was similar in patients with normal liver function and in patients with mild liver impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1-1.5 x ULN and an arbitrary value of AST).
The PK profile of isazomib was determined at doses of 4 mg in patients with normal liver function (N=12), 2.3 mg in patients with moderate liver impairment (total bilirubin > 1.5-3×ULN, N=13) or 1.5 mg in patients with severe liver impairment (total bilirubin > 3×ULN, N=18). The unconjugated dose-standardized AUC was 27% higher in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function (see [DOSAGE]).
Renal impairment
Based on the results of the population PK analysis, the PK of isazomib was similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance ≥30 mL/min).
The PK characteristics of isazomib were determined 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 patients requiring dialysis (N=6) at a dose of 3 mg. The unbound AUC was 38% higher in ESRD patients with severe renal impairment or requiring dialysis compared to patients with normal renal function. Measurement of izatzomib concentrations in dialysis patients before and after hemodialysis revealed that the two concentrations were similar during dialysis, indicating that izatzomib is not cleared by dialysis (see [DOSAGE]).
Age, sex, ethnicity
There was no clinically significant effect of age (23-91 years), gender, body surface area (1.2-2.7 m2), or ethnicity on clearance of isazomib based on the results of population PK analysis. In Asian patients, the mean AUC was 35% higher; however, there was an overlap in the AUC of isazomib between white and Asian patients.
[Storage].
Do not freeze and store at 2-30°C. To prevent moisture, store in the original packaging.
Package】
PVC-AL/AL package, 1 capsule/plate, 3 plates/box.
Expiration date
36 months
Execution Standard
Imported drug registration standard JX20170225
【Imported drug registration certificate number
【Manufacturer】
Company Name: Takeda Pharma A/S
Company Address: Dybendal Alle 10, 2630 Taastrup, Denmark
Production plant name: Haupt Pharma Amareg GmbH
Plant Address: Donaustaufer Strasse 378, Regensburg, Bayern 93055, Germany
Domestic Contact
Name: Takeda Pharmaceutical (China) Co.
Address: No. 836, Yacheng Avenue, Taizhou City, Jiangsu Province
Postcode：225300
Tel: 400-069-0980
Fax：0523-86201595