CLASSES

Small Molecule Antineoplastic Proteosome Inhibitors

DEA CLASS

Rx

DESCRIPTION

Oral proteasome inhibitor
Used in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received at least 1 prior treatment
Myelosuppression has been reported

COMMON BRAND NAMES

NINLARO

HOW SUPPLIED

Ixazomib/NINLARO Oral Cap: 2.3mg, 3mg, 4mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

4 mg/dose PO.

4 mg/dose PO.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

DOSING CONSIDERATIONS

Baseline mild hepatic impairment (AST level greater than the upper limit of normal (ULN) or a total bilirubin level of 1 to 1.5 times the ULN and any AST level): no ixazomib dose adjustment necessary.
Baseline moderate (total bilirubin level greater than 1.5 to 3 times the ULN) or severe (total bilirubin level greater than 3 times the ULN) hepatic impairment: reduce the ixazomib starting dosage to 3 mg PO on days 1, 8, and 15 repeated every 28 days.
Treatment-related grade 3 and 4 hepatotoxiciy: hold ixazomib until the toxicity recovers to baseline or grade 1 or less (at physician’s discretion); resume ixazomib at a reduced dose (from 4 mg to 3 mg or from 3 mg to 2.3 mg).

NOTE: Refer to the lenalidomide prescribing information for lenalidomide dosing recommendations in patients with renal impairment.
Baseline mild or moderate renal impairment (creatinine clearance (CrCl) of 30 mL/min or greater): no ixazomib dose adjustment necessary.
Baseline severe renal impairment (CrCl less than 30 mL/min): reduce the ixazomib starting dosage to 3 mg PO on days 1, 8, and 15 repeated every 28 days.
Baseline end-stage renal disease requiring dialysis: reduce the ixazomib starting dosage to 3 mg PO on days 1, 8, and 15 repeated every 28 days; the dose may be given without regard to the timing of dialysis because ixazomib is not dialyzable.

ADMINISTRATION

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Avoid exposure to crushed or broken capsules.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

STORAGE

NINLARO:
- Do not freeze
- Store at room temperature (between 59 to 86 degrees F)
- Store below 86 degrees F
- Store in carton until time of use

CONTRAINDICATIONS / PRECAUTIONS

Thrombocytopenia and neutropenia have been reported with ixazomib therapy. Monitor complete blood counts including a differential and platelets at least monthly during treatment; consider more frequent monitoring during the first 3 cycles of therapy. Platelet nadirs usually occur between days 14 to 21 of each 28-day cycle. Therapy interruption, dose reduction, or discontinuation may be necessary for severe thrombocytopenia or neutropenia. Administer colony stimulating growth factors and platelet transfusions per standard medical guidelines. Do not begin a new cycle of therapy until the platelet count has recovered to 75,000 cells/mm3 and the absolute neutrophil count has recovered to 1,000 cells/mm3.

Serious rash has been reported with ixazomib therapy; the most common types were maculo-papular rash and macular rash. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 2 or higher rash. Manage rash with supportive care.

Peripheral neuropathy has been reported with ixazomib therapy. Monitor patients for symptoms of neuropathy. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop new or worsening peripheral neuropathy.

Drug-induced hepatotoxicity has been reported with ixazomib therapy, including hepatocellular injury, hepatic steatosis, and cholestatic hepatitis. Reduce the ixazomib starting dose in patients who have moderate (total bilirubin level more than 1.5 to 3 times the ULN) or severe (total bilirubin level more than 3 times the ULN) hepatic disease at baseline. Regularly monitor hepatic enzymes during therapy. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 hepatotoxicity.

Use caution when administering ixazomib in combination with lenalidomide and dexamethasone in patients with renal impairment. Reduce the ixazomib starting dose in patients who have severe renal impairment (CrCl less than 30 mL/min) or end-stage renal disease requiring dialysis at baseline. Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.

Gastrointestinal (GI) toxicity has been reported with ixazomib therapy, including diarrhea, constipation, and nausea/vomiting. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 GI toxicity. Administer antidiarrheal and/or antiemetic medications and supportive care as necessary.

Peripheral edema has been reported with ixazomib therapy; evaluate patients for underlying causes and administer supportive care as necessary. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 peripheral edema. Refer to the dexamethasone prescribing information for dosing recommendations in patients who develop peripheral edema.

Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura (TTP)/hemolytic-uremic syndrome (HUS)) has been reported in patients who received ixazomib; some cases were fatal. Monitor patients for signs and symptoms of TTP or HUS. Discontinue therapy if TTP/HUS is suspected or diagnosed. Therapy may be restarted if TTP/HUS is excluded. The safety of restarting ixazomib in patients who developed TTP/HUS on therapy is unknown.

Ixazomib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and animal studies. Advise females of reproductive potential to avoid pregnancy while taking ixazomib and for 90 days following the final dose. Discuss the potential hazard to the fetus if ixazomib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including fetal skeletal variations/abnormalities in rabbits and post implantation loss and decreased fetal weight in rats were observed in pregnant animals who received ixazomib at doses that resulted in drug exposures that were higher than those observed with the recommended human dose.

Ixazomib is not recommended in patients with multiple myeloma (MM) in the maintenance setting or in newly diagnosed patients in combination with lenalidomide and dexamethasone as treatment outside of a clinical trial. Single-agent ixazomib was studied as maintenance therapy for newly diagnosed MM patients after primary therapy that either included (MM3) or excluded (MM4) autologous stem cell transplant (ASCT) in 2 global, randomized, placebo-controlled, phase 3 studies. At the interim analyses, ixazomib maintenance therapy significantly improved the primary endpoint of progression-free survival (PFS) compared with placebo in both MM3 (26.5 months vs. 21.3 months) and MM4 (17.4 months vs. 9.4 months). Overall survival in patients receiving maintenance therapy after ASCT was not significantly different in patients who received ixazomib versus placebo after 64 months of follow-up (27% vs. 26%). The overall survival trend favored the placebo arm in patients receiving ixazomib maintenance after primary therapy that excluded ASCT (30% vs. 27%) after 36 months of follow-up. Treatment of newly diagnosed MM with ixazomib, lenalidomide, and dexamethasone did not meet the primary endpoint for significantly improved PFS compared with lenalidomide and dexamethasone alone in another multicenter, randomized, phase 3 clinical trial (MM2) (35.3 months vs. 21.8 months); additionally, the hazard ratio for overall survival was 0.998.

Counsel patients about the reproductive risk and contraception requirements during ixazomib treatment. Females of reproductive potential should avoid pregnancy and use effective non-hormonal contraception (e.g., diaphragm or condom) during and for 90 days after treatment with ixazomib. Dexamethasone is used as part of combination therapy with ixazomib; therefore, the effectiveness of hormone-containing contraceptives may be decreased. Females of reproductive potential should undergo pregnancy testing prior to initiation of ixazomib. Patients who become pregnant while receiving ixazomib should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during therapy and for 90 days following the final dose of ixazomib.

It is not known if ixazomib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during ixazomib therapy and for 90 days after the last dose.

ADVERSE REACTIONS

neutropenia / Delayed / 34.0-34.0
thrombocytopenia / Delayed / 30.0-30.0
hepatotoxicity / Delayed / 10.0-10.0
diarrhea / Early / 10.0-10.0
rash / Early / 3.0-3.0
peripheral neuropathy / Delayed / 2.0-2.0
nausea / Early / 2.0-2.0
peripheral edema / Delayed / 2.0-2.0
infection / Delayed / 0-2.0
Stevens-Johnson syndrome / Delayed / 0-1.0
acute febrile neutrophilic dermatosis / Delayed / 0-1.0
vomiting / Early / 1.0-1.0
constipation / Delayed / 0-1.0
back pain / Delayed / 0-1.0
myelitis / Delayed / 0-1.0
tumor lysis syndrome (TLS) / Delayed / 0-1.0
hemolytic-uremic syndrome / Delayed / 0-1.0
thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
thrombotic microangiopathy / Delayed / 0-1.0

cataracts / Delayed / 15.0-15.0
conjunctivitis / Delayed / 9.0-9.0
blurred vision / Early / 7.0-7.0
hepatitis / Delayed / 0-1.0
steatosis / Delayed / 0-1.0
encephalopathy / Delayed / 0-1.0

xerophthalmia / Early / 6.0-6.0

DRUG INTERACTIONS

Apalutamide: (Major) Avoid the concomitant use of ixazomib and apalutamide; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the ixazomib Cmax and AUC by 54% and 74%, respectively.
Carbamazepine: (Major) Avoid the concomitant use of ixazomib and carbamazepine; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Enzalutamide: (Major) Avoid the concomitant use of ixazomib and enzalutamide; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Fosphenytoin: (Major) Avoid the concomitant use of ixazomib and phenytoin or fosphenytoin; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of ixazomib and rifampin; ixazomib levels were significantly decreased in a drug interactions evaluation. Ixazomib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. In subjects who received ixazomib with rifampin, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of ixazomib and rifampin; ixazomib levels were significantly decreased in a drug interactions evaluation. Ixazomib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. In subjects who received ixazomib with rifampin, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Phenobarbital: (Major) Avoid the concomitant use of ixazomib and phenobarbital; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of ixazomib and phenobarbital; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Phenytoin: (Major) Avoid the concomitant use of ixazomib and phenytoin or fosphenytoin; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Primidone: (Major) Avoid the concomitant use of ixazomib and primidone; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Rifampin: (Major) Avoid the concomitant use of ixazomib and rifampin; ixazomib levels were significantly decreased in a drug interactions evaluation. Ixazomib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. In subjects who received ixazomib with rifampin, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Rifapentine: (Major) Avoid the concomitant use of ixazomib and rifapentine; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the ixazomib Cmax and AUC by 54% and 74%, respectively.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of ixazomib and St. John's Wort; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.

PREGNANCY AND LACTATION

Ixazomib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and animal studies. Advise females of reproductive potential to avoid pregnancy while taking ixazomib and for 90 days following the final dose. Discuss the potential hazard to the fetus if ixazomib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including fetal skeletal variations/abnormalities in rabbits and post implantation loss and decreased fetal weight in rats were observed in pregnant animals who received ixazomib at doses that resulted in drug exposures that were higher than those observed with the recommended human dose.

Counsel patients about the reproductive risk and contraception requirements during ixazomib treatment. Females of reproductive potential should avoid pregnancy and use effective non-hormonal contraception (e.g., diaphragm or condom) during and for 90 days after treatment with ixazomib. Dexamethasone is used as part of combination therapy with ixazomib; therefore, the effectiveness of hormone-containing contraceptives may be decreased. Females of reproductive potential should undergo pregnancy testing prior to initiation of ixazomib. Patients who become pregnant while receiving ixazomib should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during therapy and for 90 days following the final dose of ixazomib.

MECHANISM OF ACTION

Ixazomib is a reversible proteasome inhibitor that preferentially binds to the beta 5 subunit of the 20S proteasome and inhibits its chymotrypsin-like activity. In vitro, ixazomib induces apoptosis of multiple myeloma cells and exhibits cytotoxicity against myeloma cells from patients who relapsed after prior therapies including bortezomib, lenalidomide, and dexamethasone. Synergistic cytotoxic effects in multiple myeloma cell lines have been observed with ixazomib and lenalidomide. Antitumor activity has been demonstrated with ixazomib in a mouse multiple myeloma tumor xenograft model.

PHARMACOKINETICS

Ixazomib is administered orally. It is highly bound to plasma proteins (99%) distributing into red blood cells with a blood-to-plasma ratio of 1:10. In a population pharmacokinetic (PK) analysis, the steady-state Vd was 543 liters (L), the systemic clearance was about 1.9 L/hour (interindividual variability, 44%), and the terminal half-life was 9.5 days. After oral administration of a radiolabeled dose, 70% of total drug-related material in plasma was the parent drug. In vitro, ixazomib is metabolized by multiple CYP450 isoenzymes (CYP3A4, 42%; CYP1A2, 26%; CYP2B6, 16%; CYP2C8, 6%; CYP2D6, 5%; CYP2C19, 5%; and CYP2C9, < 1%) and non-CYP proteins; no specific CYP isozyme predominantly contributes to ixazomib metabolism at clinically relevant ixazomib concentrations. Following a single oral dose of 14C-ixazomib given to 5 patients with advanced cancer, 62% of the dose radioactivity was recovered in the urine and 22% of the dose radioactivity was recovered in the feces. Less than 3.5% of the dose recovered in the urine was unchanged ixazomib.
 
Affected cytochrome P450 isoenzymes: CYP3A4
Ixazomib is a substrate of multiple CYP450 isoenzymes; CYP3A4 (42%) and CYP1A2 (26%) account for most of the CYP450 metabolism. Avoid the concomitant use of ixazomib and strong CYP3A4 inducers; ixazomib levels and exposure were significantly decreased when ixazomib was administered with rifampin in a drug interaction study. Concomitant use with a strong CYP3A4 inhibitor (clarithromycin) or strong CYP1A2 inhibitors did not result in clinically significant changes in ixazomib systemic exposure. Ixazomib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 or induce CYP1A2, CYP2B6, or CYP3A4/5. It is not expected to produce drug-drug interactions via CYP450 inhibition or induction. Ixazomib is a weak P-glycoprotein substrate. It is not expected to cause transporter-mediated drug-drug interactions. Ixazomib is not a substrate of BCRP, MRP2 or hepatic OATP or an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K.