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  • 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

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

    DOSAGE & INDICATIONS

    For the treatment of multiple myeloma.
    NOTE: The FDA has designated ixazomib citrate as an orphan drug for the treatment of multiple myeloma.
    For the treatment of multiple myeloma in patients who have received at least 1 prior therapy, in combination with lenalidomide and dexamethasone.
    Oral dosage
    Adults

    4 mg orally on days 1, 8, and 15 in combination with lenalidomide 25 mg orally daily on days 1 through 21 and dexamethasone 40 mg orally on days 1, 8, 15, and 22. Repeat treatment cycles every 28 days until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Consider giving an antiviral agent to decrease the risk of herpes zoster reactivation. Therapy interruption, dose reduction, or discontinuation may be necessary for treatment-related toxicity. Ensure that the absolute neutrophil count is 1,000 cells/mm3 or greater, the platelet count is 75,000 cells/mm3 or greater, and non-hematologic toxicities are recovered to baseline or grade 1 or lower prior to starting the next cycle of therapy. The median progression-free survival time was significantly improved with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone (20.6 months vs. 14.7 months; hazard ratio = 0.74; 95% CI, 0.59 to 0.94; p = 0.01) in patients with relapsed and/or refractory multiple myeloma who had received 1 to 3 prior therapies in a multinational, randomized, double-blind, phase III trial (n = 722; TOURMALINE-MM1 trial). At a median follow-up time of 23 months, the median overall survival time had not been reached in either treatment arm. The median age of patients in this study was 66 years (range, 30 to 91 years); prior therapy included a stem-cell transplant in 57% of patients, proteasome inhibitor therapy in 70% of patients, and immunomodulatory drug therapy in 55% of patients. Thromboprophylaxis was recommended for all patients.

    As maintenance therapy following autologous stem-cell transplantation in patients with multiple myeloma†.
    Oral dosage
    Adults

    3 mg orally on days 1, 8, and 15 repeated every 28 days for 26 cycles or until disease progression was evaluated as maintenance therapy in a randomized, double-blind, placebo-controlled, phase 3 trial (n = 656; the TOURMALINE-MM3 trial). The dose was increased to 4 mg starting in cycle 5 if therapy was well tolerated during cycles 1 to 4.[63976] Consider giving an antiviral agent to decrease the risk of herpes zoster reactivation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or discontinuation may be necessary for treatment-related toxicity. Ensure that the absolute neutrophil count is 1,000 cells/mm3 or greater, the platelet count is 75,000 cells/mm3 or greater, and non-hematologic toxicities are recovered to baseline or grade 1 or lower prior to starting the next cycle of therapy.[60335]

    As maintenance therapy following standard-of-care induction in patients with newly diagnosed multiple myeloma not undergoing autologous stem-cell transplantation†.
    Oral dosage
    Adults

    3 mg orally on days 1, 8, and 15 repeated every 28 days for 26 cycles or until disease progression was evaluated in a multinational, randomized (3:2), double-blind, placebo-controlled, phase 3 trial (n = 706; the TOURMALINE-MM4 trial). The dose was increased to 4 mg starting in cycle 5 if therapy was well tolerated during cycles 1 to 4. Consider giving an antiviral agent to decrease the risk of herpes zoster reactivation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or discontinuation may be necessary for treatment-related toxicity. Ensure that the absolute neutrophil count is 1,000 cells/mm3 or greater, the platelet count is 75,000 cells/mm3 or greater, and non-hematologic toxicities are recovered to baseline or grade 1 or lower prior to starting the next cycle of therapy.[60335]

    MAXIMUM DOSAGE

    Adults

    4 mg/dose PO.

    Geriatric

    4 mg/dose PO.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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).

    Renal Impairment

    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

    Oral Administration
    Oral Solid Formulations

    Ixazomib should be taken at least 1 hour before or at least 2 hours after food at approximately the same time of day as directed. Do not take dexamethasone and ixazomib at the same time; dexamethasone should be taken with food.
    Swallow whole; do not crush or cut capsules.
    If a dose is delayed or missed, take the dose if the next scheduled dose is more than 72 hours (3 days) away; otherwise, skip the dose and take it at the next scheduled time. Do not take a double dose to make up for a missed dose.
    If vomiting occurs after taking a dose, do not take another dose; resume therapy at the next scheduled dose.
    Follow procedures for proper handling and disposal of anticancer drugs. Avoid exposure to crushed or broken capsules.

    STORAGE

    NINLARO:
    - Do not freeze
    - Store at room temperature not exceeding 86 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Neutropenia, thrombocytopenia

    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

    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

    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.

    Hepatic disease, hepatotoxicity

    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.

    Renal impairment

    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.

    Constipation, diarrhea, nausea/vomiting

    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

    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.

    Hemolytic-uremic syndrome, thrombotic microangiopathy, thrombotic thrombocytopenic purpura (TTP)

    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.

    Pregnancy

    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.

    Contraception requirements, male-mediated teratogenicity, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ixazomib treatment. Females of reproductive potential should avoid pregnancy and use effective contraception 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. Women using hormonal contraceptives should also use a barrier method of contraception (e.g., diaphram or condom). 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.

    Breast-feeding

    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

    Severe

    neutropenia / Delayed / 26.0-26.0
    thrombocytopenia / Delayed / 26.0-26.0
    diarrhea / Early / 6.0-6.0
    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
    Stevens-Johnson syndrome / Delayed / 0-1.0
    vomiting / Early / 1.0-1.0
    constipation / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    myelitis / Delayed / 0-1.0
    tumor lysis syndrome (TLS) / Delayed / 0-1.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
    maculopapular rash / Early / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 0-6.0
    blurred vision / Early / 6.0-6.0
    conjunctivitis / Delayed / 6.0-6.0
    hepatitis / Delayed / 0-1.0
    steatosis / Delayed / 0-1.0
    encephalopathy / Delayed / 0-1.0

    Mild

    xerophthalmia / Early / 5.0-5.0

    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.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Belladonna Alkaloids; Ergotamine; 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.
    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.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid the concomitant use of ixazomib and rifabutin; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and rifabutin 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: (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.
    Rifabutin: (Major) Avoid the concomitant use of ixazomib and rifabutin; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and rifabutin 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

    Pregnancy

    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.

    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.

    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.

    Oral Route

    Following an oral dose of ixazomib, the mean absolute oral bioavailability was 58% and the median Tmax was 1 hour in a population pharmacokinetic analysis. The AUC values increased dose-proportionally over the range of 0.2 to 10.6 mg. The accumulation ratio was 2-fold following weekly oral dosing.
    Affects of food: When a 4-mg dose of ixazomib was administered with a high-fat meal, the Cmax and AUC values were decreased by 69% and 28%, respectively. Ixazomib should be given at least 1 hour before or at least 2 hours after food.