Ixazomib is a proteasome inhibitor that is indicated in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received at least 1 prior therapy. Myelosuppression has been reported with ixazomib therapy; platelet transfusions may be necessary.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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.
Route-Specific 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.
-Discuss with the patient the importance of carefully following all dosage instructions including taking the recommended dose as directed; overdosage, including fatal cases, has occurred. Serious reactions reported with overdose include severe nausea, vomiting, diarrhea, aspiration pneumonia, multi-organ failure, and death.
Hematologic toxicity was reported with ixazomib therapy in a clinical trial. Monitor platelet counts 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 hematologic toxicity. 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. Thrombocytopenia (85% vs. 67%; grade 3 or 4, 30% vs. 14%) and neutropenia (74% vs. 70%; grade 3 or 4, 34% vs. 37%) occurred more often with ixazomib/lenalidomide/dexamethasone (n = 361) compared with placebo/lenalidomide/dexamethasone (n = 359) in patients with relapsed and/or refractory multiple myeloma in a randomized, double-blind, placebo-controlled trial. Platelet transfusions were required in 10% of patients in the ixazomib arm compared to 7% of patients in the placebo arm.
Severe rash (e.g., Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) has been reported with ixazomib therapy; some cases were fatal. However, the most common rash types were maculopapular 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. Discontinue ixazomib if SJS or TEN occurs and manage as clinically indicated. Rash occurred in 27% (grade 3, 3%) of patients who received ixazomib/lenalidomide/dexamethasone (n = 361) compared with 16% (grade 3, 2%) of patients who received placebo/lenalidomide/dexamethasone (n = 359) in a randomized, double-blind, placebo-controlled trial. Acute febrile neutrophilic dermatosis (Sweet's syndrome) and Stevens-Johnson syndrome (including 1 fatal case) have been reported in less than 1% of patients who received ixazomib. TEN was reported in postmarketing surveillance of ixazomib.
Sensory and motor neuropathies were reported with ixazomib therapy in a clinical trial. Monitor patients for symptoms of neuropathy. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop new or worsening peripheral neuropathy. Peripheral neuropathy occurred in 32% (grade 3, 2%) of patients who received ixazomib/lenalidomide/dexamethasone (n = 361) compared with 24% (grade 3, 2%) of patients who received placebo/lenalidomide/dexamethasone (n = 359) in a randomized, double-blind, placebo-controlled trial. Peripheral sensory neuropathy was the most commonly reported reaction, occurring in 24% of ixazomib-treated patients and in 17% of patients in the placebo arm; peripheral motor neuropathy occurred rarely (less than 1%).
Hepatotoxicity occurred in 10% of multiple myeloma patients treated with ixazomib/lenalidomide/dexamethasone compared with 9% of those who received placebo/lenalidomide/dexamethasone in a randomized clinical trial. Additionally, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and cholestatic hepatitis each occurred in less than 1% of patients in the ixazomib arm. Regularly monitor patients for elevated hepatic enzymes (e.g., LFTs) during therapy. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 hepatotoxicity.
Gastrointestinal (GI) toxicity has been reported with ixazomib therapy in a clinical trial. 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. Constipation (35% vs. 28%; grade 3, less than 1% vs. less than 1%), diarrhea (52% vs. 43%; grade 3, 10% vs. 3%), nausea (32% vs. 23%; grade 3, 2% vs. 0%), and vomiting (26% vs. 13%; grade 3, 1% vs. less than 1%) occurred more often with ixazomib/lenalidomide/dexamethasone (n = 361) compared with placebo/lenalidomide/dexamethasone (n = 359) in patients with relapsed and/or refractory multiple myeloma in a randomized, double-blind, placebo-controlled trial.
Peripheral edema has been reported with ixazomib therapy in a clinical trial; evaluate patients for underlying 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 this toxicity. Peripheral edema occurred in 27% (grade 3, 2%) of patients who received ixazomib/lenalidomide/dexamethasone (n = 361) compared with 21% (grade 3, 1%) of patients who received placebo/lenalidomide/dexamethasone (n = 359) in a randomized, double-blind, placebo-controlled trial.
Infection has been reported with ixazomib therapy in a clinical trial. Upper respiratory tract infection occurred in 27% (grade 3, 1%) of patients who received ixazomib/lenalidomide/dexamethasone compared with 23% (grade 3, 1%) of those who received placebo/lenalidomide/dexamethasone in a randomized, clinical trial. Bronchitis occurred in 22% versus 17% (grade 3 or 4, 2% vs. 2% to 3%) and herpes zoster infection in 6% versus 3% of these patients, respectively. In patients who received ixazomib, antiviral prophylaxis was associated with a lower risk of herpes zoster infection compared with no antiviral prophylaxis (1% vs. 10%).
Back pain occurred in 27% (grade 3, less than 1%) of patients who received ixazomib/lenalidomide/dexamethasone (n = 361) compared with 24% (grade 3, 3%) of patients who received placebo/lenalidomide/dexamethasone (n = 361) in a randomized, double-blind, placebo-controlled trial.
Eye disorders occurred in 38% of patients who received ixazomib/lenalidomide/dexamethasone (n = 361) in a randomized, double-blind, placebo-controlled trial including cataracts (15%), conjunctivitis (9%), blurred vision (7%), and xerophthalmia (6%).
Transverse myelitis has been reported in less than 1% of patients who received ixazomib.
Posterior reversible encephalopathy syndrome has been reported in less than 1% of patients who received ixazomib.
Tumor lysis syndrome (TLS) has been reported in less than 1% of patients who received ixazomib.
Cases of thrombotic microangiopathy including thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), some fatal, have been reported in patients treated with ixazomib; TTP occurred in less than 1% of patients who received ixazomib. Monitor for signs and symptoms of TTP/HUS. Stop ixazomib and evaluate if a diagnosis of TTP or HUS is suspected; once excluded, consider restarting treatment. The safety of restarting ixazomib in patients previously experiencing TTP or HUS is not known.
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, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); some cases were fatal. The most common types of rash were maculopapular 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. Discontinue ixazomib if SJS or TEN occurs and manage as clinically indicated.
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.
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:
NOTE: Ixazomib is not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials.
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 (HR) = 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 3 trial (n = 722; TOURMALINE-MM1 trial). At a median follow-up time of 85 months, the median overall survival time was not significantly improved in the ixazomib-containing arm (53.6 months vs. 51.6 months; HR = 0.939; 95% CI, 0.784 to 1.125). In this trial, subsequent lines of therapy were given in 71.7% and 69.9% of patients who received ixazomib plus lenalidomide and dexamethasone (median, 2 subsequent therapies; range, 1 to 9) and lenalidomide and dexamethasone (median, 3 subsequent therapies; range, 1 to 12), respectively. 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.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicities
NOTE: Refer to the lenalidomide prescribing information for recommended lenalidomide dose reductions.
Recommended Ixazomib Dose Reductions
First dose reduction: 3 mg PO on days 1, 8, and 15 repeated every 28 days.
Second dose reduction: 2.3 mg PO on days 1, 8, and 15 repeated every 28 days; permanently discontinue therapy in patients unable to tolerate therapy at this dose level.
-Thrombocytopenia
First platelet count decline to less than 30,000 cells/mm3: hold ixazomib and lenalidomide until the platelet count is 30,000 cells/mm3 or greater; resume ixazomib at the original dose and resume lenalidomide at a reduced dose.
Second platelet count decline to less than 30,000 cells/mm3: hold ixazomib and lenalidomide until the platelet count is 30,000 cells/mm3 or greater; resume ixazomib at a reduced dose (from 4 mg to 3 mg or from 3 mg to 2.3 mg) and resume lenalidomide at the previous dose.
Subsequent platelet count declines to less than 30,000 cells/mm3: hold ixazomib and lenalidomide until the platelet count is 30,000 cells/mm3 or greater; alternate dose modifications for ixazomib and lenalidomide.
-Neutropenia
First absolute neutrophil count (ANC) decline to less than 500 cells/mm3: hold ixazomib and lenalidomide until the ANC is 500 cells/mm3 or greater; resume ixazomib at the original dose and resume lenalidomide at a reduced dose.
Second ANC decline to less than 500 cells/mm3: hold ixazomib and lenalidomide until the ANC is 500 cells/mm3 or greater; resume ixazomib at a reduced dose (from 4 mg to 3 mg or from 3 mg to 2.3 mg) and resume lenalidomide at the previous dose.
Subsequent ANC decline to less than 500 cells/mm3: hold ixazomib and lenalidomide until the ANC is 500 cells/mm3 or greater; alternate dose modification for ixazomib and lenalidomide.
-Rash
First occurrence of grade 2 or 3 rash: hold lenalidomide until the toxicity recovers to grade 1 or less; resume lenalidomide at a reduced dose.
Second occurrence of grade 2 or 3 rash: hold ixazomib and lenalidomide until the toxicity recovers to grade 1 or less; resume ixazomib at a reduced dose (from 4 mg to 3 mg or from 3 mg to 2.3 mg) and resume lenalidomide at the previous dose.
Subsequent occurrences of grade 2 or 3 rash: hold ixazomib and lenalidomide until the toxicity recovers to grade 1 or less; alternate dose modification for ixazomib and lenalidomide.
Grade 4 rash: Discontinue treatment regimen.
-Peripheral Neuropathy
Grade 1 peripheral neuropathy with pain or grade 2 peripheral neuropathy: hold ixazomib until the toxicity recovers to baseline or grade 1 or less; resume ixazomib at the original dose.
Grade 2 peripheral neuropathy with pain or grade 3 peripheral neuropathy: hold ixazomib until the toxicity recovers to baseline or grade 1 or less (physician's discretion); resume ixazomib at a reduced dose.
Grade 4 peripheral neuropathy: Discontinue treatment regimen.
-Other Non-Hematologic Toxicity
Grade 3 and 4 toxicity: hold ixazomib until the toxicity recovers to baseline or grade 1 or less (physician's discretion); resume ixazomib at a reduced dose.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
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).
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Encorafenib: (Major) Avoid the concurrent use of ixazomib and encorafenib; ixazomib exposure may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concurrent use of another strong CYP3A inducer decreased overall ixazomib exposure by 74%.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
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.
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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
Following a 4-mg dose of ixazomib, the dose-normalized mean AUC value was 20% higher in 13 patients with moderate hepatic impairment (defined as total bilirubin level greater than 1.5 to 3 times the upper limit of normal (ULN)) and 18 patients with severe hepatic impairment (defined as total bilirubin level greater than 3 times the ULN) compared with 12 patients who had normal hepatic function. In a population pharmacokinetic (PK) analysis, the PK parameters were similar in patients with mild hepatic impairment (defined as an AST level greater than the ULN or a total bilirubin level of 1 to 1.5 times the ULN and any AST level) and patients with normal hepatic function.
Renal Impairment
Following a 3-mg dose of ixazomib, the mean AUC value was 39% higher in 14 patients with severe renal impairment (defined as a creatinine clearance (CrCl) of less than 30 mL/min) and 6 patients with end-stage renal disease (ESRD) requiring dialysis compared with 18 patients who had normal renal function (defined as a CrCl of 90 mL/min or greater). In a population pharmacokinetic (PK) analysis, the PK parameters were similar in patients with mild and moderate renal impairment (defined as 30 to 89 mL/min) and patients with normal renal function. Ixazomib levels measured pre- and post- dialysis were similar in patients with ESRD; ixazomib is not dialyzable.
Geriatric
Age (range, 23 to 91 years) did not clinically affect the clearance of ixazomib in a population pharmacokinetic analysis.
Gender Differences
Gender did not clinically affect the clearance of ixazomib in a population pharmacokinetic analysis.
Ethnic Differences
Race did not clinically affect the clearance of ixazomib in a population pharmacokinetic analysis.
Obesity
Body surface area (range 1.2 to 2.7 m2) did not clinically affect the clearance of ixazomib in a population pharmacokinetic analysis.