Ixazomib, an inhibitor of the 20S proteasome, is an antineoplastic agent.1, 2, 5, 6, 7, 8, 9
Ixazomib is used in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received at least one prior therapy.1 Ixazomib is designated an orphan drug by FDA for this use.10 Ixazomib is not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma patients in combination with lenalidomide and dexamethasone outside of controlled clinical trials.1
The current indication for ixazomib in combination with lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma who have received at least one prior therapy is based principally on the results of a randomized, double-blind, placebo-controlled study in 722 patients (age range: 30-91 years, median age 66 years).1, 11 Patients refractory to lenalidomide or proteasome inhibitors were not included in the study.1
In this study, patients were randomized in a 1:1 ratio to receive either the combination of ixazomib, lenalidomide, and dexamethasone or the combination of placebo, lenalidomide, and dexamethasone until disease progression or unacceptable toxicity occurred.1, 11 Randomization was stratified based on the number of previous lines of therapy (1 versus 2 or 3), myeloma International Staging System (stage I or II versus III), and prior therapy with a proteasome inhibitor (exposed or naive).1, 11 Most patients in the study were Caucasian (85%), had relapsed multiple myeloma (77%), were in stage I or II of multiple myeloma (88%), and had received one prior line of therapy (61%).1, 11 Light chain disease was reported in 23% of patients, while 12% of patients had free light chain-measurable only disease.1 Patients received oral ixazomib 4 mg or placebo on days 1, 8, and 15 plus oral lenalidomide 25 mg on days 1 through 21; all patients also received oral dexamethasone 40 mg on days 1, 8, 15, and 22 of each 28-day cycle.1, 3, 11 Patients with renal impairment received an initial dose of lenalidomide according to the manufacturer's labeling for the drug.1 Thromboprophylaxis also was recommended for all patients in both treatment groups according to the manufacturer's labeling for lenalidomide.1 At the clinician's discretion, antiemetics were administered in 19 or 12% of patients assigned to the ixazomib or placebo regimen, respectively; antivirals in 64 or 60%, respectively; and antihistamines in 27 or 19%, respectively, for prophylaxis and/or management of symptoms.1 The primary end point of the study was progression-free survival defined as the time from randomization to time of first documentation of disease progression,2, 3, 11 according to the 2011 International Myeloma Working Group Consensus Uniform Response Criteria as assessed by a blinded independent review committee based on central laboratory results.1, 11 Response was assessed every 4 weeks until disease progression occurred.1
Improvement in progression-free survival was demonstrated in patients receiving the ixazomib regimen compared with those receiving the placebo regimen.1, 11 Progressive disease or death was reported in 36% of patients randomly assigned to the ixazomib treatment group compared with 43% of those assigned to the placebo group.1, 2, 11 Median times to response were 1.1 months in the ixazomib treatment group and 1.9 months in the placebo group, and median duration of response was 20.5 or 15 months for the ixazomib or placebo groups, respectively, in the evaluable population.1, 11 Furthermore, the overall response rates were 78 and 72% in patients receiving the ixazomib and placebo regimens, respectively.1, 11 A non-inferential progression-free survival analysis was conducted at a median follow-up of 23 months with 372 progression-free survival events; the hazard ratio of progression-free survival was 0.82 for patients receiving the ixazomib regimen compared with the placebo regimen.1 Estimated median progression-free survival was 20 months in patients receiving the ixazomib regimen and 15.9 months in those receiving the placebo regimen.1 At the final overall survival analysis with a median follow-up of 85 months, median overall survival was not significantly different between the treatment regimens: 53.6 months in the ixazomib group and 51.6 months in the placebo group.1, 12
Clinical studies have shown an increase in mortality in patients treated with ixazomib in the maintenance setting.1 In a study of newly diagnosed multiple myeloma patients who underwent autologous stem cell transplantation and continued on maintenance therapy for 24 months, there were 27% (105/395) deaths in patients receiving ixazomib compared with 26% (69/261) in those receiving placebo.1 Another study evaluated continued maintenance therapy with ixazomib for 24 months in newly diagnosed multiple myeloma patients not treated with stem cell transplant who achieved a partial response or better.1 There were 30% (127/425) deaths in patients receiving ixazomib compared with 27% (76/281) in patients receiving placebo.1 Ixazomib is not recommended for use as maintenance therapy for multiple myeloma outside of controlled clinical trials.1
Results of a prospective randomized trial showed lack of efficacy of ixazomib in patients with newly diagnosed multiple myeloma.1 In this study, improvement in progression-free survival did not meet the prespecified primary endpoint.1 There were 136 (39%) deaths in patients receiving ixazomib, lenalidomide, and dexamethasone compared to 148 (42%) deaths in patients receiving lenalidomide and dexamethasone only.1 Ixazomib is not recommended for use in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma outside of controlled clinical trials.1
Clinical practice guidelines for the management of relapsed/refractory multiple myeloma have been published.13 There are a variety of treatment options available for patients with relapsed/refractory disease and choice of therapy for an individual patient is dependent upon various factors including prior treatments and duration of response.13 In general, therapeutic options for previously treated multiple myeloma include systemic therapy, autologous hematopoietic cell transplantation (for eligible patients), or enrollment in a clinical trial.13 The combination of ixazomib/lenalidomide/dexamethasone is recommended as a preferred regimen option for patients with previously treated multiple myeloma after 1 to 3 prior therapies.13
Dispensing and Administration Precautions
Ixazomib is administered once weekly on the same day and at approximately the same time for the first 3 weeks of each 4-week cycle.1
Ixazomib is administered orally at least 1 hour before or at least 2 hours after food.1
Ixazomib and dexamethasone should not be administered simultaneously on days that patients receive both medications, because dexamethasone is given with food, while ixazomib is given on an empty stomach.1
Ixazomib capsules should be swallowed whole with water and should not be crushed, chewed, or opened.1
If vomiting occurs after a dose of ixazomib is administered, the dose should not be repeated.1 Instead, the next dose should be administered at the regularly scheduled time.1
If a dose of ixazomib is delayed or missed, the dose should be administered only if there are at least 72 hours until the next scheduled dose.1 A missed dose should not be administered within 72 hours of the next scheduled dose, and the dose should not be doubled to make up for the missed dose.1
Clinicians should instruct patients to take ixazomib exactly as prescribed and discuss all dosage instructions with the patient prior to initiation of therapy.1 Overdosage of ixazomib has resulted in fatality.1
Dosage of ixazomib citrate is expressed in terms of ixazomib.1
When ixazomib is used in combination with lenalidomide and dexamethasone in the treatment of multiple myeloma in patients who have received at least one prior therapy, the recommended initial dosages of each drug in each 28-day cycle are ixazomib 4 mg administered orally once weekly on days 1, 8, and 15; lenalidomide 25 mg administered orally once daily on days 1-21; and dexamethasone 40 mg administered orally on days 1, 8, 15, and 22.1, 3 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
Management of some adverse effects may require temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of ixazomib therapy.1 Up to 2 dosage reductions for toxicity may be made.1 If dosage modification from the recommended dosage of 4 mg once weekly is necessary, an initial dosage reduction to 3 mg once weekly is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 2.3 mg once weekly.1 Dosages less than 2.3 mg once weekly are not recommended.1
Dosage Modification for Hematologic Toxicity
If ANC is less than 500/mm3, ixazomib and lenalidomide should be withheld until ANC is at least 500/mm3.1 The addition of granulocyte colony-stimulating factors (G-CSF) also should be considered based on clinical guidelines.1 When ANC returns to at least 500/mm3, lenalidomide should be reduced by 1 dose level according to the manufacturer's labeling, and ixazomib should be resumed at the previous dosage (i.e., 4, 3, or 2.3 mg).1 If ANC less than 500/mm3 recurs, ixazomib and lenalidomide should be withheld until ANC is at least 500/mm3; the ixazomib dose should then be reduced by 1 dose level (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg), and lenalidomide should be resumed at the previous dosage following resolution of toxicity.1 For additional occurrences of neutropenia, dosage modifications of ixazomib and lenalidomide should be alternated.1 Following a second dosage reduction of ixazomib, the treatment regimen should be discontinued if ANC below 500/mm3 recurs.1
If the platelet count is less than 30,000/mm3, ixazomib and lenalidomide should be withheld until platelet count is at least 30,000/mm3.1 When the platelet count returns to at least 30,000/mm3, ixazomib may be continued at the previous dosage (i.e., 4, 3, or 2.3 mg), and lenalidomide should be reduced by 1 dose level according to the manufacturer's labeling.1 If platelet count less than 30,000/mm3 recurs, ixazomib and lenalidomide should be withheld until platelet count is at least 30,000/mm3.1 Following return of platelet count to at least 30,000/mm3, ixazomib should be resumed at 1 dose level lower than the previous dosage (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg), and lenalidomide should be resumed at the previous dosage.1 For additional occurrences of thrombocytopenia, dosage modifications of ixazomib and lenalidomide should be alternated.1 Following a second dosage reduction of ixazomib, the treatment regimen should be discontinued if platelet count below 30,000/mm3 recurs.1
Dosage Modification for Peripheral Neuropathy
If grade 1 peripheral neuropathy with pain or grade 2 peripheral neuropathy occurs, ixazomib should be withheld until peripheral neuropathy resolves to grade 1 or less without pain or returns to baseline.1 Following resolution, ixazomib should be resumed at the previous dosage.1 The treatment regimen should be discontinued if grade 1 with pain or grade 2 peripheral neuropathy occurs following a second dosage reduction of ixazomib.1
If grade 2 peripheral neuropathy with pain or grade 3 peripheral neuropathy occurs, ixazomib should be withheld and, at the clinician's discretion, generally should resolve to grade 1 or less or to baseline prior to resuming ixazomib.1 Following resolution, ixazomib should be resumed at 1 dose level lower than the previous dose (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg).1 The treatment regimen should be discontinued if grade 2 peripheral neuropathy with pain or grade 3 peripheral neuropathy occurs following a second dosage reduction of ixazomib.1
If any grade 4 peripheral neuropathy occurs, the treatment regimen should be discontinued.1
Dosage Modification for Dermatologic Toxicity
If grade 2 or 3 rash occurs, lenalidomide should be withheld until rash resolves to grade 1 or less.1 Following resolution, lenalidomide should be resumed at 1 dose level lower than the previous dosage according to the manufacturer's labeling.1 If grade 2 or 3 rash recurs, ixazomib and lenalidomide should be withheld until rash resolves to grade 1 or less.1 Following resolution, ixazomib should be resumed at 1 dose level lower than the previous dosage (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg), and lenalidomide should be resumed at the previous dosage.1 For additional occurrences of rash, dosage modifications of ixazomib and lenalidomide should be alternated.1 The treatment regimen should be discontinued if grade 2 or 3 rash occurs following a second dosage reduction of ixazomib.1
If any grade 4 rash occurs, the treatment regimen should be discontinued.1
Dosage Modification for Other Nonhematologic Toxicity
If other grade 3 or 4 nonhematologic toxicity occurs, ixazomib should be withheld and, at the clinician's discretion, generally should resolve to patient's condition at baseline or to grade 1 or less prior to resuming ixazomib.1 If the nonhematologic toxicity is attributable to ixazomib, then ixazomib should be resumed at 1 dose level lower than the previous dose (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg) following resolution of toxicity.1 The treatment regimen should be discontinued if grade 3 or 4 nonhematologic toxicity occurs following a second dosage reduction of ixazomib.1
The initial dosage of ixazomib should be reduced to 3 mg once weekly in patients with moderate (total bilirubin exceeding 1.5 to 3 times the upper limit of normal [ULN]) or severe (total bilirubin exceeding 3 times the ULN) hepatic impairment.1
The initial dosage of ixazomib should be reduced to 3 mg once weekly in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) or in those with end-stage renal disease (ESRD) requiring dialysis.1 Ixazomib is not dialyzable; therefore, the drug can be administered without regard to the timing of dialysis.1
Manufacturer makes no special dosage recommendations.1
Thrombocytopenia has been reported frequently in patients receiving ixazomib with platelet nadirs usually occurring on days 14-21 of each 28-day cycle and resolving to baseline by the beginning of the next cycle.1 Grade 3 or grade 4 thrombocytopenia was reported during treatment in 17% or 13% of patients receiving the ixazomib or placebo regimen, respectively.1 Platelet transfusions were required in 10 or 7% of patients receiving the ixazomib or placebo regimen, respectively.1 Platelet counts should be monitored at least monthly in patients receiving ixazomib.1 However, more frequent monitoring should be considered during the first 3 treatment cycles.1 Thrombocytopenia should be managed with dosage modifications and platelet transfusions according to the standard of care.1
Diarrhea was reported in 52 or 43% of patients receiving the ixazomib or placebo regimen, respectively; constipation in 35 or 28%, respectively; nausea in 32 or 23%, respectively; and vomiting in 26 or 13%, respectively.1 Use of antidiarrheal or antiemetic drugs and/or supportive care was required occasionally.1 In the principal efficacy study, 3% of patients receiving the ixazomib regimen discontinued 1 or more of the 3 drugs as a result of diarrhea, compared with 2% of patients in the placebo group.1 Dosage modifications should be made for patients who experience grade 3 or 4 adverse GI effects.1
Peripheral neuropathy has been reported in patients receiving ixazomib.1 Most cases were grade 1 (18 or 16% of patients receiving the ixazomib or placebo regimen, respectively) or grade 2 (11 or 6% of patients receiving the ixazomib or placebo regimen, respectively).1 Grade 3 peripheral neuropathy was reported in 2% of patients receiving either treatment regimen; no cases of grade 4 or serious peripheral neuropathy were reported.1 Peripheral sensory neuropathy was reported in 24 or 17% of patients receiving the ixazomib or placebo regimen, respectively; peripheral motor neuropathy was not commonly reported in those receiving either treatment regimen. 1 Peripheral neuropathy resulted in discontinuance of 1 or more of the 3 drugs in 4% of patients receiving the ixazomib regimen and <1% in patients receiving the placebo regimen.1 Patients should be monitored for symptoms of peripheral neuropathy, and dosage modifications may be required in those experiencing new or worsening symptoms.1
Peripheral edema was reported in 27 or 21% of patients receiving the ixazomib or placebo regimen, respectively.1 Most cases were grade 1 (17% of patients receiving the ixazomib treatment regimen compared with 14% of patients receiving the placebo regimen) or grade 2 (7% of patients receiving the ixazomib treatment regimen compared with 6% of patients receiving the placebo regimen).1 Grade 3 peripheral edema was also reported in 2 or 1% of patients receiving the ixazomib or placebo regimen, respectively.1 Less than 1% of patients required discontinuance of 1 or more of the 3 drugs in either treatment regimen because of peripheral edema.1 If peripheral edema occurs, patients should be assessed for underlying causes and supportive care should be provided, as warranted.1 Dosing of dexamethasone should be modified based on the manufacturer's labeling for the drug; dosage of ixazomib should be adjusted for grade 3 or 4 symptoms.1
Rash was reported in 27 or 16% of patients receiving the ixazomib or placebo regimen, respectively.1 Most adverse dermatologic reactions were grade 1 (15% in the ixazomib treatment group compared with 9% in the placebo group) or grade 2 (9% in the ixazomib treatment group compared with 4% in the placebo group).1 Grade 3 rash was reported in 3% of patients receiving the ixazomib regimen and 2% of patients receiving the placebo regimen.1 Grade 4 or serious rash were reported in <1% of patients receiving the ixazomib regimen.1 The most common types of rash reported in patients receiving either regimen included maculopapular and macular rash.1 Rash resulted in discontinuance of 1 or more of the 3 drugs in <1% of patients receiving either treatment regimen.1 Rash should be managed with supportive care or with dosage modification if grade 2 or higher.1
Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatalities, have been reported in patients receiving ixazomib.1 If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue ixazomib and manage as clinically indicated.1
Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura/hemolytic uremic syndrome), sometimes fatal, have been reported in patients who receiving ixazomib.1
Monitor for signs and symptoms of thrombotic thrombocytopenic purpura or hemolytic uremic syndrome.1 If manifestations suggestive of thrombotic thrombocytopenic purpura or hemolytic uremic syndrome occur, therapy with ixazomib should be temporarily interrupted and the possibility of other etiologies should be excluded.1 If the diagnosis of thrombotic thrombocytopenic purpura or hemolytic uremic syndrome is excluded, consider restarting ixazomib.1 The safety of reinitiating ixazomib therapy in patients previously experiencing thrombotic thrombocytopenic purpura or hemolytic uremic syndrome is not known.1
Hepatotoxicity, including drug-induced hepatic injury, hepatocellular injury, hepatic steatosis, cholestatic hepatitis, and hepatotoxicity, has been reported in less than 1% of patients receiving ixazomib.1 Hepatic impairment also has been reported (10% in the ixazomib group compared with 9% in the placebo group).1 Hepatic enzymes should be monitored regularly, and dosage modifications should be made in patients experiencing grade 3 or 4 symptoms.1
Fetal/Neonatal Morbidity and Mortality
Ixazomib can cause fetal harm based on its mechanism of action and animal findings.1 There are no adequate and well-controlled studies in pregnant women.1 Ixazomib caused embryofetal toxicity (e.g., skeletal variations/abnormalities, decreased fetal weight, trend toward decreased fetal viability, increased postimplantation loss) in pregnant rats and rabbits receiving the drug at dosages resulting in exposures slightly higher than those observed in patients receiving the recommended dosage.1 Verify pregnancy status in females of reproductive potential prior to initiating therapy.1 Females of reproductive potential should be advised to avoid becoming pregnant while receiving ixazomib.1 If ixazomib is used during pregnancy, or if the patient becomes pregnant while receiving ixazomib, the patient should be apprised of the potential hazard to the fetus.1 Females of reproductive potential must use effective nonhormonal methods of contraception during ixazomib treatment and for 90 days following the last dose of the drug.1 Dexamethasone is a weak to moderate inducer of CYP3A4 and other enzymes and transporters.1 Because ixazomib is administered with dexamethasone, and dexamethasone can interact with and reduce concentrations of hormonal contraceptives, consider the possibility of reduced contraceptive efficacy.1 Males who are partners of females of reproductive potential must use effective methods of contraception during ixazomib treatment and for 90 days following the last dose of the drug.1
Increased Mortality in Patients Treated with Ixazomib in the Maintenance Setting
In two prospective randomized clinical trials in patients with multiple myeloma, maintenance treatment with ixazomib resulted in increased deaths.1 Treatment of patients with ixazomib for multiple myeloma in the maintenance setting is not recommended outside of controlled trials.1
Based on its mechanism of action and animal findings, ixazomib can cause fetal harm if administered to pregnant women.1
Verify pregnancy status in females of reproductive potential prior to initiating therapy.1
It is not known whether ixazomib or its metabolites are distributed into human milk.1 The effects of the drug on breast-fed infants or on the production of milk are unknown.1 Because of the potential for adverse reactions to ixazomib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 90 days after the last dose.1
Females and Males of Reproductive Potential
Ixazomib may cause fetal harm; verify pregnancy status in females of reproductive potential prior to initiating therapy.1 Females of reproductive potential should use effective non-hormonal contraception during therapy and for 90 days after the last dose.1 Males with female partners of reproductive potential should use effective contraception during therapy and for 90 days after the last dose.1
Safety and efficacy of ixazomib have not been established in pediatric patients.1
Of the total number of patients in clinical studies evaluating ixazomib, 55% were 65 years of age or older and 17% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric patients and younger adults, and other clinical experience has not demonstrated differences in responses between the geriatric and younger patients.1 However, greater sensitivity of some older patients cannot be ruled out.1
The pharmacokinetics of ixazomib were similar in patients with normal hepatic function and in those with mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] and aspartate aminotransferase (AST) concentrations exceeding the ULN, or total bilirubin exceeding 1 to 1.5 times the ULN and any AST concentration) based on a population pharmacokinetic analysis.1 The pharmacokinetics of ixazomib were characterized in patients with normal hepatic function receiving 4 mg, in those with moderate hepatic impairment (total bilirubin exceeding 1.5 to 3 times the ULN) receiving 2.3 mg, and in those with severe hepatic impairment (total bilirubin exceeding 3 times the ULN) receiving 1.5 mg.1 Dose-normalized mean area under the concentration-time curve (AUC) increased by 20% in those with moderate or severe hepatic impairment compared with patients with normal hepatic function.1 In patients with moderate or severe hepatic impairment, the initial dosage of ixazomib should be reduced.1
The pharmacokinetics of ixazomib were similar in patients with normal renal function and in those with mild (creatinine clearance 60-89 mL/minute) or moderate (creatinine clearance 30-59 mL/minute) renal impairment based on a population pharmacokinetic analysis.1 Pre- and post-dialyzer concentrations of ixazomib measured during hemodialysis were also similar, suggesting that ixazomib is not dialyzable.1 The pharmacokinetics of ixazomib were characterized at a dose of 3 mg in patients with normal renal function (creatinine clearance 90 mL/minute or greater), severe renal impairment (creatinine clearance less than 30 mL/minute), or end-stage renal disease (ESRD) requiring dialysis.1 Mean AUC was increased by 39% in patients with severe renal impairment or ESRD requiring dialysis compared with those with normal renal function.1 The initial dosage of ixazomib should be reduced in patients with severe renal impairment or ESRD requiring dialysis.1
Adverse effects reported in 20% or more of patients receiving ixazomib in clinical studies include thrombocytopenia, neutropenia, rash, bronchitis, vomiting, peripheral edema, nausea, peripheral neuropathy, constipation, and diarrhea.1
Ixazomib is a low-affinity substrate of P-glycoprotein (P-gp); the drug is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, or hepatic organic anion transport protein (OATP).1
Ixazomib is not a reversible or time-dependent inhibitor of cytochrome (CYP) P-450 isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.1 Ixazomib also is not an inhibitor of P-gp, BCRP, MRP2, OATP 1B1 or 1B3, organic cation transporter (OCT) 2, organic anion transporter (OAT) 1 or 3, or multidrug and toxin extrusion (MATE) 1 or MATE2K transporters.1
Ixazomib does not induce CYP isoenzymes 1A2, 2B6, or 3A4/5 or corresponding immunoreactive protein concentrations and is not expected to produce pharmacokinetic interactions via CYP inhibition or induction.1 Additionally, ixazomib is not expected to cause transporter-mediated pharmacokinetic interactions.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
Concomitant administration of ixazomib with potent CYP1A2 inhibitors did not result in a clinically important change in the systemic exposure of ixazomib based on a population pharmacokinetic analysis.1
Concomitant use of ixazomib and potent CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John's wort) can potentially decrease the systemic exposure of ixazomib.4 Concomitant use of ixazomib and potent CYP3A inducers should be avoided.1
Concomitant administration of ixazomib with carbamazepine, a potent CYP3A inducer, can potentially decrease the systemic exposure of ixazomib.4 Concomitant use of ixazomib and carbamazepine should be avoided.1
Concomitant administration of ixazomib and clarithromycin, a potent CYP3A inhibitor, did not result in a clinically important change in the systemic exposure of ixazomib.1
Concomitant administration of ixazomib with phenytoin, a potent CYP3A inducer, can potentially decrease the systemic exposure of ixazomib.4 Concomitant use of ixazomib and phenytoin should be avoided.1
Concomitant administration of ixazomib with rifampin, a potent CYP3A inducer, decreased the peak plasma concentration and area under the concentration-time curve (AUC) of ixazomib by 54 and 74%, respectively.1 Concomitant use of ixazomib and rifampin should be avoided.1
Concomitant administration of ixazomib with St. John's wort ( Hypericum perforatum ), a potent CYP3A inducer, can potentially decrease the systemic exposure of ixazomib.4 Concomitant use of ixazomib and St. John's wort should be avoided.1
Ixazomib citrate is a prodrug of ixazomib, a boron-containing selective inhibitor of the 20S proteasome; ixazomib is an antineoplastic agent.1, 2, 5, 6, 7, 8, 9 Ixazomib citrate is rapidly hydrolyzed to its active form (ixazomib).1 Ixazomib reversibly binds the β5 subunit of the 20S proteasome and inhibits its chymotrypsin-like activity.1, 2 In vitro, ixazomib induces caspase-mediated apoptosis9 of multiple myeloma cell lines and has demonstrated cytotoxicity against myeloma cells obtained from patients who had relapsed following previous therapies, including bortezomib, lenalidomide, and dexamethasone.1, 5 Concomitant use of ixazomib and lenalidomide has demonstrated synergistic cytotoxic effects in multiple myeloma cell lines, and ixazomib has demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model in vivo.1, 6
Mean absolute oral bioavailability of ixazomib is 58% based on a population pharmacokinetic analysis.1 Following oral administration, the median time to peak plasma concentration is 1 hour.1 The terminal half-life of ixazomib is 9.5 days.1 Systemic exposure of the drug increases in a dose-proportional manner over a dosage range of 0.2-10.6 mg, and following weekly oral dosing, the accumulation is twofold.1 A high-fat meal decreases the area under the concentration-time curve (AUC) and peak plasma concentration of ixazomib by 28 and 69%, respectively.1 Metabolism by multiple cytochrome P-450 (CYP) isoenzymes and through non-CYP-dependent pathways is expected to be the primary clearance mechanism of ixazomib.1 Age, gender, body surface area, or race do not demonstrate a clinically important effect on the clearance of ixazomib based on a population pharmacokinetic analysis.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 2.3 mg (of ixazomib) | Ninlaro® (available as carton, 3 count blister pack, and 1 count blister pack) | |
3 mg (of ixazomib) | Ninlaro® (available as carton, 3 count blister pack, and 1 count blister pack) | Takeda | ||
4 mg (of ixazomib) | Ninlaro® (available as carton, 3 count blister pack, and 1 count blister pack) | Takeda |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions November 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Takeda Pharmaceutical Company Limited. Ninlaro® (ixazomib) capsules prescribing information. Lexington, MA; 2024 Jul.
2. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number208462Orig1s000: Medical Review. From FDA website. [Web]
3. A phase 3 study comparing oral ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in adult patients with relapsed and/or refractory multiple myeloma. From ClinicalTrials.gov Registry. [Web]
4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number208462Orig1s000: Clinical Pharmacology and Biopharmaceutics Review(s). From FDA website. [Web]
5. Chauhan D, Tian Z, Zhou B et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res . 2011; 17:5311-21. [PubMed 21724551]
6. Kumar SK, Bensinger WI, Zimmerman TM et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood . 2014; 124:1047-55. [PubMed 24904120]
7. Moreau P. Oral therapy for multiple myeloma: ixazomib arriving soon. Blood . 2014; 124:986-7. [PubMed 25124778]
8. Muz B, Ghazarian RN, Ou M et al. Spotlight on ixazomib: potential in the treatment of multiple myeloma. Drug Des Devel Ther . 2016; 10:217-26. [PubMed 26811670]
9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number208462Orig1s000: Pharmacology Review(s). From FDA website. [Web]
10. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
11. Moreau P, Masszi T, Grzasko N, et al for the TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med . 2016;374:1621-1634.
12. Richardson PG, Kumar SK, Masszi T, et al. Final overall survival analysis of the TOURMALINE-MM1 phase III trial of ixazomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol . 2021;39:2430-2442.
13. Kumar SK, Callander NS, Adekola K, et al. Multiple myeloma, version 2.2024. J Natl Compr Canc Netw. 2023;21(12):1281-1301.