Pronunciation
(ix AZ oh mib)
Index TermsIxazomib CitrateMLN9708Proteasome Inhibitor MLN9708Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Ninlaro: 2.3 mg, 3 mg, 4 mg
Brand Names: U.S.NinlaroPharmacologic CategoryAntineoplastic Agent, Proteasome InhibitorPharmacology
Ixazomib reversibly inhibits proteasomes, enzyme complexes which regulate protein homeostasis within the cell. Specifically, it reversibly inhibits chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome, leading to activation of signaling cascades, cell-cycle arrest, and apoptosis.
Absorption
High-fat meals decreased AUC by 28% and Cmax by 69%.
Distribution
543 L
Metabolism
Likely hepatic via multiple CYP enzymes and non-CYP proteins. At clinically relevant concentrations, no specific CYP isoform contributes predominantly to metabolism; possible CYP isoforms involved in metabolism include CYP3A4, 1A2, 2B6, 2C8, 2D6, 2C19, and 2C9.
Excretion
Urine (62%; <3.5% as unchanged drug); Feces (22%)
Time to Peak
Median: 1 hour
Half-Life Elimination
Terminal: 9.5 days
Protein Binding
99% to plasma proteins
Special Populations: Renal Function Impairment
Pharmacokinetics of ixazomib (at a dose of 3 mg) were evaluated in patients with normal renal function (CrCl ≥90 mL/minute), severe impairment (CrCl <30 mL/minute) or ESRD requiring dialysis. The mean AUC was 39% higher in patients with severe renal impairment and in ESRD requiring dialysis (as compared with patients with normal renal function).
Special Populations: Hepatic Function Impairment
Pharmacokinetics of ixazomib were evaluated in patients with normal hepatic function (at a dose of 4 mg), moderate impairment (total bilirubin >1.5 to 3 times ULN) at a dose of 2.3 mg, or severe impairment (total bilirubin <3 times ULN) at a dose of 1.5 mg. Dose-normalized mean AUC was 20% higher in patients with moderate or severe hepatic impairment, as compared to patients with normal hepatic function.
Use: Labeled Indications
Multiple myeloma: Treatment of multiple myeloma (in combination with lenalidomide and dexamethasone) in patients who have received at least one prior therapy
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Dosing: Adult
Note: ANC should be ≥1,000/mm3, platelets should be ≥75,000/mm3, and nonhematologic toxicities should be at baseline or ≤ grade 1 (per prescriber discretion) prior to initiating a new cycle of therapy. Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation.
Multiple myeloma: Oral: 4 mg once weekly on days 1, 8, and 15 of a 28-day treatment cycle (in combination with lenalidomide and dexamethasone); continue until disease progression or unacceptable toxicity (Moreau 2016).
Missed doses: If a dose is delayed or missed, administer only if the next scheduled dose is ≥72 hours away. Do not take a missed dose within 3 days of the next scheduled dose; do not double up on doses to make up for the missed dose. If vomiting occurs, do not repeat the dose; resume dosing at the next scheduled dose.
Dosing: Renal Impairment
The International Myeloma Working Group (IMWG) recommends the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine (Dimopoulos 2016).
Preexisting renal impairment:
CrCl ≥30 mL/minute: The IMWG suggest that ixazomib (in combination with lenalidomide and dexamethasone) may be safely administered to patients with a CrCl ≥30 mL/minute (Dimopoulos 2016).
CrCl <30 mL/minute: Reduce initial dose to 3 mg once weekly on days 1, 8, and 15 of a 28-day treatment cycle
ESRD requiring dialysis: Reduce initial dose to 3 mg once weekly on days 1, 8, and 15 of a 28-day treatment cycle; ixazomib is not dialyzable and may be administered without regarding to dialysis timing.
Renal toxicity during treatment: Grade 3 or 4 toxicity: Withhold ixazomib until recovery to baseline or improvement to ≤ grade 1 (at prescriber's discretion). If attributable to ixazomib, resume ixazomib at the next lower dose.
Dosing: Hepatic Impairment
Preexisting hepatic impairment:
Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment is necessary.
Moderate (total bilirubin >1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) impairment: Reduce initial dose to 3 mg once weekly on days 1, 8, and 15 of a 28-day treatment cycle
Hepatotoxicity during treatment: Grade 3 or 4 toxicity: Withhold ixazomib until recovery to baseline or improvement to ≤grade 1 (at prescriber’s discretion). If attributable to ixazomib, resume ixazomib at the next lower dose.
Dosing: Adjustment for Toxicity
Also refer to Lenalidomide monograph for dosage modification recommendations.
Recommended ixazomib dosage reductions for toxicity:
Initial starting dose: 4 mg
First dose reduction: 3 mg
Second dose reduction: 2.3 mg
If unable to tolerate 2.3 mg, discontinue ixazomib
Hematologic toxicity:
Neutropenia: ANC <500/mm3: Withhold ixazomib and lenalidomide until ANC is ≥500/mm3. Consider adding growth-colony stimulating factor (G-CSF). Upon recovery, resume lenalidomide at the next lower dose and resume ixazomib at the dose used prior to therapy interruption. If neutropenia to ≤500/mm3 recurs, interrupt ixazomib and lenalidomide until ANC is ≥500/mm3. Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at the dose used prior to therapy interruption. For additional occurrences, alternate dose modification of lenalidomide and ixazomib.
Thrombocytopenia: Platelet count <30,000/mm3: Withhold ixazomib and lenalidomide until platelet count is ≥30,000/mm3. Upon recovery, resume lenalidomide at the next lower dose and resume ixazomib at the dose used prior to therapy interruption. If thrombocytopenia to ≤30,000/mm3 recurs, interrupt ixazomib and lenalidomide until platelets are ≥30,000/mm3. Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at the dose used prior to therapy interruption. For additional occurrences, alternate dose modification of lenalidomide and ixazomib.
Nonhematologic toxicity:
Dermatologic toxicity:
Grade 2 or 3 rash: Withhold lenalidomide until rash recovers to ≤ grade 1. Upon recovery, resume lenalidomide at the next lower dose and resume ixazomib at the dose used prior to therapy interruption. If grade 2 or 3 rash recurs, interrupt ixazomib and lenalidomide until rash recovers to ≤ grade 1. Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at the dose used prior to therapy interruption. For additional occurrences, alternate dose modification of lenalidomide and ixazomib.
Grade 4 rash: Discontinue treatment regimen.
Peripheral neuropathy:
Grade 1 (with pain) or grade 2: Interrupt ixazomib until peripheral neuropathy recovers to ≤ grade 1 without pain or to baseline. Upon recovery, resume ixazomib at the dose used prior to therapy interruption.
Grade 2 (with pain) or grade 3: Withhold ixazomib until recovery to baseline or improvement to ≤ grade 1 (at prescriber’s discretion). Following recovery, resume ixazomib at the next lower dose.
Grade 4: Discontinue treatment regimen.
Other toxicities (nonhematologic): Grade 3 or 4 toxicity: Withhold ixazomib until recovery to baseline or improvement to ≤grade 1 (at prescriber’s discretion). If attributable to ixazomib, resume ixazomib at the next lower dose.
Administration
Oral: Administer on the same day of the week and at approximately the same time on that day; take at least 1 hour before or at least 2 hours after eating. Swallow capsule whole; do not crush, chew, or open the capsule. Avoid skin or eye exposure to capsule contents. If skin contact occurs, wash thoroughly with soap and water; if eye contact occurs, flush thoroughly with water.
Storage
Store at ≤30°C (86°F). Do not freeze. Store in original packaging until immediately prior to use.
Drug Interactions
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).Avoid combination
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Ixazomib. Avoid combination
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Estrogen Derivatives (Contraceptive): Ixazomib may decrease the serum concentration of Estrogen Derivatives (Contraceptive). More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of estrogen derivative contraceptives. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following ixazomib treatment. Consider therapy modification
Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification
Progestins (Contraceptive): Ixazomib may decrease the serum concentration of Progestins (Contraceptive). More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of contraceptive progestins. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following ixazomib treatment. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy
St John's Wort: May decrease the serum concentration of Ixazomib. Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy
Adverse Reactions
Adverse reaction percentages reported as part of a combination regimen with lenalidomide and dexamethasone.
>10%
Cardiovascular: Peripheral edema (25%)
Central nervous system: Peripheral neuropathy (28%; grade 3: 2%), peripheral sensory neuropathy (19%)
Dermatologic: Skin rash (19%)
Gastrointestinal: Diarrhea (42%), constipation (34%), nausea (26%), vomiting (22%)
Hematologic & oncologic: Thrombocytopenia (78%; grades 3/4: 26%), neutropenia (67%; grades 3/4: 26%)
Neuromuscular & skeletal: Back pain (21%)
Ophthalmic: Eye disease (26%)
Respiratory: Upper respiratory tract infection (19%)
1% to 10%:
Hepatic: Hepatic insufficiency (6%)
Infection: Herpes zoster (4%; <1% with antiviral prophylaxis)
Ophthalmic: Blurred vision (6%), conjunctivitis (6%), xerophthalmia (5%)
<1% (Limited to important or life-threatening): Cholestatic hepatitis, hepatocellular hepatitis, hepatotoxicity, liver steatosis, peripheral motor neuropathy, reversible posterior leukoencephalopathy syndrome, Stevens-Johnson syndrome, Sweet's syndrome, thrombotic thrombocytopenic purpura, transverse myelitis, tumor lysis syndrome
Warnings/Precautions
Concerns related to adverse effects:
• Bone marrow suppression: Neutropenia and thrombocytopenia were reported commonly in clinical trials; grade 3 and 4 toxicity was also observed. Platelet nadirs generally occurred between days 14 to 21 of each cycle with a recovery to baseline by the start of the subsequent cycle. Monitor platelet counts at least monthly during treatment, and consider more frequent monitoring during the initial 3 cycles. May require therapy interruption, dosage reduction and/or platelet transfusions. Monitor complete blood counts (with differential) for neutropenia; therapy interruption or dosage modification may be necessary.
• Dermatologic toxicity: Rash was reported with ixazomib use; the majority of cases were grade 1 or 2 (grade 3 rash was observed in a small number of patients). Maculopapular and macular rashes were the most commonly reported cutaneous reactions. Monitor for dermatologic toxicity and manage with supportive care or with dosage modification of ixazomib and/or lenalidomide (for grade 2 or higher toxicity).
• Gastrointestinal toxicity: Diarrhea, constipation, nausea, and vomiting have been reported. Antidiarrheals, antiemetics, and supportive care may be required to manage toxicity. Dosage adjustment is recommended for grade 3 or 4 symptoms.
• Hepatotoxicity: Drug-induced livery injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity were reported rarely in clinical trials. Monitor liver enzymes regularly; may require dosage adjustment for grade 3 or 4 toxicity.
• Herpes zoster infection: Herpes zoster infection has been reported; patients receiving antiviral prophylaxis had a lower incidence of infection. Consider antiviral prophylaxis during ixazomib treatment to decrease the risk of herpes zoster reactivation.
• Peripheral edema: Peripheral edema was reported in one-quarter of patients receiving ixazomib (generally grade 1 or 2 reactions). If peripheral edema occurs, evaluate for potential underlying causes and provide supportive care. If necessary, grade 3 or 4 symptoms may require dosage adjustment of dexamethasone and/or ixazomib.
• Peripheral neuropathy: Peripheral neuropathy (mostly grade 1 or 2) was observed. Peripheral sensory neuropathy was the most commonly reported symptom, while peripheral motor neuropathy was rarely seen. Monitor closely for signs/symptoms of neuropathy; may require dosage adjustment (of ixazomib and/or lenalidomide) or treatment discontinuation.
Disease-related concerns:
• Hepatic impairment: Reduced initial doses are recommended for patients with moderate and severe hepatic impairment (exposure is increased).
• Renal impairment: Reduced initial doses are recommended for patients with CrCl less than 30 mL/minute or end stage renal disease requiring dialysis (exposure is increased). Concomitant lenalidomide may also require dose reduction.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Monitoring Parameters
Platelet counts at least monthly during treatment (consider more frequent monitoring during the first 3 cycles), complete blood count (with differential) as clinically necessary, renal and liver function tests; signs/symptoms of gastrointestinal and dermatologic toxicity; signs/symptoms of peripheral neuropathy and peripheral edema.
Pregnancy Considerations
Based on animal data and the mechanism of action, ixazomib is expected to cause fetal harm if used during pregnancy. Males and females of reproductive potential should use effective contraception during therapy and for 90 days after the last dose.
When used for the treatment of multiple myeloma, ixazomib is indicated to be used with lenalidomide and dexamethasone. Lenalidomide is contraindicated for use during pregnancy (refer to lenalidomide monograph for details). Dexamethasone is a weak to moderate CYP3A4 inducer, and may decrease the efficacy of hormonal contraceptives. Women using hormonal contraception should also use a barrier method.
Patient Education
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience diarrhea, constipation, nausea, vomiting, or back pain. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), burning or numbness feeling, weakness, swelling in the arms or legs, weight gain, shingles, skin discoloration, signs of infection, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding; loss of strength and energy; dark urine or jaundice; pale skin; change in amount of urine passed; vision changes; change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance; or fever), signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), vision changes, eye pain, or severe eye irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
