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Ixazomib

Pronunciation

(ix AZ oh mib)

Index Terms

  • Ixazomib Citrate
  • MLN9708
  • Proteasome Inhibitor MLN9708

Dosage 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.

  • Ninlaro

Pharmacologic Category

  • Antineoplastic Agent, Proteasome Inhibitor

Pharmacology

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.

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.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of intact capsules (NIOSH 2014). 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. 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. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ixazomib. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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. 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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Ixazomib. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

Adverse reaction percentages reported as part of a combination regimen with lenalidomide and dexamethasone. Frequency not always defined.

>10%

Cardiovascular: Peripheral edema (25%)

Central nervous system: Peripheral neuropathy (28%; grade 3: 2%), peripheral sensory neuropathy (19%)

Dermatologic: Skin rash (19%; grade 3: 3%)

Gastrointestinal: Diarrhea (42%; grade 3: 6%), constipation (34%; grade 3: <1%), nausea (26%; grade 3: 2%), vomiting (22%; grade 3: 1%)

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%)

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.

• 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 severe renal impairment 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

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, which is contraindicated for use during pregnancy (refer to lenalidomide monograph for details).

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, pharyngitis, rhinitis, 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.

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