Ixazomib Citrate

Antineoplastic agent; inhibitor of 20S proteasome.1 2 5 6 7 8 9

Multiple Myeloma

Used in combination with lenalidomide and dexamethasone for previously treated (≥1 prior therapy) multiple myeloma (designated an orphan drug for this use).1 10

General

• Confirm that ANC is ≥1000/mm3 and platelet count ≥75,000/mm3 before initiating a new cycle of therapy; at clinician's discretion, generally allow nonhematologic toxicity to resolve to baseline or grade 1 or less.1

• Consult manufacturers' labeling for additional information regarding lenalidomide and dexamethasone.1

• If capsule breakage occurs, avoid direct contact of contents with skin or eyes.1 If contact occurs, wash skin thoroughly with soap and water; flush eyes thoroughly with water.1

Administration

Oral Administration

Administer orally once weekly on the same day and at approximately the same time for the first 3 weeks of each 4-week cycle.1

Administer orally at least 1 hour before or at least 2 hours after food.1

Do not administer ixazomib and dexamethasone simultaneously on days when both drugs are scheduled; administer dexamethasone with food and give ixazomib on an empty stomach.1

Swallow capsules whole with water; do not crush, chew, or open.1

If vomiting occurs following administration, do not repeat the dose.1 Resume therapy at time of next scheduled dose.1

If a dose is delayed or missed, administer the dose only if there are at least 72 hours until the next scheduled dose.1 Do not administer a missed dose within 72 hours of the next scheduled dose; do not double the dose to make up for the missed dose.1

Dosage

Available as ixazomib citrate; dosage expressed in terms of ixazomib.1

Adults

Recommended initial dosage in each 28-day cycle: Ixazomib 4 mg once weekly on days 1, 8, and 15 in combination with lenalidomide 25 mg once daily on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22.1 3

Continue treatment until disease progression or unacceptable toxicity occurs.1

Consult manufacturer's labeling for lenalidomide and dexamethasone for additional information.1

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance.1 Up to 2 dosage reductions for toxicity may be made.1

If dosage reduction from 4 mg once weekly is necessary, initially reduce dosage to 3 mg once weekly.1 If further dosage reduction is necessary, reduce dosage to 2.3 mg once weekly.1 Dosages <2.3 mg once weekly not recommended.1

If ANC <500/mm3, withhold ixazomib and lenalidomide until ANC is ≥500/mm3.1 Consider addition of granulocyte colony-stimulating factors based on clinical guidelines.1

When ANC returns to ≥500/mm3, reduce lenalidomide by 1 dose level according to manufacturer's labeling; resume ixazomib at previous dosage.1 If ANC <500/mm3 recurs, withhold ixazomib and lenalidomide until ANC ≥500/mm3; reduce ixazomib 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); resume lenalidomide at previous dosage.1

For additional occurrences of neutropenia, alternate dosage modifications between ixazomib and lenalidomide.1 Following a second dosage reduction of ixazomib, discontinue treatment if ANC <500/mm3 recurs.1

If platelet count <30,000/mm3, withhold ixazomib and lenalidomide until platelet count is ≥30,000/mm3.1

When platelet count returns to ≥30,000/mm3, resume ixazomib at previous dosage; resume lenalidomide at 1 dose level lower than the previous dosage according to manufacturer's labeling.1 If platelet count <30,000/mm3 recurs, withhold ixazomib and lenalidomide until platelet count is ≥30,000/mm3; resume ixazomib 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); resume lenalidomide at previous dosage.1

For additional occurrences of thrombocytopenia, alternate dosage modifications between ixazomib and lenalidomide.1 Following a second dosage reduction of ixazomib, discontinue treatment if platelet count <30,000/mm3 recurs.1

If grade 1 with pain or grade 2 peripheral neuropathy occurs, withhold ixazomib until toxicity resolves to grade 1 or less without pain or to baseline;1 resume ixazomib at the previous dosage.1 Discontinue treatment if grade 1 with pain or grade 2 peripheral neuropathy occurs following a second dosage reduction of ixazomib.1

If grade 2 with pain or grade 3 peripheral neuropathy occurs, withhold ixazomib; generally (at clinician's discretion) allow toxicity to resolve to baseline or grade 1 or less prior to resuming therapy.1 Resume ixazomib 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).1

Discontinue treatment if grade 2 with pain or grade 3 peripheral neuropathy occurs following a second dosage reduction of ixazomib.1

If any grade 4 peripheral neuropathy occurs, discontinue treatment.1

If grade 2 or 3 rash occurs, withhold lenalidomide until rash resolves to grade 1 or less;1 resume lenalidomide at 1 dose level lower than the previous dosage according to manufacturer's labeling.1

If grade 2 or 3 rash recurs, withhold ixazomib and lenalidomide until rash resolves to grade 1 or less;1 resume ixazomib 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); resume lenalidomide at the previous dosage.1

For additional occurrences of rash, alternate dosage modifications between ixazomib and lenalidomide.1 Discontinue treatment if grade 2 or 3 rash occurs following a second dosage reduction of ixazomib.1

Discontinue treatment if any grade 4 rash occurs.1

If other grade 3 or 4 nonhematologic toxicity occurs, withhold ixazomib; generally (at clinician's discretion) allow toxicity to resolve to baseline or grade 1 or less.1 If nonhematologic toxicity is attributable to ixazomib, resume therapy 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).1

Discontinue treatment if grade 3 or 4 nonhematologic toxicity occurs following a second dosage reduction of ixazomib.1

Special Populations

Hepatic Impairment

Reduce initial dosage of ixazomib to 3 mg weekly in patients with moderate (total bilirubin >1.5 to 3 times the ULN) or severe (total bilirubin >3 times the ULN) hepatic impairment.1 Refer to manufacturer's labeling for lenalidomide for specific dosage recommendations.1

Renal Impairment

Reduce initial dosage of ixazomib to 3 mg weekly in patients with severe renal impairment (Clcr <30 mL/minute) or in patients with end-stage renal disease (ESRD) requiring dialysis.1 Ixazomib is not dialyzable; administer without regard to timing of dialysis.1 Refer to manufacturer's labeling for lenalidomide for specific dosage recommendations.1

Geriatric Patients

Manufacturer makes no special dosage recommendations.1 (See Geriatric Use under Cautions.)

Low-affinity substrate of P-glycoprotein (P-gp); not a substrate of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, or hepatic organic anion transport protein (OATP).1

Not a reversible or time-dependent inhibitor of CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.1 Not expected to cause interactions via CYP inhibition.1

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 Not expected to cause transporter-mediated pharmacokinetic interactions.1

Not an inducer of CYP1A2, 2B6, or 3A4/5 or corresponding immunoreactive protein concentrations.1 Not expected to cause interactions via CYP induction.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP1A2 inhibitors: No clinically important change in the systemic exposure of ixazomib.1

Potent CYP3A inducers: Possible decreased systemic exposure of ixazomib.4 Avoid concomitant use.1

Specific Drugs

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.