Introduction

Antineoplastic agent; inhibitor of 20S proteasome.

Uses for Ixazomib Citrate

Multiple Myeloma

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

Ixazomib Citrate Dosage and Administration

General

Pretreatment Screening

• Confirm absolute neutrophil count (ANC) is ≥1000/mm³ and platelet count ≥75,000/mm³ before initiating each cycle of therapy.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor platelet counts at least monthly. Consider more frequent monitoring during the first 3 treatment cycles.

• Monitor patients for symptoms of peripheral neuropathy.

• Monitor for signs and symptoms of thrombotic thrombocytopenic purpura or hemolytic uremic syndrome.

• Monitor hepatic enzymes regularly.

Premedication and Prophylaxis

• Consider antiviral prophylaxis to decrease risk of herpes zoster virus reactivation. In clinical studies, antiviral prophylaxis was associated with reduced incidence of herpes zoster infection.

Dispensing and Administration Precautions

Handling and Disposal

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

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

Other General Considerations

• When used in combination with lenalidomide and dexamethasone, consider cautions, precautions, and contraindications of lenalidomide and dexamethasone.

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.

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

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.

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

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

If a dose is delayed or missed, administer the dose only if there are at least 72 hours until the next scheduled dose. 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.

Instruct patients to take ixazomib exactly as prescribed. Discuss all dosage instructions with the patient prior to initiation of therapy. Overdosage of ixazomib has resulted in fatality.

Dosage

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

Adults

Multiple Myeloma

Oral

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.

Continue treatment until disease progression or unacceptable toxicity occurs.

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

Dosage Modification for Toxicity

Oral

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

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

Neutropenia

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

When ANC returns to ≥500/mm³, reduce lenalidomide by 1 dose level according to manufacturer's labeling; resume ixazomib at previous dosage. 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.

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

Thrombocytopenia

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

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. 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 dose (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 dose.

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

Peripheral Neuropathy

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

If grade 2 peripheral neuropathy 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. 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).

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

If any grade 4 peripheral neuropathy occurs, discontinue treatment.

Dermatologic Toxicity

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

If grade 2 or 3 rash recurs, withhold ixazomib and lenalidomide until rash resolves to grade 1 or less; 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.

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

Discontinue treatment if any grade 4 rash occurs.

Other Nonhematologic Toxicity

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. 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).

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

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. Refer to manufacturer's labeling for lenalidomide for specific dosage recommendations.

Renal Impairment

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

Geriatric Patients

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

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Thrombocytopenia

Thrombocytopenia reported frequently. Platelet nadirs usually occur on days 14–21 of each 28-day cycle and resolve to baseline by beginning of next cycle.

Monitor platelet counts at least monthly. Consider more frequent monitoring during the first 3 treatment cycles. Manage thrombocytopenia with dosage modifications and platelet transfusions according to standard of care. (See Dosage Modification for Toxicity under Dosage and Administration.)

GI Toxicity

GI toxicity reported (e.g., diarrhea, constipation, nausea, vomiting), requiring occasional use of antidiarrheal or antiemetic drugs and/or supportive care. Modify dosage in patients experiencing grade 3 or 4 GI toxicity. (See Dosage Modification for Toxicity under Dosage and Administration.)

Peripheral Neuropathy

Peripheral neuropathy (usually sensory neuropathy and mostly grade 1 or 2) reported.

Monitor patients for symptoms of peripheral neuropathy; dosage modifications may be required in those experiencing new or worsening symptoms. (See Dosage Modification for Toxicity under Dosage and Administration.)

Peripheral Edema

Peripheral edema (mostly grade 1 or 2) reported. Assess for underlying causes and provide supportive care, as needed. Adjust dosage of ixazomib for grade 3 or 4 symptoms, and modify dosing of dexamethasone based on manufacturer's labeling. (See Dosage Modification for Toxicity under Dosage and Administration.)

Dermatologic Reactions

Rash (mostly grade 1 or 2) reported. Maculopapular and macular rash reported most frequently. Manage with supportive care or with dosage modification if grade 2 or greater. (See Dosage Modification for Toxicity under Dosage and Administration.)

Thrombotic Microangiopathy

Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura/hemolytic uremic syndrome), sometimes fatal, reported.

Monitor for signs and symptoms. If manifestations suggestive of these conditions occur, temporarily interrupt ixazomib therapy and exclude possibility of other etiologies. If the diagnosis of thrombotic thrombocytopenic purpura or hemolytic uremic syndrome is excluded, consider restarting ixazomib; safety of reinitiating ixazomib therapy in such patients is unknown.

Hepatotoxicity

Hepatotoxicity reported (e.g., drug-induced hepatic injury, hepatocellular injury, hepatic steatosis, cholestatic hepatitis, hepatotoxicity). Monitor hepatic enzymes regularly; adjust dosage in patients experiencing grade 3 or 4 toxicity. (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity demonstrated in animals.

Avoid pregnancy during therapy. Verify pregnancy status in females of reproductive potential prior to initiating therapy. If used during pregnancy, or patient becomes pregnant, apprise of potential fetal hazard. Females of reproductive potential and males who are partners of such females must use effective nonhormonal contraceptive methods during treatment and for 90 days following discontinuance of the drug. Because ixazomib is administered with dexamethasone, and dexamethasone can potentially interact and reduce concentrations of hormonal contraceptives, consider the possibility of reduced contraceptive efficacy.

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to initiating therapy.

Lactation

Not known whether ixazomib or its metabolites are distributed into human milk or affect milk production or breast-fed infants. Breast-feeding is not recommended during therapy and for 90 days after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In clinical trials, 55% of patients were ≥65 years of age; 17% were ≥75 years of age. No overall differences in safety or efficacy observed between geriatric patients and younger adults; other clinical experience has not demonstrated differences in responses between geriatric and younger patients. However, greater sensitivity of some older patients cannot be ruled out.

Hepatic Impairment

Pharmacokinetics similar in patients with normal hepatic function and in those with mild hepatic impairment (total bilirubin less than or equal to the ULN and AST concentrations greater than the ULN, or total bilirubin >1 to 1.5 times the ULN with any AST concentration). Mean AUC increased substantially in those with moderate or severe hepatic impairment compared with patients with normal hepatic function.

Reduce initial dosage in patients with moderate or severe hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Pharmacokinetics similar in patients with normal renal function and in those with mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment. Mean AUC increased substantially in patients with severe renal impairment or ESRD requiring dialysis compared with those with normal renal function.

Reduce initial dosage in patients with severe renal impairment or ESRD requiring dialysis. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Thrombocytopenia, rash, upper respiratory tract infection, back pain, vomiting, peripheral edema, nausea, peripheral neuropathy, constipation, diarrhea.

General

Pretreatment Screening

• Confirm absolute neutrophil count (ANC) is ≥1000/mm³ and platelet count ≥75,000/mm³ before initiating each cycle of therapy.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor platelet counts at least monthly. Consider more frequent monitoring during the first 3 treatment cycles.

• Monitor patients for symptoms of peripheral neuropathy.

• Monitor for signs and symptoms of thrombotic thrombocytopenic purpura or hemolytic uremic syndrome.

• Monitor hepatic enzymes regularly.

Premedication and Prophylaxis

• Consider antiviral prophylaxis to decrease risk of herpes zoster virus reactivation. In clinical studies, antiviral prophylaxis was associated with reduced incidence of herpes zoster infection.

Dispensing and Administration Precautions

Handling and Disposal

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

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

Other General Considerations

• When used in combination with lenalidomide and dexamethasone, consider cautions, precautions, and contraindications of lenalidomide and dexamethasone.

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.

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

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.

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

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

If a dose is delayed or missed, administer the dose only if there are at least 72 hours until the next scheduled dose. 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.

Instruct patients to take ixazomib exactly as prescribed. Discuss all dosage instructions with the patient prior to initiation of therapy. Overdosage of ixazomib has resulted in fatality.

Dosage

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

Adults

Multiple Myeloma

Oral

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.

Continue treatment until disease progression or unacceptable toxicity occurs.

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

Dosage Modification for Toxicity

Oral

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

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

Neutropenia

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

When ANC returns to ≥500/mm³, reduce lenalidomide by 1 dose level according to manufacturer's labeling; resume ixazomib at previous dosage. 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.

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

Thrombocytopenia

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

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. 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 dose (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 dose.

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

Peripheral Neuropathy

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

If grade 2 peripheral neuropathy 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. 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).

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

If any grade 4 peripheral neuropathy occurs, discontinue treatment.

Dermatologic Toxicity

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

If grade 2 or 3 rash recurs, withhold ixazomib and lenalidomide until rash resolves to grade 1 or less; 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.

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

Discontinue treatment if any grade 4 rash occurs.

Other Nonhematologic Toxicity

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. 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).

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

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. Refer to manufacturer's labeling for lenalidomide for specific dosage recommendations.

Renal Impairment

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

Geriatric Patients

Manufacturer makes no special dosage recommendations. (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).

Not a reversible or time-dependent inhibitor of CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Not expected to cause interactions via CYP inhibition.

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. Not expected to cause transporter-mediated pharmacokinetic interactions.

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

Drugs Affecting Hepatic Microsomal Enzymes

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

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

Specific Drugs