Ixazomib Citrate (Monograph)

Brand name: Ninlaro
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Sep 26, 2023. Written by ASHP.

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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).

Not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials.

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

• Based on the Institute for Safe Medication Practices (ISMP), ixazomib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

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

Oral

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

Oral

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

Oral

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

Oral

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

Oral

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.

Cautions for Ixazomib Citrate

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.

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.

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.

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.

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.

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.

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.

Increased Mortality in Patients Treated with Ixazomib in the Maintenance Setting

Increased deaths reported in multiple myeloma patients receiving maintenance treatment with ixazomib. Treatment in the maintenance setting not recommended outside of controlled trials.

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.

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.

Common Adverse Effects

Adverse effects (≥20%): thrombocytopenia, neutropenia, rash, bronchitis, vomiting, peripheral edema, nausea, peripheral neuropathy, constipation, diarrhea.

Drug Interactions

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

Ixazomib Citrate Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is 58%.

Median time to peak plasma concentration is 1 hour.

Systemic exposure increases in a dose-proportional manner over a dosage range of 0.2–10.6 mg; accumulation is twofold following weekly oral dosing.

Food

High-fat meal decreases AUC and peak plasma concentration by 28 and 69%, respectively.

Special Populations

In patients with moderate or severe hepatic impairment, mean AUC increased by 20% compared with those having normal hepatic function.

In patients with severe renal impairment or ESRD requiring dialysis, mean AUC increased by 39% compared with those having normal renal function.

Distribution

Extent

Distributes into RBCs with a blood-to-plasma ratio of 10.

Plasma Protein Binding

99%.

Elimination

Metabolism

Ixazomib citrate (a prodrug) is rapidly hydrolyzed to ixazomib (active metabolite). Metabolized by multiple CYP isoenzymes and through non-CYP-dependent pathways; in vitro studies reveal that no specific isoenzyme principally contributes to metabolism of drug at clinically relevant concentrations. Principally metabolized by CYP3A4 (42%) and 1A2 (26%) at higher than clinical concentrations.

Elimination Route

Urinary (62%) and fecal (22%) elimination.

<3.5% of dose recovered in urine as unchanged drug.

Not removed by hemodialysis.

Half-life

9.5 days.

Stability

Storage

Oral

Capsules

Room temperature in original carton until immediately prior to use; do not expose to temperatures >30°C. Do not freeze.

Actions

• Ixazomib citrate is a prodrug of ixazomib, a boron-containing selective inhibitor of the 20S proteasome.

• Reversibly binds the β5 subunit of the 20S proteasome, inhibiting its chymotrypsin-like activity.

• In vitro, induces caspase-mediated apoptosis of multiple myeloma cell lines and demonstrated cytotoxicity against myeloma cells from patients who relapsed following previous therapies (e.g., bortezomib, lenalidomide, dexamethasone).

• Demonstrates synergistic cytotoxic effects with lenalidomide in multiple myeloma cell lines; demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model in vivo.

Advice to Patients

• Importance of instructing patients to read the manufacturer's patient information carefully before starting ixazomib therapy and before each treatment.

• Importance of instructing patients to take ixazomib exactly as prescribed at least 1 hour before or 2 hours after food. Advise patients that capsules should be swallowed whole with water and that capsules should not be crushed, chewed, or opened.

• Importance of advising patients that ixazomib should be administered once weekly on the same day and at approximately the same time for the first 3 weeks of each 4-week cycle.

• Importance of advising patients that ixazomib and dexamethasone should not be administered simultaneously, because dexamethasone should be administered with food, while ixazomib should be given on an empty stomach.

• Importance of informing patients that if a dose is missed, the dose should be taken as soon as possible if there are at least 72 hours until the next scheduled dose. Patients should be advised not to take a missed dose if it is within 72 hours of the next scheduled dose.

• If vomiting occurs following administration of ixazomib, a replacement dose should not be administered. Patients should be advised to resume dosing at time of the next scheduled dose.

• Advise patients that direct contact with the contents of ixazomib capsules should be avoided. If capsule breakage occurs, direct contact with the skin or eyes should be avoided. If contact occurs, the skin should be washed thoroughly with soap and water, and the eyes should be flushed thoroughly with water.

• Importance of advising patients to store capsules in original carton until time of use.

• Risk of thrombocytopenia. Importance of advising patients of the signs or symptoms of thrombocytopenia (e.g., bleeding, easy bruising).

• Risk of GI toxicity. Importance of advising patients to report diarrhea, constipation, nausea, and vomiting to their clinician if adverse GI effects persist.

• Risk of peripheral neuropathy. Importance of advising patients to report new or worsening symptoms of peripheral neuropathy (e.g., tingling, numbness, pain, burning sensation in feet or hands, weakness in arms or legs) to their clinician.

• Risk of peripheral edema. Importance of advising patients to report unusual swelling of their extremities or weight gain from swelling to their clinician.

• Risk of cutaneous reactions. Importance of advising patients to immediately report new or worsening rash to their clinician.

• Risk of thrombotic microangiopathy. Importance of advising patients to report signs or symptoms of thrombotic microangiopathy.

• Risk of fetal harm. Importance of advising females of reproductive potential to use effective nonhormonal methods of contraception during treatment and for 90 days following discontinuance of the drug. Advise females using hormonal contraceptives to use an additional barrier method of contraception. Importance of advising males who are partners of females of reproductive potential to use effective methods of contraception during treatment and for 90 days following discontinuance of the drug. Importance of immediately informing clinician if the patient or their partner becomes pregnant during treatment or within 90 days of the last dose.

• Risk of hepatotoxicity. Importance of advising patients to report jaundice or right upper quadrant abdominal pain to their clinician.

• Importance of advising patients to discontinue breast-feeding while receiving ixazomib and for 90 days after the last dose.

• Importance of advising patients to report signs and symptoms of acute febrile neutrophilic dermatosis (Sweet syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, herpes zoster, cataracts, dry eyes, blurred vision, conjuctivitis, and thrombotic thrombocytopenic purpura.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other precautionary information.

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.

Preparations

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.

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Frequently asked questions

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