ixazomib (Rx)

Brand and Other Names:Ninlaro
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 2.3mg
  • 3mg
  • 4mg

Multiple Myeloma

Indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy

Treatment should be continued until disease progression or unacceptable toxicity

Starting doses

  • Ixazomib: 4 mg PO on days 1, 8, and 15 of a 28-day cycle; take 1 hr ac or 2 hr pc
  • Lenalidomide: 25 mg PO on days 1-21 of a 28-day cycle; take with or without food
  • Dexamethasone: 40 mg PO in morning on days 1, 8, 15, and 22 of a 28-day cycle

Dosage Modifications

Also refer to lenalidomide monograph

Hepatic impairment

  • Mild: No dosage adjustment required
  • Moderate (TB >1.5-3 x ULN) or severe (TB >3 ULN): Decrease starting dose to 3 mg
  • Grade 3-4 hepatotoxicity during treatment: Withhold therapy until recovery to baseline or improvement to grade 1 or lower (at prescribers discretion); resume dose at next lower dose if toxicity attributable to therapy

Renal impairment

  • Mild-to-moderate: No dosage adjustment required
  • Severe (CrCl <30 mL/min) or ESRD requiring dialysis: Decrease starting dose to 3 mg; ixazomib is not dialyzable and therefore can be administered without regard to the timing of dialysis

Dose reductions

  • If starting dose is 4 mg
    • First reduction to: 3 mg
    • Second reduction to: 2.3 mg
    • If unable to tolerate 2.3 mg; discontinue therapy

Thrombocytopenia

  • Platelet count <30,000/mm³
    • Withhold ixazomib and lenalidomide until platelet count is at least 30,000/mm³
    • Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume ixazomib at its most recent dose
    • If platelet count falls to <30,000/mm³ again, withhold ixazomib and lenalidomide until platelet count is at least 30,000/mm³
    • Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at its most recent dose*
    • *For additional occurrences, alternate dose modification of lenalidomide and ixazomib

Neutropenia

  • ANC count <500/mm³
    • Withhold ixazomib and lenalidomide until ANC is at least 500/mm³
    • Consider adding G-CSF as per clinical guidelines
    • Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume ixazomib at its most recent dose
    • If ANC falls to <500/mm³ again, withhold ixazomib and lenalidomide until ANC is at least 500/mm³
    • Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at its most recent dose*
    • *For additional occurrences, alternate dose modification of lenalidomide and ixazomib

Rash

  • Grade 2 or 3
    • Withhold lenalidomide until rash recovers to ≤grade 1
    • Following recovery, resume lenalidomide at the next lower dose according to its prescribing information
    • If grade 2 or 3 rash occurs again, withhold ixazomib and lenalidomide until rash recovers to ≤grade 1
    • Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at its most recent dose*
    • *For additional occurrences, alternate dose modification of lenalidomide and ixazomib
  • Grade 4
    • Discontinue treatment regimen

Peripheral neuropathy

  • Grade 1 with pain or grade 2
    • Withhold ixazomib until peripheral neuropathy recovers to ≤grade 1 without pain or patient's baseline
    • Following recovery, resume ixazomib at its most recent dose
  • Grade 2 with pain or grade 3
    • Withhold ixazomib
    • Toxicities should, at the physician’s discretion, generally recover to patient’s baseline condition or ≤grade 1 prior to resuming ixazomib
    • Following recovery, resume ixazomib at the next lower dose
  • Grade 4
    • Discontinue treatment regimen

Other nonhematologic toxicities

  • Withhold ixazomib
  • Toxicities should, at the physician’s discretion, generally recover to patient’s baseline condition or ≤grade 1 prior to resuming ixazomib
  • If attributable to ixazomib, resume at the next lower dose following recovery

Dosing Considerations

Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation

Monitor before each new cycle of therapy

  • ANC should be at least 1,000/mm³
  • Platelet count should be at least 75,000/mm³
  • Nonhematologic toxicities should, at the physician’s discretion, generally be recovered to patient’s baseline condition or ≤grade 1

Safety and efficacy not established

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Interactions

Interaction Checker

and ixazomib

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            Adverse Effects

            Percentages listed are for any grade toxicity unless otherwise stated

            >10%

            Thrombocytopenia (78%)

            Neutropenia (67%)

            Diarrhea (42%)

            Constipation (34%)

            Peripheral neuropathies (28%)

            Nausea (26%)

            Thrombocytopenia, grade 3-4 (26%)

            Neutropenia, grade 3-4 (26%)

            Peripheral edema (25%)

            Vomiting (22%)

            Back pain (21%)

            Upper respiratory tract infection (19%)

            Rash (19%)

            1-10%

            Diarrhea, grade 3 (6%)

            Blurred vision (6%)

            Conjunctivitis (6%)

            Dry eye (5%)

            Herpes zoster, without antiviral prophylaxis (4%)

            Rash, grade 3 (3%)

            Peripheral edema (2%)

            Peripheral neuropathies, grade 3 (2%)

            Nausea, grade 3 (2%)

            Vomiting, grade 3 (1%)

            <1%

            Herpes zoster, with antiviral prophylaxis

            Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic, and hepatotoxicity

            Upper respiratory tract infection, grade 3

            Constipation, grade 3

            Back pain, grade 3

            Acute febrile neutrophilic dermatosis (Sweet syndrome)

            Stevens-Johnson syndrome

            Transverse myelitis

            Posterior reversible encephalopathy syndrome

            Tumor lysis syndrome

            Thrombotic thrombocytopenic purpura

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            Warnings

            Contraindications

            None

            Cautions

            Thrombocytopenia reported with platelet nadirs typically occurring between days 14 and 21 of each 28-day cycle and recovery to baseline by the start of the next cycle; monitor platelet counts at least monthly during treatment; consider more frequent monitoring during the first 3 cycles (see Dosage Modifications)

            Diarrhea, constipation, nausea, and vomiting reported, occasionally requiring use of antidiarrheals, antiemetics, and supportive care

            Peripheral neuropathy was reported (majority grade 1); the most commonly reported reaction was peripheral sensory neuropathy; monitor for symptoms; new or worsening peripheral neuropathy may require dose modification (see Dosage Modifications)

            Peripheral edema reported; adjust dosing of dexamethasone per its prescribing information or ixazomib for grade 3 or 4 symptoms (see Dosage Modifications)

            Cutaneous reactions reported, the most common types being maculopapular and macular rash; manage with supportive care or with dose modification if ≥grade 2 (see Dosage Modifications)

            Rare occurrence of drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic, and hepatotoxicity reported; monitor hepatic enzymes regularly and adjust dosing for grade 3 or 4 symptoms (see Dosage Modifications)

            Herpes zoster infection reported; consider antiviral prophylaxis during therapy to decrease risk of herpes zoster reactivation

            Can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animals (see Pregnancy)

            Drug interaction overview

            • Avoid coadministration with strong CYP3A inducers
            • Coadministration with a strong CYP3A inhibitor (ie, clarithromycin) did not result in a clinically meaningful change in the systemic exposure of ixazomib
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            Pregnancy & Lactation

            Pregnancy

            Can cause fetal harm when administered to a pregnant woman

            There are no human data available regarding the potential effect of ixazomib on pregnancy or development of the embryo or fetus

            Animal studies

            • Ixazomib caused embryofetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose
            • Increases in fetal skeletal variations/abnormalities (fused caudal vertebrae, number of lumbar vertebrae, and full supernumerary ribs) in rabbit studies
            • Decrease fetal weights, a trend towards decreased fetal viability, and increased postimplantation losses were observed in rat studies

            Contraception

            • Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated
            • Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following the final dose
            • Dexamethasone is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters; because drug is administered with dexamethasone, consider risk for reduced efficacy of contraceptives; advise women using hormonal contraceptives to also use a barrier method of contraception

            Lactation

            No data are available in human milk; effects of drug on breast fed infant, or effects of drug on milk production; because potential for serious adverse reactions from drug in breastfed infants is unknown, advise nursing women not to breastfeed during treatment and for 90 days after last dose

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Reversible proteasome inhibitor; preferentially binds and inhibits the chymotrypsinlike activity of the beta 5 subunit of the 20S proteasome

            Absorption

            Absolute bioavailability: 58%

            Peak plasma time: 1 hr

            A food effect study conducted in patients with a single 4-mg dose showed that a high-fat meal decreased AUC by 28% and Cmax by 69% (see Administration)

            Distribution

            Protein bound: 99% bound to plasma proteins and distributes into RBCs with a blood-to-plasma ratio of 10

            Vd: 543 L

            Metabolism

            Metabolism by multiple CYP enzymes and non-CYP proteins is expected to be the major clearance mechanism

            Elimination

            Half-life: 9.5 days

            Systemic clearance: 1.9 L/hr

            Excretion: 62% urine (<3.5% unchanged); 22% feces

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            Administration

            Oral Administration

            Take once a week on the same day and at approximately the same time for the first 3 weeks of a 4-week cycle

            Taken at least 1 hr before or at least 2 hr after food

            Swallow capsule whole with water; do not crush, chew, or open (see Storage and Chemotherapy Handling)

            Missed or vomited dose

            • If a dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥72 hr away
            • A missed dose should not be taken within 72 hr of the next scheduled dose
            • A double dose should not be taken to make up for the missed dose
            • If vomiting occurs after taking a dose, the patient should not repeat the dose; resume dosing at the time of the next scheduled dose

            Storage

            Store at room temperature; not to exceed 30°C (86°F)

            Do not freeze

            Store capsules in original packaging until immediately prior to use

            Chemotherapy handling and disposal

            • Ixazomib is cytotoxic
            • Capsules should not be opened or crushed
            • Direct contact with the capsule contents should be avoided
            • In case of capsule breakage, avoid direct contact of capsule contents with the skin or eyes
            • If contact occurs with the skin, wash thoroughly with soap and water
            • If contact occurs with the eyes, flush thoroughly with water
            • Any unused medicinal product or waste material should be disposed in accordance with local requirements
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.