Ninlaro (ixazomib citrate)

Dosage of ixazomib citrate is expressed in terms of ixazomib.

If grade 2 or 3 rash occurs, lenalidomide should be withheld until rash resolves to grade 1 or less. Following resolution, lenalidomide should be resumed at 1 dose level lower than the previous dosage according to the manufacturer's labeling. If grade 2 or 3 rash recurs, ixazomib and lenalidomide should be withheld until rash resolves to grade 1 or less. Following resolution, ixazomib should be resumed 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), and lenalidomide should be resumed at the previous dosage. For additional occurrences of rash, dosage modifications of ixazomib and lenalidomide should be alternated. The treatment regimen should be discontinued if grade 2 or 3 rash occurs following a second dosage reduction of ixazomib.

If any grade 4 rash occurs, the treatment regimen should be discontinued.

If ANC is less than 500/mm3, ixazomib and lenalidomide should be withheld until ANC is at least 500/mm3. The addition of granulocyte colony-stimulating factors (G-CSF) also should be considered based on clinical guidelines. When ANC returns to at least 500/mm3, lenalidomide should be reduced by 1 dose level according to the manufacturer's labeling, and ixazomib should be resumed at the previous dosage (i.e., 4, 3, or 2.3 mg). If ANC less than 500/mm3 recurs, ixazomib and lenalidomide should be withheld until ANC is at least 500/mm3; the ixazomib dose should then be reduced 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), and lenalidomide should be resumed at the previous dosage following resolution of toxicity. For additional occurrences of neutropenia, dosage modifications of ixazomib and lenalidomide should be alternated. Following a second dosage reduction of ixazomib, the treatment regimen should be discontinued if ANC below 500/mm3 recurs.

If the platelet count is less than 30,000/mm3, ixazomib and lenalidomide should be withheld until platelet count is at least 30,000/mm3. When the platelet count returns to at least 30,000/mm3, ixazomib may be continued at the previous dosage (i.e., 4, 3, or 2.3 mg), and lenalidomide should be reduced by 1 dose level according to the manufacturer's labeling. If platelet count less than 30,000/mm3 recurs, ixazomib and lenalidomide should be withheld until platelet count is at least 30,000/mm3. Following return of platelet count to at least 30,000/mm3, ixazomib should be resumed 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), and lenalidomide should be resumed at the previous dosage. For additional occurrences of thrombocytopenia, dosage modifications of ixazomib and lenalidomide should be alternated. Following a second dosage reduction of ixazomib, the treatment regimen should be discontinued if platelet count below 30,000/mm3 recurs.

If other grade 3 or 4 nonhematologic toxicity occurs, ixazomib should be withheld and, at the clinician's discretion, generally should resolve to patient's condition at baseline or to grade 1 or less prior to resuming ixazomib. If the nonhematologic toxicity is attributable to ixazomib, then ixazomib should be resumed 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) following resolution of toxicity. The treatment regimen should be discontinued if grade 3 or 4 nonhematologic toxicity occurs following a second dosage reduction of ixazomib.

If grade 1 peripheral neuropathy with pain or grade 2 peripheral neuropathy occurs, ixazomib should be withheld until peripheral neuropathy resolves to grade 1 or less without pain or returns to baseline. Following resolution, ixazomib should be resumed at the previous dosage. The treatment regimen should be discontinued if grade 1 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, ixazomib should be withheld and, at the clinician's discretion, generally should resolve to grade 1 or less or to baseline prior to resuming ixazomib. Following resolution, ixazomib should be resumed 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). The treatment regimen should be discontinued 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, the treatment regimen should be discontinued.

Management of some adverse effects may require temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of ixazomib therapy. Up to 2 dosage reductions for toxicity may be made. If dosage modification from the recommended dosage of 4 mg once weekly is necessary, an initial dosage reduction to 3 mg once weekly is recommended. If further dosage reduction is necessary, the dosage should be reduced to 2.3 mg once weekly. Dosages less than 2.3 mg once weekly are not recommended.

Ixazomib is administered once weekly on the same day and at approximately the same time for the first 3 weeks of each 4-week cycle.

Ixazomib is administered orally at least 1 hour before or at least 2 hours after food.

Ixazomib and dexamethasone should not be administered simultaneously on days that patients receive both medications, because dexamethasone is given with food, while ixazomib is given on an empty stomach.

Ixazomib capsules should be swallowed whole with water and should notbe crushed, chewed, or opened.

If vomiting occurs after a dose of ixazomib is administered, the dose should not be repeated. Instead, the next dose should be administered at the regularly scheduled time.

If a dose of ixazomib is delayed or missed, the dose should be administered only if there are at least 72 hours until the next scheduled dose. A missed dose should not be administered within 72 hours of the next scheduled dose, and the dose should not be doubled to make up for the missed dose.

Clinicians should instruct patients to take ixazomib exactly as prescribed and discuss all dosage instructions with the patient prior to initiation of therapy. Overdosage of ixazomib has resulted in fatality.

No dosing information is available for this tab.

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

Ixazomib is not a reversible or time-dependent inhibitor of cytochrome (CYP) P-450 isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Ixazomib also is 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.

Ixazomib does not induce CYP isoenzymes 1A2, 2B6, or 3A4/5 or corresponding immunoreactive protein concentrations and is not expected to produce pharmacokinetic interactions via CYP inhibition or induction. Additionally, ixazomib is not expected to cause transporter-mediated pharmacokinetic interactions.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Ixazomib/Slt Moderate And Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ixazomib is primarily metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong or selected moderate CYP3A4 inducers will result in decreased systemic concentrations of ixazomib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of ixazomib states that concomitant use with CYP3A4 inducers should be avoided. In an interaction study, rifampin decreased ixazomib exposure(AUC) by 74%.(1) Use an alternative to the inducing agent when possible. The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer.

DISCUSSION: In an interaction study, coadministration with rifampin decreased ixazomib AUC 74% and maximum concentration (Cmax) by 54%(1) Selected moderate and strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, belzutifan, carbamazepine, cenobamate, dabrafenib, elagolix, encorafenib, enzalutamide, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's Wort, sotorasib, telotristat, and tovorafenib.(2)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Ixazomib/Hormonal Contraceptives

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ixazomib does not interact with hormonal contraceptives, but the dexamethasone used with ixazomib is a weak to moderate CYP3A4 inducer and may increase the CYP3A4 mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of ixazomib with dexamethasone may reduce the effectiveness of hormonal contraceptives.(1) Ixazomib may cause birth defects and/or miscarriage if used by pregnant women.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal back-up method of birth control during and for 90 days after ixazomib-dexamethasone therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Ixazomib-dexamethasone has not been studied with hormonal contraceptives. Dexamethasone may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during ixazomib-dexamethasone therapy.(1)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

There are no moderate interactions for this drug.

*None.

• Lactation

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Neutropenic disorder
• Peripheral neuropathy
• Pregnancy
• Severe hepatic disease
• Thrombocytopenic disorder

• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Peripheral edema

Adverse effects reported in 20% or more of patients receiving ixazomib in clinical studies include thrombocytopenia, neutropenia, rash, bronchitis, vomiting, peripheral edema, nausea, peripheral neuropathy, constipation, and diarrhea.

More Frequent

• Neutropenic disorder
• Thrombocytopenic disorder

Less Frequent

• Abnormal hepatic function tests
• Herpes zoster

Rare or Very Rare

• Angioedema
• Cholestatic hepatitis
• Hemolytic uremic syndrome
• Hepatitis
• Hepatocellular damage
• Myelitis
• Posterior reversible encephalopathy syndrome
• Steatosis of liver
• Stevens-johnson syndrome
• Sweet's syndrome
• Thrombotic microangiography
• Thrombotic thrombocytopenic purpura
• Toxic epidermal necrolysis
• Tumor lysis syndrome

More Frequent

• Arthralgia
• Back pain
• Constipation
• Diarrhea
• Fever
• Nausea
• Peripheral edema
• Peripheral neuropathy
• Skin rash
• Vomiting

Less Frequent

• Blurred vision
• Conjunctivitis
• Dry eye
• Upper respiratory infection

Rare or Very Rare

• Maculopapular rash

No enhanced messaging available.

Safety and efficacy of ixazomib have not been established in pediatric patients.

Based on its mechanism of action and animal findings, ixazomib can cause fetal harm if administered to pregnant women.

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

It is not known whether ixazomib or its metabolites are distributed into human milk. The effects of the drug on breast-fed infants or on the production of milk are unknown. Because of the potential for adverse reactions to ixazomib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 90 days after the last dose.

Manufacturer makes no special dosage recommendations.

Of the total number of patients in clinical studies evaluating ixazomib, 55% were 65 years of age or older and 17% were 75 years of age or older. No overall differences in safety or efficacy were observed between geriatric patients and younger adults, and other clinical experience has not demonstrated differences in responses between the geriatric and younger patients. However, greater sensitivity of some older patients cannot be ruled out.