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FDA approved ixazomib (Ninlaro, Takeda) in combination with lenalidomide and dexamethasone
Lisa M. HolleFDA approved ixazomib (Ninlaro, Takeda) in combination with lenalidomide and dexamethasone in November 2015 to treat patients with multiple myeloma who have received at least one prior therapy. Ixazomib was granted priority review and orphan drug designations by FDA.
When treating patients with relapsed multiple myeloma, 3-drug regimens have been shown to be superior to 2-drug regimens. Yet current treatment options often have many bothersome and dose-limiting side effects. Ixazomib is the first FDA-approved oral proteasome inhibitor. Ixazomib inhibits proteasomes that affect multiple myeloma cell growth and survival. Combined with lenalidomide and dexamethasone, this approval provides an all oral-drug regimen for patients with refractory or relapsed multiple myeloma.
Ixazomib approval was based on a double blind, placebo-controlled, phase 3 trial that enrolled 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma.1 Of note, patients who had refractory disease to lenalidomide or proteasome inhibitor-based therapy were not eligible. Patients received either oral ixazomib 4 mg or placebo on days 1, 8, and 15 of a 28-day cycle: both groups also received 25 mg of oral lenalidomide on days 1 through 21 and 40 mg of oral dexamethasone on days 1, 8, 15, and 22.
The primary endpoint-median progression-free survival-was measured at 20.6 months in the ixazomib group and 14.7 months in the placebo group. The hazard ratio for disease progression or death was 0.74 (95% confidence interval, 0.59 to 0.94; P=0.01). 129 events of disease progression or death occurred in the ixazomib group vs 157 in the placebo group. Subgroup analyses showed similar progression-free survival times in patients with a poor prognosis, high-risk cytogenetic abnormalities, and other high risk features.
Ixazomib should not to be taken with strong CYP3A4-inducing drugs as it is a substrate of CYP3A4. The most common adverse events (≥20%) include diarrhea, constipation, thrombocytopenia, neutropenia, peripheral neuropathy, nausea, vomiting, peripheral edema, and back pain. Ixazomib should not be used during pregnancy or in women who are breast feeding. Effective birth control should be used by females and males with a female partner who is able to become pregnant during treatment and for 90 days after the last dose of ixazomib. Ixazomib is classified as a low emetogenic-potential drug, requiring only as-needed antiemetics. Ixazomib is cytotoxic; capsules should not be opened or crushed and direct contact with the capsule contents should be avoided. Capsules should be stored in the original packaging and removed just before dosing.
Ixazomib is approved as a 4-mg dose to be taken by mouth on days 1, 8, and 15 of a 28-day cycle. Absorption is decreased with food; therefore, ixazomib should be taken at least one hour before or two hours after food. When taking the approved regimen, the patient take the dexamethasone and lenalidomide doses with food and the ixazomib dose on an empty stomach (at least 2 hours after food and 1 hour before food) with water. If a patient misses a dose, he or she should be instructed to take the missed dose as long as the next scheduled dose is ≥72 hours away. Ixazomib is currently available as a 4-mg, 3-mg, and 2.3-mg capsule. In patients with moderate to severe hepatic impairment, ixazomib should be decreased to a starting dose of 3 mg. Patients with severe renal impairment or end-stage renal disease who require dialysis should also begin with a starting dose of 3 mg.
Hannah Buckler, a 2017 PharmD Candidate, is a 4th year pharmacy student at UConn School of Pharmacy in Storrs, Conn. Lisa M. Holle, PharmD, BCOP, FHOPA is Associate Clinical Professor at UConn School of Pharmacy.
Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-1634