FDA Approves NINLARO® (ixazomib) for the Treatment of Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy

On November 20, 2015, the US Food and Drug Administration (FDA) approved NINLARO(ixazomib) capsules for oral use, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. The approved recommended dosage of NINLARO capsules is 4 mg orally on Days 1, 8, and 15 of a 28-day cycle. NINLARO should be taken at least one hour before or at least two hours after food. Monitor patients for thrombocytopenia, gastrointestinal toxicities, peripheral neuropathy, peripheral edema, and cutaneous reactions and adjust dosing as needed.

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Ixazomib

  • MOA: Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.
  • Dose proportionality: Ixazomib AUC increases in a dose proportional manner over a dose range of 0.2 to 10.6 mg (i.e., 0.05 to 2.65 times the approved recommended dosage).
  • Accumulation: Approximately 2-fold accumulation in AUC was observed with weekly oral dosing on Day 15.
  • Absorption: Approximately 58% absolute bioavailability (median Tmax of 1 hour) in patients.
  • Food effect: A 28% and 69% decrease in ixazomib AUC and Cmaxwas observed following the administration of NINLARO with a high-fat meal, respectively.
  • Plasma protein binding: Approximately 99%.
  • Terminal half-life (mean): Approximately 9.5 days in patients.
  • Metabolism: Extensive, with both non-CYP and CYP enzymes contributing to ixazomib metabolism. No specific CYP isozyme predominantly contributes to ixazomib metabolism at clinically relevant concentrations in vitro. At higher concentrations, CYP3A4 is predominant (42%) in vitro.
  • Excretion: Approximately 62% of the administered radioactivity was excreted in the urine (< 3.5% as unchanged drug) and 22% in the feces.
  • Exposure-safety: Exposure-Response (E-R) analyses showed significant relationships between ixazomib systemic exposure and select adverse reactions (rash, thrombocytopenia, diarrhea) and support the recommended dose reduction to manage these adverse reactions.

Drug Interaction Potential

  • Avoid concomitant administration of NINLARO with strong CYP3A inducers (such as rifampin, phenytoin, carbamazepine, and St. John's Wort). Concomitant administration of NINLARO with rifampin decreased ixazomib Cmax by 54% and AUC by 74% in a clinical drug-drug interaction study.
  • Co-administration of NINLARO with strong CYP3A or CYP1A2 inhibitors did not result in a clinically significant change in the systemic exposure of ixazomib.
  • Ixazomib is a low affinity substrate of P-gp, but is not expected to cause transporter-mediated drug-drug interactions.

Use in Specific Populations

  • Reduce starting dose of NINLARO to 3 mg in patients with severe renal impairment (RI) or end-stage renal disease (ESRD) requiring dialysis (creatinine clearance (CLcr < 30 mL/min)). Ixazomib AUC increased by 36-42% in patients with severe RI or ESRD requiring dialysis compared to patients with normal renal function.
  • Reduce starting dose of NINLARO to 3 mg in patients with moderate or severe (total bilirubin > 1.5 x ULN) hepatic impairment (HI). Ixazomib AUC increased by 13-27% in patients with moderate or severe HI compared to patients with normal hepatic function.
  • The following population characteristics were not associated with a clinically meaningful effect on the pharmacokinetics of ixazomib: sex, age (range 23-91 years), body surface area (range 1.2-2.7 m2), race, mild to moderate renal impairment (CLcr = 30-89 mL/min), or mild hepatic impairment (total bilirubin < 1.5 x ULN). No dose adjustment is needed in the above groups.

Safety and Efficacy

The effectiveness and safety of ixazomib, in combination with lenalidomide and dexamethasone (LenDex), was evaluated in a randomized, placebo-controlled trial patients with relapsed and/or refractory multiple myeloma who have received at least one prior therapy (N=722). Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the trial. Based on the most recent interim analysis, the Ixazomib+LenDex arm showed a 4.1 month median progression-free survival (PFS) improvement over the Placebo-LenDex arm (20.0 months vs. 15.9 months, hazard ratio = 0.82 [95% CI: 0.67, 1.0]). The most common adverse reactions were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting and back pain.


Full prescribing information is available at http://go.usa.gov/cPwme.

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/cPwyV).

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov.

The Office of Clinical Pharmacology (OCP) is pleased to announce the launch of the e-mail subscription service Clinical Pharmacology Corner. This is a free service from the U.S. Food & Drug Administration (FDA) to provide occasional updates from the OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today (https://public.govdelivery.com/accounts/USFDA/subscriber/new?topic_id=USFDA_407)

This burst was prepared by the OCP Review Team including Vicky Hsu, Ph.D., and Bahru Habtemariam, Pharm.D., Division of Clinical Pharmacology V, OCP, Office of Translational Sciences, CDER, FDA.