Ninlaro

— THERAPEUTIC CATEGORIES —
  • Leukemias, lymphomas, and other hematologic cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Ninlaro Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ixazomib 2.3mg, 3mg, 4mg; gel caps.

    Pharmacological Class

    Proteasome inhibitor.

    How Supplied

    Caps—1, 3

    How Supplied

    Ninlaro capsules are individually packaged in a PVC-Aluminum/Aluminum blister. 

    • 4 mg: light orange gelatin capsule imprinted with “Takeda” on the cap and “4 mg” on the body in black ink. 
    • 3 mg: light grey gelatin capsule imprinted with “Takeda” on the cap and “3 mg” on the body in black ink. 
    • 2.3 mg: light pink gelatin capsule imprinted with “Takeda” on the cap and “2.3 mg” on the body in black ink.

    Storage

    Store Ninlaro at room temperature. Do not store above 30° C (86° F). Do not freeze. 

    Manufacturer

    Takeda Pharmaceutical Company

    Generic Availability

    NO

    Mechanism of Action

    Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome. In vitro, ixazomib induced apoptosis of multiple myeloma cell lines and cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines.

    Ninlaro Indications

    Indications

    In combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy.

    Limitations of 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.

    Ninlaro Dosage and Administration

    Adult

    Swallow whole. Take ≥1hr before or ≥2hrs after food. Initially 4mg once weekly on Days 1, 8, and 15 of a 28-day cycle (give with lenalidomide 25mg daily on Days 1–21 and dexamethasone 40mg on Days 1, 8, 15, and 22). Continue until disease progression or unacceptable toxicity. Moderate or severe hepatic impairment, severe renal impairment, or ESRD on dialysis: initially 3mg. Prior to new cycle, ensure ANC ≥1,000/mm3, platelets ≥75,000/mm3, recovery of non-hematologic toxicities to baseline or Grade ≤1. Consider antiviral prophylaxis to decrease risk of herpes zoster reactivation. Dose modifications: see full labeling.

    Children

    Not established.

    Administration

    Ninlaro Contraindications

    Not Applicable

    Ninlaro Boxed Warnings

    Not Applicable

    Ninlaro Warnings/Precautions

    Warnings/Precautions

    Thrombocytopenia: monitor platelets at least monthly during treatment; consider more frequently for first 3 cycles. Adjust dose for Grade 3/4 GI symptoms or Grade ≥2 rash. Monitor for peripheral neuropathy; adjust dose if worsens. Adjust dosing of dexamethasone or ixazomib if Grade 3/4 peripheral edema symptoms occur. Discontinue if cutaneous reactions occur (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis). Thrombotic microangiopathy (including TTP/HUS). Hepatic impairment; monitor enzymes regularly and adjust for Grade 3/4 symptoms. Moderate or severe hepatic impairment, severe renal impairment or ESRD on dialysis: reduce dose (see Adult). Embryo-fetal toxicity. Advise to use effective non-hormonal contraception (females of reproductive potential) or effective contraception (males w. female partners) during and for 90 days after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for 90 days after the last dose).

    Warnings/Precautions

    Thrombocytopenia 

    • Thrombocytopenia has been reported with Ninlaro with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. 
    • Monitor platelet counts at least monthly during treatment with Ninlaro; consider more frequent monitoring during the first 3 cycles.
    • Manage thrombocytopenia with dose modifications and platelet transfusions as per standard guidelines. 

    Gastrointestinal Toxicities 

    • Diarrhea, constipation, nausea, and vomiting have been reported with Ninlaro, occasionally requiring use of antidiarrheal and antiemetic medications, and supportive care.
    • Adjust dosing for Grade 3 or 4 symptoms.

    Peripheral Neuropathy 

    • The majority of peripheral neuropathy adverse reactions were Grade 1 and Grade 2.
    • The most commonly reported reaction was peripheral sensory neuropathy (24% and 17% in the Ninlaro and placebo regimen, respectively).
    • Monitor patients for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification.

    Peripheral Edema 

    • Peripheral edema was reported in 27% and 21% of patients in the Ninlaro and placebo regimens, respectively. Peripheral edema resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens.
    • Evaluate for underlying causes; provide supportive care, as necessary.
    • Adjust dosing of dexamethasone per its prescribing information or Ninlaro for Grade 3 or 4 symptoms.

    Cutaneous Reactions

    • Rash was reported in 27% of patients in the Ninlaro regimen and 16% of patients in the placebo regimen.
    • Manage rash with supportive care or with dose modification if Grade 2 or higher.
    • Stevens-Johnson syndrome or toxic epidermal necrolysis, including a fatal case, has been reported with Ninlaro. If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue Ninlaro; manage as clinically indicated. 

    Thrombotic Microangiopathy

    • Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received Ninlaro.
    • Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Ninlaro and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting Ninlaro. 

    Hepatotoxicity 

    • Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic, and hepatotoxicity have each been reported in <1% of patients treated with Ninlaro.
    • Hepatotoxicity has been reported (10% in the Ninlaro regimen and 9% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms.

    Embryo-Fetal Toxicity 

    • Ninlaro can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animal studies. 
    • Advise pregnant women of the potential risk to a fetus. 
    • Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Ninlaro and for 90 days following the last dose. 
    • Advise males with female partners of reproductive potential to use effective contraception during treatment with Ninlaro and for 90 days following the last dose.

    Increased Mortality in Patients Treated with Ninlaro in the Maintenance Setting 

    • In two prospective randomized clinical trials in multiple myeloma in the maintenance setting, treatment with Ninlaro resulted in increased deaths.
    • Treatment of patients with Ninlaro for multiple myeloma in the maintenance setting is not recommended outside of controlled trials.

    Pregnancy Considerations

    Based on its mechanism of action and data from animal reproduction studies, Ninlaro can cause fetal harm when administered to a pregnant woman. There is no available data on Ninlaro use in pregnant women to evaluate drug-associated risk.

    Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus.

    Nursing Mother Considerations

    There is no data on the presence of ixazomib or its metabolites in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production.

    Because of the potential for serious adverse reactions from Ninlaro in a breastfed infant, advise women not to breastfeed during treatment with Ninlaro and for 90 days after the last dose.

    Pediatric Considerations

    Safety and effectiveness have not been established in pediatric patients.

    Geriatric Considerations

    No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

    Renal Impairment Considerations

    In patients with severe renal impairment or ESRD requiring dialysis, the mean AUC increased by 39% when compared to patients with normal renal function. Reduce the starting dose of Ninlaro in patients with severe renal impairment or ESRD requiring dialysis. Ninlaro is not dialyzable and therefore can be administered without regard to the timing of dialysis.

    Hepatic Impairment Considerations

    In patients with moderate or severe hepatic impairment, the mean AUC increased by 20% when compared to patients with normal hepatic function. Reduce the starting dose of Ninlaro in patients with moderate or severe hepatic impairment.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    Ninlaro can cause fetal harm when administered to pregnant women. 

    Pregnancy Testing:

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

    Ninlaro Pharmacokinetics

    Absorption

    After oral administration, the median time to achieve peak ixazomib plasma concentrations was one hour. The mean absolute oral bioavailability was 58%, based on population PK analysis. 

    A food effect study conducted in patients with a single 4 mg dose of ixazomib showed that a high-fat meal decreased ixazomib AUC by 28% and Cmax by 69%.

    Distribution

    Ixazomib is 99% bound to plasma proteins and distributes into red blood cells with a blood-to-plasma ratio of 10. The steady-state volume of distribution is 543 L.

    Metabolism

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

    Elimination

    After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for <3.5% of the administered dose recovered in urine. 

    The terminal half-life (t1/2) of ixazomib was 9.5 days.

    Ninlaro Interactions

    Interactions

    Avoid concomitant strong CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, St. John's Wort). Risk of reduced hormonal contraceptives efficacy with concomitant dexamethasone.

    Ninlaro Adverse Reactions

    Adverse Reactions

    Diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, back pain; rash, hepatotoxicity, herpes zoster, eye disorders.

    Ninlaro Clinical Trials

    Clinical Trials

    The efficacy and safety of Ninlaro in combination with lenalidomide and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy. Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the study.

    A total of 722 patients were randomized in a 1:1 ratio to receive either the combination of Ninlaro, lenalidomide and dexamethasone (n=360; Ninlaro regimen) or the combination of placebo, lenalidomide and dexamethasone (n=362; placebo regimen) until disease progression or unacceptable toxicity. Randomization was stratified according to the number of prior lines of therapy (1 versus 2 or 3), myeloma International Staging System (ISS) (stage I or II versus III), and previous therapy with a proteasome inhibitor (exposed or naïve). 

    Patients received Ninlaro 4 mg or placebo on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle. Patients with renal impairment received a starting dose of lenalidomide according to its prescribing information. Treatment continued until disease progression or unacceptable toxicities.

    The efficacy of Ninlaro was evaluated by progression-free survival (PFS) according to the 2011 International Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by a blinded independent review committee (IRC) based on central lab results.  

    At study endpoint, patients treated with the Ninlaro regimen demonstrated statistically significant improvement in PFS vs the placebo regimen (HR 0.74, [95% CI: 0.59, 0.94]; P=0.012). The median PFS for the Ninlaro regimen was 20.6 months vs the placebo regimen at 14.7 months. The median time to response and median duration of response were 1.1 months and 20.5 months in the Ninlaro regimen vs 1.9 months and 15 months in the placebo regimen, respectively.

    Ninlaro Note

    Not Applicable

    Ninlaro Patient Counseling

    Patient Counseling

    Thrombocytopenia 

    • Advise patients that they may experience low platelet counts (thrombocytopenia).
    • Signs of thrombocytopenia may include bleeding and easy bruising.

    Gastrointestinal Toxicities 

    • Advise patients they may experience diarrhea, constipation, nausea and vomiting and to contact their healthcare providers if these adverse reactions persist.

    Peripheral Neuropathy 

    • Advise patients to contact their healthcare providers if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs. 

    Peripheral Edema 

    • Advise patients to contact their healthcare providers if they experience unusual swelling of their extremities or weight gain due to swelling.

    Cutaneous Reactions

    • Advise patients to contact their healthcare providers immediately if they experience a new or worsening rash. 

    Thrombotic Microangiopathy 

    • Advise patients to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur. 

    Hepatotoxicity 

    • Advise patients to contact their healthcare providers if they experience jaundice or right upper quadrant abdominal pain. 

    Other Adverse Reactions 

    • Advise patients to contact their healthcare providers if they experience signs and symptoms of acute febrile neutrophilic dermatosis (Sweet’s syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, herpes zoster, cataracts, dry eyes, blurred vision, conjunctivitis and thrombotic thrombocytopenic purpura.

    Embryo-Fetal Toxicity 

    • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. 
    • Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. 
    • Advise females of reproductive potential to use effective contraception during treatment with Ninlaro and for 90 days following the last dose. Advise women using hormonal contraceptives to also use a barrier method of contraception. 
    • Advise males with female partners of reproductive potential to use effective contraception during treatment with Ninlaro and for 90 days following the last dose.

    Lactation 

    • Advise women not to breastfeed during treatment with Ninlaro and for 90 days after the last dose. 

    Concomitant Medications 

    • Advise patients to speak with their healthcare providers about any other medication they are currently taking and before starting any new medications. 

    Cost Savings Program

    The Ninlaro Here2Assist Program is available here.

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