NINLARO

Small Molecule Antineoplastic Proteosome Inhibitors

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Avoid exposure to crushed or broken capsules.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

Ixazomib should be taken at least 1 hour before or at least 2 hours after food at approximately the same time of day as directed. Do not take dexamethasone and ixazomib at the same time; dexamethasone should be taken with food.
Swallow whole; do not crush or cut capsules.
If a dose is delayed or missed, take the dose if the next scheduled dose is more than 72 hours (3 days) away; otherwise, skip the dose and take it at the next scheduled time. Do not take a double dose to make up for a missed dose.
If vomiting occurs after taking a dose, do not take another dose; resume therapy at the next scheduled dose.
Discuss with the patient the importance of carefully following all dosage instructions including taking the recommended dose as directed; overdosage, including fatal cases, has occurred. Serious reactions reported with overdose include severe nausea, vomiting, diarrhea, aspiration pneumonia, multi-organ failure, and death.

neutropenia / Delayed / 34.0-34.0
thrombocytopenia / Delayed / 30.0-30.0
hepatotoxicity / Delayed / 10.0-10.0
diarrhea / Early / 10.0-10.0
rash / Early / 3.0-3.0
peripheral neuropathy / Delayed / 2.0-2.0
nausea / Early / 2.0-2.0
peripheral edema / Delayed / 2.0-2.0
infection / Delayed / 0-2.0
Stevens-Johnson syndrome / Delayed / 0-1.0
acute febrile neutrophilic dermatosis / Delayed / 0-1.0
vomiting / Early / 1.0-1.0
constipation / Delayed / 0-1.0
back pain / Delayed / 0-1.0
myelitis / Delayed / 0-1.0
tumor lysis syndrome (TLS) / Delayed / 0-1.0
hemolytic-uremic syndrome / Delayed / 0-1.0
thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
thrombotic microangiopathy / Delayed / 0-1.0

cataracts / Delayed / 15.0-15.0
conjunctivitis / Delayed / 9.0-9.0
blurred vision / Early / 7.0-7.0
hepatitis / Delayed / 0-1.0
steatosis / Delayed / 0-1.0
encephalopathy / Delayed / 0-1.0

xerophthalmia / Early / 6.0-6.0

NINLARO

Rx

Oral proteasome inhibitor
Used in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received at least 1 prior treatment
Myelosuppression has been reported

4 mg orally on days 1, 8, and 15 in combination with lenalidomide 25 mg orally daily on days 1 through 21 and dexamethasone 40 mg orally on days 1, 8, 15, and 22. Repeat treatment cycles every 28 days until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Consider giving an antiviral agent to decrease the risk of herpes zoster reactivation. Therapy interruption, dose reduction, or discontinuation may be necessary for treatment-related toxicity. Ensure that the absolute neutrophil count is 1,000 cells/mm3 or greater, the platelet count is 75,000 cells/mm3 or greater, and non-hematologic toxicities are recovered to baseline or grade 1 or lower prior to starting the next cycle of therapy. The median progression-free survival time was significantly improved with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone (20.6 months vs. 14.7 months; hazard ratio (HR) = 0.74; 95% CI, 0.59 to 0.94; p = 0.01) in patients with relapsed and/or refractory multiple myeloma who had received 1 to 3 prior therapies in a multinational, randomized, double-blind, phase 3 trial (n = 722; TOURMALINE-MM1 trial). At a median follow-up time of 85 months, the median overall survival time was not significantly improved in the ixazomib-containing arm (53.6 months vs. 51.6 months; HR = 0.939; 95% CI, 0.784 to 1.125). In this trial, subsequent lines of therapy were given in 71.7% and 69.9% of patients who received ixazomib plus lenalidomide and dexamethasone (median, 2 subsequent therapies; range, 1 to 9) and lenalidomide and dexamethasone (median, 3 subsequent therapies; range, 1 to 12), respectively. The median age of patients in this study was 66 years (range, 30 to 91 years); prior therapy included a stem-cell transplant in 57% of patients, proteasome inhibitor therapy in 70% of patients, and immunomodulatory drug therapy in 55% of patients. Thromboprophylaxis was recommended for all patients.

Baseline mild hepatic impairment (AST level greater than the upper limit of normal (ULN) or a total bilirubin level of 1 to 1.5 times the ULN and any AST level): no ixazomib dose adjustment necessary.
Baseline moderate (total bilirubin level greater than 1.5 to 3 times the ULN) or severe (total bilirubin level greater than 3 times the ULN) hepatic impairment: reduce the ixazomib starting dosage to 3 mg PO on days 1, 8, and 15 repeated every 28 days.
Treatment-related grade 3 and 4 hepatotoxiciy: hold ixazomib until the toxicity recovers to baseline or grade 1 or less (at physician’s discretion); resume ixazomib at a reduced dose (from 4 mg to 3 mg or from 3 mg to 2.3 mg).

NOTE: Refer to the lenalidomide prescribing information for lenalidomide dosing recommendations in patients with renal impairment.
Baseline mild or moderate renal impairment (creatinine clearance (CrCl) of 30 mL/min or greater): no ixazomib dose adjustment necessary.
Baseline severe renal impairment (CrCl less than 30 mL/min): reduce the ixazomib starting dosage to 3 mg PO on days 1, 8, and 15 repeated every 28 days.
Baseline end-stage renal disease requiring dialysis: reduce the ixazomib starting dosage to 3 mg PO on days 1, 8, and 15 repeated every 28 days; the dose may be given without regard to the timing of dialysis because ixazomib is not dialyzable.

Apalutamide: (Major) Avoid the concomitant use of ixazomib and apalutamide; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the ixazomib Cmax and AUC by 54% and 74%, respectively.
Carbamazepine: (Major) Avoid the concomitant use of ixazomib and carbamazepine; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Enzalutamide: (Major) Avoid the concomitant use of ixazomib and enzalutamide; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Fosphenytoin: (Major) Avoid the concomitant use of ixazomib and phenytoin or fosphenytoin; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of ixazomib and rifampin; ixazomib levels were significantly decreased in a drug interactions evaluation. Ixazomib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. In subjects who received ixazomib with rifampin, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of ixazomib and rifampin; ixazomib levels were significantly decreased in a drug interactions evaluation. Ixazomib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. In subjects who received ixazomib with rifampin, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Phenobarbital: (Major) Avoid the concomitant use of ixazomib and phenobarbital; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of ixazomib and phenobarbital; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Phenytoin: (Major) Avoid the concomitant use of ixazomib and phenytoin or fosphenytoin; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Primidone: (Major) Avoid the concomitant use of ixazomib and primidone; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Rifampin: (Major) Avoid the concomitant use of ixazomib and rifampin; ixazomib levels were significantly decreased in a drug interactions evaluation. Ixazomib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. In subjects who received ixazomib with rifampin, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Rifapentine: (Major) Avoid the concomitant use of ixazomib and rifapentine; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the ixazomib Cmax and AUC by 54% and 74%, respectively.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of ixazomib and St. John's Wort; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.

Ixazomib/NINLARO Oral Cap: 2.3mg, 3mg, 4mg

4 mg/dose PO.

4 mg/dose PO.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

Ixazomib is a reversible proteasome inhibitor that preferentially binds to the beta 5 subunit of the 20S proteasome and inhibits its chymotrypsin-like activity. In vitro, ixazomib induces apoptosis of multiple myeloma cells and exhibits cytotoxicity against myeloma cells from patients who relapsed after prior therapies including bortezomib, lenalidomide, and dexamethasone. Synergistic cytotoxic effects in multiple myeloma cell lines have been observed with ixazomib and lenalidomide. Antitumor activity has been demonstrated with ixazomib in a mouse multiple myeloma tumor xenograft model.

Ixazomib is administered orally. It is highly bound to plasma proteins (99%) distributing into red blood cells with a blood-to-plasma ratio of 1:10. In a population pharmacokinetic (PK) analysis, the steady-state Vd was 543 liters (L), the systemic clearance was about 1.9 L/hour (interindividual variability, 44%), and the terminal half-life was 9.5 days. After oral administration of a radiolabeled dose, 70% of total drug-related material in plasma was the parent drug. In vitro, ixazomib is metabolized by multiple CYP450 isoenzymes (CYP3A4, 42%; CYP1A2, 26%; CYP2B6, 16%; CYP2C8, 6%; CYP2D6, 5%; CYP2C19, 5%; and CYP2C9, < 1%) and non-CYP proteins; no specific CYP isozyme predominantly contributes to ixazomib metabolism at clinically relevant ixazomib concentrations. Following a single oral dose of 14C-ixazomib given to 5 patients with advanced cancer, 62% of the dose radioactivity was recovered in the urine and 22% of the dose radioactivity was recovered in the feces. Less than 3.5% of the dose recovered in the urine was unchanged ixazomib.
 
Affected cytochrome P450 isoenzymes: CYP3A4
Ixazomib is a substrate of multiple CYP450 isoenzymes; CYP3A4 (42%) and CYP1A2 (26%) account for most of the CYP450 metabolism. Avoid the concomitant use of ixazomib and strong CYP3A4 inducers; ixazomib levels and exposure were significantly decreased when ixazomib was administered with rifampin in a drug interaction study. Concomitant use with a strong CYP3A4 inhibitor (clarithromycin) or strong CYP1A2 inhibitors did not result in clinically significant changes in ixazomib systemic exposure. Ixazomib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 or induce CYP1A2, CYP2B6, or CYP3A4/5. It is not expected to produce drug-drug interactions via CYP450 inhibition or induction. Ixazomib is a weak P-glycoprotein substrate. It is not expected to cause transporter-mediated drug-drug interactions. Ixazomib is not a substrate of BCRP, MRP2 or hepatic OATP or an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K.

Following an oral dose of ixazomib, the mean absolute oral bioavailability was 58% and the median Tmax was 1 hour in a population pharmacokinetic analysis. The AUC values increased dose-proportionally over the range of 0.2 to 10.6 mg. The accumulation ratio was 2-fold following weekly oral dosing.
Affects of food: When a 4-mg dose of ixazomib was administered with a high-fat meal, the Cmax and AUC values were decreased by 69% and 28%, respectively. Ixazomib should be given at least 1 hour before or at least 2 hours after food.

Ixazomib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and animal studies. Advise females of reproductive potential to avoid pregnancy while taking ixazomib and for 90 days following the final dose. Discuss the potential hazard to the fetus if ixazomib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including fetal skeletal variations/abnormalities in rabbits and post implantation loss and decreased fetal weight in rats were observed in pregnant animals who received ixazomib at doses that resulted in drug exposures that were higher than those observed with the recommended human dose.

Counsel patients about the reproductive risk and contraception requirements during ixazomib treatment. Females of reproductive potential should avoid pregnancy and use effective non-hormonal contraception (e.g., diaphragm or condom) during and for 90 days after treatment with ixazomib. Dexamethasone is used as part of combination therapy with ixazomib; therefore, the effectiveness of hormone-containing contraceptives may be decreased. Females of reproductive potential should undergo pregnancy testing prior to initiation of ixazomib. Patients who become pregnant while receiving ixazomib should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during therapy and for 90 days following the final dose of ixazomib.