Dosing and uses of Ninlaro (ixazomib)
Adult dosage forms and strengths
capsule
- 2.3mg
- 3mg
- 4mg
Multiple Myeloma
Indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy
Treatment should be continued until disease progression or unacceptable toxicity
Starting doses
- Ixazomib: 4 mg PO on days 1, 8, and 15 of a 28-day cycle; take 1 hr ac or 2 hr pc
- Lenalidomide: 25 mg PO on days 1-21 of a 28-day cycle; take with or without food
- Dexamethasone: 40 mg PO in morning on days 1, 8, 15, and 22 of a 28-day cycle
Dosage modifications
Also refer to lenalidomide monograph
Hepatic impairment
- Mild: No dosage adjustment required
- Moderate (TB >1.5-3 x ULN) or severe (TB >3 ULN): Decrease starting dose to 3 mg
Renal impairment
- Mild-to-moderate: No dosage adjustment required
- Severe (CrCl <30 mL/min) or ESRD requiring dialysis: Decrease starting dose to 3 mg; ixazomib is not dialyzable and therefore can be administered without regard to the timing of dialysis
Dose reductions
- If starting dose is 4 mg
- First reduction to: 3 mg
- Second reduction to: 2.3 mg
Thrombocytopenia
- Platelet count <30,000/mm³
- Withhold ixazomib and lenalidomide until platelet count is at least 30,000/mm³
- Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume ixazomib at its most recent dose
- If platelet count falls to <30,000/mm³ again, withhold ixazomib and lenalidomide until platelet count is at least 30,000/mm³
- Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at its most recent dose*
- *For additional occurrences, alternate dose modification of lenalidomide and ixazomib
Neutropenia
- ANC count <500/mm³
- Withhold ixazomib and lenalidomide until ANC is at least 500/mm³
- Consider adding G-CSF as per clinical guidelines
- Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume ixazomib at its most recent dose
- If ANC falls to <500/mm³ again, withhold ixazomib and lenalidomide until ANC is at least 500/mm³
- Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at its most recent dose*
- *For additional occurrences, alternate dose modification of lenalidomide and ixazomib
Rash
- Grade 2 or 3
- Withhold lenalidomide until rash recovers to ≤grade 1
- Following recovery, resume lenalidomide at the next lower dose according to its prescribing information
- If grade 2 or 3 rash occurs again, withhold ixazomib and lenalidomide until rash recovers to ≤grade 1
- Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at its most recent dose*
- *For additional occurrences, alternate dose modification of lenalidomide and ixazomib
- Grade 4
- Discontinue treatment regimen
Peripheral neuropathy
- Grade 1 with pain or grade 2
- Withhold ixazomib until peripheral neuropathy recovers to ≤grade 1 without pain or patient's baseline
- Following recovery, resume ixazomib at its most recent dose
- Grade 2 with pain or grade 3
- Withhold ixazomib
- Toxicities should, at the physician’s discretion, generally recover to patient’s baseline condition or ≤grade 1 prior to resuming ixazomib
- Following recovery, resume ixazomib at the next lower dose
- Grade 4
- Discontinue treatment regimen
Other nonhematologic toxicities
- Withhold ixazomib
- Toxicities should, at the physician’s discretion, generally recover to patient’s baseline condition or ≤grade 1 prior to resuming ixazomib
- If attributable to ixazomib, resume at the next lower dose following recovery
Dosing Considerations
Monitor before each new cycle of therapy
- ANC should be at least 1,000/mm³
- Platelet count should be at least 75,000/mm³
- Nonhematologic toxicities should, at the physician’s discretion, generally be recovered to patient’s baseline condition or ≤grade 1
Pediatric dosage forms and strengths
Safety and efficacy not established
Ninlaro (ixazomib) adverse (side) effects
Percentages listed are for any grade toxicity unless otherwise stated
>10%
Thrombocytopenia (78%)
Neutropenia (67%)
Diarrhea (42%)
Constipation (34%)
Peripheral neuropathies (28%)
Nausea (26%)
Thrombocytopenia, grade 3-4 (26%)
Neutropenia, grade 3-4 (26%)
Peripheral edema (25%)
Vomiting (22%)
Back pain (21%)
Upper respiratory tract infection (19%)
Rash (19%)
1-10%
Diarrhea, grade 3 (6%)
Blurred vision (6%)
Conjunctivitis (6%)
Dry eye (5%)
Rash, grade 3 (3%)
Peripheral edema (2%)
Peripheral neuropathies, grade 3 (2%)
Nausea, grade 3 (2%)
Vomiting, grade 3 (1%)
<1%
Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic, and hepatotoxicity
Upper respiratory tract infection, grade 3
Constipation, grade 3
Back pain, grade 3
Acute febrile neutrophilic dermatosis (Sweet syndrome)
Stevens-Johnson syndrome
Transverse myelitis
Posterior reversible encephalopathy syndrome
Tumor lysis syndrome
Thrombotic thrombocytopenic purpura
Warnings
Contraindications
None
Cautions
Thrombocytopenia reported with platelet nadirs typically occurring between days 14 and 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; consider more frequent monitoring during the first 3 cycles (see Dosage modifications)
Diarrhea, constipation, nausea, and vomiting reported, occasionally requiring use of antidiarrheals, antiemetics, and supportive care
Peripheral neuropathy was reported (majority grade 1); the most commonly reported reaction was peripheral sensory neuropathy; monitor for symptoms; new or worsening peripheral neuropathy may require dose modification (see Dosage modifications)
Peripheral edema reported; adjust dosing of dexamethasone per its prescribing information or ixazomib for grade 3 or 4 symptoms (see Dosage modifications)
Cutaneous reactions reported, the most common types being maculopapular and macular rash; manage with supportive care or with dose modification if ≥grade 2 (see Dosage modifications)
Rare occurrence of drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic, and hepatotoxicity reported; monitor hepatic enzymes regularly and adjust dosing for grade 3 or 4 symptoms (see Dosage modifications)
Can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animals (see Pregnancy)
Drug interaction overview
- Avoid coadministration with strong CYP3A inducers
- Coadministration with a strong CYP3A inhibitor (ie, clarithromycin) did not result in a clinically meaningful change in the systemic exposure of ixazomib
Pregnancy and lactation
Pregnancy
Can cause fetal harm when administered to a pregnant woman
There are no human data available regarding the potential effect of ixazomib on pregnancy or development of the embryo or fetus
Animal studies
- Ixazomib caused embryofetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose
- Increases in fetal skeletal variations/abnormalities (fused caudal vertebrae, number of lumbar vertebrae, and full supernumerary ribs) in rabbit studies
- Decrease fetal weights, a trend towards decreased fetal viability, and increased postimplantation losses were observed in rat studies
Contraception
- Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated
- Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment
Lactation
Unknown if distributed in human breast milk
Advise women to discontinue nursing
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Ninlaro (ixazomib)
Mechanism of action
Reversible proteasome inhibitor; preferentially binds and inhibits the chymotrypsinlike activity of the beta 5 subunit of the 20S proteasome
Absorption
Absolute bioavailability: 58%
Peak plasma time: 1 hr
A food effect study conducted in patients with a single 4-mg dose showed that a high-fat meal decreased AUC by 28% and Cmax by 69% (see Administration)
Distribution
Protein bound: 99% bound to plasma proteins and distributes into RBCs with a blood-to-plasma ratio of 10
Vd: 543 L
Metabolism
Metabolism by multiple CYP enzymes and non-CYP proteins is expected to be the major clearance mechanism
Elimination
Half-life: 9.5 days
Systemic clearance: 1.9 L/hr
Excretion: 62% urine (<3.5% unchanged); 22% feces
Administration
Oral Administration
Take once a week on the same day and at approximately the same time for the first 3 weeks of a 4-week cycle
Taken at least 1 hr before or at least 2 hr after food
Swallow capsule whole with water; do not crush, chew, or open (see Storage and Chemotherapy Handling)
Missed or vomited dose
- If a dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥72 hr away
- A missed dose should not be taken within 72 hr of the next scheduled dose
- A double dose should not be taken to make up for the missed dose
- If vomiting occurs after taking a dose, the patient should not repeat the dose; resume dosing at the time of the next scheduled dose
Storage
Store at room temperature; not to exceed 30°C (86°F)
Do not freeze
Store capsules in original packaging until immediately prior to use
Chemotherapy handling and disposaL
- Ixazomib is cytotoxic
- Capsules should not be opened or crushed
- Direct contact with the capsule contents should be avoided
- In case of capsule breakage, avoid direct contact of capsule contents with the skin or eyes
- If contact occurs with the skin, wash thoroughly with soap and water
- If contact occurs with the eyes, flush thoroughly with water
- Any unused medicinal product or waste material should be disposed in accordance with local requirements
