NINLARO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NINLARO (NINLARO).
Ixazomib is a reversible proteasome inhibitor that preferentially binds and inhibits the chymotrypsin-like activity of the 20S proteasome, leading to accumulation of misfolded proteins, induction of apoptosis, and inhibition of cell growth in multiple myeloma cells.
| Metabolism | Metabolized primarily by multiple cytochrome P450 enzymes (CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1) and non-CYP enzymes; less than 20% excreted unchanged in urine. |
| Excretion | Following oral administration of 14C-ixazomib, approximately 80% of the radioactivity is recovered in urine (11% as unchanged drug) and 5% in feces. |
| Half-life | The terminal elimination half-life of ixazomib is 9.5 days, supporting once-weekly dosing. |
| Protein binding | 99% bound to human plasma proteins, primarily albumin. |
| Volume of Distribution | The volume of distribution (Vd) is approximately 0.79 L/kg, indicating extensive distribution into extravascular tissues. |
| Bioavailability | Oral bioavailability is approximately 58% (range 52-65%) when administered under fasting conditions; high-fat meal reduces AUC by 30%. |
| Onset of Action | Not applicable; pharmacodynamic effects (proteasome inhibition) are observed within 1 hour post-dose. |
| Duration of Action | Proteasome inhibition persists for at least 168 hours (7 days) based on 20S proteasome activity assay. |
4 mg orally once weekly on days 1, 8, and 15 of a 28-day cycle, in combination with lenalidomide and dexamethasone.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for creatinine clearance >30 mL/min. For end-stage renal disease requiring hemodialysis, reduce dose to 3 mg orally once weekly. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce to 3 mg orally once weekly. Child-Pugh Class C: Avoid use; not recommended. |
| Pediatric use | Safety and efficacy not established; no approved pediatric dosing recommendations. |
| Geriatric use | No specific dose adjustment based on age alone; monitor for toxicity, especially in patients aged ≥70 years due to potential increased risk of adverse reactions. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NINLARO (NINLARO).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Excretion in animal milk is unknown. Due to potential for serious adverse reactions (e.g., hematologic toxicity, gastrointestinal toxicity) in breastfed infants, advise patients not to breastfeed during treatment and for at least 90 days after the last dose. M/P ratio not available. |
| Teratogenic Risk | NINLARO (ixazomib) is a proteasome inhibitor. Based on its mechanism of action and animal studies, there is potential for fetal harm. In pregnant rats, ixazomib caused embryofetal toxicity (increased resorptions, decreased fetal body weight) and malformations (skeletal variations) at maternal exposures below the clinical dose. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy should be avoided; if used, advise patient of potential risks. First trimester: high risk of structural abnormalities. Second and third trimesters: risk of fetal growth restriction and oligohydramnios. |
■ FDA Black Box Warning
None
| Serious Effects |
["Hypersensitivity to ixazomib or any component of the formulation"]
| Precautions | ["Thrombocytopenia","Gastrointestinal toxicities (nausea, vomiting, diarrhea, constipation)","Peripheral neuropathy","Peripheral edema","Hepatotoxicity","Cardiac toxicities","Posterior reversible encephalopathy syndrome (PRES)","Thrombotic microangiopathy (TMA)"] |
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| Fetal Monitoring | Monitor complete blood counts (CBC) at baseline and periodically during treatment due to risk of thrombocytopenia, neutropenia, and anemia. Monitor for gastrointestinal toxicity (nausea, vomiting, diarrhea) and manage with supportive care. Assess hepatic function (bilirubin, AST, ALT) at baseline and as needed. In pregnant patients, monitor fetal growth with ultrasound and assess amniotic fluid volume periodically. |
| Fertility Effects | Ixazomib has not been studied for effects on human fertility. In animal studies, no adverse effects on male or female fertility were observed in rats at doses up to 2 mg/kg (approximately 1.5 times the clinical dose based on AUC). However, based on its mechanism (proteasome inhibition) and potential for off-target effects, reversible impairment of spermatogenesis or oogenesis cannot be excluded. Advise patients of potential risk of impaired fertility. |