Ixazomib
FDA Drug Information • Also known as: Ninlaro
- Brand Names
- Ninlaro
- Route
- ORAL
- Dosage Form
- CAPSULE
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Ixazomib is a proteasome inhibitor. Ixazomib citrate, a prodrug, rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib. The chemical name of ixazomib citrate is 1,3,2-dioxaborolane-4,4-diacetic acid, 2-[(1 R )-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo- and the structural formula is: The molecular formula for ixazomib citrate is C 20 H 23 BCl 2 N 2 O 9 and its molecular weight is 517.12. Ixazomib citrate has one chiral center and is the R-stereoisomer. The solubility of ixazomib citrate in 0.1N HCl (pH 1.2) at 37°C is 0.61 mg/mL (reported as ixazomib). The solubility increases as the pH increases. NINLARO (ixazomib) capsules for oral use contain 4, 3 or 2.3 mg of ixazomib equivalent to 5.7, 4.3 or 3.3 mg of ixazomib citrate, respectively. Inactive ingredients include microcrystalline cellulose, magnesium stearate, and talc. Capsule shells contain gelatin and titanium dioxide. The 4 mg capsule shell contains red and yellow iron oxide, the 3 mg capsule shell contains black iron oxide and the 2.3 mg capsule shell contains red iron oxide. The printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide. Chemical Structure
What Is Ixazomib Used For?
1 INDICATIONS AND USAGE NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. ( 1 ) Limitations of Use : NINLARO is 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. ( 1 ) Limitations of Use : NINLARO is 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 [see Warnings and Precautions (5.9) and Clinical Studies (14.2 , 14.3) ] .
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15 of a 28-day cycle. ( 2.1 ) Dose should be taken at least one hour before or at least two hours after food. ( 2.1 ) 2.1 Dosing and Administration Guidelines NINLARO in combination with lenalidomide and dexamethasone The recommended starting dose of NINLARO is 4 mg administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle. The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 through 21 of a 28-day treatment cycle. The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle. Table 1: Dosing Schedule for NINLARO taken with Lenalidomide and Dexamethasone ✔ Take medicine 28-Day Cycle (a 4-week cycle) Week 1 Week 2 Week 3 Week 4 Day 1 Days 2-7 Day 8 Days 9-14 Day 15 Days 16-21 Day 22 Days 23-28 NINLARO ✔ ✔ ✔ Lenalidomide ✔ ✔ Daily ✔ ✔ Daily ✔ ✔ Daily Dexamethasone ✔ ✔ ✔ ✔ For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information. NINLARO should be taken once a week on the same day and at approximately the same time for the first three weeks of a four week cycle. The importance of carefully following all dosage instructions should be discussed with patients starting treatment. Instruct patients to take the recommended dosage as directed, because overdosage has led to deaths [see Overdosage (10) ] . NINLARO should be taken at least one hour before or at least two hours after food [see Clinical Pharmacology (12.3) ] . The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened [see How Supplied/Storage and Handling (16) ] . If a NINLARO dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥72 hours away. A missed dose should not be taken within 72 hours 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. The patient should resume dosing at the time of the next scheduled dose. Prior to initiating a new cycle of therapy: Absolute neutrophil count should be at least 1,000/mm 3 Platelet count should be at least 75,000/mm 3 Non-hematologic toxicities should, at the healthcare provider's discretion, generally be recovered to patient's baseline condition or Grade 1 or lower Treatment should be continued until disease progression or unacceptable toxicity. Concomitant Medications Consider antiviral prophylaxis in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation [see Adverse Reactions (6.1) ] . 2.2 Dosage Modification Guidelines The NINLARO dose reduction steps are presented in Table 2 and the dosage modification guidelines are provided in Table 3. Table 2: NINLARO Dose Reductions due to Adverse Reactions Recommended starting dose Recommended starting dose of 3 mg in patients...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following adverse reactions are described in detail in other sections of the prescribing information: Thrombocytopenia [see Warnings and Precautions (5.1) ] Gastrointestinal Toxicities [see Warnings and Precautions (5.2) ] Peripheral Neuropathy [see Warnings and Precautions (5.3) ] Peripheral Edema [see Warnings and Precautions (5.4) ] Cutaneous Reactions [see Warnings and Precautions (5.5) ] Thrombotic Microangiopathy [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] The most common adverse reactions (≥20%) are thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-617-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population from the randomized, double-blind, placebo-controlled clinical study included 720 patients with relapsed and/or refractory multiple myeloma, who received NINLARO in combination with lenalidomide and dexamethasone (NINLARO regimen; N=361) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=359). The most frequently reported adverse reactions (≥20% with a difference of ≥5% compared to placebo) in the NINLARO regimen were thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis. Serious adverse reactions reported in ≥2% of patients in the NINLARO regimen included diarrhea (3%), thrombocytopenia (2%) and bronchitis (2%). One or more of the three drugs was permanently discontinued in 4% of patients reporting peripheral neuropathy, 3% of patients reporting diarrhea and 2% of patients reporting thrombocytopenia. Permanent discontinuation of NINLARO due to an adverse reaction occurred in 10% of patients. Table 4 summarizes the non-hematologic adverse reactions occurring in at least 5% of patients with at least a 5% difference between the NINLARO regimen and the placebo regimen. Table 4: Non-Hematologic Adverse Reactions Occurring in ≥5% of Patients with a ≥5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4) System Organ Class / Preferred Term NINLARO + Lenalidomide and Dexamethasone N=361 Placebo + Lenalidomide and Dexamethasone N=359 % % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Note: Adverse reactions included as preferred terms are based on MedDRA version 23.0. Gastrointestinal disorders Diarrhea 52 10 0 43 3 0 Constipation 35 <1 0 28 <1 0 Nausea 32 2 0 23 0 0 Vomiting 26 1 0 13 <1 0 Nervous system disorders Peripheral neuropathies Represents a pooling of preferred terms 32 2 0 24 2 0 Musculoskeletal and connective tissue disorders Back pain At the time of the final analysis, these adverse reactions no longer met the criterion for a ≥5% difference between the NINLARO regimen and the placebo regimen. 27 <1 0 24 3 0 Infections and infestations Upper respiratory tract infection 27 1 0 23 1 0 Bronchitis 22 2 0 17 2 <1 Skin and subcutaneous tissue disorders Rash 27 3 0 16 2 0 General disorders and administration site conditions Edema peripheral 27 2 0 21 1 0 Table 5 represents pooled information from adverse event and laboratory data. Table 5: Thrombocytopenia and Neutropenia NINLARO + Lenalidomide and Dexamethasone N=361 Placebo + Lenalidomide and Dexamethasone N=359 % % Any Grade Grade 3-4 Any Grade Grade 3-4 Thrombocytopenia 85 30 67 14 Neutropenia 74 34 70 37 Herpes Zoster Herpes zoster was reported in 6% of patients in the NINLARO regimen and 3% of patients in the placebo regimen. Antiviral prophylaxis was...
Drug Interactions
7 DRUG INTERACTIONS Strong CYP3A inducers : Avoid concomitant use with NINLARO. ( 7.1 , 12.3 ) 7.1 Strong CYP3A Inducers Avoid concomitant administration of NINLARO with strong CYP3A inducers (such as rifampin, phenytoin, carbamazepine, and St. John's Wort) [see Clinical Pharmacology (12.3) ] .
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and data from animal reproduction studies, NINLARO can cause fetal harm when administered to a pregnant woman. There are 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 (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal variations/abnormalities (fused caudal vertebrae, number of lumbar vertebrae, and full supernumerary ribs) at doses that were also maternally toxic (≥0.3 mg/kg). Exposures in the rabbit at 0.3 mg/kg were 1.9 times the clinical time averaged exposures at the recommended dose of 4 mg. In a rat dose range-finding embryo-fetal development study, at doses that were maternally toxic, there were decreases in fetal weights, a trend towards decreased fetal viability, and increased post-implantation losses at 0.6 mg/kg. Exposures in rats at the dose of 0.6 mg/kg was 2.5 times the clinical time averaged exposures at the recommended dose of 4 mg.
Overdosage
10 OVERDOSAGE Overdosage, including fatal overdosage, has been reported in patients taking NINLARO. Manifestations of overdosage include adverse reactions reported at the recommended dosage [see Dosage and Administration (2.1) , Adverse Reactions (6.1) ] . Serious adverse reactions reported with overdosage include severe nausea, vomiting, diarrhea, aspiration pneumonia, multiple organ failure and death. In the event of an overdosage, monitor for adverse reactions and provide appropriate supportive care. NINLARO is not dialyzable.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied NINLARO is supplied as follows: Strength per Capsule Capsule Description Outer Carton 3 Count Blister Pack 1 Count Blister Pack NDC 4 mg Light orange, size 3, imprinted with "Takeda" on the cap and "4 mg" on the body in black ink. Three 4 mg capsules in a carton Each blister pack has three 4 mg capsules Each blister pack has one 4 mg capsule Outer carton NDC 63020-400-02 3 Count Blister Pack NDC 63020-400-03 1 Count Blister pack NDC 63020-400-01 3 mg Light grey, size 4, imprinted with "Takeda" on the cap and "3 mg" on the body in black ink. Three 3 mg capsules in a carton Each blister pack has three 3 mg capsules Each blister pack has one 3 mg capsule Outer carton NDC 63020-390-02 3 Count Blister Pack NDC 63020-390-03 1 Count Blister pack NDC 63020-390-01 2.3 mg Light pink, size 4, imprinted with "Takeda" on the cap and "2.3 mg" on the body in black ink. Three 2.3 mg capsules in a carton Each blister pack has three 2.3 mg capsules Each blister pack has one 2.3 mg capsule Outer carton NDC 63020-230-02 3 Count Blister Pack NDC 63020-230-03 1 Count Blister pack NDC 63020-230-01 Capsules are individually packaged in a PVC-Aluminum/Aluminum blister. Storage Store NINLARO at room temperature. Do not store above 30°C (86°F). Do not freeze. Store capsules in original packaging until immediately prior to use. Handling and Disposal NINLARO is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Do not open or crush capsules. Avoid direct contact with the capsule contents. 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.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.