Medically reviewed by Drugs.com. Last updated on June 24, 2020.
(ix AZ oh mib)
- Ixazomib Citrate
- Proteasome Inhibitor MLN9708
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Ninlaro: 2.3 mg, 3 mg, 4 mg
Brand Names: U.S.
- Antineoplastic Agent, Proteasome Inhibitor
Ixazomib reversibly inhibits proteasomes, enzyme complexes which regulate protein homeostasis within the cell. Specifically, it reversibly inhibits chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome, leading to activation of signaling cascades, cell-cycle arrest, and apoptosis.
High-fat meals decreased AUC by 28% and Cmax by 69%.
Likely hepatic via multiple CYP enzymes and non-CYP proteins. At clinically relevant concentrations, no specific CYP isoform contributes predominantly to metabolism; possible CYP isoforms involved in metabolism include CYP3A4, 1A2, 2B6, 2C8, 2D6, 2C19, and 2C9.
Urine (62%; <3.5% as unchanged drug); Feces (22%)
Time to Peak
Median: 1 hour
Terminal: 9.5 days
99% to plasma proteins
Special Populations: Renal Function Impairment
Pharmacokinetics of ixazomib (at a dose of 3 mg) were evaluated in patients with normal renal function (CrCl ≥90 mL/minute), severe impairment (CrCl <30 mL/minute) or ESRD requiring dialysis. The mean AUC was 39% higher in patients with severe renal impairment and in ESRD requiring dialysis (as compared with patients with normal renal function).
Special Populations: Hepatic Function Impairment
Pharmacokinetics of ixazomib were evaluated in patients with normal hepatic function (at a dose of 4 mg), moderate impairment (total bilirubin >1.5 to 3 times ULN) at a dose of 2.3 mg, or severe impairment (total bilirubin <3 times ULN) at a dose of 1.5 mg. Dose-normalized mean AUC was 20% higher in patients with moderate or severe hepatic impairment, as compared to patients with normal hepatic function.
Use: Labeled Indications
Multiple myeloma: Treatment of multiple myeloma (in combination with lenalidomide and dexamethasone) in patients who have received at least one prior therapy
There are no contraindications listed in the manufacturer's labeling.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to ixazomib or any component of the formulation
Note: ANC should be ≥1,000/mm3, platelets should be ≥75,000/mm3, and nonhematologic toxicities should be at baseline or ≤ grade 1 (per prescriber discretion) prior to initiating a new cycle of therapy. Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation.
Multiple myeloma: Oral: 4 mg once weekly on days 1, 8, and 15 of a 28-day treatment cycle (in combination with lenalidomide and dexamethasone); continue until disease progression or unacceptable toxicity (Moreau 2016).
Missed doses: If a dose is delayed or missed, administer only if the next scheduled dose is ≥72 hours away. Do not take a missed dose within 3 days of the next scheduled dose; do not double up on doses to make up for the missed dose. If vomiting occurs, do not repeat the dose; resume dosing at the next scheduled dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing: Adjustment for Toxicity
Also refer to Lenalidomide monograph for dosage modification recommendations.
Recommended ixazomib dosage reductions for toxicity:
Initial starting dose: 4 mg
First dose reduction: 3 mg
Second dose reduction: 2.3 mg
If unable to tolerate 2.3 mg, discontinue ixazomib
Neutropenia: ANC <500/mm3: Withhold ixazomib and lenalidomide until ANC is ≥500/mm3. Consider adding growth-colony stimulating factor (G-CSF). Upon recovery, resume lenalidomide at the next lower dose and resume ixazomib at the dose used prior to therapy interruption. If neutropenia to ≤500/mm3 recurs, interrupt ixazomib and lenalidomide until ANC is ≥500/mm3. Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at the dose used prior to therapy interruption. For additional occurrences, alternate dose modification of lenalidomide and ixazomib.
Thrombocytopenia: Platelet count <30,000/mm3: Withhold ixazomib and lenalidomide until platelet count is ≥30,000/mm3. Upon recovery, resume lenalidomide at the next lower dose and resume ixazomib at the dose used prior to therapy interruption. If thrombocytopenia to ≤30,000/mm3 recurs, interrupt ixazomib and lenalidomide until platelets are ≥30,000/mm3. Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at the dose used prior to therapy interruption. For additional occurrences, alternate dose modification of lenalidomide and ixazomib.
Grade 2 or 3 rash: Withhold lenalidomide until rash recovers to ≤ grade 1. Upon recovery, resume lenalidomide at the next lower dose and resume ixazomib at the dose used prior to therapy interruption. If grade 2 or 3 rash recurs, interrupt ixazomib and lenalidomide until rash recovers to ≤ grade 1. Following recovery, resume ixazomib at the next lower dose and resume lenalidomide at the dose used prior to therapy interruption. For additional occurrences, alternate dose modification of lenalidomide and ixazomib.
Grade 4 rash: Discontinue treatment regimen.
Grade 1 (with pain) or grade 2: Interrupt ixazomib until peripheral neuropathy recovers to ≤ grade 1 without pain or to baseline. Upon recovery, resume ixazomib at the dose used prior to therapy interruption.
Grade 2 (with pain) or grade 3: Withhold ixazomib until recovery to baseline or improvement to ≤ grade 1 (at prescriber’s discretion). Following recovery, resume ixazomib at the next lower dose.
Grade 4: Discontinue treatment regimen.
Other toxicities (nonhematologic): Grade 3 or 4 toxicity: Withhold ixazomib until recovery to baseline or improvement to ≤grade 1 (at prescriber’s discretion). If attributable to ixazomib, resume ixazomib at the next lower dose.
Oral: Administer on the same day of the week and at approximately the same time on that day; take at least 1 hour before or at least 2 hours after eating. Swallow capsule whole; do not crush, chew, or open the capsule. Avoid skin or eye exposure to capsule contents. If skin contact occurs, wash thoroughly with soap and water; if eye contact occurs, flush thoroughly with water.
Store at ≤30°C (86°F). Do not freeze. Store in original packaging until immediately prior to use.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Ixazomib. Avoid combination
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Estrogen Derivatives (Contraceptive): Ixazomib may decrease the serum concentration of Estrogen Derivatives (Contraceptive). More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of estrogen derivative contraceptives. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following ixazomib treatment. Consider therapy modification
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Progestins (Contraceptive): Ixazomib may decrease the serum concentration of Progestins (Contraceptive). More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of contraceptive progestins. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following ixazomib treatment. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
St John's Wort: May decrease the serum concentration of Ixazomib. Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Adverse reaction percentages reported as part of a combination regimen with lenalidomide and dexamethasone.
Cardiovascular: Peripheral edema (25%)
Dermatologic: Skin rash (19%)
Gastrointestinal: Constipation (34%), diarrhea (42%), nausea (26%), vomiting (22%)
Hematologic & oncologic: Neutropenia (67%; grades 3/4: 26%), thrombocytopenia (78%; grades 3/4: 26%)
Nervous system: Peripheral neuropathy (28%; grade 3: 2%), peripheral sensory neuropathy (19%)
Neuromuscular & skeletal: Back pain (21%)
Ophthalmic: Eye disease (26%)
Respiratory: Upper respiratory tract infection (19%)
1% to 10%:
Hepatic: Hepatic insufficiency (6%)
Infection: Herpes zoster infection (4%; <1% with antiviral prophylaxis)
Ophthalmic: Blurred vision (6%), conjunctivitis (6%), xerophthalmia (5%)
Hepatic: Cholestatic hepatitis, hepatocellular hepatitis, hepatotoxicity, liver steatosis
Nervous system: Peripheral motor neuropathy
Dermatologic: Stevens-Johnson syndrome, Sweet's syndrome
Hematologic & oncologic: Hemolytic-uremic syndrome, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, tumor lysis syndrome
Nervous system: Reversible posterior leukoencephalopathy syndrome, transverse myelitis
Concerns related to adverse effects:
• Bone marrow suppression: Neutropenia and thrombocytopenia were reported commonly in clinical trials; grade 3 and 4 toxicity was also observed. Platelet nadirs generally occurred between days 14 to 21 of each cycle with a recovery to baseline by the start of the subsequent cycle. Monitor platelet counts at least monthly during treatment, and consider more frequent monitoring during the initial 3 cycles. May require therapy interruption, dosage reduction and/or platelet transfusions. Monitor complete blood counts (with differential) for neutropenia; therapy interruption or dosage modification may be necessary.
• Dermatologic toxicity: Rash was reported with ixazomib use; the majority of cases were grade 1 or 2 (grade 3 rash was observed in a small number of patients). Maculopapular and macular rashes were the most commonly reported cutaneous reactions. Monitor for dermatologic toxicity and manage with supportive care or with dosage modification of ixazomib and/or lenalidomide (for grade 2 or higher toxicity).
• Gastrointestinal toxicity: Diarrhea, constipation, nausea, and vomiting have been reported. Antidiarrheals, antiemetics, and supportive care may be required to manage toxicity. Dosage adjustment is recommended for grade 3 or 4 symptoms.
• Hepatotoxicity: Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity were reported rarely in clinical trials. Monitor liver enzymes regularly; may require dosage adjustment for grade 3 or 4 toxicity.
• Herpes zoster infection: Herpes zoster infection has been reported; patients receiving antiviral prophylaxis had a lower incidence of infection. Consider antiviral prophylaxis during ixazomib treatment to decrease the risk of herpes zoster reactivation.
• Peripheral edema: Peripheral edema was reported in one-quarter of patients receiving ixazomib (generally grade 1 or 2 reactions). If peripheral edema occurs, evaluate for potential underlying causes and provide supportive care. If necessary, grade 3 or 4 symptoms may require dosage adjustment of dexamethasone and/or ixazomib.
• Peripheral neuropathy: Peripheral neuropathy (mostly grade 1 or 2) was observed. Peripheral sensory neuropathy was the most commonly reported symptom, while peripheral motor neuropathy was rarely seen. Monitor closely for signs/symptoms of neuropathy; may require dosage adjustment (of ixazomib and/or lenalidomide) or treatment discontinuation.
• Thrombotic microangiopathy: Thrombotic microangiopathy, including cases of thrombocytopenic thrombotic purpura/hemolytic uremic syndrome (TTP/HUS) has been reported (some fatal); monitor for signs/symptoms. Interrupt therapy if TTP/HUS diagnosis is suspected and manage appropriately. If TTP/HUS diagnosis is excluded, may consider reinitiating therapy; the safety of restarting ixazomib after a TTP/HUS diagnosis is not known.
• Hepatic impairment: Reduced initial doses are recommended for patients with moderate and severe hepatic impairment (exposure is increased).
• Renal impairment: Reduced initial doses are recommended for patients with CrCl less than 30 mL/minute or end stage renal disease requiring dialysis (exposure is increased). Concomitant lenalidomide may also require dose reduction.
Platelet counts at least monthly during treatment (consider more frequent monitoring during the first 3 cycles), complete blood count (with differential) as clinically necessary, renal and liver function tests; signs/symptoms of gastrointestinal and dermatologic toxicity; signs/symptoms of peripheral neuropathy and peripheral edema.
Males and females of reproductive potential should use effective contraception during therapy and for 90 days after the last dose. Women using hormonal contraception should also use a barrier method.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to ixazomib may cause fetal harm.
When used for the treatment of multiple myeloma, ixazomib is indicated to be used with lenalidomide and dexamethasone. Lenalidomide is contraindicated for use during pregnancy (refer to Lenalidomide monograph for details).
What is this drug used for?
• It is used to treat multiple myeloma.
All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
• Back pain
WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
• Burning or numbness feeling
• Swelling in the arms or legs
• Weight gain
• Skin discoloration
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome like bruising or bleeding; loss of strength and energy; dark urine or yellow skin; pale skin; change in amount of urine passed; vision changes; change in strength on one side is greater than the other, trouble speaking or thinking, change in balance; or fever
• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Vision changes
• Eye pain
• Severe eye irritation
• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.
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More about ixazomib
- Side Effects
- During Pregnancy or Breastfeeding
- Dosage Information
- Drug Interactions
- En Español
- 3 Reviews
- Drug class: proteasome inhibitors
Other brands: Ninlaro