Usual Adult Dose for Multiple Myeloma

Starting dose: 4 mg orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle
Duration of therapy: Until disease progression or unacceptable toxicity

Comments:

• Limitations of Use: This drug 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.
• The recommended starting dose of lenalidomide is 25 mg orally daily on Days 1 through 21 of a 28-day treatment cycle; the recommended starting dose of dexamethasone is 40 mg orally on Days 1, 8, 15, and 22 of a 28-day treatment cycle.
• The manufacturer product information for lenalidomide and dexamethasone should each be consulted.

Use: In combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least 1 prior therapy

Renal Dose Adjustments

Severe renal dysfunction (CrCl less than 30 mL/min): The starting dose should be reduced to 3 mg.

Liver Dose Adjustments

Moderate (total bilirubin greater than 1.5 to 3 times the upper limit of normal [1.5 to 3 x ULN]) or severe (total bilirubin greater than 3 x ULN) liver dysfunction: The starting dose should be reduced to 3 mg.

Dose Adjustments

DOSE REDUCTIONS DUE TO ADVERSE REACTIONS:

• Recommended starting dose: 4 mg
• First reduction to: 3 mg
• Second reduction to: 2.3 mg
• After second reduction: This drug should be discontinued.

An alternating dose modification approach is recommended for this drug and lenalidomide for thrombocytopenia, neutropenia, and rash as described below. The manufacturer product information for lenalidomide should be consulted if dose reduction is needed for lenalidomide.

DOSE MODIFICATION GUIDELINES FOR THIS DRUG IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE:
Thrombocytopenia (Platelet Count):

• Platelet count less than 30,000/mm3:
• This drug and lenalidomide should be withheld until platelet count is at least 30,000/mm3.
• After recovery, lenalidomide should resume at the next lower dose according to its product information and this drug should resume at its most recent dose.
• If platelet count falls to less than 30,000/mm3 again, this drug and lenalidomide should be withheld until platelet count is at least 30,000/mm3.
• After recovery, this drug should resume at the next lower dose and lenalidomide should resume at its most recent dose.
• For additional occurrences, dose modification of lenalidomide and this drug should alternate.

Neutropenia (Absolute Neutrophil Count):

• Absolute neutrophil count less than 500/mm3:
• This drug and lenalidomide should be withheld until absolute neutrophil count is at least 500/mm3; addition of granulocyte-colony stimulating factor as per clinical guidelines should be considered.
• After recovery, lenalidomide should resume at the next lower dose according to its product information and this drug should resume at its most recent dose.
• If absolute neutrophil count falls to less than 500/mm3 again, this drug and lenalidomide should be withheld until absolute neutrophil count is at least 500/mm3.
• After recovery, this drug should resume at the next lower dose and lenalidomide should resume at its most recent dose.
• For additional occurrences, dose modification of lenalidomide and this drug should alternate.

Rash:

• Grade 2 or 3:
• Lenalidomide should be withheld until rash recovers to Grade 1 or lower.
• After recovery, lenalidomide should resume at the next lower dose according to its product information.
• If Grade 2 or 3 rash occurs again, this drug and lenalidomide should be withheld until rash recovers to Grade 1 or lower.
• After recovery, this drug should resume at the next lower dose and lenalidomide should resume at its most recent dose.
• For additional occurrences, dose modification of lenalidomide and this drug should alternate.
• Grade 4: This treatment regimen should be discontinued.

Peripheral Neuropathy:

• Grade 1 peripheral neuropathy with pain or Grade 2 peripheral neuropathy:
• This drug should be withheld until peripheral neuropathy recovers to Grade 1 or lower without pain or patient's baseline.
• After recovery, this drug should resume at its most recent dose.
• Grade 2 peripheral neuropathy with pain or Grade 3 peripheral neuropathy:
• This drug should be withheld; toxicities should (at the health care provider's discretion) generally recover to patient's baseline condition or Grade 1 or lower before resuming this drug.
• After recovery, this drug should resume at the next lower dose.
• Grade 4 peripheral neuropathy: This treatment regimen should be discontinued.

Other Nonhematological Toxicities:

• Other Grade 3 or 4 nonhematological toxicities:
• This drug should be withheld; toxicities should (at the health care provider's discretion) generally recover to patient's baseline condition or Grade 1 or lower before resuming this drug.
• If attributable to this drug, it should resume at the next lower dose after recovery.

Precautions

CONTRAINDICATIONS: None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

ESRD requiring dialysis: The starting dose should be reduced to 3 mg.

Comments:

• This drug is not dialyzable; it can be administered without regard to the timing of dialysis.

Other Comments

Administration advice:

• Before starting a new cycle of therapy, absolute neutrophil count should be at least 1000/mm3, platelet count should be at least 75,000/mm3, and nonhematologic toxicities should (at the health care provider's discretion) generally be recovered to patient's baseline condition or Grade 1 or lower.
• Administer once a week on the same day at about the same time for the first 3 weeks of a 4-week cycle.
• Administer at least 1 hour before or at least 2 hours after food.
• Swallow the capsule whole with water; do not crush, chew, or open the capsule.

Storage requirements:

• Store at room temperature in original packaging until immediately prior to use.
• Do not store above 30C (86F); do not freeze.

General:

• This is a hazardous drug; applicable special handling and disposal procedures should be followed.
• Direct contact with capsule contents should be avoided; if a capsule breaks, direct contact of capsule contents with the skin or eyes should be avoided.
• If contact with the skin occurs, the skin should be washed thoroughly with soap and water; if contact with the eyes occurs, the eyes should be flushed thoroughly with water.
• The importance of carefully following all dosage instructions should be discussed with patients starting therapy.
• Antiviral prophylaxis should be considered during therapy to decrease the risk of herpes zoster reactivation.

Monitoring:

• Hematologic: Platelet counts (at least monthly during therapy; more frequently during the first 3 cycles may be considered); for signs/symptoms of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
• Hepatic: Hepatic enzymes (regularly)
• Nervous system: For symptoms of neuropathy

Patient advice:

• Read the US FDA-approved patient labeling (Patient Information).
• Take the recommended dosage as directed; overdosage has led to deaths.
• If a dose is missed or delayed, take the dose only if the next scheduled dose is at least 72 hours away; do not take a missed dose if it is within 72 hours of the next scheduled dose. Do not take a double dose to make up for the missed dose.
• If vomiting occurs after taking a dose, do not repeat the dose but resume dosing at the time of the next scheduled dose.
• Contact health care providers if gastrointestinal toxicities (e.g., diarrhea, constipation, nausea, vomiting) persist.
• Contact health care providers if new/worsening symptoms of peripheral neuropathy (e.g., tingling, numbness, pain, burning feeling in the feet/hands, weakness in the arms/legs) occur.
• Contact health care providers if you have unusual swelling of your extremities or weight gain due to swelling.
• Contact health care providers immediately if new/worsening rash develops.
• Seek immediate medical attention if any signs/symptoms of thrombotic microangiopathy occur.
• Contact health care providers if jaundice or right upper quadrant abdominal pain occurs.
• Contact health care providers if signs/symptoms of acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, herpes zoster, cataracts, dry eyes, blurred vision, conjunctivitis, or thrombotic thrombocytopenic purpura occur.
• Patients of childbearing potential: Use effective contraception during therapy and for 90 days after the last dose; if using hormonal contraceptives, also use a barrier method of contraception. Inform your health care provider of a known/suspected pregnancy.
• Male patients with partners of childbearing potential: Use effective contraception during therapy and for 90 days after the last dose.
• Do not breastfeed during therapy and for 90 days after the last dose.

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