Dosing & Administration for NINLARO^® (ixazomib)

NINLARO is taken as part of a triplet oral therapy—an all-oral PI-based regimen.¹

NINLARO (ixazomib) REGIMEN* DOSING SCHEDULE

An all-oral, PI-based regimen your patients can take at home^1-3

Dosing Schedule¹

The NINLARO® (ixazomib) regimen 28‐day dosing schedule.

A NINLARO (ixazomib) dose is administered orally on days 1, 8, and 15 of a 28-day cycle.
A lenalidomide dose is administered orally on days 1-21 of a 28-day cycle.
A dexamethasone dose is administered orally on days 1, 8, 15, and 22 of a 28-day cycle.
Please note that there is NO DOSING on days 23-28.

DOWNLOAD THE NINLARO DOSING GUIDE

Advise patients to take NINLARO once a week on the same day and at approximately the same time for the first 3 weeks of a 4-week cycle. The importance of carefully following all dosage instructions should be discussed with patients starting treatment. Advise patients to take the recommended dosage as directed because overdosage has led to deaths
The recommended starting dose of NINLARO is 4 mg (one capsule) in combination with lenalidomide and dexamethasone¹
A 3 mg starting dose is recommended for patients with moderate or severe hepatic impairment and patients with severe renal impairment or ESRD requiring dialysis. A 2.3 mg dose is also available for subsequent dose reductions due to ARs¹

*The NINLARO regimen includes NINLARO + lenalidomide + dexamethasone.¹
AR=adverse reaction; ESRD=end-stage renal disease; PI=proteasome inhibitor.

Available NINLARO (ixazomib) strengths¹

A 4 mg starting NINLARO (ixazomib) dose is recommended in combination with lenalidomide and dexamethasone. NINLARO is available in the following capsule strengths¹*:

The recommended starting NINLARO (ixazomib) dose is 4 mg (one capsule).¹

A 3 mg starting NINLARO (ixazomib) dose is recommended for patients with moderate or severe hepatic impairment and patients with severe renal impairment or ESRD requiring dialysis.¹

A 2.3 mg NINLARO (ixazomib) dose is also available for subsequent dose reductions due to ARs.¹

*Not actual capsule size.
ARs=adverse reactions; ESRD=end-stage renal disease.

DOSAGE MODIFICATION GUIDELINES¹

Thrombocytopenia

Platelet count <30,000/mm³

Withhold NINLARO 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 NINLARO at its most recent dose

If platelet count falls to <30,000/mm³ again

Withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm³
Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose*

Neutropenia

Absolute neutrophil count <500/mm³

Withhold NINLARO and lenalidomide until absolute neutrophil count 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 NINLARO at its most recent dose

If absolute neutrophil count falls to <500/mm³ again

Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm³
Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose*

Rash

Grade^† 2 or 3

Withhold lenalidomide until rash recovers to grade 1 or lower
Following recovery, resume lenalidomide at the next lower dose according to its Prescribing Information

If grade 2 or 3 rash occurs again

Withhold NINLARO and lenalidomide until rash recovers to grade 1 or lower
Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose*

Grade 4

Discontinue treatment regimen

Peripheral Neuropathy

Grade 1 with pain or grade 2

Withhold NINLARO until peripheral neuropathy recovers to grade 1 or lower without pain or patient's baseline
Following recovery, resume NINLARO at its most recent dose

Grade 2 with pain or grade 3

Withhold NINLARO. Toxicities should, at the physician's discretion, generally recover to patient's baseline condition or grade 1 or lower prior to resuming NINLARO
Following recovery, resume NINLARO at the next lower dose

Grade 4

Discontinue treatment regimen

Other non-hematologic toxicities

Grade 3 or 4

Withhold NINLARO. Toxicities should, at the physician's discretion, generally recover to patient's baseline condition or grade 1 or lower prior to resuming NINLARO
If attributable to NINLARO, resume NINLARO at the next lower dose following recovery

*For additional occurrences, alternate dose modification of lenalidomide and NINLARO.¹
^†Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.¹
G-CSF=granulocyte-colony stimulating factor.

NINLARO (ixazomib) DOSING¹

NINLARO should be taken once a week on the same day and at approximately the same time for the first 3 weeks of a 4-week cycle
NINLARO should not be taken with food. Food may interfere with the absorption of NINLARO, which may lower levels of the medication in the blood and possibly reduce effectiveness
NINLARO should be taken on an empty stomach or at least 1 hour before or at least 2 hours after food
NINLARO should not be taken at the same time as dexamethasone because dexamethasone should be taken with food
No body surface area dosing is required
NINLARO should be swallowed whole with water and should not be crushed, chewed, or opened
If a NINLARO dose is delayed or missed, the dose should be taken only if the next scheduled dose is at least 72 hours away. 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

Antiviral prophylaxis should be considered in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation.

CONSIDERATIONS PRIOR TO INITIATING A NEW CYCLE OF THERAPY¹

Absolute neutrophil count should be at least 1000/mm³
Platelet count should be at least 75,000/mm³
Nonhematologic toxicities should, at the healthcare provider’s discretion, generally be recovered to patient’s baseline condition or grade 1 or lower

Please refer to the NINLARO full Prescribing Information for dosage modification guidelines for hematologic and nonhematologic toxicities, as well as dose reduction instructions for patients with hepatic or renal impairment.

STORAGE AND HANDLING FOR NINLARO^®(IXAZOMIB)

Storage¹

NINLARO may be stored 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 Disposal¹

NINLARO 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

NINLARO patient management

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO. Platelet nadirs typically occurred between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the next cycle. Grade 3 thrombocytopenia was reported in 17% of patients in the NINLARO regimen and Grade 4 thrombocytopenia was reported in 13% in the NINLARO regimen. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea resulted in the discontinuation of one or more of the three drugs in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Adjust dosing for Grade 3 or 4 symptoms.

Peripheral Neuropathy was reported with NINLARO. The most commonly reported reaction was peripheral sensory neuropathy (24% and 17% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (<1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 4% of patients in the NINLARO regimen and <1% of patients in the placebo regimen. During treatment, monitor patients for symptoms of neuropathy and consider adjusting dosing for new or worsening peripheral neuropathy.

Peripheral Edema was reported with NINLARO. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing of NINLARO for Grade 3 or 4 symptoms or dexamethasone per its prescribing information.

Cutaneous Reactions. Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatal cases, have been reported with NINLARO. If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue NINLARO and manage as clinically indicated. Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Rash resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. Manage rash with supportive care or with dose modification if Grade 2 or higher.

Thrombotic Microangiopathy has been reported with NINLARO. Fatal cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known.

Hepatotoxicity has been reported with NINLARO. Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients treated with NINLARO. Hepatotoxicity has been reported (10% in the NINLARO regimen and 9% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms.

Embryo-fetal Toxicity: NINLARO can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the last dose.

Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting: In two prospective randomized clinical trials in multiple myeloma in the maintenance setting, treatment with NINLARO resulted in increased deaths. Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials.

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) in the NINLARO regimen compared to placebo in combination with lenalidomide plus dexamethasone, respectively were thrombocytopenia (85%, 67%; pooled from adverse event and laboratory data), neutropenia (74%, 70%; pooled from adverse event and laboratory data), diarrhea (52%, 43%), constipation (35%, 28%), peripheral neuropathy (32%, 24%), nausea (32%, 23%), edema peripheral (27%, 21%), rash (27%, 16%), vomiting (26%, 13%), and bronchitis (22%, 17%). Serious adverse reactions reported in ≥ 2% of patients in the NINLARO regimen included diarrhea (3%), thrombocytopenia (2%), and bronchitis (2%).

DRUG INTERACTIONS:

Avoid concomitant administration of NINLARO with strong CYP3A inducers.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during treatment with NINLARO and for 90 days after the last dose.

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-217-6468 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dosing & Administration for NINLARO^® (ixazomib)

NINLARO (ixazomib) REGIMEN* DOSING SCHEDULE

An all-oral, PI-based regimen your patients can take at home^1-3

Dosing Schedule¹

Available NINLARO (ixazomib) strengths¹

DOSAGE MODIFICATION GUIDELINES¹

NINLARO (ixazomib) DOSING¹

CONSIDERATIONS PRIOR TO INITIATING A NEW CYCLE OF THERAPY¹

STORAGE AND HANDLING FOR NINLARO^®(IXAZOMIB)

Storage¹

Handling and Disposal¹

NINLARO patient management

Takeda Oncology Here2Assist^®

IMPORTANT SAFETY INFORMATION, INDICATION, AND USAGE

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

DRUG INTERACTIONS:

USE IN SPECIFIC POPULATIONS

INDICATION AND USAGE

NINLARO (ixazomib) REGIMEN* DOSING SCHEDULE

An all-oral, PI-based regimen your patients can take at home1-3

Dosing Schedule1

Available NINLARO (ixazomib) strengths1

DOSAGE MODIFICATION GUIDELINES1

NINLARO (ixazomib) DOSING1

CONSIDERATIONS PRIOR TO INITIATING A NEW CYCLE OF THERAPY1

STORAGE AND HANDLING FOR NINLARO® (IXAZOMIB)

Storage1

Handling and Disposal1

NINLARO patient management

Takeda Oncology Here2Assist®

IMPORTANT SAFETY INFORMATION, INDICATION, AND USAGE

An all-oral, PI-based regimen your patients can take at home^1-3

Dosing Schedule¹

Available NINLARO (ixazomib) strengths¹

DOSAGE MODIFICATION GUIDELINES¹

NINLARO (ixazomib) DOSING¹

CONSIDERATIONS PRIOR TO INITIATING A NEW CYCLE OF THERAPY¹

STORAGE AND HANDLING FOR NINLARO^®(IXAZOMIB)

Storage¹

Handling and Disposal¹

Takeda Oncology Here2Assist^®