Safety Profile for the NINLARO^® (ixazomib) Regimen*

The NINLARO triplet regimen* demonstrated a safety profile appropriate for long-term^† treatment.^1,2

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone.³
^†Used herein to refer to treatment to disease progression or unacceptable toxicity.³

Warnings and Precautions

Thrombocytopenia: Monitor platelet counts at least monthly during treatment and adjust dosing, as needed
Gastrointestinal Toxicities: Adjust dosing for severe diarrhea, constipation, nausea, and vomiting, as needed
Peripheral Neuropathy: Monitor patients for symptoms of peripheral neuropathy and adjust dosing, as needed
Peripheral Edema: Monitor for fluid retention. Investigate for underlying causes, when appropriate. Adjust dosing, as needed
Cutaneous Reactions: Monitor patients for rash and adjust dosing, as needed. Stevens-Johnson syndrome, including a fatal case, has been reported with NINLARO
Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue NINLARO if suspected. Cases, sometimes fatal, have been reported with NINLARO
Hepatotoxicity: Monitor hepatic enzymes during treatment
Embryo-Fetal Toxicity: NINLARO can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective non-hormonal contraception
Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting: Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials

For additional details about these Warnings and Precautions, see the Important Safety Information below.

Adverse Reactions

The NINLARO regimen* demonstrated a safety profile comparable to the Rd regimen*³

Non-hematologic ARs occurring in ≥5% of patients with a ≥5% difference between oral NINLARO + Rd and Rd in TOURMALINE-MM1³

Common ARs with the NINLARO® (ixazomib) regimen include: diarrhea, constipation, peripheral neuropathies, nausea, back pain, peripheral edema, rash, upper respiratory tract infection, vomiting, and bronchitis. — Incidence of thrombocytopenia in patients in the NINLARO and Rd regimens, respectively: any grade, 85% vs 67%; grades 3-4, 30% vs 14%³
Incidence of neutropenia in the NINLARO and Rd regimens, respectively: any grade, 74% vs 70%; grades 3-4, 34% vs 37%³

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.³
^†Represents a pooling of preferred terms.³
^‡At the time of the final analysis, these adverse reactions no longer met the criterion for a ≥5% difference between the NINLARO + Rd regimen and Rd regimen.³
AR=adverse reaction; PI=proteasome inhibitor.

Safety in high-risk* patient population

The overall safety profiles in the high-risk and standard-risk cytogenetics patients in each group are consistent with data reported for the overall population²
As seen in the overall population, in both high-risk and standard-risk cytogenetics patients, common adverse events were primarily of grade 1 or 2 severity and included diarrhea, constipation, neutropenia, and anemia²

*Defined as patients with del(17p), t(4;14), and/or t(14;16).⁴

SERIOUS ADVERSE REACTIONS

Serious ARs reported in ≥2% of patients in the NINLARO regimen included diarrhea (3%), thrombocytopenia (2%), and bronchitis (2%).³

LEARN MORE ABOUT THE TOURMALINE-MM1 TRIAL

Discontinuation Rates

In TOURMALINE-MM1, discontinuation rates due to ARs were similar across regimens¹

With the NINLARO and Rd regimens* respectively

• Permanent discontinuation of NINLARO due to an adverse reaction occurred in 10% of patients^1,3

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.³

Dose tolerability

The majority of patients continued at the starting dose of NINLARO without dose reduction¹

75% of patients continued at the starting dose of the NINLARO® (ixazomib) regimen without dose reduction.

of patients receiving the NINLARO regimen in TOURMALINE-MM1 continued on their starting NINLARO dose

The median relative dose intensity for NINLARO and placebo was high and similar in the NINLARO and Rd regimens*: 97.8% and 100%, respectively
Relative dose intensity was calculated as 100 x (total amount of dose taken/total planned dose over treated cycles)

*The NINLARO regimen included NINLARO + lenalidomide + dexamethasone. The Rd regimen included placebo + lenalidomide + dexamethasone.³

NINLARO prescribing information

Learn about important information before prescribing NINLARO.

Download Prescribing Info

NINLARO clinical trial data

The TOURMALINE-MM1 trial evaluated efficacy and safety of the all-oral NINLARO regimen vs Rd regimen in relapsed patients with multiple myeloma.

Find Trial Results

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, including a fatal case of Stevens-Johnson syndrome, were reported with NINLARO. If Stevens-Johnson syndrome 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.

Safety Profile for the NINLARO^® (ixazomib) Regimen*

Warnings and Precautions

Adverse Reactions

The NINLARO regimen* demonstrated a safety profile comparable to the Rd regimen*³

Non-hematologic ARs occurring in ≥5% of patients with a ≥5% difference between oral NINLARO + Rd and Rd in TOURMALINE-MM1³

Safety in high-risk* patient population

SERIOUS ADVERSE REACTIONS

Discontinuation Rates

In TOURMALINE-MM1, discontinuation rates due to ARs were similar across regimens¹

Dose tolerability

The majority of patients continued at the starting dose of NINLARO without dose reduction¹

NINLARO prescribing information

NINLARO clinical trial data

IMPORTANT SAFETY INFORMATION AND INDICATION

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

DRUG INTERACTIONS:

USE IN SPECIFIC POPULATIONS

INDICATION AND USAGE

Warnings and Precautions

Adverse Reactions

The NINLARO regimen* demonstrated a safety profile comparable to the Rd regimen*3

Non-hematologic ARs occurring in ≥5% of patients with a ≥5% difference between oral NINLARO + Rd and Rd in TOURMALINE-MM13

Safety in high-risk* patient population

SERIOUS ADVERSE REACTIONS

Discontinuation Rates

In TOURMALINE-MM1, discontinuation rates due to ARs were similar across regimens1

Dose tolerability

The majority of patients continued at the starting dose of NINLARO without dose reduction1

NINLARO prescribing information

NINLARO clinical trial data

IMPORTANT SAFETY INFORMATION AND INDICATION

The NINLARO regimen* demonstrated a safety profile comparable to the Rd regimen*³

Non-hematologic ARs occurring in ≥5% of patients with a ≥5% difference between oral NINLARO + Rd and Rd in TOURMALINE-MM1³

In TOURMALINE-MM1, discontinuation rates due to ARs were similar across regimens¹

The majority of patients continued at the starting dose of NINLARO without dose reduction¹