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A GUIDE TO MANAGING ADVERSE REACTIONS WITH NINLARO® (ixazomib) 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. TOURMALINE-MM1: a global, phase 3, randomized (1:1), double-blind, placebo-controlled study that evaluated the safety and efficacy of NINLARO (an oral proteasome inhibitor) vs placebo, both in combination with lenalidomide and dexamethasone, until disease progression or unacceptable toxicity in 722 patients with relapsed and/or refractory multiple myeloma who received 1-3 prior lines of therapy. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS • Thrombocytopenia has been reported with NINLARO. 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. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and typically recovered to baseline by the start of the next cycle. Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information. DOSE MODIFICATION IMPORTANT SAFETY INFORMATION GUIDELINES FOR (CONTINUED) THE NINLARO® (ixazomib) REGIMEN • Hepatotoxicity has been reported with NINLARO. DrugWARNINGS ANDTOXICITIES PRECAUTIONS (CONTINUED) HEMATOLOGIC RECOMMENDED ACTIONS induced liver injury, hepatocellular injury, hepatic steatosis, • Gastrointestinal Toxicities, including diarrhea, constipation, Thrombocytopenia (platelet hepatitis cholestatic and hepatotoxicity have each been nausea and vomiting, werecount) reported with NINLARO and may 3 3 reported until in < platelet 1% of patients NINLARO. Events occasionally use of antidiarrheal and NINLARO antiemeticand lenalidomide • Withhold count istreated at leastwith 30,000/mm Platelet count require less thanthe 30,000/mm of liver impairment have been reported (6% in the medications, and supportive care. Diarrhea resulted in the • Following recovery, resume lenalidomide at the next lower dose according to its NINLARO regimen and 5% in placebo regimen). discontinuation of one or more of the three drugs Information in 1% of Prescribing and resume NINLARO atthe its most recent dose Monitor hepatic enzymes regularly during treatment and adjust dosing patients in the NINLARO regimen and• < 1% of patients in the 3 again, withhold NINLARO and lenalidomide If platelet count falls to less than 30,000/mm as needed. placebo regimen. Adjust dosing for severe symptoms. 3 until platelet count is at least 30,000/mm • Embryo-fetal Toxicity: NINLARO can cause fetal harm. • Peripheral Neuropathy (predominantly sensory) was • Following recovery, resume NINLARO at the next lower dose and resume lenalidomide Women should be advised of the potential risk to a fetus, to reported with NINLARO. The most commonly reported at its most recent dose* avoid becoming pregnant, and to use contraception during reaction was peripheral sensory neuropathy (19% and 14% Neutropenia (absolute treatment and for an additional 90 days after the final dose in the NINLARO and neutrophil placebo regimens, respectively). count) of NINLARO. Women using hormonal contraceptives should Peripheral motor neuropathy was not commonly reported also use a barrier method of contraception. in either regimen (< 1%). Peripheral neuropathy resulted in Absolute neutrophil count less than • Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3. discontinuation of one or more of the three drugs in 1% G-CSF of 3 Consider adding as per clinical guidelines 500/mm patients in both regimens. Monitor patients for symptoms REACTIONS • Following recovery, resumeADVERSE lenalidomide at the next lower dose according to its of peripheral neuropathy and adjust dosing as needed. The most common adverse reactions (≥ 20%) in the NINLARO Prescribing Information and resume NINLARO at its most recent dose • Peripheral Edema was reported with NINLARO. Monitor regimen and greater than3 the placebo regimen, respectively, • If absolute neutrophil falls to less than 500/mm again, withhold NINLARO and for fluid retention. Investigate for underlying causes when countwere diarrhea (42%, 36%), constipation (34%, 25%), lenalidomide untilAdjust absolute neutrophil count is at least 500/mm3 appropriate and provide supportive care as necessary. thrombocytopenia (78%, 54%; pooled from adverse events • Following recovery, or resumeand NINLARO at the next peripheral lower dose neuropathy and resume (28%, lenalidomide dosing of dexamethasone per its prescribing information laboratory data), 21%), at NINLARO for Grade 3 or 4 symptoms. its most recent dose* nausea (26%, 21%), peripheral edema (25%, 18%), vomiting • Cutaneous Reactions: Rash, most commonly maculo-papular (22%, 11%), and back pain (21%, 16%). Serious adverse reactions and macular rash, was reported with NINLARO. Rash resulted reported in ≥ 2% of patients included thrombocytopenia (2%) in maculo-papular discontinuation of one or more of the three drugs in < 1% of and 2 diarrhea (2%). Rash Peripheral sensory neuropathy2 patients in both regimens. Manage rash with supportive care Grade 2: macules/papules covering 10-30% body surface area (BSA) with or without Grade 1: asymptomatic; loss of deep tendon reflexes or paresthesia. symptoms pruritus, burning, tightness); limiting instrumental activities of daily Grade 2: moderate symptoms; limiting instrumental ADL. or with(eg, dose modifi cation. DRUG INTERACTIONS: Avoid concomitant administration of living (ADL). Grade 3: macules/papules covering >30% BSA with or without associated symptoms-limiting self-care ADL. Grade 3: severe symptoms; limiting self-care ADL. NINLARO with strong CYP3Aurgent inducers. Grade 4: life-threatening consequences; intervention indicated. For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information. 2 6 SPECIAL POPULATIONS NONHEMATOLOGIC TOXICITIES RECOMMENDED ACTIONS Rash 3 Grade† 2 orHEPATIC IMPAIRMENT • Withhold RENAL lenalidomide until rash recovers to grade 1 or lower LACTATION • Following recovery, resume lenalidomide at the next lower dose according to its IMPAIRMENT 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 Reduce theNeuropathy starting dose of Peripheral NINLARO to 3 mg in patients Grade 1 peripheral neuropathy with moderate or severe hepatic with pain or grade 2 peripheral impairment. neuropathy • Discontinue treatment regimen Reduce the starting dose of Advise nursing women not to NINLARO to 3 mg in patients breastfeed during treatment • Withhold NINLARO until peripheral neuropathy recovers to grade 1 or lower without pain with severe renal impairment with NINLARO and for 90 days or patient’s baseline or end-stage renal disease after the lastmost dose.recent dose • Following recovery, resume NINLARO at its requiring dialysis. Grade 2 peripheral neuropathy • Withhold NINLARO. Toxicities should, at the physician’s discretion, generally recover to patient’s with pain or grade 3 peripheral baseline condition or grade 1 or lower prior to resuming NINLARO neuropathy • Following recovery, resume NINLARO at the next lower dose Contraception: Maleneuropathy and female patients of childbearing potentialregimen must use effective contraceptive measures Grade 4 peripheral • Discontinue treatment during, and for 90 days following, treatment. OTHER NONHEMATOLOGIC TOXICITIES RECOMMENDED ACTIONS is not dialyzable and therefore can be administered Other grade 3NINLARO or 4 • Withhold NINLARO. Toxicities should, at the physician’s discretion, generally recover to patient’s nonhematologic toxicities baseline or grade 1 or lower prior to resuming NINLARO without regard to the timingcondition of dialysis. • If attributable to NINLARO, resume NINLARO at the next lower dose following recovery *For additional occurrences, alternate dose modification of lenalidomide and NINLARO. Grading based on National Cancer Institute Common Terminology Criteria Version 4.03. Please Information on on pages pages 1-2 1-2 and and accompanying accompanying full full Prescribing Prescribing Information. Information. Please see see Important Important Safety Safety Information SAFETY PROFILE PREPARE PATIENTS FOR SIDE EFFECTS AND DOSING CONCERNS Nonhematologic ARs occurring in 5% of patients with a 5% difference between the NINLARO regimen* and the placebo regimen† Placebo+len+dex (n=360) All grades Grade 3 Difference (n=360) Grade 4 All grades Grade 3 Grade 4 GI toxicity: diarrhea <1% 0 14% <1% 0 5% Peripheral neuropathies 28% 2% 0 21% 2% 0 7% Diarrhea 42% 6% 0 36% 2% 0 6% Constipation 34% <1% 0 25% <1% 0 9% Nausea 26% 2% 0 21% 0 0 5% Vomiting 22% 1% 0 11% <1% 0 11% Rash ‡ 19% 3% 0 11% 1% 0 8% Back pain 21% <1% 0 16% 3% 0 5% Peripheral edema 25% 2% 0 18% 1% 0 7% Discontinuation rates of the full regimen due to ARs1 Antidiarrheal (eg, loperamide) 40 GI toxicity: nausea/vomitingfollowed aProphylaxis or symptomatic Thrombocytopenia cyclical pattern, 3 with platelet nadirs generally occurring between daysinfection: 14-21 of a 28-day Viral herpes zoster cycle and recovering to baseline by the start of the next cycle. or symptomatic Prophylaxis 4 (reactivation) Prophylaxis (subsequent cycles) or symptomatic Rash Additional Safety information • NINLARO did not prolong the QTc interval at clinically 5 *NINLARO+lenalidomide +dexamethasone. †Placebo+lenalidomide +dexamethasone. ‡Represents a pooling of preferred terms. ARs=adverse reactions. relevant exposures • Incidence of eye disorders§ with NINLARO vs placebo: all grades, 26% vs 16%; grade 3, 2%6 vs 1%, respectively Prophylaxis or symptomatic Bacterial infection • The majority of peripheral neuropathy ARs were grade 1 (18% vs 14%, respectively) 20 0 Antiemetics, antinauseants (eg, ondansetron) Direct-acting antivirals (eg, acyclovir, 13valacyclovir)11 Antihistamines NINLARO(eg, regimen (n=360) or corticosteroids Placebo+len+dex regimen (n=360) cetirizine) (oral or topical; eg, prednisone, betamethasone) 80% of patients Antibacterials continued at the 4-mg starting dose of NINLARO without dose reduction.1 • Prophylaxis (eg, sulfonamides, trimethoprim) • Symptomatic (eg, beta-lactam antibacterials, penicillins) - Peripheral neuropathy grade 3 ARs were 2% in both regimens; The above medications and supportive therapies are examples of appropriate supportive care no grade 4 or serious ARs reported that was permitted in the phase 3 trial. Encourage patients and caregivers to report any side effects early so appropriate management measures can be taken. Most commonly reported as blurred vision, dry eye, and conjunctivitis. Serious ARs • Serious ARs reported in 2% of patients in the NINLARO regimen included thrombocytopenia (2%) and diarrhea (2%) § 4 Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information. Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information. SUPPORTIVE CARE 19% Recommendation Symptomatic 3 All grades Upper respiratory tract infection ‡ placebo regimens: all grades, 78% vs 54%, respectively; grades 3-4, 26% vs 11%, respectively Condition Prophylaxis/symptomatic • Incidence of neutropenia: all grades, 67% vs 66%, respectively; grades 3-4, 26% vs 30%, respectively Discontinuation rates (%) NINLARO regimen AR PooledConcomitant hematologicmedications adverse events data The NINLARO® (ixazomib) regimen represented mayand be laboratory given for prophylaxis and/or management of symptoms • Incidence of thrombocytopenia in patients in the NINLARO and a sustainable treatment for patients PREPARE PATIENTS FOR SIDE EFFECTS AND DOSING CONCERNS Concomitant medications may be given for prophylaxis and/or management of symptoms Recommendation Symptomatic Antidiarrheal (eg, loperamide) GI toxicity: nausea/vomiting3 Prophylaxis or symptomatic Antiemetics, antinauseants (eg, ondansetron) Viral infection: herpes zoster (reactivation)4 Prophylaxis or symptomatic Direct-acting antivirals (eg, acyclovir, valacyclovir) Prophylaxis (subsequent cycles) or symptomatic Antihistamines (eg, cetirizine) or corticosteroids (oral or topical; eg, prednisone, betamethasone) Prophylaxis or symptomatic Antibacterials • Prophylaxis (eg, sulfonamides, trimethoprim) • Symptomatic (eg, beta-lactam antibacterials, penicillins) GI toxicity: diarrhea3 Rash 5 Bacterial infection6 The above medications and supportive therapies are examples of appropriate supportive care that was permitted in the phase 3 trial. Encourage patients and caregivers to report any side effects early so appropriate management measures can be taken. Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information. SUPPORTIVE CARE Prophylaxis/symptomatic Condition AVAILABLE IMPORTANT DOSE MODIFICATION NINLARO® SAFETY INFORMATION (ixazomib) GUIDELINES STRENGTHS (CONTINUED) FOR THE NINLARO® (ixazomib) REGIMEN • Hepatotoxicity has been reported with NINLARO. DrugWARNINGS AND PRECAUTIONS (CONTINUED) HEMATOLOGIC TOXICITIES RECOMMENDED ACTIONS Recommended induced injury, hepatocellular injury, hepatic steatosis, • Gastrointestinal Toxicities, includingFirst diarrhea, constipation, Secondliver dose reduction If toxicities continue dose reduction Thrombocytopenia count) with NINLARO and may starting dose(platelet hepatitis cholestatic and hepatotoxicity have each been nausea and vomiting, were reported 3 reported inuntil < 1%platelet of patients with NINLARO.3 Events occasionally require the 30,000/mm use of antidiarrheal and antiemetic • Withhold NINLARO and lenalidomide counttreated is at least 30,000/mm Platelet count less than of liver impairment have been reported (6% into the medications, and supportive care. Diarrhea resulted in the • Following recovery, resume lenalidomide at the next lower dose according itsNINLARO 5% in the placebo regimen). discontinuation of one or more of the three drugs inInformation 1% of Prescribing andregimen resume and NINLARO at its most recent dose Monitor hepatic regularly3 again, duringwithhold treatment and adjust patients in the NINLARO regimen and <• 1% of patients theto lessenzymes NINLARO anddosing lenalidomide If platelet countinfalls than 30,000/mm as needed. placebo regimen. Adjust dosing for severe symptoms. 3 until platelet count is at least 30,000/mm • Embryo-fetal Toxicity: NINLARO can cause fetal harm. • Peripheral Neuropathy (predominantly sensory) was • Following recovery, resume NINLARO at the next lower dose and resume lenalidomide Women should be advised of the potential risk to a fetus, to reported with NINLARO. The most commonly reported at its most recent dose* avoid becoming pregnant, and to use contraception during reaction was peripheral sensory neuropathy (19% and 14% (absolute neutrophil treatment and for an additional 90 days after the final dose inNeutropenia the NINLARO and placebo regimens, respectively). count) of NINLARO. Women using hormonal contraceptives should Peripheral motor neuropathy was not commonly reported also use a barrier method of contraception. in either regimen (< 1%). Peripheral neuropathy resulted in • Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3. Absolute neutrophil count less than Discontinue starting dose discontinuation of one or more ofRecommended the three drugs in 1% ofG-CSF as per clinical guidelines Consider adding 500/mm3 forpatients patients with: NINLARO. patients in both regimens. Monitor for symptoms ADVERSE REACTIONS • Following recovery, resume lenalidomide at the next lower dose according to its • Moderate oras severe of peripheral neuropathy and adjust dosing needed. Theresume most common adverse reactions 20%) in the NINLARO Prescribing Information and NINLARO at its most recent(≥ dose hepatic impairment* • Peripheral Edema was reported with NINLARO. Monitor regimen and greater than the placebo regimen, respectively, 3 † If absolute neutrophil count falls to less than 500/mm again, withhold NINLARO and Severe•renal impairment for fluid retention. Investigate for•underlying causes when were diarrhea (42%, 36%), constipation (34%, 25%), until absolute neutrophil count is at least 500/mm3 • End-stage disease, appropriate and provide supportive care lenalidomide asrenal necessary. Adjust thrombocytopenia (78%, 54%; pooled from adverse events • Following recovery, at data), the next lower dose and resume lenalidomide at requiring dialysis dosing of dexamethasone per its prescribing information or resume andNINLARO laboratory peripheral neuropathy (28%, 21%), NINLARO for Grade 3 or 4 symptoms. its most recent dose* nausea (26%, 21%), peripheral edema (25%, 18%), vomiting • Cutaneous Reactions: Rash, most commonly maculo-papular (22%, 11%), and back pain (21%, 16%). Serious adverse reactions and macular rash, was reported with NINLARO. Rash resulted reported in ≥ 2% of patients included thrombocytopenia (2%) in discontinuation and diarrhea (2%). Rash maculo-papular2 of one or more of the three drugs in < 1% of Peripheral sensory neuropathy2 patients in both regimens. Manage rash with Grade 2: macules/papules covering 10-30% body surface areasupportive (BSA) with or care without Grade 1: asymptomatic; loss of deep tendon reflexes or paresthesia. symptoms (eg, pruritus, burning, tightness); limiting instrumental activities of daily Grade 2: moderate symptoms; limiting instrumental ADL. or with dose modifi cation. DRUG INTERACTIONS: Avoid concomitant administration of DOSE MODIFICATIONS 4mg 3mg living (ADL). *Hepatic impairment: moderate, bilirubin >1.5-3x ULN; severe, bilirubin >3x ULN. Graderenal 3: macules/papules coveringclearance >30% BSA with or without associated †Severe impairment: Creatinine <30 mL/min. symptoms-limiting self-care ADL. 2.3mg Grade 3: severe symptoms; limiting self-care ADL. NINLARO with strong CYP3A inducers. Grade 4: life-threatening consequences; urgent intervention indicated. Please see section 2 (Dosing and Administration) of the NINLARO full Prescribing Information. For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information. Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information. 2 6 SPECIAL POPULATIONS NONHEMATOLOGIC TOXICITIES RECOMMENDED ACTIONS Rash Grade† 2 or 3HEPATIC IMPAIRMENT • Withhold lenalidomide RENAL until rash recovers to grade 1 or lower LACTATION • Following recovery, resume lenalidomide at the next lower dose according to its IMPAIRMENT 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 Reduce the starting dose of Peripheral Neuropathy NINLARO to 3 mg in patients Grade 1 peripheral neuropathy with moderate or severe hepatic with pain or grade 2 peripheral impairment. neuropathy • Discontinue treatment regimen Reduce the starting dose of Advise nursing women not to NINLARO to 3 mg in patients breastfeed during treatment • Withhold NINLARO until peripheral neuropathy recovers to grade 1 or lower without pain with severe renal impairment with NINLARO and for 90 days or patient’s baseline or end-stage renal disease afteratthe dose. • Following recovery, resume NINLARO its last most recent dose requiring dialysis. Grade 2 peripheral neuropathy • Withhold NINLARO. Toxicities should, at the physician’s discretion, generally recover to patient’s with pain or grade 3 peripheral baseline condition or grade 1 or lower prior to resuming NINLARO neuropathy • Following recovery, resume NINLARO at the next lower dose Contraception: and female patients of childbearing potential must use effective contraceptive measures Grade 4 peripheralMale neuropathy • Discontinue treatment regimen during, and for 90 days following, treatment. OTHER NONHEMATOLOGIC TOXICITIES RECOMMENDED ACTIONS NINLARO is not dialyzable and therefore canshould, be administered Other grade 3 or 4 • Withhold NINLARO. Toxicities at the physician’s discretion, generally recover to patient’s nonhematologicwithout toxicitiesregard to the baseline condition or grade 1 or lower prior to resuming NINLARO timing of dialysis. • If attributable to NINLARO, resume NINLARO at the next lower dose following recovery *For additional occurrences, alternate dose modification of lenalidomide and NINLARO. Grading based on National Cancer Institute Common Terminology Criteria Version 4.03. Please see Important Safety Information onon pages 1-21-2 and accompanying fullfull Prescribing Information. Please see Important Safety Information pages and accompanying Prescribing Information. DOSE MODIFICATIONS AVAILABLE NINLARO® (ixazomib) STRENGTHS Recommended starting dose First dose reduction Second dose reduction 4mg 3mg 2.3mg If toxicities continue Recommended starting dose for patients with: • Moderate or severe hepatic impairment* • Severe renal impairment† • End-stage renal disease, requiring dialysis *Hepatic impairment: moderate, bilirubin >1.5-3x ULN; severe, bilirubin >3x ULN. †Severe renal impairment: Creatinine clearance <30 mL/min. Please see section 2 (Dosing and Administration) of the NINLARO full Prescribing Information. Please see Important Safety Information on pages 1-2 and accompanying full Prescribing Information. Discontinue NINLARO. Call 1-844-N1POINT (1-844-617-6468) for information on access, coverage, and support services. References: 1. Data on File 117, Takeda Pharmaceuticals International Co. 2. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. Published June 14, 2010. 3. Data on File 113, Takeda Pharmaceuticals International Co. 4. Data on File 109, Takeda Pharmaceuticals International Co. 5. Data on File 114, Takeda Pharmaceuticals International Co. 6. Data on File 115, Takeda Pharmaceuticals International Co. Please see attached full Prescribing Information above. Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited. NINLARO is a registered trademark of Millennium Pharmaceuticals, Inc. is a trademark of Millennium Pharmaceuticals, Inc. Copyright © 2016, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA 12/16 USO/IXA/16/0111(1)