b'LONSURF (trifluridine and tipiracil) tablets, for oral useTable 3Adverse Reactions (5%) in Patients Receiving LONSURF and atTable 5Adverse Reactions (5%) in Patients Receiving LONSURF and at 8.3 Females and Males of Reproductive Potential Initial U.S. Approval: 2015a Higher Incidence (2%) than in Patients Receiving Placebo in RECOURSEa Higher Incidence (2%) than in Patients Receiving Placebo in TAGSPregnancy TestingBrief Summary of Prescribing Information LONSURFPlaceboLONSURFPlaceboVerify pregnancy status in females of reproductive potential prior to initiating (N=533) (N=265) (N=335) (N=168) LONSURF [see Use in Specific Populations (8.1)]. For complete Prescribing Information, consult official package insert.AdverseAllGradesAllGradesAdverse Reactions Contraception 1 INDICATIONS AND USAGEReactions Grades3-4*Grades3-4*AllGradesAllGradesLONSURF can cause fetal harm when administered to a pregnant woman [see 1.1 Metastatic Colorectal Cancer(%) (%) (%) (%) Grades3-4*Grades3-4*Use in Specific Populations (8.1)]. LONSURF is indicated for the treatment of adult patients with metastatic(%) (%) (%) (%) Females colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- andGeneral Gastrointestinal Advise females of reproductive potential to use effective contraception during irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RASAsthenia/fatigue 52 7 35 9 Nausea 37 3 32 3 treatment with LONSURF and for at least 6 months after the final dose.wild-type, an anti-EGFR therapy.Pyrexia 19 1 14 1 Males 1.2 Metastatic Gastric CancerVomiting 25 4 20 2 Because of the potential for genotoxicity, advise males with female partners LONSURF is indicated for the treatment of adult patients with metastatic gastricGastrointestinal Diarrhea 23 3 14 2 of reproductive potential to use condoms during treatment with LONSURF and or gastroesophageal junction adenocarcinoma previously treated with at leastNausea 48 2 24 1 Metabolism and nutritionfor at least 3 months after the final dose [see Nonclinical Toxicology (13.1) in two prior lines of chemotherapy that included a fluoropyrimidine, a platinum,the full Prescribing Information]. either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.Diarrhea 32 3 12 1 Decreased appetite 34 9 31 7 8.4 Pediatric Use 4 CONTRAINDICATIONSVomiting 28 2 14 1 Infections23 5 16 5 Safety and effectiveness of LONSURF in pediatric patients have not been None. Abdominal pain 21 2 18 4 *No Grade 4 definition for nausea or fatigue in NCI CTCAE, version 4.03. established. 5 WARNINGS AND PRECAUTIONS Incidence reflects 46 preferred terms in the Infections and InfestationsJuvenile Animal Toxicity Data 5.1 Severe MyelosuppressionStomatitis 8 1 6 0 system organ class.Dental toxicity including whitening, breakage, and malocclusion (degeneration In the 868 patients who received LONSURF in RECOURSE and TAGS, Metabolism and nutrition Table 6Laboratory Abnormalities in TAGSand disarrangement in the ameloblasts, papillary layer cells and odontoblasts) were observed in rats treated with trifluridine/tipiracil at doses 50 mg/kg LONSURF caused severe and life-threatening myelosuppression (Grade 3-4)Decreased39 4 29 5 LONSURF Placebo (approximately 0.33 times the exposure at the clinical dose of 35 mg/m 2twice consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) andappetitefebrile neutropenia (3%). Two patients (0.2%) died due to neutropenic LaboratoryAllGradesAllGradesdaily).infection/sepsis and four other patients (0.5%) died due to septic shock. AInfections 27 6 16 5 Parameter* Grades3-4Grades3-48.5 Geriatric Use total of 12% of LONSURF-treated patients received granulocyte-colonyNervous system(%) (%) (%) (%) In RECOURSE and TAGS, 868 patients received LONSURF; 45% were 65 years stimulating factors.of age or over, while 10% were 75 and over. No overall differences in Dysgeusia 7 0 2 0 Hematologic effectiveness were observed in patients 65 or older versus younger patients. Obtain complete blood counts prior to and on Day 15 of each cycle ofSkin and subcutaneous tissue Neutropenia66 38 4 0 Patients 65 years of age or older who received LONSURF had a higher LONSURF and more frequently as clinically indicated. Withhold LONSURF for incidence of the following hematologic laboratory abnormalities compared to severe myelosuppression and resume at the next lower dosage [see DosageAlopecia 7 0 1 0 Anemia 63 19 38 7 patients younger than 65 years: Grade 3 or 4 neutropenia (46% vs. 32%), and Administration (2.2) in the full Prescribing Information].*No Grade 4 definition for nausea, abdominal pain, or fatigue in NationalThrombocytopenia 34 6 9 0 Grade 3 anemia (22% vs. 16%), and Grade 3 or 4 thrombocytopenia (7% vs. 4%). 5.2 Embryo-Fetal ToxicityCancer Institute Common Terminology* Worst Grade at least one Grade higher than baseline, with percent based8.6 Renal Impairment Based on animal studies and its mechanism of action, LONSURF can cause Incidence reflects 64 preferred terms in the Infections and Infestations systemon number of patients with post-baseline samples which may be 335No dose adjustment is recommended for patients with mild or moderate renal fetal harm when administered to a pregnant woman. Trifluridine/tipiracil causedorgan class. (LONSURF) or 168 (placebo)impairment (CLcr of 30 to 89 mL/min as determined by the Cockcroft-Gault embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orallyTable 4Laboratory Abnormalities in RECOURSEAnemia: No Grade 4 definition in CTCAE, v4.03formula). Reduce the dose of LONSURF for patients with severe renal administered during gestation at dosage levels resulting in exposures lower than those achieved at the recommended dosage of 35 mg/m 2twice daily.LONSURF Placebo In TAGS, pulmonary emboli occurred more frequently in LONSURF-treatedimpairment (CLcr of 15 to 29 mL/min) [see Dosage and Administration (2.3) Advise pregnant women of the potential risk to the fetus. Advise females ofLaboratoryAllGradesAllGradespatients (3.1%) compared to 1.8% for patients on placebo.in the full Prescribing Information]. The pharmacokinetics of trifluridine and reproductive potential to use an effective method of contraception duringParameter* Grades3-4Grades3-4Additional Clinical Experience tipiracil have not been studied in patients with end stage renal disease.treatment with LONSURF and for at least 6 months after the final dose [see(%) (%) (%) (%) Interstitial lung disease was reported in 15 (0.2%) patients, 3 of which were8.7 Hepatic Impairment Use in Specific Populations (8.1, 8.3)].fatal, among approximately 7,000 patients exposed to LONSURF in clinicalNo adjustment to the starting dosage of LONSURF is recommended for 6 ADVERSE REACTIONSHematologic studies and clinical practice settings in Asia.patients with mild hepatic impairment. Do not initiate LONSURF in patients The following clinically significant adverse reactions are described elsewhereAnemia77 18 33 3 8 USE IN SPECIFIC POPULATIONSwith baseline moderate or severe (total bilirubin 1.5 times ULN and any AST) in the labeling:8.1 Pregnancyhepatic impairment [see Clinical Pharmacology (12.3) in the full PrescribingSevere Myelosuppression [see Warnings and Precautions (5.1)]Neutropenia 67 38 1 0 Risk SummaryInformation]. 6.1 Clinical Trials ExperienceThrombocytopenia 42 5 8 1 Based on animal data and its mechanism of action [see Clinical Pharmacology17 PATIENT COUNSELING INFORMATION Because clinical trials are conducted under widely varying conditions, adverse* Worst Grade at least one grade higher than baseline, with percentages (12.2) in the full Prescribing Information], LONSURF can cause fetal harm. AdvisethepatienttoreadtheFDA-approvedpatientlabeling(Patient reaction rates observed in the clinical trials of a drug cannot be directlybased on number of patients with post-baseline samples, which may be LONSURF caused embryo-fetal lethality and embryo-fetal toxicity in pregnantInformation). compared to rates in the clinical trials of another drug and may not reflect the533 (LONSURF) or 265 (placebo)rats when given during gestation at doses resulting in exposures lower thanSevere Myelosuppression rates observed in practice.One Grade 4 anemia adverse reaction based on clinical criteria was reportedor similar to human exposures at the recommended clinical dose (see Data).Advise patients to immediately contact their healthcare provider if they The data in the WARNINGS AND PRECAUTIONS section and below reflectIn RECOURSE, pulmonary emboli occurred more frequently in LONSURF- There are no available data on LONSURF use in pregnant women. Adviseexperience signs or symptoms of infection and advise patients to keep all exposure to LONSURF at the recommended dose in 533 patients withtreated patients (2%) compared to no patients on placebo. pregnant women of the potential risk to a fetus.appointments for blood tests [see Warnings and Precautions (5.1)]. metastatic colorectal cancer in RECOURSE and 335 patients with metastaticMetastatic Gastric CancerIn the U.S. general population, the estimated background risk of major birthGastrointestinal Toxicity gastric cancer in TAGS. Among the 868 patients who received LONSURF, 11%The safety of LONSURF was evaluated in TAGS, an international, randomizeddefects and miscarriage in clinically recognized pregnancies is 2-4% and Advise patients to contact their healthcare provider for severe or persistent were exposed for 6 months or longer and 1% were exposed for 12 months or(2:1), double-blind, placebo-controlled trial in patients with metastatic gastric15-20%, respectively. nausea, vomiting, diarrhea, or abdominal pain [see Adverse Reactions (6.1)]. longer. The most common adverse reactions or laboratory abnormalitiesor gastroesophageal junction (GEJ) adenocarcinoma who were previouslyDataAdministration Instructions (10%) are anemia, neutropenia, fatigue/asthenia, nausea, thrombocytopenia,treated with at least 2 prior chemotherapy regimens for advanced disease [seeAnimal DataAdvise patients that LONSURF is available in two strengths and they may decreased appetite, diarrhea, vomiting, and pyrexia. Clinical Studies (14.2) in the full Prescribing Information]. Previous treatmentsTrifluridine/tipiracil was administered orally once daily to female rats duringreceive both strength tablets to provide the prescribed dosage. Metastatic Colorectal Cancer must have included a fluoropyrimidine, a platinum, and either a taxane ororganogenesis at dose levels of 15, 50, and 150 mg/kg [trifluridine (FTD)Advise patients to take LONSURF with food [see Dosage and Administration The safety of LONSURF was evaluated in RECOURSE, a randomized (2:1),irinotecan. Patients with HER2/neu-positive tumors must have received priorequivalent]. Decreased fetal weight was observed at FTD doses 50 mg/kg(2.1) in the full Prescribing Information]. double-blind, placebo-controlled trial in patients with previously treatedHER2/neu-targeted therapy, if available. Adjuvant chemotherapy could be(approximately 0.33 times the FTD exposure at the clinical dose of 35 mg/m 2 Advise patients that anyone else who handles their medication should wear metastatic colorectal cancer [see Clinical Studies (14.1) in the full Prescribingcounted as one prior regimen in patients who had recurrence during or withintwice daily). At the FTD dose of 150 mg/kg (approximately 0.92 times the FTDgloves [see References (15) in the full Prescribing Information]. Information]. Patients received LONSURF 35 mg/m2/dose (n=533) or placebo6 months of completion of the adjuvant chemotherapy. Patients receivedexposure at the clinical dose of 35 mg/m 2twice daily) embryolethality andEmbryo-Fetal Toxicity (n=265) twice daily on Days 1 through 5 and Days 8 through 12 of each LONSURF 35 mg/m 2 /dose (n=335) or placebo (n=168) twice daily on Days 1structural anomalies (kinked tail, cleft palate, ectrodactyly, anasarca, alterationsAdvise pregnant women and females of reproductive potential of the potential 28-day cycle. In RECOURSE, 12% of patients received LONSURF for morethrough 5 and Days 8 through 12 of each 28-day cycle with best supportivein great vessels, and skeletal anomalies) were observed.risk to the fetus. Advise females to inform their healthcare provider of a known than 6 months and 1% of patients received LONSURF for more than 1 year.care. In TAGS, 10% of patients received LONSURF for more than 6 months8.2 Lactationor suspected pregnancy [see Warnings and Precautions (5.2), Use in Specific The study population characteristics were: median age 63 years; 61% male;and 0.9% of patients received LONSURF for more than 1 year. Risk SummaryPopulations (8.3)].57% White, 35% Asian, and 1% Black. The study population characteristics were: median age 63 years (24 to There are no data on the presence of trifluridine, tipiracil or its metabolites inAdvise female patients of reproductive potential to use effective contraception The most common adverse reactions or laboratory abnormalities (10% in89 years); 73% male; 70% White, 16% Asian, and 1% Black. human milk or its effects on the breastfed child or on milk production. Induring treatment with LONSURF and for at least 6 months after the final dose incidence) in patients treated with LONSURF at a rate that exceeds the rate inThe most common adverse reactions or laboratory abnormalities (10% innursing rats, trifluridine and tipiracil or their metabolites were present in breast[see Warnings and Precautions (5.2), Use in Specific Populations (8.3)].patients receiving placebo were anemia, neutropenia, asthenia/fatigue, nausea,incidence) in patients treated with LONSURF at a rate that exceeds the rate inmilk (see Data). Because of the potential for serious adverse reactions inAdvise males with female partners of reproductive potential to use condoms thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain,patients receiving placebo were neutropenia, anemia, nausea, decreasedbreastfed children, advise women not to breastfeed during treatment withduring treatment with LONSURF and for at least 3 months after the final dose and pyrexia. appetite, thrombocytopenia, vomiting, and diarrhea. LONSURF and for 1 day following the final dose. [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1) in the full In RECOURSE, 3.6% of patients discontinued LONSURF for an adverseIn TAGS, 13% of patients discontinued LONSURF for an adverse reaction andDataPrescribing Information]. 11% of patients required a dose reduction. The most common adverseRadioactivitywasexcretedinthemilkofnursingratsdosedwithLactation reaction and 14% of patients required a dose reduction. The most commonreactionsorlaboratoryabnormalitiesleadingtodosereductionweretrifluridine/tipiracil containing14 C-FTD or14 C-tipiracil (TPI). Levels of FTD- Advise women not to breastfeed during treatment with LONSURF and foradverse reactions or laboratory abnormalities leading to dose reduction wereneutropenia, anemia, febrile neutropenia, and diarrhea. derived radioactivity were as high as approximately 50% of the exposure in1 day following the final dose [see Use in Specific Populations (8.2)]. neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. Tables 5 and 6 list the adverse reactions and laboratory abnormalities (gradedmaternal plasma an hour after dosing with trifluridine/tipiracil and were Tables 3 and 4 list the adverse reactions and laboratory abnormalities (gradedusing CTCAE v4.03), respectively, observed in TAGS.approximately the same as those in maternal plasma for up to 12 hours using CTCAE v4.03), respectively, observed in RECOURSE. following dosing. Exposure to TPI-derived radioactivity was higher in milk than in maternal plasma beginning 2 hours after dosing and continuing for at least TAIHO ONCOLOGY, INC. 06/2022LON-PM-US-163312 hours following administration of trifluridine/tipiracil. Lonsurf_VA_Sprd_Ad_7.875x10.75_BRIEF.indd All Pages 10/26/22 12:43 PM'