b'Table 6: Select Laboratory Abnormalities (10%) in SUNLIGHT 8.4Pediatric UseLONSURF + LONSURFa Safety and effectiveness of LONSURF in pediatric patients have not been Laboratory parametersBevacizumabaestablished.All Grade All Grade Juvenile Animal Toxicity DataGrades 3 or 4 Grades 3 or 4 Dental toxicity including whitening, breakage, and malocclusion (degeneration (%) (%) (%) (%) and disarrangement in the ameloblasts, papillary layer cells and odontoblasts) were observed in rats treated with trifluridine/tipiracil at doses50 mg/kgChemistry (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 Aspartate aminotransferase342.1281.2 twice daily). increased 8.5Geriatric UseAlanine aminotransferase333.3230.4 Of the 1114 patients with metastatic colorectal cancer or gastric cancer who increased received single agent LONSURF in clinical studies, 45% were 65 years of Alkaline phosphatase increased310.8361.2 age or over, and 11% were 75 and over. In the 246 patients who received LONSURF in combination with bevacizumab; 41% were 65 years of age or Sodium decreased252.1203.3 over, and 10% were 75 and over. While these studies were not designed Potassium increased170150 to detect a difference in efficacy, no overall differences were observed in Potassium decreased120.8122.5 patients 65 or older versus younger patients with either LONSURF as a single agent or LONSURF in combination with bevacizumab.Creatinine increased120.8150 Patients 65 years of age or older who received LONSURF as a single agent aEach test incidence is based on the number of patients who had bothhad a higher incidence of the following hematologic laboratory abnormalities baseline and at least one on-study laboratory measurement available:compared to patients younger than 65 years: Grade 3 or 4 neutropenia (46% LONSURF + bevacizumab group (n=242 patients) and LONSURF groupvs 32%), Grade 3 anemia (20% vs 14%), and Grade 3 or 4 thrombocytopenia (range: 240 to 242 patients). (6% vs 3%). Patients 65 years of age or older who received LONSURF in8USE IN SPECIFIC POPULATIONS combination with bevacizumab had a higher incidence of the following 8.1Pregnancy hematologic laboratory abnormalities compared to patients younger thanRisk Summary 65 years: Grade 3 or 4 neutropenia (60% vs 46%) and Grade 3 or 4 Based on animal data and its mechanism of action [see Clinical Pharmacologythrombocytopenia (5% vs 4%).(12.2) in the full Prescribing Information], LONSURF can cause fetal harm. 8.6Renal ImpairmentLONSURF caused embryo-fetal lethality and embryo-fetal toxicity in pregnantNo dose adjustment is recommended for patients with mild or moderate rats when given during gestation at doses resulting in exposures lower thanrenal impairment (CLcr of 30 to 89 mL/min as determined by the Cockcroft-or similar to human exposures at the recommended clinical dose (see Data).Gault formula). Reduce the dose of LONSURF for patients with severe renal There are no available data on LONSURF use in pregnant women. Adviseimpairment (CLcr of 15 to 29 mL/min) [see Dosage and Administration (2.3) pregnant women of the potential risk to a fetus. in the full Prescribing Information]. The pharmacokinetics of trifluridine and In the U.S. general population, the estimated background risk of major birthtipiracil have not been studied in patients with end stage renal disease.defects and miscarriage in clinically recognized pregnancies is 2-4% and8.7Hepatic Impairment15-20%, respectively.No adjustment to the starting dosage of LONSURF is recommended for patients Data with mild hepatic impairment. Do not initiate LONSURF in patients with Animal Data baseline moderate or severe (total bilirubin 1.5 times ULN and any AST) Trifluridine/tipiracil was administered orally once daily to female rats duringhepatic impairment [see Clinical Pharmacology (12.3) in the full Prescribing organogenesis at dose levels of 15, 50, and 150 mg/kg [trifluridine (FTD)Information].equivalent]. Decreased fetal weight was observed at FTD doses 50 mg/kg17PATIENT COUNSELING INFORMATION(approximately 0.33 times the FTD exposure at the clinical dose of 35 mg/m2Advise the patient to read the FDA-approved patient labeling (Patient Information).twice daily). At the FTD dose of 150 mg/kg (approximately 0.92 times theSevere MyelosuppressionFTD exposure at the clinical dose of 35 mg/m2 twice daily) embryolethalityAdvise patients to immediately contact their healthcare provider if they and structural anomalies (kinked tail, cleft palate, ectrodactyly, anasarca,experience signs or symptoms of infection and advise patients to keep all alterations in great vessels, and skeletal anomalies) were observed. appointments for blood tests [see Warnings and Precautions (5.1)].8.2Lactation Gastrointestinal ToxicityRisk Summary Advise patients to contact their healthcare provider for severe or persistent There are no data on the presence of trifluridine, tipiracil or its metabolitesnausea, vomiting, diarrhea, or abdominal pain [see Adverse Reactions (6.1)].in human milk or its effects on the breastfed child or on milk production.Administration InstructionsIn nursing rats, trifluridine and tipiracil or their metabolites were present inAdvise patients that LONSURF is available in two strengths and they may breast milk (see Data). Because of the potential for serious adverse reactionsreceive both strength tablets to provide the prescribed dosage.in breastfed children, advise women not to breastfeed during treatment with LONSURF and for 1 day following the final dose.Advise patients to take LONSURF with food [see Dosage and Administration Data (2.1) in the full Prescribing Information].Radioactivity was excreted in the milk of nursing rats dosed with trifluridine/ Advise patients not to retake doses of LONSURF that are vomited or missed tipiracil containing 14C-FTD or 14C-tipiracil (TPI). Levels of FTD-derivedand to continue with the next scheduled dose.radioactivity were as high as approximately 50% of the exposure in maternalAdvise patients that anyone else who handles their medication should wear plasma an hour after dosing with trifluridine/tipiracil and were approximatelygloves [see References (15) in the full Prescribing Information].the same as those in maternal plasma for up to 12 hours following dosing. Exposure to TPI-derived radioactivity was higher in milk than in maternalEmbryo-Fetal Toxicityplasma beginning 2 hours after dosing and continuing for at least 12 hoursAdvise pregnant women and females of reproductive potential of the potential following administration of trifluridine/tipiracil.risk to the fetus. Advise females to inform their healthcare provider of a 8.3Females and Males of Reproductive Potential known or suspected pregnancy [see Warnings and Precautions (5.2), UsePregnancy Testing in Specific Populations (8.3)]. Verify pregnancy status in females of reproductive potential prior to initiatingAdvise female patients of reproductive potential to use effective contraception LONSURF [see Use in Specific Populations (8.1)]. during treatment with LONSURF and for at least 6 months after the final dose Contraception [see Warnings and Precautions (5.2), Use in Specific Populations (8.3)].LONSURF can cause fetal harm when administered to a pregnant womanAdvise males with female partners of reproductive potential to use condoms [see Use in Specific Populations (8.1)]. during treatment with LONSURF and for at least 3 months after the final dose Females [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1) in the Advise females of reproductive potential to use effective contraception duringfull Prescribing Information].treatment with LONSURF and for at least 6 months after the final dose.LactationMales Advise women not to breastfeed during treatment with LONSURF and for 1 day Because of the potential for genotoxicity, advise males with female partnersfollowing the final dose [see Use in Specific Populations (8.2)].of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose [see Nonclinical Toxicology (13.1) in the full Prescribing Information].TAIHO ONCOLOGY, INC.08/2023LON-PM-US-1722Taiho_Directory_USMed_Dec2023_FullAd_NAout_7.875x10.75_L09.indd 5 11/27/23 6:17 PM'