26/15    LONSURF 

Name of the Drug-   LONSURF

Active Ingredient-      Trifluridine and Tippiracil

Indication-                  To treat patients with an advanced form of colorectal cancer                                             who are no longer responding to other therapies       

Date                              9/22/2015                     

HIGHLIGHTS OF PRESCRIBING INFORMATION-

 These highlights do not include all the information needed to use LONSURF safely and effectively. See full prescribing information for LONSURF.

LONSURF (trifluridine and tipiracil) tablets, for oral use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE-

LONSURF is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor, indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

DOSAGE AND ADMINISTRATION

• Recommended dose: 35 mg/m2 /dose orally twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. 

• Take LONSURF within 1 hour after completion of morning and evening meals.

 DOSAGE FORMS AND STRENGTHS Tablets:

• 15 mg trifluridine/6.14 mg tipiracil

• 20 mg trifluridine/8.19 mg tipiracil (3) CONTRAINDICATIONS None. (4)

 ADVERSE REACTIONS- (summary)-

 The most common adverse reaction (=10%) are anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

WARNINGS AND PRECAUTIONS-

 • Severe Myelosuppression: Obtain complete blood counts prior to and on Day 15 of each cycle. Reduce dose and/or hold LONSURF as clinically indicat

 • Embryo-Fetal Toxicity: Fetal harm can occur. Advise women of potential risk to a fetus. 

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Severe Myelosuppression: Advise the patient to immediately contact their healthcare provider if they experience signs or symptoms of infection and advise patients to keep all appointments for blood tests. [

Gastrointestinal toxicity: Advise patients to contact their healthcare provider for severe or persistent nausea, vomiting, diarrhea, or abdominal pain. [see Adverse Reactions

 Administration Instructions: Advise the patient that LONSURF is available in two strengths and they may receive both strength tablets to provide the prescribed dose.

Advise the patient of the importance of reading prescription labels carefully and taking the appropriate number of tablets.

Advise the patient to take LONSURF within 1 hour after eating their morning and evening meals. 

 Embryo-Fetal Toxicity: Advise pregnant women of the potential risk to the fetus.

Advise females of reproductive potential to use effective contraception during treatment with LONSURF. 

 Lactation: Advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. 

Your healthcare provider should do blood tests before you receive LONSURF, at day 15 during treatment with LONSURF, and as needed to check your blood cell counts.

LONSURF may cause serious side effects, including: Low blood counts. Low blood counts are common with LONSURF and can sometimes be severe and life-threatening.

LONSURF can cause a decrease in your white blood cells, red blood cells, and platelets. Low white blood cells can make you more likely to get serious

Specific Populations (8.2)] 16 Reference ID: 3823053 PATIENT INFORMATION LONSURF® (trifluridine and tipiracil) tablets What is the most important information I should know about LONSURF?

CLINICAL PHARMACOLOGY-

1. Mechanism of Action -

LONSURF consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil, at a molar ratio 1:0.5 (weight ratio, 1:0.471). Inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase.

DNA synthesis and inhibits cell proliferation. Trifluridine/tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice.

2. Pharmacodynamics-

Cardiac Electrophysiology -                                                                                      LONSURF administered to 42 patients with advanced solid tumors at the recommended dosage regimen had no large effect (i.e. > 20 ms) in the mean QTc interval when compared to placebo and no evident exposure-QT relationship was identified. Two of 42 patients (4.8%) had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec.

3 Pharmacokinetics After twice daily dosing of LONSURF, systemic exposure (area under the concentration curve, AUC) of trifluridine increased more than dose-proportionally over the dose range of 15 to 35 mg/m2 .

After administration of LONSURF 35 mg/m2 twice daily, the mean elimination half-life (t1/2 ) of trifluridine was 1.4 hours and of tipiracil was 2.1 hours after a single dose. The mean elimination half-life at steady state of trifluridine was 2.1 hours and of tipiracil was 2.4 hours.

Absorption-

 Following a single oral administration of LONSURF at 35 mg/m2 in patients with cancer, the mean time to peak plasma concentration (Tmax ) of trifluridine was around 2 hours. A standardized high-fat, high-calorie meal decreased trifluridine Cmax , tipiracil Cmax and AUC by approximately 40%, but did not change trifluridine AUC compared to those in a fasting state in patients with cancer following administration of a single dose of LONSURF 35 mg/m2 .

It is recommended to take LONSURF within 1 hour after completion of the morning and evening meals based on the observed correlation between the increase in the Cmax of trifluridine and the decrease in neutrophil count

Distribution-                                                                                                                 Trifluridine mainly binds to human serum albumin. The in vitro protein binding of trifluridine in human plasma is greater than 96%, independent of drug concentration and presence of tipiracil. Plasma protein binding of tipiracil is below 8%.

Elimination Metabolism-                                                                                             Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). No other major metabolites were detected in plasma or urine.

Excretion-                                                                                                                    Following a single dose of LONSURF at 60 mg, the mean 48-hour cumulative urinary excretion was 1.5% for unchanged trifluridine, 19.2% for FTY, and 29.3% for unchanged tipiracil.

Specific Populations-                                                                                                   Age, Sex, and Race- Based on the population pharmacokinetic analysis, there is no clinically relevant effect of age, sex, or race (White or Asian) on the pharmacokinetics of trifluridine or tipiracil.

Renal Impairment-                                                                                                               In Study 1, the estimated mean AUC of trifluridine at steady state was 31% higher in patients with mild renal impairment (CLcr = 60 to 89 mL/min, n= 38) and 43% higher in patients with moderate renal impairment (CLcr = 30 to 59 mL/min, n= 16) than that in patient with normal renal function (CLcr = 90 mL/min, n= 84) based on the population pharmacokinetic analysis.

Patients with normal liver function-                                                                              (TB and AST less than or equal to the ULN, n=96) and patients with mild hepatic impairment (TB less than or equal to the ULN and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST, n= 42), there is no clinically relevant effect of mild hepatic impairment on the exposure of either trifluridine or tipiracil based on the population pharmacokinetic analysis.

Patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 time ULN and any AST) hepatic impairment were not enrolled in Study 1. The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with moderate to severe hepatic impairment. 

Drug Interaction Studies -Trifluridine is a substrate of thymidine phosphorylase, and is not metabolized by cytochrome P450 (CYP) enzyme. Tipiracil is not metabolized in either human liver or hepatocytes. In vitro studies indicated that trifluridine, tipiracil, and FTY did not inhibit the CYP enzymes and had no inductive effect on CYP1A2, CYP2B6, or CYP3A4/5. In vitro studies indicated that trifluridine was not an inhibitor of or substrate for human uptake and efflux transporters.

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary 6 Reference ID: 3823053 Based on animal data and its mechanism of action, LONSURF can cause fetal harm. LONSURF caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when given during gestation at doses resulting in exposures lower than or similar to exposures at the recommended dose in humans. [see Data]

There are no available data on LONSURF exposure in pregnant women. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data Trifluridine/tipiracil was administered orally once daily to female rats during organogenesis at dose levels of 15, 50, and 150 mg/kg [trifluridine (FTD) equivalent]. Decrease fetal weight was observed at FTD doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily). At the FTD dose of 150 mg/kg (approximately 0.92 times the FTD exposure at the clinical dose of 35 mg/m2 twice daily) embryolethality and structural anomalies (kinked tail, cleft palate, ectrodactyly, anasarca, alterations in great vessels, and skeletal anomalies) were observed

. 8.2 Lactation Risk Summary It is not known whether LONSURF or its metabolites are present in human milk. In nursing rats, trifluridine and tipiracil or their metabolites were present in breast milk

There are no data to assess the effects of LONSURF or its metabolites on the breastfed infant or the effects on milk production.

Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. Data Radioactivity was excreted in the milk of nursing rats dosed with trifluridine/tipiracil containing 14C-FTD or 14C-tipiracil (TPI). Levels of FTD-derived radioactivity were as high as approximately 50% of the exposure in maternal plasma an hour after dosing with trifluridine/tipiracil and were approximately 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 maternal plasma beginning 2 hours after dosing and continuing for at least 12 hours following administration of trifuridine/tipiracil. 8.3 Females and Males of Reproductive Potential

Contraception Females LONSURF can cause fetal harm when administered to a pregnant woman. [see Use in Specific Populations (8.1)] Advise females of reproductive potential to use effective contraception during treatment.

Males 7 Reference ID: 3823053 Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for a at least 3 months after the final dose. [see Nonclinical Toxicology (13.1)]

8.4 Pediatric Use Safety and effectiveness of LONSURF in pediatric patients have not been established. Animal Data 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 doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily).

8.5 Geriatric Use In Study 1, 533 patients received LONSURF; 44% were 65 years of age or over, while 7% were 75 and over.

No overall differences in effectiveness were observed in patients 65 or older versus younger patients, and no adjustment is recommended for the starting dose of LONSURF based on age. Patients 65 years of age or older who received LONSURF had a higher incidence of the following compared to patients younger than 65 years: Grade 3 or 4 neutropenia (48% vs 30%), Grade 3 anemia (26% vs 12%, and Grade 3 or 4 thrombocytopenia (9% vs 2%).

8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of LONSURF. No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (TB) less than or equal to the upper limit of normal (ULN) and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST).

Patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment were not enrolled in Study 1. [see Clinical Pharmacology (12.3)

8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of LONSURF. In Study 1, patients with moderate renal impairment (CLcr = 30 to 59 mL/min, n= 47) had a higher incidence (difference of at least 5%) of = Grade 3 adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr = 90 mL/min, n= 306) or patients with mild renal impairment (CLcr = 60 to 89 mL/min, n= 178). No dose adjustment to the starting dose of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min); however patients with moderate renal impairment may require dose modification for increased toxicity.

No patients with severe renal impairment (CLcr < 30 mL/min) were enrolled in Study 1. [see Clinical Pharmacology (12.3)] 8 Reference ID: 3823053

8.8 Ethnicity There were no clinically meaningful differences in Study 1 between Western and Asian subgroups with respect to overall incidence of adverse events or = Grade 3 adverse events in either the LONSURF or placebo groups.

 OVERDOSAGE The highest dose of LONSURF administered in clinical studies was 180 mg/m2 per day. There is no known antidote for LONSURF overdosage. 11 DESCRIPTION LONSURF contains trifluridine and tipiracil hydrochloride at a molar ratio of 1:0.5. Trifluridine Trifluridine, an antineoplast