Lonsurf

Trifluridine, tipiracil.

Each Lonsurf Film-coated Tablet 15 mg/6.14 mg, for oral use, contains 15 mg of trifluridine and 6.14 mg of tipiracil equivalent to 7.065 mg of tipiracil hydrochloride as active ingredients.
Each Lonsurf Film-coated Tablet 20 mg/8.19 mg, for oral use, contains 20 mg of trifluridine and 8.19 mg of tipiracil equivalent to 9.420 mg of tipiracil hydrochloride as active ingredients.
Lonsurf contains trifluridine and tipiracil hydrochloride at a molar ratio of 1:0.5.
Trifluridine: Trifluridine, a nucleoside metabolic inhibitor, is described chemically as 2'-deoxy-5-(trifluoromethyl) uridine.
Trifluridine has a molecular formula C₁₀H₁₁F₃N₂O₅ and a molecular weight of 296.20. Trifluridine is a white crystalline powder, soluble in water, ethanol, 0.01 mol/L hydrochloric acid, 0.01 mol/L sodium hydroxide solution; freely soluble in methanol, acetone; sparingly soluble in 2-propanol, acetonitrile; slightly soluble in diethyl ether; and very slightly soluble in isopropyl ether.
Tipiracil hydrochloride: Tipiracil hydrochloride, a thymidine phosphorylase inhibitor, is described chemically as 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride or 2,4-(1H,3H)-pyrimidinedione,5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl] hydrochloride (1:1).
Tipiracil hydrochloride has a molecular formula C₉H₁₁ClN₄O₂·HCl and a molecular weight of 279.12. Tipiracil hydrochloride is a white crystalline powder, soluble in water, 0.01 mol/L hydrochloric acid, and 0.01 mol/L sodium hydroxide; slightly soluble in methanol; very slightly soluble in ethanol; and practically insoluble in acetonitrile, 2-propanol, acetone, diisopropyl ether, and diethyl ether.
Excipients/Inactive Ingredients: Lonsurf Film-coated Tablet 15 mg/6.14 mg contains the following inactive ingredients: lactose monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene glycol, titanium dioxide, and magnesium stearate.
Lonsurf Film-coated Tablet 20 mg/8.19 mg contains the following inactive ingredients: lactose monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene glycol, titanium dioxide, ferric oxide (red), and magnesium stearate.
Both Lonsurf Film-coated Tablet 15 mg/6.14 mg and Lonsurf Film-coated Tablet 20 mg/8.19 mg are imprinted with ink containing shellac, ferric oxide (red), ferric oxide (yellow), titanium dioxide, FD&C Blue No. 2 - Lakes, carnauba wax, and talc.

Pharmacology: Mechanism of Action: Lonsurf consists of a thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, 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.
Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Trifluridine/tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice.
Pharmacodynamics: Cardiac Electrophysiology: Lonsurf administered to 42 patients with advanced solid tumors at the recommended dosage had no large effect (i.e. >20 ms) in the mean QTc interval when compared to placebo and no exposure-QT relationship was identified. Two of 42 patients (4.8%) had QTc ˃500 msec and 2.4% had a QTc increase from baseline ˃60 msec.
Clinical Studies: Metastatic Colorectal Cancer: The efficacy of Lonsurf was evaluated in the RECOURSE study (NCT01607957), an international, randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer (mCRC). Key eligibility criteria included prior treatment with at least 2 lines of standard chemotherapy for metastatic CRC, ECOG performance status (PS) 0-1, absence of brain metastasis, and absence of ascites requiring drainage in the past four weeks. Patients were randomized 2:1 to receive Lonsurf 35 mg/m² or matching placebo orally twice daily after meals on Days 1-5 and 8-12 of each 28-day cycle until disease progression or unacceptable toxicity. Randomization was stratified by KRAS status (wild-type vs. mutant), time since diagnosis of first metastasis (<18 months vs. ≥18 months), and region (Japan vs. US, Europe and Australia). The major efficacy outcome measure was overall survival (OS) and an additional efficacy outcome measure was progression-free survival (PFS).
A total of 800 patients were randomized to Lonsurf (N=534) with best supportive care (BSC) or matching placebo (N=266) plus BSC. The median age was 63 years, 61% were male, 58% and 35% were White and Asian respectively, and all patients had baseline ECOG PS of 0 or 1. The primary site of disease was colon (62%) or rectum (38%). KRAS status was wild-type (49%) or mutant (51%) at study entry. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. All but one patient received bevacizumab, and all but two patients with KRAS wild-type tumors received panitumumab or cetuximab.
Efficacy results are summarized in Table 1 and Figure 1. (See Table 1 and Figure 1.)

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Metastatic Gastric Cancer: The efficacy of Lonsurf was evaluated in the TAGS study (NCT02500043) an international, randomized, double-blind, placebo-controlled study in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma previously treated with at least 2 prior regimens for advanced disease. Previous treatments must have included a fluoropyrimidine, a platinum, and either a taxane or irinotecan. Patients with HER2/neu-positive tumors must have received prior HER2/neu-targeted therapy, if available. Adjuvant chemotherapy could be counted as one prior regimen in patients who had recurrence during or within 6 months of completion of the adjuvant chemotherapy. Other key eligibility criteria included ECOG performance status (PS) 0 or 1. Patients were randomized 2:1 to receive Lonsurf 35 mg/m² orally twice daily on Days 1-5 and 8-12 of each 28-day cycle with best supportive care (BSC) or matching placebo with BSC until disease progression or unacceptable toxicity. Randomization was stratified by ECOG PS at baseline (0 vs. 1), prior ramucirumab (yes vs. no), and geographic region (Japan vs. rest of world). The major efficacy outcome measure was OS and an additional outcome measure was PFS.
A total of 507 patients were randomized to Lonsurf (N=337) or placebo (N=170). The median age was 63 years, 73% were male, 70% and 16% were White and Asian respectively, and 38% had a baseline ECOG PS of 0. Seventy-one percent of patients had gastric tumors, 29% had GEJ tumors, and two patients had gastric/GEJ tumors. All patients received platinum-based chemotherapy, 99% received fluoropyrimidine-based therapy, 91% received a taxane, 55% received irinotecan, and 33% received ramucirumab. The HER2 status was negative in 62%, positive in 19% and unknown in 20% of patients. Among the 94 patients with HER2 positive tumors, 89% received prior anti-HER2 therapy.
Efficacy results are summarized in Table 2 and Figure 2. (See Table 2 and Figure 2.)

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Pharmacokinetics: After twice daily dosing of Lonsurf, systemic exposure (AUC) of trifluridine increased more than dose-proportionally over the dose range of 15 mg/m² (0.43 times the recommended dose) to 35 mg/m².
The accumulation of trifluridine was 3-fold for AUC_0-12hr and 2-fold for C_max at steady state while no accumulation was observed for tipiracil.
Administration of a single dose of Lonsurf 35 mg/m² increased the mean AUC_0-last of trifluridine by 37-fold and C_max by 22-fold with reduced variability compared to administration of a single dose of trifluridine 35 mg/m² alone.
Absorption: Following a single oral administration of Lonsurf at 35 mg/m² in patients with cancer, the mean time to peak plasma concentration (T_max) of trifluridine was around 2 hours.
Food Effect: A standardized high-fat, high-calorie meal decreased trifluridine C_max, tipiracil C_max 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 C_max of trifluridine and the decrease in neutrophil counts.
Distribution: Trifluridine mainly binds to human serum albumin. The in vitro protein binding of trifluridine in human plasma is ˃96%, independent of drug concentration and presence of tipiracil. Plasma protein binding of tipiracil is below 8%.
Elimination: After administration of Lonsurf 35 mg/m², the mean elimination half-life (t_1/2) 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.
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: After single oral administration of Lonsurf (60 mg) with [¹⁴C]-trifluridine, the total cumulative excretion of radioactivity was 60% of the administered dose. The majority of recovered radioactivity was eliminated into urine (55% of the dose) as FTY and trifluridine glucuronide isomers within 24 hours, and the excretion into feces and expired air was <3% for both. The unchanged trifluridine was <3% of administered dose recovered in the urine and feces.
After single oral administration of Lonsurf (60 mg) with [¹⁴C]-tipiracil hydrochloride, recovered radioactivity was 77% of the dose, which consisted of 27% urinary excretion and 50% fecal excretion. Tipiracil was the major component and 6-HMU was the major metabolite in urine, and feces.
Specific Populations: 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.
Patients with Renal Impairment: In a dedicated renal impairment study, all patients received Lonsurf 35 mg/m² twice daily except for patients with severe renal impairment who received 20 mg/m² twice daily. Mild renal impairment (CLcr of 60 to 89 mL/min as determined by the Cockcroft-Gault formula) had no clinically important effect on steady-state AUC_0-last of trifluridine and tipiracil. Moderate renal impairment (CLcr of 30 to 59 mL/min) increased steady-state AUC_0-last of trifluridine by 56% and tipiracil by 139% compared to normal renal function (CLcr ≥90 mL/min). Severe renal impairment (CLcr of 15 to 29 mL/min) increased the dose-normalized steady-state AUC_0-last of trifluridine by 140% and tipiracil by 614% compared to normal renal function. The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with end-stage renal disease.
Patients with Hepatic Impairment: No clinically important differences in the mean exposures of trifluridine and tipiracil were observed between patients with mild hepatic impairment (total bilirubin ≤ ULN and AST ˃ ULN or total bilirubin ˃1 to 1.5 times ULN and any AST) to moderate hepatic impairment (total bilirubin ˃1.5 to 3 times ULN and any AST) and patients with normal hepatic function (total bilirubin and AST ≤ ULN); however, 5 of 6 patients with moderate hepatic impairment experienced Grade 3 or 4 increased bilirubin levels. The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with severe hepatic impairment. [See Hepatic Impairment under Precautions.]
Drug Interaction Studies: 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.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies evaluating the carcinogenic potential of trifluridine/tipiracil in animals have been performed. Trifluridine/tipiracil was genotoxic in a reverse mutation test in bacteria, a chromosomal aberration test in mammalian-cultured cells, and a micronucleus test in mice.
Animal studies did not indicate an effect of trifluridine/tipiracil on male fertility in rats. Dose-related increases in the corpus luteum count and implanted embryo count were observed, but female fertility was not affected.

Metastatic Colorectal Cancer: Lonsurf is indicated for the treatment of adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
Metastatic Gastric Cancer: Lonsurf is indicated for the treatment of adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.

Recommended Dosage: The recommended dosage of Lonsurf is 35 mg/m² up to a maximum of 80 mg per dose (based on the trifluridine component) orally twice daily within one hour of completion of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity. Round dose to the nearest 5 mg increment.
Instruct patients to swallow Lonsurf tablets whole.
Instruct patients not to retake doses of Lonsurf that are vomited or missed and to continue with the next scheduled dose.
Table 3 shows the calculated initial daily dose based on body surface area (BSA). (See Table 3.)

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Dosage Modifications for Adverse Reactions: Obtain complete blood cell counts prior to and on Day 15 of each cycle. [See Severe Myelosuppression under Precautions.]
Do not initiate the cycle of Lonsurf until: Absolute neutrophil count (ANC) is greater than or equal to 1,500/mm³ or febrile neutropenia is resolved; Platelets are greater than or equal to 75,000/mm³; Grade 3 or 4 non-hematological adverse reactions are resolved to Grade 0 or 1.
Within a treatment cycle, withhold Lonsurf for any of the following: Absolute neutrophil count (ANC) less than 500/mm³ or febrile neutropenia; Platelets less than 50,000/mm³; Grade 3 or 4 non-hematological adverse reactions.
After recovery, resume Lonsurf after reducing the dose by 5 mg/m²/dose from the previous dose, if the following occur: Febrile neutropenia; Uncomplicated Grade 4 neutropenia (which has recovered to greater than or equal to 1,500/mm³) or thrombocytopenia (which has recovered to greater than or equal to 75,000/mm³) that results in more than 1 week delay in start of next cycle; Non-hematologic Grade 3 or Grade 4 adverse reaction except for Grade 3 nausea and/or vomiting controlled by antiemetic therapy or Grade 3 diarrhea responsive to antidiarrheal medication.
A maximum of 3 dose reductions are permitted. Permanently discontinue Lonsurf in patients who are unable to tolerate a dose of 20 mg/m² orally twice daily. Do not escalate Lonsurf dosage after it has been reduced.
Recommended Dosage for Renal Impairment: Severe Renal Impairment: In patients with severe renal impairment [creatinine clearance (CLcr) of 15 to 29 mL/min as determined by the Cockcroft-Gault formula], the recommended initial dosage is 20 mg/m² (based on the trifluridine component) orally twice daily within one hour of completion of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle (Table 4) [see Renal Impairment under Precautions; Pharmacology: Pharmacokinetics under Actions]. Reduce dose to 15 mg/m² twice daily in patients with severe renal impairment who are unable to tolerate a dose of 20 mg/m² twice daily (Table 4). Permanently discontinue Lonsurf in patients who are unable to tolerate a dose of 15 mg/m² twice daily. (See Table 4.)

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None.

Severe Myelosuppression: In the 868 patients who received Lonsurf in the RECOURSE and TAGS studies, Lonsurf caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia (3%). Two patients (0.2%) died due to neutropenic infection/sepsis and four other patients (0.5%) died due to septic shock. A total of 12% of Lonsurf-treated patients received granulocyte-colony stimulating factors.
Obtain complete blood counts prior to and on Day 15 of each cycle of Lonsurf and more frequently as clinically indicated. Withhold Lonsurf for severe myelosuppression and resume at the next lower dosage. [See Dosage Modifications for Adverse Reactions under Dosage & Administration.]
Embryo-Fetal Toxicity: Based on animal studies and its mechanism of action, Lonsurf can cause fetal harm when administered to a pregnant woman. Trifluridine/tipiracil caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at dosage levels resulting in exposures lower than those achieved at the recommended dosage of 35 mg/m² twice daily.
Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with Lonsurf and for at least 6 months after the final dose. [See Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation.]
Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min as determined by the Cockcroft-Gault formula). Reduce the initial dose of Lonsurf for patients with severe renal impairment (CLcr of 15 to 29 mL/min). [See Recommended Dosage for Renal Impairment under Dosage & Administration.] The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with end stage renal disease.
Hepatic Impairment: No adjustment to the starting dose of Lonsurf is recommended for patients with mild hepatic impairment. Do not initiate Lonsurf in patients with baseline moderate or severe (total bilirubin ˃1.5 times ULN and any AST) hepatic impairment. [See Pharmacology: Pharmacokinetics under Actions.]
Use in Children: Safety and effectiveness of Lonsurf in pediatric patients have not been established.
Juvenile Animal Toxicity 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 ≥50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m² twice daily).
Use in the Elderly: In the RECOURSE and TAGS studies, 868 patients received Lonsurf; 45% were 65 years of age or over, while 10% were 75 and over. No overall differences in effectiveness were observed in patients 65 years or older versus younger patients. Patients 65 years of age or older who received Lonsurf had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (46% vs 32%), Grade 3 anemia (22% vs 16%), and Grade 3 or 4 thrombocytopenia (7% vs 4%).

Pregnancy: Risk Summary: Based on animal data and its mechanism of action [see Pharmacology: Mechanism of Action under Actions], 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 human exposures at the recommended clinical dose (see Data as follows). There are no available data on Lonsurf use in pregnant women. Advise pregnant women of the potential risk to a fetus.
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]. Decreased fetal weight was observed at FTD doses ≥50 mg/kg (approximately 0.33 times the FTD 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.
Lactation: Risk Summary: There are no data on the presence of trifluridine, tipiracil or its metabolites in human milk or its effects on the breastfed child or on milk production. In nursing rats, trifluridine and tipiracil or their metabolites were present in breast milk (see Data as follows). Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Lonsurf and for 1 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 trifluridine/tipiracil.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating Lonsurf [see Pregnancy as previously mentioned].
Contraception: Lonsurf can cause fetal harm when administered to a pregnant woman. [See Pregnancy as previously mentioned.]
Females: Advise females of reproductive potential to use effective contraception during treatment with Lonsurf and for at least 6 months after the final dose.
Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with Lonsurf and for at least 6 months after the final dose. [See Pharmacology: Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions.]

The following clinically significant adverse reactions are discussed in Precautions: Severe Myelosuppression.
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data in Precautions and as follows reflect exposure to Lonsurf at the recommended dose in 533 patients with metastatic colorectal cancer in the RECOURSE study and 335 patients with metastatic gastric cancer in the TAGS study. Among the 868 patients who received Lonsurf, 11% were exposed for 6 months or longer and 1% were exposed for 12 months or longer. The most common adverse reactions or laboratory abnormalities (≥10%) are anemia, neutropenia, fatigue/asthenia, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting and pyrexia.
Metastatic Colorectal Cancer: The safety of Lonsurf was evaluated in the RECOURSE study, a randomized (2:1), double-blind, placebo-controlled trial in patients with previously treated metastatic colorectal cancer [see Pharmacology: Pharmacodynamics: Clinical Studies: Metastatic Colorectal Cancer under Actions]. Patients received Lonsurf 35 mg/m²/dose (n=533) or placebo (n=265) twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. In the RECOURSE study, 12% of patients received Lonsurf for more than 6 months and 1% of patients received Lonsurf for more than 1 year.
The study population characteristics were: median age 63 years; 61% male; 57% White, 35% Asian, and 1% Black.
The most common adverse drug reactions or laboratory abnormalities (≥10% in incidence) in patients treated with Lonsurf at a rate that exceeds the rate in patients receiving placebo were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.
In the RECOURSE study, 3.6% of patients discontinued Lonsurf for an adverse reaction and 14% of patients required a dose reduction. The most common adverse reactions or laboratory abnormalities leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.
Tables 5 and 6 list the adverse reactions and laboratory abnormalities (graded using CTCAE v4.03), respectively, observed in the RECOURSE study. (See Tables 5 and 6.)

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In the RECOURSE study, pulmonary emboli occurred more frequently in Lonsurf-treated patients (2%) compared to no patients on placebo.
Metastatic Gastric Cancer: The safety of Lonsurf was evaluated in the TAGS study, an international, randomized (2:1), double-blind, placebo-controlled trial in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who were previously treated with at least 2 prior chemotherapy regimens for advanced disease [see Pharmacology: Pharmacodynamics: Clinical Studies: Metastatic Gastric Cancer under Actions]. Previous treatments must have included a fluoropyrimidine, a platinum, and either a taxane or irinotecan. Patients with HER2/neu-positive tumors must have received prior HER2/neu-targeted therapy, if available. Adjuvant chemotherapy could be counted as one prior regimen in patients who had recurrence during or within 6 months of completion of the adjuvant chemotherapy. Patients received Lonsurf 35 mg/m²/dose (n=335) or placebo (n=168) twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle with best supportive care. In the TAGS study, 10% of patients received Lonsurf for more than 6 months and 0.9% of patients received Lonsurf for more than 1 year.
The study population characteristics were: median age 63 years (24 to 89 years); 73% male; 70% White, 16% Asian, and 1% Black.
The most common adverse reactions or laboratory abnormalities (≥10% in incidence) in patients treated with Lonsurf at a rate that exceeds the rate in patients receiving placebo were neutropenia, anemia, nausea, decreased appetite, thrombocytopenia, vomiting and diarrhea.
In the TAGS study, 13% of patients discontinued Lonsurf for an adverse reaction and 11% of patients required a dose reduction. The most common adverse reactions or laboratory abnormalities leading to dose reduction were neutropenia, anemia, febrile neutropenia, and diarrhea.
Tables 7 and 8 list the adverse reactions and laboratory abnormalities (graded using CTCAE v4.03), respectively, observed in TAGS. (See Tables 7 and 8.)

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In the TAGS study, pulmonary emboli occurred more frequently in Lonsurf-treated patients (3.1%) compared to 1.8% for patients on placebo.
Additional Clinical Experience: Interstitial lung disease was reported in 15 (0.2%) patients, 3 of which were fatal, among approximately 7,000 patients exposed to Lonsurf in clinical studies and clinical practice settings in Asia.

Lonsurf is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Store at or below 30°C.

Severe Myelosuppression: Advise patients to immediately contact their healthcare provider if they experience signs or symptoms of infection and advise patients to keep all appointments for blood tests. [See Severe Myelosuppression under Precautions.]
Gastrointestinal Toxicity: Advise patients to contact their healthcare provider for severe or persistent nausea, vomiting, diarrhea, or abdominal pain. [See Clinical Trials Experience under Adverse Reactions.]
Administration Instructions: Advise patients that Lonsurf is available in two strengths and they may receive both strength tablets to provide the prescribed dosage.
Advise patients of the importance of reading prescription labels carefully and taking the appropriate number of tablets.
Advise patients to take Lonsurf within 1 hour after eating their morning and evening meals. [See Recommended Dosage under Dosage & Administration.]
Advise patients that anyone else who handles their medication should wear gloves.
Embryo-Fetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to the fetus.
Advise females to inform their healthcare provider of a known or suspected pregnancy. [See Embryo-Fetal Toxicity under Precautions; Females and Males of Reproductive Potential under Use in Pregnancy & Lactation.]
Advise female patients of reproductive potential to use effective contraception during treatment with Lonsurf and for at least 6 months after the final dose. [See Embryo-Fetal Toxicity under Precautions; Females and Males of Reproductive Potential under Use in Pregnancy & Lactation.]
Advise males with female partners of reproductive potential to use condoms during treatment with Lonsurf and for at least 6 months after the final dose. [See Females and Males of Reproductive Potential under Use in Pregnancy & Lactation; Pharmacology: Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions.]
Lactation: Advise women not to breastfeed during treatment with Lonsurf and for 1 day following the final dose. [See Lactation under Use in Pregnancy & Lactation.]

Cytotoxic Chemotherapy

L01BC59 - trifluridine, combinations ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

P₁S₁S₃