繁体中文
设为首页
加入收藏
当前位置:药品说明书与价格首页 >> 上市新药 >> LONSURF(trifluridine and tipiracil)tablets

LONSURF(trifluridine and tipiracil)tablets

2015-11-01 03:26:44  作者:新特药房  来源:互联网  浏览次数:8  文字大小:【】【】【
简介: 新类晚期结肠直肠癌复方片Lonsurf(trifluridine/tipiracil,FTD/TPI)获美国FDA提前3个月批准上市2015年9月22日,美国FDA批准Lonsurf(一种由屈氟尿苷与Tipiracil组合而成的药丸)用于不再对其它治疗 ...

新类晚期结肠直肠癌复方片Lonsurf(trifluridine/tipiracil,FTD/TPI)获美国FDA提前3个月批准上市
2015年9月22日,美国FDA批准Lonsurf(一种由屈氟尿苷与Tipiracil组合而成的药丸)用于不再对其它治疗药物响应的晚期结直肠癌患者。
过去10年已对结直肠癌带来新的理解,懂得了如何检测及治疗这种通常灾难性的疾病,FDA 药物评价与研究中心代谢及肿瘤产品办公室主任、医学博士Pazdur称。但仍有许多患者需要额外的选择,今天的批准凸显了FDA在仍有未满足需求疾病领域内与制药公司一起致力于开发新的药物的承诺。
据美国国家癌症研究所提供的信息,在美国结直肠癌是男女中第三大常见非皮肤癌。同时,也是美国癌症相关死亡的第二个主要因素,在过去10年,结直肠癌及相关死亡病例的数量已经下降,在某种程度上说这得益于疾病的筛查,如结肠镜检查。
Lonsurf是一种口服药物,其旨在治疗既往有过化疗及生物制剂治疗的晚期(转移性)结直肠癌患者。Lonsurf的有效性及安全性在一项由800名既往有过治疗的转移性结直肠癌受试者参与的国际、随机、双盲研究中得到评价。 
研究受试者接受Lonsurf+最佳支持治疗或安慰剂+最佳支持治疗,直到疾病恶化或副作用变得不耐受为止。这项研究的主要终点是总生存期,次要终点为无进展生存期。以Lonsurf治疗患者平均生存了7.1个月,相比之下,以安慰剂治疗患者平均生存了 5.3个月。通常,患者在服用Lonsurf2个月后疾病开始进展,而服用安慰的患者在 1.7个月后疾病开始进展。
Lonsurf 治疗最常见副作用有贫血、抗感染白细胞(嗜中性白血球减少症)或血小板(血小板减少症)计算降低、身体虚弱、极度疲劳及缺乏精力 (疲劳)、恶心、食欲下降、腹泻、呕吐、腹痛和发热。
FDA建议医疗保健供应商在开始每轮Lonsurf治疗前获得完整的血液计数,并在整个治疗期间对患者进行监测,因为Lonsurf可能引起血液细胞及血小板产生(骨髓抑制)严重降低。
同时,鼓励医疗保健供应商告知女性在服用Lonsurf时胎儿可能发生的潜在风险。正在服用Lonsurf的女性不应母乳喂养。Lonsurf由新泽西州普林斯顿Taiho肿瘤公司生产。
包装规格:
15mg/6.14mg/片 *20片、40片、60片|瓶
20mg/8.19mg/片 *20片、40片、60片|瓶


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. (1)
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. (2.1)
Take LONSURF within 1 hour after completion of morning and evening meals. (2.1)
DOSAGE FORMS AND STRENGTHS
Tablets:

15 mg trifluridine/6.14 mg tipiracil (3)
20 mg trifluridine/8.19 mg tipiracil (3)
CONTRAINDICATIONS
None. (4)
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 indicated. (5.1)
Embryo-Fetal Toxicity: Fetal harm can occur. Advise women of potential risk to a fetus. (5.2)
ADVERSE REACTIONS
The most common adverse reaction (≥10%) are anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Taiho Oncology, Inc. at 1-844-878-2446 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Lactation: Do not breastfeed. (8.2)
Geriatric Use: Grade 3 or 4 neutropenia and thrombocytopenia and Grade 3 anemia occurred more commonly in patients 65 years old or older who received LONSURF. (8.5)
Renal Impairment: Patients with moderate renal impairment may require dose modifications for increased toxicity. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
LONSURF is 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.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended starting dose 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.
Do not take additional doses to make up for missed or held doses.
LONSURF is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
2.2 Dose Modifications
Obtain complete blood cell counts prior to and on Day 15 of each cycle.
Do no 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 level, 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 to a minimum dose of 20 mg/m2 twice daily. Do not escalate LONSURF dose after it has been reduced.
3 DOSAGE FORMS AND STRENGTHS
LONSURF (15 mg trifluridine/6.14 mg tipiracil) is a white, biconvex, round, film-coated tablet, imprinted with ‘15’ on one side, and ‘102’ and ‘15 mg’ on the other side, in gray ink.
LONSURF (20 mg trifluridine/8.19 mg tipiracil) is a pale red, biconvex, round, film-coated tablet, imprinted with ‘20’ on one side, and ‘102’ and ‘20 mg’ on the other side, in gray ink.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Severe Myelosuppression
In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% 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 febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery resume LONSURF at a reduced dose. [see Dosage and Administration (2.2)]
5.2 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 dose levels resulting in exposures lower than those achieved at the recommended dose of 35 mg/m2 twice daily.
Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)]
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in detail in other sections of the labeling:
Severe Myelosuppression [see Warnings and Precautions (5.1)]
6.1 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 described below are from Study 1, a randomized (2:1), double-blind, placebo-controlled trial in which 533 patients (median age 63 years; 61% men; 57% White, 35% Asian, 1% Black) with previously treated metastatic colorectal cancer received LONSURF as a single agent at a dose of 35 mg/m2/dose administered twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. The mean duration of LONSURF therapy was 12.7 weeks.
The most common adverse drug reactions or laboratory abnormalities (all Grades and greater than or equal to 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 Study 1, 3.6% of patients discontinued LONSURF for an adverse event and 13.7% of patients required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.
Table 1 Per Patient Incidence of Adverse Drug Reactions (≥5%) in Study 1 Occurring More Commonly (>2%) than in Patients Receiving Placebo. 

Adverse Reactions LONSURF
(N=533)
Placebo
(N=265)
All Grades Grades 3-4* All Grades Grades 3-4*
Gastrointestinal disorders
Nausea 48% 2% 24% 1%
Diarrhea 32% 3% 12% <1%
Vomiting 28% 2% 14% <1%
Abdominal pain 21% 2% 18% 4%
Stomatitis 8% <1% 6% 0%
General disorders and administration site conditions
Asthenia/fatigue 52% 7% 35% 9%
Pyrexia 19% 1% 14% <1%
Metabolism and nutrition disorders
Decreased appetite 39% 4% 29% 5%
Nervous system disorders
Dysgeusia 7% 0% 2% 0%
Skin and subcutaneous tissue disorders
Alopecia 7% 0% 1% 0%
No Grade 4 definition for nausea, abdominal pain, or fatigue in National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
Table 2 Laboratory Test Abnormalities

Laboratory Parameter LONSURF
(N=533*)
Placebo
(N=265*)
Grade† Grade†
All
%
3
%
4
%
All
%
3
%
4
%
Blood and lymphatic system disorders
Anemia 77 18 N/A# 33 3 N/A
Neutropenia 67 27 11 1 0 0
Thrombocytopenia 42 5 1 8 <1 <1

% based on number of patients with post-baseline samples, which may be less than 533 (LONSURF) or 265 (placebo)
Common Terminology Criteria for Adverse Events (CTCAE), v4.03
Anemia: No Grade 4 definition for these laboratory parameters in CTCAE, v4.03
One Grade 4 anemia adverse reaction based on clinical criteria was reported
In Study 1, infections occurred more frequently in LONSURF-treated patients (27%) compared to those receiving placebo (15%). The most commonly reported infections which occurred more frequently in LONSURF-treated patients were nasopharyngitis (4% versus 2%), and urinary tract infections (4% versus 2%).
In Study 1, pulmonary emboli occurred more frequently in LONSURF-treatment patients (2%) compared to no patients on placebo.
Additional Clinical Experience
Interstitial lung disease was reported in fifteen (0.2%) patients, three of which were fatal, among approximately 7,000 patients exposed to LONSURF in clinical studies and clinical practice settings in Asia.
7 DRUG INTERACTIONS
No pharmacokinetic drug-drug interaction studies have been conducted with LONSURF.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
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
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)]
8.8 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.
10 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 antineoplastic thymidine-based nucleoside analogue, is described chemically as 2’-deoxy-5-(trifluoromethyl) uridine, and has the following structural formula:


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), and has the following structural formula:


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.
LONSURF Tablet (15 mg trifluridine/6.14 mg tipiracil)
Each film-coated tablet of LONSURF, 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. LONSURF tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene glycol, titanium dioxide, and magnesium stearate.
LONSURF Tablet (20 mg trifluridine/8.19 mg tipiracil)
Each film-coated tablet of LONSURF, 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 tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene glycol, titanium dioxide, ferric oxide, and magnesium stearate.
Both film-coated tablets (LONSURF 15 mg/6.14 mg and 20 mg/8.19 mg) are imprinted with ink containing shellac, ferric oxide red, ferric oxide yellow, titanium dioxide, FD&C Blue No. 2 Aluminum Lake, carnauba wax, and talc.
12 CLINICAL PHARMACOLOGY
12.1 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.
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.
12.2 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.
12.3 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 (t½) 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.
The accumulation of trifluridine was 3-fold for AUC0-last and 2-fold for peak plasma concentration (Cmax) at steady state while no accumulation was observed for tipiracil.
Administration of a single dose of LONSURF containing tipiracil and trifluridine 35 mg/m2 increased the mean AUC0-last of trifluridine by 37-fold and Cmax by 22-fold with reduced variability compared to 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 (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 counts.
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. The estimated mean AUC of tipiracil was 34% higher in patients with mild renal impairment and 65% higher in patients with moderate renal impairment than that in patients with normal renal function. The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease. [see Use in Specific Populations (8.7)]
Hepatic Impairment
In Study 1, with data from 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. [see Use in Specific Populations (8.6)]
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.
13 NONCLINICAL TOXICOLOGY
13.1 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.
14 CLINICAL STUDIES
14.1 Colorectal Cancer
Study 1
The clinical efficacy and safety of LONSURF were evaluated in an international, randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer (CRC).
A total of 800 patients were randomized 2:1 to receive LONSURF (N=534) plus best supportive care (BSC) or matching placebo (N=266) plus BSC. 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). Key eligibility criteria included prior treatment with at least 2 lines of standard chemotherapy for metastatic CRC, ECOG 0-1, absence of brain metastasis, and absence of ascites requiring drainage in the past four weeks. Patients received 35 mg/m2 LONSURF or matching placebo orally twice daily after meals on Days 1 - 5and 8–12 of each 28-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS) and an additional efficacy outcome measure was progression-free survival (PFS). The median age was 63 years, 61% were male, 58% and 35% were White and Asian respectively, and all patients had baseline ECOG Performance Status (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. [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]
A statistically significant improvement in overall survival and progression-free survival were demonstrated in patients in the LONSURF plus BSC arm compared to those who received placebo plus BSC (see Table 3 and Figure 1)
Table 3 Efficacy Results 

LONSURF
(N=534)
Placebo
(N=266)
Overall Survival
Number of deaths, N (%) 364 (68) 210 (79)
Median OS (months)a [95% CI]b 7.1 [6.5, 7.8] 5.3 [4.6, 6.0]
Hazard ratio [95% CI] 0.68 [0.58, 0.81]
P-valuec <0.001
Progression-Free Survival
Number of Progression or Death, N (%) 472 (88) 251 (94)
Hazard ratio [95% CI] 0.47 (0.40, 0.55)
P-valuec <0.001
a Kaplan-Meier estimates
b Methodology of Brookmeyer and Crowley
c Stratified log-rank test (strata: KRAS status, time since diagnosis of first metastasis, region)
Figure 1 Kaplan-Meier Curves of Overall Survival


15 REFERENCES
1. “OSHA Hazardous Drugs”. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
LONSURF 15 mg/6.14 mg tablets are supplied as white, biconvex, round, film-coated tablet, imprinted with ‘15’ on one side, and ‘102’ and ’15 mg’ on the other side, in gray ink. The tablets are packaged in HDPE bottles with child resistant closures in the following presentations:
20 count: NDC 64842-1025-1
40 count: NDC 64842-1025-2
60 count: NDC 64842-1025-3
LONSURF 20 mg/8.19 mg tablets are supplied as pale red, biconvex, round, film-coated tablet, imprinted with ‘20’ on one side, and ‘102’ and ‘20 mg’ on the other side, in gray ink. The tablets are packaged in HDPE bottles with child resistant closures in the following presentations:
20 count: NDC 64842-1020-1
40 count: NDC 64842-1020-2
60 count: NDC 64842-1020-3
16.2 Storage and Handling
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].
LONSURF is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
If stored outside of original bottle, discard after 30 days.
17 PATIENT COUNSELING INFORMATION
Advise 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. [see Warnings and Precautions (5.1)]
Gastrointestinal toxicity:
Advise patients to contact their healthcare provider for severe or persistent nausea, vomiting, diarrhea, or abdominal pain. [see Adverse Reactions (6.1)]
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. [see Dosage and Administration (2.1)]
Advise the patient that anyone else who handles their medication should wear gloves. [see References (15)]
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. [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)]
Lactation:
Advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. [see Use in Specific Populations (8.2)]
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5beed22-d71d-4c0d-8dca-2c7317d65d85

责任编辑:admin


相关文章
Lonsurf tablet(trifluridine/tipiracil,FTD/TPI)复方片
Lonsurf(tipiracil盐酸盐和曲氟尿苷 trifluridine)复方片
新型晚期结肠直肠癌药物Lonsurf获美国FDA批准即将上市
 

最新文章

更多

· Stribild(埃替拉韦/cobi...
· VIIBRYD(vilazodone hyd...
· VARUBI(rolapitant tablets)
· LONSURF(trifluridine a...
· 狄诺塞麦注射剂|XGEVA(D...
· LYMPHOSEEK KIT(TECHNE...
· ADEMPAS(RIOCIGUAT)TABL...
· RIXUBIS(Coagulation Fa...
· GLIADEL Wafer(Polifepr...
· 尼达尼布软胶囊|Ofev(ni...

推荐文章

更多

· Stribild(埃替拉韦/cobi...
· VIIBRYD(vilazodone hyd...
· VARUBI(rolapitant tablets)
· LONSURF(trifluridine a...
· 狄诺塞麦注射剂|XGEVA(D...
· LYMPHOSEEK KIT(TECHNE...
· ADEMPAS(RIOCIGUAT)TABL...
· RIXUBIS(Coagulation Fa...
· GLIADEL Wafer(Polifepr...
· 尼达尼布软胶囊|Ofev(ni...

热点文章

更多

· 狄诺塞麦注射剂|XGEVA(D...
· VIIBRYD(vilazodone hyd...
· LONSURF(trifluridine a...
· VARUBI(rolapitant tablets)
· Stribild(埃替拉韦/cobi...