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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
LONSURF (NDA-207981)
(TIPIRACIL HYDROCHLORIDE; TRIFLURIDINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
08/02/2023 (SUPPL-12)
5 Warnings and Precautions
5.1 Severe MyelosuppressionAdditions and/or revisions underlined:
In the 1114 patients who received LONSURF as a single agent, LONSURF caused severe or life-threatening myelosuppression (Grade 3-4) consisting of neutropenia (38%), anemia (17%), thrombocytopenia (4%) and febrile neutropenia (3%). Three patients (0.3%) died due to neutropenic infection/sepsis; four other patients (0.5%) died due to septic shock. A total of 14% of patients received granulocyte-colony stimulating factors.
In the 246 patients who received LONSURF in combination with bevacizumab, LONSURF caused severe or life-threatening myelosuppression (Grade 3-4) consisting of neutropenia (52%), anemia (5%), thrombocytopenia (4%) and febrile neutropenia (0.4%). One patient (0.4%) died due to abdominal sepsis and two other patients (0.8%) died due to septic shock. A total of 29% of patients received granulocyte-colony stimulating factors.
…
6 Adverse Reactions
6.1 Clinical Trials ExperienceExtensive additions and/or revisions, please refer to label for complete information.
8 Use in Specific Populations
8.5 Geriatric UseAdditions and/or revisions underlined:
Of the 1114 patients with metastatic colorectal cancer or gastric cancer who received single agent LONSURF in clinical studies, 45% were 65 years of 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 over, and 10% were 75 and over. While these studies were not designed to detect a difference in efficacy, no overall differences were observed in patients 65 or older versus younger patients with either LONSURF as a single agent or LONSURF in combination with bevacizumab.
Patients 65 years of age or older who received LONSURF as a single agent 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 (20% vs 14%), and Grade 3 or 4 thrombocytopenia (6% vs 3%). Patients 65 years of age or older who received LONSURF in combination with bevacizumab had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (60% vs 46%) and Grade 3 or 4 thrombocytopenia (5% vs 4%).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
…
Administration Instructions
…
Advise patients not to retake doses of LONSURF that are vomited or missed and to continue with the next scheduled dose.
…
PATIENT INFORMATION
Additions and/or revisions underlined:
…
What is LONSURF?
LONSURF is a prescription medicine used:
alone or in combination with the medicine bevacizumab to treat adults with colorectal cancer:
that has spread to other parts of the body, and
who have been previously treated with certain chemotherapy medicines.
alone to treat adults with a kind of stomach cancer called gastric cancer including adenocarcinoma of the gastroesophageal junction:
that has spread to other parts of the body, and
who have been previously treated with at least 2 types of treatment which included certain medicines. It
…
What are the possible side effects of LONSURF?
LONSURF may cause serious side effects, including:
See “What is the most important information I should know about LONSURF?”
The most common side effects of LONSURF when used alone include:
low blood counts
…
The most common side effects of LONSURF when used in combination with bevacizumab include:
low blood counts
decreased salt (sodium) in your blood
tiredness and weakness
diarrhea
nausea
stomach-area (abdominal) pain
certain abnormal liver function blood tests
decreased appetite
…
02/22/2019 (SUPPL-8)
5 Warnings and Precautions
5.1 Severe Myelosuppression(Additions and/or revisions are underlined)
In the 868 patients who received LONSURF in RECOURSE and TAGS, 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.
5.2 Embryo-Fetal Toxicity
(Additions and/or revisions are underlined)
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.
6 Adverse Reactions
6 ADVERSE REACTIONS(Additions and/or revisions are underlined)
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Severe Myelosuppression
6.1 Clinical Trials Experience
(Additions and/or revisions are underlined)
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 the WARNINGS AND PRECAUTIONS section and below reflect exposure to LONSURF at the recommended dose in 533 patients with metastatic colorectal cancer in RECOURSE and 335 patients with metastatic gastric cancer in TAGS. 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 RECOURSE, a randomized (2:1), double-blind, placebo-controlled trial in patients with previously treated metastatic colorectal cancer. 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 RECOURSE, 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 reactions or laboratory abnormalities (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 RECOURSE, 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 2 and 3 list the adverse reactions and laboratory abnormalities (graded using CTCAE v4.03), respectively, observed in RECOURSE.
(Tables 2 and 3 have been revised, please refer to the label
In RECOURSE, 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 TAGS, 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. 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 TAGS, 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 (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 neutropenia, anemia, nausea, decreased appetite, thrombocytopenia, vomiting, and diarrhea.
In TAGS, 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 4 and 5 list the adverse reactions and laboratory abnormalities (graded using CTCAE v4.03), respectively, observed in TAGS.
(Tables have been added, please refer to the label)
In TAGS, 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.
8 Use in Specific Populations
8.1 PregnancyRisk 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 human exposures at the recommended clinical dose (see Data). There are no available data on LONSURF use 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]. Decreased fetal weight was observed at FTD doses greater than or equal to 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.
8.2 Lactation
(Additions and/or revisions are underlined)
Risk Summary
ItThere 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. 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.
8.3 Females and Males of Reproductive Potential
(Additions and/or revisions are underlined)
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating LONSURF.
Contraception
LONSURF can cause fetal harm when administered to a pregnant woman.
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 3 months after the final dose.
8.4 Pediatric Use.
(Additions and/or revisions are underlined)
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 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
(Additions and/or revisions are underlined)
In RECOURSE and TAGS, 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 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%).
8.6 Renal Impairment
(Additions and/or revisions are underlined)
No adjustment to the starting dosage of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min). Patients with severe renal impairment (CLcr < 30 mL/min) were not studied.
8.7 Hepatic Impairment
(Additions and/or revisions are underlined)
No adjustment to the starting dosage 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
…
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 to take LONSURF with food.
Advise patients that anyone else who handles their medication should wear glovesEmbryo-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.
Advise female patients of reproductive potential to use effective contraception during treatment with LONSURF and for at least 6 months after the final dose.
Advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose.
Lactation
Advise women not to breastfeed during treatment with LONSURF and for 1 day following the final dose.
Other
PATIENT INFORMATION(Additions and/or revisions are underlined)
What is the most important information I should know about LONSURF?
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 cell counts. ….
What is LONSURF?
LONSURF is a prescription medicine used to treat people with
colorectal cancer that has spread to other parts of the body and who have been previously treated or cannot receive certain chemotherapy medicines.
a kind of stomach cancer called gastric cancer including adenocarcinoma of the gastroesophageal junction that has spread to other parts of the body and who have been previously treated or cannot receive certain chemotherapy medications.
It is not known if LONSURF is safe and effective in children.
Before you take LONSURF, tell your healthcare provider about all of your medical conditions, including if you:
have kidney or liver problems
are pregnant or plan to become pregnant. LONSURF can harm your unborn baby.
For females who can become pregnant:
Your healthcare provider will verify your pregnancy status before you start treatment with LONSURF.
You should use effective birth control during treatment with LONSURF and for at least 6 months after your last dose of LONSURF.
Tell your healthcare provider right away if you become pregnant.
…
How should I take LONSURF?
Take LONSURF exactly as your healthcare provider tells you.
LONSURF comes in two strengths. Your healthcare provider may prescribe both strengths for your prescribed dose.
Take LONSURF 2 times a day with food.
Swallow LONSURF tablets whole.
…
06/29/2017 (SUPPL-6)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION(addition underlined)
…
Before you take LONSURF, tell your healthcare provider about all of your medical conditions, including if you:
have kidney or liver problems
are pregnant or plan to become pregnant. LONSURF can harm your unborn baby.
…
03/30/2017 (SUPPL-4)
8 Use in Specific Populations
8.6 Hepatic ImpairmentAdditions and/or revisions underlined:
In a pharmacokinetic trial comparing 10 patients with mild hepatic impairment (total bilirubin 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) and 6 patients with moderate hepatic impairment (total bilirubin greater than 1.5 to 3 times ULN and any AST) to 8 patients with normal hepatic function, no clinically important differences in the mean exposures of trifluridine and tipiracil were observed. Five of 6 patients with moderate hepatic impairment experienced Grade 3 or 4 increased bilirubin levels. Patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST) were not studied. 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 greater than 1.5 times ULN and any AST) hepatic impairment..
Additions and/or revisions underlined:
… Patients with severe renal impairment (CLcr < 30 mL/min) were not studied.