Trifluridine; tipiracil, a combination product, is a nucleoside metabolic inhibitor and thymidine phosphorylase inhibitor. It is indicated as a single agent and in combination with bevacizumab in adults 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. Trifluridine; tipiracil is also indicated as a single agent in adults with gastric or gastroesophageal junction adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy. Severe myelosuppression has been reported with trifluridine; tipiracil therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
-When handling medication, wear gloves and wash hands afterward.
Emetic Risk
-Moderate/High
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take with food.
-Swallow tablets whole. Do not crush or chew tablets; round dose to the nearest 5-mg increment.
-Do not take additional doses to make up for doses that are vomited or missed.
Infection was reported in 23% to 27% (grade 3 or 4, 5% to 8%) of patients who received single-agent trifluridine; tipiracil and 31% (grade 3 or 4, 8%) of patients who received trifluridine; tipiracil in combination with bevacizumab in randomized trials. The incidence of fatal infection was 0.8% (neutropenic infection/sepsis, n = 3 [0.3%]; septic shock, n = 4 [0.5%]) in patients who received single-agent trifluridine; tipiracil (n = 1,114) and 1.2% (abdominal sepsis, n = 1 [0.4%]; septic shock, n = 2 [0.8%]) of patients who received trifluridine; tipiracil in combination with bevacizumab (n = 246); 14% and 29% of patients received granulocyte-colony stimulating factors, respectively.
Severe myelosuppression, including neutropenia (66% to 80%; grade 3 or 4, 38% to 52%), anemia (63% to 77%; grade 3 or 4, 5% to 19%), and thrombocytopenia (29% to 54%; grade 3 or 4, 0.8% to 8%), was reported with trifluridine; tipiracil as a single agent or in combination with bevacizumab in clinical trials. Monitor complete blood counts prior to and on day 15 of each cycle; an interruption of therapy or dose reduction may be necessary in patients who develop severe myelosuppression. Grade 3 or 4 neutropenia (38%), anemia (17%), thrombocytopenia (4%), and febrile neutropenia (3%) occurred in patients who received single-agent trifluridine; tipiracil in a pooled analysis of clinical trials (n = 1,114). Additionally, grade 3 or 4 neutropenia (52%), anemia (5%), thrombocytopenia (4%), and febrile neutropenia (0.4%) were reported in patients who received trifluridine; tipiracil in combination with bevacizumab (n = 246) in a randomized trial. Patients aged 65 or older who received trifluridine; tipiracil had a higher incidence of hematologic adverse reactions compared with younger patients, including grade 3 or 4 neutropenia (single agent: 46% vs. 32%; plus bevacizumab, 60% vs. 46%), anemia (single agent, 20% vs. 14%), and thrombocytopenia (single agent, 6% vs. 3%; plus bevacizumab, 5% vs. 4%).
Nausea (27% to 48%; grade 3 or 4, 1.6% to 3%), diarrhea (19% to 32%; grade 3 or 4, 1.2% to 3%), vomiting (15% to 28%; grade 3 or 4, 0.8% to 4%), abdominal pain (18% to 21%; grade 3 or 4, 2.4% to 3.7%), decreased appetite/anorexia (15% to 39%; grade 3 or 4 less than 0.8% to 9%) and constipation (11% or less; grade 3 or 4, 0.8% or less) were reported in patients who received trifluridine; tipiracil as a single agent or in combination with bevacizumab in randomized trials.
Asthenia/fatigue or fatigue occurred in 37% to 52% (grade 3 or 4, 5% to 8%) of patients who received trifluridine; tipiracil as a single agent or in combination with bevacizumab in randomized trials.
Dysgeusia occurred in 7% of patients with heavily pretreated metastatic colorectal cancer who received single-agent trifluridine; tipiracil (n = 533) compared with 2.3% of patients who received placebo (n = 265) in a randomized trial.
Alopecia occurred in 7% of patients with heavily pretreated metastatic colorectal cancer who received single-agent trifluridine; tipiracil (n = 533) compared with 1.1% of patients who received placebo (n = 265) in a randomized trial.
Pulmonary embolism was reported more often with single-agent trifluridine; tipiracil compared with placebo in patients with metastatic gastric cancer (3.1% vs. 1.8%) and metastatic colorectal cancer (2% vs. 0%) in 2 randomized trials.
Interstitial lung disease was reported in 15 patients (0.2%) exposed to trifluridine; tipiracil during clinical studies and clinical practice settings in Asia (approximate n = 7,000); 3 cases were fatal.
Trifluridine; tipiracil did not have a large effect (greater than 20 msec) on the mean QTc interval when compared to placebo in patients with advanced solid tumors at the recommended dosing (n = 42); no relationship with the QT interval and drug exposure was identified. However, 2 patients (4.8%) had QT prolongation to greater than 500 msec, and one of these patients (2.4%) had an increase from baseline greater than 60 msec.
Fever was reported in 4.9% to 19% (grade 3 or 4, 1.3% or less) of patients who received trifluridine; tipiracil as a single agent or in combination with bevacizumab in randomized trials.
Stomatitis was reported in 4.1% and 8% (grade 3 or 4, 0.4%) of patients who received single-agent trifluridine; tipiracil and 13% (grade 3 or 4, less than 0.4%) of patients who received trifluridine; tipiracil in combination with bevacizumab in randomized trials.
Musculoskeletal pain occurred in 18% (grade 3 or 4, 1.2%) of patients who received trifluridine; tipiracil plus bevacizumab (n = 246) and 11% (grade 3 or 4, 2%) of patients who received trifluridine; tipiracil alone (n = 246) for the treatment of metastatic colorectal cancer in a randomized trial.
Headache occurred in 8% of patients who received trifluridine; tipiracil plus bevacizumab (n = 246) and 3.7% of patients who received trifluridine; tipiracil alone (n = 246) for the treatment of metastatic colorectal cancer in a randomized trial.
Hypertension occurred in 11% (grade 3 or 4, 6%) of patients who received trifluridine; tipiracil plus bevacizumab (n = 246) and 2% (grade 3 or 4, 1.2%) of patients who received trifluridine; tipiracil alone (n = 246) for the treatment of metastatic colorectal cancer in a randomized trial.
Bleeding occurred in 10% (grade 3 or 4, 1.2%) of patients who received trifluridine; tipiracil plus bevacizumab (n = 246) and 3.7% (grade 3 or 4, 0.8%) of patients who received trifluridine; tipiracil alone (n = 246) for the treatment of metastatic colorectal cancer in a randomized trial.
Proteinuria occurred in 6% (grade 3 or 4, 0.8%) of patients who received trifluridine; tipiracil plus bevacizumab (n = 246) and 1.2% of patients who received trifluridine; tipiracil alone (n = 246) for the treatment of metastatic colorectal cancer in a randomized trial. Additionally, increased serum creatinine level was reported in 12% (grade 3 or 4, 0.8%) and 15% of patients in the trifluridine; tipiracil plus bevacizumab and trifluridine; tipiracil alone arms, respectively.
Elevated hepatic enzymes, including increased AST (34% vs. 28%; grade 3 or 4, 2.1% vs. 1.2%) and ALT (33% vs. 23%; grade 3 or 4, 3.3% vs. 0.4%) levels, occurred more often in patients with metastatic colorectal cancer who received trifluridine; tipiracil plus bevacizumab (n = 246) compared with trifluridine; tipiracil alone (n = 246) in a randomized trial. Additionally, increased alkaline phosphatase level was reported in 31% (grade 3 or 4, 0.8%) and 36% (grade 3 or 4, 1.2%) of patients in the trifluridine; tipiracil plus bevacizumab and trifluridine; tipiracil alone arms, respectively.
Electrolyte abnormalities that occurred in patients with metastatic colorectal cancer who received trifluridine; tipiracil plus bevacizumab (n = 246) and trifluridine; tipiracil alone (n = 246) in a randomized trial included hyponatremia (25% and 20%; grade 3 or 4%, 2.1% and 3.3%), hyperkalemia (17% and 15%), and hypokalemia (12% and 12%; grade 3 or 4%, 0.8% and 2.5%).
Intestinal/GI obstruction occurred in 2.8% of patients with metastatic colorectal cancer who received trifluridine; tipiracil plus bevacizumab (n = 246) in a randomized trial; fatal rectal fistula (0.4%) and bowel/GI perforation (0.4%) were also reported in patients who received trifluridine; tipiracil plus bevacizumab.
Fatal atrial fibrillation occurred in 0.4% of patients with metastatic colorectal cancer who received trifluridine; tipiracil plus bevacizumab (n = 246) in a randomized trial.
Trifluridine; tipiracil is associated with severe bone marrow suppression including neutropenia, anemia, and thrombocytopenia; do not begin a course of therapy if the ANC is less than 1,500 cells/mm3 or platelets are less than 75,000 cells/mm3. Obtain complete blood counts prior to and on day 15 of each cycle, and more frequently as clinically indicated; an interruption or delay of therapy may be necessary for myelosuppression or neutropenic fever. In clinical trials, geriatric patients (65 years and older) had a higher incidence of grade 3 and 4 hematologic toxicity than patients younger than 65 years. Patients who have had previous myelosuppressive therapy such as chemotherapy or radiation therapy are also at risk of increased bone marrow suppression during trifluridine; tipiracil treatment. Patients with an active infection should be treated prior to receiving trifluridine; tipiracil. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.
The safety and effectiveness of trifluridine; tipiracil have not been established in children younger than 18 years of age or infants. 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 approximately 0.33 times the exposure in humans at the clinical dose of 35 mg/m2 twice daily.
Pregnancy should be avoided by females of reproductive potential during trifluridine; tipiracil treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, trifluridine; tipiracil can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving trifluridine; tipiracil should be apprised of the potential hazard to the fetus. When administered once daily to female rats during organogenesis, decreased fetal weight was observed at approximately 0.33 times the exposure achieved with the recommended dosing. Embryolethality and structural abnormalities (kinked tail, cleft palate, ectrodactyly, anasarca, alterations in great vessels, and skeletal abnormalities) occurred at exposures 0.92 times that achieved with the recommended dose.
Counsel patients about the reproductive risk and contraception requirements during trifluridine; tipiracil treatment. Trifluridine; tipiracil can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during treatment with trifluridine; tipiracil and for at least 6 months after the last dose. Because of the potential for male-mediated teratogenicity, males with female partners taking trifluridine; tipiracil should use effective contraception during treatment and for at least 3 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of trifluridine; tipiracil. Women who become pregnant while receiving trifluridine; tipiracil or while their male partner is being treated should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of trifluridine; tipiracil on human fertility, there was not an effect on male or female fertility in animal studies.
It is not known whether trifluridine; tipiracil is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, females should avoid breast-feeding during treatment and for 1 day after the final dose.
For the treatment of colorectal cancer:
-for the treatment of metastatic colorectal cancer in patients who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic therapy, and if RAS wild-type, an anti-EGFR therapy:
Oral dosage:
Adults: 35 mg/m2 based on trifluridine component (maximum, 80 mg) orally twice daily with food on days 1, 2, 3, 4, and 5 and days 8, 9, 10, 11, and 12 repeated every 28 days until disease progression or unacceptable toxicity. Round the dose up or down to the nearest 5 mg; one or both strength tablets (15 mg or 20 mg of trifluridine component) may be used to make a dose. Specific dose and recommended tablets per dose based on body surface area are provided by the manufacturer. In a randomized, double-blind clinical trial, treatment with trifluridine; tipiracil (n = 534) significantly improved overall survival (7.1 months vs. 5.3 months) and progression-free survival (2 months vs. 1.7 months) compared with placebo in patients with heavily previously treated metastatic colorectal cancer (n = 266); all patients but one had received prior bevacizumab, and all but two KRAS wild-type patients had been previously treated with either panitumumab or cetuximab. The objective response rate (ORR) was 1.6% for trifluridine; tipiracil-treated patients and 0.4% for placebo; however, the rate of disease control was 44% vs. 16%, respectively. The addition of trifluridine; tipiracil to best supportive care also significantly delayed the time to worsening of ECOG performance status to 2 or higher (5.7 months vs. 4 months).
-for the treatment of metastatic colorectal cancer in patients who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic therapy, and if RAS wild-type, an anti-EGFR therapy, in combination with bevacizumab:
Oral dosage:
Adults: 35 mg/m2 based on trifluridine component (maximum, 80 mg) orally twice daily with food on days 1, 2, 3, 4, and 5 and days 8, 9, 10, 11, and 12 repeated every 28 days until disease progression or unacceptable toxicity. Round the dose up or down to the nearest 5 mg; one or both strength tablets (15 mg or 20 mg of trifluridine component) may be used to make a dose. Specific dose and recommended tablets per dose based on body surface area are provided by the manufacturer. At a median follow-up time of approximately 14 months in a randomized, phase 3 (SUNLIGHT) trial (n = 492), the median overall survival time was significantly longer in the trifluridine; tipiracil plus bevacizumab arm compared with the trifluridine; tipiracil alone arm (10.8 months vs. 7.5 months; hazard ratio (HR) = 0.61; 95% CI, 0.49 to 0.77) in patients with unresectable adenocarcinoma of the colon or rectum who had received previous chemotherapy regimens for advanced colorectal cancer and had progressive disease or unacceptable adverse effects to their last regimen. Additionally, investigator-assessed progression-free survival time was significantly longer in patients who received trifluridine; tipiracil plus bevacizumab (5.6 months vs. 2.4 months; HR = 0.44; 95% CI, 0.36 to 0.54). In this trial, 92.1% of patients had received 2 prior treatment regimens for metastatic disease that included fluoropyrimidine-based therapy (100%) and anti-VEGF therapy (72%); 93.7% of the patients with RAS wild-type disease had received prior anti-EGFR therapy.
For the treatment of metastatic gastric cancer or gastroesophageal junction cancer in patients who have previously been treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum agent, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy:
Oral dosage:
Adults: 35 mg/m2 based on trifluridine component (maximum, 80 mg) orally twice daily with food on days 1, 2, 3, 4, and 5 and days 8, 9, 10, 11, and 12 repeated every 28 days until disease progression or unacceptable toxicity. Round the dose up or down to the nearest 5 mg; one or both strength tablets (15 mg or 20 mg of trifluridine component) may be used to make a dose. Specific dose and recommended tablets per dose based on body surface area are provided by the manufacturer. In a randomized, double-blind clinical trial, treatment with trifluridine; tipiracil significantly improved median overall survival (5.7 months vs. 3.6 months) compared with placebo in patients with heavily pretreated metastatic gastric or gastroesophageal junction cancer. Median progression-free survival was also significantly improved but amounted to a difference of only 0.2 months (2 months vs. 1.8 months). Grade 3 or higher adverse reactions occurred in 79.4% of patients in the treatment arm compared with 57.7% in the placebo arm.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Neutropenia: Do not initiate a cycle of trifluridine; tipiracil until the ANC is 1,500 cells/mm3 or higher.
-Grade 4 (ANC less than 500 cells/mm3): Hold trifluridine; tipiracil. When ANC is 1,500 cells/mm3 or higher, resume therapy. If neutropenia resulted in longer than a 1-week delay in the start of the next cycle, reduce the dose by 5 mg/m2 per dose (minimum, 20 mg/m2 twice daily) and resume therapy. Permanently discontinue therapy in patients unable to tolerate a dose of 20 mg/m2 twice daily. Do not escalate the dose of trifluridine; tipiracil after it has been reduced.
Neutropenic Fever
-Hold trifluridine; tipiracil. When neutropenic fever is resolved, reduce the dose by 5 mg/m2 per dose (minimum, 20 mg/m2 twice daily) and resume therapy. Permanently discontinue therapy in patients unable to tolerate a dose of 20 mg/m2 twice daily. Do not escalate the dose of trifluridine; tipiracil after it has been reduced.
Thrombocytopenia: Do not initiate a cycle of trifluridine; tipiracil until platelets are 75,000 cells/mm3 or higher.
-Grade 3 or 4 (platelets less than 50,000 cells/mm3): Hold trifluridine; tipiracil. When platelets are 75,000 cells/mm3 or higher, resume therapy. If thrombocytopenia resulted in longer than a 1-week delay in the start of the next cycle, reduce the dose by 5 mg/m2 per dose (minimum, 20 mg/m2 twice daily) and resume therapy. Permanently discontinue therapy in patients unable to tolerate a dose of 20 mg/m2 twice daily. Do not escalate the dose of trifluridine; tipiracil after it has been reduced.
Non-hematologic toxicities:
-Grade 3 or 4: Hold trifluridine; tipiracil. When toxicity resolves to grade 1 or less, reduce the dose by 5 mg/m2 per dose (minimum, 20 mg/m2 twice daily) and resume therapy. No dose reduction is necessary for grade 3 nausea/vomiting controlled by antiemetic therapy or grade 3 diarrhea controlled by antidiarrheal therapy. Permanently discontinue therapy in patients unable to tolerate a dose of 20 mg/m2 twice daily. Do not escalate the dose of trifluridine; tipiracil after it has been reduced.
Maximum Dosage Limits:
-Adults
160 mg (trifluridine component) PO total daily dose (80 mg PO administered twice daily) on days 1, 2, 3, 4, 5 and days 8, 9, 10, 11, 12, repeated every 28 days.
-Geriatric
160 mg (trifluridine component) PO total daily dose (80 mg PO administered twice daily) on days 1, 2, 3, 4, 5 and days 8, 9, 10, 11, 12, repeated every 28 days.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment:
-Mild hepatic impairment (total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN; OR total bilirubin 1.1 to 1.5 times ULN and any AST): No adjustment to the starting dose is recommended.
-Moderate to severe hepatic impairment (total bilirubin level greater than 1.5 times ULN and any AST): Do not administer trifluridine; tipiracil.
Patients with Renal Impairment Dosing
Baseline Renal Impairment:
-Mild to moderate renal impairment (CrCl 30 mL/min or higher): No adjustment to the starting dose is recommended.
-Severe renal impairment (CrCl 15 to 29 mL/min): Reduce the dose of trifluridine; tipiracil to 20 mg/m2 based on the trifluridine component (maximum, 50 mg) PO twice daily with food on days 1 to 5 and days 8 to 12 of each 28-day cycle. Further reduce the dose to 15 mg/m2 based on the trifluridine component (maximum, 40 mg) PO twice daily in patients unable to tolerate a dose of 20 mg/m2. Permanently discontinue trifluridine; tipiracil in patients unable to tolerate a dose of 15 mg/m2 twice daily. For patients with a calculated twice-daily dose of 25 mg which is unable to be administered with available tablet strengths, the total daily dose of 50 mg may be divided unequally (i.e., 20 mg PO in the morning and 30 mg PO in the evening).
-End-stage renal disease (ESRD): The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with ESRD.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Trifluridine is a thymidine-based nucleoside metabolic inhibitor, believed to act as a thymidylate synthase inhibitor (similar to 5-fluorouracil). Following uptake into cancer cells, it is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Tipiracil increases trifluridine exposure by inhibiting thymidine phosphorylase, which is responsible for rapid inactivation of trifluridine after administration. Trifluridine; tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice.
Trifluridine; tipiracil is administered orally. Trifluridine is highly protein bound (greater than 96%) to human serum albumin, independent of drug concentration and the presence of tipiracil. The plasma protein binding of tipiracil is less than 8%. After twice daily dosing, systemic exposure of trifluridine increased more than dose-proportionally over a range of 15 mg/m2 to 35 mg/m2. After a single dose, the mean half-life of trifluridine is 1.4 hours and tipiracil is 2.1 hours when administered in combination; at steady state, the mean half-lives are 2.1 hours and 2.4 hours, respectively. When trifluridine was administered as an intravenous single agent, the half-life was 12 minutes. Trifluridine is mainly eliminated via thymidine phosphorylase metabolism to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY); tipiracil is not metabolized in either human liver or hepatocytes. No other metabolites were detected in plasma or urine. Following a single oral 60-mg dose of trifluridine; tipiracil with radiolabeled trifluridine, 60% of the radioactivity was recovered within 24 hours, including 55% of the dose in the urine (as FTY and trifluridine glucuronide isomers), less than 3% of the dose in the feces, and less than 3% of the dose in expired air. Unchanged trifluridine accounted for less than 3% of the administered dose recovered in the urine and feces. Following a single oral 60-mg dose of trifluridine; tipiracil with radiolabeled tipiracil, 77% of the radioactivity was recovered, including 27% of the dose excreted in the urine and 50% of the dose excreted in the feces. Tipiracil was the major component and 6-HMU was the major metabolite in the urine and feces.
Affected CYP450 isoenzymes or other drug transporters: None.
Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP450) enzymes.
-Route-Specific Pharmacokinetics
Oral Route
After a single dose administered to patients with cancer, the Tmax of trifluridine; tipiracil was approximately 2 hours. Administration of a single dose of trifluridine; tipiracil 35 mg/m2 increased the mean Cmax of trifluridine by 22-fold and AUC by 37-fold, with reduced variability, compared to trifluridine 35 mg/m2 alone. The accumulation of trifluridine at steady-state was 2-fold for Cmax and 3-fold for AUC; no accumulation was observed for tipiracil.
The Cmax of both trifluridine and tipiracil as well as the AUC of tipiracil were decreased by approximately 40% by a standardized high-fat, high-calorie meal in patients with cancer compared to those in a fasting state; the AUC of trifluridine did not change with food. The recommendation to take trifluridine; tipiracil with meals is based on an observed correlation between an increase in Cmax and a decrease in neutrophil counts.
-Special Populations
Hepatic Impairment
There were no clinically important differences in the mean exposure of trifluridine and tipiracil in patients with mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal (ULN) and AST greater than ULN; OR total bilirubin 1.1 to 1.5 times ULN and any AST) or moderate hepatic impairment (total bilirubin greater than 1.5 to 3 times ULN and any AST) compared to patients who had normal hepatic function; however, 5 of 6 patients (83%) with moderate hepatic impairment experienced grade 3 or 4 increases in bilirubin levels. The pharmacokinetics of trifluridine or tipiracil in patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST) have not been evaluated.
Renal Impairment
In a dedicated renal impairment study, all patients received trifluridine; tipiracil 35 mg/m2 twice daily except for patients with severe renal impairment who received 20 mg/m2 twice daily. Mild renal impairment (CrCl 60 to 89 mL/min) did not have a clinically important effect on the steady-state AUC of trifluridine or tipiracil. Moderate renal impairment (CrCl 30 to 59 mL/min) increased the steady-state AUC of trifluridine by 56% and the steady-state AUC of tipiracil by 139% compared to normal renal function. Severe renal impairment (CrCl 15 to 29 mL/min) increased the dose-normalized steady-state AUC of trifluridine and tipiracil by 140% and 614%, respectively, compared to normal renal function. The pharmacokinetics of trifluridine; tipiracil have not been studied in patients with end-stage renal disease (ESRD).
Geriatric
Age does not have a clinically relevant effect the pharmacokinetics of trifluridine; tipiracil.
Gender Differences
Sex does not have a clinically relevant effect the pharmacokinetics of trifluridine; tipiracil.
Ethnic Differences
Ethnicity (Caucasian or Asian) does not have a clinically relevant effect the pharmacokinetics of trifluridine; tipiracil.