Trifluridine and tipiracil hydrochloride (trifluridine/tipiracil) is a fixed combination antineoplastic agent containing the antimetabolite trifluridine (a thymidine-based nucleoside analog) and the thymidine phosphorylase inhibitor tipiracil; tipiracil enhances the oral bioavailability of trifluridine by inhibiting its metabolism by thymidine phosphorylase.1, 5, 6, 8, 9
The fixed combination of trifluridine and tipiracil hydrochloride (trifluridine/tipiracil) is used, as a single agent or in combination with bevacizumab, for the treatment of metastatic colorectal cancer in adult patients who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens; a vascular endothelial growth factor inhibitor (anti-VEGF therapy); and, in those with tumors bearing the wild-type (nonmutated) KRAS gene, an epidermal growth factor receptor inhibitor (anti-EGFR therapy).1, 2, 4, 17
The current indication for trifluridine/tipiracil as a single agent in the treatment of metastatic colorectal cancer is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (RECOURSE) in 800 patients with previously treated metastatic colorectal cancer.1, 2 2
Patients enrolled in the RECOURSE study had received at least 2 prior therapies for their disease; all patients had received previous treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens.1, 2 With one exception, all patients had previously received bevacizumab therapy.1, 2 Patients were randomized (stratified by KRAS mutation status, time since diagnosis of initial metastasis, and geographic region) in a 2:1 ratio to receive either trifluridine/tipiracil (35 mg/m2 [of trifluridine] orally twice daily after meals) or placebo on days 1-5 and 8-12 of each 28-day cycle; all patients received best supportive care.1, 2 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 2 The primary measure of efficacy was overall survival.1
The median age of patients was 63 years; 61% were male, 58% were white, 49% had wild-type KRAS , and 51% had KRAS mutations.1, 2 All except 2 patients with tumors bearing the wild-type KRAS gene had previously received panitumumab or cetuximab therapy.1, 2 In addition, 17 or 20% of patients receiving trifluridine/tipiracil or placebo, respectively, had previously received regorafenib, an inhibitor of multiple receptor tyrosine kinases.2 Most patients (over 90%) enrolled in the study had disease refractory to fluoropyrimidine therapy during their last exposure to these drugs.2
The median duration of treatment was 6.7 weeks for patients receiving trifluridine/tipiracil and 5.7 weeks for those receiving placebo.2 At the time of the primary analysis, patients receiving trifluridine/tipiracil had a longer median overall survival (7.1 versus 5.3 months; hazard ratio 0.68) and longer median progression-free survival (2 versus 1.7 months; hazard ratio 0.48) than those receiving placebo.1, 2 Overall response rates were low (1.6 versus 0.4%, respectively) and were not substantially different between patients receiving trifluridine/tipiracil and those receiving placebo, suggesting that the drug's main effect in this patient population was disease stabilization; one patient (a placebo recipient) achieved a complete response.2 Results of a subgroup analysis (based on age, gender, geographic region, Eastern Cooperative Oncology Group [ECOG] performance status, time since diagnosis of initial metastasis, number of metastatic sites, primary site of disease, disease refractory to fluoropyrimidine, number of prior therapies, prior use of regorafenib, and KRAS mutation status) suggested that the drug's effect on overall survival was consistent in most subgroups.2 Subgroup analysis suggested that the drug's effect on progression-free survival was consistent across all the subgroups.2
Combination Therapy with Bevacizumab
The current indication for trifluridine/tipiracil in combination with bevacizumab in the treatment of metastatic colorectal cancer is based principally on the results of a randomized, open-label, phase 3 study (SUNLIGHT) in 492 patients with previously-treated metastatic colorectal cancer.1, 17 Patients enrolled in the SUNLIGHT study received ≤2 prior therapies for advanced disease, including a fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody, and an anti-EGFR monoclonal antibody (for tumors bearing the wild-type KRAS gene).1 Patents had an ECOG performance status of 0-1 and no symptomatic brain metastases.1
Patients were randomized (stratified by KRAS mutation status, time since diagnosis of initial metastasis, and geographic region) in a 1:1 ratio to receive trifluridine/tipiracil (35 mg/m2) orally twice daily on days 1-5 and 8-12 of each 28-day cycle either alone or in combination with bevacizumab (5 mg/kg) IV every 2 weeks on days 1 and 15 of each 4-week cycle; treatment was continued until disease progression or unacceptable toxicity occurred.1, 17 The primary measure of efficacy was overall survival, with an additional outcome of progression-free survival.1
Enrolled patients were a median 63 years of age, 52% male, and 88% white; 46% had an ECOG performance status of 0 and 54% had an ECOG performance status of 1.1 The primary site of disease was the colon in 73% of patients and the rectum in 27%; a KRAS mutation was present in 71%.1 Most patients (92%) had received 2 prior anticancer treatment regimens for advanced colorectal cancer.1 Prior therapies included irinotecan (99.8%), oxaliplatin (98%), a fluoropyrimidine (100%), and anti-VEGF treatment (76%).1 Among the 142 patients with a wild-type KRAS , 94% received an anti-EGFR monoclonal antibody.1
Median follow-up was 13.6 months for trifluridine/tipiracil single agent therapy and 14.2 months for trifluridine/tipiracil in combination with bevacizumab.17 Median overall survival was 7.5 months for single agent therapy versus 10.8 months for combination therapy (hazard ratio, 0.61; 95% confidence interval, 0.49 to 0.77).1, 17 Median progression-free survival was 2.4 months for single agent therapy versus 5.6 months for combination therapy (hazard ratio 0.44).17
The American Society of Clinical Oncology (ASCO) guideline on metastatic colorectal cancer does not discuss the specific place in therapy for trifluridine/tipiracil.18 Guidelines on metastatic colorectal cancer from international experts state that trifluridine/tipiracil is recommended in patients pre-treated with fluoropyrimidines, oxaliplatin, irinotecan, and biologics (if available), or in earlier lines of therapy following oxaliplatin and irinotecan regimen failure, depending on local approvals.19 An update to these recommendations states that trifluridine/tipiracil plus bevacizumab is recommended for patients previously treated with fluoropyrimidines, oxaliplatin, irinotecan, and biologics, or in earlier lines of therapy following oxaliplatin and irinotecan regimen failure.20 The regimen of trifluridine/tipiracil plus bevacizumab was estimated to have a greater magnitude of clinical benefit than trifluridine/tipiracil alone, based on the results of the SUNLIGHT trial.17, 19, 20
The fixed combination of trifluridine/tipiracil is used for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma in patients previously treated with at least 2 lines of chemotherapy, including a fluoropyrimidine, platinum agent, taxane or irinotecan, and, if appropriate, an anti-HER2/neu agent.1, 15 Trifluridine/tipiracil has been designated an orphan drug by FDA for the treatment of gastric cancer.16
The current indication for trifluridine/tipiracil in the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (TAGS) in 507 patients with previously treated metastatic gastric or gastroesophageal junction adenocarcinoma.1, 15 Patients enrolled in the TAGS study were previously treated with at least 2 prior regimens, including a fluoropyrimidine, a platinum, and either a taxane or irinotecan; HER2/neu-positive tumors must have received prior HER2/neu-targeted therapy.1 In this study, previous therapy included adjuvant chemotherapy if disease recurrence occurred during or within 6 months of adjuvant therapy.1 Patients had an ECOG performance status of 0 or 1.1 Patients were randomized (stratified by ECOG performance status, prior therapy with ramucirumab, and geographic region) in a 2:1 ratio to receive either trifluridine/tipiracil (35 mg/m2 [of trifluridine] orally twice daily) or placebo on days 1-5 and 8-12 of each 28-day cycle; all patients received best supportive care.1, 15 Treatment was continued until disease progression, death, unacceptable toxicity, or patient withdrawal.1, 15 The primary measure of efficacy was overall survival.1, 15
The median age of patients was 63 years; 73% of patients were male, 70% were white, 16% were Asian, 71% had gastric tumors, 29% had gastroesophageal junction tumors, 62% had HER2-negative tumors, 19% had HER2-positive tumors, and 38% had a baseline ECOG performance status of 0.1, 15 All patients previously received platinum-based chemotherapy, 99% received prior fluoropyrimidine-based therapy, 91% received prior therapy with a taxane, 55% received prior therapy with irinotecan, 33% received prior therapy with ramucirumab, and 7% received prior immunotherapy with an anti-PD-1 or anti-PD-L1 agent.1
The median duration of treatment was 6.7 weeks in patients receiving trifluridine/tipiracil and 5.7 weeks in those receiving placebo.15 At the time of the primary analysis, median overall survival was 5.7 months in patients receiving trifluridine/tipiracil versus 3.6 months in patients receiving placebo (hazard ratio, 0.69) and median progression-free survival was 2 months in patients receiving trifluridine/tipiracil versus 1.8 months in patients receiving placebo (hazard ratio, 0.57). 1, 15 Objective response rates were low (4 versus 2%, respectively) and were not substantially different between patients receiving trifluridine/tipiracil and those receiving placebo.15 Results of a subgroup analysis (based on age, sex, ethnicity, geographic region, ECOG performance status, primary site of disease, disease measurability, histology, HER2 status, number and location of metastatic sites, history of gastrectomy, number of prior therapies, prior use of ramucirumab, prior use of irinotecan, and prior taxane use) suggested that the drug's effect on overall survival and progression-free survival were consistent in most subgroups.15
According to the National Cancer Institute, therapies for patients with stage IV, inoperable, and recurrent gastric cancer include a combination of chemotherapy, targeted therapies, immunotherapies, and palliative locoregional therapies.21 For HER2-negative tumors, first-line palliative systemic therapies include palliative chemotherapy with or without immunotherapy (e.g., 5-fluorouracil or capecitabine with oxaliplatin and nivolumab), triplet chemotherapy regimens (e.g., 5-fluorouracil with either epirubicin and cisplatin, etoposide and leucovorin, doxorubicin and methotrexate, leucovorin and irinotecan, or docetaxel and cisplatin or oxaliplatin), doublet regimens (e.g., a taxane with either cisplatin or carboplatin, 5-fluorouracil with cisplatin, or capecitabine with oxaliplatin), or single agents (e.g., 5-fluorouracil, capecitabine, taxanes).21 For HER2-positive tumors, first-line palliative systemic therapies include chemotherapy with immunotherapy (e.g., nivolumab or trastuzumab).21 Second-line palliative systemic therapies include palliative chemotherapy, ramucirumab with or without chemotherapy, pembrolizumab, or trastuzumab deruxtecan.21 Trifluridine/tipiracil is listed as a third-line palliative systemic therapy.21
Recommendations from ASCO on the treatment of advanced gastroesophageal cancer focus primarily on immunotherapy and targeted therapies; however, the guidelines do mention that trifluridine/tipiracil may be offered to patients with gastric or gastroesophageal junction adenocarcinoma after progression on second-line therapy.22 Guidelines on gastric cancer from international experts similarly state that trifluridine/tipracil is recommended for patients with advanced or metastatic gastric cancer previously treated with 2 lines of therapy.23
Dispensing and Administration Precautions
The fixed combination of trifluridine and tipiracil hydrochloride (trifluridine/tipiracil) is administered orally with food.1 Trifluridine/tipiracil tablets should be swallowed whole.1
If a dose of trifluridine/tipiracil is missed or vomited, do not take an additional dose to replace the missed or vomited dose; the next dose should be taken at the regularly scheduled time.1
Store at 20—25ºC; excursions permitted between 15—30°C.1 Discard tablets stored outside of the original bottle after 30 days.1
Dosage of the fixed combination of trifluridine and tipiracil hydrochloride is expressed in terms of the trifluridine content.1
Each fixed combination tablet of trifluridine and tipiracil hydrochloride contains 15 or 20 mg of trifluridine and 6.14 or 8.19 mg of tipiracil, respectively (equivalent to a molar ratio of 1:0.5).1
For the treatment of metastatic colorectal cancer (as a single agent or in combination with bevacizumab) in patients who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens, anti-vascular endothelial growth factor (anti-VEGF) therapy, and, in those with tumors bearing the wild-type (nonmutated) KRAS gene, anti-epidermal growth factor receptor (anti-EGFR) therapy, the recommended dosage of trifluridine/tipiracil is 35 mg/m2 (of trifluridine) twice daily on days 1-5 and days 8-12 of each 28-day cycle (see Table 1).1 Doses should be rounded to the nearest 5-mg increment and should not exceed 80 mg (of trifluridine) twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 Refer to the bevacizumab prescribing information for the dosage of bevacizumab.1
BSA (m2) | Recommended Initial Dosage of Trifluridine/tipiracil (35 mg/m2 [of trifluridine]) |
|---|---|
<1.07 | 35 mg twice dailya |
1.07-1.22 | 40 mg twice dailya |
1.23-1.37 | 45 mg twice dailya |
1.38-1.52 | 50 mg twice dailya |
1.53-1.68 | 55 mg twice dailya |
1.69-1.83 | 60 mg twice dailya |
1.84-1.98 | 65 mg twice dailya |
1.99-2.14 | 70 mg twice dailya |
2.15-2.29 | 75 mg twice dailya |
≥2.3 | 80 mg twice dailya |
aTrifluridine and tipiracil hydrochloride fixed combination tablets are commercially available as 15 mg trifluridine/6.14 mg tipiracil and 20 mg trifluridine/8.19 mg tipiracil tablets.1 Any combination of dosage strengths may be used to provide a prescribed dosage (e.g., one 15 mg tablet and one 20 mg tablet to provide a 35 mg dose).1
For the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma in patients who previously received at least 2 lines of chemotherapy, including a fluoropyrimidine, platinum agent, taxane or irinotecan, and, if appropriate, an anti-HER2/neu agent, the recommended dosage of trifluridine/tipiracil is 35 mg/m2 (of trifluridine) twice daily on days 1-5 and days 8-12 of each 28-day cycle.1 Doses should be rounded to the nearest 5-mg increment and should not exceed 80 mg (of trifluridine) twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Follow recommendations in Table 1 for calculated dosages of trifluridine/tipiracil based on BSA.1
Dosage Modification for Toxicity
When dosage modification is necessary, dosage of trifluridine/tipiracil should be reduced by 1 dose level in decrements of 5 mg/m2 (of trifluridine) (from 35 to 30 mg/m2, from 30 to 25 mg/m2, from 25 to 20 mg/m2); however, no more than 3 dosage adjustments are permitted.1 If a reduced dosage of 20 mg/m2 twice daily is not tolerated, trifluridine/tipiracil should be discontinued.1
For dosage modifications due to adverse reactions associated with bevacizumab, consult bevacizumab prescribing information.1
Dosage of trifluridine/tipiracil should not be re-escalated following a dosage reduction.1
If uncomplicated grade 4 neutropenia or thrombocytopenia delays initiation of a cycle by more than 1 week, trifluridine/tipiracil therapy should be withheld until ANC reaches or exceeds 1500/mm3 and platelet counts reach or exceed 75,000/mm3; the next cycle may then be initiated at 1 dose level lower than the previous dosage.1
If grade 4 neutropenia (ANC less than 500/mm3) occurs or platelet counts decrease to less than 50,000/mm3 during a cycle, trifluridine/tipiracil therapy should be withheld; therapy may be resumed at 1 dose level lower than the previous dosage when ANC reaches or exceeds 1500/mm³ and platelet counts reach or exceed 75,000/mm3.1
If febrile neutropenia occurs, trifluridine/tipiracil therapy should be withheld; therapy may be resumed at 1 dose level lower than the previous dosage when febrile neutropenia resolves.1
If grade 3 or 4 nonhematologic toxicity (excluding grade 3 nausea and/or vomiting controlled by antiemetic agents and grade 3 diarrhea responsive to antidiarrheal agents) occurs, trifluridine/tipiracil therapy should be withheld; therapy may be resumed at 1 dose level lower than the previous dosage when the toxicity improves to grade 1 or less.1
No initial dosage adjustment is necessary in patients with mild hepatic impairment.1 Use of trifluridine/tipiracil should be avoided in patients with preexisting moderate or severe hepatic impairment (total bilirubin concentration exceeding 1.5 times the upper limit of normal [ULN] with any AST concentration).1
No dosage adjustment is necessary in patients with mild or moderate renal impairment.1
For patients with severe renal impairment (creatinine clearance of 15-29 mL/minute based on Cockroft-Gault), the manufacturer recommends a trifluridine/tipiracil dosage of 20 mg/m2 (of trifluridine) twice daily on days 1-5 and days 8-12 of each 28-day cycle, as described in Table 2.1 If a reduced dosage of 20 mg/m2 twice daily is not tolerated, the manufacturer recommends a trifluridine/tipiracil dosage of 15 mg/m2 (of trifluridine) twice daily on days 1-5 and days 8-12 of each 28-day cycle (see Table 2).1 If a reduced dosage of 15 mg/m2 twice daily is not tolerated, trifluridine/tipiracil should be discontinued.1
| Trifluridine and Tipiracil dosage of 20 mg/m2 (of trifluridine) twice daily |
|---|---|
BSA (m2) | Calculated Dosage |
<1.14 | 20 mg twice daily |
1.14-1.34 | 20 mg in the morning and 30 mg in the eveninga |
1.35-1.59 | 30 mg twice dailya |
1.6-1.94 | 35 mg twice dailya |
1.95-2.09 | 40 mg twice dailya |
2.1-2.34 | 45 mg twice dailya |
≥2.35 | 50 mg twice dailya |
| Trifluridine and Tipiracil dosage of 15 mg/m2 (of trifluridine) twice daily |
BSA (m2) | Calculated Dosage |
<1.15 | 15 mg twice daily |
1.15-1.49 | 20 mg twice daily |
1.5-1.84 | 20 mg in the morning and 30 mg in the eveninga |
1.85-2.09 | 30 mg twice dailya |
2.1-2.34 | 35 mg twice dailya |
≥2.35 | 40 mg twice dailya |
aTrifluridine and tipiracil hydrochloride fixed combination tablets are commercially available as 15 mg trifluridine/6.14 mg tipiracil and 20 mg trifluridine/8.19 mg tipiracil tablets.1 Any combination of dosage strengths may be used to provide a prescribed dosage (e.g., one 15 mg tablet and one 20 mg tablet to provide a 35 mg dose).1
No initial dosage adjustment is necessary in geriatric patients.1
Severe and life-threatening myelosuppression (anemia, neutropenia, thrombocytopenia) has been reported in patients receiving trifluridine/tipiracil.1 In patients who received trifluridine/tipiracil as a single agent, grade 3 or 4 neutropenia, anemia, or thrombocytopenia occurred in 38, 18, or 4%, respectively, of patients.1 Febrile neutropenia, fatal neutropenic infection/sepsis, and fatal septic shock occurred in 3, 0.3, and 0.5%, respectively, of patients receiving trifluridine/tipiracil.1
In patients who received trifluridine/tipiracil in combination with bevacizumab, grade 3 or 4 neutropenia, anemia, or thrombocytopenia occurred in 52, 5, or 4% of patients, respectively.1 Febrile neutropenia, fatal abdominal sepsis, and fatal septic shock occurred in 0.4, 0.4, and 0.8% of patients, respectively.1
Complete blood cell (CBC) counts should be monitored prior to initiation of each cycle, on day 15 of each cycle, and as clinically indicated.1 Patients should have an absolute neutrophil count (ANC) of at least 1500/mm3 and a platelet count of at least 75,000/mm3 prior to each cycle.1 In patients who develop neutropenia or thrombocytopenia, temporary interruption of therapy, dosage reduction, or drug discontinuance may be required.1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of trifluridine/tipiracil in pregnant women; however, based on its mechanism of action and animal findings, trifluridine/tipiracil may cause fetal harm.1 Embryofetal toxicity (i.e., decreased fetal weight), teratogenicity (i.e., kinked tail, cleft palate, ectrodactyly, anasarca, great vessel and skeletal abnormalities), and lethality were observed in pregnant animals receiving trifluridine/tipiracil at exposure levels similar to or less than the human exposure at the recommended dosage.1
Pregnancy should be avoided during trifluridine/tipiracil therapy.1 Verify pregnancy status in females of reproductive potential prior to initiating therapy.1 Females of reproductive potential should be advised to use an effective method of contraception while receiving trifluridine/tipiracil and for at least 6 months after discontinuance of the drug.1 Male patients should be advised to use an effective method of contraception while receiving trifluridine/tipiracil and for at least 3 months after discontinuance of therapy each time they have sexual contact with females of reproductive potential.1 If trifluridine/tipiracil is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1
Trifluridine/tipiracil may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1
Trifluridine and tipiracil, or metabolites of these drugs, are distributed into milk in rats; it is not known whether trifluridine and tipiracil, or their metabolites, are distributed into milk in humans.1 Because of the potential for serious adverse reactions to trifluridine/tipiracil in breast-fed infants, women should be advised to discontinue nursing during therapy.1 Females should not breastfeed during treatment and for 1 day following the last dose.1 The effects of trifluridine and tipiracil, or metabolites of these drugs, on breast-fed infants or on the production of milk are unknown.1
Females and Males of Reproductive Potential
Pregnancy should be avoided during trifluridine/tipiracil therapy.1 Verify pregnancy status in females of reproductive potential prior to initiating therapy.1 Females of reproductive potential should be advised to use an effective method of contraception while receiving trifluridine/tipiracil and for at least 6 months after discontinuance of the drug.1 Male patients should be advised to use an effective method of contraception while receiving trifluridine/tipiracil and for at least 3 months after discontinuance of therapy each time they have sexual contact with females of reproductive potential.1 If trifluridine/tipiracil is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1
Safety and efficacy of trifluridine/tipiracil have not been established in pediatric patients.1
Dental abnormalities (e.g., whitening, malocclusions, broken teeth) have been observed in juvenile animals receiving trifluridine/tipiracil at exposure levels approximately 0.33 times the human exposure at the recommended dosage.1
In studies of patients with previously treated metastatic colorectal or gastric cancer, 45% of patients receiving single-agent trifluridine/tipiracil were ≥65 years of age and 11% were ≥75 years of age.1 Of the patients who received trifluridine/tipiracil in combination with bevacizumab, 41% were ≥65 years of age and 10% were ≥75 years of age.1 Although these studies were not designed to detect differences in efficacy, no overall differences were observed between geriatric and younger patients with either single-agent trifluridine/tipiracil or combination therapy with bevacizumab.1 Patients ≥65 years of age receiving single-agent trifluridine/tipiracil or combination therapy with bevacizumab had higher rates of grade 3 or 4 hematologic adverse effects (i.e., neutropenia, anemia, thrombocytopenia) compared to younger adult patients.1
In population pharmacokinetic analyses, systemic exposure to trifluridine and tipiracil was similar in patients with mild hepatic impairment (total bilirubin concentration not exceeding the upper limit of normal [ULN] with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration) and those with normal hepatic function.1 No initial dosage adjustment of trifluridine or tipiracil is necessary in patients with mild hepatic impairment.1
Systemic exposure was similar in patients with moderate hepatic impairment (total bilirubin exceeding 1.5 times the ULN, but no more than 3 times the ULN, with any AST concentration) and those with normal hepatic function; however, 5 of 6 patients with moderate hepatic impairment developed grade 3 or 4 hyperbilirubinemia.1 The pharmacokinetic profiles of trifluridine and tipiracil have not been established in patients with severe hepatic impairment.1 Use of trifluridine/tipiracil should be avoided in patients with moderate or severe hepatic impairment (total bilirubin >1.5 times ULN and any AST).1
In a dedicated renal impairment study, patients with mild (creatinine clearance of 60-89 mL/minute based on Cockroft-Gault) or moderate (creatinine clearance of 30-59 mL/minute based on Cockroft-Gault) renal impairment received trifluridine/tipiracil 35 mg/m2 (of trifluridine) twice daily and patients with severe renal impairment (creatinine clearance of 15-29 mL/minute based on Cockroft-Gault) received trifluridine/tipiracil 20 mg/m2 (of trifluridine) twice daily.1 Mild renal impairment had no clinically important effect on the AUCs of trifluridine and tipiracil at steady state; however, steady-state AUCs of trifluridine and tipiracil were increased 56 and 139%, respectively, in patients with moderate renal impairment compared with patients with normal renal function.1 The dose-normalized steady-state AUCs of trifluridine and tipiracil were increased by 140 and 614%, respectively, in patients with severe renal impairment compared with patients with normal renal function.1 No dosage adjustment of trifluridine or tipiracil is necessary in patients with mild to moderate renal impairment; however, a reduced dosage of 20 mg/m2 twice daily is recommended in severe renal impairment.1
The pharmacokinetic profiles of trifluridine and tipiracil have not been established in patients with end-stage renal disease; these patients were excluded from the RECOURSE and TAGS studies.1, 2, 15
Adverse effects and laboratory abnormalities reported in at least 10% of patients receiving trifluridine/tipiracil as a single agent include anemia, neutropenia, fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.1
Adverse effects and laboratory abnormalities reported in at least 20% of patients receiving trifluridine/tipiracil in combination with bevacizumab include anemia, neutropenia, thrombocytopenia, fatigue, nausea, increased AST/ALT, increased alkaline phosphatase, decreased sodium levels, diarrhea, abdominal pain, and decreased appetite.1
Trifluridine is a substrate of thymidine phosphorylase; the drug is not metabolized by cytochrome P-450 (CYP) isoenzymes.1 In vitro, trifluridine, tipiracil, and 5-(trifluoromethyl)uracil (the primary inactive metabolite of trifluridine) did not inhibit CYP isoenzymes or induce CYP isoenzymes 1A2, 2B6, or 3A4/5.1
In vitro studies indicate that trifluridine is not a substrate or inhibitor of human hepatic uptake transport proteins or efflux transporters;1 however, in vitro data indicate that tipiracil is a substrate and inhibitor of organic cation transporter (OCT) 2 at concentrations of 3 or more times clinically relevant concentrations.10
Drugs Affected by Organic Cation Transporter
Limited data suggest that concomitant administration of trifluridine/tipiracil with OCT2 inhibitors (e.g., famotidine, metformin) does not result in clinically important changes in the pharmacokinetics of trifluridine or tipiracil.10
Trifluridine and tipiracil hydrochloride (trifluridine/tipiracil) is a fixed-combination antineoplastic agent containing the antimetabolite trifluridine (a thymidine-based nucleoside analog) and the thymidine phosphorylase inhibitor tipiracil; tipiracil enhances the oral bioavailability of trifluridine by inhibiting its metabolism by thymidine phosphorylase.1, 5, 6, 8, 9 Although initial development of trifluridine and fluorouracil occurred at approximately the same time, early clinical studies evaluating oncologic use of IV trifluridine were discontinued because of the drug's rapid metabolism by thymidine phosphorylase and severe adverse effects associated with the IV dosing schedule.2, 5, 6, 8, 13 When trifluridine was administered orally alone, plasma concentrations of the drug were very low, suggesting extensive first-pass metabolism in the liver and intestine.5, 6, 8, 9 Subsequent development of an inhibitor of thymidine phosphorylase, tipiracil, resulted in enhanced oral bioavailability and maintenance of therapeutic plasma concentrations of trifluridine when the drugs were used concomitantly.2, 5, 6, 8, 9, 13 In vivo, maximum antitumor activity and low trifluridine toxicity were achieved with a 1:0.5 molar ratio of trifluridine to tipiracil.5, 6, 8 Following oral administration of the drugs in this molar ratio as trifluridine/tipiracil (single dose containing 35-mg/m2 of trifluridine), the AUC and peak plasma concentration of trifluridine exhibited less variability and were increased by 38- and 22-fold, respectively, compared with administration of trifluridine alone.1, 10
Trifluridine is converted intracellularly by thymidine kinase to trifluoromethyl deoxyuridine 5'-monophosphate (F3dTMP), a reversible tight-binding inhibitor of thymidylate synthase (TS), and trifluoromethyl deoxyuridine 5'-triphosphate (F3dTTP).5, 6, 8 These active metabolites interfere with DNA synthesis and inhibit the cell cycle via several mechanisms including inhibition of TS and incorporation of F3dTTP into the DNA chain.5, 6, 8, 9 In vitro, inhibition of TS declines rapidly following a trifluridine wash-out period; therefore, in contrast to fluorouracil, inhibition of TS is not the major mechanism by which trifluridine exerts antitumor activity.5, 6, 7, 9 Preclinical studies suggest that the predominant mechanism by which trifluridine/tipiracil exerts antitumor activity is prolonged incorporation of trifluridine into tumor cell DNA.5, 6, 9, 11 In vitro, F3dTTP is incorporated into DNA to a substantially greater degree than fluorouracil (approximately 300-fold greater).5, 8 Tipiracil may inhibit tumor angiogenesis via inhibition of thymidine phosphorylase (platelet derived endothelial cell growth factor-1 [PD-ECGF-1]), an enzyme with angiogenic properties;5, 6 however, the clinical relevance of this finding has not been established.8 Trifluridine/tipiracil has demonstrated antitumor activity in mice bearing tumor xenografts that expressed mutated and wild-type (nonmutated) KRAS .1 Trifluridine/tipiracil also has demonstrated antitumor activity in mice bearing fluorouracil-sensitive and fluorouracil-resistant tumor xenografts.6, 14
Following oral administration of trifluridine/tipiracil as a single dose of 35 mg/m2 (of trifluridine) in cancer patients, peak plasma concentrations of trifluridine occur in approximately 2 hours.1 With twice-daily dosing of trifluridine/tipiracil, the AUC of trifluridine increases more than proportionally with dose over the trifluridine dose range of 15-35 mg/m2.1 Following repeated administration of trifluridine/tipiracil, accumulation of trifluridine (3-fold and 2-fold increases in AUC and peak plasma concentrations, respectively), but no accumulation of tipiracil, was observed.1 Administration of trifluridine/tipiracil 35 mg/m2 (of trifluridine) with a high-fat, high-calorie meal in cancer patients decreased peak plasma concentrations of trifluridine by 40% and systemic exposure and peak plasma concentrations of tipiracil by 45% compared with administration in the fasted state;10, 12 however, systemic exposure of trifluridine was not affected.1, 10, 12 The manufacturer recommends administration of trifluridine/tipiracil with food.1 In vitro, trifluridine is highly bound (exceeding 96%) to plasma proteins, independent of drug concentrations and presence of tipiracil; however, tipiracil is less than 8% bound to plasma proteins.1 Following administration of trifluridine/tipiracil 35 mg/m2 (of trifluridine) twice daily, the mean elimination half-lives of trifluridine and tipiracil at steady state are 2.1 and 2.4 hours, respectively.1 Trifluridine and tipiracil are not metabolized by cytochrome P-450 (CYP) pathways; trifluridine is metabolized mainly by thymidine phosphorylase to its primary inactive metabolite, 5-(trifluoromethyl)uracil.1, 10 Following oral administration of trifluridine/tipiracil as a single radiolabeled dose of 60 mg (of trifluridine), 60 and 77% of radioactive trifluridine and tipiracil, respectively, were recovered following excretion.1 The majority of radiolabeled trifluridine (55% of the dose) was recovered in urine within 24 hours as 5-(trifluoromethyl)uracil and glucuronide metabolites; <3% of trifluridine was recovered as metabolites in feces and expired air and <3% of trifluridine was recovered as unchanged drug in urine and feces.1 Radiolabeled tipiracil was recovered in urine (27% of the dose) and feces (50% of the dose) as unchanged drug and as the metabolite, 6-hydroxymethyluracil.1
The pharmacokinetics of trifluridine and tipiracil do not appear to be affected substantially by age (33-82 years),10 sex, or ethnicity.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | Trifluridine 15 mg and Tipiracil 6.14 mg | ||
Trifluridine 20 mg and Tipiracil 8.19 mg | Lonsurf® | Taiho Oncology |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Taiho Oncology. Lonsurf® (trifluridine and tipiracil hydrochloride) tablets prescribing information. Princeton, NJ; 2023 Aug.
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