Trifluridine and Tipiracil (Monograph)
Drug class: Antineoplastic Agents
Introduction
Antineoplastic agent; fixed combination containing trifluridine (antimetabolite; thymidine-based nucleoside analog) and tipiracil hydrochloride (thymidine phosphorylase inhibitor).
Uses for Trifluridine and Tipiracil
Colorectal Cancer
Treatment of metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens; a vascular endothelial growth factor inhibitor (anti-VEGF therapy); and, in patients with tumors bearing wild-type (nonmutated) KRAS gene, an epidermal growth factor receptor inhibitor (anti-EGFR therapy).
Used as a single agent or in combination with bevacizumab.
International experts recommend trifluridine/tipiracil (alone or in combination with bevacizumab) in patients previously treated with ≥2 lines of chemotherapy, including fluoropyrimidines, oxaliplatin, irinotecan, and biologics (if available), or in earlier lines of therapy following oxaliplatin and irinotecan regimen failure; trifluridine/tipiracil plus bevacizumab estimated to have greater magnitude of clinical benefit than trifluridine/tipiracil alone.
Gastric Cancer
Treatment of metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with ≥2 lines of chemotherapy, including a fluoropyrimidine, platinum agent, taxane or irinotecan, and, if appropriate, an anti-HER2/neu agent (designated an orphan drug by FDA for this use).
Guidelines recommend trifluridine/tipiracil as a third-line agent for patients with advanced or metastatic gastric cancer.
Trifluridine and Tipiracil Dosage and Administration
General
Pretreatment Screening
-
Obtain CBC prior to initiation of therapy. Do not initiate if ANC is <1500/mm3 or platelet count is <75,000/mm3.
-
Verify non-hematological adverse reactions are resolved to Grade 0 or 1.
-
Verify pregnancy status in females of reproductive potential.
-
Assess baseline renal and hepatic function.
Patient Monitoring
-
Monitor CBC prior to initiation of each cycle, on day 15 of each cycle, and as clinically indicated.
-
Monitor renal and hepatic function as clinically indicated.
-
Monitor for Grade 3 or 4 non-hematological adverse reactions.
Dispensing and Administration Precautions
-
Based on the Institute for Safe Medication Practices (ISMP), trifluridine/tipiracil is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.
- Handling and Disposal
-
Procedures for proper handling (e.g., use of gloves) and disposal of antineoplastic agents should be followed.
Other General Considerations
-
May be used in combination with bevacizumab for metastatic colorectal cancer; consult bevacizumab prescribing information for bevacizumab dosing information, including dosage modification for toxicity.
Administration
Oral Administration
Administer orally with food.
Swallow tablets whole.
If a dose of trifluridine/tipiracil is missed or vomited, do not take an additional dose to replace the missed or vomited dose; take the next dose at the regularly scheduled time.
Dosage
Available as trifluridine and tipiracil hydrochloride in fixed combination; dosage expressed in terms of trifluridine.
Each trifluridine/tipiracil tablet contains trifluridine 15 or 20 mg and tipiracil 6.14 or 8.19 mg, respectively (equivalent to molar ratio of 1:0.5).
Adults
Colorectal Cancer
Oral
35 mg/m2 (of trifluridine) twice daily on days 1–5 and days 8–12 of each 28-day cycle. Continue therapy until disease progression or unacceptable toxicity occurs.
Round dose to nearest 5-mg increment. Do not exceed dosage of 80 mg (of trifluridine) twice daily.
Refer to bevacizumab prescribing information for bevacizumab dosage recommendations if used in combination with trifluridine/tipiracil.
Trifluridine 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. 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).
BSA (m2) |
Recommended Initial Dosage of Trifluridine/tipiracil (35 mg/m2 [of trifluridine]) |
---|---|
<1.07 |
35 mg twice daily |
1.07–1.22 |
40 mg twice daily |
1.23–1.37 |
45 mg twice daily |
1.38–1.52 |
50 mg twice daily |
1.53–1.68 |
55 mg twice daily |
1.69–1.83 |
60 mg twice daily |
1.84–1.98 |
65 mg twice daily |
1.99–2.14 |
70 mg twice daily |
2.15–2.29 |
75 mg twice daily |
≥2.3 |
80 mg twice daily |
Gastric Cancer
Oral
35 mg/m2 (of trifluridine) twice daily on days 1–5 and days 8–12 of each 28-day cycle. Continue therapy until disease progression or unacceptable toxicity occurs.
Round dose to nearest 5-mg increment. Do not exceed dosage of 80 mg (of trifluridine) twice daily.
Follow recommendations in Table 1 for calculated dosages of trifluridine/tipiracil based on BSA.
Dosage Modification for Toxicity
Oral
Adjust dosage 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); no more than 3 dosage adjustments permitted.
Permanently discontinue drug if 20 mg/m2 twice daily is not tolerated.
Do not re-escalate dosage following a dosage reduction.
Consult bevacizumab prescribing information for dosage modifications due to adverse reactions from bevacizumab.
Hematologic Toxicity
OralIf uncomplicated grade 4 neutropenia or thrombocytopenia delays initiation of a cycle by >1 week, withhold trifluridine/tipiracil therapy until ANC ≥1500/mm3 and platelet counts ≥75,000/mm3, and then initiate next cycle at 1 dose level lower than the previous dosage.
If grade 4 neutropenia (ANC <500/mm3) occurs or platelet counts decrease to <50,000/mm3 during a cycle, interrupt trifluridine/tipiracil therapy until ANC ≥1500/mm3 and platelet counts ≥75,000/mm3, and then resume at 1 dose level lower than the previous dosage.
If febrile neutropenia occurs, interrupt trifluridine/tipiracil therapy until febrile neutropenia resolves, and then resume at 1 dose level lower than the previous dosage.
Nonhematologic Toxicity
OralIf 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, interrupt trifluridine/tipiracil therapy until toxicity improves to grade 1 or less, and then resume at 1 dose level lower than the previous dosage.
Special Populations
Hepatic Impairment
Mild hepatic impairment: No dosage adjustment required.
Moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration): Avoid use.
Renal Impairment
Mild (Clcr 60–89 mL/minute based on Cockroft-Gault) or moderate (Clcr 30–59 mL/minute based on Cockroft-Gault) renal impairment: No dosage adjustment required.
Severe renal impairment (Clcr 15–29 mL/minute based on Cockroft-Gault): Reduce dosage to 20 mg/m2 (of trifluridine) twice daily on days 1–5 and days 8–12 of each 28-day cycle (see Table 2). If reduced dosage of 20 mg/m2 twice daily is not tolerated, reduce trifluridine/tipiracil dosage to 15 mg/m2 (of trifluridine) twice daily on days 1–5 and days 8–12 of each 28-day cycle (see Table 2). If a reduced dosage of 15 mg/m2 twice daily is not tolerated, discontinue trifluridine/tipiracil.
Trifluridine 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. 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).
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 evening |
1.35–1.59 |
30 mg twice daily |
1.6–1.94 |
35 mg twice daily |
1.95–2.09 |
40 mg twice daily |
2.1–2.34 |
45 mg twice daily |
≥2.35 |
50 mg twice daily |
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 evening |
1.85–2.09 |
30 mg twice daily |
2.1–2.34 |
35 mg twice daily |
≥2.35 |
40 mg twice daily |
Geriatric Patients
No initial dosage adjustment required.
Cautions for Trifluridine and Tipiracil
Contraindications
-
None.
Warnings/Precautions
Severe Myelosuppression
Severe and life-threatening myelosuppression (anemia, neutropenia, thrombocytopenia), including febrile neutropenia and fatal neutropenia, reported.
Monitor CBCs prior to each cycle, on day 15 of each cycle, and as clinically indicated. Do not initiate cycle until ANC ≥1500/mm3 and platelet count ≥75,000/mm3. If neutropenia or thrombocytopenia occurs, interrupt therapy, reduce dosage, or permanently discontinue drug.
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm. Embryofetal toxicity, teratogenicity, and lethality demonstrated in animals.
Verify pregnancy status in females of reproductive potential. Females of reproductive potential should avoid pregnancy during therapy and for at least 6 months after discontinuance of therapy. Male patients should use an effective method of contraception each time they have sexual contact with females of reproductive potential during and for at least 3 months after therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Specific Populations
Pregnancy
May cause fetal harm.
If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Lactation
Trifluridine and tipiracil, or their metabolites, are distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing during therapy and for 1 day after drug discontinuance.
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential. Females of reproductive potential should avoid pregnancy during therapy and for at least 6 months after discontinuance of therapy.
Male patients should use an effective method of contraception each time they have sexual contact with females of reproductive potential during and for at least 3 months after therapy.
If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Pediatric Use
Safety and efficacy not established.
Dental abnormalities (e.g., whitening, malocclusions, broken teeth) observed in animals.
Geriatric Use
No overall differences in efficacy in geriatric patients (≥65 years of age) compared with younger adults, but grade 3 or 4 hematologic toxicity (i.e., neutropenia, anemia, thrombocytopenia) occurred more frequently in geriatric patients.
Hepatic Impairment
Systemic exposure to trifluridine or tipiracil not altered by mild hepatic impairment; initial dosage adjustment not necessary in such patients.
Systemic exposure to trifluridine and tipiracil not altered by moderate hepatic impairment, but risk of grade 3 or 4 hyperbilirubinemia increased.
Pharmacokinetics of trifluridine/tipiracil not established in patients with severe hepatic impairment.
Avoid use in patients with moderate or severe hepatic impairment.
Renal Impairment
Systemic exposure to trifluridine and tipiracil increased in moderate or severe renal impairment, but not in mild renal impairment. No dosage adjustment required in mild or moderate renal impairment; reduce dosage to 20 mg/m2 twice daily in severe renal impairment.
Pharmacokinetics not established in patients with end-stage renal disease.
Common Adverse Effects
Adverse effects and laboratory abnormalities reported in ≥10% of patients receiving trifluridine/tipiracil as a single agent: Anemia, neutropenia, fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, pyrexia.
Adverse effects and laboratory abnormalities reported in ≥20% of patients receiving trifluridine/tipiracil in combination with bevacizumab: Anemia, neutropenia, thrombocytopenia, fatigue, nausea, increased AST/ALT, increased alkaline phosphatase, decreased sodium levels, diarrhea, abdominal pain, decreased appetite.
Drug Interactions
Trifluridine: Substrate of thymidine phosphorylase; not metabolized by CYP isoenzymes. Neither a substrate nor inhibitor of human hepatic uptake transport proteins or efflux transporters in vitro. Trifluridine and 5-(trifluoromethyl)uracil (primary inactive metabolite) do not inhibit CYP isoenzymes or induce CYP isoenzymes 1A2, 2B6, or 3A4/5 in vitro.
Tipiracil: Does not inhibit CYP isoenzymes or induce CYP isoenzymes 1A2, 2B6, or 3A4/5 in vitro. Substrate and inhibitor of organic cation transporter (OCT) 2 in vitro at concentrations ≥3 times clinically relevant concentrations.
Specific Drugs
Drug |
Interaction |
---|---|
Famotidine |
No clinically important effect on pharmacokinetics of trifluridine or tipiracil |
Metformin |
No clinically important effect on pharmacokinetics of trifluridine or tipiracil |
Trifluridine and Tipiracil Pharmacokinetics
Absorption
Bioavailability
When trifluridine is administered as trifluridine/tipiracil rather than as trifluridine alone, AUC and peak plasma concentrations of trifluridine are less variable and are increased by 38- and 22-fold, respectively.
Following oral administration of trifluridine/tipiracil in cancer patients, peak plasma concentrations of trifluridine are attained in approximately 2 hours.
With repeated dosing of trifluridine/tipiracil, trifluridine accumulates (3-fold and 2-fold increases in AUC and peak plasma concentrations, respectively); tipiracil does not accumulate.
With twice-daily dosing of trifluridine/tipiracil, trifluridine AUC increases more than proportionally with dose over the trifluridine dose range of 15–35 mg/m2.
Food
Administration of trifluridine/tipiracil with high-fat, high-calorie meal in cancer patients decreased trifluridine peak plasma concentrations by 40%, decreased tipiracil AUC and peak plasma concentrations by 45%, but did not affect trifluridine AUC.
Special Populations
Mild hepatic impairment: Systemic exposure to trifluridine/tipiracil similar to that in patients with normal hepatic function.
Moderate hepatic impairment: Systemic exposure to trifluridine/tipiracil similar to that in patients with normal hepatic function, but increased risk of grade 3 or 4 hyperbilirubinemia.
Severe hepatic impairment: Pharmacokinetics of trifluridine/tipiracil not established.
Mild renal impairment (Clcr 60–89 mL/minute): Systemic exposure to trifluridine/tipiracil similar to that in patients with normal renal function.
Moderate renal impairment (Clcr 30–59 mL/minute): Trifluridine and tipiracil AUCs increased by 56 and 139%, respectively.
Severe renal impairment (Clcr 15–29 mL/minute): Trifluridine and tipiracil AUCs increased by 140 and 614%, respectively.
Age (33–82 years), sex, and ethnicity do not substantially affect trifluridine/tipiracil pharmacokinetics.
Distribution
Extent
Not known whether trifluridine and tipiracil, or their metabolites, are distributed into human milk.
Plasma Protein Binding
Trifluridine: >96%.
Tipiracil: <8%.
Elimination
Metabolism
Trifluridine is converted intracellularly to active phosphorylated forms.
Trifluridine and tipiracil not metabolized by CYP pathways.
Trifluridine: Metabolized mainly by thymidine phosphorylase to inactive metabolite (5-[trifluoromethyl]uracil). Administered concomitantly with tipiracil to prevent extensive first-pass metabolism by thymidine phosphorylase and increase oral bioavailability.
Elimination Route
Following single 60-mg (of trifluridine) radiolabeled dose of trifluridine/tipiracil, 60 and 77% of trifluridine and tipiracil, respectively, recovered following excretion.
Majority of radiolabeled trifluridine (55% of the dose) recovered in urine within 24 hours as 5-(trifluoromethyl)uracil and glucuronide metabolites; <3% of trifluridine recovered as metabolites in feces and expired air and <3% of trifluridine recovered as unchanged drug in the urine and feces.
Radiolabeled tipiracil was recovered in urine (27% of dose) and feces (50% of dose), as unchanged drug and as the metabolite, 6-hydroxymethyluracil.
Half-life
Trifluridine: 2.1 hours.
Tipiracil: 2.4 hours.
Stability
Storage
Oral
Tablets
20–25°C (excursions permitted between 15–30°C).
Discard after 30 days if repackaged.
Actions
-
Tipiracil enhances oral bioavailability of trifluridine (antimetabolite; thymidine-based nucleoside analog) by inhibiting its metabolism by thymidine phosphorylase.
-
In vivo, maximum antitumor activity and low trifluridine toxicity achieved with 1:0.5 molar ratio of trifluridine to tipiracil.
-
Trifluridine converted intracellularly to active metabolites trifluoromethyl deoxyuridine 5′-monophosphate (F3dTMP) and trifluoromethyl deoxyuridine 5′-triphosphate (F3dTTP) by thymidine kinase.
-
Active metabolites interfere with DNA synthesis and inhibit cell cycle via inhibition of thymidylate synthase (TS) and incorporation of F3dTTP into DNA chain.
-
Unlike fluorouracil, predominant mechanism of antitumor activity is incorporation of trifluridine into tumor cell DNA.
-
In vitro, F3dTTP incorporated into DNA to a substantially greater degree than fluorouracil (approximately 300-fold greater).
-
Tipiracil may inhibit tumor angiogenesis; however, clinical relevance not established.
-
Trifluridine/tipiracil demonstrated antitumor activity in mice bearing tumor xenografts expressing mutated and wild-type (nonmutated) KRAS and also in mice bearing fluorouracil-sensitive and fluorouracil-resistant tumor xenografts.
Advice to Patients
-
Importance of taking trifluridine/tipiracil exactly as prescribed. If receiving 2 strengths of trifluridine/tipiracil tablets, importance of taking appropriate number of tablets of each strength.
-
Advise patients to take trifluridine/tipiracil with food. If a dose is missed, withheld, or vomited, do not take an additional dose to replace the missed, withheld, or vomited dose.
-
Advise patients that individuals other than the patient should not handle trifluridine/tipiracil tablets without protection (e.g., gloves).
-
Importance of CBC monitoring before and during trifluridine/tipiracil therapy. Importance of immediately reporting any manifestations of infection.
-
Importance of contacting a clinician if severe or persistent nausea, vomiting, diarrhea, or abdominal pain occurs.
-
Risk of fetal harm. Necessity of determining pregnancy status in females of reproductive potential prior to treatment with trifluridine/tipiracil. Advise females of reproductive potential to use an effective method of contraception while receiving the drug and for at least 6 months after discontinuance of therapy. Advise men to use a condom during sexual encounters with females of reproductive potential; these contraceptive measures are required during and for at least 3 months after discontinuance of trifluridine/tipiracil therapy. If pregnancy occurs, advise pregnant females of potential fetal risk.
-
Advise females to avoid breast-feeding while receiving trifluridine/tipiracil and for 1 day after discontinuance of therapy.
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
-
Inform patients of other important precautionary information.
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.
Preparations
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 |
Lonsurf |
Taiho Oncology |
Trifluridine 20 mg and Tipiracil 8.19 mg |
Lonsurf |
Taiho Oncology |
AHFS DI Essentials™. © Copyright 2025, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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