Trifluridine and Tipiracil (Monograph)

Drug class: Antineoplastic Agents
Chemical name: α,α,α-Trifluorothymidine
Molecular formula: C₁₀H₁₁F₃N₂O₅C₉H₁₁ClN₄O₂ • HCl
CAS number: 70-00-8

Medically reviewed by Drugs.com on Jun 23, 2022. Written by ASHP.

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).

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.

Trifluridine and Tipiracil Dosage and Administration

General

Pretreatment Screening

• Obtain CBCs prior to initiation of therapy. Do not initiate if absolute neutrophil count (ANC) is <1500/mm³ or platelet count is <75,000/mm³.

• 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.

Dispensing and Administration Precautions

Handling and Disposal

• Procedures for proper handling (e.g., use of gloves) and disposal of antineoplastic agents should be followed.

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.

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).

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.

Hematologic Toxicity

Oral

If uncomplicated grade 4 neutropenia (ANC <500/mm³) or thrombocytopenia (platelet count <25,000/mm³) 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 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

Oral

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, interrupt trifluridine/tipiracil therapy until toxicity improves to grade 1 or less, and then resume at 1 dose level lower than the previous dosage.

Prescribing Limits

Adults

Colorectal Cancer

Oral

Do not exceed dosage of 80 mg (of trifluridine) twice daily.

Dosage <20 mg/m² (of trifluridine) twice daily not recommended.

Dosage <15 mg/m² (of trifluridine) twice daily not recommended in patients with severe renal impairment.

Gastric Cancer

Oral

Do not exceed dosage of 80 mg (of trifluridine) twice daily.

Dosage <20 mg/m² (of trifluridine) twice daily not recommended.

Dosage <15 mg/m² (of trifluridine) twice daily not recommended in patients with severe renal impairment.

Special Populations

Hepatic Impairment

Mild hepatic impairment: No dosage adjustment required.

Moderate or severe hepatic impairment (total bilirubin concentration exceeding 1.5 times the ULN with any AST concentration): Avoid use.

Renal Impairment

Mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment: No initial dosage adjustment required.

Severe renal impairment (Cl_cr 15–29 mL/minute): 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 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).

Geriatric Patients

No initial dosage adjustment required.

Related/similar drugs

Keytruda, capecitabine, pembrolizumab, Avastin, Xeloda, Herceptin, docetaxel

Cautions for Trifluridine and Tipiracil

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Hematologic Effects

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 ≥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 ≥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.

Pediatric Use

Safety and efficacy not established.

Dental abnormalities (e.g., whitening, malocclusions, broken teeth) observed in animals.

Geriatric Use

In the principal clinical trials in patients with previously treated metastatic colorectal cancer, gastric cancer, or gastroesophageal junction adenocarcinoma, 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

In population pharmacokinetic analyses, 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

In a dedicated renal impairment study, systemic exposure to trifluridine and tipiracil increased in patients with moderate or severe renal impairment, but not in mild renal impairment. No initial dosage adjustment required in mild or moderate renal impairment; reduce initial dosage to 20 mg/m² twice daily in severe renal impairment.

Pharmacokinetics of trifluridine/tipiracil not established in patients with end-stage renal disease; such patients were not included in the principal clinical trials.

Common Adverse Effects

Adverse effects and laboratory abnormalities reported in ≥10% of patients receiving trifluridine/tipiracil: Anemia, neutropenia, fatigue/asthenia, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, pyrexia.

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

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 (threefold and twofold 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 (Cl_cr 60–89 mL/minute): Systemic exposure to trifluridine/tipiracil similar to that in patients with normal renal function.

Moderate renal impairment (Cl_cr 30–59 mL/minute): Trifluridine and tipiracil AUCs increased by 56 and 139%, respectively.

Severe renal impairment (Cl_cr 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. (See Lactation under Cautions.)

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.

• Importance of taking trifluridine/tipiracil with food. If a dose is missed or withheld, do not take an additional dose to replace the missed or withheld dose.

• Importance of advising 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. Necessity of advising 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. Necessity of advising men to use a condom during sexual encounters with females of reproductive potential; these contraceptive measures are required during and for ≥3 months after discontinuance of trifluridine/tipiracil therapy. If pregnancy occurs, advise pregnant females of potential fetal risk.

• Importance of advising 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.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

Reload page with references included

Medical Disclaimer