Trifluridine and Tipiracil
(trye FLURE i deen & tye PIR a sil)
- Tipiracil and Trifluridine
- Trifluridine and Tipiracil Hydrochloride
- Trifluridine/Tipiracil HCl
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Lonsurf: Trifluridine 15 mg and tipiracil 6.14 mg, Trifluridine 20 mg and tipiracil 8.19 mg
Brand Names: U.S.
- Antineoplastic Agent, Antimetabolite
- Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)
- Thymidine Phosphorylase Inhibitor
Trifluridine, the active cytotoxic component of trifluridine/tipiracil, is a thymidine-based nucleic acid analogue; the triphosphate form of trifluridine is incorporated into DNA which interferes with DNA synthesis and inhibits cell proliferation. Tipiracil is a potent thymidine phosphorylase inhibitor which prevents the rapid degradation of trifluridine, allowing for increased trifluridine exposure (Mayer 2015).
Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY)
Trifluridine: Urine (55% [as inactive metabolite FTY and trifluridine glucuronide isomers]; <3% [as unchanged drug]); feces (<3% [as unchanged drug]); expired air (<3%)
Tipiracil: Urine (27% [as tipiracil and 6-HMU]); feces (50% [as tipiracil and 6-HMU])
Time to Peak
Plasma: ~2 hours
Trifluridine: 2.1 hours; Tipiracil: 2.4 hours
Trifluridine: >96% (primarily to albumin); Tipiracil: <8%
Special Populations: Renal Function Impairment
The estimated mean AUC of trifluridine was 31% and 43% higher in patients with mild or moderate renal impairment, respectively, as compared to patients with normal renal function. The estimated mean AUC of tipiracil was 34% and 65% higher, respectively, in patients with mild or moderate impairment as compared to patients with normal renal function.
Special Populations: Hepatic Function Impairment
In a pharmacokinetic study of patients with hepatic impairment, grade 3 or 4 bilirubin elevations were seen in patients with moderate (total bilirubin >1.5 to 3 times ULN and any AST) impairment (compared to patients with normal hepatic function). No clinically important differences in mean exposures were noted.
Use: Labeled Indications
Colorectal cancer, metastatic: Treatment of metastatic colorectal cancer in patients 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.
There are no contraindications listed in the manufacturer's labeling.
Note: Obtain blood counts prior to starting each cycle and on day 15 of each cycle. Do not initiate a cycle until ANC ≥1,500/mm3 or febrile neutropenia is resolved, platelets are ≥75,000/mm3, and/or grade 3 or 4 nonhematologic reactions are ≤ grade 1. Trifluridine/tipiracil is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.
Colorectal cancer, metastatic: Oral: 35 mg/m2 (based on the trifluridine component) twice daily on days 1 to 5 and days 8 to 12 of a 28-day cycle (maximum per dose: trifluridine 80 mg); continue until disease progression or unacceptable toxicity (Mayer 2015). The manufacturer recommends rounding each dose to the nearest 5 mg increment.
Missed dose: Do not take additional doses to make up for missed or held doses.
Refer to adult dosing.
Dosing: Renal Impairment
CrCl ≥30 mL/minute: No initial dosage adjustment is necessary. Monitor closely; patients with moderate impairment (CrCl 30 to 59 mL/minute) may experience greater toxicity and may require dose reduction during treatment.
CrCl <30 mL/minute and ESRD: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Dosing: Hepatic Impairment
Mild impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin <1 to 1.5 times ULN and any AST): No dosage adjustment necessary.
Moderate impairment (total bilirubin >1.5 to 3 times ULN and any AST) or severe impairment (total bilirubin >3 times ULN and any AST): Do not initiate therapy.
Dosing: Adjustment for Toxicity
A maximum of 3 dose reductions are allowed (to a minimum dose of 20 mg/m2). Do not re-escalate dose after it has been reduced.
ANC <500/mm3 (uncomplicated or resulting in >1 week delay in the start of the next cycle) or febrile neutropenia: Interrupt therapy; following recovery to ANC ≥1,500/mm3 or resolution of febrile neutropenia, may resume therapy with the dose reduced by 5 mg/m2/dose from the previous dose
Platelets <50,000/mm3 (or resulting in >1 week delay in the start of the next cycle): Interrupt therapy; following recovery to platelets ≥75,000/mm3, may resume therapy with the dose reduced by 5 mg/m2/dose from the previous dose
Nonhematologic toxicity: Grade 3 or 4 toxicity: Interrupt therapy until recovery to ≤ grade 1; following recovery, may resume with the dose reduced by 5 mg/m2/dose from the previous dose (excludes dose reduction for grade 3 nausea and/or vomiting controlled by antiemetic therapy or grade 3 diarrhea responsive to antidiarrheal treatment).
Trifluridine/tipiracil is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.
Administer orally twice daily within 1 hour of completion of morning and evening meals.
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F). If stored outside the original bottle, discard tablets after 30 days.
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
QTc-Prolonging Agents (Moderate Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination
Central nervous system: Fatigue (≤52%)
Gastrointestinal: Nausea (48%), decreased appetite (39%), diarrhea (32%), vomiting (28%), abdominal pain (21%)
Hematologic & oncologic: Anemia (77%; grade 3: 18%), neutropenia (67%; grade 3: 27%; grade 4: 11%), thrombocytopenia (42%; grade 3: 5%; grade 4: 1%)
Neuromuscular & skeletal: Weakness (≤52%)
Miscellaneous: Fever (19%)
1% to 10%:
Cardiovascular: Pulmonary embolism (2%)
Dermatologic: Alopecia (7%)
Gastrointestinal: Stomatitis (8%), dysgeusia (7%)
Genitourinary: Urinary tract infection (4%)
Respiratory: Nasopharyngitis (4%)
<1% (Limited to important or life-threatening): Lung disease
Concerns related to adverse effects:
• Bone marrow suppression: Severe and life-threatening bone marrow suppression (anemia, neutropenia, thrombocytopenia) has occurred, including a fatality related to neutropenic infection. In one clinical trial, close to 10% of patients received growth factor support. Monitor blood counts prior to the start of each cycle as well as on day 15, or more frequently if clinically necessary. May require therapy interruption and/or dose reduction.
• Gastrointestinal toxicity: Trifluridine/tipiracil is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting. Nausea, vomiting, diarrhea, and abdominal pain have been commonly reported. Stomatitis may also occur. Advise patients to report severe gastrointestinal toxicity to their health care provider.
• Hepatic impairment: Patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) were not included in studies; do not initiate in patients with baseline moderate or severe hepatic impairment. In a pharmacokinetic study in patients with hepatic impairment, several patients with moderate impairment experienced grade 3 or 4 bilirubin elevations.
• Renal impairment: Use with caution. Dosage adjustments due to toxicities may be necessary in patients with moderate impairment. Patients with severe renal impairment (CrCl <30 mL/minute) or end-stage renal disease (ESRD) were excluded from the clinical trial.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Elderly: Patients ≥65 years experienced a higher incidence of grade 3 and grade 4 neutropenia and thrombocytopenia, as well as increased grade 3 anemia compared to younger patients.
Dosage form specific issues:
• Tablet strength: Trifluridine/tipiracil is available in two tablet strengths (trifluridine 15 mg/tipiracil 6.14 mg and trifluridine 20 mg/tipiracil 8.19 mg); both tablet strengths may be necessary to provide the correct dose. Read labels carefully in order to ensure the appropriate dose is administered. Dosing is based on the trifluridine component. The manufacturer recommends rounding doses to the nearest 5 mg increment.
Complete blood counts prior to each cycle and on day 15 of each cycle (or more frequently if clinically necessary); signs/symptoms of gastrointestinal toxicity.
Based on animal studies and on the mechanism of action, use of trifluridine/tipiracil would be expected to cause fetal harm when used during pregnancy. Females of reproductive potential should use effective contraception during therapy. Males who have female partners of reproductive potential should use condoms during therapy and for at least 3 months following the final dose.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience lack of appetite, mouth sores, mouth irritation, change in taste, or hair loss. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), severe loss of strength and energy, severe nausea, severe vomiting, severe diarrhea, or severe abdominal pain (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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- Drug class: antineoplastic combinations
Other brands: Lonsurf