Trifluridine and Tipiracil
Medically reviewed by Drugs.com. Last updated on Aug 16, 2020.
(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
In a study of patients who received a trifluridine/tipiracil dose of 35 mg/m2 twice daily (except patients with CrCl 15 to 29 mL/minute who received a dose of 20 mg/m2 twice daily), the steady-state AUC0-last of trifluridine was 56% and 140% higher in patients with CrCl 30 to 59 mL/minute and CrCl 15 to 29 mL/minute, respectively, as compared to patients with normal renal function. The steady-state AUC0-last of tipiracil was 139% and 614% higher in patients with CrCl 30 to 59 mL/minute and CrCl 15 to 29 mL/minute, respectively, 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 adults previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
Gastric cancer, metastatic: Treatment of metastatic gastric or gastroesophageal junction adenocarcinoma in adults previously treated with at least two prior lines of chemotherapy which included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Additional contraindication (not in the US labeling): Hypersensitivity to trifluridine, tipiracil, or any component of the formulation.
Note: The manufacturer recommends rounding each dose to the nearest 5 mg increment. 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 (Hesketh 2017).
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).
Gastric 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 (Shitara 2018).
Missed dose: Do not re-administer doses that are missed or vomited; continue with the next scheduled dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Refer to adult dosing.
Dosing: Adjustment for Toxicity
A maximum of 3 dose reductions are allowed (to a minimum dose of 20 mg/m2); permanently discontinue in patients unable to tolerate 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 (Hesketh 2017).
Oral: Administer with food. Swallow tablets whole.
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.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification
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
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
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. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. 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
Inebilizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
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
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. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. 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
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. Consider therapy modification
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification
Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Talimogene Laherparepvec: Immunosuppressants may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk for disseminated herpetic infection may be increased. 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
Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Avoid combination
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated less than 2 weeks before starting or 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
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Central nervous system: Fatigue (≤52%)
Gastrointestinal: Nausea (37% to 48%), decreased appetite (34% to 39%), diarrhea (23% to 32%), vomiting (25% to 28%), abdominal pain (21%)
Hematologic & oncologic: Anemia (63% to 77%; grades 3/4: 18% to 19%), neutropenia (66% to 67%; grades 3/4: 38%;), thrombocytopenia (34% to 42%; grades 3/4: 5% to 6%), febrile neutropenia (grades 3/4: 3%)
Infection: Infection (23% to 27%)
Neuromuscular & skeletal: Asthenia (≤52%)
Miscellaneous: Fever (19%)
1% to 10%:
Cardiovascular: Pulmonary embolism (2% to 3%)
Dermatologic: Alopecia (7%)
Gastrointestinal: Stomatitis (8%; grades 3/4: <1%), dysgeusia (7%)
<1%, postmarketing, and/or case reports: Interstitial pulmonary disease
Concerns related to adverse effects:
• Bone marrow suppression: Severe and life-threatening (grade 3 or 4) bone marrow suppression (anemia, neutropenia, thrombocytopenia) has occurred, including fatalities (rare) related to neutropenic infection, sepsis, or septic shock. In clinical trials, slightly over 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 (Hesketh 2017). 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: Dosage adjustment is recommended in patients with severe renal impairment (CrCl 15 to 29 mL/minute). Trifluridine/tipiracil has not been studied in patients with end-stage renal disease.
• 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); verify pregnancy status in females of reproductive potential prior to therapy initiation. Monitor for signs/symptoms of GI toxicity. Monitor adherence.
Verify pregnancy status in females of reproductive potential prior to therapy initiation. Females of reproductive potential should use effective contraception during therapy and for at least 6 months after the final trifluridine and tipiracil dose. Males who have female partners of reproductive potential should use condoms during therapy and for at least 3 months following the final dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to trifluridine/tipiracil may cause fetal harm.
What is this drug used for?
• It is used to treat colorectal cancer.
• It is used to treat stomach cancer.
All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
• Mouth sores
• Mouth irritation
• Change in taste
• Hair loss
• Abdominal pain
WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; 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
• Severe lack of appetite
• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.
More about tipiracil / trifluridine
- Side Effects
- During Pregnancy
- Dosage Information
- Drug Interactions
- En Español
- Drug class: antineoplastic combinations
- Other brands
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