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Trifluridine and Tipiracil

Generic name: tipiracil/trifluridine systemic

Brand names: Lonsurf

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Lonsurf: Trifluridine 15 mg and tipiracil 6.14 mg, Trifluridine 20 mg and tipiracil 8.19 mg

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

Metabolism

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)

Excretion

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

Half-Life Elimination

Trifluridine: 2.1 hours; Tipiracil: 2.4 hours

Protein Binding

Trifluridine: >96% (primarily to albumin); Tipiracil: <8%

Use in Specific Populations

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 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.

Contraindications

There are no contraindications listed in the US manufacturer's labeling.

Canadian labeling: Additional contraindication (not in US labeling): Hypersensitivity to trifluridine, tipiracil, or any component of the formulation.

Dosage and Administration

Dosing: Adult

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.

Dosing: Geriatric

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.

Hematologic toxicity:

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).

Administration

Trifluridine/tipiracil is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017).

Administer orally twice daily with food. Swallow tablets whole.

Storage

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.

Drug Interactions

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. 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

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. 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

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

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

Warnings/Precautions

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.

Disease-related concerns:

  • 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.

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.

Special populations:

  • 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.

Monitoring Parameters

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.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to trifluridine/tipiracil may cause fetal harm.

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.

Patient Education

What is this drug used for?

  • It is used to treat colorectal cancer.
  • It is used to treat stomach cancer.

Frequently reported side effects of this drug

  • Lack of appetite
  • Mouth sores
  • Mouth irritation
  • Change in taste
  • Hair loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Infection
  • 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 abdominal pain
  • Signs of a significant reaction like 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. 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated January 30, 2020.