tipiracil/trifluridine (Lonsurf)
Classes: Thymidine Phosphorylase Inhibitors; Thymidylate Synthetase Inhibitors
Dosing and uses of Lonsurf (tipiracil/trifluridine)
Adult dosage forms and strengths
tipiracil/trifluridine
tablet
- 6.14mg/15mg
- 8.19mg/20mg
Colorectal Cancer
Indicated for metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy
Dose is based on trifluridine component rounded to the nearest 5-mg increment
35 mg/m² PO BID on Days 1-5 and Days 8-12 of each 28-day cycle; not to exceed 80 mg/dose
Administer within 1 hr of completion of morning and evening meals
Administer until disease progression or unacceptable toxicity
Dosage modifications
Obtain CBC counts prior to and on Day 15 of each cycle
Do not initiate the cycle untiL
- ANC ≥1500/mm³ or febrile neutropenia is resolved
- Platelets ≥75,000/mm³ grade 3 or 4 nonhematological adverse reactions are resolved to Grade 0 or 1
Within a treatment cycle, withhold for any of the following
- ANC <500/mm³ or febrile neutropenia
- Platelets <50,000/mm³ grade 3 or 4 nonhematological adverse reactions
Resume drug with reduced dose
- After recovery, resume drug after reducing the dose by 5 mg/m²/dose from the previous
dose level, if the following occur
- Febrile neutropenia
- Uncomplicated grade 4 neutropenia (which has recovered to ≥1500/mm³) or thrombocytopenia (which has recovered to ≥75,000/mm³) that results >1 week delay in start of next cycle
- Nonhematologic grade 3 or 4 adverse reaction, except for grade 3 nausea and/or vomiting controlled by antiemetic therapy or grade 3 diarrhea responsive to antidiarrheal medication
- A maximum of 3 dose reductions are permitted to a minimum dose 20mg/m² BID
- Do not escalate dose after it has been reduced
Hepatic impairment
- Mild (total bilirubin [TB] ≤ULN and AST >ULN, or TB <1-1.5 xULN and any AST): No dosage adjustment required
- Moderate-to-severe: Not studied
Renal impairment
- Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment required; however, patients with moderate impairment (30-59 mL/min) may require dose modification for increased toxicity
- Severe (CrCl <30 mL/min): Not studied
Pediatric dosage forms and strengths
Safety and efficacy not established
Lonsurf (tipiracil/trifluridine) adverse (side) effects
>10%
Anemia, all grades (77%)
Neutropenia, all grades (67%)
Asthenia/fatigue, all grades (52%)
Nausea, all grades (48%)
Thrombocytopenia, all grades (42%)
Decreased appetite, all grades (39%)
Diarrhea, all grades (32%)
Vomiting, all grades (28%)
Neutropenia, grades 3-4 (11-27%)
Abdominal pain, all grades (21%)
Pyrexia, all grades (19%)
Anemia, grade 3 (18%)
1-10%
Stomatitis, all grades (8%)
Dysgeusia (7%)
Alopecia (7%)
Asthenia/fatigue, grades 3-4 (7%)
Thrombocytopenia, grades 3-4 (1-5%)
Decreased appetite, grades 3-4 (4%)
Diarrhea, grades 3-4 (3%)
Vomiting, grades 3-4 (2%)
Abdominal pain, grades 3-4 (2%)
Nausea, grades 3-4 (2%)
Pyrexia, grades 3-4 (1%)
<1%
Stomatitis, grades 3-4
Warnings
Contraindications
None
Cautions
Severe and life-threatening myelosuppression reported, including anemia, neutropenia, thrombocytopenia, and febrile neutropenia; obtain CBC count prior to and on Day 15 of each cycle, or more frequently as indicated
Based on animal studies and its mechanism of action, trifluridine/tipiracil can cause fetal harm when administered to pregnant women
Pregnancy
Pregnancy
Based on animal studies and its mechanism of action, trifluridine/tipiracil can cause fetal harm when administered to pregnant women
Caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at dose levels resulting in exposures lower than those achieved at the recommended dose of 35 mg/m² BId
Advise pregnant women of the potential risk to the fetus
Advise females of reproductive potential to use effective contraception during treatment
Lactation
Unknown if distributed in human breast milk
In nursing rats, trifluridine and tipiracil or their metabolites were present in breast milk
Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment and for 1 day following the final dose
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Lonsurf (tipiracil/trifluridine)
Mechanism of action
Tipiracil: Thymidine phosphorylase inhibitor; inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase
Trifluridine: Thymidine-based nucleoside analog that incorporates into DNA, interferes with DNA synthesis, and inhibits cell proliferation
Absorption
Peak plasma time (trifluridine): 2 hr
Distribution
Protein bound: 96% trifluridine (mainly albumin); <8% tipiraciL
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)
Elimination
Half-life (steady-state): 2.1 hr trifluridine; 2.4 hr tipiraciL
Urinary excretion: 1.5% unchanged trifluridine; 19.2% FTY; 29.3% unchanged tipiraciL
Administration
Instructions
Dose is based on trifluridine component rounded to nearest 5-mg increment
Administer within 1 hr of completion of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle
Do not take additional doses to make up for missed or held doses
Cytotoxic drug; follow applicable special handling and disposal procedures
Storage
Store at controlled room temperature 20-25°C (68-77°F); excursions are permitted from 15-30°C (59-86°F)
If stored outside of original bottle, discard after 30 days
