tipiracil/trifluridine (Lonsurf)

Dosing and uses of Lonsurf (tipiracil/trifluridine)

• Adult
• Pediatric

 

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