Lonsurf (Trifluridine and tipiracil) is an oral combination pill containing two chemotherapeutic drugs used in the treatment of patients with metastatic gastric and metastatic colorectal cancer.

Trifluridine and tipiracil Uses:

• Metastatic Colorectal cancer:

  • Used in the 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.

• Metastatic Gastric cancer:

  • Also used for treating metastatic gastric or gastroesophageal junction adenocarcinoma in adults previously treated with at least two prior lines of chemotherapy which included a fluoropyrimidine, platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.

Lonsurf (Trifluridine and tipiracil) Dose in Adults

 Note:

• As per the manufacturer's recommendations, each dose should be rounded to the nearest 5 mg increment & blood counts should be obtained before starting each cycle and on day 15 of each cycle.
• A cycle should not be started 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 has a moderate emetic potential; antiemetics should be used for the prevention of nausea and vomiting.

Lonsurf (Trifluridine and tipiracil) Dose in the treatment of metastatic colorectal cancer:

• Oral: 35 mg/m² (based on the trifluridine component) every 12 hourly on days 1 to 5 and days 8 to 12 of a 28-day cycle (maximum per dose: trifluridine 80 mg); therapy should be continued until disease progression or unacceptable toxicity.

Lonsurf (Trifluridine and tipiracil) Dose in the treatment of metastatic gastric cancer:

• Oral: 35 mg/m² (based on the trifluridine component) every 12 hourly on days 1 to 5 and days 8 to 12 of a 28-day cycle (maximum per dose: trifluridine 80 mg); therapy should be continued until disease progression or unacceptable toxicity.

  • Missed dose:

    • The missed or vomited doses should not be re-administered & continued with the next scheduled dose.

Use in Children:

Not indicated. 

Pregnancy Risk Category: X

• Based on data from animal studies and the mechanism of action, it is possible for fetal harm to occur when used during pregnancy.
• Pregnancy status should be checked before starting therapy in women of reproductive potential.
• Effective contraception should also be used during therapy and for at most 6 months after the last trifluridine or tipiracil dose.
• Condoms should only be used by males with female partners who are capable of reproducing.

Use while breastfeeding

• It is not known if it is present in breast milk.
• Manufacturers recommend that you stop breastfeeding during therapy and for 24 hours following the last dose.
• There is the potential for serious adverse effects in breastfed babies.

Dose in Kidney Disease:

• CrCl ≥30 mL/minute:

  • Dosage adjustment not necessary.

• CrCl <30 mL/minute and ESRD:

  • No dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dose in Liver disease:

• Mild impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin <1 to 1.5 times ULN and any AST):
  • Dosage adjustment not 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):
  • Therapy should not be started.

Common Side Effects of Lonsurf (Trifluridine and tipiracil):

• Central Nervous System:

  • Fatigue

• Gastrointestinal:

  • Nausea
  • Decreased Appetite
  • Diarrhea
  • Vomiting
  • Abdominal Pain

• Hematologic & Oncologic:

  • Anemia
  • Neutropenia
  • Thrombocytopenia
  • Febrile Neutropenia

• Infection:

  • Infection

• Neuromuscular & Skeletal:

  • Asthenia

• Miscellaneous:

  • Fever

Less Common Side Effects of Lonsurf (Trifluridine and tipiracil):

• Cardiovascular:

  • Pulmonary Embolism

• Dermatologic:

  • Alopecia

• Gastrointestinal:

  • Stomatitis
  • Dysgeusia

Contraindications to Lonsurf (Trifluridine and tipiracil):

There are no contraindications in the labeling.

Warnings and precautions

• Suppression of bone marrow

  • It can cause severe and potentially life-threatening bone marrow suppression (anemia or neutropenia) (grades 3 or 4), as well as fatalities (rarely) due to sepsis, neutropenia, or septic shock.
  • Clinical trials showed that growth factor support was offered to just over 10% of patients.
  • Before starting any cycle, blood counts should be checked.
  • It is possible to interrupt therapy and/or reduce doses.

• Gastrointestinal toxicities:

  • Trifluridine/tipiracil is moderately emetic and requires antiemetic treatment to prevent nausea and vomiting.
  • It can cause nausea, vomiting and diarrhea as well as stomatitis and abdominal pain.
  • Patients should inform their doctor if they experience severe gastrointestinal symptoms.

• Hepatic impairment

  • Patients with severe hepatic dysfunction (total Bilirubin >3x ULN or any AST) were not included in the studies.
  • Therapy should not be initiated for patients with baseline moderate to severe hepatic impairment.
  • During a pharmacokinetic investigation, several patients with mild hepatic impairment were found to have bilirubin elevations of grade 3 or 4.

Trifluridine and tipiracil: Drug Interaction

Monitoring parameters:

• Blood CP before each cycle and on day 15 of each cycle (or more frequently if clinically necessary)
• Pregnancy status in females of reproductive potential before starting therapy
• GI toxicity
• Adherence should also be monitored.

How to administer Lonsurf (Trifluridine and tipiracil)?

• Trifluridine/tipiracil has a moderate emetic potential requiring antiemetics for the prevention of nausea and vomiting.
• Should be given every 12 hourly with a meal. Advise patients to swallow tablets as a whole.

Mechanism of action of Lonsurf (Trifluridine and tipiracil):

• Trifluridine/tipiracil's active cytotoxic constituent is trifluridine.
• It is a thymidine based nucleic acid analogue; the triphosphate version of trifluridine is incorporated into DNA, causing interference with DNA synthesis, and inhibition of cell growth.
• Tipiracil inhibits the thymidine-phosphorylase in a powerful manner, which prevents rapid degradation of trifluridine. This allows for an increase in trifluridine intake.

Protein binding: >96% for Trifluridine (primarily to albumin) & <8% for Tipiracil

Metabolism: The cytochrome P450 (CYP) enzymes do not cause the metabolism of trifluridine and tipiracil. Trifluridine is mainly metabolized via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY)

Half-life elimination: 2.1 hours  for Trifluridine (at steady state) &  2.4 hours for Tipiracil (at steady state)

Time to peak plasma: Almost 120minutes

Excretion:

• Trifluridine undergoes urinary excretion (55% [as inactive metabolite FTY and trifluridine glucuronide isomers]; <3% [as unchanged drug]); feces (<3% [as unchanged drug]); expired air (<3%)
• Tipiracil: 27% is excreted via urine as tipiracil and 6-HMU & 50%  is excreted in feces as tipiracil and 6-HMU

International Brand Names of Trifluridine and tipiracil:

• Lonsurf

Trifluridine and Tipiracil Brand Names in Pakistan:

No Brands Available in Pakistan.