Lonsurf

Other Antineoplastic Agents

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
When handling medication, wear gloves and wash hands afterward.[60166]
Emetic Risk
Moderate/High
Administer routine antiemetic prophylaxis prior to treatment.

Take with food.
Swallow tablets whole. Do not crush or chew tablets; round dose to the nearest 5-mg increment.
Do not take additional doses to make up for doses that are vomited or missed.[60166]

neutropenia / Delayed / 38.0-52.0
anemia / Delayed / 5.0-19.0
anorexia / Delayed / 0-9.0
infection / Delayed / 5.0-8.0
fatigue / Early / 5.0-8.0
asthenia / Delayed / 0-7.0
thrombocytopenia / Delayed / 0.8-6.0
hypertension / Early / 0-6.0
vomiting / Early / 0.8-4.0
abdominal pain / Early / 2.4-3.7
hyponatremia / Delayed / 0-3.3
pulmonary embolism / Delayed / 2.0-3.1
nausea / Early / 1.6-3.0
diarrhea / Early / 1.2-3.0
GI obstruction / Delayed / 0-2.8
hypokalemia / Delayed / 0-2.5
elevated hepatic enzymes / Delayed / 0-2.1
musculoskeletal pain / Early / 1.2-2.0
fever / Early / 0-1.3
bleeding / Early / 0-1.2
constipation / Delayed / 0-0.8
proteinuria / Delayed / 0-0.8
stomatitis / Delayed / 0-0.4
rectal fistula / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
atrial fibrillation / Early / Incidence not known

hyperkalemia / Delayed / 0-17.0
interstitial lung disease / Delayed / 0.2-0.2
QT prolongation / Rapid / Incidence not known

headache / Early / 0-8.0
dysgeusia / Early / 0-7.0
alopecia / Delayed / 0-7.0

Lonsurf

Rx

Nucleoside metabolic inhibitor and thymidine phosphorylase inhibitor
Used in adults for metastatic colorectal cancer as a single agent and in combination with bevacizumab and metastatic gastric or gastroesophageal cancer as a single agent after progression on several previous lines of chemotherapy
Severe myelosuppression has been reported

35 mg/m2 based on trifluridine component (maximum, 80 mg) orally twice daily with food on days 1, 2, 3, 4, and 5 and days 8, 9, 10, 11, and 12 repeated every 28 days until disease progression or unacceptable toxicity. Round the dose up or down to the nearest 5 mg; one or both strength tablets (15 mg or 20 mg of trifluridine component) may be used to make a dose. Specific dose and recommended tablets per dose based on body surface area are provided by the manufacturer. In a randomized, double-blind clinical trial, treatment with trifluridine; tipiracil (n = 534) significantly improved overall survival (7.1 months vs. 5.3 months) and progression-free survival (2 months vs. 1.7 months) compared with placebo in patients with heavily previously treated metastatic colorectal cancer (n = 266); all patients but one had received prior bevacizumab, and all but two KRAS wild-type patients had been previously treated with either panitumumab or cetuximab. The objective response rate (ORR) was 1.6% for trifluridine; tipiracil-treated patients and 0.4% for placebo; however, the rate of disease control was 44% vs. 16%, respectively. The addition of trifluridine; tipiracil to best supportive care also significantly delayed the time to worsening of ECOG performance status to 2 or higher (5.7 months vs. 4 months).

35 mg/m2 based on trifluridine component (maximum, 80 mg) orally twice daily with food on days 1, 2, 3, 4, and 5 and days 8, 9, 10, 11, and 12 repeated every 28 days until disease progression or unacceptable toxicity. Round the dose up or down to the nearest 5 mg; one or both strength tablets (15 mg or 20 mg of trifluridine component) may be used to make a dose. Specific dose and recommended tablets per dose based on body surface area are provided by the manufacturer. At a median follow-up time of approximately 14 months in a randomized, phase 3 (SUNLIGHT) trial (n = 492), the median overall survival time was significantly longer in the trifluridine; tipiracil plus bevacizumab arm compared with the trifluridine; tipiracil alone arm (10.8 months vs. 7.5 months; hazard ratio (HR) = 0.61; 95% CI, 0.49 to 0.77) in patients with unresectable adenocarcinoma of the colon or rectum who had received previous chemotherapy regimens for advanced colorectal cancer and had progressive disease or unacceptable adverse effects to their last regimen. Additionally, investigator-assessed progression-free survival time was significantly longer in patients who received trifluridine; tipiracil plus bevacizumab (5.6 months vs. 2.4 months; HR = 0.44; 95% CI, 0.36 to 0.54). In this trial, 92.1% of patients had received 2 prior treatment regimens for metastatic disease that included fluoropyrimidine-based therapy (100%) and anti-VEGF therapy (72%); 93.7% of the patients with RAS wild-type disease had received prior anti-EGFR therapy.

35 mg/m2 based on trifluridine component (maximum, 80 mg) orally twice daily with food on days 1, 2, 3, 4, and 5 and days 8, 9, 10, 11, and 12 repeated every 28 days until disease progression or unacceptable toxicity. Round the dose up or down to the nearest 5 mg; one or both strength tablets (15 mg or 20 mg of trifluridine component) may be used to make a dose. Specific dose and recommended tablets per dose based on body surface area are provided by the manufacturer. In a randomized, double-blind clinical trial, treatment with trifluridine; tipiracil significantly improved median overall survival (5.7 months vs. 3.6 months) compared with placebo in patients with heavily pretreated metastatic gastric or gastroesophageal junction cancer. Median progression-free survival was also significantly improved but amounted to a difference of only 0.2 months (2 months vs. 1.8 months). Grade 3 or higher adverse reactions occurred in 79.4% of patients in the treatment arm compared with 57.7% in the placebo arm.

Baseline Hepatic Impairment:
Mild hepatic impairment (total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN; OR total bilirubin 1.1 to 1.5 times ULN and any AST): No adjustment to the starting dose is recommended.
Moderate to severe hepatic impairment (total bilirubin level greater than 1.5 times ULN and any AST): Do not administer trifluridine; tipiracil.[60166]

Baseline Renal Impairment:
Mild to moderate renal impairment (CrCl 30 mL/min or higher): No adjustment to the starting dose is recommended.
Severe renal impairment (CrCl 15 to 29 mL/min): Reduce the dose of trifluridine; tipiracil to 20 mg/m2 based on the trifluridine component (maximum, 50 mg) PO twice daily with food on days 1 to 5 and days 8 to 12 of each 28-day cycle. Further reduce the dose to 15 mg/m2 based on the trifluridine component (maximum, 40 mg) PO twice daily in patients unable to tolerate a dose of 20 mg/m2. Permanently discontinue trifluridine; tipiracil in patients unable to tolerate a dose of 15 mg/m2 twice daily. For patients with a calculated twice-daily dose of 25 mg which is unable to be administered with available tablet strengths, the total daily dose of 50 mg may be divided unequally (i.e., 20 mg PO in the morning and 30 mg PO in the evening).
End-stage renal disease (ESRD): The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with ESRD.

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

Lonsurf Oral Tab: 15-6.14mg, 20-8.19mg

160 mg (trifluridine component) PO total daily dose (80 mg PO administered twice daily) on days 1, 2, 3, 4, 5 and days 8, 9, 10, 11, 12, repeated every 28 days.

160 mg (trifluridine component) PO total daily dose (80 mg PO administered twice daily) on days 1, 2, 3, 4, 5 and days 8, 9, 10, 11, 12, repeated every 28 days.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Trifluridine is a thymidine-based nucleoside metabolic inhibitor, believed to act as a thymidylate synthase inhibitor (similar to 5-fluorouracil). Following uptake into cancer cells, it is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Tipiracil increases trifluridine exposure by inhibiting thymidine phosphorylase, which is responsible for rapid inactivation of trifluridine after administration. Trifluridine; tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice.[60165] [60166]

Trifluridine; tipiracil is administered orally. Trifluridine is highly protein bound (greater than 96%) to human serum albumin, independent of drug concentration and the presence of tipiracil. The plasma protein binding of tipiracil is less than 8%. After twice daily dosing, systemic exposure of trifluridine increased more than dose-proportionally over a range of 15 mg/m2 to 35 mg/m2. After a single dose, the mean half-life of trifluridine is 1.4 hours and tipiracil is 2.1 hours when administered in combination; at steady state, the mean half-lives are 2.1 hours and 2.4 hours, respectively.[60166] When trifluridine was administered as an intravenous single agent, the half-life was 12 minutes.[60165] Trifluridine is mainly eliminated via thymidine phosphorylase metabolism to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY); tipiracil is not metabolized in either human liver or hepatocytes. No other metabolites were detected in plasma or urine. Following a single oral 60-mg dose of trifluridine; tipiracil with radiolabeled trifluridine, 60% of the radioactivity was recovered within 24 hours, including 55% of the dose in the urine (as FTY and trifluridine glucuronide isomers), less than 3% of the dose in the feces, and less than 3% of the dose in expired air. Unchanged trifluridine accounted for less than 3% of the administered dose recovered in the urine and feces. Following a single oral 60-mg dose of trifluridine; tipiracil with radiolabeled tipiracil, 77% of the radioactivity was recovered, including 27% of the dose excreted in the urine and 50% of the dose excreted in the feces. Tipiracil was the major component and 6-HMU was the major metabolite in the urine and feces.[60166]
 
Affected CYP450 isoenzymes or other drug transporters: None.
Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP450) enzymes.[60166]

After a single dose administered to patients with cancer, the Tmax of trifluridine; tipiracil was approximately 2 hours. Administration of a single dose of trifluridine; tipiracil 35 mg/m2 increased the mean Cmax of trifluridine by 22-fold and AUC by 37-fold, with reduced variability, compared to trifluridine 35 mg/m2 alone. The accumulation of trifluridine at steady-state was 2-fold for Cmax and 3-fold for AUC; no accumulation was observed for tipiracil.[60166]
 
The Cmax of both trifluridine and tipiracil as well as the AUC of tipiracil were decreased by approximately 40% by a standardized high-fat, high-calorie meal in patients with cancer compared to those in a fasting state; the AUC of trifluridine did not change with food.[60166] The recommendation to take trifluridine; tipiracil with meals is based on an observed correlation between an increase in Cmax and a decrease in neutrophil counts.[63982]

Pregnancy should be avoided by females of reproductive potential during trifluridine; tipiracil treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, trifluridine; tipiracil can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving trifluridine; tipiracil should be apprised of the potential hazard to the fetus. When administered once daily to female rats during organogenesis, decreased fetal weight was observed at approximately 0.33 times the exposure achieved with the recommended dosing. Embryolethality and structural abnormalities (kinked tail, cleft palate, ectrodactyly, anasarca, alterations in great vessels, and skeletal abnormalities) occurred at exposures 0.92 times that achieved with the recommended dose.

It is not known whether trifluridine; tipiracil is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, females should avoid breast-feeding during treatment and for 1 day after the final dose.