LONSURF

Trifluridine is a fluorinated pyrimidine nucleoside that is structurally related to idoxuridine 1.

It is an active antiviral agent in ophthalmic solutions used mainly in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus.

It displays effective antiviral activity against

Herpes simplex virus type and 2 1.

The of trifluridine with tipiracil marketed as Lonsurf has been approved in Japan, the United States, and the European Union for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin.

• and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

In the anticancer therapy, trifluridine acts as a thymidine-based nucleoside metabolic inhibitor that gets incorporated into DNA of cancer cells following cell uptake to aberrate DNA function during cell replication 10.

As a standalone product, trifluridine is used for the ophthalmic treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types and 2.

Trifluridine is also available as a with tipiracil, which is indicated either alone or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin.

• and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

This is also used for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma and were previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.

Trifluridine exhibits an antiviral effect against herpes simplex virus, types and 2 and vacciniavirus both in vitro and in vivo 1.

Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro 1.

While there is evidence from a study that cross-resistance may develop between trifluridine and idoxuridine or vidarabine, trifluridine was shown to effective in treating dendritic ulcers in patients with herpetic keratitis who are unresponsive to idoxuridine or vidarabine based on the results from masked comparative trials 1.

In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines 10.

The cytotoxic activity of trifluridine and tipiracil against several human tumour xenografts show high correlation with the amount of trifluridine incorporated into DNA, indicating that the primary mechanism of action of trifluridine involves the direct incorporation into the cancer cell DNA 10.

Trifluridine and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice Label.

In clinical studies comprised of patients with previously treated metastatic colorectal cancer, treatment of trifluridine in combination with tipiracil in addition to best supportive care over a 5.

• or 7-month period resulted in increased progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) compared to placebo 10.

In an open-label study, administration of trifluridine at the recommended dosage in patients with advanced solid tumors had no clinically relevant effect on QT/QTc prolongation compared with placebo Label.

Two out of 48 patients displayed had QTc greater than 500 msec and of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec Label.

After oral administration of

LONSURF with -trifluridine, at least 57% of the administered trifluridine was absorbed.

Following a single dose of

LONSURF (35 mg/m 2 ) in patients with advanced solid tumors, the mean times to peak plasma concentrations (T max ) of trifluridine was around 2 hours.

Trifluridine area under the concentration-time curve from time to the last measurable concentration (AUC 0-last ) was approximately 3-fold higher and maximum concentration (C max ) was approximately 2-fold higher after multiple dose administration (twice daily for 5 days a week with 2 days rest for 2 weeks followed by a 14-day rest, repeated every 4 weeks) than after single-dose administration.

Following a single oral administration of

LONSURF at 35 mg/m in patients with cancer, the mean time to peak plasma concentration (T max ) of trifluridine was around 2 hours.

For the ophthalmic formulation, systemic absorption appears to be negligible.

A standardized high-fat, high-calorie meal decreased trifluridine C max by approximately 40% but did not change trifluridine AUC compared to those in a fasting state in patients with cancer following administration of a single dose of LONSURF 35 mg/m 2.

In a dose finding study (15-35 mg/m 2 twice daily), the AUC from time 0-10 hours (AUC0-10) of trifluridine tended to increase more than expected based on the increase in dose.

Following a single dose of

LONSURF (35 mg/m 2 ) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L.

Trifluridine is 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).

No other major metabolites were detected in plasma or urine.

Other minor metabolites, such as 5-carboxy-2'-deoxyuridine found on the endothelial side of the cornea or 5-carboxyuraci, were also detected, but only at low or trace level in plasma and urine. 4, 9 Hover over products below to view reaction partners Trifluridine 5-carboxy-2'-deoxyuridine 5-(trifluoromethyl) uracil.

After single oral administration of

LONSURF (60 mg) with -trifluridine, the total cumulative excretion of radioactivity was 60% of the administered dose. recovered radioactivity was eliminated into urine (55% of the dose) as FTY and trifluridine glucuronide isomers within 24 hours and the excretion into feces and expired air was <3%

The unchanged trifluridine was <3% of administered dose recovered in the urine and feces.

After administration of

LONSURF 35 mg/m 2, the mean elimination and steady-state half-life (t 1/2 ) of trifluridine was 1.4 hours and 2.1 hours respectively.

For the ophthalmic formulation, the half-life is significantly shorter, approximately only 12 minutes.

Following a single dose of

LONSURF (35 mg/m 2 ) in patients with advanced solid tumours, the oral clearance (CL/F) for trifluridine was 10.5 L/hr.

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LD50 in rat was 2946 mg/kg MSDS.

LD50 in rat and mouse were > 4379 mg/kg MSDS.

Overdosage via ocular instillation is unlikely.

The highest dose of Oral-administered

Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day.

There is no known antidote for trifluridine overdose: in case of an overdose, management should include customary therapeutic and supportive medical intervention aimed at correcting the presenting clinical manifestations and preventing their possible complications 10.

Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients 10.

The recommended dosage and frequency of administration should not be exceeded See DOSAGE AND ADMINISTRATION.

Solution is contraindicated for patients who develop hypersensitivity reactions or chemical intolerance to trifluridine.

Instill one drop of Trifluridine Ophthalmic

Solution onto the cornea of the affected eye every 2 hours while awake for a maximum daily dosage of nine drops until the cornea ulcer has completely re-epithelialized.

Following re-epithelialization, treatment for an additional 7 days of one drop every 4 hours while awake for a minimum daily dosage of five drops is recommended.

If there are no signs of improvement after 7 days of therapy or complete re-epithelialization has not occurred after 14 days of therapy, other forms of therapy should be considered.

Continuous administration of trifluridine for periods exceeding 21 days should be avoided because of potential ocular toxicity.

Solution, 1% in a 7.5 mL fill packaged in a natural plastic bottle with a natural plastic flat tip and a white plastic closure. 7.5mL.

• NDC 61314-044-75 Store under refrigeration 2-8°C (36-46°F).

Trifluridine was not teratogenic at doses up to 5 mg/kg/day (23 times the estimated human exposure) when given subcutaneously to rats and rabbits.

However, fetal toxicity consisting of delayed ossification of portions of the skeleton occurred at dose levels of 2.5 and 5 mg /kg /day in rats and at 2.5 mg/kg/day in rabbits.

In addition, both 2.5 and 5 mg/kg/day produced fetal death and resorption in rabbits.

In both rats and rabbits, 1 mg/kg/day (5 times the estimated human exposure) was a no-effect level.

There were no teratogenic or fetotoxic effects after topical application of trifluridine (approximately 5 times the estimated human exposure) to the eyes of rabbits on the 6th through the 18th days of pregnancy.

In a non-standard test, trifluridine solution has been shown to be teratogenic when injected directly into the yolk sac of chicken eggs.

There are no adequate and well-controlled studies in pregnant women.

Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is unlikely that trifluridine is excreted in human milk after ophthalmic instillation of trifluridine because of the relatively small dosage (5mg/day), its dilution in body fluids and its extremely short half-life (approximately 12 minutes).

The drug should not be prescribed for nursing mothers unless the potential benefits outweigh the potential risks.

Safety and effectiveness in pediatric patients below six years of age have not been established.

No overall differences in safety or effectiveness have been observed between elderly and younger patients.