Trifluridine
Trifluridine Uses, Dosage, Side Effects, Food Interaction and all others data.
Trifluridine is a fluorinated pyrimidine nucleoside analog which interferes with DNA synthesis of herpes simplex virus, type 1 and 2 and vaccinia virus. It stops replication of herpes viral DNA in 3 ways:
Competitive inhibition of viral DNA polymerase,Incorporation into and termination of the growing viral DNA chain andInactivation of the viral DNA polymerase.Trifluridine exhibits an antiviral effect against herpes simplex virus, types 1 and 2 and vacciniavirus both in vitro and in vivo . Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro . 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 . In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines . 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 . Trifluridine and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice .
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 . 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 . Two out of 48 patients displayed had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec .
| Trade Name | Trifluridine |
| Generic | Trifluridine |
| Trifluridine Other Names | Trifluoromethyldeoxyuridine, Trifluorothymidine, Trifluorothymine deoxyriboside, Trifluridin, Trifluridina, Trifluridine, Trifluridinum |
| Weight | 1% |
| Type | Ophthalmic solution |
| Formula | C10H11F3N2O5 |
| Weight | Average: 296.1999 Monoisotopic: 296.062006087 |
| Protein binding | In vitro findings suggest that the protein binding of trifluridine in human plasma is greater than 96%, where it is mainly bound to human serum albumin. Protein binding of trifluridine is independent of drug concentration and presence of tipiracil . |
| Groups | Approved, Investigational |
| Therapeutic Class | Ophthalmic Anti-viral Products |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Trifluridine Sterile Eye Drops is used for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, type 1 and 2.
Trifluridine is also used to associated treatment for these conditions: Metastatic Colorectal Cancer (MCRC), Primary keratoconjunctivitis caused by herpes simplex virus type 2, Recurrent epithelial keratitis caused by herpes simplex 2, Vaccinia infection in the cornea and conjunctiva, Vaccinia virus ophthalmic infections
How Trifluridine works
The mechanism of action of trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Trifluridine gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Trifluridine also mediates antineoplastic activities via this mechanism; following uptake into cancer cells, trifluridine is rapidly phosphorylated by thymidine kinase to its active monophosphate form . Subsequent phosphorylation produces trifluridine triphosphate , which is readily incorporated into the DNA of tumour cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumour cell proliferation . As trifluridine is subject to rapid degradation by TPase and readily metabolised by a first-pass effect following oral administration, tipiracil is added in the antineoplastic combination product as an inhibitor of TPase to increase the bioavailability of trifluridine . Trifluridine monophosphate also reversibly inhibits thymidylate synthetase (TS), an enzyme that is necessary for DNA synthesis and which levels are shown to be elevated different cancer cell lines . Up-regulation of the expression of the TS enzyme may also lead to the resistance to antineoplastic therapies, such as 5-fluorouracil (5-FU) . However, this inhibitory effect is not considered to be sufficient enough to fully contribute to the cytotoxicity in cancer cells .
Dosage
Trifluridine dosage
Children above 6 years of age & adults: Instill 1 drop every 2 hrs while awake; maximum 9 drops/day until the corneal ulcer has completely re-epithelialized.
After re-epithelialization: Instill 1 drop every 4 hrs or at least 5 drops/day for 7 days 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 Trifluridineeye drops for periods exceeding 21 days should be avoided because of potential ocular toxicity.
Side Effects
Reported side effects are mild, transient burning or stinging sensation upon instillation. Other side effects are superficial punctate keratopathy, epithelial keratopathy, hypersensitivity reaction, stromal edema, irritation, keratitis sicca, hyperemia and increased intraocular pressure.
Toxicity
Intravenous LD50 in rat was 2946 mg/kg . Oral LD50 in rat and mouse were > 4379mg/kg . Overdosage via ocular instillation is unlikely. The highest dose of orally-administered Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day. The primary anticipated complication of an overdose is bone marrow suppression. 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 . Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients .
Precaution
Trifluridine should be prescribed only for patients who have a clinical diagnosis of herpetic keratitis.
Food Interaction
- Take with food.
Volume of Distribution
Following a single dose of Lonsurf (35 mg/m2) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L .
Elimination Route
Systemic absorption of trifluridine following therapeutic dosing with ophthalmic trifluridine appears to be negligible .
At least 57% of the orally-administered trifluridine is absorbed . Following twice daily oral dosing of trifluridine in combination with tipiracil, systemic exposure of trifluridine increased more than dose-proportionally over the dose range of 15 to 35 mg/m^2. Trifluridine accumulation was 3-fold for AUC0-last and 2-fold for peak plasma concentration (Cmax) at steady state . The time to reach the peak plasma concentrations (Cmax) was 2 hours . Tipiracil increases the AUC and Cmax of trifluridine. Food intake was shown to decrease the Cmax and AUC compared to those in a fasting state .
Half Life
The half life is 12 to 18 minutes following ophthalmic administration .
After administration of trifluridine with tipiracil at oral doses 35 mg/m^2 twice daily, the mean elimination half-life (t1/2) of trifluridine was 1.4 hours following a single dose . At steady state, the mean elimination half-life was 2.1 hours .
Clearance
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.
Elimination Route
About 55% of the total recovered radio-labelled trifluridine was detected in the urine within 24 hours . Following oral administration of trifluridine in combination with tipiracil, only 3% of the total dose was excreted into faeces and expired air . Administration of a 60mg single oral dose of the combination product resulted in the mean urinary recovery of 1.5% of unchanged trifluridine and 19.2% for the inactive metabolite FTY after the 48-hour cumulative excretion .
Pregnancy & Breastfeeding use
Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Trifluridine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in lactation: It is unlikely that Trifluridine is excreted in human milk after instillation of Trifluridine eye drops because of the relatively small dosage. The drug should not be prescribed for nursing mothers unless the potential benefits outweigh the potential risks.
Contraindication
Contraindicated in patients who develop hypersensitivity reactions or chemical intolerance to Trifluridine.
Special Warning
Use in children: Safety and effectiveness in pediatric patients below 6 years of age have not been established.
Use in elderly patients: No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.
Innovators Monograph
You find simplified version here Trifluridine
Trifluridine contains Trifluridine see full prescribing information from innovator Trifluridine Monograph, Trifluridine MSDS, Trifluridine FDA label
FAQ
What is Trifluridine used for?
Trifluridine is an antiviral medicine. It is used to treat eye infections caused by a virus, such as herpes infection.
How long does it take Trifluridine to work?
Trifluridine usually takes 6 to 12 days of using for ulcers to heal.
How does Trifluridine work?
It works by killing the virus that causes the infection.
What are the common side effects of Trifluridine?
Common side effects of Trifluridine are include: severe burning, stinging, or irritation after using this medicine; you feel like something is in your eye; or. your eyes are red, watery, and more sensitive to light.
How long should I use Trifluridine?
You should not use this medicine for longer than 21 days.
Is Trifluridine safe during pregnancy?
Use is not recommended. Based on animal data and its mechanism of action this drug can cause fetal harm. It caused embryofetal toxicity and lethality in pregnant animals when given during gestation at doses resulting in exposures lower than equivalent human exposures at the recommended dose.
Is Trifluridine safe during breastfeeding?
Trifluridine ophthalmic is unlikely to be distributed into breast milk. Use caution while breastfeeding.
How should I use Trifluridine?
The usual recommended adult dose of Trifluridine eye drops is 1 drop into the affected eye(on the cornea) every 2 hours while awake (up to a maximum of 9 drops per day).
What happen If I missed Trifluridine?
If you miss a dose, instill it as soon as possible and continue with your regular schedule. If it is almost time for your next dose, skip the missed dose and continue with your regular dosing schedule. Do not instill a double dose to make up for a missed one.
Who should not take Trifluridine?
You should not be used by anyone who is allergic to Trifluridine or to any of the ingredients of the medication.
What is the effect of Trifluridine on the Kidneys?
Using Trifluridine does not have any harmful effects on kidneys.
What is the effect of Trifluridine on the Heart?
Trifluridine is completely safe for the heart.
What is the effect of Trifluridine on the Liver?
Trifluridine does not damage the liver.
Can I drive after taking Trifluridine?
Trifluridine ophthalmic may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly
Can I drink alcohol with Trifluridine?
Consuming limited amounts of alcohol while taking Trifluridine does not cause any harmful effects. But it is best to observe caution.
Does Trifluridine need to be refrigerated?
Store in the refrigerator, do not freeze. Keep the bottle tightly closed when not in use.
Can I overdose on Trifluridine?
An overdose of Trifluridine ophthalmic is not expected to be dangerous. Seek emergency medical attention or call the Poison Help line.
How fast does Trifluridine work?
Depending on how serious the damage is, it usually takes 6 to 12 days of using Trifluridine for ulcers to heal. Remember to go to your follow-up appointments to make sure that your infection is going away properly.
