Tipiracil Hydrochloride – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

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 tumor cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumor cell proliferation. As trifluridine is subject to rapid degradation by TPase and readily metabolized by a first-pass effect following oral administration, tipiracil is added to 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 whose levels are shown to be elevated in different cancer cell lines. Up-regulation of the expression of the TS enzyme may also lead to 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.

or

Trifluridine is a fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus, types 1 and 2, and vaccinia virus. Some strains of adenovirus are also inhibited in vitro. …Trifluridine interferes with DNA synthesis in cultured mammalian cells. However, its antiviral mechanism of action is not completely known

Trifluridine exhibits an antiviral effect against herpes simplex virus, types 1 and 2, and vaccinia virus 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 be 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 antitumor activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines. The cytotoxic activity of trifluridine and tipiracil against several human tumor xenografts show a 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.

Indications

  • Trifluridine is used for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus types 1 and 2 in ophthalmic solutions. Trifluridine, in combination with [tipiracil], is indicated 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 combination use is also used to treat metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, platinum, either a taxane or irinotecan and if appropriate, HER2/neu-targeted therapy.
  • Trifluridine is a nucleoside metabolic inhibitor used to treat keratoconjunctivitis and epithelial keratitis caused by simplex virus, and as a part of chemotherapy for certain types of metastatic gastrointestinal cancers.
  • Trifluridine/tipiracil is the combination of an antineoplastic pyrimidine analog (trifluridine) with an inhibitor of its metabolism (tipiracil) that is used in the therapy of refractory, metastatic colorectal cancer.
  • Trifluridine Ophthalmic Solution is indicated for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus types 1 and 2.
  • Trifluridine is also effective in the treatment of epithelial keratitis that has not responded clinically to the topical administration of idoxuridine or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients found to be resistant to topical vidarabine, trifluridine was also effective.
  • Trifluridine, in combination with tipiracil, is indicated 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 combination use is also used to treat metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, platinum, either a taxane or irinotecan and if appropriate, HER2/neu-targeted therapy.[rx]
  • Metastatic Colorectal Cancer (CRC)
  • Metastatic Gastric Adenocarcinoma
  • Metastatic Gastroesophageal Junction Adenocarcinoma
  • 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

Use in Cancer

Trifluridine and tipiracil hydrochloride are approved to treat:

  • Colorectal cancer that has metastasized (spread to other parts of the body). It is used in adults who have already been treated with a fluoropyrimidineoxaliplatin, irinotecan hydrochloride, and a VEGF inhibitor. Patients whose cancer has the wild-type KRAS gene should have also received an EGFR inhibitor.
  • Stomach adenocarcinoma or gastroesophageal junction adenocarcinoma (a rare type of esophageal cancer) that has metastasized. It is used in adults who have already received at least two treatments with fluoropyrimidine and platinum chemotherapy and either a taxane or irinotecan and, in some cases, HER2/neu-targeted therapy.

Trifluridine and tipiracil hydrochloride is also being studied in the treatment of other types of cancer.

Contraindications

  • Trifluridine ophthalmic solution is contraindicated for patients who develop hypersensitivity reactions or chemical intolerance to trifluridine.
  • Continuous administration of trifluridine for periods exceeding 21 days should be avoided because of potential ocular toxicity.[32394] Punctate lesions in the corneal epithelium are clinical manifestations of trifluridine cytotoxicity. Upon discontinuation, toxic changes to the surface of the eye are generally reversible
  • Safe and effective use of trifluridine ophthalmic solution has not been established in neonates, infants, and children below six years of age. No overall differences in safety or effectiveness have been observed between young adult and geriatric patients.

Dosage

The usual recommended adult dose of trifluridine eye drops is 1 drop into the affected eye(s) (on the cornea) every 2 hours while awake (up to a maximum of 9 drops per day).

This dose is continued until the eye lesion heals, usually within 7 to 14 days. Then, the usual dose is 1 drop into the affected eye(s) every 4 hours (up to a maximum of 5 drops per day) while awake for 7 days. The medication should not be used for longer than 21 days. If no improvement is seen in 7 days, or if the lesion has not healed within 14 days, see your doctor.

The bottle is only partially full to provide proper drop control.

  • First, wash your hands. Then tilt the head back and pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Do not blink. Keep the eyes closed for 1 or 2 minutes to allow the medicine to come into contact with the infection.
  • If you think you did not get the drop of medicine into your eye properly, use another drop.
  • To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Also, keep the container tightly closed.

Do not use this medicine more often or for a longer time than your doctor ordered. To do so may cause problems in the eyes. If you have any questions about this, check with your doctor. To help clear up your infection completely, keep using this medicine for the full time of treatment, even if your symptoms have disappeared. Do not miss any doses.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For ophthalmic solution dosage forms:
    • For viral eye infection:
      • Adults and children 6 years of age and older—One drop every two hours while you are awake. After healing has occurred, the dose may be reduced for seven more days to one drop every four hours (at least 5 doses a day) while you are awake.
      • Children up to 6 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Side Effects

The Most Common

  • hair loss
  • change in the way things taste
  • loss of appetite
  • mouth sores or swelling inside the mouth
  • lack of energy
  • excessive tiredness
  • fever, body aches, chills, or other signs of infection
  • nausea, vomiting, diarrhea, or abdominal pain that is severe or does not go away
  • weakness or shortness of breath when exercising
  • pale skin
  • chest pain
  • pain with deep breathing
  • coughing up blood
  • unusual bleeding or bruising

More Common

  • Blurred vision or other change in vision
  • dryness of eye
  • irritation of eye
  • itching, redness, swelling, or other sign of irritation not present before use of this medicine
  • burning or stinging
  • mild irritation of the eye
  • swelling and redness of the eyelid
  • itching, redness, swelling, or other sign of irritation not present before use of this medication
  • signs of an allergic reaction (e.g., skin itching, rash, redness, swelling, or hives)

Rare

  • Blurred vision or other change in vision
  • dryness of eye
  • irritation of eye
  • itching, redness, swelling, or other sign of irritation not present before use of this medicine

Drug Interaction

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Pregnancy and Lactation

FDA pregnancy risk category C

Pregnancy

There are no adequate and well-controlled studies in pregnant women. In animal studies, no teratogenic or fetotoxic effects were observed in rabbits following ophthalmic administration of doses approximately 5 times the estimated human exposure. However, offspring of rats and rabbits receiving subcutaneous doses of 2.5—5 mg/kg/day (11.5—23 times the estimated human exposure) experienced toxicities that included delayed ossification, fetal death, and resorption. While systemic absorption following ophthalmic administration is minimal, do not use or prescribed in pregnant women unless clearly needed.

Lactation

Trifluridine is not likely to be excreted in the breast milk after ophthalmic administration due to its relatively small dosage, its dilution in body fluids, and its extremely short half-life. According to the manufacturer, it should not be prescribed for nursing mothers unless the potential benefits outweigh the potential risks. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Why is this medication prescribed?

The combination of trifluridine and tipiracil is used to treat colon (large intestine) or rectal cancer that has spread to other parts of the body in people who have already been treated with other chemotherapy medications or cannot receive these chemotherapy medications. The combination of trifluridine and tipiracil is also used to treat certain types of stomach cancer or cancer located in the area where the stomach meets the esophagus (the tube between the throat and stomach) that has spread to other parts of the body in people who have already received at least two other chemotherapy treatments. Trifluridine is in a class of medications called thymidine-based nucleoside analogues. It works by stopping the growth of cancer cells. Tipiracil is in a class of medications called thymidine phosphorylase inhibitors. It works by slowing the breakdown of trifluridine by the body.

How should this medicine be used?

The combination of trifluridine and tipiracil comes as a tablet to take by mouth. It is usually taken twice a day with food for 5 days in a row, followed by a 2-day break. This dosing schedule is repeated and then followed by a 2-week break. This 28-day cycle may be repeated depending on how well this medication works for you and the side effects you experience. Take trifluridine and tipiracil at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take trifluridine and tipiracil exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

Trifluridine and tipiracil tablets come in two different strengths. Your doctor may want you to take a combination of both strengths of tablets to make up your full dose. Be sure that you know what each type of tablet looks like and how many you are to take of each. Ask your doctor or pharmacist if you have any questions.

Your doctor may delay your treatment or decrease your dose of trifluridine and tipiracil depending on the side effects that you experience. Be sure to talk to your doctor about how you are feeling during your treatment. Do not stop taking trifluridine and tipiracil without talking to your doctor.

Wash your hands after handling trifluridine and tipiracil tablets. If someone else is handling your trifluridine and tipiracil tablets, they should wear rubber or latex gloves so that their skin does not come into contact with the tablets. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking trifluridine and tipiracil,

  • tell your doctor and pharmacist if you are allergic to trifluridine and tipiracil, any other medications, or any of the ingredients in trifluridine and tipiracil tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • tell your doctor if you are 65 years of age or older, or have or have ever had liver or kidney disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or if you plan to father a child. You or your partner should not become pregnant during your treatment with trifluridine and tipiracil. If you are female, you will need to have a pregnancy test before you start treatment, and you should use birth control to prevent pregnancy during your treatment and for 6 months after your final dose. Talk to your doctor about birth control methods that you can use during your treatment. If you are a man and your partner can become pregnant, you should use a condom while taking this medication, and for 3 months after your treatment. If you or your partner become pregnant while you are receiving trifluridine and tipiracil, call your doctor immediately. Trifluridine and tipiracil may harm the fetus.
  • tell your doctor if you are breastfeeding. Your doctor will probably tell you not to breastfeed during your treatment and for 1 day after your last dose.

What should I do if I forget a dose?

If you miss a dose of trifluridine and tipiracil, do not take another dose to make up for the missed dose. Call your doctor for instructions about what to do for a missed dose.

References