Tegafur

Usage

Tegafur is an antineoplastic antimetabolite and a prodrug of 5-fluorouracil (5-FU). It is primarily used in combination with uracil (sometimes referred to as 5-FU in this context) and calcium folinate for the first-line treatment of metastatic colorectal cancer. It is also used in combination with other antineoplastic agents, like gimeracil and oteracil, to treat other cancers such as gastric cancer, head and neck cancer, non-small cell lung cancer, breast cancer, pancreatic cancer, and biliary tract cancer.

Alternate Names

Tegafur is often combined with other agents, resulting in different drug names. A common combination is tegafur-uracil, sometimes marketed under brand names like UFToral, Fimer, Furil, Tegracil, Teroful, UFT, UFT ET, Ufur, and Unitoral. Another combination includes tegafur, gimeracil, and oteracil, known as Teysuno or TS-1.

How It Works

Pharmacodynamics: Tegafur itself is inactive, but it is metabolized in the liver to 5-FU, its active form. 5-FU disrupts DNA and RNA synthesis by inhibiting thymidylate synthase, thus blocking cell division and leading to cell death. The addition of uracil helps maintain higher concentrations of 5-FU in the body, enhancing its cytotoxic effects. Calcium folinate further augments 5-FU’s activity by stabilizing the 5-FU-thymidylate synthase complex.

Pharmacokinetics: Tegafur is well-absorbed orally. It is metabolized primarily in the liver by cytochrome P450 2A6 (CYP2A6) to 5-FU. Gimeracil, when part of the combination, inhibits dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5-FU degradation, further increasing 5-FU’s availability. 5-FU crosses the blood-brain barrier. Elimination occurs through renal and hepatic pathways.

Dosage

Standard Dosage

Adults: For metastatic colorectal cancer, the typical dose of tegafur-uracil is 300 mg/m² of tegafur, combined with 90 mg/day of calcium folinate, administered orally in three divided doses every 8 hours for 28 consecutive days, followed by a 7-day rest period. This 35-day cycle can be repeated. For other cancers, the dosage regimens may vary based on the combination used (e.g., with gimeracil and oteracil) and the specific cancer type. Doses may range from 300-600 mg of tegafur per day in 2-3 divided doses.

Children: Tegafur is generally not recommended for children as its safety and effectiveness have not been established in pediatric populations.

Special Cases:

• Elderly Patients: Dose adjustments may be needed based on renal and hepatic function.
• Patients with Renal Impairment: Dose reduction is necessary in moderate to severe renal impairment. It is contraindicated in end-stage renal disease requiring dialysis.
• Patients with Hepatic Dysfunction: Caution is advised, and dosage adjustments may be needed.
• Patients with Comorbid Conditions: Consideration for dose adjustments should be made in patients with cardiac disease.

Clinical Use Cases

Dosage recommendations for specific medical settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations are not specifically defined for tegafur. Clinical use typically focuses on its role in cancer treatment as described above.

Dosage Adjustments

Dose modifications are necessary for renal and hepatic impairment, and consideration should be given for patients with cardiac disease. Genetic polymorphisms affecting DPD activity may require dose adjustments, as patients with DPD deficiency are at increased risk of severe toxicity.

Side Effects

Common Side Effects

Diarrhea, nausea, vomiting, fatigue, increased risk of infection, fever, bruising and bleeding, anemia, changes in skin and nails, stomatitis, abdominal pain, anorexia, malaise, and conjunctivitis.

Rare but Serious Side Effects

Facial and body swelling, severe skin rashes, severe diarrhea, liver injury, cardiotoxicity (including myocardial infarction), leucoencephalopathy, anosmia, interstitial pneumonia, limbal stem cell deficiency, and severe myelosuppression (anemia, leukopenia, thrombocytopenia).

Long-Term Effects

Chronic complications from prolonged use are possible, but information is limited. Regular monitoring of blood counts and organ function is crucial during treatment.

Adverse Drug Reactions (ADR)

Severe myelosuppression, severe diarrhea, cardiotoxicity, and allergic reactions require immediate intervention.

Contraindications

Pregnancy, breastfeeding, hypersensitivity to tegafur or any component of the formulation, DPD deficiency, severe myelosuppression, end-stage renal disease requiring dialysis, concomitant use with sorivudine or other fluoropyrimidines (e.g., capecitabine, 5-FU, flucytosine). Relative contraindications include significant cardiac disease, hepatic or renal impairment, acute infections, varicella, and glucose intolerance.

Drug Interactions

Clinically significant interactions exist with sorivudine (potentially fatal), other fluoropyrimidines (additive toxicities), and CYP2A6 inhibitors. Interactions are also possible with phenytoin, warfarin, colony-stimulating factors, tamoxifen, folic acid, and some antiviral agents. Consult drug interaction resources for a complete list. The effect of alcohol is unknown, but caution is advisable. Grapefruit juice does not appear to significantly interact with tegafur.

Pregnancy and Breastfeeding

Tegafur is contraindicated in pregnancy and breastfeeding due to the risk of fetal harm and potential excretion in breast milk. Effective contraception is necessary during and for up to 6 months after treatment.

Drug Profile Summary

• Mechanism of Action: Prodrug metabolized to 5-FU, which inhibits thymidylate synthase, disrupting DNA/RNA synthesis.
• Side Effects: Diarrhea, nausea, vomiting, fatigue, myelosuppression, stomatitis. Rarely, cardiotoxicity, severe diarrhea.
• Contraindications: Pregnancy, breastfeeding, DPD deficiency, severe myelosuppression, end-stage renal disease.
• Drug Interactions: Sorivudine, fluoropyrimidines, CYP2A6 inhibitors.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Varies based on indication and combination. Metastatic colorectal cancer: 300 mg/m² tegafur with calcium folinate for 28 days, followed by a 7-day rest.
• Monitoring Parameters: Complete blood count, liver function tests, renal function tests, cardiac function (if indicated).

Popular Combinations

Tegafur-uracil with calcium folinate is commonly used for colorectal cancer. Tegafur-gimeracil-oteracil (Teysuno/TS-1) is used for various cancers, often in combination with cisplatin.

Precautions

Standard precautions include screening for allergies, metabolic disorders, and organ dysfunction. Special attention should be paid to renal and hepatic function, cardiac history, and potential drug interactions. Premenopausal women should use effective contraception. Caution is advised in elderly patients.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Tegafur?

A: It depends on the formulation and the specific cancer being treated. For metastatic colorectal cancer, tegafur-uracil 300 mg/m² with 90 mg calcium folinate daily, divided into three doses, for 28 days followed by a 7-day rest is common. Other cancer types and combinations have different dosing regimens. Always refer to specific product information.

Q2: What is the mechanism of action of Tegafur?

A: Tegafur is a prodrug converted to 5-FU, which inhibits thymidylate synthase, disrupting DNA and RNA synthesis in cancer cells.

Q3: What are the most common side effects of Tegafur?

A: Diarrhea, nausea, vomiting, fatigue, myelosuppression (low blood counts), stomatitis (mouth sores) are common.

Q4: Is Tegafur safe to use during pregnancy or breastfeeding?

A: No, Tegafur is contraindicated during pregnancy and breastfeeding due to the risk of fetal harm.

Q5: What are the major drug interactions with Tegafur?

A: Sorivudine, other fluoropyrimidines, and CYP2A6 inhibitors can interact significantly with Tegafur.

Q6: How should Tegafur be administered?

A: Tegafur is available in oral forms, usually as capsules. It is usually taken with food.

Q7: What should be monitored in patients receiving Tegafur?

A: Blood counts, liver and renal function tests, and cardiac function (if indicated) should be monitored regularly.

Q8: Are there any specific precautions for elderly patients taking Tegafur?

A: Yes, elderly patients often require dose adjustments due to potential age-related decline in organ function.

Q9: What should patients do if they miss a dose of Tegafur?

A: Patients should not double the dose. They should consult their physician for advice. Generally, they should resume their normal dosing schedule.

Q10: Can Tegafur be used in patients with liver or kidney problems?

A: Caution is required, and dose adjustments are often necessary. It is contraindicated in patients with end-stage renal disease requiring dialysis.