Usage
Tegafur + Uracil is an antineoplastic agent, specifically a pyrimidine analog, primarily indicated for the first-line treatment of metastatic colorectal cancer in conjunction with calcium folinate. It has also shown efficacy in treating other cancers like gastric, head and neck, esophageal, breast, bladder, cervical, lung, liver, gallbladder, bile duct, pancreas, and prostate cancers.
Alternate Names
Tegafur-uracil. Brand names include UFToral, Fimer, Furil, Tegracil, Teroful, UFT, UFT ET, Ufur, and Unitoral (India); Ftorafur, Luporal, Tefudex (International).
How It Works
Pharmacodynamics: Tegafur is a prodrug of 5-fluorouracil (5-FU). Uracil inhibits dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5-FU degradation. This dual action leads to higher 5-FU concentrations in tumor tissue compared to surrounding healthy tissue, maximizing the chemotherapeutic effect while potentially minimizing systemic toxicity. 5-FU’s active metabolites, 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), disrupt DNA and RNA synthesis, respectively. FdUMP inhibits thymidylate synthase, a crucial enzyme in DNA synthesis, while FUTP is incorporated into RNA, impairing its function.
Pharmacokinetics: Tegafur and Uracil are rapidly absorbed after oral administration, reaching peak plasma concentrations within 1-2 hours. Tegafur is metabolized in the liver, primarily by CYP2A6, into 5-FU. Less than 20% of tegafur is excreted unchanged in urine. The elimination half-life of tegafur is approximately 11 hours, while uracil’s is 20-40 minutes.
Mode of Action: At the cellular level, 5-FU disrupts DNA and RNA synthesis, leading to cell cycle arrest and apoptosis (programmed cell death) in rapidly dividing cancer cells. Uracil potentiates 5-FU’s effect by inhibiting DPD and increasing its bioavailability.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: FdUMP inhibits thymidylate synthase. Uracil inhibits DPD.
Elimination Pathways: Tegafur is primarily metabolized in the liver and excreted in the urine (less than 20% unchanged). Uracil has a shorter half-life and is also primarily eliminated via hepatic metabolism.
Dosage
Standard Dosage
Children: Safety and effectiveness have not been established in pediatric patients.
Special Cases:
- Elderly Patients: Exercise caution due to potential age-related decline in organ function.
- Patients with Renal Impairment: Caution is advised, although specific dose adjustments have not been established.
- Patients with Hepatic Dysfunction: Caution is advised, especially in patients with moderate to severe hepatic dysfunction. Monitor liver function tests closely.
- Patients with Comorbid Conditions: Use with caution in patients with heart disease, bone marrow suppression, diabetes, and bowel obstruction. Patients with dihydropyrimidine dehydrogenase (DPD) deficiency should not receive tegafur.
Clinical Use Cases
Dosage guidelines for specific clinical use cases like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations are not explicitly defined for Tegafur + Uracil. Dosing decisions should be individualized based on the patient’s condition and the primary indication for which it is being prescribed.
Dosage Adjustments
Dose adjustments may be necessary based on individual tolerability and toxicity, including myelosuppression, gastrointestinal toxicity, and other adverse effects. Renal and hepatic function should be considered, though specific adjustments are not well-defined. Genetic polymorphisms affecting DPD activity are crucial to consider, as DPD deficiency contraindicates the use of Tegafur + Uracil.
Side Effects
Common Side Effects:
Diarrhea, nausea, vomiting, fatigue, anorexia, stomatitis, abdominal pain, asthenia, increased risk of infection, bruising or bleeding, anemia, skin rash, nail changes.
Rare but Serious Side Effects:
Cardiovascular events (including myocardial infarction), severe myelosuppression, hemorrhagic enteritis, severe diarrhea, liver injury (including fulminant hepatitis), leucoencephalopathy, interstitial pneumonia, Stevens-Johnson Syndrome.
Long-Term Effects:
Chronic complications from prolonged use have not been extensively studied but may include cumulative myelosuppression, cardiac toxicity, and secondary malignancies.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include severe myelosuppression, cardiotoxicity, severe diarrhea, stomatitis, and hepatotoxicity, all of which warrant immediate medical attention.
Contraindications
Hypersensitivity to tegafur, uracil, or 5-FU; DPD deficiency; pregnancy; breastfeeding; concurrent use with sorivudine.
Drug Interactions
- Anticoagulants (e.g., warfarin)
- Antiepileptics (e.g., phenytoin)
- Folic acid supplements
- Metoclopramide
- Other fluoropyrimidines (e.g., capecitabine, 5-FU)
- Cimetidine
- Sorivudine
- Leflunomide
- CYP2A6 substrates or inhibitors
Pregnancy and Breastfeeding
Tegafur + Uracil is contraindicated during pregnancy and breastfeeding due to potential teratogenic effects and excretion in breast milk.
Drug Profile Summary
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Mechanism of Action: Prodrug of 5-FU; uracil inhibits DPD, increasing 5-FU bioavailability. 5-FU metabolites disrupt DNA and RNA synthesis.
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Side Effects: Diarrhea, nausea, vomiting, myelosuppression, stomatitis. Serious side effects include cardiotoxicity, severe diarrhea, and hepatotoxicity.
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Contraindications: Hypersensitivity, DPD deficiency, pregnancy, breastfeeding.
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Drug Interactions: Anticoagulants, antiepileptics, folic acid, sorivudine, CYP2A6 substrates/inhibitors.
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Pregnancy & Breastfeeding: Contraindicated.
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Dosage: Metastatic colorectal cancer: 300mg/m² tegafur daily in three divided doses with calcium folinate for 28 days followed by 7 days rest. Other cancers: 300-600mg/m² daily.
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Monitoring Parameters: Complete blood count, liver function tests, renal function, prothrombin time.
Popular Combinations
Calcium folinate is commonly combined with Tegafur + Uracil in the treatment of metastatic colorectal cancer. Calcium folinate enhances the cytotoxic effects of 5-FU.
Precautions
Monitor for myelosuppression, cardiotoxicity, hepatotoxicity, and gastrointestinal toxicity. Pre-screening for DPD deficiency is essential. Exercise caution in patients with pre-existing medical conditions such as renal or hepatic impairment and heart disease. Advise patients to avoid alcohol and other potential interacting substances.
FAQs (Frequently Asked Questions)
A: 300 mg/m² of tegafur daily, divided into three doses, in combination with calcium folinate, for 28 days followed by a 7-day rest.
Q2: What is the role of uracil in this combination?
A: Uracil inhibits DPD, increasing 5-FU’s bioavailability and antitumor activity.
Q3: What are the most common side effects?
A: Diarrhea, nausea, vomiting, fatigue, myelosuppression, and stomatitis.
Q4: Is Tegafur + Uracil safe to use during pregnancy?
A: No, it is contraindicated due to the risk of fetal harm.
Q5: Are there any specific genetic considerations before prescribing Tegafur + Uracil?
A: Yes, patients must be screened for DPD deficiency, which is a contraindication to its use.
Q6: What monitoring parameters are essential during treatment?
A: Complete blood count, liver function tests, renal function, and prothrombin time should be monitored.
Q7: Can Tegafur + Uracil be used in patients with liver or kidney dysfunction?
A: Use with caution and consider dose adjustments; close monitoring is essential.
Q8: What are the potential drug interactions with Tegafur + Uracil?
A: Interactions can occur with anticoagulants, antiepileptics, folic acid, other fluoropyrimidines, and CYP2A6 substrates/inhibitors. Sorivudine is absolutely contraindicated.
Q9: How should Tegafur + Uracil be administered?
A: Orally, as a capsule, at least one hour before or after meals.
Q10: What should be done in case of a missed dose?
A: Take the missed dose as soon as possible unless it is almost time for the next dose. Do not double the dose.
