Usage
Gimeracil is an antineoplastic antimetabolite drug primarily used in combination with other medications, specifically tegafur and oteracil potassium, for the treatment of advanced gastric cancer. It is not typically prescribed on its own. It belongs to the pharmacological classification of antineoplastic antimetabolites, specifically a dihydropyrimidine dehydrogenase (DPD) inhibitor. Gimeracil enhances the effect of 5-fluorouracil (5-FU), a chemotherapy drug, by preventing its breakdown by DPD.
Alternate Names
Gimeracil is sometimes referred to as CDHP (its chemical abbreviation). It doesn’t have widely recognized international or regional variations. It is primarily known as a component of combination products, and the combination, rather than gimeracil itself, is usually given a brand name, for example Teysuno (tegafur/gimeracil/oteracil) and TS-1/TS-ONE (tegafur/gimeracil/oteracil potassium).
How It Works
Pharmacodynamics: Gimeracil inhibits DPD, the enzyme responsible for the rapid metabolism and inactivation of 5-fluorouracil (5-FU). By inhibiting DPD, Gimeracil increases 5-FU’s bioavailability and prolongs its effects, enabling 5-FU to be more effective at lower doses, thus reducing systemic toxicity to the body. The increase in 5-FU exposure can lead to intensified chemotherapeutic effects against cancer cells.
Pharmacokinetics: Gimeracil is administered orally. The absorption of Gimeracil itself hasn’t been extensively studied as it is normally measured as a combined treatment alongside tegafur and oteracil potassium. The primary route of elimination is renal excretion. In patients with renal impairment, its clearance is reduced, therefore an adjustment to dosage is necessary.
Mechanism of Action: Gimeracil acts by competitively and reversibly inhibiting DPD. It has approximately 180 times higher DPD inhibitory activity than uracil. It does not directly interact with DNA or other cellular components like some other antineoplastic agents. Its role is solely to enhance the effects of the co-administered 5-FU.
Dosage
Gimeracil is not administered alone but is given in combination with tegafur and oteracil. Dosages here reflect common practices but may vary and individual patient factors must be considered.
Standard Dosage
Adults:
The standard recommended dose of Teysuno (tegafur/gimeracil/oteracil) is 25 mg/m² (expressed as tegafur content), taken orally twice daily (morning and evening) for 21 consecutive days, followed by a 7-day rest period. This 28-day cycle is then repeated. Capsules should be taken with water at least one hour before or after a meal. TS-1/TS-ONE dosing depends on body surface area, with dose adjustments as needed.
Children:
The safety and efficacy of Teysuno/TS-1 have not been established in children under 18 years old, therefore it should not be used in the pediatric population.
Special Cases:
- Elderly Patients (over 70 years): No standard dose adjustment is typically recommended, but caution is advised due to potential age-related decline in organ function. Close monitoring for adverse reactions is crucial.
- Patients with Renal Impairment: Dose reduction is necessary. The recommended standard dose in patients with moderate renal impairment is 20 mg/m² twice daily (expressed as tegafur content). It is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).
- Patients with Hepatic Dysfunction: No dose adjustment is typically recommended for mild to moderate hepatic impairment. For severe hepatic impairment, use is generally not recommended.
- Patients with Comorbid Conditions: Careful evaluation and potential dose adjustments are necessary for patients with other medical conditions, especially those affecting bone marrow function or impacting drug metabolism.
Clinical Use Cases
Gimeracil, as a component of Teysuno/TS-1, is specifically indicated for advanced gastric cancer and is not used in clinical scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations outside of its oncology indication.
Dosage Adjustments
Dose modifications are based on individual patient characteristics, including renal function, age, tolerance to the medication, and other comorbidities. Dose reductions are commonly made during a treatment cycle if toxicity develops. It’s essential to follow clinical guidelines and tailor adjustments to the individual patient.
Side Effects
Common Side Effects
Nausea, vomiting, diarrhea, constipation, fatigue, anorexia, stomatitis, hand-foot syndrome (palmar-plantar erythrodysaesthesia), bone marrow suppression (neutropenia, leukopenia, thrombocytopenia, anemia), increased lacrimation, dry eye.
Rare but Serious Side Effects
Severe bone marrow suppression, acute renal failure, severe hepatic dysfunction (including fulminant hepatitis), Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial pneumonitis, ocular toxicity (blurred vision, diplopia, photopsia, decreased visual acuity, blindness), severe diarrhea, dehydration, electrolyte disturbances.
Long-Term Effects
Chronic complications from prolonged use are possible, including cumulative bone marrow suppression, renal toxicity, and secondary malignancies.
Adverse Drug Reactions (ADR)
Clinically significant ADRs include severe bone marrow suppression, acute renal failure, hepatotoxicity, severe diarrhea, dehydration, and ocular toxicity, requiring prompt medical intervention.
Contraindications
- Hypersensitivity to any of the active substances (tegafur, gimeracil, or oteracil) or any of the excipients.
- History of severe or unexpected reactions to fluoropyrimidine therapy.
- Known DPD deficiency.
- Pregnancy and breastfeeding.
- Severe bone marrow suppression.
- Severe renal impairment (CrCl below 30 mL/min).
- Concomitant use of other fluoropyrimidines.
- Recent treatment (within 4 weeks) with DPD inhibitors (e.g., sorivudine, brivudine).
Drug Interactions
- Other fluoropyrimidines (e.g., capecitabine, 5-FU, flucytosine): Increased risk of toxicity.
- DPD inhibitors (e.g., sorivudine, brivudine): Increased risk of severe toxicity.
- Coumarin-derivative anticoagulants (e.g., warfarin): Increased risk of bleeding.
- Phenytoin: Increased serum phenytoin levels.
- Clozapine: Increased myelotoxicity and hematologic toxicity.
Pregnancy and Breastfeeding
Gimeracil is contraindicated in pregnancy and breastfeeding. It is classified as Pregnancy Category X (representing a high risk of fetal harm). It is not known if gimeracil is excreted in breast milk, but due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is contraindicated.
Drug Profile Summary
- Mechanism of Action: DPD inhibitor, enhances 5-FU activity.
- Side Effects: Nausea, vomiting, diarrhea, bone marrow suppression, ocular toxicity.
- Contraindications: Pregnancy, breastfeeding, DPD deficiency, severe renal/bone marrow suppression.
- Drug Interactions: Other fluoropyrimidines, DPD inhibitors, warfarin, phenytoin.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: See detailed dosage section above.
- Monitoring Parameters: Complete blood count (CBC), renal function tests, liver function tests.
Popular Combinations
Gimeracil is most commonly combined with tegafur and oteracil (as Teysuno or TS-1), occasionally cisplatin is also added to this treatment regimen.
Precautions
- Monitor patients closely for bone marrow suppression, renal function, hepatic function, and ocular toxicity.
- Pre-screening for DPD deficiency is crucial.
- Patients with mild to moderate renal or hepatic impairment require careful monitoring and possible dose adjustment.
- Consider use of prophylactic antiemetics to manage nausea and vomiting.
- Provide patient education regarding side effects, precautions, and the importance of adherence to the prescribed dosage and schedule.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Gimeracil?
A: Gimeracil is not used alone; it is administered as part of a combined regimen including tegafur and oteracil (Teysuno or TS-1). See detailed dosage section above.
Q2: How does Gimeracil work in the body?
A: It enhances the efficacy of 5-FU by inhibiting the enzyme DPD, which is responsible for its breakdown.
Q3: What are the most common side effects?
A: Common side effects include nausea, vomiting, diarrhea, constipation, fatigue, anorexia, and bone marrow suppression.
Q4: Is Gimeracil safe during pregnancy or while breastfeeding?
A: No, it is contraindicated in both pregnancy and breastfeeding due to the potential for fetal harm and adverse effects on the nursing infant.
Q5: What are the serious side effects to watch out for?
A: Severe bone marrow suppression, acute renal failure, severe hepatic dysfunction, ocular toxicity, severe diarrhea, and dehydration.
Q6: Can Gimeracil interact with other medications?
A: Yes, it can interact with other medications, especially other fluoropyrimidines, DPD inhibitors, warfarin, and phenytoin. See detailed drug interactions section above.
Q7: What patient monitoring is necessary during Gimeracil therapy?
A: Regular monitoring of complete blood count (CBC), renal function tests, and liver function tests is essential. Ocular examinations are also recommended.
Q8: How should Gimeracil be administered?
A: Gimeracil is given orally as part of a combination therapy with tegafur and oteracil (Teysuno or TS-1). Capsules should be taken with water at least 1 hour before or after a meal.
Q9: What are the contraindications for Gimeracil?
A: Contraindications include known DPD deficiency, pregnancy, breastfeeding, severe bone marrow suppression, and severe renal impairment.
Q10: Are there any special dosage adjustments needed for elderly patients?
A: While no standard dose adjustment is routinely made, caution is advised and close monitoring is essential in elderly patients due to the potential for reduced organ function.
