Usage
Capecitabine is an antineoplastic antimetabolite specifically classified as a fluoropyrimidine carbamate. It is prescribed for the treatment of various cancers, including:
- Colon Cancer: Adjuvant treatment of Dukes’ C colon cancer after complete resection of the primary tumor.
- Colorectal Cancer: First-line treatment of metastatic colorectal cancer, often in combination with other chemotherapeutic agents. Also used in the peri-operative setting for rectal cancer, with or without radiation therapy.
- Breast Cancer: Treatment of metastatic breast cancer, particularly in patients who have received prior anthracycline or taxane therapy. It may be used as a single agent or in combination with docetaxel.
- Esophageal, Gastric (Stomach), or Gastroesophageal Junction Cancers: In combination with other cancer treatments for cases where the cancer has spread or cannot be surgically removed.
Capecitabine’s mechanism of action involves its conversion to 5-fluorouracil (5-FU) within tumor tissues. 5-FU disrupts DNA and RNA synthesis, inhibiting cancer cell growth and division.
Alternate Names
- International Nonproprietary Name (INN): Capecitabine
- Brand Name: Xeloda®
How It Works
Pharmacodynamics: Capecitabine itself is a prodrug, meaning it is inactive until metabolized. It undergoes a three-step enzymatic conversion, culminating in the formation of 5-FU preferentially within tumor tissues. 5-FU is an antimetabolite that inhibits thymidylate synthase, a key enzyme in DNA and RNA synthesis. This inhibition leads to impaired cell division and ultimately apoptosis (cell death) in rapidly dividing cancer cells.
Pharmacokinetics:
- Absorption: Orally administered capecitabine is rapidly and extensively absorbed. Food may decrease the rate but not the extent of absorption.
- Metabolism: Capecitabine undergoes a three-step enzymatic conversion: First, it is converted to 5’-deoxy-5-fluorocytidine (5’-DFCR) by carboxylesterase in the liver. Then, 5’-DFCR is converted to 5’-deoxy-5-fluorouridine (5’-DFUR) by cytidine deaminase, primarily in the liver and tumor tissues. Finally, 5’-DFUR is converted to the active 5-FU by thymidine phosphorylase, which is present in higher concentrations in tumor tissue compared to healthy tissues. This targeted activation minimizes systemic exposure to 5-FU and reduces its associated side effects.
- Elimination: Primarily eliminated via the kidneys.
Mode of Action: The primary mode of action is through the inhibition of thymidylate synthase by its metabolite, 5-FU. This interferes with DNA and RNA synthesis, leading to cell cycle arrest and apoptosis.
Dosage
Standard Dosage
Adults:
Dosage is calculated based on body surface area (BSA) and typically administered within 30 minutes after a meal.
- Monotherapy (Metastatic Breast Cancer, Adjuvant Colon Cancer, Metastatic Colorectal Cancer): 1250 mg/m² orally twice daily for 14 days followed by a 7-day rest period. This 21-day cycle is repeated until disease progression or unacceptable toxicity.
- Adjuvant Colon Cancer: Treatment is usually continued for a total of 6 months.
- Combination Therapy: Starting doses are generally reduced when capecitabine is part of a combination regimen. The exact dose depends on the specific combination used and should be determined by the treating physician. Refer to the specific combination therapy guidelines (e.g., XELOX, CAPEDOCE) for detailed dosage information.
- Rectal Cancer (Peri-operative): With concurrent radiation: 825 mg/m² orally twice daily. Without radiation: 1250 mg/m² orally twice daily.
Children:
There is no established standard dosage for children. Use in pediatric patients is generally avoided, except in specific clinical trials under strict supervision.
Special Cases:
- Elderly Patients: Close monitoring is recommended, as elderly patients, especially those over 80, are more susceptible to side effects. Dosage adjustments may be needed.
- Patients with Renal Impairment: Dose reduction is necessary for patients with moderate to severe renal impairment. Capecitabine is contraindicated in patients with creatinine clearance < 30 mL/min.
- Patients with Hepatic Dysfunction: Careful monitoring is advised in patients with mild to moderate hepatic impairment due to liver metastases. No data are available for patients with severe hepatic dysfunction.
- Patients with Comorbid Conditions: Caution should be exercised in patients with pre-existing heart conditions, as capecitabine can exacerbate cardiac issues.
Clinical Use Cases
Capecitabine’s dosage in clinical use cases, including intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations, would be determined based on the underlying cancer being treated and the specific combination regimen used, if any. There are no specific dosage guidelines unique to these clinical settings.
Dosage Adjustments
Dosage adjustments are necessary based on patient-specific factors such as:
- Renal/Hepatic Dysfunction: As detailed above, dose reductions are often required.
- Myelosuppression: Capecitabine can cause a decrease in blood cell counts. Dosage adjustments or treatment interruptions may be necessary based on the severity of myelosuppression.
- Hand-Foot Syndrome: Dose reductions are recommended for severe hand-foot syndrome.
- Other Toxicities: Other significant adverse effects may necessitate dosage modifications or temporary cessation of treatment.
- Dihydropyrimidine Dehydrogenase (DPD) Deficiency: Patients with DPD deficiency are at increased risk of severe toxicity. Genetic testing for DPD deficiency should be considered before starting treatment, especially in cases of unexplained toxicity. Dose adjustments or avoidance of capecitabine may be necessary.
Side Effects
Common Side Effects
- Diarrhea
- Nausea and Vomiting
- Fatigue
- Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia)
- Stomatitis (mouth sores)
- Anorexia (loss of appetite)
- Abdominal pain
Rare but Serious Side Effects
- Cardiotoxicity (heart problems, including heart failure and arrhythmias)
- Severe Myelosuppression (neutropenia, thrombocytopenia, anemia)
- Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
- Severe Diarrhea and Dehydration
- Hepatic Dysfunction (liver problems)
- Renal Dysfunction (kidney problems)
Long-Term Effects
Chronic complications from prolonged use can include secondary cancers, cardiac dysfunction, and pulmonary fibrosis.
Adverse Drug Reactions (ADR)
Clinically significant ADRs requiring immediate intervention include severe allergic reactions, cardiotoxicity, severe myelosuppression, Stevens-Johnson syndrome/toxic epidermal necrolysis, severe diarrhea/dehydration, hepatic and renal dysfunction, and DPD deficiency-related toxicity.
Contraindications
- Hypersensitivity to capecitabine or 5-FU
- DPD deficiency (complete or near-complete absence)
- Pregnancy and breastfeeding
- Severe renal impairment (creatinine clearance < 30 mL/min)
Drug Interactions
Capecitabine has numerous drug interactions, including:
- Anticoagulants (e.g., warfarin): Increased risk of bleeding.
- Anticonvulsants (e.g., phenytoin): Altered metabolism of both drugs.
- CYP450 substrates: Capecitabine is not extensively metabolized by CYP450 enzymes, but its metabolite 5-FU can interact with CYP2C9 substrates.
- Brivudine: Concomitant use is contraindicated due to the increased risk of severe toxicity.
- Leucovorin: Can enhance the effects of capecitabine, potentially increasing toxicity.
- Other Chemotherapy Drugs: Combination therapy with other myelosuppressive agents can increase the risk of bone marrow suppression.
Interactions with OTC drugs, supplements, food, and lifestyle factors (e.g., alcohol, smoking, grapefruit juice) are not as well-defined, but it’s important to consider the potential for interactions.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Category D (positive evidence of human fetal risk) - contraindicated.
- Fetal risks: Teratogenicity (birth defects), embryolethality.
- Breastfeeding: Capecitabine is excreted in breast milk. Breastfeeding is contraindicated during treatment and for 2 weeks after the final dose.
Drug Profile Summary
- Mechanism of Action: Prodrug converted to 5-FU, which inhibits thymidylate synthase, leading to impaired DNA/RNA synthesis and apoptosis in cancer cells.
- Side Effects: Diarrhea, nausea, vomiting, hand-foot syndrome, stomatitis, fatigue. Serious side effects include cardiotoxicity, severe myelosuppression, and severe skin reactions.
- Contraindications: Hypersensitivity, DPD deficiency, pregnancy, breastfeeding, severe renal impairment.
- Drug Interactions: Anticoagulants, anticonvulsants, brivudine, leucovorin.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Determined by BSA, administered twice daily after meals. Dosage varies with cancer type and combination regimens.
- Monitoring Parameters: Complete blood counts, liver and kidney function tests, cardiac function, and signs of hand-foot syndrome and other toxicities.
Popular Combinations
- XELOX: Capecitabine + Oxaliplatin (colorectal cancer)
- CAPEDOCE: Capecitabine + Docetaxel (breast cancer)
- Capecitabine + Bevacizumab: (colorectal cancer)
- Capecitabine + Irinotecan: (colorectal cancer)
- Capecitabine + Cisplatin: (esophageal, gastric cancers)
Precautions
- General Precautions: Assess for DPD deficiency, monitor closely for toxicities, provide patient education on managing side effects.
- Specific Populations:
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Contraindicated.
- Children & Elderly: Use with caution, dose adjustment may be necessary.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Capecitabine?
A: The dosage is individualized based on BSA, cancer type, and combination regimen. For monotherapy, the standard adult dose is 1250 mg/m² orally twice daily for 14 days followed by a 7-day break. Adjustments are necessary for renal or hepatic impairment, elderly patients, and DPD deficiency.
Q2: What are the most common side effects of Capecitabine?
A: Diarrhea, nausea, vomiting, hand-foot syndrome, stomatitis, fatigue, and anorexia are common side effects.
A: Severe diarrhea, cardiotoxicity, severe myelosuppression, severe skin reactions (e.g., Stevens-Johnson syndrome), and signs of liver or kidney dysfunction require immediate intervention.
Q4: What are the contraindications for Capecitabine?
A: Hypersensitivity to capecitabine or 5-FU, complete or near-complete DPD deficiency, pregnancy, breastfeeding, and severe renal impairment.
Q5: What are the key drug interactions with Capecitabine?
A: Significant interactions occur with anticoagulants (e.g., warfarin), anticonvulsants (e.g., phenytoin), and brivudine (contraindicated).
Q6: Can Capecitabine be used during pregnancy or breastfeeding?
A: No, Capecitabine is contraindicated during pregnancy and breastfeeding due to the risk of fetal harm and drug excretion in breast milk.
Q7: How should Capecitabine be administered?
A: Orally, within 30 minutes after a meal, twice daily, with doses approximately 12 hours apart. Tablets should be swallowed whole with water and not crushed or chewed.
Q8: What monitoring parameters are essential for patients on Capecitabine?
A: Close monitoring of complete blood counts, liver and kidney function, cardiac function, and signs of hand-foot syndrome or other toxicities is crucial.
Q9: Are there any special considerations for elderly patients taking Capecitabine?
A: Elderly patients are more prone to side effects, so close monitoring and potential dose adjustments are necessary.
Q10: What should a patient do if they miss a dose of Capecitabine?
A: If a dose is missed, skip the missed dose and resume the usual dosing schedule. Do not double the dose.
