Capecitabine is a fluoropyrimidine carbamate belonging to the class of antineoplastic agents called antimetabolites. As a prodrug, capecitabine is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil (5-FU); subsequently, 5-FU is metabolized to two active metabolites, 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) by both tumor cells and normal cells. FdUMP inhibits DNA synthesis and cell division by reducing normal thymidine production, while FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate for incorporation into the RNA strand. (NCI04).
Mechanism of Action of Capecitabine
Capecitabine is a prodrug that is selectively tumor-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase, an enzyme found in higher concentrations in many tumors compared to normal tissues or plasma. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumor cells. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2′-deaxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, therefore a deficiency of this compound can inhibit cell division. Secondly, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis through the production of fraudulent RNA.
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Capecitabine is a prodrug and has little pharmacologic activity until it is converted to fluorouracil, an antimetabolite. Because capecitabine is converted to fluorouracil by enzymes that are expressed at higher concentrations in many tumors than in adjacent normal tissues or plasma, it is thought that high tumor concentrations of the active drug may be achieved with less systemic toxicity. Fluorouracil is metabolized in both normal and tumor cells to 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate(FUTP). Although the precise mechanisms of action of fluorouracil have not been fully elucidated, the main mechanism is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor (N5-10-methylenetetrahydrofolate) to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from 2′-deoxyuridylate, thereby interfering with DNA synthesis. In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. Capecitabine has bee
Drug Indications of Capecitabine
- For the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen. May also be used in combination with docetaxel for the treatment of metastatic breast cancer in patients who have failed to respond to, or recurred or relapsed during or following anthracycline-containing chemotherapy.
- Capecitabine is used alone as adjuvant therapy following the complete resection of the primary tumor in patients with stage III colon cancer when monotherapy with fluoropyrimidine is preferred. The use of capecitabine in combination regimens for advanced gastric cancer is currently being investigated.
- Breast Cancer
- Colorectal Cancer
- Breast Cancer, Metastatic
- Anal Cancer
- Non-Small Cell Lung Cancer
- Pancreatic Cancer
- Prostate Cancer
- Renal Cell Carcinoma
- Stomach Cancer
- Esophageal Cancers
- Hepatobiliary Cancers
- Malignant Neoplasm of Stomach
- Metastatic Breast Cancer
- Metastatic Colorectal Carcinoma
- Pancreatic Cancer Metastatic
- Metastatic pancreatic endocrine carcinoma
- Refractory Ovarian cancer
- Refractory falopian tube cancer
- Refractory peritoneal cancer
- Refractory, metastatic Colorectal carcinoma
Therapeutic Uses of Capecitabine
- Antimetabolites, Antineoplastic Agent
- Capecitabine is indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither Capecitabine nor combination chemotherapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent capecitabine in the adjuvant treatment of Dukes’ C colon cancer.
- Capecitabine is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with Capecitabine monotherapy. Use of capecitabine instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
- Capecitabine in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
- Capecitabine monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/sqm of doxorubicin or doxorubicin equivalents. Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.
Dosage of Capecitabine
- Strengths: 150 mg; 500 mg
Breast Cancer
- Monotherapy
1250 mg/m2 orally 2 times a day (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period combined with docetaxel 75 mg/m2 as a 1 hour IV infusion, every 3 weeks - In combination with docetaxel
1250 mg/m2 orally 2 times a day (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period given as 3-week cycles.
Colorectal Cancer
Monotherapy
- For first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred
- 1250 mg/m2 orally 2 times a day (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period given as 3-week cycles
- 250 mg/m2 orally 2 times a day (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period given as 3-week cycles for a total of 8 cycles (24 weeks).
Adult Dose for Breast Cancer
Monotherapy
- 1250 mg/m2 orally 2 times a day (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period combined with docetaxel 75 mg/m2 as a 1 hour IV infusion, every 3 weeks
- 1250 mg/m2 orally 2 times a day (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period given as 3-week cycles
Side Effects of Capecitabine
The Most Common
- Abdominal or stomach pain
- diarrhea
- loss of fingerprints
- nausea
- numbness, pain, tingling, or other unusual sensations in the palms of the hands or bottoms of the feet
- pain, blistering, peeling, redness, or swelling of the palms of the hands or bottoms of the feet
- pain, redness, swelling, sores, or ulcers in your mouth or on your lips
- unusual tiredness or weakness
- vomiting
Common
- Abdominal or stomach cramping or pain (severe)
- agitation
- back pain
- bleeding and bruising
- bleeding gums
- blood in the urine or stools
- blurred vision
- burning, dry, or itching eyes
- chest pain
- clumsiness or unsteadiness
- confusion
- constipation
- convulsions
- a cough or hoarseness (accompanied by fever or chills)
- coughing or spitting up blood
- the difficulty with swallowing or pain in the back of throat or chest when swallowing
- drowsiness
- dry mouth
- extra heartbeats
- eye redness, irritation, or pain
Drug Interactions of Capecitabine
Capecitabine may interact with following drugs, supplements & may change the efficacy of drugs
- adalimumab
- anisindione
- golimumab
- leflunomide
- leucovorin
- levoleucovorin
- multivitamin with minerals
- natalizumab
- pimecrolimus
- teriflunomide
- thalidomide
- tofacitinib
- other cancer medications (e.g., cyclophosphamide, doxorubicin, etoposide)
- sulfamethoxazole
- sulfasalazine
- trastuzumab
- vemurafenib
- verapamil
- voriconazole
- trimethoprim
- vaccines (e.g., yellow fever, BCG, cholera, typhoid, varicella, meningococcal, diphtheria)
- warfarin
Pregnancy & Lactation
FDA Pregnancy Category – D
Pregnancy
This medication may harm the baby if used during pregnancy. Both men and women should use effective birth control (e.g., condoms, birth control pill) during treatment. If you or your partner become pregnant while taking this medication, contact your doctor immediately.
Lactation
It is not known if capecitabine passes into breast milk. Because of the risks associated with this medication, women should not breast-feed while taking capecitabine. The safety and effectiveness of using this medication have not been established for children under 18 years of age.
References
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