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Antitumor agent, antimetabolite. Capecitabine is a fluoropyrimidine carbamate derivative, an oral cytostatic agent that is activated in tumor tissue and has a selective cytotoxic effect on it. In vitro capecitabine has no cytotoxic effect, in vivo it is converted into 5-fluorouracil (5-FU), which undergoes further metabolism. Formation of 5-FU occurs mainly in tumor tissue under the action of tumor angiogenic factor - thymidine phosphorylase, which minimizes the systemic effect of 5-FU on healthy body tissues.
Sequential enzymatic biotransformation of capecitabine into 5-FU creates higher concentrations of the drug in tumor tissues than in the surrounding healthy tissues. After oral administration of capecitabine to patients with colorectal cancer (n=8), the concentration of 5-FU in tumor tissue is 3.2 times higher than its concentration in adjacent healthy tissues (range 0.9 to 8.0).
The ratio of 5-FU concentrations in tumor tissue to plasma was 21.4 (range 3.9 to 59.9), the ratio of its concentration in healthy tissues to plasma was 8.9 (range 3 to 25.8). Thymidine phosphorylase activity in the primary colorectal tumor was also 4 times higher than in the adjacent healthy tissues.
Tumor cells from patients with breast, stomach, colorectal, cervical, and ovarian cancers contain higher levels of thymidine phosphorylase capable of converting 5'-DFUR (5'-deoxy-5-fluoruridine) to 5-FU than the corresponding healthy tissues.
Both healthy and tumor cells metabolize 5-FU into 5-fluoro-2-deoxyuridine monophosphate (FDUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites damage cells through two different mechanisms. First, FDUMF and the folate cofactor N5-10-methyltetrahydrofolate bind to thymidylate synthase (TC) to form a covalently bound tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is an essential precursor of thymidine triphosphate, which, in turn, is crucial for DNA synthesis, so that a lack of it can lead to inhibition of cell division.
Second, during RNA synthesis, nucleus transcriptional enzymes can mistakenly incorporate FUTP instead of uridine triphosphate (UTP). This metabolic "mistake" disrupts RNA processing and protein synthesis.
After oral administration capecitabine is quickly and completely absorbed, after which it is transformed into metabolites - 5'-deoxy-5-fluorocytidine (5'-DFCT) and 5'-DFUR. Food reduces the rate of absorption of capecitabine, but has little effect on the AUC value of 5'-DFCUR and the following metabolite of 5-FU.
When capecitabine was administered after a meal at a dose of 1250 mg/m2 on day 14, the Cmax of capecitabine, 5'-DFTCT, 5'-DFUR, 5-FU and FBL were 4.47, 3.05, 12.1, 0.95 and 5.46 µg/mL, respectively. Tmax was 1.50, 2.00, 2.00, 2.00, and 3.34 hr. AUC0-∞ was 7.75, 7.24, 24.6, 2.03, and 36.3 μg × h/mL, respectively.
An in vitro study in human plasma showed that for capecitabine, 5'-DFCT, 5'-DFUR and 5-FU the binding to proteins (mainly to albumin) was 54%, 10%, 62% and 10%, respectively.
Primarily metabolized in the liver under the influence of carboxylesterase to the metabolite 5'-DFCT, which is then transformed into 5'-DFUR under the influence of cytidine deaminase, located mainly in the liver and tumor tissues. Further transformation to active cytotoxic metabolite 5-FU occurs mainly in tumor tissue under the action of tumor angiogenic factor - thymidine phosphorylase (dTdPhase).
The AUC of 5-FU in plasma is 6-22 times lower than after an intravenous bolus injection of 5-FU at a dose of 600 mg/m2. Capecitabine metabolites become cytotoxic only after conversion to 5-FU and 5-FU metabolites. 5-FU is further catabolized to form the inactive metabolites dihydro-5-fluorouracil (FUN2), 5-fluorouraidopropionic acid (FUPC), and α-fluoro-β-alanine (FBAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.
The T1/2 of capecitabine, 5'-DFCT, 5'-DFUR, 5-FU, and FBAL is 0.85, 1.11, 0.66, 0.76, and 3.23 h, respectively.
The pharmacokinetics of capecitabine were studied at doses ranging from 502 to 3514 mg/m2/day. The pharmacokinetic parameters of capecitabine, 5'-DFCT, and 5'-DFUR on days 1 and 14 were similar. The AUC of 5-FU increased 30-35% by day 14 and did not increase again (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, except for 5-FU, were dose-dependent.
After oral administration of capecitabine its metabolites are excreted mainly in the urine. Most (95.5%) of the administered dose of capecitabine is excreted with the urine. Excretion with the feces is minimal (2.6%). The main metabolite in the urine is FBL, which accounts for 57% of the dose taken. About 3% of the administered dose is excreted unchanged in the urine.
No effect of Xeloda on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and no effect of docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the main metabolite of capecitabine) was found.
Pharmacokinetics in special clinical cases
Gender, presence or absence of liver metastases before treatment, patient's general status index, concentration of total bilirubin, serum albumin, ALT and AST activity had no statistically significant effect on pharmacokinetic properties of 5'-DFUR, 5-FU and FBL.
Patients with hepatic failure due to metastatic liver injury
In patients with mild to moderate hepatic impairment due to metastatic liver injury, there is no clinically significant change in the pharmacokinetics and bioactivation of capecitabine. There are no data on pharmacokinetics in patients with severe hepatic impairment.
Patients with impaired renal function
Results of pharmacokinetic study show that pharmacokinetics of unchanged drug and 5-FU is independent of CKD in patients with various degrees (from mild to severe) of renal impairment. CK affects the AUC of 5'-DFUR (35% increase in AUC when CK decreases by 50%) and FBL (114% increase in AUC when CK decreases by 50%). FBAL is a metabolite with no antiproliferative activity; 5'-DFUR is a direct precursor of 5-FU.
Age has no effect on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBL increased with age (a 20% increase in age of patients was accompanied by a 15% increase in AUC of FBL), which is probably due to changes in renal function.
The pharmacokinetics of Xeloda in patients of Negro race do not differ from those in patients of Caucasoid race.
Contraindications to use
- established DPD (dihydropyrimidine dehydrogenase) deficiency, as for other fluoropyrimidines;
- concomitant administration of sorivudine and its structural analogues such as brivudine;
- severe renal insufficiency (CKR less than 30 ml/min);
- baseline neutrophil count <1.5 × 109/l and/or platelets <100 × 109/l;
- Xeloda should not be administered if there are contraindications to one of the drugs in combination therapy;
- breast-feeding period;
- childhood (efficacy and safety of use have not been established);
- hypersensitivity to capecitabine or any other component of the drug;
- hypersensitivity to fluorouracil or in reported cases of unexpected or severe adverse reactions to treatment with fluoropyrimidine derivatives in history.
Caution should be exercised when the drug is prescribed for CHD, moderate renal failure, hepatic failure, concomitant use with oral coumarin anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption, patients aged over 60 years.
Administration during pregnancy and lactation
The drug is contraindicated for use during pregnancy and lactation.
During Xeloda therapy and for at least 3 months after its termination, reliable contraceptive methods must be used. If pregnancy occurs during therapy, the patient should be informed about potential danger to fetus.
Use in liver dysfunction
In patients with liver metastases and mild to moderate hepatic impairment, the initial dose does not need to be changed. However, these patients should be closely monitored. The drug has not been studied in patients with severe hepatic impairment.
Administration in renal dysfunction
In patients with baseline renal insufficiency of moderate degree of severity (CKD 30-50 ml/min) it is recommended to reduce the initial dose to 75% of standard one. In patients with mild renal insufficiency (CKD 51-80 ml/min) correction of the initial dose is not required. If during the subsequent dose adjustment in accordance with the above table adverse events of grade 2, 3 or 4 toxicity are noted, a temporary withdrawal of the drug and close monitoring of the patient's condition is required. Recommendations for dosage adjustment in moderate renal insufficiency apply to both monotherapy and combination therapy with capecitabine.
It is contraindicated in severe renal failure (CKR less than 30 ml/min).
Administration in children
Contraindication: childhood and adolescence under 18 years (efficacy and safety of use have not been established.
Administration in elderly patients
Caution should be exercised when prescribing the drug in patients over 60 years of age.
Indications for Xeloda
- Combination therapy with docetaxel for locally advanced or metastatic breast cancer, if chemotherapy with an anthracycline fails
- monotherapy of locally advanced or metastatic breast cancer that is resistant to chemotherapy with taxanes or anthracycline-type drugs, or if there are contraindications to them.
- Adjuvant therapy for stage III colorectal cancer after surgical treatment;
- Therapy of metastatic colorectal cancer.
- First-line therapy for advanced gastric cancer.
The drug is taken orally with water, not later than 30 minutes after a meal.
Standard dosing regimen
Colorectal, colorectal and breast cancer
Xeloda is administered on 1250 mg/m2 2 times per day, in the morning and in the evening (total daily dose 2500 mg/m2) during two weeks with a 7-day break.
Xeloda is administered on 1250 mg/m2 2 times per day for two weeks with a 7-day break, in combination with docetaxel in dose of 75 mg/m2 once per 3 weeks as an intravenous infusion during 1 hour.
Premedication is given prior to administration of docetaxel according to the instructions for its use.
Colorectal cancer and gastric cancer
In combination therapy the dose of Xeloda should be decreased up to 800-1000 mg/m2 2 times per day for two weeks followed by a seven-day break or up to 625 mg/m2 2 times per day in continuous regimen. The addition of immunobiological agents to combination therapy does not affect the dose of Xeloda.
Antiemetics and premedication to ensure adequate hydration are administered before the administration of cisplatin and oxaliplatin according to the instructions for use of cisplatin and oxaliplatin when used in combination with Xeloda.
In adjuvant therapy of stage III colorectal cancer the recommended duration of therapy with Xeloda is 6 months, i.e. 8 courses.
In combination with cisplatin.
It is administered on 1000 mg/m2 2 times per day during two weeks with 7-day break in combination with cisplatin (80 mg/m2 once in 3 weeks, by infusion during 2 hours, the first infusion is administered on the first day of a cycle). The first dose of Xeloda® is administered in the evening on the first day of the therapy cycle, the last dose on the morning of day 15.
In combination with oxaliplatin and/or bevacizumab
It is administered at 1000 mg/m2 twice a day for two weeks followed by a seven-day break in combination with oxaliplatin and/or bevacizumab. The first dose of Xeloda is administered in the evening on the first day of the treatment cycle and the last dose on the morning of day 15. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, by IV infusion for 30-90 minutes, with the first infusion starting on the first day of the cycle. After bevacizumab, oxaliplatin is administered at a dose of 130 mg/m2, IV infusion for 2 h.
In combination with epirubicin and a platinum-based drug
Administered at 625 mg/m2 2 times/day in a continuous regimen in combination with epirubicin (50 mg/m2 once every 3 weeks, by IV bolus from day 1 of the cycle) and a platinum-based drug. The platinum-based drug (cisplatin at a dose of 60 mg/m2 or oxaliplatin at a dose of 130 mg/m2) should be given on the first day of the cycle as an IV infusion for 2 hours, then once every 3 weeks.
In combination with irinotecan.
Administered as 1000 mg/m2 2 times/day for 2 weeks followed by a 7-day break in combination with irinotecan (250 mg/m2 once every 3 weeks, IV infusion for 30 min, first infusion administered on the first day of the cycle).
In combination with irinotecan and bevacizumab
Administered at 800 mg/m2 twice daily for two weeks followed by a seven-day break in combination with irinotecan and bevacizumab. Irinotecan is administered at a dose of 200 mg/m2 once every 3 weeks, by IV infusion for 30 minutes, the first infusion on the first day of the cycle. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, IV infusion for 30-90 min, with the first infusion starting on the first day of the cycle.
The tables below show examples of standard and reduced dose calculations for Xeloda® for an initial dose of 1,250 mg/m2 or 1,000 mg/m2.
General recommendations for combination therapy
If toxicity occurs during combination therapy, the recommendations for adjusting the dose of Xeloda in Table 3 above and the corresponding recommendations in the instructions for use of other drugs should be followed.
At the beginning of the therapy cycle, if Xeloda or other drug(s) are expected to be delayed, all drugs should be delayed until conditions for resuming therapy with all drugs are met.
If, in the opinion of the physician, toxicity is not related to the use of Xeloda during the combination therapy cycle, Xeloda should be continued and the dose of the other drug should be adjusted according to the recommendations in the instructions for its use.
If the other drug(s) have to be discontinued, treatment with Xeloda can be continued if the requirements for resumption of Xeloda therapy are met.
These recommendations apply for all indications and all special patient groups.