Cabecin 500 mg 120 coated tablets

Breast Cancer

• Combined therapy with docetaxel for locally advanced or metastatic breast cancer when chemotherapy including anthracycline agents is ineffective;

• Monotherapy for locally advanced or metastatic breast cancer resistant to chemotherapy with taxanes or anthracycline agents, or in the presence of contraindications to them.

Colorectal Cancer

• Adjuvant therapy for stage III colon cancer after surgical treatment;

• Treatment of metastatic colorectal cancer.

Stomach Cancer

• First-line therapy for advanced stomach cancer.

Contraindications

• Hypersensitivity to capecitabine or any other components of the drug;

• Hypersensitivity to fluorouracil or in cases of unexpected or severe adverse reactions to fluoropyrimidine derivatives in the medical history;

• Established DPD (dihydropyrimidine dehydrogenase) deficiency, as with other fluoropyrimidines;

• Simultaneous use of sorivudine or its structural analogs such as brivudine;

• Severe liver failure, leukopenia;

• Severe renal failure (creatinine clearance below 30 ml/min);

• Baseline neutrophil count

Orally, with water, no later than 30 minutes after a meal.
Standard dosing regimen
Monotherapy
Colorectal cancer, colon cancer, and breast cancer
1250 mg/m² twice daily - in the morning and evening (total daily dose 2500 mg/m²) for 14 days followed by a seven-day break.
Combination therapy
Breast cancer
1250 mg/m² twice daily for 14 days followed by a seven-day break, in combination with docetaxel at a dose of 75 mg/m² once every three weeks as an intravenous infusion over 1 hour.
Premedication is administered before the administration of docetaxel according to its usage instructions.
Colorectal cancer and stomach cancer
In combination therapy (except therapy in combination with irinotecan), the dose of Capecitabine is up to 800-1000 mg/m² twice daily for 14 days followed by a seven-day break or up to 625 mg/m² twice daily in a continuous regimen.
In combination therapy with irinotecan (XELIRI regimen - capecitabine and irinotecan), the recommended dose of capecitabine is 800 mg/m² twice daily for 14 days followed by a seven-day break. The addition of bevacizumab to combination therapy does not affect the initial dose of Capecitabine.
Antiemetics and premedication for adequate hydration are prescribed before the administration of cisplatin and oxaliplatin according to the instructions for the use of cisplatin and oxaliplatin when used in combination with Capecitabine.
In adjuvant therapy for stage III colon cancer, the recommended duration of therapy with Capecitabine is 6 months, i.e., 8 cycles.
In combination with cisplatin
1000 mg/m² twice daily for 14 days followed by a seven-day break in combination with cisplatin (80 mg/m² once every 3 weeks, IV infusion over 2 hours, the first infusion is administered on the first day of the cycle). The first dose of Capecitabine is administered in the evening on the first day of the treatment cycle, the last dose in the morning on day 15.
In combination with oxaliplatin or with oxaliplatin and bevacizumab
1000 mg/m² twice daily for 14 days followed by a seven-day break in combination with oxaliplatin or with oxaliplatin and bevacizumab. The first dose of Capecitabine is administered in the evening on the first day of the treatment cycle, the last dose in the morning on day 15. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, IV infusion over 30-90 minutes, the first infusion is administered on the first day of the cycle. After bevacizumab, oxaliplatin is administered at a dose of 130 mg/m², IV infusion over 2 hours.
In combination with epirubicin and a platinum-based drug
625 mg/m² twice daily in a continuous regimen in combination with epirubicin (50 mg/m² once every 3 weeks, IV bolus, starting on the first day 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 administered on the first day of the cycle as an IV infusion over 2 hours, then once every 3 weeks.
In combination with irinotecan or with irinotecan and bevacizumab
The recommended dose of Capecitabine is 800 mg/m² twice daily for 14 days followed by a seven-day break in combination with irinotecan or with irinotecan and bevacizumab.
Irinotecan is administered at a dose of 200 mg/m² once every 3 weeks, IV infusion over 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 over 30-90 minutes, the first infusion starts on the first day of the cycle.
The tables below show examples of calculating the standard and reduced doses of Capecitabine for an initial dose of 1250 mg/m² or 1000 mg/m².

Table 1. Standard and reduced doses of Capecitabine for an initial dose of 1250 mg/m², calculated based on body surface area
Dose - 1250 mg/m² twice daily
Total dose 1250 mg/m² Number of tablets 150 mg and/or 500 mg per dose (for each dose 2 times a day - morning and evening) Reduced dose (75% of initial dose) 950 mg/m² Reduced dose (50% of initial dose) 625 mg/m²
Body surface area (m²) Dose per dose (mg) 150 mg 500 mg Dose per dose (mg) Dose per dose (mg)
≤1.26 1500 - 3 1150 800
1.27-1.38 1650 1 3 1300 800
1.39-1.52 1800 2 3 1450 950
1.53-1.66 2000 - 4 1500 1000
1.67-1.78 2150 1 4 1650 1000
1.79-1.92 2300 2 4 1800 1150
1.93-2.06 2500 - 5 1950 1300
2.07-2.18 2650 1 5 2000 1300
≥2.19 2800 2 5 2150 1450

Table 2. Standard and reduced doses of Capecitabine for an initial dose of 1000 mg/m², calculated based on body surface area.
Dose - 1000 mg/m² twice daily
Total dose 1000 mg/m² Number of tablets 150 mg and/or 500 mg per dose (for each dose 2 times a day - morning and evening) Reduced dose (75% of initial dose) 750 mg/m² Reduced dose (50% of initial dose) 500 mg/m²
Body surface area (m²) Dose per dose (mg) 150 mg 500 mg Dose per dose (mg) Dose per dose (mg)
≤1.26 1150 1 2 800 600
1.27-1.38 1300 2 2 1000 600
1.39-1.52 1450 3 2 1100 750
1.53-1.66 1600 4 2 1200 800
1.67-1.78 1750 5 2 1300 800
1.79-1.92 1800 2 3 1400 900
1.93-2.06 2000 - 4 1500 1000
2.07-2.18 2150 1 4 1600 1050
≥2.19 2300 2 4 1750 1100

Dose adjustment during treatment
General recommendations
Toxic effects of Capecitabine can be managed with symptomatic therapy and/or dose adjustment (by interrupting treatment or reducing the dose). If the dose has been reduced, it should not be increased subsequently.
If, in the treating physician's assessment, the toxic effect of Capecitabine is not serious or life-threatening, treatment may continue at the initial dose without reduction or interruption of therapy.
In cases of grade 1 toxicity, the dose remains unchanged. In cases of grade 2 or 3 toxicity, therapy with Capecitabine should be interrupted.
If signs of toxicity resolve or decrease to grade 1, therapy with Capecitabine may be resumed at full dose or adjusted according to the recommendations in Table 3.
In cases of grade 4 toxicity, treatment should be discontinued or temporarily interrupted until symptoms resolve or decrease to grade 1, after which the drug may be resumed at a dose of 50% of the initial dose. The patient must immediately inform the physician of any adverse events that occur. Capecitabine should be immediately discontinued in cases of severe or moderate toxicity. If several doses of Capecitabine have been missed due to toxic effects, those doses are not made up.
Hematological toxicity
Capecitabine therapy should not be initiated in patients with a baseline neutrophil count < 1.5 x 10⁹ and/or a baseline platelet count < 100 x 10⁹/L. Capecitabine treatment should be interrupted if during an unscheduled assessment of laboratory parameters the neutrophil count drops below 1.0 x 10⁹/L and the platelet count drops below 75 x 10⁹/L (hematological toxicity grade 3 or 4). The table below provides recommendations for dose adjustment of Capecitabine in the event of toxic effects associated with its use.Table 3. Dose adjustment scheme for Capecitabine. Toxicity grade NCIC* Dose adjustment during the treatment cycle Dose adjustment during the next treatment cycle (% of initial dose) Grade 1 Continue at the same dose Continue at the same dose Grade 2 1st occurrence Interrupt therapy until resolution to grade 0-1 100% 2nd occurrence 75% 3rd occurrence 50% 4th occurrence Discontinue therapy completely Not applicable Grade 3 1st occurrence Interrupt therapy until resolution to grade 0-1 75% 2nd occurrence 50% 3rd occurrence Discontinue therapy completely Not applicable Grade 4 1st occurrence Discontinue therapy completely OR, if the physician believes it is in the patient's best interest to continue treatment, interrupt therapy until resolution to grade 0-1 50% 2nd occurrence Discontinue therapy completely Not applicable *According to the general toxicity criteria of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG, version 1) or the common terminology criteria for adverse events of the National Cancer Institute of the USA (CTCAE, version 3). Criteria for hand-foot syndrome and hyperbilirubinemia are detailed in the "Special Instructions" section.General recommendations for combination therapy In cases of toxicity during combination therapy, the recommendations for dose adjustment of Capecitabine outlined above in Table 3 and the corresponding recommendations in the instructions for use of other drugs should be followed. At the beginning of the treatment cycle, if a delay in the administration of Capecitabine or other drug(s) is anticipated, the administration of all drugs should be postponed until conditions for resuming therapy with all drugs are met. If during the cycle of combination therapy, the toxicity is deemed by the physician to be unrelated to the use of Capecitabine, therapy with Capecitabine should be continued, and the dose of the other drug should be adjusted according to the recommendations in its instructions for use. If another drug(s) must be discontinued, treatment with Capecitabine may continue if the requirements for resuming therapy with Capecitabine are met. These recommendations apply to all indications and all special patient groups. Dose adjustment in special cases Liver function impairment in patients with liver metastases No change in the initial dose is required for patients with liver metastases and mild to moderate liver function impairment. However, these patients should be closely monitored. The use of the drug in patients with severe liver failure has not been studied. Kidney function impairment It is recommended to reduce the initial dose to 75% of 1250 mg/m² in patients with baseline moderate renal impairment (creatinine clearance 30-50 mL/min, using the Cockcroft-Gault formula); no dose adjustment is required for an initial dose of 1000 mg/m². In patients with mild renal impairment (creatinine clearance 51-80 mL/min), no adjustment of the initial dose is required. In cases of grade 2, 3, or 4 adverse events, careful monitoring is necessary, and immediate interruption of therapy is required for subsequent dose adjustment according to the recommendations in Table 3. If the calculated creatinine clearance drops below 30 mL/min during therapy, treatment with Capecitabine should be discontinued. The recommendations for dose adjustment in moderate renal impairment apply to both monotherapy and combination therapy. Dose calculations are provided in Tables 1 and 2. Children The safety and efficacy of Capecitabine in children have not been established. Elderly patients No adjustment of the initial dose is required for monotherapy with Capecitabine. However, severe adverse events of grade 3 and 4 related to therapy occurred more frequently in patients over 80 years of age than in younger patients. When using Capecitabine in combination with other antitumor drugs in elderly patients (aged ≥65 years), grade 3 and 4 adverse reactions, as well as adverse reactions requiring therapy discontinuation, were observed more frequently than in younger patients. Careful monitoring of elderly patients is recommended. In treatment in combination with docetaxel, an increase in the frequency of grade 3 and 4 adverse events and serious adverse events related to therapy was noted in patients aged 60 years and older. For patients aged 60 years and older who will receive a combination of Capecitabine with docetaxel, it is recommended to reduce the initial dose of Capecitabine to 75% (950 mg/m² twice daily). Dose calculations are provided in Table 1. If no signs of toxicity occur, the dose may be increased to 1250 mg/m² twice daily. In treatment in combination with irinotecan, for patients aged 65 years and older, it is recommended to reduce the initial dose of Capecitabine to 800 mg/m² twice daily.

Composition per tablet:
Active ingredient:
Capecitabine 500.00 mg
Excipients:
Microcrystalline cellulose, type 102 73.50 mg
Pre-gelatinized corn starch 30.30 mg
Croscarmellose sodium 15.80 mg
Povidone K-30 22.70 mg
Croscarmellose sodium 10.80 mg
Colloidal silicon dioxide 1.50 mg
Magnesium stearate 5.00 mg
Core tablet weight 659.60 mg
Film coating:
Opadry II blue:
Partially hydrolyzed polyvinyl alcohol 40.00 %
Titanium dioxide 20.00 %
Macrogol - 3350 20.20 %
Talc 14.80 %
Aluminum lake based on indigo carmine (11-14% solution) (E132) 5.00 %
Weight of the film-coated tablet 680.00 mg

Oblong biconvex tablets coated with a blue film, engraved with "500" on one side and a stylized company logo on the other side. The core is white in cross-section.

• hypersensitivity to capecitabine or any other components of the drug;

• hypersensitivity to fluorouracil or in cases of documented unexpected or severe adverse reactions to treatment with fluoropyrimidine derivatives in the medical history;

• established DPD (dihydropyrimidine dehydrogenase) deficiency, as with other fluoropyrimidines;

• simultaneous use of sorivudine or its structural analogs such as brivudine;

• severe liver failure, leukopenia;

• severe renal failure (creatinine clearance below 30 ml/min);

• baseline neutrophil count

The side effects that limit the dosage of the drug include diarrhea, abdominal pain, nausea, stomatitis, and hand-foot syndrome.
Careful medical monitoring for signs of toxicity is required in patients receiving capecitabine therapy.
Most adverse events are reversible and do not require complete discontinuation of the drug, although dose adjustment or temporary discontinuation may be necessary.
Diarrhea. Treatment with Capecitabine can cause diarrhea, sometimes severe. Patients with severe diarrhea should be closely monitored, and in cases of dehydration, rehydration and electrolyte replacement should be performed. Standard anti-diarrheal medications (e.g., loperamide) should be prescribed as soon as possible based on medical indications. According to the criteria of the National Cancer Institute of Canada (NCIC, CTC, version 2), grade 2 diarrhea is defined as an increase in bowel movements to 4-6 times per day or bowel movements at night; grade 3 diarrhea is defined as an increase in bowel movements to 7-9 times per day or incontinence and malabsorption syndrome; grade 4 diarrhea is defined as an increase in bowel movements to 10 or more times per day, the presence of visible blood in the stool, or the need for parenteral supportive therapy. If necessary, the dose of capecitabine should be reduced.
Dehydration. Dehydration should be prevented or addressed at the onset. Dehydration can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea.
Dehydration can lead to acute renal failure, in some cases with fatal outcomes, especially in patients with impaired kidney function at the start of therapy or if the patient is taking capecitabine concurrently with nephrotoxic drugs.
In cases of grade 2 dehydration or higher, capecitabine treatment should be immediately discontinued, and rehydration should be performed. Treatment cannot be resumed until rehydration is complete and the factors causing it have been resolved or corrected. The drug dose should be modified according to the recommendations for adverse events that led to dehydration.
The spectrum of cardiotoxicity associated with capecitabine treatment is similar to that of other fluoropyrimidines and includes myocardial infarction, angina, arrhythmias, cardiac arrest, heart failure, and ECG changes. These adverse events are more characteristic in patients with a history of coronary artery disease. Caution is advised in patients with a history of arrhythmias and angina.
During capecitabine therapy, hypo- or hypercalcemia has been observed. Caution is advised in patients with previously diagnosed hypo- or hypercalcemia.
Caution is also advised in patients with central and peripheral nervous system diseases (e.g., with brain metastases and neuropathy), as well as in patients with diabetes and electrolyte imbalances, as capecitabine treatment may exacerbate these conditions.
Dihydropyrimidine dehydrogenase deficiency. In rare cases, unexpected severe toxicity events (e.g., stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity) associated with fluorouracil (5-FU) are due to insufficient activity of dihydropyrimidine dehydrogenase (DPD). Patients with significant reduction or complete absence of DPD activity (an enzyme involved in the breakdown of 5-FU) are at increased risk of severe life-threatening or fatal adverse reactions due to 5-FU use. The highest risk of life-threatening or fatal toxicity events is noted in patients with certain homozygous or specific sets of heterozygous mutations in the DPYD gene locus, causing complete or partial DPD deficiency. Such patients should not be prescribed capecitabine therapy. For patients with complete DPD deficiency, there are no doses that meet the safety profile. In patients with partial DPD deficiency, if the benefits of capecitabine therapy (considering the possibility of using alternative non-fluoropyrimidine chemotherapy regimens) outweigh the potential risks, special caution should be exercised. In such patients, the initial dose of the drug should be significantly reduced, and sequential monitoring and dose adjustment should be performed based on toxicity manifestations. In patients with undiagnosed DPD deficiency receiving capecitabine therapy, life-threatening toxicity events may occur, manifesting as symptoms of acute overdose. In cases of acute toxicity of grade 2-4, therapy should be immediately discontinued. The decision to completely discontinue therapy should be based on a clinical assessment of the onset, duration, and severity of the observed toxicity events.
Patients should be monitored for the development of ophthalmological complications, such as keratitis or corneal pathology, especially if there is a history of eye disorders. In the event of complications related to the eye, appropriate treatment should be initiated.
Capecitabine may cause serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). If severe skin reactions occur during capecitabine use, the drug should be discontinued and not resumed.
A manifestation of capecitabine skin toxicity is the development of hand-foot syndrome (synonyms - hand-foot erythrodysesthesia or chemotherapy-induced acral erythema). The median time to the onset of toxicity in patients receiving monotherapy with capecitabine is 79 days (ranging from 11 to 360 days), and the severity varies from grade 1 to grade 3. Grade 1 hand-foot syndrome does not interfere with the patient's daily activities and is characterized by numbness, dysesthesias/paresthesias, tingling, or redness of the palms and/or soles, and discomfort. Grade 2 hand-foot syndrome is characterized by painful redness and swelling of the hands and/or feet, with discomfort from these symptoms interfering with the patient's daily activities. Grade 3 hand-foot syndrome is defined as moist desquamation, ulceration, blister formation, and severe pain in the hands and/or feet, as well as significant discomfort that makes any form of daily activity impossible for the patient. In cases of grade 2 or 3 hand-foot syndrome, capecitabine therapy should be interrupted until symptoms resolve or decrease to grade 1. In cases of grade 3 syndrome, subsequent doses of capecitabine should be reduced.
Vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of hand-foot syndrome when capecitabine is administered in combination with cisplatin, as it may reduce the effectiveness of cisplatin. There is evidence of the effectiveness of dexpanthenol in preventing the development of hand-foot syndrome during capecitabine therapy.
Capecitabine may cause hyperbilirubinemia. If hyperbilirubinemia >3.0 x ULN (upper limit of normal) or an increase in "liver" aminotransferase activity (ALT, AST) >2.5 x ULN is noted due to capecitabine treatment, therapy should be discontinued. Therapy can be resumed when bilirubin levels and "liver" aminotransferase activity fall below the specified thresholds.
Patients concurrently taking capecitabine and oral anticoagulants - coumarin derivatives should have their coagulation parameters (prothrombin time or INR) monitored and the anticoagulant dose adjusted accordingly.
Use of the drug in elderly and geriatric patients
The frequency of gastrointestinal toxicities in patients with colorectal cancer aged 60-79 years receiving monotherapy with capecitabine did not differ from that in the general patient population. In patients aged 80 years and older, reversible adverse events of grade 3 and 4, such as diarrhea, nausea, and vomiting, occurred more frequently. In patients aged 65 years and older receiving combination therapy with capecitabine and other antitumor agents, there was an increase in the frequency of grade 3 and 4 adverse reactions and adverse events leading to treatment discontinuation compared to patients younger than 65 years.
In the analysis of safety data in patients aged 60 years and older receiving combination therapy with capecitabine and docetaxel, an increase in the frequency of therapy-related adverse events of grade 3 and 4 severity, serious adverse events, and early treatment discontinuation due to adverse events was noted compared to patients younger than 60 years.
Renal insufficiency
Caution should be exercised when prescribing capecitabine to patients with moderate renal insufficiency. As with fluorouracil treatment, the frequency of therapy-related adverse events of grade 3 and 4 severity was higher in patients with moderate renal insufficiency (creatinine clearance 30-50 mL/min).
Hepatic insufficiency
Patients with hepatic insufficiency during capecitabine therapy should be under careful medical supervision. The effect of liver function impairment, not due to metastatic liver involvement or severe hepatic insufficiency, on the distribution of capecitabine is unknown.
During capecitabine therapy and for at least 3 months after its completion, reliable methods of contraception should be used. If pregnancy occurs during therapy, the patient should be informed of the potential risk to the fetus.
Disposal of unused drug and expired medications
Minimize the release of the drug into the environment along with waste. Do not dispose of the drug via wastewater or with household waste. Whenever possible, use special systems for the disposal of medications.

Effect of the drug on the ability to drive vehicles and operate machinery
Capecitabine has a minor or moderate effect on the ability to drive vehicles and operate machinery. Patients who experience adverse events such as dizziness, weakness, or nausea should refrain from driving vehicles or operating machinery.

The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100 and

Symptoms of acute overdose include nausea, vomiting, diarrhea, mucosal inflammation (mucositis), gastrointestinal tract irritation and bleeding, as well as bone marrow function suppression.
Treatment of overdose should include a standard set of therapeutic and supportive measures aimed at correcting clinical symptoms and preventing possible complications.

Anticoagulants of the coumarin group. In patients taking capecitabine simultaneously with anticoagulants of the coumarin group (warfarin and fenprocoumon), disturbances in coagulation parameters and/or bleeding have been reported several days or months after the start of capecitabine therapy, and in some cases, within one month after its completion. In a drug interaction study, after a single dose of warfarin at 20 mg, capecitabine increased the AUC of S-warfarin by 57%, and the international normalized ratio (INR) by 91%. Patients taking capecitabine and anticoagulants of the coumarin group should be closely monitored for coagulation parameters (prothrombin time or INR), and the dose of the anticoagulant should be adjusted according to these parameters.

CYP2C9 isoenzyme substrates. Specific studies on the drug interaction of capecitabine with other drugs metabolized by the CYP2C9 isoenzyme of the cytochrome P450 system have not been conducted. Caution should be exercised when prescribing capecitabine together with these drugs.

Phenytoin. Co-administration of capecitabine and phenytoin has been reported to increase the concentration of the latter in plasma. Specific studies on the drug interaction of capecitabine and phenytoin have not been conducted; however, it is assumed that the mechanism of interaction is based on the inhibition of the CYP2C9 isoenzyme by capecitabine (see above "Anticoagulants of the coumarin group"). Patients receiving both phenytoin and capecitabine should have their phenytoin plasma concentration regularly monitored.

Antacids. When evaluating the pharmacokinetic parameters of capecitabine when taken simultaneously with antacids containing aluminum hydroxide and magnesium hydroxide, a slight increase in the concentration of capecitabine and one of its metabolites (5'-DFCT) in the blood plasma was noted. The three main metabolites of capecitabine (5'-DFUR, FU, and FBAL) were not affected by the studied agents.

Allopurinol. Co-administration of allopurinol and capecitabine should be avoided, as it may reduce the effectiveness of fluorouracil due to the interaction of fluorouracil with allopurinol.

Interferon alpha. The maximum tolerated dose of capecitabine in combination with interferon 2-alpha (3 million international units/m² per day) was 2000 mg/m² per day, while the maximum tolerated dose of capecitabine as monotherapy was 3000 mg/m² per day.

Radiation therapy. The maximum tolerated dose of capecitabine in combination with radiation therapy for patients with rectal cancer was 2000 mg/m² per day (in a continuous therapy regimen or in a regimen from Monday to Friday with a 6-day course of radiation therapy), while the maximum tolerated dose of capecitabine as monotherapy was 3000 mg/m² per day (intermittent regimen).

Calcium folinate (Leucovorin). Calcium folinate does not affect the pharmacokinetic properties of capecitabine and its metabolites. However, it may enhance the toxic effect of capecitabine due to its influence on the pharmacodynamics of capecitabine.

Sorivudine and its analogs. Clinically significant drug interaction between sorivudine and FU has been described in the literature, based on the inhibitory effect of sorivudine on DPD. This interaction may lead to a fatal enhancement of the toxicity of fluoropyrimidines. Therefore, capecitabine should not be prescribed simultaneously with sorivudine or its structural analogs such as brivudine. A minimum four-week interval should be observed between the end of therapy with sorivudine or its structural analogs (including brivudine) and the start of treatment with capecitabine.

Oxaliplatin. No clinically significant difference in the exposure of capecitabine or metabolites of oxaliplatin (free platinum or total platinum) has been noted with the combined use of capecitabine and oxaliplatin, regardless of the presence of bevacizumab.

Bevacizumab. No clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites has been noted.

Capecitabine is a carbamate derivative of fluoropyrimidine, an oral cytostatic that is activated in tumor tissue and exerts selective cytotoxic effects on it. In vitro, capecitabine does not have a cytotoxic effect; in vivo, it is converted to fluorouracil (FU), which undergoes further metabolism. The formation of FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase, which minimizes the systemic impact of FU on healthy tissues of the body.

The sequential enzymatic biotransformation of capecitabine to FU creates higher concentrations of the drug in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine to patients with colorectal cancer (N=8), the concentration of FU in tumor tissue is 3.2 times greater than its concentration in adjacent healthy tissues (range from 0.9 to 8.0).

The ratio of FU concentrations in tumor tissue to plasma is 21.4 (range from 3.9 to 59.9), while the ratio of its concentration in healthy tissues to plasma is 8.9 (range from 3.0 to 25.8). The activity of thymidine phosphorylase in primary colorectal tumors is also 4 times higher than in adjacent healthy tissues.

In tumor cells of patients with breast cancer, stomach cancer, colorectal cancer, cervical cancer, and ovarian cancer, there is a higher level of thymidine phosphorylase capable of converting 5'-DFUR (5'-deoxy-5-fluorouridine) to FU than in the corresponding healthy tissues.

Both healthy and tumor cells metabolize FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites damage cells through two different mechanisms. First, FdUMP and the folate cofactor N5-10-methylenetetrahydrofolate bind to thymidylate synthase (TS) to form a covalently linked tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is a necessary precursor of thymidine triphosphate, which is critically important for DNA synthesis, so a deficiency of this substance can lead to the suppression of cell division. Second, during RNA synthesis, nuclear transcription enzymes may mistakenly incorporate FUTP instead of uridine triphosphate (UTP). This metabolic "error" disrupts RNA processing and protein synthesis.

Absorption
After oral administration, capecitabine is rapidly and completely absorbed, after which it is transformed into the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCT) and 5'-DFUR. Food decreases the absorption rate of capecitabine; however, it has a negligible effect on the area under the concentration-time curve (AUC) of 5'-DFUR and the subsequent metabolite, FU. When capecitabine is administered after a meal at a dose of 1250 mg/m² on day 14, the maximum plasma concentrations (Cmax) of capecitabine, 5'-DFCT, 5'-DFUR, FU, and FBAL were 4.47, 3.05, 12.1, 0.95, and 5.46 µg/ml, respectively. The time to reach maximum concentration (Tmax) was 1.50, 2.00, 2.00, 2.00, and 3.34 hours. AUC0-? was 7.75, 7.24, 24.6, 2.03, and 36.3 µg × h/ml, respectively.
Distribution (Protein Binding)
In vitro studies in human plasma showed that for capecitabine, 5'-DFCT, 5'-DFUR, and FU, the protein binding (mainly to albumin) is 54%, 10%, 62%, and 10%, respectively.
Metabolism
Capecitabine is primarily metabolized in the liver by carboxylesterase to the metabolite 5'-DFCT, which is then transformed into 5'-DFUR by cytidine deaminase, predominantly found in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite FU occurs mainly in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase.
The AUC for FU in plasma is 6-22 times lower than after intravenous bolus administration of FU at a dose of 600 mg/m². The metabolites of capecitabine become cytotoxic only after conversion to FU and FU metabolites.
Subsequently, FU is catabolized to form inactive metabolites - dihydro-5-fluorouracil (FUN2), 5-fluorouridine propionic acid (FUPA), and β-fluoro-β-alanine (FBAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), the activity of which limits the reaction rate.
Excretion
The half-life (t1/2) of capecitabine, 5'-DFCT, 5'-DFUR, FU, and FBAL is 0.85, 1.11, 0.66, 0.76, and 3.23 hours, respectively. The pharmacokinetics of capecitabine have been studied at doses ranging from 502 to 3514 mg/m² per day. The pharmacokinetic parameters of capecitabine, 5'-DFCT, and 5'-DFUR on days 1 and 14 were the same. The AUC of FU increased by 30-35% by day 14 and did not increase further (day 22). Within the therapeutic dose range, the pharmacokinetic parameters of capecitabine and its metabolites, except for FU, were dose-dependent.
After oral administration of capecitabine, its metabolites are primarily excreted in urine. The majority (95.5%) of the administered dose of capecitabine is excreted in urine. Fecal excretion is minimal (2.6%). The main metabolite in urine is FBAL, accounting for 57% of the administered dose. About 3% of the administered dose is excreted unchanged in urine.
Combination Therapy
No effect of capecitabine on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC), nor any effect of docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the main metabolite of capecitabine) was found.
Pharmacokinetics in Special Clinical Groups
Gender, presence or absence of liver metastases before treatment, patient performance status index, total bilirubin concentration, serum albumin, AST and ALT activity did not have a statistically significant effect on the pharmacokinetic properties of 5'-DFUR, FU, and FBAL.
Patients with Liver Dysfunction Due to Metastatic Liver Involvement
In patients with mild to moderate liver function impairment due to metastases, there is no clinically significant change in the bioactivation and pharmacokinetics of capecitabine. Data on pharmacokinetics in patients with severe liver dysfunction are lacking.
Patients with Renal Dysfunction
Pharmacokinetic study results show that in varying degrees (from mild to severe) of renal insufficiency, the pharmacokinetics of the unchanged drug and FU are independent of creatinine clearance (CC). CC affects the AUC of 5'-DFUR - the direct precursor of FU (AUC increases by 35% with a 50% reduction in CC) and FBAL (AUC increases by 114% with a 50% reduction in CC). FBAL is a metabolite that does not possess anti-proliferative activity; 5'-DFUR is the direct precursor of FU.
Elderly Patients
Age does not affect the pharmacokinetics of 5'-DFUR and FU. The AUC of FBAL increased with age (an increase in patient age by 20% was accompanied by a 15% increase in AUC of FBAL), which is likely due to changes in kidney function.
Race
The pharmacokinetics of capecitabine in patients of African descent did not differ from that in patients of Caucasian descent.