Kaxita

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CAXETA (CAXETA)

Composition:

Active substance: capecitabine;

One film-coated tablet contains 500 mg of capecitabine;

Excipients: microcrystalline cellulose, sodium croscarmellose, hypromellose 2910, anhydrous lactose, talc, magnesium stearate, Opadry II Orange 30F530001 [hypromellose; lactose monohydrate; titanium dioxide (E 171); polyethylene glycol PEG 4000; iron oxide yellow (E 172); iron oxide red (E 172)].

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex, oval-shaped, film-coated tablets of peach color, with "500" embossed on one side and smooth on the other.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01B C06.

Pharmacological Properties

Pharmacodynamics

Capecitabine is a non-cytotoxic fluoropyrimidine carbamate and an oral prodrug of the cytotoxic agent 5-fluorouracil (5-FU). Capecitabine is activated through a multi-enzyme process. The final conversion to 5-FU occurs under the action of thymidine phosphorylase in tumor tissue as well as in healthy tissues of the body, although generally at low levels. In human cancer xenograft models, capecitabine demonstrated a synergistic effect in combination with docetaxel, which may be related to docetaxel-induced upregulation of thymidine phosphorylase activity.

Evidence indicates that the anabolic metabolism of 5-FU inhibits the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with deoxyribonucleic acid (DNA) synthesis. Incorporation of 5-FU also suppresses RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, 5-FU can cause thymidine deficiency, leading to unbalanced growth and cell death. Effects on DNA and RNA are more pronounced in cells with higher proliferative activity and greater 5-FU metabolism.

Pharmacokinetics

The pharmacokinetics of capecitabine were evaluated over a dose range of 502–3514 mg/m²/day. Pharmacokinetic parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) on day 1 and day 14 were similar. On day 14, the AUC of 5-FU was 30–35% higher. Dose reduction of capecitabine resulted in a greater-than-proportional decrease in 5-FU exposure due to the nonlinear pharmacokinetics of the active metabolite.

Absorption

After oral administration, capecitabine is rapidly and completely absorbed and undergoes biotransformation into metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Food intake reduces the rate of absorption of capecitabine but has no significant effect on the area under the concentration–time curve (AUC) of 5'-DFUR and the subsequent metabolite 5-FU. When administered at a dose of 1250 mg/m² after food intake on day 14, maximum plasma concentrations (C_max) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL were 4.67, 3.05, 12.1, 0.95, and 5.46 µg/mL, respectively. Time to maximum concentration (T_max) was 1.50, 2.00, 2.00, 2.00, and 3.34 hours, and AUC was 7.75, 7.24, 24.6, 2.03, and 36.3 µg×h/mL, respectively.

Distribution

In vitro human plasma studies demonstrated protein binding (primarily to albumin) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU at 54%, 10%, 62%, and 10%, respectively.

Metabolism

Capecitabine is metabolized in the liver by carboxylesterase to the metabolite 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, primarily located in the liver and tumor tissues. Further catalytic activation of 5'-DFUR occurs via thymidine phosphorylase. The enzymes involved in catalytic activation are present in both tumor and normal tissues, although generally at lower levels. Subsequent enzymatic biotransformation of capecitabine to 5-FU results in higher concentrations in tumor tissues. In colorectal tumors, a significant portion of 5-FU is localized in stromal cells of the tumor. After oral administration of capecitabine to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumors to that in adjacent normal tissue was 3.2 (range: 0.9–8.0). The tumor-to-plasma concentration ratio of 5-FU was 21.4 (range: 3.9–59.9, N = 8), while the normal tissue-to-plasma concentration ratio was 8.9 (range: 3.0–25.8, N = 8). Thymidine phosphorylase activity was four times higher in primary colorectal tumors compared to adjacent normal tissues. Immunohistochemical studies indicate that most thymidine phosphorylase is localized in tumor stromal cells.

Subsequently, 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD) to form the less toxic dihydro-5-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-ureidopropionic acid (FUPA). The final step is the cleavage of FUPA by β-ureidopropionase to α-fluoro-β-alanine (FBAL), which is excreted in urine. DPD activity is the rate-limiting step. DPD deficiency may lead to increased toxicity of capecitabine.

Elimination

The elimination half-life (T_1/2) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL is 0.85, 1.11, 0.66, 0.76, and 3.23 hours, respectively. Capecitabine and its metabolites are primarily eliminated via urine. Renal excretion accounts for 95.5%, fecal excretion for 2.6%. The main urinary metabolite is FBAL, representing 57% of the administered dose. Approximately 3% of the administered dose is excreted unchanged in urine.

Combination Therapy

Phase I studies showed no effect of capecitabine on the pharmacokinetics of docetaxel and paclitaxel (C_max and AUC), and no effect of docetaxel or paclitaxel on the pharmacokinetics of capecitabine and 5'-DFUR.

Pharmacokinetics in Special Clinical Populations

Population pharmacokinetic analysis was performed in 505 patients with colorectal cancer treated with capecitabine at 1250 mg/m² twice daily. Gender, presence or absence of liver metastases at baseline, Karnofsky performance status, total bilirubin, serum albumin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels had no significant effect on the pharmacokinetics of 5'-DFUR, 5-FU, and FBAL.

Patients with hepatic metastases. Pharmacokinetic data indicate that in patients with mild to moderate hepatic impairment due to metastases, bioavailability of capecitabine and exposure to 5-FU may be increased compared to patients without hepatic dysfunction. Pharmacokinetic data in patients with severe hepatic impairment are lacking.

Patients with renal impairment. In oncology patients with varying degrees (mild to severe) of renal impairment, the pharmacokinetics of unchanged drug and 5-FU are independent of creatinine clearance (CrCl). However, CrCl affects the AUC of 5'-DFUR (35% increase in AUC with a 50% reduction in CrCl) and FBAL (114% increase in AUC with a 50% reduction in CrCl). FBAL is a metabolite without antiproliferative activity.

Elderly patients. Population pharmacokinetic analysis, including patients across a wide age range (27–86 years), of whom 234 (46%) were aged 65 years or older, showed that age does not affect the pharmacokinetics of 5'-DFUR and 5-FU. AUC of FBAL increases with age (a 20% increase in age was associated with a 15% increase in FBAL AUC), likely due to age-related changes in renal function.

Ethnic factors. After oral administration of 825 mg/m² capecitabine twice daily for 14 days in Japanese patients (N = 18), C_max of capecitabine was 36% lower and AUC 24% lower compared to Caucasian patients (N = 22). Japanese patients also had 25% lower C_max and 34% lower AUC of FBAL compared to Caucasian patients. The clinical significance of this difference is unknown. No substantial differences in exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU) were observed.

Clinical characteristics.

Indications.

Breast cancer:

• Locally advanced or metastatic breast cancer – the drug is used in combination with docetaxel after ineffective chemotherapy containing anthracycline agents;
• Locally advanced or metastatic breast cancer – the drug is used as monotherapy after ineffective chemotherapy that included taxanes and anthracycline agents, or in the presence of contraindications to anthracycline therapy.

Colorectal cancer:

• Colon cancer – the drug is used in adjuvant therapy after surgical treatment of stage III cancer (Dukes' stage C);
• Metastatic colorectal cancer.

Gastric cancer:

• Used as a first-line treatment for advanced gastric cancer, in combination with platinum-based agents.

Contraindications.

Severe, including unexpected, reactions to fluoropyrimidine therapy in medical history. Hypersensitivity to capecitabine or to any component of the drug, or to fluorouracil. Complete deficiency of dihydropyrimidine dehydrogenase (DPD) activity (see section "Special precautions").

Pregnancy and breastfeeding.

Severe leukopenia, neutropenia, thrombocytopenia.

Severe hepatic dysfunction.

Severe renal impairment (creatinine clearance < 30 mL/min).

Concomitant administration of sorivudine or its structural analogs such as brivudine.

Contraindications to any medicinal product used in combination.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adult patients.

Interaction with other medicinal products

Coumarin anticoagulants. Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), which may lead to coagulation disorders and bleeding several days or months after initiation of capecitabine therapy, and in some cases, within one month after discontinuation of capecitabine. In a clinical pharmacokinetic interaction study, following a single 20 mg dose of S-warfarin, treatment with capecitabine resulted in a 57% increase in warfarin AUC and a 91% increase in international normalized ratio. Since R-warfarin metabolism was not affected, this indicates that capecitabine inhibits CYP2C9 isoenzyme and does not affect CYP1A2 and CYP3A4 isoenzymes. In patients receiving both capecitabine and oral anticoagulants – coumarin derivatives – careful monitoring of coagulation parameters (international normalized ratio or prothrombin time) and dose adjustment of the anticoagulant are required.

Cytochrome P450 2C9 substrates. Interaction studies between capecitabine and other drugs metabolized by CYP2C9 isoenzyme of the cytochrome P450 system, except warfarin, have not been conducted. Caution is required when prescribing capecitabine with these drugs (e.g., phenytoin).

Phenytoin. Cases of increased plasma phenytoin concentrations, accompanied by symptoms of phenytoin toxicity, have been reported with concomitant use of capecitabine and phenytoin. In patients receiving capecitabine together with phenytoin, regular monitoring of plasma phenytoin concentrations is recommended.

Folinic/folic acid. Folinic acid does not significantly affect the pharmacokinetics of capecitabine and its metabolites. However, folinic acid affects the pharmacodynamics of capecitabine, potentially increasing its toxicity: the maximum tolerated dose of capecitabine in monotherapy with intermittent dosing schedule is 3000 mg/m² per day, whereas when used in combination with folinic acid (30 mg orally twice daily), it is only 2000 mg/m² per day. Increased toxicity may occur when switching from 5-FU/leucovorin to capecitabine regimens. This may also occur when using folic acid to correct folic acid deficiency due to the similarity between folinic and folic acid.

Sorivudine and its analogs. Clinically significant interaction between sorivudine and 5-FU has been described in scientific literature due to sorivudine-induced inhibition of dihydropyrimidine dehydrogenase. Such interaction may potentially lead to fatal enhancement of fluoropyrimidine toxicity. Therefore, Kaxita must not be used concomitantly with sorivudine or its structural analogs such as brivudine (see section "Contraindications"). The interval between discontinuation of sorivudine or its structural analogs and initiation of Kaxita therapy should be at least 4 weeks.

Antacids. The effect of antacids containing aluminum and magnesium hydroxide on the pharmacokinetics of capecitabine has been studied. Antacids containing aluminum and magnesium hydroxide slightly increase plasma concentrations of capecitabine and its metabolite 5'-DFCR; they do not affect the three main metabolites (5'-DFUR, 5-FU, and FBA) of capecitabine.

Allopurinol. An interaction between allopurinol and 5-fluorouracil has been observed, potentially reducing the efficacy of 5-fluorouracil. Therefore, concomitant use of Kaxita and allopurinol should be avoided.

Interferon alpha. The maximum tolerated dose of capecitabine is 2000 mg/m² per day when used in combination with interferon alfa-2a (3 million IU/m² per day), compared to 3000 mg/m² per day when capecitabine is used as monotherapy.

Radiation therapy. The maximum tolerated dose of capecitabine in monotherapy with intermittent dosing schedule is 3000 mg/m² per day; when used in combination with radiation therapy for rectal cancer, it is 2000 mg/m² per day with continuous radiation course or daily 6-week radiation course from Monday to Friday.

Oxaliplatin. When capecitabine and oxaliplatin are used concomitantly, with or without bevacizumab, no clinically significant differences in exposure to capecitabine or its metabolites, free platinum, or total platinum have been observed.

Bevacizumab. No clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites has been observed in the presence of oxaliplatin.

Interaction of the medicinal product with food

In all clinical trials, patients were instructed to take capecitabine within 30 minutes after food intake. Since safety and efficacy data are based on administration of capecitabine with food, Kaxita is recommended to be taken with food. Taking Kaxita with food results in slower absorption rate of capecitabine.

Special precautions for use.

Dose-dependent toxic effects manifest as diarrhea, abdominal pain, nausea, stomatitis, and hand-foot syndrome (hand-foot skin reactions, hand-foot erythrodysesthesia). Most adverse reactions are reversible and do not require complete discontinuation of the drug, although dose adjustment or temporary interruption of treatment may be necessary.

Diarrhea. Patients with severe diarrhea require close monitoring and should receive rehydration and electrolyte replacement if dehydration occurs. Standard anti-diarrheal agents (e.g., loperamide) may be administered. According to the National Cancer Institute of Canada (NCIC CTCAE, version 2), Grade II diarrhea is defined as an increase in bowel movements to 4–6 times per day or nocturnal defecation; Grade III diarrhea is defined as an increase in bowel movements to 7–9 times per day, fecal incontinence, or malabsorption. Grade IV diarrhea is defined as ≥10 bowel movements per day, massive diarrhea with blood, or requirement for parenteral fluid administration. Dose reduction may be necessary when indicated (see section "Dosage and administration").

Dehydration. Dehydration must be prevented and corrected if it occurs. Dehydration may rapidly develop in patients with anorexia, asthenia, nausea, vomiting, or diarrhea. It may lead to acute renal failure, particularly in patients with pre-existing renal impairment or when capecitabine is used concomitantly with nephrotoxic drugs. Acute renal failure due to dehydration may be potentially fatal. Treatment with Kaxita must be immediately discontinued in case of Grade II (or higher) dehydration, and dehydration must be corrected. Resumption of treatment is possible after adequate correction of dehydration and management/control of precipitating causes (see section "Dosage and administration"). Dose adjustment should be considered if precipitating adverse events occur.

Hand-foot syndrome (synonyms: hand-foot skin reactions, hand-foot erythrodysesthesia, or chemotherapy-induced peripheral erythema).

Grade I hand-foot syndrome does not interfere with daily activities and is characterized by numbness, paresthesia, dysesthesia, tingling, painless swelling or redness of palms and/or soles, or discomfort.

Grade II hand-foot syndrome is characterized by painful redness and swelling of hands and/or soles; discomfort caused by these symptoms interferes with daily activities.

Grade III hand-foot syndrome is defined as moist desquamation, ulceration, blistering, severe pain of palms and/or soles, or severe discomfort preventing patients from working or performing daily activities.

Persistent or severe hand-foot syndrome (Grade II or higher) may eventually lead to loss of fingerprints, potentially affecting patient identification.

If Grade II or III hand-foot syndrome occurs, capecitabine should be discontinued until symptoms resolve or improve to Grade I. Upon recurrence of Grade III hand-foot syndrome, the dose of capecitabine should be reduced. The use of vitamin B6 (pyridoxine) for symptomatic or secondary prophylactic treatment of hand-foot syndrome is not recommended in patients receiving Kaxita and cisplatin, as published data suggest it may reduce cisplatin efficacy. Some evidence indicates that dexpanthenol may be effective in preventing hand-foot syndrome in patients receiving capecitabine.

Cardiotoxicity. The spectrum of cardiotoxicity associated with capecitabine treatment is similar to that observed with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiogenic shock, sudden death, cardiac arrest, heart failure, and ECG changes (including very rare cases of QT interval prolongation). These adverse effects are more commonly observed in patients with ischemic heart disease. Cases of cardiac arrhythmias (including ventricular fibrillation, torsades de pointes, bradycardia), angina pectoris, myocardial infarction, heart failure, and cardiomyopathy have been reported during capecitabine treatment. Caution is advised when prescribing Kaxita to patients with clinically significant heart disease, arrhythmias, or angina pectoris.

Hypo- or hypercalcemia. Hypo- or hypercalcemia have been reported during capecitabine treatment.

Diseases of the central or peripheral nervous system. Caution is advised when prescribing Kaxita to patients with diseases of the central or peripheral nervous system, such as brain metastases or neuropathy.

Diabetes mellitus or electrolyte disturbances. Caution is advised when prescribing Kaxita to patients with diabetes mellitus or electrolyte imbalances, as capecitabine may exacerbate these conditions.

Anticoagulants — coumarin derivatives. In a drug interaction study with single-dose warfarin, a significant increase in the mean area under the concentration-time curve (AUC) of S-warfarin (by 57%) was observed, indicating a potential interaction, likely due to inhibition of the CYP2C9 isoenzyme of the cytochrome P450 system by capecitabine. Patients receiving capecitabine concomitantly with oral anticoagulant coumarin derivatives require close monitoring of coagulation parameters (international normalized ratio or prothrombin time), and anticoagulant dosage should be adjusted accordingly.

Hepatic impairment. Due to lack of safety and efficacy data in patients with hepatic impairment, careful monitoring is required in patients with mild to moderate hepatic dysfunction, regardless of the presence or absence of liver metastases. If hyperbilirubinemia exceeding three times the upper limit of normal or increases in hepatic aminotransferase activity (ALT, AST) greater than 2.5 times the upper limit of normal occur during capecitabine treatment, the drug should be temporarily discontinued. Monotherapy with capecitabine may be resumed when bilirubin levels and hepatic transaminase activities decrease below these thresholds.

Renal impairment. The incidence of Grade III and IV adverse reactions is increased in patients with moderate renal impairment (creatinine clearance 30–50 mL/min) compared to the general patient population.

Deficiency of dihydropyrimidine dehydrogenase (DPD). Severe unexpected toxicity (e.g., stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity) associated with 5-fluorouracil (5-FU) has occasionally been observed in patients with DPD deficiency.

Patients with low or absent DPD activity, the enzyme responsible for fluorouracil catabolism, are at increased risk of severe, life-threatening, or fatal adverse reactions due to fluorouracil. Although DPD deficiency cannot be precisely determined, patients with certain homozygous or some combined heterozygous mutations in the DPYD gene locus (e.g., DPYD*2A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3 variants), which may result in complete or near-complete absence of DPD enzyme activity (as defined by laboratory assays), have the highest risk of life-threatening or fatal toxicity and should not be treated with Kaxita (see section "Contraindications"). No safe dose has been established for patients with complete absence of DPD activity.

Patients with known heterozygous DPYD variants (particularly DPYD*2A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3 variants) have an increased risk of developing severe toxicity when treated with capecitabine.

The frequency of heterozygous DPYD*2A genotype in the DPYD gene among Caucasian patients is approximately 1%, 1.1% for c.2846A>T, 2.6–6.3% for c.1236G>A/HapB3 variants, and 0.07–0.1% for c.1679T>G. Genotyping for these alleles is recommended to identify patients at increased risk of severe toxicity. Data on the frequency of these DPYD variants in different Caucasian populations are limited. Other rare variants may also be associated with increased risk of severe toxicity.

Patients with partial DPD deficiency, particularly those with heterozygous DPYD gene mutations, should be treated with extreme caution and closely monitored, with dose adjustments based on toxicity, if the benefit of Kaxita treatment outweighs the risks, considering the feasibility of alternative non-fluoropyrimidine-based chemotherapy regimens. Consideration should be given to reducing the initial dose in such patients to prevent severe toxicity. Insufficient data are available to recommend a specific dose for patients with partial DPD activity based on specific testing. DPYD*2A and c.1679T>G variants have been reported to cause greater reduction in enzyme activity and higher risk of adverse reactions compared to other variants. The impact of dose reduction on efficacy is currently unclear. Therefore, in the absence of severe toxicity, the dose may be increased with careful patient monitoring.

Patients who test negative for the above-mentioned alleles may still be at risk of developing severe adverse reactions.

Life-threatening toxicity similar to acute overdose may occur in patients with unrecognized DPD deficiency treated with capecitabine, as well as in patients with negative test results for specific DPYD variants (see section "Overdose"). In case of acute Grade II–IV toxicity, treatment should be immediately discontinued. Permanent discontinuation of treatment should be considered based on clinical assessment of the onset, duration, and severity of observed toxicity.

Ophthalmological complications. Patients should be closely monitored for ophthalmological complications such as keratitis or corneal disorders, especially if there is a history of ocular disorders. Treatment of visual disturbances should be initiated if clinically indicated.

Severe skin reactions. Capecitabine treatment may cause severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. The use of Kaxita must be permanently discontinued in patients who develop severe skin reactions during treatment.

Since the drug contains anhydrous lactose as an excipient, Kaxita should not be administered to patients with congenital galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Disposal of unused or expired medication: Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be performed via a designated "waste collection system," if available.

Use during pregnancy or breastfeeding.

Women of childbearing potential / contraception in men and women

Women of childbearing potential should be advised to avoid pregnancy during capecitabine treatment. If pregnancy occurs during treatment, the patient should be informed of the potential adverse effects on the fetus. Effective contraceptive methods should be used during treatment.

Pregnancy

Kaxita has not been studied in pregnant women; however, it can be assumed that its use during pregnancy may be harmful to the fetus. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. Kaxita should not be used during pregnancy.

Breastfeeding

It is unknown whether Kaxita passes into human breast milk. Significant levels of capecitabine and its metabolites have been detected in the milk of lactating animals. Therefore, breastfeeding is not recommended during treatment with Kaxita.

Fertility

There are no data on the effect of capecitabine on fertility. Only women of childbearing potential and men who agreed to use acceptable methods of birth control to prevent pregnancy during the study and for a specified period thereafter were included in the core studies of capecitabine use. Effects on fertility were observed in animal studies.

Ability to affect reaction speed when driving or operating machinery.

The drug has negligible or moderate influence on the ability to drive or operate machinery. Kaxita may cause dizziness, weakness, and nausea.

Dosage and Administration

Kaxita must be prescribed only by a qualified physician experienced in the use of antineoplastic agents. Close monitoring during the first treatment cycle is recommended for all patients.

Treatment should be discontinued in the event of disease progression or development of unacceptable toxicity.

The medication is taken orally, no later than 30 minutes after food intake, with water.

Monotherapy

Colorectal cancer and breast cancer. The recommended initial daily dose of Kaxita when used as adjuvant therapy is 2,500 mg/m² body surface area, administered in 3-week cycles: taken daily for 2 weeks, followed by a 1-week rest period. The total daily dose of Kaxita should be divided into two doses (1,250 mg/m² body surface area in the morning and evening). The recommended total duration of adjuvant therapy for patients with stage III colorectal cancer is 6 months.

Combination Therapy

Breast cancer. When used in combination with docetaxel, the recommended initial dose for the treatment of metastatic breast cancer is 1,250 mg/m² twice daily for 2 weeks, followed by a 1-week rest period (in combination with docetaxel 75 mg/m² once every 3 weeks as intravenous infusion). Premedication with oral corticosteroids such as dexamethasone should be administered prior to docetaxel infusion, according to the prescribing information for docetaxel, in patients receiving the combination of capecitabine plus docetaxel.

Colorectal cancer, gastric cancer. In combination regimens, the initial dose of Kaxita should be reduced to 800–1,000 mg/m² twice daily for 2 weeks followed by a 1-week rest period, or 625 mg/m² twice daily with continuous administration. When combined with irinotecan (200 mg/m² on day 1), the recommended initial dose is 800 mg/m² twice daily for 2 weeks followed by a 1-week rest period. The addition of bevacizumab to the combination regimen does not affect the initial dose of Kaxita.

Anti-emetic agents and premedication to ensure adequate hydration should be administered to patients receiving Kaxita in combination with cisplatin or oxaliplatin, according to the prescribing information for cisplatin and oxaliplatin. The recommended total duration of adjuvant therapy for patients with stage III colorectal cancer is 6 months.

The dose of Kaxita is calculated based on body surface area.

Tables 1 and 2 provide calculations for standard and reduced (see "Dose Modifications During Treatment" below) initial doses of Kaxita at 1,250 mg/m² or 1,000 mg/m².

Table 1

Calculation of standard and reduced initial doses of Kaxita at 1,250 mg/m² according to body surface area

• For a lower dosage (150 mg), capecitabine should be administered in another pharmaceutical form.

Table 2

Calculations of standard and reduced initial doses of Xeloda 1000 mg/m² depending on body surface area

Dose Adjustment During Treatment

General Recommendations

Signs of toxicity during treatment with Xeloda can be managed with symptomatic therapy and/or by modifying the Xeloda dose (by interrupting or reducing the dose). If the dose has been reduced, it should not be increased again later.

Treatment may be continued at the same dose without interruption or dose reduction in cases of toxicity considered by the physician not to be serious or life-threatening, such as alopecia, altered taste sensation, or nail changes.

Patients receiving Xeloda therapy should be advised to discontinue treatment immediately in the event of moderate or severe toxic reactions. If several doses of capecitabine have been missed due to toxicity, the missed doses should not be made up.

Hematological Toxicity

Capecitabine therapy should not be initiated in patients with baseline neutrophil counts < 1.5 × 10⁹/L and/or platelet counts < 100 × 10⁹/L. Treatment should be suspended if, during unplanned laboratory testing, neutrophil counts fall below 1.0 × 10⁹/L or platelet counts fall below 75 × 10⁹/L.

Dosage modification recommendations in the event of toxicities, according to the National Cancer Institute of Canada (NCIC CTCAE, version 1) toxicity grading criteria, are provided below.

Table 3

Dose reduction scheme for Xeloda (3-week cycle or continuous treatment)

* according to the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Common Toxicity Criteria (version 1) or the National Cancer Institute of the United States Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0). For information on hand-foot syndrome and hyperbilirubinemia, see section "Special Warnings and Precautions for Use".

Dosage modification in the event of toxicity during administration of capecitabine in a 3-week cycle in combination with other medicinal products

Dosage adjustments due to toxicity during treatment with Kaxita in a 3-week cycle in combination with other medicinal products should be performed according to Table 3 and the prescribing information for the other medicinal products.

At the beginning of treatment, if a delay in therapy with Kaxita or another medicinal product is required, the administration of all other components of the regimen should also be postponed until it becomes possible to resume all components of the treatment regimen.

If toxicities occur during treatment that, in the physician’s opinion, are not related to capecitabine, treatment with Kaxita should be continued, and the dosage of the other medicinal products in the regimen should be adjusted according to their respective prescribing information.

If discontinuation of other medicinal products in the Kaxita treatment regimen becomes necessary, Kaxita may be continued once the conditions for re-initiating Kaxita treatment have been met.

These recommendations apply to all indications and all patient groups.

Dosage modification in the event of toxicity during continuous administration of capecitabine in combination with other medicinal products

Dosage adjustments due to toxicity during continuous administration of capecitabine in combination with other medicinal products should be performed according to Table 3 and the prescribing information for the other medicinal products.

Dose adjustments in special situations

Patients with hepatic impairment

There are insufficient safety and efficacy data in patients with hepatic impairment to provide dose adjustment recommendations. No data are available on hepatic impairment due to cirrhosis or hepatitis.

Patients with renal impairment

Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min by Cockcroft-Gault at baseline). The incidence of grade 3 or 4 adverse reactions is increased in patients with moderate renal impairment (baseline creatinine clearance of 30–50 mL/min) compared to the general population. For patients with pre-existing moderate renal impairment, it is recommended to reduce the initial dose to 75% of the standard dose (1250 mg/m²). For patients with pre-existing moderate renal impairment, a reduction from the initial dose of 1000 mg/m² is not required. No initial dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 51–80 mL/min).

Close monitoring is recommended, and treatment should be interrupted immediately upon occurrence of adverse events of grade 2, 3, or 4, with subsequent dose adjustments according to Table 3. If creatinine clearance decreases to less than 30 mL/min, treatment with Kaxita should be discontinued. Dose adjustment recommendations for moderate renal impairment are the same for both monotherapy with capecitabine and combination therapy.

Elderly patients

No initial dose adjustment is required for monotherapy with capecitabine. However, treatment-related adverse reactions of grade 3 and 4 occurred more frequently in patients aged ≥ 60 years compared to younger patients.

When capecitabine is used in combination with other medicinal products in elderly patients (≥ 65 years), a higher incidence of grade 3 and 4 toxicities leading to treatment discontinuation has been observed compared to younger patients. Careful monitoring of patients aged ≥ 60 years is recommended.

In treatment with capecitabine in combination with docetaxel, an increased incidence of grade 3 and 4 toxicities has been observed in patients over 60 years of age. For patients in this age group receiving combination therapy with Kaxita and docetaxel, it is recommended to reduce the initial dose of Kaxita to 75% (950 mg/m² twice daily). In the absence of toxicity during treatment with the reduced initial dose of capecitabine in combination with docetaxel in patients aged ≥ 60 years, the dose of capecitabine may be gradually increased to 1250 mg/m² twice daily.

Children

The safety and efficacy of Kaxita in children have not been established.

Overdose

Symptoms of acute overdose: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, as well as bone marrow suppression. Management should include standard supportive and therapeutic measures to address clinical manifestations and prevent potential complications.

Adverse Reactions

The overall safety profile of capecitabine is based on data from more than 3000 patients who received treatment with capecitabine as monotherapy or in combination with various chemotherapy regimens for different indications. The safety profile of capecitabine monotherapy in metastatic breast cancer, metastatic colorectal cancer, and adjuvant colon cancer therapy is comparable.

The most common and/or clinically significant treatment-related adverse reactions were gastrointestinal reactions (diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (hand-foot erythrodysesthesia), weakness, asthenia, anorexia, cardiotoxicity, worsening of renal function in patients with pre-existing renal impairment, thrombosis/embolism.

Adverse reactions considered possibly related to capecitabine use were observed in clinical trials of capecitabine monotherapy and in clinical trials of capecitabine used in combination with various chemotherapy regimens for different indications.

The following frequency categories are used to describe the incidence of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Monotherapy with Capecitabine

The adverse reactions listed below are associated with capecitabine monotherapy and are based on a pooled safety analysis from three main studies involving 1900 patients (M66001, SO14695, and SO14796). Adverse reactions are categorized according to their overall frequency in the pooled analysis.

Infections and infestations: common — herpes (viral infection), nasopharyngitis, lower respiratory tract infections; uncommon — sepsis, urinary tract infections, cellulitis, tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, infection, dental abscess.

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon — lipoma.

Blood and lymphatic system disorders: common — anemia, neutropenia; uncommon — febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased international normalized ratio (INR)/prolonged prothrombin time.

Immune system disorders: uncommon — hypersensitivity reactions.

Metabolism and nutrition disorders: very common — anorexia; common — dehydration, weight decreased; uncommon — diabetes mellitus, hypokalemia, appetite disorders, malnutrition, hypertriglyceridemia.

Psychiatric disorders: common — insomnia, depression; uncommon — confusion, acute anxiety with panic reaction, depressed mood, decreased libido.

Nervous system disorders: common — headache, lethargy, dizziness, paresthesia; uncommon — aphasia, memory impairment, ataxia, syncope, balance disorders, sensory disturbances, peripheral neuropathy; very rare — toxic leukoencephalopathy.

Eye disorders: common — lacrimation, conjunctivitis, eye irritation; uncommon — visual acuity reduced, diplopia; rare — lacrimal duct stenosis, corneal disorders, keratitis, punctate keratitis.

Ear and labyrinth disorders: uncommon — vertigo, ear pain.

Cardiac disorders: uncommon — unstable angina pectoris, angina pectoris, myocardial ischemia, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations; rare — ventricular fibrillation, QT interval prolongation, torsades de pointes ventricular tachycardia, bradycardia, vasospasm.

Vascular disorders: common — thrombophlebitis; uncommon — deep vein thrombosis, arterial hypertension, petechiae, arterial hypotension, hot flushes, peripheral cold sensation.

Respiratory, thoracic and mediastinal disorders: common — dyspnea, epistaxis, cough, rhinorrhea; uncommon — pulmonary embolism, pneumothorax, hemoptysis, asthma, exertional dyspnea.

Gastrointestinal disorders: very common — diarrhea, vomiting, nausea, stomatitis, abdominal pain; common — gastrointestinal hemorrhage, constipation, upper abdominal pain, dyspepsia, flatulence, dry mouth; uncommon — intestinal obstruction, ascites, enteritis, gastritis, dysphagia, lower abdominal pain, esophagitis, abdominal discomfort, gastroesophageal reflux disease, colitis, fecal blood.

Hepatobiliary disorders: common — hyperbilirubinemia, liver function test abnormalities; uncommon — jaundice; rare — liver failure and cholestatic hepatitis.

Skin and subcutaneous tissue disorders: very common — hand-foot skin reaction (hand-foot erythrodysesthesia) (according to post-marketing experience, persistent or severe hand-foot erythrodysesthesia may eventually lead to loss of fingerprints — see section "Special precautions");

common — rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, maculopapular rash, skin desquamation, dermatitis, pigmentation disorders, nail disorders; uncommon — skin blistering and ulceration, urticaria, photosensitivity reactions, palmar erythema, facial edema, purpura, reversible radiation recall reaction; rare — cutaneous lupus erythematosus; very rare — severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: common — limb pain, back pain, arthralgia; uncommon — joint swelling, bone pain, facial pain, musculoskeletal stiffness, muscle weakness.

Renal and urinary disorders: uncommon — hydronephrosis, urinary incontinence, hematuria, nocturia, increased blood creatinine.

Reproductive system and breast disorders: uncommon — vaginal bleeding.

General disorders and administration site conditions: very common — weakness, asthenia; common — hyperthermia, peripheral edema, malaise, chest pain; uncommon — edema, pyrexia, influenza-like symptoms, chills, increased body temperature.

In the "Monotherapy with Capecitabine" section, the category "common adverse reactions" includes severe (grade 3–4) and/or life-threatening adverse reactions or medically significant adverse reactions.

Combination Therapy

The adverse reactions listed below were observed during the use of capecitabine in combination with various chemotherapy regimens for different indications, based on safety data from more than 3000 patients, in addition to those already reported with monotherapy or observed with higher frequency in any of the main clinical trials.

Some adverse reactions are commonly observed with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, an exacerbating effect of capecitabine on these adverse reactions cannot be excluded.

Infections and infestations: common — herpes zoster, urinary tract infections, oral candidiasis, upper respiratory tract infections, rhinitis, influenza, infections*, oral herpes.

Blood and lymphatic system disorders: very common — neutropenia*, leukopenia*, febrile neutropenia*, thrombocytopenia*, anemia*; common — bone marrow depression, febrile neutropenia*.

Immune system disorders: common — hypersensitivity reactions; rare — angioneurotic edema.

Metabolism and nutrition disorders: very common — decreased appetite; common — hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia.

Psychiatric disorders: common — sleep disorders, restlessness.

Nervous system disorders: very common — paresthesia and dysesthesia, peripheral neuropathy, peripheral sensory neuropathy, taste alteration, headache; common — neurotoxicity, tremor, neuralgia, hypersensitivity reactions, hypoesthesia.

Eye disorders: very common — lacrimation; common — visual disturbance, dry eyes, eye pain, blurred vision.

Ear and labyrinth disorders: common — tinnitus, hearing decreased.

Cardiac disorders: common — atrial fibrillation, myocardial ischemia/infarction.

Vascular disorders: very common — lower limb edema, arterial hypertension, thrombosis/embolism*; common — hot flushes, arterial hypotension, hypertensive crisis, hyperemia, phlebitis.

Respiratory, thoracic and mediastinal disorders: very common — angina, pharyngeal dysesthesia; common — hiccup, pharyngolaryngeal pain, dysphonia.

Gastrointestinal disorders: very common — constipation, dyspepsia; common — upper gastrointestinal hemorrhage, oral mucosal ulceration, gastritis, abdominal distension, gastroesophageal reflux disease, mouth pain, dysphagia, rectal bleeding, lower abdominal pain, oral dysesthesia, oral paresthesia, oral hypoesthesia, abdominal discomfort.

Hepatobiliary disorders: common — liver function test abnormalities.

Skin and subcutaneous tissue disorders: very common — alopecia, nail disorders; common — hyperhidrosis, erythematous rash, urticaria, night sweats.

Musculoskeletal and connective tissue disorders: very common — arthralgia, myalgia, limb pain; common — jaw pain, muscle spasms, trismus, muscle weakness.

Renal and urinary disorders: common — hematuria, proteinuria, decreased creatinine clearance, dysuria; rare — acute renal failure due to dehydration (see section "Special precautions").

General disorders and administration site conditions: very common — increased body temperature, weakness, lethargy*, heat sensation, asthenia; common — mucosal inflammation, extremity pain, pain, chills, chest pain, influenza-like symptoms, pyrexia*, infusion reactions, injection site reactions, infusion site pain, injection site pain.

Injury, poisoning and procedural complications: common — contusion.

*Frequency includes all grades of severity except for adverse reactions marked with "*", which include only grade 3–4 adverse reactions.

Specific Adverse Reactions

Hand-Foot Syndrome

With capecitabine administered at a dose of 1250 mg/m² twice daily for 2 weeks followed by a 1-week break, hand-foot syndrome of all grades was reported in 53–60% of patients in monotherapy trials (adjuvant colon cancer therapy, metastatic colorectal cancer treatment, breast cancer treatment) and in 63% of patients with metastatic breast cancer in the capecitabine/docetaxel treatment group. With capecitabine administered at a dose of 1000 mg/m² twice daily for 2 weeks followed by a 1-week break, hand-foot syndrome of all grades was observed in 22–30% of patients receiving combination therapy with capecitabine.

Diarrhea

Diarrhea occurred in nearly 50% of patients treated with capecitabine. According to a meta-analysis of data from more than 4700 patients across 14 clinical trials, the following covariates were statistically significantly associated with an increased risk of diarrhea across all studied combinations: higher initial capecitabine dose (in grams), longer treatment duration (weeks), increased patient age (per 10-year increment), and female sex. Statistically significant covariates associated with a reduced risk of diarrhea included higher cumulative capecitabine dose (0.1*kg) and relative dose intensity during the first 6 weeks of treatment.

Cardiotoxicity

In addition to the cardiac adverse reactions listed above, the following adverse reactions occurred at a frequency of less than 0.1% with capecitabine monotherapy, based on a pooled safety analysis of 949 patients enrolled in 7 clinical trials (2 phase III and 5 phase II trials in metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, heart failure, ventricular extrasystoles, sudden death.

Encephalopathy

In addition to the adverse reactions listed above, capecitabine monotherapy, according to a pooled safety analysis from 7 clinical trials, was associated with encephalopathy at a frequency of less than 0.1%.

Adverse Reactions in Special Patient Populations

Elderly Patients. In patients aged ≥60 years receiving capecitabine monotherapy or combination therapy with capecitabine and docetaxel, there was an increased risk of grade 3 and 4 adverse reactions and serious treatment-related adverse reactions compared to patients aged <60 years. More patients aged ≥60 years receiving combination therapy with capecitabine and docetaxel required earlier discontinuation of treatment due to adverse reactions compared to patients aged <60 years.

A meta-analysis of data from more than 4700 patients in 14 clinical trials demonstrated that in all combination studies, older age (per 10-year increase) was statistically significantly associated with increased risk of hand-foot syndrome and diarrhea, and decreased risk of neutropenia.

Sex

A meta-analysis of data from more than 4700 patients in 14 clinical trials demonstrated that female sex was statistically significantly associated with an increased risk of hand-foot syndrome and diarrhea, and a decreased risk of neutropenia.

Patients with Impaired Renal Function

In patients with pre-existing renal impairment receiving capecitabine monotherapy (for colorectal cancer), there was an increased frequency of grade 3 and 4 treatment-related adverse reactions compared to patients with normal renal function [36% in patients without renal impairment (N = 268), 41% in patients with mild renal impairment (N = 257), and 54% in patients with moderate renal impairment (N = 59)]. Patients with moderate renal impairment more frequently required dose reductions (44%) compared to 33% and 32% of patients without renal impairment and with mild renal impairment, respectively, and earlier discontinuation of treatment (21% during the first two cycles) compared to 5% and 8% in patients without renal impairment and with mild renal impairment, respectively.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Packaging.

10 film-coated tablets in a blister pack, 12 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Ltd.

Manufacturer's address.

Baroda Highway, Halol, Gujarat, 389350, India.