Capecitabine accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CAPECITABINE ACCORD (Capecitabine Accord)

Composition:

Active substance: capecitabine;

One tablet contains 500 mg of capecitabine;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate;

Film coating: hypromellose, talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: elongated, biconvex, film-coated tablets of orange-pink color, with the imprint "500" on one side and plain on the other side.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites.

ATC code: L01B C06.

Pharmacological Properties

Pharmacodynamics

Capecitabine is a non-cytotoxic fluoropyrimidine carbamate and an oral prodrug of the cytotoxic compound 5-fluorouracil (5-FU). Capecitabine is activated through a multi-enzyme process. The final conversion to 5-FU occurs primarily 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 have been characterized over a dose range of 502–3514 mg/m²/day. Pharmacokinetic parameters for capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) were similar on Day 1 and Day 14. 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 non-linear pharmacokinetics of the active metabolite.

Absorption

After oral administration, capecitabine is rapidly and completely absorbed and subsequently undergoes biotransformation into metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Food intake reduces the absorption rate of capecitabine but does not significantly affect the area under the concentration-time curve (AUC) of 5'-DFUR or the subsequent metabolite 5-FU. When the drug was administered after food intake at a dose of 1250 mg/m² on Day 14, maximum concentrations (Cmax) 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 (Tmax) was 1.50, 2.00, 2.00, 2.00, and 3.34 hours, and AUC values were 7.75, 7.24, 24.6, 2.03, and 36.3 µg×h/mL, respectively.

Distribution

In vitro human plasma studies have shown that the plasma protein binding (primarily to albumin) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU is 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, but 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 tumor cells. 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 ratio of 5-FU concentration in tumor tissue to plasma concentration was 21.4 (range: 3.9–59.9, N=8), while the ratio of concentration in healthy tissue to plasma concentration was 8.9 (range: 3.0–25.8, N=8). Thymidine phosphorylase activity was measured to be four times higher in primary colorectal tumors compared to adjacent normal tissues. Immunohistochemical studies indicate that most thymidine phosphorylase is localized in stromal tumor cells.

Subsequently, 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD) to form less toxic dihydro-5-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-ureidopropionic acid (FUPA). The final reaction 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.

Excretion

The elimination half-life (T½) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL is 0.85, 1.11, 0.66, 0.76, and 3.23 hours, respectively. After oral administration, capecitabine metabolites are primarily excreted in 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 (Cmax and AUC), nor any effect of docetaxel and paclitaxel on the pharmacokinetics of capecitabine and 5'-DFUR.

Pharmacokinetics in Special Clinical Populations

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

Patients with Hepatic Metastases. Pharmacokinetic data in patients with mild to moderate hepatic impairment due to metastases suggest that the 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. Based on a population pharmacokinetic analysis including patients across a wide age range (27–86 years), of whom 234 patients (46%) were aged 65 years or older, 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), Cmax of capecitabine was 36% lower and AUC 24% lower compared to Caucasian patients (N=22). Japanese patients also had 25% lower Cmax 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, in combination with docetaxel after ineffective chemotherapy including anthracycline agents;
• Locally advanced or metastatic breast cancer, as monotherapy after ineffective chemotherapy including taxanes and anthracycline agents, or in the presence of contraindications to anthracycline therapy.

Colorectal cancer:

• Colon cancer, in adjuvant therapy following surgical treatment of stage III cancer (Dukes' stage C);
• Metastatic colorectal cancer.

Gastric cancer:

• 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 medicinal product, or to fluorouracil. Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special precautions"). Pregnancy or breastfeeding. Severe leukopenia, neutropenia, thrombocytopenia. Severe hepatic impairment. Severe renal impairment (creatinine clearance < 30 ml/min). Contraindications for any medicinal product used in combination. Recent or concomitant treatment with brivudine (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction" regarding interactions with other medicinal products).

Special precautions.

Procedures for safe handling of cytotoxic agents must be observed.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adult patients.

Brivudine.

A clinically significant interaction between brivudine and fluoropyrimidines (e.g., capecitabine, 5-fluorouracil, tegafur) has been described, due to inhibition of dihydropyrimidine dehydrogenase by brivudine. This interaction, which increases fluoropyrimidine toxicity, may potentially lead to fatal outcomes. Therefore, concomitant use of brivudine and capecitabine is contraindicated (see sections "Contraindications" and "Special precautions"). A waiting period of at least 4 weeks must elapse between the end of brivudine treatment and the start of capecitabine therapy. Brivudine treatment may be initiated 24 hours after the last dose of capecitabine.

Coumarin anticoagulants. Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), potentially leading to coagulation abnormalities and hemorrhage within several days or months after initiation of capecitabine therapy, and in some cases up to one month after discontinuation of capecitabine. In a clinical interaction study, following a single 20 mg dose of S-warfarin, capecitabine treatment increased the AUC of warfarin by 57% and the international normalized ratio (INR) by 91%. Since the metabolism of R-warfarin was unaffected, this indicates that capecitabine inhibits the CYP2C9 isoenzyme and does not affect CYP1A2 and CYP3A4 isoenzymes. Patients receiving capecitabine concomitantly with oral coumarin-derived anticoagulants should be closely monitored for coagulation parameters (INR or prothrombin time), and anticoagulant dosage should be adjusted accordingly.

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

Phenytoin. Isolated cases of increased plasma phenytoin concentrations, accompanied by symptoms of phenytoin intoxication, have been observed during concomitant administration of capecitabine and phenytoin. Regular monitoring of plasma phenytoin concentrations is recommended in patients receiving both capecitabine and phenytoin.

Folinic acid/folic acid. Folinic acid does not significantly affect the pharmacokinetics of capecitabine or its metabolites. However, folinic acid influences the pharmacodynamics of capecitabine, potentially increasing its toxicity: the maximum tolerated dose of capecitabine monotherapy under an intermittent dosing regimen is 3000 mg/m²/day, whereas when combined with folinic acid (30 mg orally twice daily), it is only 2000 mg/m²/day.

Increased toxicity may occur when switching from 5-FU/LV to a capecitabine-based regimen. This may also occur when folic acid is administered to correct folic acid deficiency, due to the structural similarity between folinic acid and folic acid.

Antacids. The effect of antacids containing aluminium and magnesium hydroxide on the pharmacokinetics of capecitabine has been studied in patients with tumors. Such antacids slightly increase plasma concentrations of capecitabine and one 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 administration of capecitabine and allopurinol should be avoided.

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

Radiation therapy. The maximum tolerated dose of capecitabine as monotherapy under an intermittent dosing regimen is 3000 mg/m²/day. When combined with radiation therapy for rectal cancer, it is 2000 mg/m²/day with continuous radiation therapy or a daily 6-week course of radiation therapy administered Monday through Friday.

Oxaliplatin. No clinically significant differences in exposure to capecitabine or its metabolites, free platinum, or total platinum were observed when capecitabine was administered in combination with oxaliplatin, with or without bevacizumab.

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

Drug–food interaction. Throughout all clinical trials, patients were instructed to take capecitabine within 30 minutes after a meal. Since safety and efficacy data are based on administration of capecitabine with food, it is recommended to take capecitabine with food. Administration of capecitabine with food results in a slower absorption rate of capecitabine.

Special precautions for use.

Toxic effects dependent on dose. Dose-dependent toxic effects include diarrhea, abdominal pain, nausea, stomatitis, and hand-foot syndrome (synonyms: hand-foot erythrodysesthesia or chemotherapy-induced peripheral erythema). Most adverse effects 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 should be closely monitored and managed with rehydration and electrolyte replacement in case of dehydration. Standard anti-diarrheal medications (e.g., loperamide) should be initiated as early as possible when indicated. Grade II diarrhea according to the National Cancer Institute of Canada (NCIC CTC, version 2) 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 or fecal incontinence and malabsorption; Grade IV diarrhea is defined as ≥10 bowel movements per day or massive diarrhea with blood or requiring parenteral fluid administration. If necessary, the dose of the drug should be reduced (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. Dehydration may lead to acute renal failure, especially in patients with pre-existing renal impairment or when capecitabine is used concomitantly with drugs known to have nephrotoxic potential. Acute renal failure due to dehydration may be potentially fatal. Treatment with Capecitabine Accord must be immediately discontinued upon development 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 reactions occur.

Hand-foot syndrome (synonyms: hand-foot erythrodysesthesia or chemotherapy-induced peripheral erythema). Grade I hand-foot syndrome does not interfere with the patient's daily activities and manifests as numbness, paresthesia, dysesthesia, tingling, painless edema, or erythema of palms and/or soles, and discomfort.

Grade II hand-foot syndrome manifests as painful erythema and edema of hands and/or feet; discomfort caused by these symptoms interferes with the patient’s daily activities.

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

Persistent or severe hand-foot syndrome (Grade II or higher) may eventually lead to loss of fingerprints, which may affect 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 syndrome, the dose of capecitabine should be reduced (see section "Dosage and administration"). Patients receiving Capecitabine Accord concomitantly with cisplatin should not be given vitamin B6 (pyridoxine) for symptomatic or secondary prophylactic treatment of hand-foot syndrome, as this may reduce the efficacy of cisplatin.

Some data suggest that dexpanthenol is 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 required when prescribing Capecitabine Accord to patients with clinically significant cardiac 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 required when prescribing Capecitabine Accord to patients with diseases of the central or peripheral nervous system, such as brain metastases or neuropathy.

Diabetes mellitus or electrolyte imbalance. Caution is required when prescribing Capecitabine Accord to patients with diabetes mellitus or electrolyte imbalances, as capecitabine use 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 anticoagulants (coumarin derivatives) should undergo close monitoring of coagulation parameters (INR or prothrombin time), and the anticoagulant dose should be adjusted accordingly.

Brivudine.

Brivudine is contraindicated for concomitant use with capecitabine. Fatal cases have been reported following this drug interaction. A waiting period of at least 4 weeks should elapse between the end of brivudine treatment and the initiation of capecitabine therapy. Brivudine treatment may be initiated 24 hours after the last dose of capecitabine (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

In case of accidental brivudine intake by patients receiving capecitabine, effective measures should be taken to reduce capecitabine toxicity. Immediate hospitalization is recommended. All necessary measures should be initiated to prevent systemic infections and dehydration.

Hepatic impairment. Due to lack of safety and efficacy data, capecitabine use should be closely monitored in patients with mild to moderate hepatic impairment, regardless of the presence or absence of liver metastases. If hyperbilirubinemia exceeding the upper limit of normal by more than 3 times or an increase in hepatic aminotransferase activity (ALT, AST) by more than 2.5 times the upper limit of normal occurs during treatment, capecitabine should be discontinued. Capecitabine monotherapy 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). DPD activity is the rate-limiting factor in the catabolism of 5-fluorouracil (see section "Pharmacokinetics"); therefore, patients with DPD deficiency have an increased risk of toxicity associated with fluoropyrimidines, including stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity.

Toxicity associated with DPD deficiency usually occurs during the first treatment cycle or after dose escalation.

Complete DPD deficiency. Complete DPD deficiency is rare (0.01–0.5% of Caucasian population). Patients with complete DPD deficiency have an increased risk of life-threatening or fatal toxicity and should not receive Capecitabine Accord (see section "Contraindications").

Partial DPD deficiency. Partial DPD deficiency is estimated to occur in 3–9% of the Caucasian population. Patients with partial DPD deficiency have an increased risk of severe and potentially life-threatening toxicity. To reduce this risk, consideration should be given to reducing the initial dose. DPD deficiency should be considered as a parameter to be taken into account along with other routine dose-reduction measures. Reducing the initial dose may affect treatment efficacy. If no severe toxicity occurs, subsequent doses may be increased under close monitoring.

Testing for DPD deficiency. Testing for phenotype and/or genotype is recommended before initiating treatment with Capecitabine Accord, despite uncertainty regarding optimal testing methodologies. Relevant clinical guidelines should be considered.

In patients with moderate renal impairment, increased blood urea levels may occur, increasing the risk of falsely diagnosing DPD deficiency. Capecitabine Accord is contraindicated in patients with severe renal impairment (see section "Contraindications").

Genotypic characterization of DPD deficiency. Pre-treatment testing for rare DPYD gene mutations can identify patients with DPYD deficiency. The following DPYD variants—c.1905+1G>A (also known as DPYD*2A), c.1679T>G (DPYD*13), c.2846A>T, and c.1236G>A/HapB3—may result in complete absence or reduced enzymatic activity of DPD. Other rare variants may also be associated with an increased risk of severe or life-threatening toxicity.

Homozygous and compound heterozygous mutations in the DPYD gene locus (e.g., combinations of the 4 variants with at least one allele c.1905+1G>A or c.1679T>G) are known to cause complete or near-complete absence of DPD enzymatic activity.

Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) have an increased risk of severe toxicity during fluoropyrimidine treatment.

The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene among Caucasians 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.

Data on the frequency of the 4 DPYD variants in non-Caucasian populations are limited. Currently, the 4 DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) are considered virtually absent in African or Asian populations.

Phenotypic characterization of DPD deficiency. For phenotypic characterization of DPD deficiency, measurement of baseline plasma uracil levels—the endogenous substrate of DPD—is recommended.

Elevated uracil concentrations before treatment initiation are associated with an increased risk of toxicity. Despite uncertainty regarding threshold values defining complete or partial DPD deficiency, a DPD level in blood ≥16 ng/mL and <150 ng/mL should be considered indicative of partial DPD deficiency and associated with an increased risk of fluoropyrimidine toxicity. A blood uracil level ≥150 ng/mL should be considered indicative of complete absence of DPD and associated with life-threatening or fatal fluoropyrimidine toxicity. Blood urea levels in patients with renal impairment should be interpreted with caution (see "Testing for DPD deficiency" above).

Ophthalmological complications. Patients should be closely monitored for ophthalmological complications such as keratitis or corneal disorders, especially in those with a history of ocular disorders. Treatment of visual disturbances should be initiated when clinically necessary.

Severe skin reactions. Capecitabine treatment may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Capecitabine Accord must be permanently discontinued in patients who develop severe skin reactions during treatment.

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

Sodium

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

The tablet must not be crushed or split. Contact of patients or healthcare workers with crushed or split tablets may result in adverse reactions (see section "Adverse reactions").

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

Use during pregnancy or breastfeeding.

Women of reproductive potential/contraception in men and women

Women of reproductive potential should be advised to avoid pregnancy during treatment with capecitabine. If pregnancy occurs during treatment, the patient should be informed of the potential adverse effects on the fetus. Effective contraception methods should be used during treatment and for 6 months after the last dose of capecitabine.

Based on genotoxicity study results, male patients with partners of reproductive potential should use effective contraception methods during treatment and for 3 months after the last dose of capecitabine.

Pregnancy

The use of capecitabine in pregnant women has not been studied, but 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. Capecitabine should not be used during pregnancy.

Lactation

It is unknown whether capecitabine passes into human breast milk. Studies on the effect of capecitabine on breast milk production or the presence of capecitabine in human breast milk have not been conducted. Significant amounts of capecitabine and its metabolites have been detected in the milk of lactating animals. Because the potential harm to breastfed infants is unknown, breastfeeding should be discontinued during treatment with capecitabine and for 2 weeks after the last dose.

Fertility

There are no data on the effect of capecitabine on fertility. The pivotal studies of capecitabine use included only women of reproductive potential and men who agreed to use acceptable methods of contraception to prevent pregnancy during the study and for a specified period thereafter. Effects on fertility were observed in animal studies.

Ability to drive and use machines.

The drug has a minor or moderate influence on the ability to drive and use machinery. Capecitabine Accord may cause dizziness, weakness, and nausea.

Method of Administration and Dosage

Capecitabine Accord should only be prescribed by a qualified physician experienced in the use of antineoplastic agents. All patients should be carefully monitored during the first cycle of treatment.

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

Standard Dosage

Capecitabine Accord tablets should be swallowed whole, no later than 30 minutes after a meal, with water.

Capecitabine Accord tablets must not be crushed or split.

Monotherapy

Colorectal cancer and breast cancer: The recommended initial daily dose of Capecitabine Accord as adjuvant therapy is 2500 mg/m² body surface area administered in three-week cycles: daily administration for 2 weeks followed by a 1-week rest period. The total daily dose of Capecitabine Accord should be divided into two doses (1250 mg/m² body surface area in the morning and evening). The recommended total duration of adjuvant therapy in patients with stage III colorectal cancer is 6 months.

Combination Therapy

Breast cancer: The recommended initial dose of capecitabine for the treatment of metastatic breast cancer is 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period, in combination with docetaxel (75 mg/m² every 3 weeks as an intravenous infusion). Premedication with oral corticosteroids, such as dexamethasone, should be administered prior to docetaxel administration, in accordance with the docetaxel prescribing information, for patients receiving the combination of capecitabine plus docetaxel.

Colorectal cancer, gastric cancer: In combination regimens, the initial dose of Capecitabine Accord should be reduced to 800–1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period, or to 625 mg/m² twice daily for 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 has not affected the initial dose of Capecitabine Accord. The recommended total duration of adjuvant therapy in patients with stage III colorectal cancer is 6 months.

Antiemetics and premedication to ensure adequate hydration should be administered to patients receiving Capecitabine Accord in combination with cisplatin or oxaliplatin, prior to cisplatin administration, in accordance with the prescribing information for cisplatin and oxaliplatin.

The dose of Capecitabine Accord should be calculated based on body surface area. Tables 1 and 2 provide dosage calculations for standard and reduced doses (see "Dose Modification During Treatment") for initial doses of Capecitabine Accord of 1250 mg/m² or 1000 mg/m².

Calculation of Standard and Reduced Initial Doses of Capecitabine Accord

1250 mg/m² according to body surface area

Table 1

Calculation of the standard and reduced initial dose of Capecitabine Accord

1000 mg/m2

depending on body surface area

Table 2

Dosage adjustment during treatment

General recommendations

Toxicity symptoms during treatment with Capecitabine Accord can be managed by symptomatic therapy and/or adjustment of the Capecitabine Accord dosage (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 symptoms that, in the physician’s opinion, are unlikely to become severe or life-threatening, such as alopecia, taste alterations, or nail changes.

Patients receiving Capecitabine Accord treatment 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 later.

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 interrupted if, during routine or unscheduled laboratory monitoring, neutrophil counts fall below 1.0 × 10⁹/L or platelet counts fall below 75 × 10⁹/L.

Dosage modification recommendations for toxicity events are provided below, according to the toxicity grading criteria established by the Canadian National Cancer Institute (NCIC CTG, version 1).

Capecitabine Accord dose reduction schedule (three-week cycle or continuous treatment)

Table 3

* according to the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Common Toxicity Criteria (version 1) or the National Cancer Institute 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 modifications due to toxicity during a 3-week cycle of capecitabine in combination with other medicinal products

Dosage modifications due to toxicity during a 3-week cycle of capecitabine in combination with other medicinal products should be performed according to Table 3 for capecitabine and in accordance with the medical instructions for the other medicinal products.

At the beginning of treatment, if delay of therapy with capecitabine or another medicinal product is necessary, the administration of all other components of the regimen should also be delayed until the time when all components can be resumed.

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

If discontinuation of other components of the treatment regimen is necessary, capecitabine may be continued once the conditions for resuming capecitabine treatment are met.

These recommendations apply to all indications and all patient groups.

Dosage modifications due to toxicity during continuous administration of capecitabine in combination with other medicinal products

Dosage modifications due to toxicity during continuous administration of capecitabine in combination with other medicinal products should be performed according to Table 3 for capecitabine and in accordance with the medical instructions for the other medicinal products.

Dose modifications in special situations

Patients with hepatic impairment

There is insufficient safety and efficacy data in patients with hepatic impairment to provide dose adjustment recommendations. There is no information 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 III or IV adverse reactions is increased in patients with moderate renal impairment (creatinine clearance 30–50 mL/min at baseline) compared to the general population. For patients with baseline moderate renal impairment, it is recommended to reduce the initial dose to 75% of the standard dose (1250 mg/m²). Patients with baseline moderate renal impairment do not require a reduction in the initial dose of 1000 mg/m². No initial dose adjustment is required for patients with mild renal impairment (creatinine clearance 51–80 mL/min).

If Grade II, III, or IV adverse events occur, careful monitoring, immediate interruption of treatment, and dose modification according to Table 3 are recommended. If creatinine clearance decreases to less than 30 mL/min, treatment with capecitabine must be discontinued. Dose adjustment recommendations for moderate renal impairment are the same for both monotherapy and combination therapy with capecitabine.

Elderly patients

No initial dose adjustment is required for monotherapy with capecitabine. However, treatment-related adverse reactions of Grade III and IV were observed more frequently in patients aged ≥60 years compared to younger patients.

Close monitoring of patients aged ≥60 years is recommended. When capecitabine is used in combination with other medicinal products in elderly patients (≥65 years), a higher incidence of Grade III and IV adverse effects leading to treatment discontinuation has been observed compared to younger patients.

In treatment with capecitabine in combination with docetaxel, an increased incidence of Grade III and IV adverse effects was observed in patients aged 60 years and older. For patients in this age group receiving combination therapy with capecitabine and docetaxel, it is recommended to reduce the initial dose of capecitabine to 75% (950 mg/m² twice daily).

If no toxicities occur during treatment with the reduced initial dose of capecitabine in combination with docetaxel in patients aged ≥60 years, the capecitabine dose may be gradually increased to 1250 mg/m² twice daily.

Children

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

Overdose. Symptoms of acute overdose include nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, as well as bone marrow suppression. Treatment should include standard therapeutic and supportive measures to manage clinical manifestations and prevent possible 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 monotherapy with capecitabine in metastatic breast cancer, metastatic colorectal cancer, and adjuvant treatment of colorectal cancer 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 skin reaction), weakness, asthenia, anorexia, cardiotoxicity, progression of renal function impairment in patients with pre-existing renal insufficiency, and thrombosis/embolism.

Adverse reactions considered by the investigator as possibly, probably, or remotely related to capecitabine administration were observed in clinical trials of capecitabine monotherapy (in adjuvant treatment of colorectal cancer, treatment of metastatic colorectal cancer, and metastatic breast cancer) and in clinical trials of capecitabine in combination with various chemotherapy regimens. For classification of frequency of adverse reactions, the following categories are used: 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

Below are adverse reactions associated with capecitabine monotherapy, based on a pooled safety analysis from three pivotal trials. Adverse reactions are assigned to the appropriate frequency group according to their overall incidence 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: uncommon – lipoma.

Blood and lymphatic system disorders: common – anemia, neutropenia; uncommon – febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased INR/prolonged prothrombin time.

Immune system disorders: uncommon – hypersensitivity reactions; rare – angioneurotic edema.

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, drowsiness, dizziness, paresthesia, taste alteration; uncommon – aphasia, memory impairment, ataxia, syncope, balance disorder, sensory disturbance, 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/infarction, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations; rare – ventricular fibrillation, QT interval prolongation, torsades de pointes, bradycardia, vasospasm.

Vascular disorders: common – thrombophlebitis; uncommon – deep vein thrombosis, arterial hypertension, petechiae, arterial hypotension, hot flushes, peripheral coldness.

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, blood in stool.

Hepatobiliary disorders: common – hyperbilirubinemia, abnormal liver function tests; uncommon – jaundice; rare – hepatic failure, cholestatic hepatitis.

Skin and subcutaneous tissue disorders: very common – hand-foot syndrome (based on post-marketing experience, persistent or severe hand-foot skin reaction may eventually lead to loss of fingerprint patterns (see section "Special precautions")); common – rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, macular rash, skin desquamation, dermatitis, pigmentation disorders, nail disorders; uncommon – skin blistering and ulceration, rash, urticaria, photosensitivity reactions, palmar erythema, facial edema, purpura, reversible radiation recall; 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 – pyrexia, peripheral edema, malaise, chest pain; uncommon – edema, fever, influenza-like symptoms, chills, increased body temperature.

In this context, "common adverse reactions" in the "Monotherapy" section refer to severe adverse reactions and/or life-threatening (Grade III–IV) or medically significant adverse reactions.

Combination therapy

Below are adverse reactions observed during treatment with 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 and/or observed with higher frequency. Some adverse reactions are commonly associated with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, the possibility of exacerbation of these adverse events with capecitabine 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 fever*, thrombocytopenia*, anemia*; common – bone marrow suppression, febrile neutropenia.

Immune system disorders: common – hypersensitivity reactions.

Metabolism and nutrition disorders: very common – appetite decreased; 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 – vision disorders, dry eyes, eye pain, visual acuity reduced, blurred vision.

Ear and labyrinth disorders: uncommon – 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 – hiccups, 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 – abnormal liver function tests.

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, back pain, muscle spasms, trismus, muscle weakness.

Renal and urinary disorders: common – hematuria, proteinuria, decreased renal 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, drowsiness*, sensitivity to heat, asthenia; common – mucosal inflammation, limb pain, pain, chills, chest pain, influenza-like symptoms, fever*, infusion reactions, injection site reactions, infusion site pain, injection site pain.

Injury, poisoning and procedural complications: common – contusion.

* Frequencies include all grades unless otherwise indicated; adverse reactions marked with “*” include only Grade III–IV events.

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 rest period, hand-foot syndrome of all grades was observed in 53–60% of patients in monotherapy trials (adjuvant treatment of colorectal cancer, treatment of metastatic colorectal cancer, treatment of breast cancer) 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 rest period, hand-foot syndrome of all grades occurred in 22–30% of patients receiving combination therapy with capecitabine.

A meta-analysis of data from more than 4700 patients in 14 clinical trials showed that hand-foot syndrome of all grades occurred in 43% (2066) of patients treated with capecitabine as monotherapy or in combination with various chemotherapy regimens for different indications (colorectal cancer, gastric cancer, breast cancer), with a median onset of 239 days after initiation of capecitabine. Statistically significant covariates associated with increased risk of hand-foot syndrome across all studied combinations included: higher initial capecitabine dose (in grams), lower cumulative capecitabine dose (0.1 *kg), higher relative dose intensity during the first 6 weeks of treatment, longer treatment duration (weeks), older age (per 10-year increase), female sex, and better baseline performance status (0 vs ≥1).

Diarrhea

Diarrhea occurred in nearly 50% of patients during treatment with capecitabine. According to a meta-analysis of 14 clinical trials, statistically significant covariates associated with increased risk of diarrhea included: higher initial capecitabine dose (in grams), longer treatment duration (weeks), older age (per 10-year increase), and female sex. Covariates associated with decreased risk of diarrhea included: higher cumulative capecitabine dose (0.1 *kg) and higher relative dose intensity during the first 6 weeks of treatment.

Cardiotoxicity

In addition to the above-mentioned cardiac adverse reactions, the following adverse reactions occurred at a frequency of less than 0.1% during capecitabine monotherapy, based on a pooled safety analysis from 949 patients in 7 clinical trials: cardiomyopathy, heart failure, ventricular extrasystoles, sudden fatal outcome.

Encephalopathy

In addition to the above-mentioned adverse reactions, encephalopathy occurred at a frequency of less than 0.1% during capecitabine monotherapy, based on a pooled safety analysis from 7 clinical trials.

Exposure to crushed or split tablets of Capecitabine Accord

The following adverse reactions have been reported following exposure to crushed or split tablets of Capecitabine Accord: eye mucous membrane irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, gastric irritation, and vomiting.

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 III and IV adverse reactions and serious treatment-related adverse reactions compared to patients aged <60 years. A higher proportion of patients aged ≥60 years discontinued treatment earlier due to adverse reactions compared to those aged <60 years, particularly in the combination therapy group.

Clinical trials have shown that with increasing age (per 10-year increase), there was a statistically significant increase in the risk of developing hand-foot syndrome and diarrhea, and a decreased risk of neutropenia.

Sex

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

Patients with impaired renal function

In patients with pre-existing renal impairment receiving capecitabine monotherapy (for colorectal cancer), the incidence of Grade III and IV treatment-related adverse reactions was higher compared to patients with normal renal function (36% in patients without renal impairment, 41% in patients with mild renal impairment, and 54% in patients with moderate renal impairment). In patients with moderate renal impairment, dose reductions were required more frequently (44%) compared to 33% and 32% in patients without renal impairment and with mild renal impairment, respectively, and premature discontinuation of treatment occurred more frequently (21% during the first two cycles) compared to 5% and 8% in patients without renal impairment and with mild renal impairment, respectively.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: http://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Packaging. 10 tablets in a blister. 3, 6, or 12 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's Warehouse / Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and place of business.

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing authorization holder. Accord Healthcare S.L.U.

Complaints regarding substandard quality of the medicinal product, safety concerns, improper use, or adverse events are accepted 24/7 via phone: +380993100335 or by email: [email protected].

Marketing authorization holder's address. World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain.