Capcitabine-vista
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CAPECITABINE-VISTA
Composition:
Active substance: capecitabine;
One film-coated tablet contains 150 mg or 500 mg of capecitabine;
Excipients: sodium croscarmellose, microcrystalline cellulose PH 101, microcrystalline cellulose PH 200, hypromellose 5cP, colloidal anhydrous silicon dioxide (E 551), magnesium stearate (E 470b);
Film coating: hypromellose 5cP, titanium dioxide (E 171), talc (E 553b), macrogol 400, iron oxide red (E 172), iron oxide yellow (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: film-coated tablets, oval-shaped, light peach-colored, with "150" engraved on one side. Approximate dimensions: 11.4 mm × 5.9 mm;
film-coated tablets, elongated capsule-shaped, peach-colored, with "500" engraved on one side. Approximate dimensions: 17.1 mm × 8.1 mm.
Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01BC06.
Pharmacological Properties.
Pharmacodynamics.
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate that acts as an oral prodrug of the cytotoxic agent 5-fluorouracil (5-FU). Capecitabine is activated through a series of enzymatic steps. The final conversion to 5-FU occurs under the influence 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 when combined with docetaxel, which may be related to docetaxel-induced upregulation of thymidine phosphorylase activity. Evidence indicates that the anabolic metabolism of 5-FU interferes with the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby inhibiting 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 may 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 of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) on days 1 and 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 non-linear pharmacokinetics of the active metabolite. Absorption. After oral administration, capecitabine is rapidly and completely absorbed and subsequently biotransformed 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 capecitabine was administered at a dose of 1250 mg/m² after food intake on day 14, maximum concentrations (Cmax) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and α-fluoro-β-alanine (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 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 54%, 10%, 62%, and 10% for capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU, 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 tumor stromal 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), whereas the ratio of 5-FU concentration in normal tissue to plasma concentration was 8.9 (range: 3.0–25.8, N = 8). Thymidine phosphorylase activity was found to be 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 to α-fluoro-β-alanine (FBAL) by β-ureidopropionase, which is excreted in urine. Dihydropyrimidine dehydrogenase activity is rate-limiting. DPD deficiency may lead to increased toxicity of capecitabine.
Elimination. 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. Capecitabine and its metabolites are primarily excreted in urine. Renal excretion accounts for 95.5%, fecal excretion for 2.6%. The main metabolite in urine is FBAL, representing 57% of the administered dose. Approximately 3% of the administered dose is excreted unchanged in urine.
Combination therapy. In phase I studies, no effect of capecitabine on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC), or of docetaxel or paclitaxel on the pharmacokinetics of capecitabine and 5'-DFUR, was observed.
Pharmacokinetics in special clinical populations. A population pharmacokinetic analysis was performed in 505 patients with colorectal cancer treated with capecitabine 1250 mg/m² twice daily. Gender, presence or absence of liver metastases at baseline, Karnofsky performance status, total bilirubin concentration, serum albumin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels had no significant effect on the pharmacokinetics of 5'-DFUR, 5-FU, or FBAL.
Patients with hepatic metastases. Pharmacokinetic data in patients with mild to moderate hepatic impairment due to metastases indicate 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 capecitabine and 5-FU are independent of creatinine clearance (CrCl). 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), Cmax of capecitabine was 36% lower and AUC 24% lower compared to Caucasian patients (N = 22). Cmax of the capecitabine metabolite FBAL in Japanese patients was 25% lower and AUC 34% lower 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.
Colorectal cancer:
- Colon cancer — use the medicinal product as adjuvant therapy following surgical treatment of stage III cancer (Dukes' stage C);
- Metastatic colorectal cancer.
Gastric cancer:
- Use as first-line treatment for advanced gastric cancer in combination with platinum-based agents.
Breast cancer:
- Locally advanced or metastatic breast cancer — use in combination with docetaxel after ineffective chemotherapy containing anthracycline agents;
- Locally advanced or metastatic breast cancer — use as monotherapy after ineffective chemotherapy containing taxanes and anthracyclines, or when anthracycline therapy is contraindicated.
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. Diagnosed complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special precautions").
- Pregnancy and breastfeeding.
- Severe leukopenia, neutropenia, thrombocytopenia.
- Severe hepatic impairment.
- Severe renal impairment (creatinine clearance < 30 mL/min).
- Recent or concomitant treatment with brivudine (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
- 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.
Brivudine.
A clinically significant interaction between brivudine and fluoropyrimidines (e.g., capecitabine, 5-fluorouracil, tegafur) due to inhibition of dihydropyrimidine dehydrogenase by brivudine has been described. 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 should be observed 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.
Cytochrome P450 2C9 substrates.
Interaction studies between capecitabine and other medicinal products metabolized by the cytochrome P450 2C9 isoenzyme, except for warfarin, have not been conducted. Caution is advised when prescribing capecitabine with these medicinal products (e.g., phenytoin).
Coumarin anticoagulants.
Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), which may lead to coagulation abnormalities and bleeding within several days or months after initiation of capecitabine therapy, and in some cases, up to one month after discontinuation of capecitabine treatment. In a clinical pharmacokinetic interaction study, following a single 20 mg dose of S-warfarin, capecitabine treatment increased warfarin AUC by 57% and INR (International Normalized Ratio) by 91%. Since R-warfarin metabolism was unaffected, this indicates that capecitabine inhibits the 2C9 isoenzyme and does not affect 1A2 and 3A4 isoenzymes. Patients receiving capecitabine concomitantly with oral anticoagulants — coumarin derivatives — require close monitoring of coagulation parameters (International Normalized Ratio or prothrombin time) and dose adjustment of the anticoagulant.
Phenytoin.
Cases of increased plasma phenytoin concentrations, accompanied by symptoms of phenytoin intoxication, have been reported with concomitant use of capecitabine and phenytoin. Regular monitoring of plasma phenytoin concentrations is recommended in patients receiving capecitabine together with phenytoin.
Folinic acid / folic acid.
Folinic acid does not significantly affect the pharmacokinetics of capecitabine and its metabolites. However, folinic acid influences the pharmacodynamics of capecitabine, potentially increasing its toxicity: the maximum tolerated dose of the medicinal product Capecitabine-Vista in monotherapy under an intermittent dosing regimen is 3000 mg/m²/day, whereas in combination with folinic acid (30 mg orally twice daily) it is only 2000 mg/m²/day. Increased toxicity may occur when switching from a 5-fluorouracil/leucovorin regimen to a capecitabine regimen. This may also occur when folic acid is used to correct folic acid deficiency due to the similarity between folinic and folic acid.
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 one of its metabolites (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 resulting in reduced efficacy of 5-fluorouracil has been observed. Therefore, concomitant use of the medicinal product Capecitabine-Vista and allopurinol should be avoided.
Interferon alpha.
The maximum tolerated dose of the medicinal product Capecitabine-Vista is 2000 mg/m²/day when used in combination with interferon alfa-2a (3 million IU/m²/day), compared to 3000 mg/m²/day when Capecitabine-Vista is used as monotherapy.
Radiation therapy.
The maximum tolerated dose of the medicinal product Capecitabine-Vista in monotherapy under an intermittent dosing regimen is 3000 mg/m²/day, whereas in combination with radiation therapy for rectal cancer it is 2000 mg/m²/day when administered concurrently with continuous radiation therapy or a daily 6-week course of radiation therapy from Monday to Friday.
Oxaliplatin.
When capecitabine is used in combination with oxaliplatin, with or without bevacizumab, no clinically significant differences in exposure to capecitabine or its metabolites, free platinum, or total platinum were observed.
Bevacizumab.
No clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites was 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 available safety and efficacy data are based on administration of capecitabine with food, Capecitabine-Vista is recommended to be taken with food. Administration of Capecitabine-Vista with food results in a slower absorption rate of capecitabine.
Special precautions for use.
Toxic effects dependent on dose.
Toxic effects dependent on dose are manifested as diarrhoea, abdominal pain, nausea, stomatitis, and palmar-plantar syndrome (palmar-plantar skin reactions, palmar-plantar 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.
Diarrhoea. Patients with severe diarrhoea should be closely monitored and rehydrated, with electrolyte replacement if dehydration occurs. Standard anti-diarrhoeal agents (e.g., loperamide) may be administered. Grade II diarrhoea according to the National Cancer Institute of Canada (NCIC CTCAE, version 2) is defined as an increase in bowel movements to 4–6 times per day or nocturnal defecation; Grade III diarrhoea is defined as an increase in bowel movements to 7–9 times per day, faecal incontinence, or malabsorption. Grade IV diarrhoea is defined as an increase in bowel movements to ≥10 per day, or massive diarrhoea with blood, or requirement for parenteral fluid administration. If necessary, the dose of the drug should be reduced (see section "Dosage and administration").
Dehydration. Dehydration should be prevented and corrected if it occurs. Dehydration may rapidly develop in patients with anorexia, asthenia, nausea, vomiting, or diarrhoea. Dehydration may lead to acute renal failure, particularly 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 fatal. If Grade II (or higher) dehydration occurs, treatment with capecitabine must be immediately discontinued and dehydration corrected. Treatment may be resumed once adequate correction of dehydration and control of precipitating causes have been achieved (see section "Dosage and administration"). Dose adjustments should be considered if precipitating adverse events occur.
Palmar-plantar syndrome.
Palmar-plantar syndrome, also known as palmar-plantar skin reactions or palmar-plantar erythrodysesthesia, or chemotherapy-induced peripheral erythema, is characterized as follows: Grade I palmar-plantar syndrome does not interfere with daily activities and is manifested by numbness, paraesthesia, dysesthesia, tingling, painless swelling, or erythema of palms and/or soles, and/or discomfort.
Grade II palmar-plantar syndrome is characterized by painful erythema and swelling of hands and/or soles; discomfort caused by these symptoms interferes with the patient's daily activities.
Grade III palmar-plantar syndrome is defined as moist desquamation, ulceration, blistering, and acute pain in palms and/or soles, and/or severe discomfort preventing the patient from working or performing daily activities. Persistent or severe palmar-plantar syndrome (Grade II or higher) may eventually lead to loss of fingerprints, potentially affecting patient identification. In case of Grade II or III palmar-plantar syndrome, 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. Vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of palmar-plantar syndrome in patients receiving capecitabine and cisplatin, as published data suggest this may reduce the efficacy of cisplatin. Some data indicate that dexpanthenol is effective in preventing palmar-plantar 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 ischaemic 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 to patients with clinically significant cardiac disease, arrhythmias, or angina.
Hypo- or hypercalcaemia.
Hypo- or hypercalcaemia have been reported during capecitabine treatment.
Diseases of the central or peripheral nervous system.
Caution is required when prescribing capecitabine to patients with diseases of the central or peripheral nervous system, such as brain metastases or neuropathy.
Caution is also required when prescribing capecitabine to patients with diabetes mellitus or electrolyte imbalances, as capecitabine treatment may worsen their condition.
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. In patients receiving capecitabine concomitantly with oral anticoagulants (coumarin derivatives), close monitoring of coagulation parameters (international normalized ratio or prothrombin time) and dose adjustment of the anticoagulant are required.
Brivudine.
Concomitant use of brivudine and capecitabine is contraindicated. 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 start 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 to prevent systemic infections and dehydration should be initiated.
Hepatic impairment.
Due to the lack of safety and efficacy data in patients with hepatic impairment, careful monitoring of patients with mild to moderate hepatic dysfunction is required when using capecitabine, regardless of the presence or absence of liver metastases. If hyperbilirubinaemia exceeding three times the upper limit of normal or an increase in hepatic aminotransferase activity (ALT, AST) 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 fall 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 a rate-limiting factor in the catabolism of 5-fluorouracil (see section "Pharmacological properties"). Therefore, patients with DPD deficiency are at increased risk of fluoropyrimidine-related toxicity, including stomatitis, diarrhoea, mucositis, neutropenia, and neurotoxicity. DPD deficiency-related toxicity usually occurs during the first treatment cycle or after dose escalation.
Complete DPD deficiency.
Complete DPD deficiency is a rare condition (0.01–0.5% of Caucasian individuals). Patients with complete DPD deficiency are at high risk of life-threatening, including fatal, toxicity and must not receive capecitabine treatment (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 are at increased risk of severe and potentially life-threatening toxicity. To mitigate this risk, consideration should be given to reducing the initial dose. DPD deficiency should be considered alongside other routine factors when deciding on dose reduction. Reducing the initial dose may affect treatment efficacy. In the absence of severe toxicity, subsequent doses may be increased with careful monitoring.
Testing for DPD deficiency.
Before initiating capecitabine treatment, phenotypic and/or genotypic testing is recommended, despite uncertainty regarding optimal pre-treatment testing methods. Relevant clinical guidelines should be considered.
Genotypic characterization of DPD deficiency.
Testing for rare DPYD gene mutations prior to treatment may identify patients with DPD deficiency.
Four 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 increased risk of severe, including life-threatening, toxicity. Certain homozygous or combined heterozygous mutations in the DPYD gene locus (e.g., combinations of the four variants with at least one c.1905+1G > A or c.1679T > G allele) are known to cause complete or near-complete absence of DPD enzymatic activity. Patients with certain heterozygous DPYD variants (particularly c.1905+1G > A, c.1679T > G, c.2846A > T, and c.1236G > A/HapB3) are at increased risk of severe toxicity during fluoropyrimidine treatment.
In Caucasian patients, the frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene is approximately 1%, c.2846A > T — 1.1%, c.1236G>A/HapB3 variants — 2.6–6.3%, and c.1679T > G — 0.07 to 0.1%.
Data on the frequency of the four DPYD variants in populations other than Caucasian are limited. Currently, the four DPYD variants (c.1905+1G > A, c.1679T > G, c.2846A > T, and c.1236G > A/HapB3) are considered practically absent in patients of African (American) or Asian origin.
Phenotypic characterization of DPD deficiency.
For phenotypic characterization of DPD deficiency, measurement of endogenous DPD substrate uracil in blood plasma before treatment is recommended.
Elevated pre-treatment uracil concentrations are associated with increased risk of toxicity. Despite uncertainty regarding threshold values indicating complete or partial DPD deficiency, a plasma uracil level ≥16 ng/mL and <150 ng/mL should be considered indicative of partial DPD deficiency and associated with increased risk of fluoropyrimidine toxicity. A plasma uracil level ≥150 ng/mL should be considered indicative of complete DPD deficiency and associated with risk of life-threatening, including fatal, fluoropyrimidine toxicity.
Ophthalmological complications.
Patients should be carefully 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 if clinically indicated.
Severe skin reactions.
Capecitabine treatment may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The use of capecitabine must be permanently discontinued in patients who develop severe skin reactions during treatment.
Capecitabine tablets must not be crushed or split. Contact of patients or caregivers with crushed or split tablets may result in adverse reactions (see section "Adverse reactions").
Disposal of unused and expired medicinal product. Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. "Waste collection systems" should be used for disposal if available.
Important information on excipients.
One 150 mg tablet contains 7.5 mg of sodium, i.e., the medicinal product is practically sodium-free.
One 500 mg tablet contains 25 mg of sodium. Caution is required when administering to patients on a sodium-restricted diet.
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 foetus. Effective contraceptive methods should be used during treatment and for 6 months after the last dose of capecitabine.
Based on genotoxicity study results, effective contraceptive methods should be used by male patients and their female partners of childbearing potential 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 is expected to be harmful to the foetus. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. Capecitabine must not be used during pregnancy.
Breastfeeding.
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 mice. Because the potential harm to breastfed infants is unknown, women should discontinue breastfeeding during capecitabine treatment and for 2 weeks after the last dose.
Fertility.
There are no data on the effect of capecitabine on fertility. In pivotal clinical trials, only women of childbearing potential and men who agreed to use acceptable methods of contraception to prevent pregnancy during the study and for a specified period thereafter were included. Effects on fertility were observed in animal studies.
Ability to affect reaction speed when driving or operating machinery.
The medicinal product has a minor or moderate effect on the ability to drive or operate machinery. Capecitabine may cause dizziness, weakness, and nausea.
Dosage and Administration
The medicinal product Capcitabine-Vista should be prescribed only by a qualified physician experienced in the use of antineoplastic agents. Close monitoring of all patients is recommended during the first treatment cycle.
Treatment should be discontinued in case of disease progression or development of unacceptable toxicity.
Capcitabine-Vista tablets should be taken orally no later than 30 minutes after a meal, swallowing the tablets whole with water. Capcitabine-Vista tablets must not be crushed or split.
Special precautions for disposal and other special handling of the medicinal product. Safe handling procedures for cytotoxic medicinal products should be followed.
Monotherapy .
Colon cancer, colorectal cancer, and breast cancer. The recommended initial daily dose of Capcitabine-Vista as adjuvant therapy is 2500 mg/m² body surface area. It should be administered in 3-week cycles: daily administration for 2 weeks followed by a 1-week treatment break. The total daily dose of Capcitabine-Vista should be divided into two doses (1250 mg/m² body surface area in the morning and evening). The recommended total duration of adjuvant therapy for patients with stage III colon 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 1250 mg/m² twice daily for 2 weeks, followed by a 1-week break (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 docetaxel product instructions, for patients receiving the combination of capcitabine + docetaxel.
Colon cancer, colorectal cancer, gastric cancer. In combination regimens, the initial dose of Capcitabine-Vista should be reduced to 800–1000 mg/m² twice daily for 2 weeks followed by a 1-week break, or to 625 mg/m² twice daily for continuous administration. When used in combination 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 break. The addition of bevacizumab to the combination regimen does not affect the initial dose of Capcitabine-Vista. Antiemetic agents and premedication to ensure adequate hydration should be administered to patients receiving Capcitabine-Vista in combination with cisplatin or oxaliplatin, according to the product instructions for cisplatin and oxaliplatin. The recommended total duration of adjuvant therapy for patients with stage III colon cancer is 6 months.
The dose of Capcitabine-Vista is calculated based on body surface area. Tables 1 and 2 provide calculations for standard and reduced initial doses (see "Dose modifications during treatment" below) of Capcitabine-Vista at 1250 mg/m² or 1000 mg/m².
Table 1
Calculations of standard and reduced initial doses of Capcitabine-Vista 1250 mg/m² according to body surface area.
| Dose 1250 mg/m² (twice daily) |
|||||
| Body surface area, m² |
Full dose 1250 mg/m² |
Number of 150 mg and/or 500 mg tablets per dose (morning and evening) |
Reduced dose (75%) 950 mg/m² |
Reduced dose (50%) 625 mg/m² |
|
| Dose per administration, mg |
150 mg |
500 mg |
Dose per administration, mg |
Dose per administration, mg |
|
| ≤ 1.26 |
1500 |
- |
3 |
1150 |
800 |
| 1.27–1.38 |
1650 |
1 |
3 |
1300 |
800 |
| 1.39–1.52 |
1800 |
2 |
3 |
1450 |
950 |
| 1.53–1.66 |
2000 |
- |
4 |
1500 |
1000 |
| 1.67–1.78 |
2150 |
1 |
4 |
1650 |
1000 |
| 1.79–1.92 |
2300 |
2 |
4 |
1800 |
1150 |
| 1.93–2.06 |
2500 |
- |
5 |
1950 |
1300 |
| 2.07–2.18 |
2650 |
1 |
5 |
2000 |
1300 |
| ≥ 2.19 |
2800 |
2 |
5 |
2150 |
1450 |
Table 2
Calculations of standard and reduced initial dose of Capcitabine-Vista 1000 mg/m2 depending on body surface area.
| Body surface area, m2 |
Dose 1000 mg/m2 (twice daily) |
||||
| Full dose 1000 mg/m2 |
Number of 150 mg and/or 500 mg tablets per dose (morning and evening) |
Reduced dose (75%) 750 mg/m2 |
Reduced dose (50%) 500 mg/m2 |
||
| Dose per administration, mg |
150 mg |
500 mg |
Dose per administration, mg |
Dose per administration, mg |
|
| ≤ 1.26 |
1150 |
1 |
2 |
800 |
600 |
| 1.27–1.38 |
1300 |
2 |
2 |
1000 |
600 |
| 1.39–1.52 |
1450 |
3 |
2 |
1100 |
750 |
| 1.53–1.66 |
1600 |
4 |
2 |
1200 |
800 |
| 1.67–1.78 |
1750 |
5 |
2 |
1300 |
800 |
| 1.79–1.92 |
1800 |
2 |
3 |
1400 |
900 |
| 1.93–2.06 |
2000 |
- |
4 |
1500 |
1000 |
| 2.07–2.18 |
2150 |
1 |
4 |
1600 |
1050 |
| ≥ 2.19 |
2300 |
2 |
4 |
1750 |
1100 |
Dose modification during treatment.
General recommendations.
Toxicity symptoms associated with the use of the medicinal product Capecitabine-Vista can be managed by symptomatic therapy and/or dose adjustment (by interrupting treatment or reducing the dose). If a dose reduction is required, the dose should not be increased thereafter.
Treatment with Capecitabine-Vista may be continued at the same dose in the presence of toxicity symptoms that, in the physician’s opinion, are unlikely to be serious or life-threatening, such as alopecia, taste alterations, or nail changes. Patients receiving Capecitabine-Vista should be advised to discontinue treatment in case 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 tests, neutrophil counts drop to < 1.0 × 10⁹/L or platelet counts to < 75 × 10⁹/L.
Dosage modification recommendations in the event of toxicities according to the toxicity grading criteria are provided below. The criteria were developed by the Canadian National Cancer Institute (NCIC CTG, version 1).
Table 3
Dose reduction scheme for the medicinal product Capecitabine-Vista (3-week cycle or continuous treatment)
| Toxicity Grade* |
Dose modifications during the treatment course |
Dose adjustment for the next cycle (% of initial dose) |
| Grade I |
Dose unchanged |
Dose unchanged |
| Grade II |
||
|
Discontinue therapy until toxicity signs resolve to Grade 0–1 |
100 % |
|
75 % |
|
|
50 % |
|
|
Discontinue the medicinal product |
Not applicable |
| Grade III |
||
|
Discontinue therapy until toxicity signs resolve to Grade 0–1 |
75 % |
|
50 % |
|
|
Discontinue the medicinal product |
Not applicable |
| Grade IV |
||
|
Discontinue the medicinal product or, if continuation of treatment is in the patient's best interest, discontinue therapy until toxicity signs resolve to Grade 0–1 |
50 % |
|
Discontinue the medicinal product |
Not applicable |
*According to the National Cancer Institute of Canada's Common Toxicity Criteria (NCIC CTG), version 1, or the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. For hand-foot syndrome and hyperbilirubinemia, see section "Special Instructions".
Dose modifications in the event of toxicity during a 3-week cycle of capecitabine in combination with other medicinal products.
Dose modifications in the event of toxicity during treatment with capecitabine within a 3-week cycle in combination with other medicinal products should be performed according to Table 3 and in accordance with the medical instructions for the other medicinal products used.
At the beginning of a treatment cycle, if a delay in treatment with capecitabine or another medicinal product is required, the administration of all other components of the regimen should also be delayed until all components can be administered again. If toxicities occur during treatment that, in the physician's opinion, are not related to capecitabine, treatment with capecitabine should be continued, and the doses of the other medicinal products in the regimen should be adjusted according to their respective medical instructions.
If discontinuation of other medicinal products in the regimen is required, treatment with capecitabine may be continued once the necessary conditions for re-initiation are met.
The above recommendations apply to all indications and all patient groups.
Dose modifications in the event of toxicity during continuous administration of capecitabine in combination with other medicinal products.
Dose modifications in the event of toxicity during continuous administration of capecitabine in combination with other medicinal products should be performed according to Table 3 and in accordance with the medical instructions for the other medicinal products used.
Dose adjustments in special situations.
Patients with hepatic impairment.
There is insufficient safety and efficacy data in patients with hepatic impairment to provide dose adjustment recommendations. No information is available regarding hepatic impairment due to cirrhosis or hepatitis.
Patients with renal impairment.
Capecitabine is contraindicated in patients with severe renal impairment (baseline creatinine clearance calculated by the Cockcroft-Gault formula < 30 ml/min). The incidence of grade 3 or 4 adverse reactions is increased in patients with moderate renal impairment (baseline creatinine clearance 30–50 ml/min) compared to the general population. For patients with pre-existing moderate renal impairment, a reduced initial dose of 75% of the standard dose (1250 mg/m²) is recommended. For patients with pre-existing moderate renal impairment, a reduction from the initial dose of 1000 mg/m² is not required. Patients with mild renal impairment (creatinine clearance 51–80 ml/min) do not require initial dose adjustment. Careful monitoring is recommended, and treatment should be interrupted immediately upon occurrence of adverse events of grade 2, 3, or 4, followed by further dose adjustments according to Table 3. If creatinine clearance decreases to less than 30 ml/min, treatment with capecitabine should be discontinued. Dose adjustment recommendations for moderate renal impairment are the same for both monotherapy with capecitabine and combination therapy.
Elderly patients.
Initial dose adjustment is not required for monotherapy with capecitabine. However, in patients aged ≥ 60 years, treatment-related adverse reactions of grade 3 and 4 occurred more frequently than in 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. When capecitabine is used in combination with docetaxel in patients over 60 years of age, an increased incidence of grade 3 and 4 toxicities has been observed. 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. Symptoms of acute overdose include nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, as well as bone marrow suppression.
Treatment. Treatment should include standard therapeutic and supportive measures aimed at managing clinical manifestations and preventing 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 capecitabine monotherapy 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 disorders (diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (hand-foot erythrodysesthesia), 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 to be possibly, probably, or remotely related to capecitabine were observed in clinical studies 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 (≥ 1/10000 to < 1/1000), very rare (< 1/10000). Within each frequency group, adverse reactions are listed in order of decreasing severity.
Monotherapy with Capecitabine
The adverse reactions associated with capecitabine monotherapy listed below are based on a pooled safety analysis from three pivotal trials involving 1900 patients (M66001, SO14695, and SO14796). Adverse reactions are categorized according to their 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:
Uncommon — lipoma.
Blood and lymphatic system disorders:
Common — anemia, neutropenia;
Uncommon — febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased international normalized ratio (INR)/prothrombin time prolongation.
Immune system disorders:
Uncommon — hypersensitivity reactions, angioneurotic edema.
Metabolism and nutrition disorders:
Very common — anorexia;
Common — dehydration, weight loss;
Uncommon — diabetes mellitus, hypokalemia, appetite disorders, decreased nutrition, 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, sensory disturbances, peripheral neuropathy;
Very rare — toxic leukoencephalopathy.
Eye disorders:
Common — lacrimation, conjunctivitis, eye irritation;
Uncommon — decreased visual acuity, diplopia;
Rare — lacrimal duct stenosis, corneal disorders, keratitis, punctate keratitis.
Ear and labyrinth disorders:
Uncommon — vertigo, ear pain.
Cardiac disorders:
Uncommon — unstable angina, angina pectoris, myocardial ischemia/infarction, 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, flushing, 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, abnormal liver function tests;
Uncommon — jaundice;
Rare — liver failure and cholestatic hepatitis.
Skin and subcutaneous tissue disorders:
Very common — hand-foot erythrodysesthesia syndrome (based on 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, 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 syndrome;
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:
Very common — weakness, asthenia;
Common — hyperthermia, peripheral edema, malaise, chest pain;
Uncommon — edema, fever, influenza-like symptoms, chills, increased body temperature.
In the context of "common adverse reactions" in the "Capecitabine Monotherapy" section, severe and/or life-threatening (grade 3–4) or medically significant adverse reactions are indicated.
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 during monotherapy and/or observed with higher frequency in any of the main clinical trials.
Some adverse reactions are commonly associated with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, an exacerbation of these adverse reactions with capecitabine cannot be ruled out.
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 suppression, 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, decreased visual acuity, blurred vision.
Ear and labyrinth disorders:
Common — tinnitus, hearing loss.
Cardiac disorders:
Common — atrial fibrillation, myocardial ischemia/infarction.
Vascular disorders:
Very common — lower limb edema, arterial hypertension, thrombosis/embolism*;
Common — flushing, 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, 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:
Very common — increased body temperature, weakness, drowsiness*, heat sensitivity;
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.
*Frequency includes all grades of severity, except for adverse reactions marked with "*", which include only grade 3–4 adverse reactions.
Description of selected adverse reactions
Hand-Foot Syndrome
When capecitabine was 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. When capecitabine was administered at 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 across 14 clinical trials showed that hand-foot syndrome of all grades occurred in 43% (2066) of patients receiving 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 treatment (95% CI: 201–288). 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 in 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 capecitabine treatment. According to a meta-analysis of data from more than 4700 patients in 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 in the first 6 weeks of treatment.
Cardiotoxicity
In addition to the cardiac adverse reactions listed above, the following adverse reactions were reported with a frequency of less than 0.1% during capecitabine monotherapy, based on a pooled safety analysis from 949 patients 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, based on a pooled safety analysis from 7 clinical trials, was associated with encephalopathy at a frequency of less than 0.1%.
Exposure to crushed or split capecitabine tablets
Adverse reactions reported following exposure to crushed or split capecitabine tablets include: eye irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, stomach 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 3 and 4 adverse reactions and serious treatment-related adverse events compared to patients aged <60 years. A higher proportion of patients aged ≥60 years receiving combination therapy with capecitabine and docetaxel discontinued treatment earlier due to adverse reactions compared to those aged <60 years.
A meta-analysis of data from more than 4700 patients in 14 clinical trials demonstrated that, across all study combinations, increasing age (per 10-year increment) 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, combining data from all studies, showed that female sex was statistically significantly associated with increased risk of hand-foot syndrome and diarrhea, and decreased risk of neutropenia.
Patients with impaired renal function
In patients with pre-existing renal impairment receiving capecitabine monotherapy (for colorectal cancer), the incidence of grade 3 and 4 treatment-related adverse reactions was higher 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% vs. 33% and 32% in patients without renal impairment and with mild renal impairment, respectively) and more frequently discontinued treatment prematurely (21% during the first two cycles vs. 5% and 8% in patients without renal impairment and with mild renal impairment, respectively).
Reporting suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua
Shelf life
3 years.
Storage conditions
Store at temperatures not exceeding 30°C in a place inaccessible to children.
Packaging
10 tablets in a blister; 6 blisters (150 mg strength) or 12 blisters (500 mg strength) per cardboard pack.
Prescription status
By prescription only.
Manufacturer:
Remedica Limited
Manufacturer’s address and place of business:
Acharnon Street, Limassol Industrial Estate, Limassol, 3056, Cyprus.