Capcitabine amaksa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CAPECITABINE AMAXA CapecitabineAmaxa
Composition:
Active substance: capecitabine;
1 tablet contains 150 mg or 500 mg of capecitabine;
Excipients: anhydrous lactose, sodium croscarmellose, hypromellose, microcrystalline cellulose, magnesium stearate;
Film coating:
for 150 mg tablets – Opadry II pink 85F240015: polyvinyl alcohol (E 1203), titanium dioxide (E 171), polyethylene glycol (E 1521), talc (E 553b), iron oxide red (E 172), iron oxide yellow (E 172);
for 500 mg tablets – Opadry II pink 85F240045: polyvinyl alcohol (E 1203), titanium dioxide (E 171), polyethylene glycol (E 1521), talc (E 553b), iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
film-coated tablets 150 mg: light peach-colored, biconvex, elongated shape;
film-coated tablets 500 mg: peach-colored, biconvex, elongated shape.
Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01B C06.
Pharmacological Properties
Pharmacodynamics
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate and an oral prodrug of the cytotoxic agent 5-fluorouracil (5-FU). Capecitabine is activated through a multi-enzymatic process (see section "Pharmacokinetics"). The final conversion to 5-FU occurs under the action of thymidine phosphorylase in tumor tissue as well as in healthy tissues of the body, although usually 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 blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with deoxyribonucleic acid (DNA) synthesis. Incorporation of 5-FU also inhibits ribonucleic acid (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. The effects on DNA and RNA are more pronounced in cells with higher proliferative activity and greater 5-FU metabolism.
Pharmacokinetics
The pharmacokinetics of capecitabine were evaluated over a dose range of 502–3514 mg/m²/day. Pharmacokinetic parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) were similar on Day 1 and Day 14. On Day 14, the area under the plasma concentration-time curve (AUC) for 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 undergoes biotransformation into metabolites 5'-DFCR and 5'-DFUR. Food intake reduces the rate of absorption of capecitabine but does not significantly affect the AUC of 5'-DFUR or the subsequent metabolite 5-FU. When administered after food intake at a dose of 1250 mg/m² on Day 14, the maximum plasma concentration (Cmax) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and α-fluoro-β-alanine (FBAL) was 4.67, 3.05, 12.1, 0.95, and 5.46 µg/mL, respectively. The time to reach maximum plasma 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 studies in human plasma demonstrated that protein binding (primarily to albumin) for capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU was 54%, 10%, 62%, and 10%, respectively.
Metabolism
Capecitabine is metabolized in the liver by carboxylesterase to the metabolite 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, primarily located in the liver and tumor tissues. Further catalytic activation of 5'-DFUR occurs via thymidine phosphorylase. The enzymes involved in catalytic activation are present in both tumor and normal tissues, although usually at lower levels. This 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 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 normal tissue concentration 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 the less toxic dihydro-5-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-ureidopropionic acid (FUPA). The final step is the breakdown of FUPA to FBAL by β-ureidopropionase, which is excreted in urine. DPD activity is the rate-limiting step. DPD deficiency may lead to increased toxicity of capecitabine (see sections "Contraindications" and "Special Warnings and Precautions for Use").
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. Capecitabine and its metabolites are primarily excreted in urine. Renal excretion accounts for 95.5% of the dose, 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 or paclitaxel (Cmax and AUC), nor any effect of docetaxel or 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 concentration, serum albumin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) had no significant effect on the pharmacokinetics of 5'-DFUR, 5-FU, or FBAL.
Patients with Metastatic Liver Involvement
According to pharmacokinetic data in patients with mild to moderate hepatic impairment due to metastases, the bioavailability of capecitabine and exposure to 5-FU may be increased compared to patients without hepatic impairment. 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 (a 50% reduction in CrCl leads to a 35% increase in AUC) and FBAL (a 50% reduction in CrCl leads to a 114% increase in AUC). FBAL is a metabolite without antiproliferative activity.
Elderly Patients
According to population pharmacokinetic analysis including patients across a wide age range (27–86 years), of whom 234 (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 is associated with a 15% increase in FBAL AUC), likely due to age-related changes in renal function.
Ethnic Factors
After oral administration of capecitabine 825 mg/m² 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 were observed in exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).
Clinical characteristics.
Indications.
Breast cancer:
- Locally advanced or metastatic breast cancer in combination with docetaxel after ineffective chemotherapy containing anthracycline agents;
- Locally advanced or metastatic breast cancer as monotherapy after ineffective chemotherapy containing taxanes and anthracycline agents, or in cases where anthracycline therapy is contraindicated.
Colorectal cancer:
- Colorectal cancer in adjuvant therapy following surgical treatment of stage III cancer (Dukes' stage C);
- Metastatic colorectal cancer.
Gastric cancer:
- First-line treatment of advanced gastric cancer in combination with platinum-based agents.
Contraindications.
Hypersensitivity to capecitabine, to any component of the medicinal product, or to fluorouracil.
Severe, including unexpected, reactions to fluoropyrimidine therapy in medical history.
Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special precautions").
Pregnancy and breastfeeding period.
Severe leukopenia, neutropenia, or thrombocytopenia.
Severe hepatic impairment.
Severe renal impairment (creatinine clearance < 30 mL/min).
Recent or concomitant treatment with brivudine (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions" regarding interactions with other medicinal products).
Contraindications to any medicinal product used in combination.
Special safety measures.
Unused medicinal product or waste materials must be disposed of in accordance with local regulations. Environmental contamination should be minimized.
Interaction with other medicinal products and other types of interactions.
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-FU, tegafur) due to inhibition of DPD by brivudine has been described. This interaction increases fluoropyrimidine toxicity and may potentially lead to fatal outcomes. Therefore, concomitant use of brivudine with capecitabine is contraindicated (see sections "Contraindications" and "Special precautions"). The interval between discontinuation of brivudine treatment and initiation of capecitabine therapy should be at least 4 weeks. Brivudine treatment may be initiated 24 hours after the last dose of capecitabine.
Cytochrome P450 2C9 substrates. Interaction studies between capecitabine and other drugs metabolized by the CYP2C9 isoenzyme of the cytochrome P450 system, except for warfarin, have not been conducted. Caution is advised when prescribing capecitabine with these drugs (e.g., phenytoin).
Coumarin-derived anticoagulants. Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), potentially leading 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. In a clinical pharmacokinetic interaction study, single-dose administration of 20 mg warfarin resulted in a 57% increase in AUC of S-warfarin and a 91% increase in the international normalized ratio (INR) during capecitabine treatment. Since the metabolism of R-warfarin was unaffected, this indicates that capecitabine inhibits the CYP2C9 isoenzyme and does not affect CYP1A2 or CYP3A4 isoenzymes. Patients receiving both capecitabine and oral coumarin-derived anticoagulants require close monitoring of coagulation parameters (INR or prothrombin time) and anticoagulant dose adjustment.
Phenytoin. Cases of increased plasma phenytoin concentrations associated with symptoms of phenytoin toxicity have been reported during concomitant use of capecitabine and phenytoin. Regular monitoring of plasma phenytoin concentrations is recommended in patients receiving both drugs.
Folinic acid/folic acid. Combination studies of capecitabine and folinic acid have shown that folinic acid does not significantly affect the pharmacokinetics of capecitabine or its metabolites. However, folinic acid affects the pharmacodynamics of capecitabine, potentially increasing its toxicity: the maximum tolerated dose of capecitabine in monotherapy with intermittent dosing 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 5-FU/leucovorin to capecitabine regimens. This may also occur when folic acid is administered to correct folate 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 metabolite (5'-DFCR), but do not affect the three main metabolites (5'-DFUR, 5-FU, and FBAL).
Allopurinol. An interaction between allopurinol and 5-FU has been observed, potentially reducing the efficacy of 5-FU. Therefore, concomitant use of capecitabine and allopurinol should be avoided.
Interferon alfa. The maximum tolerated dose of capecitabine 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 used as monotherapy.
Radiation therapy. The maximum tolerated dose of capecitabine in monotherapy with intermittent dosing is 3000 mg/m²/day, whereas in combination with radiation therapy for rectal cancer, it is 2000 mg/m²/day during continuous radiation therapy or a 6-week daily 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 have been observed.
Bevacizumab. No clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites has been observed in the presence of oxaliplatin.
Medicinal product – food interaction
In all clinical trials, patients were instructed to take Capecitabine Amaksa within 30 minutes after food intake. Since safety and efficacy data are based on administration of capecitabine with food, it is recommended to take the medicinal product with food. Administration of capecitabine with food slows the absorption rate of capecitabine (see section "Pharmacokinetics").
Special precautions for use.
Dose-dependent toxicity. Dose-dependent toxic effects manifest as diarrhea, abdominal pain, nausea, stomatitis, and hand-foot syndrome (hand-foot 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.
Diarrhea. Patients with severe diarrhea should be closely monitored, with rehydration and electrolyte replacement performed in cases of dehydration. Standard anti-diarrheal agents (e.g., loperamide) may be administered. Diarrhea graded as NCIC CTCAE (National Cancer Institute of Canada Common Toxicity Criteria, version 2) Grade II 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 to 7–9 bowel movements per day, fecal incontinence, or malabsorption. Grade IV diarrhea is defined as ≥10 bowel movements per day, massive diarrhea with blood, or requirement for parenteral fluid administration. Dose reduction of the drug may be necessary if required (see section "Dosage and administration").
Dehydration. Dehydration should be prevented or corrected promptly 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 nephrotoxic drugs. Acute renal failure resulting from dehydration may be potentially fatal. If Grade II (or higher) dehydration occurs, treatment with Capecitabine Amaksa must be discontinued immediately and dehydration corrected. Resumption of treatment is possible after adequate correction of dehydration and management/control of precipitating causes (see section "Dosage and administration"). Dose adjustment should be considered if precipitating adverse events occur.
Hand-foot syndrome (synonyms: palmar-plantar skin reactions, palmar-plantar erythrodysesthesia, chemotherapy-induced peripheral erythema). Grade I hand-foot syndrome does not interfere with daily activities and is characterized by numbness, paresthesia, dysesthesia, tingling, painless edema, or erythema of palms and/or soles, or discomfort.
Grade II hand-foot syndrome is characterized by painful erythema and swelling of hands and/or feet; discomfort caused by these symptoms interferes with daily activities.
Grade III hand-foot syndrome is defined as moist desquamation, ulceration, blistering, acute pain in palms and/or soles, or severe discomfort preventing patients from working or performing daily activities. Persistent or severe hand-foot syndrome (Grade II or higher) may eventually lead to loss of fingerprints, which may affect patient identification. In cases of Grade II or III hand-foot syndrome, capecitabine administration should be interrupted until symptoms resolve or improve to Grade I; upon recurrence of Grade III syndrome, the dose of capecitabine should be reduced. Concomitant use of vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of hand-foot syndrome in patients receiving both capecitabine and cisplatin, as published data suggest this may reduce cisplatin efficacy. Some data indicate that dexpanthenol is effective in preventing hand-foot syndrome in patients treated with Capecitabine Amaksa.
Cardiotoxicity. The spectrum of cardiotoxicity associated with capecitabine therapy is similar to that observed with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiogenic shock, sudden death, cardiac arrest, heart failure, and electrocardiographic changes (including very rare cases of QT interval prolongation). These adverse reactions 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 to patients with clinically significant heart disease, arrhythmias, or angina (see section "Adverse reactions").
Hypo- or hypercalcemia. Hypo- or hypercalcemia has been reported during capecitabine treatment. Caution is advised in patients with pre-existing hypo- or hypercalcemia (see section "Adverse reactions").
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 (see section "Adverse reactions").
Diabetes mellitus or electrolyte disturbances. Caution is required when prescribing capecitabine 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 mean S-warfarin AUC (by 57%) was observed, indicating an interaction, likely due to inhibition of cytochrome P450 isoenzyme 2C9 by capecitabine. In patients receiving capecitabine concomitantly with oral anticoagulants (coumarin derivatives), close monitoring of coagulation parameters (INR or prothrombin time) and anticoagulant dose adjustment are required (see section "Interaction with other medicinal products and other forms of interaction").
Brivudine. Concomitant use of brivudine with capecitabine is contraindicated. Fatal outcomes have been reported following this drug interaction. A waiting period of at least 4 weeks must elapse between the end of brivudine treatment and 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 in patients with hepatic dysfunction, patients with mild to moderate hepatic impairment, regardless of the presence or absence of liver metastases, should be carefully monitored during capecitabine treatment. If hyperbilirubinemia exceeding 3 times the upper limit of normal (ULN) or an increase in hepatic aminotransferase activity (ALT, AST) exceeding 2.5 times ULN occurs during capecitabine treatment, the drug should be temporarily discontinued. Capecitabine monotherapy may be resumed when bilirubin levels and hepatic transaminase activities decrease below the specified 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.
Dihydropyrimidine dehydrogenase (DPD) deficiency. DPD activity is a rate-limiting factor in 5-FU catabolism (see section "Pharmacological properties"). Therefore, patients with DPD deficiency are at increased risk of fluoropyrimidine-associated toxicity, manifesting as stomatitis, diarrhea, mucositis, neutropenia, and neurotoxicity.
DPD deficiency-related toxicity typically 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. Dose reduction may affect treatment efficacy. If no serious toxicity occurs, subsequent doses may be increased with careful monitoring.
Testing for DPD deficiency. Prior to initiating capecitabine treatment, phenotypic and/or genotypic testing is recommended, despite uncertainty regarding optimal pre-treatment testing methods. Relevant clinical guidelines should be considered.
Renal impairment may lead to elevated plasma uracil levels, increasing the risk of false diagnosis of DPD deficiency in patients with moderate renal impairment. Capecitabine is contraindicated in patients with severe renal impairment (see section "Contraindications").
Genotypic characterization of DPD deficiency. Testing for rare DPYD gene mutations before 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 cause 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 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 (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 genotype c.1905+1G>A in the DPYD gene is approximately 1%, c.2846A>T – 1.1%, c.1236G>A/HapB3 – 2.6–6.3%, and c.1679T>G – 0.07–0.1%.
Data on the frequency of the four DPYD variants in populations other than Caucasian are limited. To date, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) are considered virtually 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 plasma before treatment is recommended.
Elevated pre-treatment uracil concentrations are associated with increased risk of toxicity. Despite uncertainty regarding threshold uracil values indicating complete or partial DPD deficiency, plasma uracil levels ≥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 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 indicated.
Severe skin reactions. Capecitabine treatment may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Capecitabine must be permanently discontinued in patients who develop severe skin reactions during treatment.
Since the product contains the excipient anhydrous lactose (15.6 mg), Capecitabine Amaksa should not be administered to patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Capecitabine Amaksa tablets should not be crushed or split. Contact with crushed or split tablets by patients or caregivers may result in adverse reactions (see section "Adverse reactions").
Disposal of unused or expired medication: Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be performed via a 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 capecitabine treatment. If pregnancy occurs during treatment, patients should be informed of the potential adverse effects of the drug 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 capecitabine may be harmful to the fetus when administered during pregnancy. 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.
Lactation
It is unknown whether capecitabine passes into human breast milk. Studies on the effect of capecitabine on breast milk production or 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, breastfeeding must be discontinued 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 studies, only women of reproductive potential and men who agreed to use acceptable methods of birth control to prevent pregnancy during the study and for a specified period thereafter were included. Effects on fertility were observed in animal studies.
Ability to affect reaction speed when driving or operating machinery.
The drug has a minor or moderate effect on the ability to drive or operate machinery. Capecitabine may cause dizziness, weakness, and nausea.
Dosage and Administration
Capecitabine Amaksa should be prescribed only by a qualified physician experienced in the use of antineoplastic agents. Close monitoring during the first treatment cycle is recommended for all patients.
Treatment should be discontinued in the event of disease progression or development of unacceptable toxicity.
The tablets are taken orally, no later than 30 minutes after a meal, swallowed whole with water. Capecitabine Amaksa tablets should not be crushed or split.
Special precautions for disposal and other handling of the medicinal product
Standard procedures for safe handling of cytotoxic medicinal products should be followed.
Monotherapy
Colorectal cancer and breast cancer. The recommended initial daily dose of capecitabine as adjuvant therapy is 2500 mg/m² body surface area administered in 3-week cycles: daily administration for 2 weeks followed by a 1-week rest period. The total daily dose of Capecitabine Amaksa is 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. 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 rest period (in combination with docetaxel 75 mg/m² administered intravenously once every 3 weeks). Premedication with oral corticosteroids, such as dexamethasone, should be administered prior to docetaxel administration according to the docetaxel prescribing information for patients receiving the combination of capecitabine plus docetaxel.
Colorectal cancer and gastric cancer. In combination regimens, the initial dose of capecitabine 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 does not affect the initial dose of capecitabine.
Antiemetics and premedication for adequate hydration should be administered to patients receiving capecitabine in combination with cisplatin or oxaliplatin prior to cisplatin administration, according to the prescribing information for cisplatin and oxaliplatin. The recommended total duration of adjuvant therapy in patients with stage III colorectal cancer is 6 months.
The dose of capecitabine is calculated based on body surface area. Tables 1 and 2 provide dosage calculations for standard and reduced doses (see "Dose adjustments during treatment" below) for initial doses of Capecitabine Amaksa of 1250 mg/m² or 1000 mg/m².
Table 1
Calculations of standard and reduced initial doses of Capecitabine Amaksa 1250 mg/m² according to body surface area
| Dose 1250 mg/m2 (twice daily) |
|||||
| 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 |
||
| Body surface area, 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 Capecitabine Amaksa 1000 mg/m² depending on body surface area
| 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 |
||
| Body surface area, 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 Modifications During Treatment
General Recommendations
Toxicities associated with capecitabine treatment can be managed by symptomatic therapy and/or modification of the capecitabine dose (by interrupting treatment 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 toxicities 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 should be advised to discontinue treatment immediately in the event of moderate or severe toxic reactions. If several doses of capecitabine have been missed due to toxicity, the missed doses should not be made up.
Hematological Toxicity
Capecitabine therapy should not be initiated in patients with baseline neutrophil counts < 1.5×109/L and/or platelet counts < 100×109/L. Treatment should be suspended if, during unscheduled laboratory testing, neutrophil counts fall below 1.0×109/L or platelet counts fall below 75×109/L.
Dose modification recommendations for toxicities are provided below according to the toxicity grading criteria developed by the Canadian National Cancer Institute (NCIC CTG, version 1).
Table 3
Dose reduction scheme for Capecitabine Amaksa (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 |
No dose change |
No dose change |
| Grade II |
||
|
Discontinue therapy until signs of toxicity resolve to Grade 0–I |
100 % |
|
75 % |
|
|
50 % |
|
|
Discontinue the drug |
Not applicable |
| Grade III |
||
|
Discontinue therapy until signs of toxicity resolve to Grade 0–I |
75 % |
|
50 % |
|
|
Discontinue the drug |
Not applicable |
| Grade IV |
||
|
Discontinue the drug, or if continuation of treatment is considered necessary for the patient's benefit, discontinue therapy until signs of toxicity resolve to Grade 0–I |
50 % |
|
Discontinue the drug |
Not applicable |
*According to the National Cancer Institute's Common Toxicity Criteria (version 1) of the Canadian Oncology Group (NCIC CTG) or the National Cancer Institute's 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".
Dose modification in the event of toxicity during a 3-week cycle of capecitabine in combination with other medicinal products
Dose modification in the event of 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 instructions for medical use of the other medicinal products.
At the beginning of treatment, if a delay in capecitabine or another medicinal product is required, the administration of other agents should also be delayed until all components of the regimen can be administered.
If toxicities occur during treatment that, in the physician's opinion, are not related to capecitabine, treatment with capecitabine should be continued and dose adjustments of the other medicinal products in the regimen should be made according to their instructions for medical use.
If discontinuation of other components of the treatment regimen is necessary, capecitabine may be continued once the required conditions for re-initiation of capecitabine are met.
These recommendations apply to all indications and all patient groups.
Dose modification in the event of toxicity during continuous administration of capecitabine in combination with other medicinal products
Dose modification in the event of 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 instructions for medical use of the other medicinal products.
Dose adjustment 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 <30 mL/min at baseline according to Cockcroft-Gault). 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). For patients with baseline moderate renal impairment, a reduction from an initial dose of 1000 mg/m² is not required. Dose adjustment of the initial dose is not necessary for patients with mild renal impairment (creatinine clearance 51–80 mL/min).
Close monitoring of the patient is recommended, and treatment should be immediately interrupted in the event of grade II, III, or IV adverse effects, followed by further dose adjustment according to Table 3. Treatment with capecitabine must be discontinued if creatinine clearance decreases to less than 30 mL/min. Dose adjustment recommendations for moderate renal impairment are the same for both monotherapy with capecitabine and combination therapy.
Elderly patients
No adjustment of the initial dose is required for monotherapy with capecitabine. However, in elderly patients (aged ≥60 years), grade III and IV toxicities occurred more frequently than in younger patients.
When capecitabine is used in combination with other medicinal products in elderly patients, a higher incidence of grade III and IV adverse effects leading to treatment discontinuation has been observed compared to younger patients. Close monitoring of elderly patients is recommended.
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 elderly patients 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 elderly patients, the dose of capecitabine may be gradually increased to 1250 mg/m² twice daily.
Children
The safety and efficacy of this medicinal product in children have not been established.
Overdose
Symptoms of acute overdose: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, as well as bone marrow suppression. Treatment should include standard therapeutic and supportive measures to manage clinical manifestations and prevent possible complications.
Adverse Reactions.
Safety profile summary
The overall safety profile of capecitabine is based on data from more than 3000 patients who received capecitabine treatment 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 therapy 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 renal insufficiency, and thrombosis/embolism.
Adverse reactions considered by the investigator to be possibly, probably, or remotely related to capecitabine administration were observed in clinical trials of capecitabine monotherapy and in clinical trials of capecitabine used in combination with various chemotherapy regimens for different indications.
The following frequency categories are used to describe 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 category, adverse reactions are listed in order of decreasing severity.
Monotherapy
The adverse reactions listed below are associated with capecitabine monotherapy and are based on a pooled safety analysis of data from three pivotal trials involving 1900 patients (M66001, SO14695, and SO14796). Adverse reactions are categorized by frequency according to the 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 disorders, sensory disturbances, peripheral neuropathy; very rare – toxic leukoencephalopathy.
Eye disorders: common – lacrimation, conjunctivitis, eye irritation; uncommon – visual acuity reduced, diplopia; rare – lacrimal duct stenosis, corneal disorders, keratitis, punctate keratitis.
Ear and labyrinth disorders: uncommon – vertigo, ear pain.
Cardiac disorders: uncommon – unstable angina pectoris, angina pectoris, myocardial ischemia/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, liver function test abnormalities; uncommon – jaundice; rare – hepatic failure, cholestatic hepatitis.
Skin and subcutaneous tissue disorders: very common – hand-foot erythrodysesthesia syndrome (based on post-marketing experience, persistent or severe hand-foot erythrodysesthesia syndrome 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, erythema of palms, facial edema, purpura, reverse radiation recall; rare – cutaneous lupus erythematosus; very rare – severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (see section "Special precautions").
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 hemorrhage.
General disorders: very common – weakness, asthenia; common – pyrexia, peripheral edema, malaise, chest pain; uncommon – edema, fever, influenza-like symptoms, chills, hyperthermia.
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
The adverse reactions listed below were reported 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 during monotherapy and/or observed with higher frequency in any of the main clinical trials.
Some adverse reactions are commonly observed with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, an 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 neutropenia*, 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 – visual disturbance, dry eyes, eye pain, 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 – liver function test abnormalities.
Skin and subcutaneous tissue disorders: very common – alopecia, nail disorders; common – hyperhidrosis, erythematous rash, urticaria, night sweats.
Musculoskeletal and connective tissue disorders: very common – arthralgia, myalgia, limb pain; common – jaw pain, muscle spasms, trismus, muscle weakness.
Renal and urinary disorders: common – hematuria, proteinuria, decreased renal creatinine clearance, dysuria; rare – acute renal failure due to dehydration (see section "Special precautions").
General disorders: very common – pyrexia, weakness, drowsiness*, sensitivity to heat; 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 – injury by impact.
*Frequency includes all grades of severity, except for adverse reactions marked with "*", which include only Grade III–IV adverse reactions.
Specific 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 break, hand-foot syndrome of all grades of severity occurred in 53–60% of patients in monotherapy trials (adjuvant therapy 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 a dose of 1000 mg/m² twice daily for 2 weeks followed by a 1-week break, hand-foot syndrome of all grades of severity was observed 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 of severity 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 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 duration of treatment (weeks), increased patient age (per 10-year increment), female sex, and better baseline performance status (0 vs ≥1).
Diarrhea
Diarrhea during capecitabine treatment was observed in nearly 50% of patients. 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 across all studied combinations included: higher initial capecitabine dose (in grams), longer duration of treatment (weeks), increased patient age (per 10-year increment), and female sex. Statistically significant 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 listed cardiac adverse reactions, the following adverse reactions were reported with a frequency of less than 0.1% during capecitabine monotherapy based on a pooled safety analysis of data 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 listed adverse reactions, capecitabine monotherapy based on a pooled safety analysis of data 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, an increased risk of Grade III and IV adverse reactions and serious treatment-related adverse reactions was observed compared to patients under 60 years of age. A higher proportion of patients aged ≥60 years receiving combination therapy with capecitabine and docetaxel discontinued treatment earlier due to adverse reactions compared to patients under 60 years of age.
A meta-analysis of data from more than 4700 patients in 14 clinical trials demonstrated that in all combination studies, 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, demonstrated that female sex was statistically significantly associated with increased risk of hand-foot syndrome and diarrhea, and decreased risk of neutropenia.
Patients with renal impairment
In patients with pre-existing renal impairment receiving capecitabine monotherapy (for colorectal cancer), a higher frequency of Grade III and IV treatment-related adverse reactions was observed 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)). In patients with moderate renal impairment, dose reductions were more frequently required (44%) compared to 33% and 32% in patients without renal impairment and with mild renal impairment, respectively, and premature discontinuation of treatment was more frequently observed (21% during the first two cycles) compared to 5% and 8% in patients with normal renal function and mild renal impairment, respectively.
Reporting of suspected adverse reactions
It is important to report suspected adverse reactions after marketing authorization. This allows for continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions through the national reporting system.
Shelf life.
30 months.
Storage conditions.
Store below 30 °C in a place inaccessible to children.
Packaging.
For 150 mg: 10 tablets in a blister, 6 blisters in a cardboard box.
For 500 mg: 10 tablets in a blister, 12 blisters in a cardboard box.
Prescription category.
Prescription only.
Manufacturer.
Laboratorios Normon S.A./Laboratorios Normon, S.A.
Manufacturer's location and address of place of business.
Ronda de Valdecarrizo, 6, Tres Cantos, 28760 Madrid, Spain.
Marketing authorization holder.
Amaxa LTD.
Marketing authorization holder's location.
31 John Islip Street, London SW1P 4FE, United Kingdom.