Xeloda
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product Xeloda® (Xeloda®)
Composition:
Active substance: capecitabine;
One film-coated tablet contains capecitabine 150 mg or 500 mg;
Excipients: anhydrous lactose, sodium croscarmellose, hypromellose, microcrystalline cellulose, magnesium stearate; film coating: for 150 mg tablets – Opadry® pink 03A14309 (hypromellose, talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172)); for 500 mg tablets – Opadry® pink 03A14380 (hypromellose, talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172)).
Medicinal form. Film-coated tablets.
Main physicochemical properties: 150 mg tablets are biconvex, elongated, film-coated, light peach-colored, with "XELODA" imprinted on one side and "150" on the other;
500 mg tablets are biconvex, elongated, film-coated, peach-colored, with "XELODA" imprinted on one side and "500" on the other.
Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues.
ATC code L01B C06.
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 undergoes activation through a multi-enzyme process. The final conversion to 5-FU occurs primarily via thymidine phosphorylase, an enzyme present in both tumor tissues and normal body tissues, although generally at lower levels in the latter. In human cancer xenograft models, capecitabine has demonstrated a synergistic effect when combined with docetaxel, which may be attributed to docetaxel-induced upregulation of thymidine phosphorylase activity.
Evidence indicates that the anabolic metabolism of 5-FU interferes with the methylation of deoxyuridylic acid to thymidylic acid, thereby inhibiting deoxyribonucleic acid (DNA) synthesis. Incorporation of 5-FU into RNA also suppresses RNA and protein synthesis. Since both DNA and RNA are essential for cell division and growth, 5-FU can induce thymine deficiency, leading to imbalanced 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 have been characterized over a dose range of 502–3514 mg/m²/day. Pharmacokinetic parameters for capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), and 5'-deoxy-5-fluorouridine (5'-DFUR) were similar on Day 1 and Day 14. On Day 14, the AUC 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 nonlinear pharmacokinetics of the active metabolite.
Absorption
After oral administration, capecitabine is rapidly and completely absorbed and undergoes biotransformation into the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Food intake reduces the rate of capecitabine absorption but has no significant effect on the area under the concentration–time curve (AUC) of 5'-DFUR or the subsequent metabolite 5-FU. When administered at a dose of 1250 mg/m² after food intake on Day 14, maximum plasma concentrations (Cmax) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL were 4.67, 3.05, 12.1, 0.95, and 5.46 µg/mL, respectively. Time to maximum concentration (Tmax) was 1.50, 2.00, 2.00, 2.00, and 3.34 hours, and AUC values were 7.75, 7.24, 24.6, 2.03, and 36.3 µg × h/mL, respectively.
Distribution
In vitro studies in human plasma have shown that the protein binding (primarily to albumin) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU is 54%, 10%, 62%, and 10%, respectively.
Metabolism
Capecitabine is metabolized in the liver by carboxylesterase to the intermediate metabolite 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, an enzyme predominantly found in the liver and tumor tissues. Subsequent catalytic activation of 5'-DFUR occurs via thymidine phosphorylase. These enzymes are present in both tumor and normal tissues, although generally at lower levels in the latter. This enzymatic biotransformation leads to higher concentrations of 5-FU in tumor tissues. In colorectal tumors, a significant portion of 5-FU is localized in stromal tumor cells. After oral administration of capecitabine to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumors to that in adjacent normal tissue was 3.2 (range: 0.9–8.0). The tumor-to-plasma concentration ratio of 5-FU was 21.4 (range: 3.9–59.9, N=8), whereas the normal tissue-to-plasma concentration ratio 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 stromal tumor cells.
Subsequently, 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD) into the less toxic metabolite dihydro-5-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to form 5-fluoro-β-ureidopropionic acid (FUPA). The final step involves the cleavage of FUPA by β-ureidopropionase into α-fluoro-β-alanine (FBAL), which is excreted in urine. DPD activity is the rate-limiting step in this pathway. 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% of the dose, and fecal excretion accounts for 2.6%. The main urinary metabolite is FBAL, which constitutes 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 Xeloda® on the pharmacokinetics (Cmax and AUC) of docetaxel or paclitaxel, and no effect of docetaxel or paclitaxel on the pharmacokinetics of Xeloda® or 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, ECOG performance status, total bilirubin, serum albumin, ALT, and AST levels had no significant effect on the pharmacokinetics of 5'-DFUR, 5-FU, or FBAL.
Patients with Liver Metastases. Pharmacokinetic data in patients with mild to moderate hepatic impairment due to metastases suggest that bioavailability of capecitabine and exposure to 5-FU may be increased compared to patients without hepatic dysfunction. Pharmacokinetic data in patients with severe hepatic impairment are lacking.
Patients with Renal Impairment. In oncology patients with varying degrees (mild to severe) of renal impairment, the pharmacokinetics of unchanged drug and 5-FU are independent of creatinine clearance (CrCl). However, CrCl affects the AUC of 5'-DFUR (AUC increases by 35% when CrCl decreases by 50%) and FBAL (AUC increases by 114% when CrCl decreases by 50%). 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 or 5-FU. However, 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, Japanese patients (N=18) had a 36% lower Cmax and 24% lower AUC of capecitabine compared to Caucasian patients (N=22). For FBAL, Japanese patients had a 25% lower Cmax and 34% lower AUC than 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:
- Adjuvant treatment of stage III (Dukes' C stage) colon cancer after surgical resection;
- Metastatic colorectal cancer.
Gastric cancer:
- First-line treatment of advanced gastric cancer in combination with platinum-based agents.
Breast cancer:
- Locally advanced or metastatic breast cancer in combination with docetaxel after failure of anthracycline-containing chemotherapy;
- Locally advanced or metastatic breast cancer as monotherapy after failure of both taxane- and anthracycline-containing chemotherapy, or in patients with contraindications to anthracycline therapy.
Contraindications.
Severe, including unexpected, reactions to prior fluoropyrimidine therapy. Hypersensitivity to capecitabine or to any component of the product, or to 5-fluorouracil. Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special warnings and precautions for use").
Pregnancy and breastfeeding.
Severe leukopenia, neutropenia, or thrombocytopenia.
Severe hepatic impairment.
Severe renal impairment (creatinine clearance < 30 mL/min).
Recent or concomitant brivudine treatment (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction" regarding interactions with other medicinal products).
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) has been described, due to inhibition of dihydropyrimidine dehydrogenase by brivudine. This interaction, which increases fluoropyrimidine toxicity, may potentially lead to fatal outcomes. Therefore, concomitant administration of brivudine and capecitabine is contraindicated (see sections "Contraindications" and "Special warnings and precautions for use"). A washout 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.
Cytochrome P450 2C9 substrates.
Interaction studies between capecitabine and other drugs metabolized by the cytochrome P450 2C9 isoenzyme, except warfarin, have not been conducted. Caution is advised when co-administering capecitabine with such drugs (e.g., phenytoin).
Coumarin anticoagulants.
Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), which may result in coagulation abnormalities and bleeding, occurring several days or months after initiation of capecitabine therapy, and in some cases, up to one month after discontinuation of Xeloda®. In a clinical pharmacokinetic interaction study, following a single 20 mg dose of S-warfarin, treatment with Xeloda® resulted in a 57% increase in warfarin AUC and a 91% increase in MHO. Since R-warfarin metabolism was unaffected, this indicates that capecitabine inhibits the 2C9 isoenzyme and does not affect 1A2 or 3A4 isoenzymes. Patients receiving capecitabine concomitantly with oral anticoagulants (coumarin derivatives) require close monitoring of coagulation parameters (International Normalized Ratio or Prothrombin Time) and appropriate dose adjustment of the anticoagulant.
Phenytoin.
Cases of increased plasma phenytoin concentrations, accompanied by symptoms of phenytoin toxicity, have been reported when Xeloda® and phenytoin were administered concomitantly. 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 or its metabolites. However, folinic acid affects the pharmacodynamics of Xeloda®, potentially increasing capecitabine toxicity: the maximum tolerated dose of Xeloda® as monotherapy in an intermittent dosing regimen is 3000 mg/m²/day, whereas when combined with folinic acid (30 mg orally twice daily), it is only 2000 mg/m²/day. Increased toxicity may occur when switching from 5-FU/LV to capecitabine regimens. This may also occur when folic acid is administered to correct folic acid deficiency due to the structural similarity between folic acid and folinic acid.
Antacids.
The effect of antacids containing aluminum and magnesium hydroxide on the pharmacokinetics of Xeloda® has been studied. Antacids containing aluminum and magnesium hydroxide slightly increase plasma concentrations of capecitabine and one of its metabolites (5'-DFCR), but do not affect the three main metabolites (5'-DFUR, 5-FU, and FBAL) of capecitabine.
Allopurinol.
An interaction between allopurinol and 5-fluorouracil has been observed, potentially reducing the efficacy of 5-fluorouracil. Therefore, concomitant use of Xeloda® and allopurinol should be avoided.
Interferon alpha.
The maximum tolerated dose of Xeloda® is 2000 mg/m²/day when administered in combination with interferon alfa-2a (3 million IU/m²/day), compared to 3000 mg/m²/day when Xeloda® is used as monotherapy.
Radiation therapy.
The maximum tolerated dose of Xeloda® as monotherapy in an intermittent dosing regimen is 3000 mg/m²/day, whereas when combined with radiotherapy for rectal cancer, it is 2000 mg/m²/day, either with continuous radiation therapy or with a daily 6-week course of radiation therapy from Monday to Friday.
Oxaliplatin.
When capecitabine is co-administered 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.
Bevacizumab has no clinically significant effect on the pharmacokinetic parameters of capecitabine and its metabolites in the presence of oxaliplatin.
Medicinal product – food interaction
In all clinical trials, patients were instructed to take Xeloda® within 30 minutes after a meal. Since safety and efficacy data are based on administration of Xeloda® with food, it is recommended to take Xeloda® with food. Administration of Xeloda® with food results in a slower rate of absorption of capecitabine.
Special precautions for use.
Dose-dependent toxicity
Dose-dependent toxic effects are manifested 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 and rehydrated, with correction of electrolyte losses in case of dehydration. Standard anti-diarrheal agents (e.g., loperamide) may be prescribed. Grade II diarrhea according to the National Cancer Institute of Canada (NCIC CTC, version 2) criteria is defined as an increase in defecation frequency to 4–6 times per day or nocturnal defecation; Grade III diarrhea is defined as an increase in defecation frequency to 7–9 times per day, fecal incontinence, or malabsorption. Grade IV diarrhea is defined as an increase in defecation frequency to ≥10 times per day, or massive diarrhea 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 diarrhea. Dehydration may lead to acute renal failure, especially in patients with pre-existing renal impairment or when capecitabine is used concomitantly with drugs known to have nephrotoxic potential. Acute renal failure due to dehydration may be potentially fatal. In case of Grade II (or higher) dehydration, treatment with Xeloda® should be immediately discontinued and dehydration corrected. Resumption of treatment is possible after adequate correction of dehydration and management/controlling of precipitating causes (see section "Dosage and administration"). Dose adjustment should be considered if precipitating adverse events occur.
Hand-foot syndrome
Hand-foot syndrome, also known as hand-foot skin reactions, palmar-plantar erythrodysesthesia, or chemotherapy-induced peripheral erythema, is characterized as follows: Grade I hand-foot syndrome does not interfere with daily activities and is manifested by numbness, paresthesia, dysesthesia, tingling, painless swelling, or redness of palms and/or soles, and/or discomfort.
Grade II hand-foot syndrome is characterized by painful redness and swelling of hands and/or soles; discomfort caused by these symptoms interferes with the patient’s daily activities.
Grade III hand-foot syndrome is defined as moist desquamation, ulceration, blistering, severe pain in palms and/or soles, and/or severe discomfort preventing the patient from working or performing daily activities. Persistent or severe hand-foot syndrome (Grade II or higher) may eventually lead to loss of fingerprints, potentially affecting patient identification. In case of Grade II or III hand-foot 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. The use of vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of hand-foot syndrome in patients receiving Xeloda® and cisplatin, as published data suggest this may reduce the efficacy of cisplatin. Some data indicate that dexpanthenol is effective in preventing hand-foot syndrome in patients receiving Xeloda®.
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 common 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 treatment with Xeloda®. Caution is advised when prescribing Xeloda® to patients with clinically significant heart disease, arrhythmias, or angina.
Hypo- or hypercalcemia
Hypo- or hypercalcemia have been reported during treatment with Xeloda®.
Diseases of the central or peripheral nervous system
Caution is advised when prescribing Xeloda® to patients with diseases of the central or peripheral nervous system, such as brain metastases or neuropathy.
Diabetes mellitus or electrolyte disturbances
Caution is advised when prescribing Xeloda® to patients with diabetes mellitus or electrolyte imbalances, as capecitabine use may worsen the course of these conditions.
Anticoagulants – coumarin derivatives
In a drug interaction study with single-dose warfarin, a significant increase in the mean area under the concentration-time curve (AUC) of S-warfarin by 57% was observed, indicating a potential interaction, likely due to inhibition of the CYP2C9 isoenzyme of the cytochrome P450 system by capecitabine. Close monitoring of coagulation parameters (international normalized ratio or prothrombin time) and dose adjustment of the anticoagulant are required in patients receiving both capecitabine and oral anticoagulants – coumarin derivatives.
Brivudine
Concomitant use of brivudine with capecitabine is contraindicated. Fatal cases have been reported following this drug interaction. A minimum interval of 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 (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 impairment, careful monitoring is required when administering Xeloda® to patients with mild to moderate hepatic impairment, regardless of the presence or absence of liver metastases. If hyperbilirubinemia exceeding the upper limit of normal by more than 3 times or an increase in hepatic aminotransferase activity (ALT, AST) by more than 2.5 times the upper limit of normal occurs during capecitabine treatment, capecitabine administration should be suspended. 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.
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-associated toxicity, manifested particularly as stomatitis, diarrhea, 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 treatment with Xeloda® (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 parameters when deciding on dose reduction. Reducing the initial dose may affect treatment efficacy. If no severe toxicity occurs, subsequent doses may be increased under close monitoring.
DPD deficiency testing
Before initiating treatment with Xeloda®, 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 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 4 variants with at least one allele of 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 is 1.1%, c.1236G>A/HapB3 variants are 2.6–6.3%, and c.1679T>G is 0.07–0.1%.
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 levels in blood plasma before treatment is recommended.
Elevated uracil concentrations before treatment 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 blood uracil level ≥150 ng/mL should be considered a sign 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
Treatment with Xeloda® may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Xeloda® should be permanently discontinued in patients who develop severe skin reactions during treatment.
Lactose
Patients with rare hereditary problems such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take Xeloda®.
Sodium
This medicinal product contains less than 1 mmol (less than 23 mg) of sodium per tablet, i.e., essentially "sodium-free."
Xeloda® tablets should not be crushed or split. Contact of patients or caregivers with crushed or split Xeloda® tablets may result in adverse reactions (see section "Adverse reactions").
Disposal of unused or expired medicine. Environmental contamination by the medicinal product should be minimized. The medicine should not be disposed of via wastewater or household waste. Disposal should be performed via a designated "waste collection system" if available.
Use during pregnancy or breastfeeding.
Women of 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, the patient should be informed of the potential adverse effects on the fetus. 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 reproductive potential during treatment and for 3 months after the last dose of capecitabine.
Pregnancy
The use of Xeloda® in pregnant women has not been studied, but it can be assumed that Xeloda® may be harmful to the fetus when used during pregnancy. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. Xeloda® should not be used during pregnancy.
Breastfeeding
It is unknown whether Xeloda® 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, breastfeeding should be discontinued during treatment with capecitabine and for 2 weeks after the last dose.
Fertility
There are no data on the effect of Xeloda® on fertility. In the core studies of Xeloda® use, only women of reproductive age 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. Xeloda® may cause dizziness, weakness, and nausea.
Method of Administration and Dosage
Xeloda® must be prescribed only by a qualified physician experienced in the use of antineoplastic agents. Careful monitoring during the first treatment cycle is recommended for all patients.
Treatment should be discontinued in case of disease progression or development of unacceptable toxicity.
Xeloda® tablets are taken orally no later than 30 minutes after a meal, swallowing the tablets whole with water. Xeloda® tablets must not be crushed or split.
Special precautions for disposal and other special handling instructions
Standard procedures for safe handling of cytotoxic drugs must be followed.
Monotherapy
Colon cancer, colorectal cancer, and breast cancer. The recommended initial daily dose of Xeloda® as adjuvant therapy is 2,500 mg/m² body surface area, administered in 3-week cycles: daily for 2 weeks, followed by a 1-week rest period. The total daily dose of Xeloda® should be divided into two doses (1,250 mg/m² body surface area in the morning and in the evening). The recommended total duration of adjuvant therapy in patients with stage III colon cancer is 6 months.
Combination Therapy
Breast cancer. In combination with docetaxel, the recommended initial dose for the treatment of metastatic breast cancer is 1,250 mg/m² twice daily for 2 weeks, followed by a 1-week rest period (in combination with docetaxel 75 mg/m² once every 3 weeks as intravenous infusion). Premedication with oral corticosteroids such as dexamethasone should be administered prior to docetaxel administration, according to the prescribing information for docetaxel in patients receiving the combination of capecitabine plus docetaxel.
Colon cancer, colorectal cancer, gastric cancer. In combination regimens, the initial dose of Xeloda® should be reduced to 800–1,000 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 Xeloda®.
Antiemetic agents and premedication to ensure adequate hydration should be administered to patients receiving Xeloda® in combination with cisplatin or oxaliplatin, according to the prescribing information for cisplatin and oxaliplatin. The recommended total duration of adjuvant therapy in patients with stage III colon cancer is 6 months.
The dose of Xeloda® is calculated based on body surface area.
Tables 1 and 2 provide dosage calculations for standard and reduced (see "Dose Modifications During Treatment") initial doses of Xeloda® at 1,250 mg/m² or 1,000 mg/m².
Table 1
Calculations of standard and reduced initial doses of Xeloda® at 1,250 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 the standard and reduced initial dose of Xeloda® 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 administration (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 Adjustment During Treatment
General Recommendations
Toxicity symptoms during treatment with Xeloda® can be managed with symptomatic therapy and/or by modifying the Xeloda® dose (by interrupting treatment or reducing the dose). If a dose reduction is required, the dose should not be increased again later.
Treatment may be continued at the same dose without interruption or dose reduction in cases of toxicity symptoms that, in the physician’s opinion, are unlikely to be serious or life-threatening, such as alopecia, taste alterations, or nail changes.
Patients receiving Xeloda® treatment should be advised to discontinue treatment immediately upon development of moderate or severe toxic reactions. If several doses of capecitabine have been missed due to toxicity, the missed doses should not be administered as supplementary doses.
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 the course of therapy and based on unscheduled laboratory tests, neutrophil counts fall below 1.0 × 10⁹/L or platelet counts fall below 75 × 10⁹/L.
The following recommendations for dose modification in the event of toxicity are based on the toxicity grading criteria established by the Canadian National Cancer Institute (NCIC CTG, version 1).
Table 3
Dose reduction scheme for Xeloda® (3-week cycle or continuous treatment)
| Toxicity Grade* |
Dose modification during the treatment course |
Dose adjustment for the next cycle (% of initial dose) |
| Grade I |
No dose adjustment |
No dose adjustment |
| Grade II |
||
|
Discontinue treatment until signs of toxicity resolve to Grade 0–1 |
100% |
|
75% |
|
|
50% |
|
|
Discontinue drug |
not applicable |
| Grade III |
||
|
Discontinue treatment until signs of toxicity resolve to Grade 0–1 |
75% |
|
50% |
|
|
Discontinue drug |
not applicable |
| Grade IV |
||
|
Discontinue drug, or if clinically necessary, discontinue treatment until signs of toxicity resolve to Grade 0–1 |
50% |
|
Discontinue drug |
not applicable |
*According to the National Cancer Institute of Canada's National Cancer Institute Common Toxicity Criteria (NCIC CTG), version 1, or the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. See information on hand-foot syndrome and hyperbilirubinemia in the section "Special Warnings and Precautions for Use".
Dose modifications in the event of toxicity during administration of capecitabine in a 3-week cycle in combination with other medicinal products
Dose modifications in the event of toxicity during administration of Xeloda® in a 3-week cycle 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 therapy with Xeloda® or another medicinal product is required, the administration of other agents should also be delayed until the time when 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 Xeloda® should be continued and the dose of the other medicinal products in the regimen should be adjusted according to their respective instructions for medical use.
If discontinuation of other medicinal products in the treatment regimen is required, Xeloda® may be continued provided the necessary conditions for re-initiation of Xeloda® have been met.
These 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 for capecitabine and in accordance with the instructions for medical use of the other medicinal products.
Dose adjustments in special situations
Patients with hepatic impairment
Insufficient safety and efficacy data are available in patients with hepatic impairment to provide dose adjustment recommendations. There is no information 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 by the Cockcroft-Gault method at baseline). The incidence of grade 3 or 4 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 the initial dose of 1000 mg/m² is not required. No initial dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 51–80 mL/min).
Careful monitoring is recommended, and immediate interruption of treatment is required in the event of grade 2, 3, or 4 adverse events, followed by further dose adjustments according to Table 3. Treatment with Xeloda® should 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 initial dose adjustment is required for monotherapy with capecitabine. However, treatment-related grade 3 and 4 adverse reactions occurred more frequently in patients aged ≥ 60 years than in younger patients.
When Xeloda® 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 treating with Xeloda® in combination with docetaxel, an increased frequency of grade 3 and 4 toxicities has been observed in patients over 60 years of age. For patients in this age group receiving combination therapy with Xeloda® and docetaxel, it is recommended to reduce the initial dose of Xeloda® 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 dose of capecitabine may be gradually increased to 1250 mg/m² twice daily.
Children
The safety and efficacy of Xeloda® in children have not been studied.
Overdose
Symptoms of acute overdose: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, and bone marrow suppression. Treatment should include standard therapeutic and supportive measures to manage clinical manifestations and prevent possible complications.
Adverse Reactions
Summary of Safety Profile
The overall safety profile of Xeloda® is based on data from more than 3000 patients who received treatment with Xeloda® as monotherapy or in combination with various chemotherapy regimens for different indications. The safety profile of Xeloda® 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 reactions (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 Xeloda® administration were obtained from clinical studies of Xeloda® monotherapy and from clinical studies of Xeloda® used in combination with various chemotherapy regimens for different indications.
The following frequency categories are used to describe the incidence of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.
Monotherapy with Xeloda®
Below are the adverse reactions associated with capecitabine monotherapy, based on a pooled analysis of safety data from three pivotal trials involving 1900 patients (M66001, SO14695, and SO14796). Adverse reactions are categorized according to their overall frequency in the pooled analysis.
Infections and infestations: common – herpes (viral infection), nasopharyngitis, lower respiratory tract infections; uncommon – sepsis, urinary tract infections, cellulitis, tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, infection, dental abscess.
Benign, malignant and unspecified neoplasms: uncommon – lipoma.
Blood and lymphatic system disorders: common – anemia, neutropenia; uncommon – febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased international normalized ratio (INR)/prolonged prothrombin time.
Immune system disorders: uncommon – hypersensitivity reactions; rare – angioneurotic edema.
Metabolism and nutrition disorders: very common – anorexia; common – dehydration, weight decreased; 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, balance disorders, 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, torsade 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 – hepatic 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 warnings and precautions for use")); 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, reversible radiation recall reaction; rare – cutaneous lupus erythematosus; very rare – severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: common – limb pain, back pain, arthralgia; uncommon – joint swelling, bone pain, facial pain, musculoskeletal rigidity, 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 – pyrexia, peripheral edema, malaise, chest pain; uncommon – edema, fever, influenza-like symptoms, chills, increased body temperature.
Within the context of "common adverse reactions" in the "Monotherapy with Xeloda®" section, severe and/or life-threatening (Grade 3–4) and/or medically significant adverse reactions are listed.
Combination Therapy
Below are adverse reactions observed during treatment with Xeloda® in combination with various chemotherapy regimens for different indications, based on safety data from more than 3000 additional patients, beyond those already reported during monotherapy or observed with higher frequency in any of the main clinical trials.
Some adverse reactions are commonly observed with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, an enhancement of these adverse reactions with Xeloda® cannot be excluded.
Infections and infestations: common – herpes zoster, urinary tract infections, oral candidiasis, upper respiratory tract infections, rhinitis, influenza, infections*, oral herpes.
Blood and lymphatic system disorders: very common – neutropenia*, leukopenia*, febrile neutropenia*, thrombocytopenia*, anemia*; common – bone marrow depression, febrile neutropenia*.
Immune system disorders: common – hypersensitivity reactions.
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 creatinine clearance, dysuria; rare – acute renal failure due to dehydration (see section "Special warnings and precautions for use").
General disorders: very common – increased body temperature, weakness, drowsiness*, heat sensation; common – mucosal inflammation, limb pain, pain, chills, chest pain, influenza-like symptoms, pyrexia*, infusion reactions, injection site reactions, infusion site pain, injection site pain.
Injury, poisoning and procedural complications: common – contusion.
*Frequency includes all grades of severity, except for adverse reactions marked with "*", which include only Grade 3–4 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 rest period, hand-foot syndrome of all grades of severity occurred 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 a dose of 1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period, hand-foot syndrome of all grades was observed in 22–30% of patients receiving combination therapy with capecitabine.
A meta-analysis of data from more than 4700 patients across 14 clinical trials demonstrated that hand-foot syndrome of all grades occurred in 43% (2066) of patients treated with capecitabine as monotherapy or in combination with various chemotherapy regimens for different indications (colorectal cancer, gastric cancer, breast cancer), with a median onset of 239 days after initiation of capecitabine treatment (95% CI 201–288). Statistically significant covariates associated with an increased risk of hand-foot syndrome across all studied combinations were: higher initial capecitabine dose (in grams), lower cumulative capecitabine dose (0.1*kg), higher relative dose intensity during the first 6 weeks of treatment, longer duration of treatment (weeks), older patient age (per 10-year increase), female sex, and better baseline performance status (0 vs. ≥1).
Diarrhea
Diarrhea occurred in nearly 50% of patients treated with Xeloda®. According to a meta-analysis of data from more than 4700 patients in 14 clinical trials, statistically significant covariates associated with an increased risk of diarrhea across all studied combinations were: higher initial capecitabine dose (in grams), longer duration of treatment (weeks), older patient age (per 10-year increase), and female sex. Covariates associated with a decreased risk of diarrhea were: higher cumulative capecitabine dose (0.1*kg) and higher relative dose intensity during 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 from 949 patients enrolled in 7 clinical trials (2 Phase III and 5 Phase II trials in metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, heart failure, ventricular extrasystoles, sudden death.
Encephalopathy
In addition to the listed adverse reactions, capecitabine monotherapy, based on a pooled safety analysis from 7 clinical trials, was associated with encephalopathy occurring 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 Specific Patient Populations
Elderly Patients. In patients aged ≥60 years receiving Xeloda® monotherapy or combination therapy with Xeloda® and docetaxel, there was an increased risk of Grade 3 and 4 adverse reactions and serious treatment-related adverse reactions compared to patients aged <60 years. A higher proportion of patients aged ≥60 years receiving combination therapy with Xeloda® 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 an increased risk of hand-foot syndrome and diarrhea, and a decreased risk of neutropenia.
Sex
A meta-analysis of data from more than 4700 patients in 14 clinical trials, combining data across all studies, demonstrated that female sex was statistically significantly associated with an increased risk of hand-foot syndrome and diarrhea, and a decreased risk of neutropenia.
Patients with Impaired Renal Function
In patients with pre-existing renal impairment receiving Xeloda® 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)). In patients with moderate renal impairment, dose reductions were required more frequently (44%) compared to 33% and 32% in patients without renal impairment and with mild renal impairment, respectively, and premature discontinuation of treatment was more common (21% during the first two cycles) compared to 5% and 8% in patients with normal renal function and mild renal impairment, respectively.
Shelf life
3 years.
Storage conditions
Store at temperatures not exceeding 30°C in the original packaging to protect from moisture. Keep out of reach and sight of children.
Packaging
10 tablets of 150 mg or 500 mg in a blister pack. 6 blisters containing 150 mg tablets (60 tablets) or 12 blisters containing 500 mg tablets (120 tablets) in a cardboard box.
Prescription status
Prescription only.
Manufacturer
Excella GmbH & Co. KG
Manufacturer's address
Nürnberger Str. 12, 90537 Feucht, Germany