Xeloda film-coated tablets 500 mg No. 120

Instructions for Xeloda film-coated tablets 500 mg No. 120

Composition

active substance: capecitabine;

1 film-coated tablet contains 150 mg or 500 mg of capecitabine;

excipients: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose, magnesium stearate; film coating: for 150 mg tablets – Opadry® pink 0ZA14309 (hypromellose, talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172)); for 500 mg tablets – Opadry® pink 0ZA14380 (hypromellose, talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties: 150 mg tablets are biconvex, oblong, film-coated, light peach in color, with XELODA imprinted on top and 150 on the bottom;

500 mg tablets are biconvex, oblong, film-coated, peach-colored, with XELODA imprinted on top and 500 on the bottom.

Pharmacotherapeutic group

Antineoplastic agents. Antimetabolites. Structural pyrimidine analogues.

ATX code L01B C06.

Pharmacological properties

Pharmacodynamics.

Capecitabine is a non-cytotoxic fluoropyrimidine carbamate derivative, an oral precursor of the cytotoxic compound 5-fluorouracil (5-FU). Capecitabine is activated in several enzymatic steps. Final conversion to 5-FU occurs by thymidine phosphorylase in tumor tissue as well as in healthy tissues, but is generally at low levels. In human cancer xenograft models, capecitabine has shown a synergistic effect in combination with docetaxel, which may be due to docetaxel increasing thymidine phosphorylase activity.

Evidence suggests that 5-FU metabolism anabolically blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby inhibiting the synthesis of deoxyribonucleic acid (DNA). Incorporation of 5-FU also inhibits RNA and protein synthesis. Because DNA and RNA are essential for cell division and growth, 5-FU can cause thymidine deficiency, which contributes to unbalanced cell growth and death. The effects on DNA and RNA are more pronounced in cells with more rapid proliferation and higher levels of 5-FU metabolism.

Pharmacokinetics.

The pharmacokinetics of capecitabine were determined over a dose range of 502–3514 mg/m2/day. Capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCT) and 5'-deoxy-5-fluorouridine (5'-DFUR) parameters were similar on days 1 and 14. On day 14, the AUC of 5-FU was 30–35% higher. Reducing the capecitabine dose resulted in a greater than dose-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 is then biotransformed to the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCT) and 5'-DFUR. Food intake reduces the rate of absorption of capecitabine, but has no significant effect on the area under the concentration-time curve (AUC) of 5'-DFUR and the subsequent metabolite 5-FU. When administered at a dose of 1250 mg/m2 after food on day 14, the maximum concentrations (Cmax) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 4.67, 3.05, 12.1, 0.95 and 5.46 μg/ml, respectively. The time to reach maximum concentration (Tmax) is 1.50, 2.00, 2.00, 2.00 and 3.34 h, and the AUC is 7.75, 7.24, 24.6, 2.03 and 36.3 μg × h/ml, respectively.

Distribution

In vitro studies in human plasma have demonstrated that for capecitabine, 5'-DFCT, 5'-DFUR and 5-FU, protein binding (mainly to albumin) is 54%, 10%, 62% and 10%, respectively.

Metabolism

5-FU is then catabolized by dihydropyrimidine dehydrogenase (DPD) to form the less toxic dihydro-5-fluorouracil (FUN2). Dihydropyrimidinease cleaves the pyrimidine ring to form 5-fluoroureidopropionic acid (FUPA). The final reaction is the cleavage of FUPA by β-ureidopropionase to α-fluoro-β-alanine (FBA), which is detected in the urine. Dihydropyrimidine dehydrogenase activity is rate-limiting. DPD deficiency may lead to increased toxicity of capecitabine.

Breeding

The elimination half-lives (T1/2) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL are 0.85, 1.11, 0.66, 0.76 and 3.23 hours, respectively. Capecitabine and metabolites of capecitabine are mainly excreted in the urine. Excretion in the urine is 95.5%, in the feces - 2.6%. The main metabolite in the urine is FBAL, which accounts for 57% of the administered dose. Approximately 3% of the administered dose is excreted in the urine unchanged.

Combination therapy

In phase I studies, no effect of Xeloda® on the pharmacokinetics of docetaxel and paclitaxel (Cmax and AUC) and no effect of docetaxel and paclitaxel on the pharmacokinetics of Xeloda® and 5'-DFUR was detected.

Pharmacokinetics in special clinical groups

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

Patients with metastatic liver disease: Pharmacokinetic studies suggest that capecitabine bioavailability and 5-FU exposure may be increased in patients with mild to moderate hepatic impairment due to metastases compared to patients without hepatic impairment. Pharmacokinetic data are not available in patients with severe hepatic impairment.

Patients with renal impairment. With varying degrees (from mild to severe) of renal failure in cancer patients, the pharmacokinetics of the unchanged drug and 5-FU do not depend on creatinine clearance (CC). CC affects the AUC of 5'-DFUR (increase in AUC by 35% with a decrease in CC by 50%) and FBAL (increase in AUC by 114% with a decrease in CC by 50%). FBAL is a metabolite that does not have antiproliferative activity.

Elderly: In a population pharmacokinetic analysis that included patients of a wide age range (27–86 years), of whom 234 patients (46%) were 65 years or older, age did not affect the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (a 20% increase in age was accompanied by a 15% increase in the AUC of FBAL), which is likely due to 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). Also for FBAL, Japanese patients had a 25% lower Cmax and 34% lower AUC of capecitabine compared to Caucasian patients. The clinical significance of this difference is unknown. No significant difference in exposure was observed for other metabolites (5'-DFCT, 5'-DFUR and 5-FU).

Indication

Colon cancer, colorectal cancer:

colon cancer, in adjuvant therapy after surgical treatment of stage III cancer (Duke stage C);

metastatic colorectal cancer.

Stomach cancer:

a drug for first-line treatment of advanced gastric cancer, in combination with platinum-based drugs.

Breast cancer:

locally advanced or metastatic breast cancer, in combination with docetaxel after failure of chemotherapy including anthracyclines;

Locally advanced or metastatic breast cancer as monotherapy after ineffective chemotherapy including taxanes and anthracyclines, or in the presence of contraindications to anthracycline therapy.

Contraindication

History of severe, including unexpected, reactions to fluoropyrimidine treatment. Hypersensitivity to capecitabine or to any component of the drug, or to fluorouracil. Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) (see section "Special warnings and precautions for use").

Pregnancy and breastfeeding.

Severe leukopenia, neutropenia, thrombocytopenia.

Severe liver dysfunction.

Severe renal failure (creatinine clearance < 30 ml/min).

Recent or concomitant treatment with brivudine (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction” for interactions with other medicinal products).

Contraindications for the use of any medicinal product used in combination.

Interaction with other medicinal products and other types of interactions

Interaction studies have only been performed in adult patients.

Interaction with other drugs

A clinically significant interaction has been described between brivudine and fluoropyrimidines (e.g. capecitabine, 5-fluorouracil, tegafur) as a result of inhibition of dihydropyrimidine dehydrogenase by brivudine. This interaction, which leads to increased fluoropyrimidine toxicity, can potentially be fatal. Therefore, brivudine is contraindicated for use with capecitabine (see sections 4.3 and 4.4). There should be a waiting period of at least 4 weeks between the end of brivudine treatment and the start of capecitabine therapy. Brivudine treatment can be started 24 hours after the last dose of capecitabine.

Cytochrome P450 2C9 substrates.

Interaction studies with capecitabine and other drugs metabolized by the cytochrome P450 2C9 isoenzyme, except warfarin, have not been conducted. Caution should be exercised when prescribing capecitabine with these drugs (e.g. phenytoin).

Coumarin anticoagulants.

Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), which can lead to impaired coagulation parameters and bleeding several days or months after the start of capecitabine therapy, and in some cases within one month after the end of treatment with Xeloda®. In a clinical pharmacokinetic interaction study after a single administration of S-warfarin at a dose of 20 mg, treatment with Xeloda® led to an increase in warfarin AUC by 57% and MHO by 91%. Since the metabolism of R-warfarin was not impaired, this indicates that capecitabine inhibits the 2C9 isoenzyme and does not affect the 1A2 and 3A4 isoenzymes. Patients who simultaneously take capecitabine and oral anticoagulants - coumarin derivatives, it is necessary to conduct detailed monitoring of blood coagulation parameters (international normalization ratio or prothrombin time) and select the dose of the anticoagulant.

Phenytoin.

Isolated cases of increased phenytoin plasma concentrations, accompanied by symptoms of phenytoin intoxication, have been reported with concomitant use of Xeloda® and phenytoin. Regular monitoring of phenytoin plasma concentrations is recommended in patients receiving capecitabine concomitantly with phenytoin.

Folinic acid/folic acid.

Folinic acid does not significantly affect the pharmacokinetics of capecitabine and its metabolites. However, folinic acid affects the pharmacodynamics of Xeloda®, which may lead to increased toxicity of capecitabine: the maximum tolerated dose of Xeloda® as monotherapy with an intermittent dosing regimen is 3000 mg/m2 per day, and when combined with folinic acid (30 mg orally twice daily) is only 2000 mg/m2 per day. Increased toxicity is possible when switching from 5-FU/LV to a capecitabine regimen. This may also be observed when folic acid is used to correct folic acid deficiency due to the similarity between folinic and folic acids.

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 the plasma concentrations of capecitabine and one of its metabolites (5'-DFPR); they do not affect the three major metabolites (5'-DFPR, 5-FU and FBA) of capecitabine.

Allopurinol.

An interaction between allopurinol and 5-fluorouracil has been observed, with a possible reduction in the efficacy of 5-fluorouracil. Therefore, the concomitant use of Xeloda® and allopurinol should be avoided.

Interferon alpha.

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

Radiation therapy.

The maximum tolerated dose of Xeloda® in monotherapy with an intermittent dosing regimen is 3000 mg/m2 per day, when combined with radiotherapy for rectal cancer - 2000 mg/m2 per day with a continuous course of radiotherapy or a daily 6-week course of radiotherapy from Monday to Friday.

Oxaliplatin.

When capecitabine and oxaliplatin were combined with or without bevacizumab, there was no clinically significant difference in the exposure of capecitabine or its metabolites, free platinum, or total platinum.

Bevacizumab.

There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites in the presence of oxaliplatin.

Drug-food interaction

In all clinical studies, patients were instructed to take Xeloda® within 30 minutes of a meal. Since the available safety and efficacy data are based on the use of Xeloda® with food, it is recommended that Xeloda® be taken with food. Taking Xeloda® with food results in a slower rate of absorption of capecitabine.

Application features

Dose-dependent toxicity is manifested by diarrhea, abdominal pain, nausea, stomatitis, palmar-plantar syndrome (palmar-plantar skin reactions, palmar-plantar erythrodysesthesia). Most adverse reactions are reversible and do not require complete discontinuation of the drug, although dose adjustment or temporary discontinuation of the drug may be necessary.

Diarrhea. Patients with severe diarrhea should be closely monitored for rehydration and electrolyte replacement in case of dehydration. Standard antidiarrheal agents (e.g. loperamide) may be used. Grade II diarrhea according to the National Cancer Institute of Canada criteria (NCIC CTS, version 2) is defined as an increase in the number of bowel movements to 4–6 times per day or bowel movements at night; grade III diarrhea is defined as an increase in the number of bowel movements to 7–9 times per day or fecal incontinence and malabsorption. Grade IV diarrhea is defined as an increase in the number of bowel movements to ≥ 10/day or massive diarrhea with blood, or the need for parenteral infusions. If necessary, the dose of the drug should be reduced (see section “Method of administration and dosage”).

Dehydration. Dehydration should be prevented and corrected if it occurs. Dehydration may develop rapidly in patients with anorexia, asthenia, nausea, vomiting or diarrhoea. Dehydration may lead to acute renal failure, especially in patients with pre-existing renal impairment or when capecitabine is used concomitantly with medicinal products known to be nephrotoxic. Acute renal failure resulting from dehydration may be potentially fatal. If Grade II (or higher) dehydration occurs, Xeloda® treatment should be discontinued immediately and dehydration corrected. Treatment may be resumed if dehydration is adequately corrected and the precipitating cause corrected/controlled (see section 4.2). Dose adjustments for precipitating adverse events should be made as necessary.

Palmar-plantar syndrome

Palmoplantar syndrome is also known as palmoplantar skin reactions or palmoplantar erythrodysesthesia, or chemotherapy-induced peripheral erythema. Grade I palmoplantar syndrome does not interfere with the patient's daily activities and is characterized by numbness, paresthesia, dysesthesia, tingling, painless swelling or redness of the palms and/or soles, and/or discomfort.

Grade II palmar-plantar syndrome is manifested by painful redness and swelling of the hands and/or soles; the discomfort caused by these manifestations disrupts the patient's daily activities.

Grade III palmoplantar syndrome is defined as moist desquamation, ulceration, blistering, and acute pain of the palms and/or soles, and/or severe discomfort that prevents patients from working or engaging in daily activities. Persistent or severe palmoplantar syndrome (grade II or higher) may eventually result in loss of fingerprints, which may affect patient identification. In the event of grade II or grade III palmoplantar syndrome, capecitabine should be discontinued until symptoms resolve or improve to grade I; if grade III syndrome recurs, the capecitabine dose should be reduced. Vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylaxis of palmoplantar syndrome in patients receiving Xeloda® and cisplatin, as published data suggest that it may reduce the efficacy of cisplatin. Some evidence suggests that dexpanthenol is effective in preventing palmar-plantar syndrome in patients treated with Xeloda®.

Cardiotoxicity.

The spectrum of cardiotoxicity with capecitabine is similar to that seen with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiogenic shock, sudden death, cardiac arrest, cardiac failure and ECG changes (including very rare cases of QT prolongation). These adverse events are more common in patients with coronary artery disease. Cases of cardiac arrhythmias (including ventricular fibrillation, torsades de pointes, bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported with Xeloda®. Caution should be exercised when prescribing Xeloda® to patients with clinically significant cardiac disease, arrhythmias and angina pectoris.

Hypo- or hypercalcemia.

Hypo- or hypercalcemia has been reported during treatment with Xeloda®.

Diseases of the central or peripheral nervous system.

Caution should be exercised when prescribing Xeloda® to patients with central or peripheral nervous system disease, such as brain metastases or neuropathy.

Diabetes or electrolyte imbalance.

Caution should be exercised when prescribing Xeloda® to patients with diabetes mellitus or electrolyte disturbances, as the use of capecitabine may worsen their condition.

In a single-dose warfarin interaction study, a significant increase in the mean area under the concentration-time curve (AUC) of S-warfarin (by 57%) was observed, indicating an interaction likely due to inhibition of the cytochrome P450 2C9 isoenzyme by capecitabine. In patients receiving capecitabine and oral coumarin anticoagulants, close monitoring of blood coagulation parameters (international normalized ratio or prothrombin time) and adjustment of the anticoagulant dose are necessary.

Brivudin.

Brivudine is contraindicated for use with capecitabine. Fatalities have been reported following this drug interaction. There should be a waiting period of at least 4 weeks between the end of brivudine treatment and the start of capecitabine therapy. Brivudine treatment can be started 24 hours after the last dose of capecitabine (see sections “Contraindications” and “Interaction with other medicinal products and other forms of interaction”).

In the event of accidental ingestion of brivudine by patients receiving capecitabine treatment, 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.

Liver dysfunction.

Due to the lack of data on the safety and efficacy of Xeloda® in patients with hepatic impairment, the use of Xeloda® should be carefully monitored in patients with mild to moderate hepatic impairment, regardless of the presence or absence of liver metastases. If, as a result of capecitabine treatment, hyperbilirubinemia exceeding the upper limit of normal by more than 3 times or an increase in the activity of hepatic aminotransferases (ALT, ACT) by more than 2.5 times compared to the upper limit of normal is observed, capecitabine should be discontinued. Capecitabine as monotherapy can be resumed when bilirubin levels and hepatic transaminases decrease below the specified limits.

Kidney dysfunction.

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

Dihydropyrimidine dehydrogenase (DPD) deficiency.

DPD activity is a factor limiting the catabolism of 5-fluorouracil (see section 5.1). Therefore, patients with DPD deficiency are at increased risk of fluoropyrimidine-related toxicity, manifested in particular by stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.

Toxicity associated with DPD deficiency usually occurs during the first course of treatment or after dose increases.

Complete DPD deficiency

Complete DPD deficiency is a rare condition (0.01-0.5% of Caucasians). Patients with complete DPD deficiency are at high risk of life-threatening, including fatal, toxicity and should not be treated with Xeloda® (see section 4.3).

Partial deficiency of DPD

It is estimated that partial DPD deficiency occurs in 3–9% of the Caucasian population. Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. To limit this toxicity, a reduction in the starting dose should be considered. DPD deficiency should be considered as a factor to be considered in conjunction with other routine parameters when deciding on a dose reduction. A reduction in the starting dose may affect the efficacy of treatment. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.

Testing for DPD deficiency

Phenotypic and/or genotypic determination is recommended before initiating treatment with Xeloda®, despite uncertainty regarding the optimal pre-treatment testing methods. Appropriate clinical guidelines should be considered.

Genotypic characterization of DPD deficiency

Testing for rare mutations in the DPYD gene before treatment can identify patients with DPYD deficiency.

Four DPYD variations – c.1905+1G>A [also known as DPYD*2A], c.1679T>G [DPYD*13], c.2846A>T and c.1236G>A/HapB3 – can cause complete absence or reduction of DPD enzymatic activity. Other rare variations may also be associated with an increased risk of severe, including life-threatening, toxicity.

It is known that certain homozygous or compound heterozygous mutations in the DPYD gene locus (e.g. combinations of 4 variations with at least one allele c.1905+1G>A or c.1679T>G) cause complete or near-complete absence of DPD enzymatic activity.

Patients with certain heterozygous DPYD variations (including c.1905+1G>A, c.1679T>G, c.2846A>T, and c.1236G>A/HapB3) are at increased risk of severe toxicity during treatment with fluoropyrimidines.

In Caucasian patients, the frequency of heterozygous genotype c.1905+1G>A in the DPYD gene is approximately 1%, c.2846A>T – 1.1%, variations c.1236G>A/HapB3 – 2.6–6.3% and c.1679T>G – from 0.07 to 0.1%.

Data on the frequency of the four DPYD variations in populations other than Caucasians are limited. At present, four DPYD variations (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 descent.

For phenotypic characterization of DPD deficiency, it is recommended to determine the level of the endogenous DPD substrate uracil in blood plasma before treatment.

High pretreatment uracil concentrations are associated with an increased risk of toxicity. Although the thresholds for uracil indicating complete or partial DPD deficiency are uncertain, plasma uracil levels ≥ 16 ng/mL and < 150 ng/mL should be considered indicative of partial DPD deficiency and associated with an increased risk of fluoropyrimidine toxicity. Blood uracil levels ≥ 150 ng/mL should be considered indicative of complete DPD deficiency and associated with a risk of life-threatening, including fatal, fluoropyrimidine toxicity.

Ophthalmological complications.

Patients should be closely monitored for ophthalmic complications such as keratitis or corneal disorders, especially if there is a history of visual impairment. Treatment of visual impairment should be initiated as 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 while taking the drug.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Xeloda®.

Sodium

This medicine contains less than 1 mmol (less than 23 mg) sodium per tablet, i.e. essentially 'sodium-free'.

Xeloda® tablets should not be crushed or broken. Contact of the patient or caregiver with crushed or broken Xeloda® tablets may result in adverse reactions (see section 4.8).

Disposal of unused and expired medicinal products. Release of medicinal products into the environment should be minimised. The medicinal product should not be disposed of in wastewater or household waste. For disposal, use a so-called “waste collection system” if available.

Use during pregnancy or breastfeeding

Women of reproductive age/contraception in men and women

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

Given the results of genotoxicity studies, male patients and their female partners of reproductive age should use effective contraception during treatment and for 3 months after the last dose of capecitabine.

Pregnancy

Xeloda® has not been studied in pregnant women, but it is likely that Xeloda® may cause fetal harm when administered to pregnant women. In animal reproductive toxicity studies, capecitabine was embryolethal and teratogenic, which are expected effects of fluoropyrimidine derivatives. Xeloda® should not be used during pregnancy.

Breast-feeding

It is not known whether Xeloda® is excreted in human milk. Studies on the effects of capecitabine on human milk production or the presence of capecitabine in human 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, breast-feeding 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. The pivotal studies of Xeloda® included only women of reproductive age and men who agreed to use acceptable methods of birth control to prevent pregnancy during the study and for an appropriate period thereafter. Effects on fertility were observed in animal studies.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug has minor or moderate influence on the ability to drive and use machines. Xeloda® may cause dizziness, weakness and nausea.

Method of administration and doses

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

Treatment should be discontinued if disease progression or unacceptable toxicity occurs.

Xeloda® tablets should be taken orally no later than 30 minutes after a meal, swallowed whole with water. Xeloda® tablets should not be crushed or broken.

Safe handling procedures for cytotoxic drugs should 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 and is administered in three-week cycles: daily for 2 weeks, followed by a week-long rest period. The total daily dose of Xeloda® 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 colon cancer is 6 months.

Combination therapy

Breast cancer: In combination with docetaxel, the recommended starting 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 once every 3 weeks as an intravenous infusion). Premedication with oral corticosteroids, such as dexamethasone, should be administered prior to docetaxel administration in accordance with the docetaxel prescribing information for patients receiving capecitabine plus docetaxel.

Colon cancer, colorectal cancer, gastric cancer. In the combination treatment regimen, the initial dose of Xeloda® should be reduced to 800-1000 mg/m2 2 times a day for 2 weeks followed by a 1-week break or to 625 mg/m2 2 times a day for continuous use. In combination with irinotecan (200 mg/m2 on day 1), the recommended initial dose is 800 mg/m2 2 times a day for 2 weeks followed by a 1-week break. The inclusion of bevacizumab in the combination treatment regimen does not affect the initial dose of Xeloda®.

Antiemetics and premedication to ensure adequate hydration are administered to patients receiving Xeloda® in combination with cisplatin or oxaliplatin prior to cisplatin administration according to the cisplatin and oxaliplatin prescribing information. The total recommended 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 calculations of the standard and reduced (see “Dose adjustment during treatment”) starting dose of Xeloda® 1250 mg/m2 or 1000 mg/m2.

Table 1

Calculations of the standard and reduced starting dose of Xeloda® 1250 mg/m2 depending on body surface area

Table 2

Calculations of the standard and reduced starting dose of Xeloda® 1000 mg/m2 depending on body surface area

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