Capecitabine KRKA film-coated tablets 500 mg blister No. 120

Instructions Capecitabine KRKA film-coated tablets 500 mg blister No. 120

Composition

active substance: capecitabine;

1 film-coated tablet contains 500 mg of capecitabine;

excipients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate;
film coating: hypromellose, talc, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: oblong, biconvex, peach-colored, film-coated tablets engraved with “500” on one side and plain on the other.

Pharmacotherapeutic group

Antineoplastic agents. 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 by several enzymatic steps. Final conversion to 5-FU occurs under the action of thymidine phosphorylase in tumor tissue, as well as in healthy tissues of the body, but usually at low levels. In human cancer xenograft models, capecitabine has demonstrated a synergistic effect in combination with docetaxel, which may be due to an increase in thymidine phosphorylase activity by docetaxel.

It has been shown that the metabolism of 5-FU 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 the synthesis of RNA and proteins. Since 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 intensive proliferation and with 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, followed by biotransformation to the metabolites 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 the drug was administered after meals at a dose of 1250 mg/m2 on day 14, the maximum concentrations of capecitabine, 5'-DFCT, 5'-DFUR, 5-FU and α-fluoro-β-alanine (FBAL) were 4.67, 3.05, 12.1, 0.95 and 5.46 μg/ml, respectively. The time to reach the maximum concentration Tmax is 1.50, 2.00, 2.00, 2.00 and 3.34 hours, and 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

It is metabolized in the liver by carboxylesterase to the metabolite 5'-DFCT, which is then transformed into 5'-DFUR by cytidine deaminase, which is mainly found in the liver and tumor tissues. Further catalytic activation of 5'-DFUR occurs due to thymidine phosphorylase. The enzymes involved in catalytic activation are found in both tumor tissues and normal tissues, but usually at lower levels. Further enzymatic biotransformation of capecitabine to 5-FU leads to higher concentrations in tumor tissues. In the case of colorectal tumors, a significant part of 5-FU is localized in tumor stromal cells. After oral administration of capecitabine to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumors to the concentration in adjacent tissues was 3.2 (range 0.9 to 8.0). The ratio of 5-FU concentration in the tumor to the concentration in the blood plasma was 21.4 (range 3.9 to 59.9, N=8), while the ratio of the concentration in healthy tissues to the concentration in the blood plasma was 8.9 (range 3.0 to 25.8, N=8). Thymidine phosphorylase activity was 4-fold higher in the primary colorectal tumor compared with the adjacent normal tissues. According to immunohistochemical studies, most of the thymidine phosphorylase is localized in the stromal cells of the tumor.

Elimination: The elimination half-lives (T1/2) of capecitabine, 5'-DFCT, 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, there was no effect of capecitabine on the pharmacokinetics of docetaxel and paclitaxel (Cmax and AUC) and no effect of docetaxel and paclitaxel on the pharmacokinetics of capecitabine and 5'-DFUR.

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 baseline, Karnowski performance status, total bilirubin, serum albumin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities 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 does 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 over 65 years of age, age did not affect the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (with a 20% increase in age, the AUC of FBAL increased by 15%), which is likely due to changes in renal function.

Ethnic factors. Following 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). Japanese patients also had a 25% lower Cmax and 34% lower AUC of FBAL compared to Caucasian patients. The clinical significance of this difference is unknown. There was no significant difference in exposure to other metabolites (5'-DFCT, 5'-DFUR and 5-FU).

Indication

Breast cancer:

locally advanced or metastatic breast cancer - the drug is used in combination with docetaxel after ineffective chemotherapy that included anthracyclines; locally advanced or metastatic breast cancer - the drug is used as monotherapy after ineffective chemotherapy that included taxanes and anthracyclines, or in the presence of contraindications to anthracycline therapy.

Colon cancer, colorectal cancer:

Colon cancer – the drug is used in adjuvant therapy after surgical treatment of stage III cancer (Duke stage C); metastatic colorectal cancer.

Stomach cancer:

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

Contraindication

Severe, including unexpected reactions to fluoropyrimidine treatment in history. Hypersensitivity to capecitabine or to any component of the drug or fluorouracil. Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity (see section "Special instructions"). Pregnancy and breastfeeding. Severe leukopenia, neutropenia, thrombocytopenia. Severe liver dysfunction. Severe renal failure (creatinine clearance < 30 ml/min). Concomitant use of sorivudine or its structural analogues such as brivudine (see section "Interaction with other medicinal products and other forms of interaction"). 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 conducted in adult patients.

Interaction with other drugs

Anticoagulants - coumarin derivatives. Capecitabine enhances the effects of indirect anticoagulants (warfarin and phenprocoumon), which can lead to impaired blood clotting 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 Capecitabine KRKA. In a clinical pharmacokinetic interaction study after a single administration of warfarin at a dose of 20 mg, capecitabine treatment led to an increase in AUC of S-warfarin by 57% and INR (international normalized ratio) - 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. In patients who are simultaneously taking capecitabine and oral coumarin anticoagulants, careful monitoring of blood coagulation parameters (INR or prothrombin time) and adjustment of the anticoagulant dose are necessary.

Phenytoin: There have been isolated cases of increased phenytoin plasma concentrations with symptoms of phenytoin intoxication when capecitabine and phenytoin were co-administered. It is recommended that phenytoin plasma concentrations be monitored regularly in patients receiving capecitabine and 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 capecitabine, which may lead to increased toxicity of capecitabine: the maximum tolerated dose of capecitabine as monotherapy with an intermittent dosing regimen is 3000 mg/m2/day, and when combined with folinic acid (30 mg orally twice daily) is only 2000 mg/m2/day. Increased toxicity may occur when switching from 5-FU/LV (5-fluorouracil and leucovorin) to a capecitabine regimen. This phenomenon may also be observed when folic acid is used to correct folic acid deficiency due to the similarity between folinic and folic acids.

Sorivudine and its analogues. A clinically significant interaction between sorivudine and 5-FU has been described in the literature as a result of inhibition of dihydropyrimidine dehydrogenase by sorivudine. This interaction could potentially lead to a lethal increase in the toxicity of fluoropyrimidines. Therefore, Capecitabine Krka should not be used concomitantly with sorivudine or its structural analogues such as brivudine (see section 4.3). The period between the start of treatment with capecitabine and the end of treatment with sorivudine or its structural analogues should be at least 4 weeks.

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 the plasma concentrations of capecitabine and one metabolite (5'-DFCT); they do not affect the three major metabolites (5'-DFUR, 5-FU and FBAL) 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 Capecitabine and allopurinol should be avoided.

Interferon alpha: 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 capecitabine is used as monotherapy.

Radiotherapy. The maximum tolerated dose of capecitabine 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 relevant difference in the exposure of capecitabine or its metabolites, free platinum, or total platinum.

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

Interaction with food

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

Application features

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 (NCIC) criteria 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 ≥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. If grade II (or higher) dehydration occurs, Capecitabine treatment should be discontinued immediately and dehydration should be corrected. Treatment may be resumed after adequate correction of dehydration and correction/control of the precipitating causes. Dose adjustments should be made for precipitating adverse events as necessary (see section 4.2). Acute renal failure (potentially fatal) may occur in patients with preexisting renal impairment or concomitant nephrotoxic medicinal products.

Palmoplantar syndrome (synonyms: palmoplantar skin reactions, palmoplantar erythrodysesthesia, chemotherapy-induced peripheral erythema). Grade I palmoplantar syndrome does not interfere with the patient's daily activities and is manifested by numbness, paresthesias, dysesthesias, 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, acute pain in the palms and/or soles, and/or severe discomfort that prevents patients from working or engaging in daily activities.

In case of grade II or III palmar-plantar syndrome, capecitabine should be discontinued until symptoms resolve or decrease 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 palmar-plantar syndrome in patients receiving Capecitabine and cisplatin, as published data suggest that this may reduce the efficacy of cisplatin. There is some evidence that dexpanthenol is effective in preventing palmar-plantar syndrome in patients receiving capecitabine.

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 reactions are more common in patients with coronary artery disease. Cardiac arrhythmias (including ventricular fibrillation, torsades de pointes, bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported with capecitabine. Capecitabine should be used with caution in patients with clinically significant cardiac disease, arrhythmias and angina pectoris.

Hypo- or hypercalcemia. Hypo- or hypercalcemia has been reported during treatment with capecitabine. Capecitabine should be administered with caution to patients with known hypo- or hypercalcemia.

Central or peripheral nervous system disease: Capecitabine should be used with caution in patients with central or peripheral nervous system disease, such as brain metastases or neuropathy.

Diabetes mellitus or electrolyte disturbances. Capecitabine should be administered with caution to patients with diabetes mellitus or electrolyte disturbances, as the use of capecitabine may lead to complications of these conditions.

Hepatic impairment. Due to the lack of safety and efficacy data in patients with hepatic impairment, patients with mild to moderate hepatic impairment should be closely monitored during the use of Capecitabine KRKA, regardless of the presence 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.

Renal impairment. 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 population.

Dihydropyrimidine dehydrogenase (DPD) deficiency: Unexpected severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-fluorouracil (5-FU) has occasionally been observed due to deficiency of DPD activity.

Patients with low or absent DPD activity, the enzyme involved in the breakdown of fluorouracil, are at increased risk of severe, life-threatening or fatal adverse reactions caused by fluorouracil. Although DPD deficiency cannot be precisely defined, it is known that patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus, which may result in complete or near complete absence of DPD enzyme activity (as determined by laboratory tests), are at highest risk of life-threatening or fatal toxicity and should not be treated with Capecitabine Krka (see section 4.3). There is no established safe dose for patients with complete absence of DPD activity.

Patients with partial DPD deficiency (particularly those with heterozygous mutations in the DPYD gene) and for whom the benefits of capecitabine outweigh the risks (taking into account the feasibility of alternative non-fluoropyrimidine-based chemotherapy regimens) should be treated with extreme caution and frequent monitoring with dose adjustments based on toxicity. There are insufficient data to recommend a specific dose for patients with partial DPD activity based on specific test results.

Patients with unrecognized DPD deficiency treated with capecitabine may experience life-threatening toxicities similar to those seen in acute overdose (see section 4.8). In the event of acute toxicity of Grade II to IV, treatment should be discontinued immediately. Permanent discontinuation of treatment should be considered based on clinical assessment of the onset, duration, and severity of the observed toxicity.

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

Since the drug contains anhydrous lactose as an excipient, patients with hereditary galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take Capecitabine KRKA.

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. Capecitabine may cause dizziness, weakness and nausea.

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.

Pregnancy

The use of capecitabine in pregnant women has not been studied, however, it is assumed that the use of Capecitabine KRKA may be harmful to the fetus when administered to pregnant women. In reproductive toxicity studies in animals, capecitabine caused embryolethality and teratogenicity, which are expected effects of fluoropyrimidine derivatives. The use of capecitabine during pregnancy is contraindicated.

Breast-feeding

There are no data on the excretion of capecitabine in human milk. Significant amounts of capecitabine and its metabolites have been detected in the milk of lactating mice. Therefore, breast-feeding is not recommended during treatment with capecitabine.

There are no data on the effects of capecitabine on fertility. The pivotal studies of capecitabine included only men and women of reproductive potential 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.

Method of administration and doses

Capecitabine Krka should only be prescribed by a qualified physician experienced in the use of antineoplastic medicinal products. Careful monitoring of all patients is recommended during the first cycle of treatment.

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

The drug is taken orally, no later than 30 minutes after eating, with water.

Monotherapy

Colon cancer, colorectal cancer and breast cancer: the recommended starting daily dose of Capecitabine KRKA as adjuvant therapy is 2500 mg/m2 body surface area and is administered in 3-week cycles: taken daily for 2 weeks, followed by a 1-week rest period. The total daily dose of Capecitabine KRKA is divided into two doses (1250 mg/m2 body surface area in the morning and evening). The recommended total duration of adjuvant therapy for patients with stage III colon cancer is 6 months.

Combination therapy

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

Colon cancer, colorectal cancer, gastric cancer: in the combination regimen, the starting dose of Capecitabine KRKA 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 use. In combination with irinotecan (200 mg/m2 on day 1), the recommended starting dose is 800 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. The inclusion of bevacizumab in the combination regimen does not affect the starting dose of Capecitabine KRKA.

Antiemetics and premedication to ensure adequate hydration are administered to patients receiving Capecitabine in combination with cisplatin or oxaliplatin prior to cisplatin administration according to the cisplatin and oxaliplatin product information. The total recommended duration of adjuvant therapy for patients with stage III colon cancer is 6 months.

The dose of Capecitabine is calculated based on body surface area. Tables 1 and 2 provide standard and reduced dose calculations (see “Dose adjustments during treatment”) for a starting dose of Capecitabine of 1250 mg/m2 or 1000 mg/m2.

Table 1. Calculations of the standard and reduced starting dose of Capecitabine KRKA 1250 mg/m2 depending on body surface area

Table 2. Calculations of the standard and reduced starting dose of Capecitabine KRKA 1000 mg/m2 depending on body surface area

Dose adjustment during treatment

Toxicities during treatment with Capecitabine Krka can be managed by symptomatic therapy and/or dose modification of Capecitabine Krka (interrupting treatment or reducing the dose of the drug). If the dose has to be reduced, it should not be increased further.

In case of toxicity phenomena that, in the opinion of the doctor, will not become serious and will not threaten life (for example, alopecia, change in taste, nail changes), the use of the drug can be continued at the same dose, without interrupting treatment or reducing the dose of the drug.

Patients receiving Capecitabine should be advised that treatment should be discontinued if moderate or severe toxicities develop. If multiple doses of capecitabine have been missed due to toxicities, the missed doses should not be administered.

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. Therapy should be discontinued if laboratory tests reveal a decrease in neutrophil counts to <1.0 × 109/L or platelet counts to <75 × 109/L.

Table 3 provides recommendations for dose modification in the event of toxicities according to the criteria for toxicity signs commonly encountered in the clinic. The criteria were developed by the National Cancer Institute of Canada (NCIC CTC, version 1).

Table 3. Capecitabine CRKA dose reduction schedule (3-week cycle or continuous treatment)

Dose modification in case of toxicity when using capecitabine during a 3-week cycle in combination with other drugs

Dose modification in the event of toxicity during the use of Capecitabine KRKA during a 3-week cycle in combination with other medicinal products should be carried out according to Table 3 for capecitabine and in accordance with the instructions for medical use of other medicinal products.

At the beginning of the treatment course, if it is necessary to delay treatment with Capecitabine or another medicinal product, the use of other medicinal products should also be postponed until all components of the regimen can be administered.

If toxic events occur during treatment that, in the opinion of the physician, are not related to the use of capecitabine, therapy with Capecitabine KRKA should be continued and the dose of other drugs - components of the regimen - should be adjusted in accordance with the instructions for medical use.

If it is necessary to cancel other medicines or components of the regimen, treatment with Capecitabine Krka can be continued when the necessary conditions for re-administration of Capecitabine Krka are met.

These recommendations apply to all indications for use and all patient groups.

Dose modification for toxicity during continuous capecitabine administration in combination with other medicinal products

Dose modification in case of toxicity during continuous Capecitabine CRKA administration in combination