combination therapy with docetaxel for locally advanced or metastatic breast cancer when chemotherapy that includes an anthracycline drug is ineffective;

Monotherapy for locally advanced or metastatic breast cancer when chemotherapy with taxanes or anthracyclines is ineffective, or if there are contraindications to anthracycline therapy;

Adjuvant therapy for colon cancer;

First-line therapy for metastatic colorectal cancer;

First-line therapy for advanced gastric cancer.

Release form of the drug Xeloda

Tablets, coated film-coated 150 mg; polyethylene bottle (bottle) 60, cardboard pack 1;

Film-coated tablets 150 mg; blister 10, cardboard pack 6;

Film-coated tablets 500 mg; polyethylene bottle (bottle) 120, cardboard pack 1;

Film-coated tablets 500 mg; blister 10, cardboard pack 12;

Film-coated tablets 500 mg; blister 10, cardboard pack 12;

Film-coated tablets 150 mg; blister 10, cardboard pack 6;

Pharmacodynamics of the drug Xeloda

Capecitabine is a fluoropyrimidine carbamate derivative, an oral cytostatic agent that is activated in tumor tissue and has a selective cytotoxic effect on it. In vitro, capecitabine does not have a cytotoxic effect; in vivo, it is converted to 5-FU, which undergoes further metabolism. The formation of 5-FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - dTdPase, which minimizes the systemic effect of 5-FU on healthy tissues of the body.

The sequential enzymatic biotransformation of capecitabine into 5-FU creates more high concentrations drug in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine to patients with colon cancer, the concentration of 5-FU in tumor tissue is 3.2 times greater than its concentration in adjacent healthy tissue. The ratio of 5-FU concentrations in tumor tissue and plasma is 21.4, the ratio of its concentration in healthy tissues and plasma is 8.9. Thymidine phosphorylase activity in a primary colorectal tumor is 4 times higher than in adjacent healthy tissues.

Tumor cells in patients with breast, stomach, colon, cervical and ovarian cancer contain more thymidine phosphorylase, which can convert 5'-DFUR to 5-FU, than in corresponding healthy tissues.

Both healthy and tumor cells metabolize 5-FU into 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites damage cells through two different mechanisms. First, FdUMP and the folate cofactor N5–10-methylenetetrahydrofolate bind to thymidylate synthetase (TS) to form a covalently linked tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is an essential precursor to thymidine triphosphate, which in turn is essential for DNA synthesis, so a deficiency of this substance can lead to inhibition of cell division. Secondly, during RNA synthesis, nuclear transcription enzymes may mistakenly include FUTP instead of uridine triphosphate (UTP). This metabolic "error" disrupts RNA processing and protein synthesis.

Pharmacokinetics of the drug Xeloda

Suction

After oral administration, capecitabine is absorbed quickly and completely, after which it is transformed into metabolites - 5"-deoxy-5-fluorocytidine (5"-DFCT) and 5"-deoxy-5-fluorouridine (5"-DFUR). Food reduces the rate of absorption of capecitabine, but the AUC of 5"-DFUR and the next metabolite, 5-fluorouracil (5-FU), is slightly affected. When the drug is prescribed after a meal at a dose of 1250 mg/m2 on the 14th day, Cmax of capecitabine, 5"-DFCT, 5-FU and α-fluoro-β-alanine (FBAL) were 4.47; 12.1 and 5.46 μg/ml, respectively. reaching the maximum concentration (Tmax) was 1.50; 2.00; 2.00 and 3.34 hours, and AUC - 7.24; µg×h/ml, respectively.

Communication with proteins

For capecitabine, 5"-DFCT, 5"-DFUR and 5-FU, the binding to proteins (mainly albumin) is 54, 10, 62 and 10%, respectively.

Metabolism

Metabolized in the liver under the influence of carboxylesterase to the metabolite 5"-DFCT, which is then transformed into 5"-DFUR under the action of cytidine deaminase, located mainly in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite 5-FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase (dTdPase). The concentrations of 5-FU and its active phosphorylated anabolites in the tumor significantly exceed the levels in healthy tissues, which ensures the relative selectivity of the cytotoxic effect.

The AUC for 5-FU is 6–22 times less than after intravenous bolus administration of 5-FU at a dose of 600 mg/m2. Capecitabine metabolites become cytotoxic only after conversion to 5-FU and 5-FU anabolites. Next, 5-FU is catabolized to form inactive metabolites - dihydro-5-fluorouracil (FUN2), 5-fluororeidopropionic acid (FUPA) and FBAL; this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), the activity of which limits the rate of the reaction.

Removal

T1/2 of capecitabine, 5"-DFCT, 5"-DFUR, 5-FU and FBAL is 0.85, respectively; 1.11; 0.66; 0.76 and 3.23 hours. The pharmacokinetic parameters of capecitabine, 5"-DFCT and 5"-DFUR on days 1 and 14 are the same. The AUC of 5-FU increases by 30–35% by day 14 and does not increase further (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of 5-FU, are dose-dependent. Excretion in urine - 95.5%, in feces - 2.6%. The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose taken is excreted unchanged in the urine.

Pharmacokinetics in special clinical groups

Gender, presence or absence of liver metastases before treatment, index general condition patient, concentration total bilirubin, serum albumin, ALT and AST activity in patients with colon cancer did not have a significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.

Patients with metastatic lesion liver. In patients with mild and moderate degree liver dysfunction caused by metastases, clinically significant change The pharmacokinetics of capecitabine do not occur. Data on pharmacokinetics in patients with severe liver dysfunction are not available.

Patients with impaired renal function. At varying degrees(mild to severe) renal failure The pharmacokinetics of the unchanged drug and 5-FU do not depend on creatinine clearance. Creatinine clearance affects the AUC value of 5"-DFUR - the immediate precursor of 5-FU (increase in AUC by 35% with a decrease in creatinine Cl by 50%) and FBAL - a metabolite that does not have antiproliferative activity (increase in AUC by 114% with a decrease in creatinine Cl by 50%). 50%).

Old age. Age does not affect the pharmacokinetics of 5"-DFUR and 5-FU. FBAL AUC increased in patients aged 65 years and older (a 20% increase in age was accompanied by a 15% increase in FBAL AUC), which is likely due to changes in renal function.

Race. Pharmacokinetics in patients of the Negroid race did not differ from those in patients of the Caucasian race.

Using Xeloda during pregnancy

If Xeloda is used during pregnancy, or pregnancy occurs while taking the drug, the patient should be informed about potential danger for the fetus.
Women childbearing age should use reliable contraception and avoid pregnancy during Xeloda therapy.
During the period of use of the drug Xeloda breast-feeding should be stopped.

Use of Xeloda for renal impairment

In patients with underlying renal failure medium degree severity (creatinine clearance 30-50 ml/min), it is recommended to reduce the initial dose to 75% of the standard dose. In patients with renal failure mild degree severity (creatinine clearance 51-80 ml/min), no adjustment of the initial dose is required. If, upon subsequent dose adjustment in accordance with the table above, adverse events of grade 2, 3 or 4 are observed, temporary discontinuation of the drug and careful monitoring of the patient's condition are necessary. Recommendations for dose adjustment in moderate renal impairment apply to both monotherapy and combination therapy with capecitabine.
Contraindicated in severe renal failure (creatinine clearance less than 30 ml/min).

Other special cases when taking Xeloda

In patients with liver and lung metastases or moderate impairment liver function, no change in the initial dose is required. However, these patients should be carefully monitored. In patients with severe liver failure the drug has not been studied.

Contraindications to the use of Xeloda

hypersensitivity to capecitabine and other fluoropyrimidine derivatives or any components of the drug;

Established deficiency of DPD (dihydropyrimidine dehydrogenase) as for other fluoropyrimidines;

Concomitant use of sorivudine or its structural analogues, such as brivudine;

Severe renal failure (creatinine Cl below 30 ml/min);

Pregnancy and lactation;

Age up to 18 years (efficacy and safety of use have not been established);

Presence of contraindications for other components of combination therapy.

With caution:

Kidney or liver failure;

Age over 60 years;

When used simultaneously with oral coumarin anticoagulants.

Side effects of Xeloda

Most Frequent side effects(≥10%): diarrhea, stomatitis, nausea, vomiting, hand-foot syndrome, increased fatigue, weakness, lethargy, drowsiness.

From the digestive system: diarrhea, vomiting, stomatitis (including ulcerative), lack of appetite, loss of appetite, abdominal pain, epigastric pain, constipation, dry mouth, dyspepsia, oral candidiasis; in less than 5% of cases - bloating, esophagitis, gastritis, duodenitis, colitis, hiccups, gastrointestinal bleeding, isolated cases of liver failure and cholestatic hepatitis; their causation with the use of capecitabine has not been established.

From the skin and skin appendages: palmar-plantar syndrome (paresthesia, edema, hyperemia, skin peeling, blistering), dermatitis, dry skin, erythematous rash, erythema, alopecia, itching, focal peeling, skin hyperpigmentation, abnormal structure and discoloration of nails , onycholysis; in less than 5% of cases - photosensitivity reactions, a syndrome resembling radiation dermatitis, skin cracks.

From the outside nervous system: headache, sleep disturbance (severe drowsiness, insomnia), paresthesia, dizziness, peripheral neuropathy; in less than 5% of cases - confusion, encephalopathy, cerebellar symptoms (ataxia, dysarthria, impaired balance and coordination), depression.

From the senses: increased lacrimation, conjunctivitis, taste disturbance; very rarely - stenosis of the nasolacrimal canal.

From the outside respiratory system: sore throat, shortness of breath, cough, nosebleed, dysphonia.

From the outside musculoskeletal system: arthralgia, myalgia.

From the outside cardiovascular system: swelling of the lower extremities; in less than 5% of cases - cardialgia, angina pectoris, cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including atrial fibrillation, ventricular extrasystoles.

From the hematopoietic system: anemia, neutropenia, granulocytopenia, lymphocytopenia, thrombocytopenia; in less than 5% of cases - pancytopenia.

Infections: in less than 5% of cases - infectious complications due to myelosuppression, weakened immunity and impaired integrity of the mucous membranes, local and systemic (bacterial, viral and fungal) infections, possibly fatal, sepsis.

Changes laboratory parameters: regardless of their connection with taking capecitabine - hyperbilirubinemia, increased ALT/AST activity, hypercreatininemia, increased alkaline phosphatase activity, hyperglycemia, hypo- or hypercalcemia, hypoalbuminemia, hyponatremia, hypokalemia.

Other: fever; increased fatigue; weakness; dehydration; weight loss; back pain; lethargy.

Method of administration and dosage of Xeloda

Orally, 30 minutes after meals, at a daily dose of 2.5 g/m2/day (in 2 doses) for 2 weeks, followed by a break for 1 week. Calculation of the total daily dose depending on the body surface: less than 1.24 sq.m - 3 g, 1.25-1.36 sq.m - 3.3 g, 1.37-1.51 sq.m - 3.6 g, 1.52-1.64 sq.m - 4 g, 1.65 -1.76 sq.m - 4.3 g, 1.77-1.91 sq.m - 4.6 g, 1.92-2.04 sq.m - 5 g, 2.05-2.17 sq.m - 5.3 g, more than 2.18 sq.m - 5.6 g. Manifestations of toxicity during treatment can be eliminated with symptomatic therapy and/or dose reduction. Changing the dose depending on the degree of toxicity (Canadian classification of cytotoxicity): I st. - the dose is not changed; II Art. - at the first appearance of signs of toxicity, it is necessary to stop therapy until they disappear or decrease to grade I. Treatment is resumed at 100% of the recommended dose; at the second appearance of signs of toxicity - from 75%, at the third appearance - from 50%; at the fourth appearance of signs of toxicity, the drug is discontinued; III Art. - at the first appearance of signs of toxicity, it is necessary to stop therapy until they disappear or decrease to grade I. Treatment is resumed with 75% of the recommended dose; at the second appearance of signs of toxicity - from 50%; at the third appearance of signs of toxicity, the drug is discontinued; IV Art. - the drug is discontinued.

Overdose of Xeloda

Symptoms of acute overdose: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, inhibition of bone marrow hematopoiesis.
Treatment: standard medical and supportive care medical events aimed at correcting clinical symptoms and prevention of their complications.

Interactions of Xeloda with other drugs

In patients taking Xeloda simultaneously with anticoagulants from the group of coumarin derivatives, such as warfarin or phenoprocoumon, changes in coagulation parameters and/or bleeding were observed. They occurred within a period of several days to several months from the start of taking Xeloda. When studying drug interactions Xeloda has shown that concomitant administration of a single dose of warfarin 20 mg leads to an increase in warfarin AUC by 57% and an increase in INR by 91%. In patients concomitantly taking capecitabine and coumarin-derived oral anticoagulants, clotting parameters (prothrombin time) should be carefully monitored and the dose of the anticoagulant adjusted accordingly.
Special Research There has been no study of the interaction of capecitabine and drugs that are metabolized with the participation of the 2C9 isoenzyme of cytochrome P450. Therefore, co-administration with Xeloda requires caution.
With simultaneous use of Xeloda with phenytoin, an increase in its concentration in the blood plasma is observed. The mechanism of this interaction can be explained by the fact that capecitabine inhibits the 2C9 isoenzyme of cytochrome P450. In case of simultaneous use, it is necessary to monitor the concentration of phenytoin in the blood plasma.
The effect of antacids containing aluminum and magnesium hydroxides was a slight increase in the concentration of capecitabine and one metabolite (5"-DFCR) in plasma; they did not affect the three main metabolites (5"-DFUR, 5-FU and FBAL).
Leucovorin does not affect the pharmacokinetics of Xeloda and its metabolites, which was confirmed in a study of the pharmacokinetics of capecitabine when taken simultaneously with leucovorin in cancer patients. However, leucovorin affects the pharmacodynamics of Xeloda, and its toxicity may be enhanced in the presence of leucovorin.
The clinically significant interaction between sorivudine and 5-FU, resulting from the inhibition of DPD by sorivudine, leads to a potentially fatal increase in fluoropyrimidine toxicity. Therefore, Xeloda should not be taken simultaneously with sorivudine or its chemical analogues, such as brivudine.
When combining capecitabine and oxaliplatin with or without bevacizumab, no changes were observed in the pharmacokinetics of capecitabine and its metabolites, free or bound platinum.
There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites.
In all clinical studies patients took Xeloda within 30 minutes after meals. Because All safety and efficacy data were obtained from study participants who took Xeloda after meals, and this is recommended for other patients.

Special instructions when taking Xeloda

Xeloda can cause diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and, if dehydrated, replacement therapy on restoration of water and electrolyte balance. Prescribe appropriate medications (loperamide) as early as possible. If necessary, reduce the dose.
Dehydration should be prevented or treated as early as possible if it occurs. Patients with anorexia, asthenia, nausea and vomiting, or diarrhea are more susceptible to dehydration. Xeloda should be stopped immediately if grade 2 (or higher) dehydration occurs. Until fluid balance is restored and any causes of thrombosis are eliminated, treatment should not be resumed. If necessary, adjust the dose relative to side effects associated with increased blood clotting.
The spectrum of cardiotoxicity of Xeloda is similar to other fluoropyrimidines. It includes ECG changes, myocardial infarction, angina, arrhythmias, cardiac arrest and heart failure. These adverse events are more common in patients suffering from coronary artery disease.
IN in rare cases Severe unexpected toxicities characteristic of 5-FU (such as stomatitis, diarrhea, neutropenia and neurotoxicity) have been reported and attributed to insufficient DPD activity. It is impossible to exclude a connection between low level DPD and more severe, potentially fatal, toxicity of 5-FU.
A manifestation of skin toxicity is the development of palmoplantar syndrome of grade 1-3 severity (synonyms: palmoplantar erythrodysesthesia or acral erythema caused by chemotherapy). Time to development ranges from 11 to 360 days, with an average of 79 days.
Hand-foot syndrome grade 1 does not interfere with the patient’s daily activities and is manifested by numbness, dysesthesia and paresthesia, tingling or redness of the palms and/or soles, and discomfort.
Hand-foot syndrome grade 2 is characterized by painful redness and swelling of the hands and/or feet, and the discomfort caused by these symptoms interferes with the patient's daily activities.
Grade 3 hand-foot syndrome is characterized by wet desquamation, ulceration, blistering and sharp pain in the hands and/or feet, causing severe discomfort in the patient, making any type of daily activity impossible.
If grade 2 or 3 hand-foot syndrome develops, the use of Xeloda should be suspended until symptoms disappear or decrease to grade 1; at initial stage 3 of the syndrome, subsequent doses of capecitabine should be reduced (Table 3). When combining Xeloda with cisplatin, in case of development of hand-foot syndrome, it is not recommended to prescribe vitamin B6 (pyridoxine) for its symptomatic treatment or prevention, because this may affect the effectiveness of cisplatin.
When treated with Xeloda, it is possible to increase the level of bilirubin in the blood. If the bilirubin level is more than 3 times, and the activity of liver transaminases (ALT, AST) is more than 2.5 times higher than ULN, Xeloda should be stopped. It can be resumed if the level of bilirubin and the activity of liver transaminases decrease below the specified limits.
When studying the drug interaction of Xeloda, it was shown that simultaneous administration of a single dose of warfarin leads to an increase in exposure to warfarin (AUC + 57%). This is attributed to the suppression of cytochrome P450 isoenzyme 2C9 by capecitabine. In patients concomitantly taking capecitabine and coumarin-derived oral anticoagulants, clotting parameters (prothrombin time) should be carefully monitored and the dose of the anticoagulant adjusted accordingly.
Patients taking Xeloda require close monitoring for signs of toxicity. Majority adverse events are reversible and do not require discontinuation of treatment, but may require interruption of treatment or dose reduction.
Among mCRC patients aged 60-79 years who received Xeloda as monotherapy, the incidence of gastrointestinal side effects was the same as in the general population. In the group of patients 80 years of age and older, the frequency of reversible side effects from the gastrointestinal tract of grade 3 and 4 (including diarrhea, nausea and vomiting) was higher. At combination treatment in older people (over 65 years of age), grade 3 and 4 adverse reactions requiring discontinuation of Xeloda occur more often than in younger people. When treated with Xeloda in combination with docetaxel, there is a higher incidence of adverse reactions Grades 3 and 4 and serious adverse events significantly associated with treatment were noted in the group of patients over 60 years of age, compared with younger ones.
Clinicians should use caution when prescribing Xeloda to patients with impaired renal function. Experience with 5-FU shows that treatment-related grade 3 and 4 adverse reactions occur more often in patients with renal failure moderate severity(CC 30-50 ml/min).
Patients with hepatic impairment require careful monitoring when treated with Xeloda. The effect of liver dysfunction not associated with cancer metastases to the liver or severe liver failure on the pharmacodynamics of Xeloda is not known.
Impact on the ability to drive vehicles and operate machinery
The possibility of developing side effects that may impair the ability to perform work that requires concentration and speed of psychomotor reactions should be taken into account.

Storage conditions for Xeloda

List B.: At a temperature not exceeding 30 °C.

Shelf life of Xeloda

The drug Xeloda belongs to the ATX classification:

L Antineoplastic drugs and immunomodulators

L01 Antineoplastic drugs

L01B Antimetabolites

L01BC Pyrimidine analogues

Film-coated tablets - 1 tablet. capecitabine - 150 mg - 500 mg excipients: lactose (anhydrous), croscarmellose sodium; hypromellose (3 mPa.s); MCC; magnesium stearate shell: Opadry peach Ys-1-17255-A (hypromellose 6 mPa.s); talc; titanium dioxide; iron oxide yellow; iron oxide red in a blister 10 pcs.; in a cardboard pack of 6 (150 mg) or 12 (500 mg) blisters and in a polyethylene bottle high pressure 60 (150 mg) or 120 (500 mg) pieces; 1 bottle in a cardboard pack.

Description of the dosage form

150 mg tablets: biconvex, oblong, film-coated tablets, light peach in color, engraved “XELODA” on one side of the tablet and “150” on the other side of the tablet. 500 mg tablets: biconvex, oblong, peach-colored film-coated tablets, engraved with “XELODA” on one side of the tablet and “500” on the other side of the tablet.

Pharmacokinetics

Absorption After oral administration, capecitabine is absorbed quickly and completely, after which it is transformed into metabolites - 5"-deoxy-5-fluorocytidine (5"-DFCT) and 5"-deoxy-5-fluorouridine (5"-DFUR). Food reduces the rate of absorption of capecitabine, but the AUC of 5"-DFUR and the next metabolite, 5-fluorouracil (5-FU), is slightly affected. When the drug is prescribed after a meal at a dose of 1250 mg/m2 on the 14th day, Cmax of capecitabine, 5"-DFCT, 5"-DFUR and alpha-fluoro-beta-alanine (FBAL) were, respectively, 4.47; 12.1; 0.95 and 5.46 μg/ml. reaching the maximum concentration (Tmax) was 1.50; 2.00; 2.00 and 3.34 hours, and AUC - 7.24; µgxh/ml, respectively. Protein binding For capecitabine, 5"-DFCT, 5"-DFUR and 5-FU, protein binding (mainly albumin) is 54, 10, 62 and 10%, respectively. Metabolism Metabolized in the liver. under the influence of carboxylesterase to the metabolite 5"-DFCT, which is then transformed into 5"-DFUR under the action of cytidine deaminase, located mainly in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite 5-FU occurs mainly in tumor tissue under the influence of tumor tissue. angiogenic factor - thymidine phosphorylase (dTdPase). The concentrations of 5-FU and its active phosphorylated anabolites in the tumor significantly exceed the levels in healthy tissues, which ensures the relative selectivity of the cytotoxic effect. AUC for 5-FU is 6-22 times less than after intravenous bolus administration of 5-FU at a dose of 600 mg/m2. Capecitabine metabolites become cytotoxic only after conversion to 5-FU and 5-FU anabolites. Next, 5-FU is catabolized to form inactive metabolites - dihydro-5-fluorouracil (FUN2), 5-fluororeidopropionic acid (FUPA) and FBAL; this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), the activity of which limits the rate of the reaction. The elimination T1/2 of capecitabine, 5"-DFCT, 5"-DFUR, 5-FU and FBAL is 0.85, respectively; 1.11; 0.66; 0.76 and 3.23 hours. The pharmacokinetic parameters of capecitabine, 5"-DFCT and 5"-DFUR on days 1 and 14 are the same. The AUC of 5-FU increases by 30-35% by day 14, and does not increase further (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of 5-FU, are dose-dependent. Excretion in urine - 95.5%, in feces - 2.6%. The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose taken is excreted unchanged in the urine. Pharmacokinetics in special clinical groups Gender, the presence or absence of liver metastases before treatment, the patient’s general condition index, the concentration of total bilirubin, serum albumin, ALT and AST activity in patients with colon cancer did not have a significant effect on the pharmacokinetics of 5"-DFUR, 5 -FU and FBAL. Patients with metastatic liver disease. In patients with mild to moderate liver dysfunction caused by metastases, there are no clinically significant changes in the pharmacokinetics of capecitabine in patients with severe liver dysfunction. With varying degrees (from mild to severe) renal failure, the pharmacokinetics of the unchanged drug and 5-FU do not depend on creatinine clearance. Creatinine clearance affects the AUC value of 5"-DFUR - the immediate precursor of 5-FU (AUC increase by 35% with a decrease in Cl). creatinine by 50%) and FBAL - a metabolite that does not have antiproliferative activity (increase in AUC by 114% with a decrease in creatinine Cl by 50%). Old age. Age does not affect the pharmacokinetics of 5"-DFUR and 5-FU. FBAL AUC increased in patients aged 65 years and older (a 20% increase in age was accompanied by a 15% increase in FBAL AUC), which is likely due to changes in renal function. Race Pharmacokinetics in patients of the Negroid race did not differ from those in patients of the Caucasian race.

Pharmacodynamics

Capecitabine is a fluoropyrimidine carbamate derivative, an oral cytostatic agent that is activated in tumor tissue and has a selective cytotoxic effect on it. In vitro, capecitabine does not have a cytotoxic effect; in vivo, it is converted to 5-FU, which undergoes further metabolism. The formation of 5-FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - dTdPase, which minimizes the systemic effect of 5-FU on healthy tissues of the body. The sequential enzymatic biotransformation of capecitabine into 5-FU creates higher concentrations of the drug in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine to patients with colon cancer, the concentration of 5-FU in tumor tissue is 3.2 times greater than its concentration in adjacent healthy tissue. The ratio of 5-FU concentrations in tumor tissue and plasma is 21.4, the ratio of its concentration in healthy tissues and plasma is 8.9. Thymidine phosphorylase activity in a primary colorectal tumor is 4 times higher than in adjacent healthy tissues. Tumor cells in patients with breast, gastric, colon, cervical and ovarian cancer contain more thymidine phosphorylase, which can convert 5"-DFUR to 5-FU, than in the corresponding healthy tissues. Both healthy and tumor cells metabolize 5- FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) These metabolites damage cells through two different mechanisms. First, FdUMP and the folate cofactor N5-10-methylenetetrahydrofolate bind to thymidylate synthetase (TS). with the formation of a covalently bound tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is an essential precursor of thymidine triphosphate, which, in turn, is essential for DNA synthesis, so a deficiency of this substance can lead to inhibition of cell division. During RNA synthesis, nuclear transcription enzymes may mistakenly include FUTP instead of uridine triphosphate (UTP). This metabolic “error” disrupts RNA processing and protein synthesis.

Indications for use of Xeloda

Combination therapy with docetaxel for locally advanced or metastatic breast cancer, when chemotherapy including anthracycline drugs is ineffective. Monotherapy for locally advanced or metastatic breast cancer, when chemotherapy with taxanes or anthracyclines is ineffective, or when there are contraindications to anthracycline therapy. 1st line therapy for metastatic colon cancer.

Contraindications to the use of Xeloda

Hypersensitivity to capecitabine or any components of the drug. Severe reactions during treatment with fluoropyrimidine or a history of hypersensitivity to fluorouracil; simultaneous use of sorivudine or its structural analogs such as brivudine; severe renal failure (creatinine clearance below 30 ml/min); established DPD deficiency. When conducting combination therapy with Xeloda and docetaxel, contraindications to the use of docetaxel should be taken into account. Pregnancy and lactation.

Xeloda Use during pregnancy and children

Contraindicated during pregnancy and lactation.

Xeloda Side Effects

From the nervous system and sensory organs: fatigue, headache, paresthesia, weakness, asthenia, dizziness, taste disturbance, peripheral neuropathy, insomnia, drowsiness, increased lacrimation, conjunctivitis, eye irritation; confusion, encephalopathy, cerebellar symptoms (ataxia, dysarthria , imbalance and coordination). From the cardiovascular system (hematopoiesis, hemostasis): anemia; cardialgia, cardiomyopathy, angina pectoris, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmia (including atrial fibrillation), ventricular extrasystole, hypo- or hypertension, thrombophlebitis, phlebitis; depression bone marrow, pancytopenia. From the respiratory system: shortness of breath, cough, sore throat; bronchospasm, dyspnea, respiratory distress syndrome, pulmonary embolism. From the gastrointestinal tract: diarrhea, nausea, vomiting, stomatitis, abdominal pain, epigastric pain, constipation , anorexia, decreased appetite, dyspepsia, dry mouth, flatulence, impaired stool consistency (soft stools), oral candidiasis, hyperbilirubinemia; ulcerative-inflammatory damage to the mucous membranes (esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding). Cases of liver failure and cholestatic hepatitis have been described (their causal relationship with the use of capecitabine has not been established). From the musculoskeletal system: pain in the limbs, myalgia, arthralgia, lower back pain, swelling of the lower extremities. From the skin: palm-plantar syndrome (numbness, paresthesia, tingling, swelling, redness, peeling, blistering and sharp pain syndrome), dermatitis, dry skin, erythematous rash, alopecia, itching, focal peeling, hyperpigmentation, nail lesions; skin cracks, photosensitivity, syndrome resembling radiation dermatitis, onycholysis, fragility, discoloration and dystrophy of nails. Other: weakened immunity and impaired integrity mucous membranes (bacterial, viral and fungal; local and systemic, fatal), sepsis; chest pain, changes in ALT, AST levels, hyperglycemia; dehydration, weight loss; very rarely - stenosis of the nasolacrimal canal, nosebleeds.

Drug interactions

Coumarin anticoagulants: capecitabine enhances effects indirect anticoagulants, which may lead to abnormal coagulation parameters and bleeding several days or months after the start of capecitabine therapy (in one case, a month after its completion). Increases warfarin AUC by 57% and INR by 91%. Cytochrome P450 2C9 substrates: Interaction studies between capecitabine and other drugs metabolized by the 2C9 isoenzyme of the cytochrome P450 system have not been conducted. Caution is advised when administering capecitabine with these drugs. Phenytoin: Capecitabine increases plasma concentrations of phenytoin. It is assumed that it is based on the suppression of the CYP2C9 isoenzyme under the influence of capecitabine. In patients taking capecitabine concomitantly with phenytoin, it is recommended that phenytoin plasma concentrations be regularly monitored. Antacids containing aluminum and magnesium hydroxide: slightly increase plasma concentrations of capecitabine and one metabolite (5"-DFCT); they do not affect the three main metabolites (5"-DFUR, 5-FU and PBA) of capecitabine. Calcium folinate (leucovorin) does not affect the pharmacokinetics of capecitabine and its metabolites; may enhance the toxic effect of capecitabine. Sorivudine and its analogues: May potentially lead to a fatal increase in fluoropyrimidine toxicity due to inhibition of dihydropyrimidine dehydrogenase (DPD) by sorivudine.

Xeloda dosage

Orally, with water, 30 minutes after meals (not later). The average daily dose is 2500 mg/m2, in 2 doses (morning and evening), for 2 weeks. After a week's break, the course is repeated. In combination with docetaxel - 1250 mg/m2 2 times a day for 2 weeks, break 1 week (docetaxel - intravenous infusion for 1 hour at a dose of 75 mg/m2 once every 3 weeks). The daily dose of capecitabine is calculated based on body surface area. For body surface area less than 1.26 m2, the total daily dose is 3000 mg; 1.27-1.38 m2 - 3300 mg; 1.39-1.52 m2 - 3600 mg; 1.53-1.66 m2 - 4000 mg; 1.67-1.78 m2 - 4300 mg; 1.79-1.92 m2 - 4600 mg; 1.93-2.06 m2 - 5000 mg; 2.07-2.18 m2 - 5300 mg; more than 2.19 m2 - 5600 mg. In patients with moderate renal failure (creatinine clearance - 30-50 ml/min) or with manifestations of toxicity, the dose is reduced to 75 and 50% of the original dose, both in monotherapy and in combination therapy.

Overdose

Symptoms: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, bone marrow suppression. Treatment: symptomatic.

Catad_pgroup Antimetabolites

Xeloda - official* instructions for use

*registered by the Ministry of Health of the Russian Federation (according to grls.rosminzdrav.ru)

INSTRUCTIONS

By medical use drug

(XELODA®)

Registration number : P N 016022/01

Trade name of the drug: Xeloda ®

International generic name(INN): Capecitabine

Chemical name: 5-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine

Dosage form: Film-coated tablets

Compound: One film-coated tablet, 150 mg contains:
Active substance : capecitabine - 150 mg;
Excipients : 15.6 mg, microcrystalline cellulose - 7.2 mg, croscarmellose sodium - 6.0 mg, hypromellose (3 mPa*s) - 4.5 mg, magnesium stearate - 2.7 mg;
Shell: Opadry pink 03A14309 (hypromellose (6 mPa*s), talc, titanium dioxide (E171), yellow iron oxide dye (E172), red iron oxide dye (E172)) - 8.5 mg.

One film-coated tablet, 500 mg, contains:
Active substance: capecitabine - 500 mg;
Excipients: lactose - 52.0 mg, microcrystalline cellulose - 24.0 mg, croscarmellose sodium - 20.0 mg, hypromellose (3 mPa.s) - 15.0 mg, magnesium stearate - 9.0 mg;
Shell: Opadry pink 03A14380 (hypromellose (6 mPa.s), talc, titanium dioxide (E171), yellow iron oxide dye (E172), red iron oxide dye (E172)) - 18.0 mg.

Description:
Tablets 150 mg: biconvex, oblong, film-coated tablets of light peach (light milky pink) color, engraved “XELODA” on one side of the tablet and “150” on the other side of the tablet.
Tablets 500 mg: biconvex, oblong-shaped, peach (milky pink) film-coated tablets, engraved “XELODA” on one side of the tablet and “500” on the other side of the tablet.

Pharmacotherapeutic group: Antitumor agent, antimetabolite
ATX Code L01BC06

Pharmacological properties
Pharmacodynamics
Capecitabine is a fluoropyrimidine carbamate derivative, an oral cytostatic agent that is activated in tumor tissue and has a selective cytotoxic effect on it.
In vitro capecitabine does not have a cytotoxic effect; in vivo it is converted to 5-fluorouracil (5-FU), which is further metabolized.
The formation of 5-FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase, which minimizes the systemic effect of 5-FU on healthy tissues of the body.
The sequential enzymatic biotransformation of capecitabine into 5-FU creates higher concentrations of the drug in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine to patients colorectal cancer(N=8) the concentration of 5-FU in tumor tissue is 3.2 times higher than its concentration in adjacent healthy tissues (range from 0.9 to 8.0).
The ratio of 5-FU concentrations in tumor tissue and plasma is 21.4 (range from 3.9 to 59.9), the ratio of its concentration in healthy tissues and plasma is 8.9 (range from 3.0 to 25.8). Thymidine phosphorylase activity in a primary colorectal tumor is also 4 times higher than in adjacent healthy tissues.
Tumor cells from patients with breast, stomach, colorectal, cervical and ovarian cancer contain more high level thymidine phosphorylase, capable of converting 5'-DFUR (5'-deoxy-5-fluorouridine) into 5-FU than in corresponding healthy tissues.
Both healthy and tumor cells metabolize 5-FU into 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites damage cells through two different mechanisms. First, FdUMP and the folate cofactor N5-10-methylenetetrahydrofolate bind to thymidylate synthase (TS) to form a covalently linked tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is an essential precursor to thymidine triphosphate, which in turn is essential for DNA synthesis, so a deficiency of this substance can lead to inhibition of cell division.
Secondly, during RNA synthesis, nuclear transcription enzymes may mistakenly include FUTP instead of uridine triphosphate (UTP). This metabolic "error" disrupts RNA processing and protein synthesis.

Pharmacokinetics
Suction
After oral administration, capecitabine is absorbed quickly and completely, after which it is transformed into the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCT) and 5'-DFUR. Food reduces the rate of absorption of capecitabine, but has little effect on the area under the concentration-time curve (AUC) of 5'-DFUR and its downstream metabolite, 5-FU. When prescribing capecitabine after meals at a dose of 1250 mg/m2; on the 14th day, the maximum plasma concentrations (Cmax) of capecitabine, 5'-DFCT, 5'-DFUR, 5-FU and FBAL were, respectively: 4.47, 3.05, 12.1, 0.95 and 5.46 μg/ml. The time to reach maximum concentration (Tmax) was 1.50, 2.00, 2.00, 2.00 and 3.34 hours. AUC 0-∞ was 7.75, 7.24, 24.6, 2.03 and 36.3 μg x h/ml, respectively.
Distribution (protein binding)
An in vitro study in human plasma showed that for capecitabine, 5'-DFCT, 5'-DFUR and 5-FU protein binding (mainly albumin) was 54%, 10%, 62% and 10%, respectively. .
Metabolism
It is primarily metabolized in the liver under the influence of carboxylesterase to the metabolite 5'-DFCT, which is then transformed into 5'-DFUR by the action of cytidine deaminase, located mainly in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite 5-FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase.
The AUC for 5-FU in plasma is 6-22 times less than after an intravenous bolus administration of 5-FU at a dose of 600 mg/m 2 . Capecitabine metabolites become cytotoxic only after conversion to 5-FU and 5-FU metabolites.
Next, 5-FU is catabolized to form inactive metabolites: dihydro-5-fluorouracil (FUN 2), 5-fluororeidopropionic acid (FUPA) and α-fluoro-β-alanine (FBAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), the activity of which limits the rate of the reaction.
Removal
The body half-life (t1/2) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL is 0.85, 1.11, 0.66, 0.76 and 3.23 hours, respectively. The pharmacokinetics of capecitabine were studied in doses from 502 to 3514 mg/m2 per day. The pharmacokinetic parameters of capecitabine, 5'-DFCT and 5'-DFUR on days 1 and 14 were similar. The AUC of 5-FU increased by 30-35% by day 14 and did not increase further (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of 5-FU, were dose-dependent.
After oral administration of capecitabine, its metabolites are excreted primarily in the urine. The majority (95%) of the administered dose of capecitabine is excreted in the urine. Excretion in feces is minimal (2.6%). The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose taken is excreted unchanged in the urine.
Combination therapy
There was no effect of Xeloda on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC), or any effect of docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the main metabolite of capecitabine).
Pharmacokinetics in special clinical groups
Gender, the presence or absence of liver metastases before treatment, the patient's general condition index, the concentration of total bilirubin, serum albumin, AST and ALT activity did not have a statistically significant effect on the pharmacokinetic properties of 5'-DFUR, 5-FU and FBAL.
Patients with liver failure caused by metastatic liver disease
In patients with mild to moderate liver dysfunction caused by metastases, there is no clinically significant change in the bioactivation and pharmacokinetics of capecitabine. Data on pharmacokinetics in patients with severe liver dysfunction are not available.
Patients with impaired renal function
The results of a pharmacokinetic study show that in varying degrees of renal impairment (from mild to severe) the pharmacokinetics of unchanged drug and 5-FU are independent of creatinine clearance (CC). CC affects the AUC value of 5'-DFUR - the immediate precursor of 5-FU (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; 5'-DFUR is the immediate predecessor of 5-FU.
Elderly patients
Age does not affect the pharmacokinetics of 5'-DFUR and 5-FU. FBAL AUC increased with age (a 20% increase in patient age was accompanied by a 15% increase in FBAL AUC), which is likely due to changes in renal function.
Race
The pharmacokinetics of the drug Xeloda ® in patients of the Negroid race do not differ from that in patients of the Caucasian race.

Indications
Breast cancer

• Combination therapy with docetaxel for locally advanced or metastatic breast cancer when chemotherapy that includes an anthracycline drug is ineffective.
• Monotherapy for locally advanced or metastatic breast cancer resistant to chemotherapy with taxanes or anthracyclines or if there are contraindications to them.

Colorectal cancer

• Adjuvant therapy for stage III colon cancer after surgical treatment.
• Therapy of metastatic colorectal cancer.

Stomach cancer

• First-line therapy for advanced gastric cancer.

Contraindications
Hypersensitivity to capecitabine or any other components of the drug.
Hypersensitivity to fluorouracil or with a history of unexpected or severe adverse reactions to treatment with fluoropyrimidine derivatives.
Established deficiency of DPD (dihydropyrimidine dehydrogenase), as for other fluoropyrimidines.
Concomitant use of sorivudine or its structural analogues such as brivudine.
Severe renal failure (creatinine clearance below 30 ml/min).
Initial neutrophil content<1.5 x 10 9 /л и/или тромбоцитов <100 x 10 9 /л.
If there are contraindications to one of the combination therapy drugs, it should not be used.
Pregnancy and lactation period.
Children's age (efficacy and safety of use have not been established).

With caution
With ischemic heart disease, moderate renal failure or liver failure, age over 60 years, simultaneous use with oral coumarin anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Directions for use and doses
Orally, with water, no later than 30 minutes after meals.
Standard dosage regimen
Monotherapy
Colorectal cancer, colon cancer and breast cancer
1250 mg/m2; 2 times a day - morning and evening (total daily dose 2500 mg/m 2 ;) for two weeks, followed by a seven-day break.
Combination therapy
Breast cancer
1250 mg/m2; 2 times a day for two weeks, followed by a seven-day break, in combination with docetaxel at a dose of 75 mg/m2; once every three weeks in the form intravenous infusion within 1 hour.
Premedication is carried out before the administration of docetaxel in accordance with the instructions for its use.
Colorectal and stomach cancer
As part of combination therapy, the dose of Xeloda ® should be reduced to 800-1000 mg/m 2 2 times a day for two weeks, followed by a seven-day break, or to 625 mg/m 2 2 times a day in a continuous mode. The addition of immunobiological drugs to combination therapy does not affect the dose of Xeloda ® .
Antiemetics and premedication to ensure adequate hydration are prescribed before the administration of cisplatin and oxaliplatin according to the instructions for use of cisplatin and oxaliplatin when used in combination with Xeloda ® .
In the adjuvant treatment of stage III colon cancer, the recommended duration of therapy with Xeloda ® is 6 months, i.e. 8 courses.
In combination with cisplatin
1000 mg/m2 2 times a day for two weeks, followed by a seven-day break in combination with cisplatin (80 mg/m2 once every 3 weeks, IV infusion over 2 hours, the first infusion is prescribed on the first day of the cycle ). The first dose of Xeloda ® is prescribed in the evening on the first day of the therapy cycle, the last dose in the morning on the 15th day.
In combination with oxaliplatin and/or bevacizumab
1000 mg/m2 2 times a day for two weeks, followed by a seven-day break in combination with oxaliplatin and/or bevacizumab. The first dose of Xeloda ® is prescribed in the evening on the first day of the therapy cycle, the last dose in the morning on the 15th day. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, intravenous infusion over 30-90 minutes, the first infusion begins on the first day of the cycle. After bevacizumab, oxaliplatin is administered at a dose of 130 mg/m2, intravenous infusion over 2 hours.
In combination with epirubicin and a platinum-based drug
625 mg/m2 2 times a day continuously in combination with epirubicin (50 mg/m2 once every 3 weeks, IV bolus, starting from the first day of the cycle) and a platinum-based drug. A platinum-based drug (cisplatin at a dose of 60 mg/m2 or oxaliplatin at a dose of 130 mg/m2) should be administered on the first day of the cycle as an intravenous infusion for 2 hours, then once every 3 weeks.
In combination with irinotecan
1000 mg/m2 2 times a day for two weeks, followed by a seven-day break in combination with irinotecan (250 mg/m2 once every 3 weeks, IV infusion over 30 minutes, the first infusion is prescribed on the first day of the cycle ).
In combination with irinotecan and bevacizumab
800 mg/m2 2 times a day for two weeks, followed by a seven-day break in combination with irinotecan and bevacizumab. Irinotecan is administered at a dose of 200 mg/m2 once every 3 weeks, intravenous infusion over 30 minutes, the first infusion on the first day of the cycle. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, intravenous infusion over 30-90 minutes, the first infusion begins on the first day of the cycle.
The tables below show examples of standard and reduced dose calculations for Xeloda ® for a starting dose of 1250 mg/m2 or 1000 mg/m2.

Table 1. Standard and reduced doses of Xeloda ® for an initial dose of 1250 mg/m2, calculated depending on body surface area.

	Dose - 1250 mg/m2; twice a day
	Full dose 1250 mg/m2			950 mg/m2	625 mg/m2
	Dose per intake (mg)	150 mg	500 mg	Dose per intake (mg)	Dose per intake (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. Standard and reduced doses of Xeloda ® for an initial dose of 1000 mg/m 2, calculated depending on body surface area.

	Dose - 1000 mg/m² twice a day
	Full dose 1000 mg/m2	Number of tablets 150 mg and/or 500 mg per dose (for each dose, twice a day - morning and evening)		Reduced dose (75% of initial dose) 750 mg/m2	Reduced dose (50% of initial dose) 500 mg/m2
Body surface area (m2)	Dose per intake (mg)	150 mg	500 mg	Dose per intake (mg)	Dose per intake (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

Toxic effects of the drug Xeloda ® can be eliminated by symptomatic therapy and/or dose adjustment of the drug (by interrupting treatment or reducing the dose of the drug). If the dose had to be reduced, it should not be increased subsequently.
If, according to the assessment of the attending physician, the toxic effect of Xeloda ® is not serious or life-threatening for the patient, treatment can be continued at the initial dose without reducing it or interrupting therapy.
In case of grade 1 toxicity, the dose is not changed. In case of grade 2 or 3 toxicity, Xeloda ® therapy should be interrupted.
If signs of toxicity disappear or decrease to grade 1, therapy with Xeloda ® can be resumed at full dose or adjusted according to the recommendations specified in Table 3.
If signs of grade 4 toxicity develop, treatment should be stopped or temporarily interrupted until symptoms are relieved or reduced to grade 1, after which the use of the drug can be resumed at a dose of 50% of the initial dose. The patient should immediately inform the doctor about any adverse events that have developed. Xeloda should be stopped immediately if severe or moderate toxicity occurs. If several doses of Xeloda ® were missed due to toxic effects, these doses are not replenished.
Hematological toxicity
Therapy with Xeloda should be interrupted if signs of grade 3 or 4 hematological toxicity are detected.
The table below contains recommendations for changing the dose of Xeloda ® in the event of toxic phenomena associated with its use.

Table 3. Dose adjustment scheme for Xeloda ®.

NCIC Toxicity Grade*	Changing the dose during the treatment cycle	Dose adjustment during the next cycle of therapy (% of initial dose)
Degree 1	Continue at the same dose	Continue at the same dose
Degree 2
1st appearance		100%
2nd appearance		75%
3rd appearance		50%
4th appearance	Stop therapy completely	Not applicable
Degree 3
1st appearance	Interrupt therapy until resolution to grade 0 - 1	75%
2nd appearance		50%
3rd appearance	Stop therapy completely	Not applicable
Degree 4
1st appearance	Stop therapy completely OR, if the physician believes it is in the patient's best interest to continue treatment, interrupt therapy until resolution to grade 0 - 1	50%
2nd appearance	Stop therapy completely	Not applicable

*According to the National Cancer Institute of Canada Clinical Trials Group Common Toxicity Criteria (NCIC CTG, version 1) or the National Cancer Institute Tumor Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE, version 3). The toxicity criteria for hand-foot syndrome and hyperbilirubinemia are described in detail in the section " Special instructions».

General recommendations for combination therapy
If toxicity occurs during combination therapy, you should adhere to the recommendations for dose adjustment of Xeloda ® indicated above in Table 3, and the corresponding recommendations in the instructions for use of other drugs.
At the beginning of a treatment cycle, if a delay in taking Xeloda ® or other drug(s) is expected, all drugs should be delayed until conditions for restarting therapy with all drugs have been achieved.
If, during a cycle of combination therapy, toxicity phenomena, in the opinion of the doctor, are not associated with the use of the drug Xeloda ® , then therapy with the drug Xeloda ® should be continued, and the dose of the other drug should be adjusted in accordance with the recommendations of the instructions for its use.
If the other drug(s) must be discontinued, treatment with Xeloda ® can be continued if the requirements for restarting therapy with Xeloda ® are met.
These recommendations apply to all indications and all special patient populations.
Dose adjustment in special cases
Liver dysfunction in patients with liver metastases
No change in the starting dose is required in patients with liver metastases and mild to moderate liver dysfunction. However, these patients should be carefully monitored. The use of the drug in patients with severe liver failure has not been studied.
Renal dysfunction
It is recommended to reduce the initial dose to 75% of 1250 mg/m2 in patients with initial moderate renal failure (creatinine clearance 30-50 ml/min, according to the Cockroft-Gault formula). In patients with mild renal failure (creatinine clearance 51-80 ml/min), no adjustment of the initial dose is required.
If a patient experiences an adverse event of 2nd, 3rd or 4th degree of severity, careful monitoring and immediate interruption of the therapy is necessary for the purpose of subsequent adjustment of the drug dose in accordance with the recommendations specified in Table 3. If the calculated creatinine clearance decreased during therapy to a level of less than 30 ml/min, therapy with Xeloda ® should be discontinued. Recommendations for adjusting the dose of the drug in moderate renal failure apply to both monotherapy and combination therapy. Dose calculations are shown in Tables 1 and 2.
Children
The safety and effectiveness of Xeloda ® in children have not been studied.
Elderly and old age
No adjustment of the initial dose is required when using Xeloda ® as monotherapy. However, treatment-related grade 3 and 4 severe adverse events occurred more often in patients over 80 years of age than in younger patients.
When using Xeloda ® in combination with other anticancer drugs in elderly patients (aged > 65 years), adverse reactions of the 3rd and 4th severity, as well as adverse reactions requiring discontinuation of therapy, were observed more often than in younger patients. Careful monitoring of the condition of elderly patients is recommended.
During treatment in combination with docetaxel In patients aged 60 years and older, there was an increased incidence of grade 3 and 4 adverse events and treatment-related serious adverse events. For patients aged 60 years and older who will receive a combination of Xeloda ® with docetaxel, it is recommended to reduce the initial dose of Xeloda ® to 75% (950 mg/m 2 twice daily). Dose calculations are shown in Table 1.
During treatment in combination with irinotecan in patients aged 65 years and older, it is recommended to reduce the initial dose of Xeloda ® to 800 mg/m 2 twice daily.

Overdose
Symptoms of acute overdose include nausea, vomiting, diarrhea, inflammation of the mucous membrane (mucositis), irritation gastrointestinal tract and bleeding, as well as suppression of bone marrow function. Treatment of overdose should include a standard set of therapeutic and supportive measures aimed at correcting clinical symptoms and preventing possible complications.

Interaction with other drugs
Coumarin anticoagulants
In patients taking Xeloda ® concomitantly with coumarin anticoagulants (warfarin and phenprocoumon), coagulation abnormalities and/or bleeding were reported several days or months after the start of capecitabine therapy, and in several cases within one month after its completion.
In a drug interaction study, after a single dose of 20 mg warfarin, Xeloda ® increased the AUC of S-warfarin by 57% and the international normalized ratio (INR) by 91%. In patients simultaneously taking Xeloda ® and coumarin anticoagulants, coagulation parameters (prothrombin time or INR) should be carefully monitored, and the dose of the anticoagulant should be adjusted according to these parameters.
Substrates of cytochrome P4502C9
There have been no special studies of drug interactions between capecitabine and other drugs metabolized by the 2C9 isoenzyme of the cytochrome P450 system. Caution should be exercised when prescribing Xeloda ® together with these drugs.
Phenytoin
When taking Xeloda ® and phenytoin simultaneously, an increase in the concentration of the latter in plasma was reported. Special studies of drug-drug interactions between Xeloda ® and phenytoin have not been conducted, but it is assumed that the mechanism of interaction is based on the suppression of the CYP2C9 isoenzyme under the influence of capecitabine (see above “Coumarin anticoagulants”). In patients receiving phenytoin and Xeloda simultaneously, plasma phenytoin concentrations should be regularly monitored.
Antacids
When assessing the pharmacokinetic parameters of the drug Xeloda ® when taken simultaneously with antacids containing aluminum hydroxide and magnesium hydroxide, a slight increase in the concentration of capecitabine and one of the metabolites (5'-DFCT) in the blood plasma was noted. The three main metabolites of capecitabine (5'-DFUR, 5 FU and FBAL) were not affected by the studied agents.
Calcium folinate (Leucovorin)
Calcium folinate does not affect the pharmacokinetic properties of capecitabine and its metabolites. However, it is possible that the toxic effect of capecitabine may be enhanced due to the effect of calcium folinate on the pharmacodynamics of Xeloda ® .
Sorivudin and its analogues
The literature describes a clinically significant drug interaction between sorivudine and 5-FU, which is based on the inhibitory effect of sorivudine on DPD. This interaction can lead to a fatal increase in the toxicity of fluoropyrimidines. Therefore, Xeloda ® should not be prescribed concomitantly with sorivudine or its structural analogues such as brivudine. A minimum four-week interval should be observed between the end of therapy with sorivudine or its structural analogues (including brivudine) and the start of treatment with Xeloda.
Oxaliplatin
There was no clinically significant difference in exposure to capecitabine or oxaliplatin metabolites (free platinum or total platinum) when capecitabine and oxaliplatin were combined, regardless of the presence of bevacizumab.
Bevacizumab
There was no clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites.

Special instructions
It is necessary to conduct careful medical monitoring for manifestations of toxicity in patients receiving therapy with Xeloda ® .
Most adverse events are reversible and do not require complete discontinuation of the drug, although it may be necessary to adjust the dose or temporarily discontinue the drug.
Diarrhea: Treatment with Xeloda ® may cause diarrhea, sometimes severe. Patients with severe diarrhea should be closely monitored, and if dehydration develops, rehydration and replacement of electrolytes should be carried out. Standard antidiarrheal drugs (eg, loperamide) should be prescribed as early as medically indicated. If necessary, the dose of Xeloda ® should be reduced.
Dehydration: Dehydration should be prevented or eliminated at the very beginning of its occurrence. Dehydration can develop quickly in patients with anorexia, asthenia, nausea, vomiting or diarrhea.
If grade 2 or higher dehydration develops, treatment with Xeloda ® should be immediately interrupted and rehydration performed. Treatment should not be resumed until rehydration is completed and the factors that caused it are eliminated or corrected. The dose of the drug should be modified in accordance with the recommendations for adverse events leading to dehydration.
The spectrum of cardiotoxicity with capecitabine is similar to that with other fluoropyrimidines and includes myocardial infarction, angina, arrhythmias, cardiac arrest, heart failure and ECG changes. These adverse events are more typical for patients with a history of coronary artery disease.
In rare cases, unexpected severe toxicities (eg, stomatitis, diarrhea, neutropenia, and neurotoxicity) associated with 5-FU are due to insufficient dihydropyrimidine dehydrogenase (DPD) activity. Thus, a connection between reduced DPD activity and more severe, potentially lethal toxicity of 5-FU cannot be ruled out.
A manifestation of skin toxicity of the drug Xeloda ® is the development of palmar-plantar syndrome (synonyms - palmar-plantar erythrodysesthesia or acral erythema caused by chemotherapy). The median time to toxicity in patients receiving Xeloda monotherapy was 79 days (range, 11 to 360 days), and severity ranged from grade 1 to grade 3. Hand-foot syndrome of the 1st degree does not interfere with the patient’s daily activities and is manifested by numbness, dysesthesia/paresthesia, tingling or redness of the palms and/or soles, and discomfort. Grade 2 hand-foot syndrome is characterized by painful redness and swelling of the hands and/or feet, and the discomfort caused by these symptoms interferes with the patient's daily activities. Grade 3 hand-foot syndrome is defined as moist desquamation, ulceration, blistering and sharp pain in the hands and/or feet, as well as severe discomfort that makes it impossible for the patient to carry out any daily activities. If hand-foot syndrome of the 2nd or 3rd degree occurs, therapy with Xeloda ® should be interrupted until the symptoms disappear or decrease to the 1st degree. If grade 3 syndrome occurs, subsequent doses of Xeloda should be reduced.
Vitamin B 6 (pyridoxine) is not recommended for the symptomatic or secondary preventive treatment of hand-foot syndrome when Xeloda is administered in combination with cisplatin, as it may reduce the effectiveness of cisplatin.
Xeloda ® may cause hyperbilirubinemia. If, in connection with treatment with Xeloda ®, hyperbilirubinemia >3.0xULN (upper limit of normal) or increased activity of hepatic aminotransferases (ALT, AST)>2.5xULN is observed, treatment should be interrupted.
Therapy can be resumed if the level of bilirubin and the activity of hepatic aminotransferases decrease below the specified limits.
In patients simultaneously taking Xeloda ® and oral anticoagulants - coumarin derivatives, coagulation parameters (prothrombin time or INR) should be monitored and the dose of the anticoagulant should be adjusted accordingly.
Use of the drug in elderly and senile patients
The frequency of toxic events from the gastrointestinal tract in patients with colorectal cancer aged 60-79 years who received monotherapy with Xeloda ® did not differ from that in the general patient population. In patients 80 years of age and older, reversible grade 3 and 4 gastrointestinal adverse events, such as diarrhea, nausea and vomiting, occurred more frequently. In patients >65 years of age receiving combination therapy capecitabine and other anticancer drugs, there was an increase in the frequency adverse reactions Grade 3 and 4 severity and adverse events that led to discontinuation of therapy compared to patients under 65 years of age.
When analyzing safety data in patients > 60 years of age receiving combination therapy with Xeloda ® and docetaxel, an increase in the incidence of treatment-related grade 3 and 4 adverse events, serious adverse events, and early discontinuation of therapy due to adverse events was noted. compared with those in patients younger than 60 years.
Kidney failure
Caution should be exercised when prescribing Xeloda ® to patients with moderate renal failure. As with fluorouracil treatment, the incidence of treatment-related grade 3 and 4 adverse events was higher in patients with moderate renal failure (creatinine clearance 30-50 ml/min).
Liver failure
Patients with liver failure should be under close medical supervision during therapy with Xeloda ®. The effect of impaired liver function, not due to metastatic liver disease or severe liver failure, on the distribution of Xeloda ® is unknown.
During therapy with Xeloda ® and for at least 3 months after its completion, reliable methods of contraception should be used. If pregnancy occurs during therapy, the patient should be aware of potential threat for the fetus.
Handling unused drug and drug with expired validity
Hit medicinal product along with waste in environment should be kept to a minimum. The drug should not be disposed of with wastewater or household waste. Where possible, special systems should be used to dispose of medications.

Effect on ability to drive vehicles and mechanisms
The drug Xeloda ® has a slight or moderate effect on the ability to drive vehicles and machinery. Patients who experience undesirable effects such as dizziness, weakness or nausea should refrain from driving vehicles or machinery.

Release form and packaging
Film-coated tablets, 150 mg and 500 mg
10 tablets per blister made of PVC/PVDC film and aluminum foil.
6 (150 mg tablets) or 12 (500 mg tablets) blisters along with instructions for use are placed in a cardboard box.

Storage conditions
Store at a temperature not exceeding 30°C.
Keep out of the reach of children.

Best before date
3 years. Do not use after the expiration date stated on the packaging.

Conditions for dispensing from pharmacies
According to the recipe.

Owner Registration certificate
F. Hoffmann-La Roche Ltd., Switzerland
F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland

Manufacturer
Hoffmann-La Roche Inc., USA
Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, N.J. 07110, USA
Productos Roche S.A. de C.V., Mexico
Productos Roche S.A. de C.V., Via Isidro Fabela Nte. 1536-B, CP50030 Col. Parque Industrial, Toluca, Edo de Mexico, Mexico

Consumer complaints should be sent to the address of the Representative Office of F. Hoffmann-La Roche Ltd.:
107031, Russia, Moscow, Trubnaya Square, 2

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The drug "Xeloda" (capecitabine) belongs to the category of cytostatic. Its main active substance disrupts the process of growth and division of rapidly dividing cells in the body, which include malignant ones, thereby provoking apoptosis (programmed death) in them.

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Indications

The drug "Xeloda", instructions for use of which are provided to your attention, undergoes rapid absorption, activating in the tumor, and not in the surrounding tissues. This slows down the growth of harmful cells and stops tumor development.

"Xeloda" is prescribed only by a specialist. They do this in the following situations:

• in combination with the drug "Docetaxel" in the treatment of breast cancer (metastatic or locally advanced), in case of ineffectiveness of the use of anthracycline drugs;
• in case of diagnosis of colorectal metastatic cancer;
• with advanced stomach cancer;
• colon cancer.

Dosage

Xeloda tablets are available in 500 mg (120 pieces per package) and 150 mg (60 pieces) tablets. They should be taken half an hour after meals with water. Daily dosage is 1250 mg per m² of body surface.

They drink the medicine twice a day - morning and evening - for 3 weeks, after which the patient is supposed to take a break for a week.

In combination therapy, the prescription of the drug "Xeloda" requires strict adherence to its compatibility with other drugs, taking into account the characteristics of the course of the disease and the patient's condition.

Contraindications

In some cases, Xeloda is not prescribed:

1. In case of hypersensitivity to its components.
2. When taking the drug Sorivudin or its analogues simultaneously;
3. When diagnosing severe renal failure;
4. Women during pregnancy and breastfeeding;
5. Children under 18 years old.

Caution is required when treating patients with coronary artery disease, patients 60 years of age and older, and during concomitant treatment with oral anticoagulants.

Side effects

When treated with Xeloda (500 or 150 mg), the following side effects may develop:

• diarrhea;
• stomatitis;
• weakness, severe fatigue;
• nausea, vomiting;
• increased drowsiness and lethargy;
• hand-foot syndrome.

In addition, some patients had disturbances in digestive activity, in a state skin, as well as in the functioning of the organs of the cardiovascular, respiratory systems, etc.

KNF (medicine included in the Kazakhstan National Formulary of Medicines)

ALO (Included in the List of free outpatient drug provision)

ED (Included in the List of drugs within the framework of the guaranteed volume of free medical care, subject to purchase from the Single Distributor)

Manufacturer: Productos Roche S.A. de S.V.

Anatomical-therapeutic-chemical classification: Capecitabine

Registration number: No. RK-LS-5 No. 014411

Registration date: 05.03.2015 - 05.03.2020

Limit price: 452.45 KZT

Instructions

• Russian

Trade name

International nonproprietary name

Capecitabine

Dosage form

Film-coated tablets, 500 mg

Compound

One 500 mg tablet contains

active substance: capecitabine 500 mg,

excipients: lactose anhydrous, croscarmellose sodium, hypromellose (3 mPa.s), microcrystalline cellulose, magnesium stearate

shell composition: Opadry 03А14380 pink (hypromellose, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172))

Description

Tablets are oblong in shape, with a biconvex surface, peach-colored film-coated tablets with the inscription “XELO-DA” embossed on one side and “500” on the other side.

Pharmacotherapeutic group

Antitumor drugs. Antimetabolites. Pyrimidine analogues. Capecitabine.

ATX code L01BC06

Pharmacological properties

Pharmacokinetics

Absorption

After oral administration, capecitabine is absorbed quickly and completely, after which it is transformed into metabolites - 5"-deoxy-5-fluorocytidine (5"-DFCT) and 5"-deoxy-5-fluorouridine (5"-DFUR). Food slows the rate of absorption of capecitabine, but the AUC of 5"-DFUR and the next metabolite, 5-fluorouracil (5-FU), is slightly affected. When the drug is administered after a meal at a dose of 1250 mg/m2 on the 14th day, Cmax of capecitabine, 5"-DFCT, 5-FU and α-fluoro-β-alanine (FBAL) were 4.47; 12.1 and 5.46 μg/ml, respectively. reaching the maximum concentration (Tmax) was 1.50; 2.00; 2.00 and 3.34 hours, and AUC - 7.24; µg×h/ml, respectively.

Distribution

Research in vitro showed that for capecitabine, 5"-DFCT, 5"-DFUR and 5-FU the binding to proteins (mainly albumin) is 54%, 10%, 62% and 10%, respectively.

Metabolism

Capecitabine is metabolized in the liver by carboxylesterase to the metabolite 5"-DFCT, which is then transformed into 5"-DFUR by cytidine deaminase, located mainly in the liver and tumor tissues.

Further transformation to the active cytotoxic metabolite 5-FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase (dTdPase); at the same time, the systemic effect of 5-FU on healthy tissue is minimized.

The AUC for 5-FU is 6-22 times less than after intravenous (IV) bolus administration of 5-FU at a dose of 600 mg/m2. Metabolites of capecitabine become cytotoxic only after conversion to 5-FU and 5-FU anabolites (see section "Mechanism of Action").

Next, 5-FU is catabolized to form inactive metabolites - dihydro-5-fluorouracil (FUN2), 5-fluororeidopropionic acid (FUPA) and α-fluoro-β-alanine (FBAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), the activity of which limits the rate of the reaction.

Removal

The half-life (T1/2) of capecitabine, 5"-DFCT, 5"-DFUR, 5-FU and FBAL is 0.85; 1.11; 0.66; 0.76 and 3.23 hours, respectively. The pharmacokinetics of capecitabine were determined in the dose range from 502 to 3514 mg/m2/day. The pharmacokinetic parameters of capecitabine, 5"-DFCT and 5"-DFUR on days 1 and 14 are the same. The AUC of 5-FU increases by 30-35% by day 14, and does not increase further (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of 5-FU, are dose-dependent.

After oral administration, capecitabine metabolites are excreted mainly in the urine (95.5%). Excretion in feces is minimal (2.6%). The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose taken is excreted unchanged in the urine.

Combination therapy

Phase 1 studies evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and paxitaxel and inverse relationship did not find an effect of capecitabine on the pharmacokinetic parameters of docetaxel and paxitaxel (Cmax and AUC) or an effect of docetaxel and paxitaxel on the pharmacokinetics of 5"-DFUR (the main metabolite of capecitabine).

Based on data from the use of capecitabine in 505 patients with colorectal cancer (1250 mg/m2 2 times a day), a population pharmacokinetic analysis was conducted. Gender, the presence or absence of liver metastases before treatment, the patient’s general condition index (Karnofsky index), the concentration of total bilirubin, serum albumin, ALT and AST activity did not have a statistical effect significant impact on the pharmacokinetics of 5"-DFUR, 5-FU and FBAL.

Patients with metastatic liver disease

In patients with mild to moderate liver dysfunction due to metastases, there is no clinically significant change in the pharmacokinetics of capecitabine and its biological activity (see dosing section for special categories patients).

There are no pharmacokinetic data in patients with severe hepatic impairment.

According to a pharmacokinetic study with varying degrees (from mild to severe) renal failure, the pharmacokinetics of the unchanged drug and 5-FU do not depend on creatinine clearance. Creatinine clearance affects the AUC value of 5"-DFUR (increase in AUC by 35% with a decrease in creatinine clearance by 50%) and FBAL (increase in AUC by 114% with a decrease in creatinine clearance by 50%). FBAL is a metabolite that does not have antiproliferative activity; 5"-DFUR is a direct precursor to 5-FU (see section on dosing for special categories of patients).

Elderly patients

Population pharmacokinetic analysis, which included patients from the most different ages(27 to 86 years), including 234 (46%) patients aged ≥ 65 years, showed that age did not affect the pharmacokinetics of 5"-DFUR and 5-FU. FBAL AUC increased in patients aged 65 years and older (a 20% increase in age was associated with a 15% increase in FBAL AUC), which is likely due to changes in renal function (see section on dosing in special populations and section " Pharmacokinetics in special categories of patients", subsection " Patients with kidney failure»).

Race

A population pharmacokinetic analysis that included 455 Caucasian patients (90.1%), 22 Black patients (4.4%), and 28 patients of other races and ethnicities (5.5%) showed that pharmacokinetics in Black patients did not differ from those in Caucasian patients. race.

Pharmacodynamics

Mechanism of action

Xeloda is a fluoropyrimidine carbamate derivative, an oral cytostatic that is activated in tumor tissue and has a selective cytotoxic effect on it. In vitro capecitabine does not have a cytotoxic effect, whereas in vivo turns into 5-FU, which undergoes further metabolism. The formation of 5-FU occurs in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase (dTdPase), which minimizes the systemic effect of 5-FU on healthy tissues of the body. The sequential enzymatic biotransformation of capecitabine into 5-FU creates higher concentrations of the drug in tumor tissues than in surrounding healthy tissues. After oral administration of Xeloda to patients with colon cancer, the concentration of 5-FU in tumor tissue was 3.2 times higher than in adjacent healthy tissue. The ratio of 5-FU concentrations in tumor tissue and plasma is on average 21.4 (3.9-59.9), the ratio of its concentration in healthy tissues and plasma is 8.9 (3.0 - 25.8). Thymidine phosphorylase activity in a primary colorectal tumor is 4 times higher than in adjacent healthy tissues.

Tumor cells from patients with breast, gastric, colon, cervical and ovarian cancer contain more thymidine phosphorylase, which can convert 5"-DFUR (5"-deoxy-5-fluorouridine) to 5-FU, than in corresponding healthy tissues.

Both healthy and tumor cells metabolize 5-FU into 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites damage cells through two different mechanisms. First, FdUMP and the folate cofactor N5-10-methylenetetrahydrofolate bind to thymidylate synthetase to form a covalently linked tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is a necessary precursor to thymidine triphosphate, which in turn is essential for DNA synthesis, so a deficiency of this substance can lead to inhibition of cell division. Secondly, during RNA synthesis, nuclear transcription enzymes may mistakenly include FUTP instead of uridine triphosphate (UTP). This metabolic "error" disrupts RNA replication and protein synthesis.

Indications for use

Breast cancer

in combination with docetaxel is used to treat patients with locally advanced or metastatic cancer breast (BC) after ineffective chemotherapy, including anthracyclines

as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer (mBC) after ineffective chemotherapy that included taxanes and anthracyclines, or those for whom anthracyclines are contraindicated

Colorectal cancer

as adjuvant therapy for patients with colon cancer

for the treatment of patients with metastatic colorectal cancer (mCRC)

Esophagogastric cancer

as first line therapy for patients with advanced esophagogastric cancer.

Stomach cancer

in combination with oxaliplatin, used as adjuvant therapy for patients with stage II and III gastric adenocarcinoma after complete resection

Directions for use and doses

Standard dosage

Xeloda tablets are taken orally, 30 minutes after meals, with water.

Monotherapy

Breast, colon and colorectal cancer:

The recommended starting dose of Xeloda for monotherapy is 1250 mg/m2 twice daily (morning and evening), which is equivalent to a total daily dose of 2500 mg/m2 for two weeks followed by a break of 7 days.

Combination therapy

Breast cancer:

In combination with docetaxel, Xeloda is prescribed at a dose of 1250 mg/m2 2 times a day for 2 weeks, followed by a break of 7 days. Docetaxel is administered at a dose of 75 mg/m2 as an hour-long intravenous infusion once every 3 weeks. Before administering docetaxel with Xeloda, premedication is carried out in accordance with the instructions for use of docetaxel.

Esophagogastric, stomach, colon and colorectal cancer:

In combination therapy (with the exception of irinotecan), the recommended initial dose of Xeloda is reduced to 800-1000 mg/m2 twice daily for two weeks followed by a break of 7 days, or to 625 mg/m2 twice daily with continuous therapy (see section Clinical/Efficacy Studies).

In combination therapy with irinotecan (XELIRI), the recommended starting dose of Xeloda is 800 mg/m2 twice daily for 2 weeks, followed by a break of 7 days. Irinotecan is administered at 200 mg/m2 on the first day of each three-week cycle (see Clinical Studies/Efficacy Studies).

The inclusion of bevacizumab in combination therapy does not affect the initial dose of Xeloda. Adjuvant therapy for patients with stage III colorectal cancer is recommended for a total of 6 months.

Antiemetics and premedication to ensure adequate hydration are prescribed before the administration of cisplatin or oxaliplatin in accordance with the instructions for their use.

The dose of Xeloda is calculated depending on the body surface area. Tables 1 and 2 below show standard and reduced doses of Xeloda, calculated at 1250 mg/m2 or 1000 mg/m2 of body surface.

Table 1. Standard and reduced doses of Xeloda, calculated at 1250 mg/m2 body surface.

	Dose 1250 mg/m2 (twice daily)
	Full dose 1250 mg/m2			75% of dose 950 mg/m2	50% dose 625 mg/m2
Surface area	Dose per dose (mg)*			Dose for 1 dose, mg	Dose for 1 dose, mg

Table 2. Standard and reduced doses of Xeloda, calculated at 1000 mg/m2 body surface.

	Dose 1000 mg/m2 (twice daily)
	Full dose 1000 mg/m2	Number of tablets 150 mg and/or 500 mg per dose (morning and evening)		75% of dose 750 mg/m2	50% of dose 500 mg/m2
Surface area	Dose per dose (mg)*			Dose for 1 dose, mg	Dose for 1 dose, mg

Dose adjustment during treatment

General toxicity

Toxicity phenomena during treatment with Xeloda can be eliminated using symptomatic therapy and/or changing the dose of Xeloda (by interrupting treatment or reducing the dose of the drug). If you once had to reduce the dose of Xeloda, then it should not be increased subsequently. In situations where the attending physician believes that the symptoms of toxicity do not pose a threat to the patient's life, or their severity is not severe, treatment with Xeloda can be continued at the initial dose without reducing the dose or interrupting treatment.

For grade 1 toxicity, no dose adjustment should be made. In case of grade 2 and 3 toxicity, Xeloda should be stopped. After resolution of adverse events or reduction of their severity to grade 1, Xeloda can be resumed at the full dose, or adjusted in accordance with the recommendations given in Table 7. If signs of grade 4 toxicity develop, treatment should be stopped or temporarily interrupted until relief or reduction in severity symptoms up to grade 1, after which the use of the drug can be resumed at a dose of 50% of the previous one. Patients taking Xeloda should be advised to immediately discontinue treatment if severe or moderate toxicity occurs. Several doses of Xeloda missed due to toxicity are not made up, but simply continue the planned cycles of therapy.

Hematological toxicity

Patients with original number neutrophils<1.5 x 109/l и/или тромбоцитов <100 x 109/l нельзя назначать лечение Кселодой. Если результаты внеплановых лабораторных исследований, проводимых в ходе лечения, указывают на гематологическую токсичность 3-й и 4-й степени, терапию Кселодой необходимо прекратить.

Degree of toxicity NCIC *	Dose changes during the treatment cycle	Dose adjustment for the next cycle (5 times the initial dose)
Degree 1	Maintain dose	Maintain dose
Degree 2
	Suspend treatment until symptoms disappear or severity decreases to grade 1
	Stop treatment completely	Not applicable
Degree 3
	Stop treatment until symptoms disappear or severity decreases to grade 1
	Stop treatment completely	Not applicable
Degree 4
	Stop treatment or, if the treating physician considers it to be in the patient's best interests, resume treatment once symptoms have resolved or severity has decreased to grade 1.
	Stop treatment completely	Not applicable

(*) - in accordance with the Common Toxicity Criteria (version 1) of the National Cancer Institute of Canada (NCIC CTG) and the Common Terminology Criteria for Adverse Events (CTCAE) of the US National Cancer Institute Cancer Therapy Evaluation Program (version 3.0). Data for hand-foot syndrome and hyperbilirubinemia are given in the section "Special Instructions and Precautions."

General provisions of combination therapy

In case of toxic reactions when using Xeloda in combination with other drugs, dose adjustment is carried out in accordance with the recommendations indicated in Table 3 and the instructions for use of the corresponding drugs used in conjunction with Xeloda.

At the beginning of the cycle: If a delay in taking Xeloda or another chemotherapy drug is necessary, then administration of all drugs should be delayed until all requirements for restarting therapy are met.

During the treatment cycle: If toxic reactions, in the opinion of the attending physician, are not associated with Xeloda, Xeloda should be continued and the dose of the co-administered drug should be changed in accordance with the instructions for its use.

If other drug(s) must be discontinued, treatment with Xeloda can be continued provided that the requirements for restarting Xeloda therapy are met.

Patients with liver failure due to liver metastasis

In patients with hepatic mild insufficiency or moderate severity there is no need to reduce the dose at the beginning of treatment. However, they need careful monitoring throughout treatment. Patients with severe liver failure were not included in the study.

Patients with kidney failure

In patients with moderate renal failure (creatinine clearance (CC) 30-50 ml/min), at the beginning of treatment the dose should be reduced to 75% of 1250 mg/m2. Patients with mild renal failure (creatinine clearance 51-80 ml/min) do not need to reduce the dose.

If an adverse event of grade 2-4 occurs, immediate measures should be taken to carefully monitor its condition, if necessary, discontinuation of treatment and further dose adjustment in accordance with the recommendations in Table 3. If during treatment the CC dropped below 30 ml/min, take Xeloda should be stopped. Recommendations for dose adjustment in patients with moderate renal failure apply to both Xeloda monotherapy and combination regimens. To calculate the daily dose, see tables 1 and 2.

Children

The safety and effectiveness of Xeloda in children has not been established.

Elderly patients

When monotherapy with Xeloda there is no need for dose adjustment. However, patients over 80 years of age are more likely to experience grade 3 and 4 side effects than younger people. With combined treatment in elderly people (over 65 years of age), grade 3 and 4 adverse reactions requiring discontinuation of Xeloda occur more often than in younger people. Close monitoring of elderly patients is recommended. When treated with Xeloda in combination with docetaxel, a higher incidence of grade 3 and 4 adverse reactions and serious adverse events significantly related to treatment was observed in patients over 60 years of age compared to younger patients. Therefore, for persons over 60 years of age, when combining Xeloda with docetaxel, a reduction in the initial dose to 75% (950 mg/m2 2 times a day) is required. To calculate the dose, refer to Table 2.

Side effects

Clinical studies

A possible, probable and remote relationship between Xeloda and adverse drug reactions (ADRs) was found in clinical studies of Xeloda monotherapy (adjuvant therapy for colon cancer, metastatic colorectal cancer and metastatic breast cancer), as well as in combination therapy studies with Xeloda and others chemotherapy drugs for various diseases. In the tables below, ADRs are listed based on the frequency of their occurrence, determined as a result of a comprehensive analysis of data from seven clinical studies. Within each category, ADR frequencies are listed in descending order of severity. The incidence of adverse reactions is determined as follows: very often ≥ 1/10, often ≥ 5/100 -< 1/10 и редко ≥ 1/1000 и < 1/100.

Monotherapy with Xeloda

Safety data for Xeloda monotherapy were obtained in patients receiving adjuvant therapy for colon cancer and in patients receiving treatment for metastatic breast cancer and metastatic colorectal cancer. Safety information includes data from a phase III study of adjuvant therapy for colon cancer (995 patients received Xeloda and 974 patients received intravenous 5-FU/leucovorin), data from 4 phase II studies in patients with breast cancer (N=319), and data from 3 studies (1 phase II and 2 phase III studies) of patients of both sexes with colorectal cancer (N=630). The safety profile of Xeloda in patients receiving adjuvant therapy for colon cancer and in patients receiving the drug for the treatment of metastatic breast cancer and metastatic colorectal cancer is similar. ADR intensity was classified according to NCIC CTC toxicity categories.

Table 4. ADRs observed in 5% of patients receiving Xeloda monotherapy

Organ system class	Very often (≥ 10%)	Often (≥ 5% - < 10%)
	Anorexia (Art. 3/4:1%)	Dehydration (st. 3/4: 3%) Decreased appetite (Art. 3/4:<1%)
		Paresthesia, Dysgeusia (Art. 3/4:<1%), Headache (Art. 3/4:<1%), Dizziness (except vertigo) (Art. 3/4:<1%)
		Increased lacrimation Conjunctivitis (Art. 3/4:<1%)
	Diarrhea (art. 3/4: 13%) Vomiting (st. 3/4: 4%) Nausea (st. 3/4: 4%) Stomatitis (all types)* (st. 3/4: 4%) Abdominal pain (st. 3/4: 3%)	Constipation (Art. 3/4:<1%), Pain in the upper abdominal cavity (art. 3/4:<1%), Indigestion (Art. 3/4:<1%),
Disorders of the liver and biliary tract		Hyperbilirubinemia (st. 3/4:1%)
	Hand-foot syndrome (grade 3/4: 17%), Dermatitis (Art. 3/4:<1%)	Alopecia, Erythema (st. 3/4:1%), Dry skin (Art. 3/4:<1%),
	Fatigue (st. 3/4: 3%), Lethargy (v. 3/4:<1%)	High temperature (stage 3/4:<1%), Weakness (v. 3/4:<1%), Asthenia (Art. 3/4:<1%)

* stomatitis, inflammation of the mucous membrane, ulceration of the mucous membrane, ulceration of the oral cavity

A remote association between skin lesions and Xeloda use was found in less than 2% of patients participating in 7 clinical studies (N=949).

The following ADRs are fluoropyrimidine toxicities and were at least remotely related to Xeloda in less than 5% of patients in seven clinical studies (N=949):

Gastrointestinal disorders: dry mouth, flatulence, adverse reactions associated with inflammation/ulceration of mucous membranes, including esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding.

Cardiac disorders: swelling of the lower extremities, chest pain, including angina pectoris, cardiomyopathy, myocardial ischemia/infarction, heart failure, sudden death, tachycardia, atrial arrhythmias, including atrial fibrillation and ventricular extrasystoles.

Nervous system disorders: distortion of taste, insomnia, confusion, encephalopathy, cerebellar symptoms (ataxia, dysarthria, impaired balance and coordination).

Blood and lymphatic system disorders: anemia, bone marrow suppression/pancytopenia.

Disorders of the skin and subcutaneous tissues: itching, focal peeling, skin hyperpigmentation, disruption of the structure and discoloration of nails, photosensitivity reactions, relapse of side effects of radiation therapy.

General disorders and reactions at the injection site: asthenia, pain in the limbs, lethargy, chest pain (not related to the heart).

Visual disorders: eye irritation

Respiratory system disorders: shortness of breath, cough

Musculoskeletal disorders: back pain, myalgia, arthralgia

Mental disorders: depression

During clinical trials and during post-marketing surveillance, cases of liver failure and cholestatic hepatitis were recorded. The cause-and-effect relationship of these pathologies with Xeloda has not been established.

Use of Xeloda in combination therapy

Table 5 lists ADRs associated with the use of Xeloda in combination therapy for various diseases along with other chemotherapy drugs that were not reported among reactions associated with capecitabine monotherapy or were associated with a higher incidence. The safety profile of the drug when used in all combinations and for all indications was the same. These reactions occurred in ≥5% of patients receiving Xeloda in combination with other chemotherapy drugs. Some reactions are typical of chemotherapy (peripheral sensory neuropathy in response to docetaxel or oxaplatin), or associated with bevacizumab (hypertension); however, it cannot be excluded that the exacerbation was associated with capecitabine

Table 5. Common and very common adverse reactions to Xeloda in combination with various chemotherapy drugs (in addition to reactions associated with capecitabine monotherapy).

Organ system class	Very often (≥ 10%)	Often (≥ 5% - < 10%)
		Infections+ Oral candidiasis
Blood and lymphatic system disorders	Neutropenia + Leukopenia + Febrile neutropenia + Thrombocytopenia +
Metabolic and nutritional disorders	Decreased appetite	Hypokalemia Weight loss
Mental disorders		Insomnia
Nervous system disorders	Peripheral neuropathy, Peripheral sensory neuropathy, Neuropathy, Distortion of taste sensations, Paresthesia, Dysgeusia, Dysesthesia, Headache	Hypesthesia
Visual disorders	Increased tear production
Vascular disorders	Thrombosis/embolism High blood pressure Edema of the lower extremities
Respiratory system disorders	Pharyngeal dysesthesia Sore throat	Nosebleed Dysphonia
Gastrointestinal disorders	Digestive disorder	Dry mouth
Skin and subcutaneous tissue disorders	Alopecia, Violation of the structure and color of nails
Musculoskeletal and connective tissue disorders	Arthralgia, Pain in limbs	Jaw pain Back pain
General disorders and reactions at the injection site	Elevated temperature Weakness	Fever + Heat intolerance

Combination therapy with Xeloda and other chemotherapy drugs was associated with the occurrence of hypersensitivity reactions (2%) and myocardial ischemia/infarction (3%); however, these reactions were observed in less than 5% of patients.

Rare and infrequent ADRs that occurred during combination therapy coincided with reactions that occurred with capecitabine monotherapy or combination drug monotherapy (see instructions for use of the combination drug).

Changes in laboratory parameters

Table 6 provides information on laboratory abnormalities observed in 995 patients receiving adjuvant therapy for colon cancer and in 949 patients with metastatic breast cancer and metastatic colorectal cancer, regardless of whether these abnormalities were related to Xeloda use.

Table 6. Laboratory changesa: Xeloda monotherapy for colon cancer, metastatic colorectal cancer and metastatic breast cancer

Parameter a	Xeloda 1250 mg/m2 twice a day with breaks
	Patients with grade 3/4 deviations (%)
Increased ALT (SGPT) levels
Increasing AST (SGOT) levels
Increased alkaline phosphatase levels
Increased calcium levels
Decreased calcium levels
Decreased granulocyte count
Decreased hemoglobin levels
Decreased lymphocyte count
Decreased number of neutrophils
Decreased number of neutrophils/granulocytes
Decreased platelet count
Decreased potassium levels
Increased serum creatinine levels
Reducing sodium levels
Increased bilirubin levels
Hyperglycemia

a Laboratory abnormalities are classified according to the NCIC CTC scoring system.

Post-registration experience

During post-registration surveillance, information was received about the following adverse drug reactions:

Organ system class
Urinary system disorders	Acute renal failure due to dehydration see section "Special instructions"	Rarely
Nervous system disorders	Toxic leukodystrophy	Unknown
Disorders of the liver and biliary tract	Liver failure, cholestatic hepatitis	Very rarely
Skin and subcutaneous tissue disorders	Cutaneous lupus erythematosus Severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, see section "Special instructions"	Very rarely
Visual disorders	Stenosis of the lacrimal ducts (organ-nonspecific), corneal pathology, including keratitis	Very rarely

Contraindications

known hypersensitivity to capecitabine or other components of the drug

known hypersensitivity to fluorouracil or serious and unexpected reactions to fluoropyrimidine therapy

Dihydropyrimidine dehydrogenase (DPD) deficiency

simultaneous use with sorivudine or its chemical analogues, for example, brivudine

severe renal failure (creatinine clearance below 30 ml/min)

children under 18 years of age (efficacy and safety have not been studied)

If there are contraindications to any other drug in the combination therapy regimen, then this drug should not be used.

Drug interactions

Anticoagulants - coumarin derivatives

In patients taking Xeloda concomitantly with anticoagulants from the group of coumarin derivatives, such as warfarin or phenoprocoumon, changes in coagulation parameters and/or bleeding were observed. They occurred within a period of several days to several months from the start of taking Xeloda (in one case, a month after its completion). A drug interaction study of Xeloda showed that concomitant administration of a single dose of warfarin 20 mg resulted in an increase in warfarin exposure (AUC) by 57% and an increase in INR (international normalizing ratio) by 91%. In patients concomitantly taking capecitabine and coumarin-derived oral anticoagulants, clotting parameters (prothrombin time) should be carefully monitored and the dose of the anticoagulant adjusted accordingly.

Cytochrome P450 2C9 substrates

No special studies have been conducted to study the interaction of capecitabine and drugs that are metabolized through the 2C9 isoenzyme of cytochrome P450. Therefore, co-administration with Xeloda requires caution.

Phenytoin

When Xeloda is used simultaneously with phenytoin, an increase in its concentration in the blood plasma is observed. The mechanism of this interaction can be explained by the fact that capecitabine inhibits the 2C9 isoenzyme system of cytochrome P450. If a patient takes phenytoin simultaneously with Xeloda, it is necessary to monitor the concentration of phenytoin in their blood plasma.

Interaction with food

In all clinical studies, patients took Xeloda within 30 minutes after meals. Since all safety and effectiveness data are from study participants who took Xeloda after meals, it is recommended for other patients as well.

Antacids

The effect of antacids containing aluminum and magnesium hydroxides was a slight increase in the concentration of capecitabine and one metabolite (5"-DFCR) in plasma; they did not affect the three main metabolites (5"-DFUR, 5-FU and FBAL).

Leucovorin does not affect the pharmacokinetics of Xeloda and its metabolites, which was confirmed in a study of the pharmacokinetics of capecitabine when taken simultaneously with leucovorin in cancer patients. However, leucovorin affects the pharmacodynamics of Xeloda, and its toxicity may be enhanced in the presence of leucovorin.

Sorivudine and analogues

The clinically significant interaction between sorivudine and 5-FU, resulting from the inhibition of DPD by sorivudine, leads to a potentially fatal increase in fluoropyrimidine toxicity. Therefore, Xeloda should not be taken simultaneously with sorivudine or its chemical analogues, such as brivudine.

Oxaliplatin

When combined with capecitabine and oxaliplatin with or without bevacizumab, no changes were observed in the pharmacokinetics of capecitabine and its metabolites, free or bound platinum.

Bevacizumab

There is no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine and its metabolites.

Special instructions

Diarrhea

Xeloda can cause diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored, and in case of dehydration, replacement therapy should be performed to restore water and electrolyte balance. Prescribe appropriate medications (loperamide) as early as possible. If necessary, reduce the dose.

Dehydration

Dehydration should be prevented or treated as soon as possible if it occurs. Patients with anorexia, asthenia, nausea and vomiting, or diarrhea are more susceptible to dehydration. Xeloda should be stopped immediately in case of grade 2 (or higher) dehydration. Until fluid balance is restored and any causes of thrombosis are eliminated, treatment should not be resumed. If necessary, adjust the dose for side effects associated with increased blood clotting.

The spectrum of cardiotoxicity of Xeloda is similar to other fluoropyrimidines. It includes ECG changes, myocardial infarction, angina, arrhythmias, cardiac arrest and heart failure. These adverse events are more common in patients suffering from coronary heart disease.

In rare cases, severe unexpected toxicities characteristic of 5-FU (such as stomatitis, diarrhea, neutropenia, and neurotoxicity) have been reported and attributed to insufficient DPD activity. An association between low DPD levels and more severe, potentially fatal, 5-FU toxicity cannot be ruled out.

Xeloda may cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) (see Post-Marketing Experience, Adverse Events). If severe skin reactions, possibly associated with the use of Xeloda, occur, you must completely stop taking the drug.

A manifestation of skin toxicity is the development of palmoplantar syndrome of grade 1-3 severity (synonyms: palmoplantar erythrodysesthesia or acral erythema caused by chemotherapy). Time to development ranges from 11 to 360 days, with an average of 79 days.

Hand-foot syndrome 1st degree does not interfere with the patient’s daily activity and is manifested by numbness, dysesthesia and paresthesia, tingling or redness of the palms and/or soles, and discomfort. Hand-foot syndrome 2 degrees manifests itself as painful redness and swelling of the hands and/or feet, and the discomfort caused by these symptoms interferes with the patient's daily activities.

Third degree Hand-foot syndrome is characterized by moist desquamation, ulceration, blistering and sharp pain in the hands and/or feet, causing severe discomfort in the patient, making all daily activities impossible.

If grade 2 or 3 hand-foot syndrome develops, the use of Xeloda should be suspended until symptoms disappear or decrease to grade 1; at initial stage 3 of the syndrome, subsequent doses of capecitabine should be reduced (Table 3). When combining Xeloda with cisplatin, in the event of the development of hand-foot syndrome, it is not recommended to prescribe vitamin B6 (pyridoxine) for its symptomatic treatment or prevention, as this may affect the effectiveness of cisplatin.

When treated with Xeloda, the level of bilirubin in the blood may increase. If the bilirubin level is more than 3 times, and the activity of hepatic aminotransferases (ALT, AST) is more than 2.5 times the upper limit of normal, Xeloda should be stopped. It can be resumed if the level of bilirubin and the activity of liver transaminases decrease below the specified limits.

When studying the drug interaction of Xeloda, it was shown that simultaneous administration of a single dose of warfarin leads to an increase in exposure to warfarin (AUC + 57%). This is attributed to the suppression of the cytochrome P450 2C9 isoenzyme system by capecitabine. In patients concomitantly taking capecitabine and coumarin-derived oral anticoagulants, clotting parameters (prothrombin time) should be carefully monitored and the dose of the anticoagulant adjusted accordingly.

Patients taking Xeloda should be closely monitored for signs of toxicity. Most adverse events are reversible and do not require discontinuation of treatment, but a dose reduction may be required.

Elderly patients

Among mCRC patients aged 60-79 years who received Xeloda as monotherapy, the incidence of gastrointestinal side effects was the same as in the general population. In the group of patients 80 years and older, the incidence of reversible grade 3 and 4 gastrointestinal side effects, such as diarrhea, nausea and vomiting, was higher. With combined treatment in elderly people (over 65 years of age), grade 3 and 4 adverse reactions requiring discontinuation of Xeloda occur more often than in younger people. When treated with Xeloda in combination with docetaxel, a higher incidence of grade 3 and 4 adverse reactions and serious adverse events significantly related to treatment was observed in patients over 60 years of age compared to younger patients.

Kidney failure

Clinicians should use caution when prescribing Xeloda to patients with impaired renal function. Experience with the use of 5-FU shows that treatment-related grade 3 and 4 adverse reactions occur more often in patients with moderate renal failure (creatinine clearance 30-5 ml/min).

Liver failure

Patients with hepatic impairment require careful monitoring when treated with Xeloda. The effect of liver dysfunction not associated with cancer metastases to the liver or severe liver failure on the pharmacodynamics of Xeloda is not known.

Pregnancy

If Xeloda is used during pregnancy, or the patient becomes pregnant while taking the drug, the patient should be informed of the potential danger to the fetus. Women of childbearing potential should be protected from pregnancy during treatment with Xeloda.

Breast-feeding

Breastfeeding should be stopped during treatment with Xeloda.

Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

The possibility of developing side effects that may impair the ability to perform work that requires concentration and psychomotor reaction speed should be taken into account.

Overdose

Symptoms Acute overdose: nausea, vomiting, diarrhea, mucositis, gastrointestinal disorders and bleeding, bone marrow depression.

Treatment: standard therapeutic and supportive medical measures aimed at correcting clinical symptoms and preventing possible complications.

Release form and packaging