Capecitabine, 150 mg 60 pcs

Antitumor agent, antimetabolite

ATX code:

L01BC06

Pharmacological properties

Pharmacodynamics

Capecitabine 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 has no cytotoxic effect, in vivo it is converted to fluorouracil (FU), which undergoes further metabolism.

The formation of FP occurs primarily in tumor tissue under the action of the tumor angiogenic factor, thymidine phosphorylase, which minimizes the systemic effects of FP on healthy body tissues.

The sequential enzymatic biotransformation of capecitabine into FP creates higher concentrations of the drug in tumor tissues than in the surrounding healthy tissues. After oral administration of capecitabine by a patient with colorectal cancer (N=8), the concentration of FP in tumor tissue was 3.2 times higher than its concentration in the surrounding healthy tissue (range 0.9 to 8.0).

The ratio of PV concentrations in tumor tissue to plasma was 21.4 (range 3.9 to 59.9), the ratio of its concentration in healthy tissues to plasma was 8.9 (range 3.0 to 25.8). Thymidine phosphorylase activity in the primary colorectal tumor is also 4 times higher than in the adjacent healthy tissues.

Tumor cells from patients with breast, gastric, colorectal, cervical and ovarian cancers contain more thymidine phosphorylase capable of converting 5′-DFUR (5′-deoxy-5-fluoruridine) to FAs than those in corresponding healthy tissues.

Both healthy and tumor cells metabolize PV into 5-fluoro-2-deoxyuridine monophosphate (FDUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites damage cells through two different mechanisms. First, FDUMF and the folate cofactor M5-10-methyltetrahydrofolate bind to thymidylate synthase (TS) to form 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 lack of this substance can lead to inhibition of cell division.

Secondly, during RNA synthesis, the core transcriptional enzymes can mistakenly include FUTP instead of uridine triphosphate (UTP). This metabolic “mistake” disrupts RNA processing and protein synthesis.

Pharmacokinetics

Intake

. After oral administration, capecitabine is rapidly and completely absorbed from the gastrointestinal tract (GIT), followed by its transformation into the metabolites, 5′-deoxy-5-fluorocytidine (5-DFCT) and 5′-DFUR. Simultaneous intake of food decreases the rate of absorption of capecitabine, but the value of the area under the curve “concentration-time” (AUC) of 5′-DFCP and the following metabolite, FP, is not significantly affected.

When administered at a dose of 1250 mg/m² after a meal, the maximum plasma concentrations (Cmax) of capecitabine, 5′-DFTCT, 5′-DFUR, FU, and the inactive metabolite alpha-fluorobeta alanine (FBAL) at day 14 were 4.47; 3.05; 12.1; 0.95 and 5.46 µg/mL, respectively. The time to reach was 1.5; 2.0; 2.0; 2.0 and 3.34 h, and the AUC0-∞ was 7.75; 7.24; 24.6; 2.03 and 36.3 μgxh/mL, respectively.

Distribution (protein binding)

In vitro studies in human plasma have shown that for capecitabine, 5′-DFCT, 5′-DFUR and FU the binding to proteins (mainly to albumin) is 54%, 10%, 62% and 10%, respectively

.

Metabolism

Metabolized in the liver under the influence of carboxylesterase to the metabolite 5′-DFCTC, which is then transformed into 5′-DFUR under the action of cytidine deaminase, which is mainly located in the liver and tumor tissues.

The further transformation to active cytotoxic metabolite of FP occurs primarily in tumor tissue under the action of tumor angiogenic factor – thymidine phosphorylase.
AUC for FP is 6-22 times lower than after intravenous jet injection of FP at a dose of 600 mg/m². Capecitabine metabolites become cytotoxic only after conversion to FU and FU metabolites.

FU is further catabolized to form inactive metabolites, dihydro-5-fluorouracil (FUN2), 5-fluorouraidopropionic acid (FUPC) and FBAL; this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.

The elimination half-life (T1/2) of capecitabine, 5′-DPCT, 5′-DFUR, FU, and FBAL is 0.85; 1.11; 0.66; 0.76, and 3.23 hours, respectively. Pharmacokinetic parameters of capecitabine, 5′-DFCT and 5′-DFUR are the same on days 1 and 14. The AUC of FU increases by 30-35% by day 14, and no longer increases (day 22).

In the therapeutic dose range, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of FP, are dose-dependent. After oral administration of capecitabine its metabolites are excreted mainly by the kidneys – 95.5%, by the intestine – 2.6%. The main metabolite in the urine is FBL, which accounts for 57% of the dose taken.

About 3% of the taken dose is excreted unchanged by the kidneys.

Combination therapy

Capecitabine has no effect on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and no effect of docetaxel or paclitaxel on the pharmacokinetics of 5′-DFUR (the main metabolite of capecitabine).

Pharmacokinetics in Special Patient Groups

Gender, presence or absence of liver metastases prior to treatment, patient’s general status index, total bilirubin concentration, serum albumin, alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) activity in patients with colorectal cancer had no significant effect on the pharmacokinetics of 5′-DFUR, FU and FBAL.

Patients with hepatic impairment due to metastatic liver injury
No clinically significant changes in the pharmacokinetics and bioactivation of capecitabine occurred in patients with mild to moderate hepatic impairment due to metastases. There are no data on pharmacokinetics in patients with severe hepatic impairment.

Patients with impaired renal function

The results of a pharmacokinetic study show that in various degrees (from mild to severe) of renal impairment the pharmacokinetics of unchanged drug and FP are independent of creatinine clearance (CK). CK affects the AUC of 5′-DFUR (35% increase in AUC when CK decreases by 50%) and FBL (114% increase in AUC when CK decreases by 50%). FBAL is a metabolite with no antiproliferative activity; 5′-DFUR is a direct precursor of FU.

Elderly patients

Age has no effect on the pharmacokinetics of 5′-DFUR and FU. The AUC of FBL increased with age (a 20% increase in patient age was accompanied by a 15% increase in AUC of FBL), which is probably due to changes in renal function.

Race

The pharmacokinetics of capecitabine in patients of the Negro race are not different from those 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 for metastatic colorectal cancer.

Stomach cancer

First-line therapy for advanced gastric cancer.

Pharmacological effect

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 fluorouracil (FU), which is further metabolized.

The formation of FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor – thymidine phosphorylase, which minimizes the systemic effect of FU on healthy tissues of the body.

The sequential enzymatic biotransformation of capecitabine into FU creates higher concentrations of the drug in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine to a patient with colorectal cancer (N=8), the concentration of FU in tumor tissue was 3.2 times greater than its concentration in adjacent healthy tissue (range, 0.9 to 8.0).

The ratio of 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, gastric, colorectal, cervical and ovarian cancer contain more thymidine phosphorylase, which can convert 5′-DFUR (5′-deoxy-5-fluorouridine) into FU, than in corresponding healthy tissues.

Both healthy and tumor cells metabolize 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 M5-10-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 rapidly and completely absorbed from the gastrointestinal tract (GIT), after which it is transformed into metabolites, 5′-deoxy-5-fluorocytidine (5-DFCT) and 5′-DFUR. Concomitant food intake reduces the rate of absorption of capecitabine, but the area under the concentration-time curve (AUC) of 5′-DFUR and the next metabolite, FU, is slightly affected.

When taking the drug at a dose of 1250 mg/m² after a meal, the maximum plasma concentrations (Cmax) of capecitabine, 5′-DFCT, 5′-DFUR, FU and the inactive metabolite alpha-fluoro-beta alanine (FBAL) on the 14th day were 4.47, respectively; 3.05; 12.1; 0.95 and 5.46 µg/ml. The time to reach was 1.5; 2.0; 2.0; 2.0 and 3.34 hours, and AUC0-∞ – 7.75; 7.24; 24.6; 2.03 and 36.3 μgh/ml, respectively.

Distribution (protein binding)

An in vitro study in human plasma showed protein binding (mainly albumin) of 54%, 10%, 62% and 10% for capecitabine, 5′-DFCT, 5′-DFUR and FU, 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 FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor – thymidine phosphorylase.
AUC for FU is 6-22 times less than after intravenous bolus administration of FU at a dose of 600 mg/m². Capecitabine metabolites become cytotoxic only after conversion to FU and FU metabolites.

Further, 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

The half-life (T1/2) of capecitabine, 5′-DFCT, 5′-DFUR, FU and FBAL is 0.85, respectively; 1.11; 0.66; 0.76 and 3.23 hours, respectively. The pharmacokinetic parameters of capecitabine, 5′-DFCT and 5′-DFUR on days 1 and 14 are the same. The AUC of FU increases by 30-35% by the 14th day, and does not increase any further (day 22).

In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of FU, are dose-dependent. After taking capecitabine orally, its metabolites are excreted primarily by the kidneys – 95.5%, and by the intestines – 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 by the kidneys.

Combination therapy

There was no effect of capecitabine 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 groups of patients

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

Patients with liver failure due to metastatic liver disease
In patients with mild to moderate liver dysfunction caused by metastases, there is no clinically significant change in the pharmacokinetics and bioactivation 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 for varying degrees (from mild to severe) renal failure, the pharmacokinetics of the unchanged drug and FU are independent of creatinine clearance (CC). CC affects the AUC value of 5′-DFUR (increase in AUC by 35% – with a decrease in CC by 50%) and FBAL (increase in AUC by 114% with a decrease in CC by 50%). FBAL is a metabolite that does not have antiproliferative activity; 5′-DFUR is the immediate precursor of FU.

Elderly patients

Age does not affect the pharmacokinetics of 5′-DFUR and 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 capecitabine in black patients does not differ from that in Caucasian patients.

Special instructions

Dose-limiting adverse reactions are diarrhea, abdominal pain, nausea, stomatitis and hand-foot syndrome.

It is necessary to conduct careful medical monitoring for manifestations of toxicity in patients receiving therapy with capecitabine.

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 Capecitabine may cause diarrhea, sometimes severe. Patients with severe diarrhea should be closely monitored, and if dehydration develops, rehydration or replacement of electrolytes should be performed.

Standard antidiarrheal drugs (eg, loperamide) should be prescribed as early as medically indicated.

According to the criteria of the National Cancer Institute of Canada (NCIC CTC, version 2), grade 2 diarrhea is defined as an increase in stool frequency up to 4-6 times a day or bowel movements at night, grade 3 diarrhea is defined as an increase in stool frequency up to 7-9 times a day or fecal incontinence and malabsorption syndrome, grade 4 diarrhea is defined as an increase in stool frequency up to 10 or more times a day, the appearance of visible blood in the stool, or the need for parenteral maintenance therapy. If necessary, reduce the dose of capecitabine.

Dehydration: Dehydration should be prevented or corrected as soon as it occurs. Dehydration can develop quickly in patients with anorexia, asthenia, nausea, vomiting or diarrhea.

Dehydration can cause acute renal failure, sometimes fatal, especially in patients with impaired renal function at the time of initiation of therapy or if the patient is taking capecitabine concomitantly with drugs that have nephrotoxic effects.

If grade 2 or higher dehydration develops, treatment with Capecitabine 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, including cases of QT prolongation.

These adverse events are more typical for patients suffering from coronary artery disease. Caution must be exercised in patients with a history of arrhythmia and angina pectoris.

During therapy with capecitabine, the development of hypo- or hypercalcemia was observed. Caution should be exercised when treating capecitabine in patients with previously diagnosed hypo- or hypercalcemia.

Caution should be exercised when treating patients with diseases of the central and peripheral nervous system with capecitabine (for example, in the presence of brain metastases or neuropathy), as well as in patients with diabetes mellitus and fluid and electrolyte imbalances, since during treatment with capecitabine, exacerbation of these diseases is possible.

In rare cases, unexpected severe toxicities (eg, stomatitis, diarrhea, neutropenia, and neurotoxicity) associated with FU are due to insufficient dihydropyrimidine dehydrogenase (DPD) activity. Thus, a connection between reduced DPD activity and more severe, potentially lethal FU toxicity cannot be ruled out.

During treatment with capecitabine, close monitoring should be performed for ocular complications such as keratitis and corneal lesions, especially in patients with a history of ocular disease.

Treatment of the identified pathology should be carried out in accordance with the clinical situation. A manifestation of skin toxicity of the drug Capecitabine is the development of palmoplantar syndrome (synonyms – palmoplantar erythrodysesthesia or acral erythema caused by chemotherapy).

The median time to toxicity in patients receiving capecitabine 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 grade 2 or 3 hand-foot syndrome occurs, capecitabine therapy should be interrupted until symptoms disappear or decrease to grade 1. If grade 3 syndrome occurs, subsequent doses of capecitabine should be reduced.

Vitamin B6 (pyridoxine) is not recommended for the symptomatic or secondary preventive treatment of hand-foot syndrome when using capecitabine in combination with cisplatin, as it may reduce the effectiveness of cisplatin. There is evidence of the effectiveness of dexapanthenol in preventing the development of hand-foot syndrome during therapy with capecitabine.

Capecitabine may cause hyperbilirubinemia. If, in connection with treatment with Capecitabine, hyperbilirubinemia >3.0 x ULN (upper limit of normal) or an increase in the activity of hepatic aminotransferases (ALT, AST) >2.5 x ULN is observed, treatment should be interrupted.

Therapy can be resumed if the concentration of bilirubin and the activity of hepatic aminotransferases decrease below the specified limits.

In patients simultaneously taking Capecitabine and oral anticoagulants – coumarin derivatives, coagulation parameters (prothrombin time or INR) should be monitored and the dose of the anticoagulant should be adjusted accordingly.

Capecitabine can cause the development of serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome), incl. with fatal outcome. If severe skin reactions develop while using capecitabine, the drug should be discontinued and not restarted.

Use of the drug in elderly and senile patients

The incidence of gastrointestinal toxicities in patients with colorectal cancer aged 60-79 years who received capecitabine monotherapy 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 with capecitabine and other antineoplastic agents, there was an increased incidence of grade 3 and 4 adverse reactions and adverse events leading to discontinuation of therapy compared with younger patients.

In an analysis of safety data in patients ≥60 years of age receiving combination therapy with capecitabine and docetaxel, there was 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 compared with those in patients younger than 60 years of age.

Kidney failure

Caution should be exercised when prescribing capecitabine to patients with moderate renal impairment. 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 hepatic impairment should be under close medical supervision during therapy with capecitabine. The effect of liver dysfunction not due to liver metastases or severe liver failure on the distribution of capecitabine is unknown.

Impact on the ability to drive vehicles and machinery

Some adverse reactions of the drug, such as dizziness, drowsiness or nausea, may adversely affect the ability to drive a car and perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

If the above adverse events occur, you should refrain from performing these activities.

Active ingredient

Capecitabine

Composition

Active ingredient: capecitabine – 150.00 mg.

Excipients (core): microcrystalline cellulose – 78.00 mg; lactose monohydrate (milk sugar) – 59.40 mg; croscarmellose sodium – 9.00 mg; colloidal silicon dioxide – 2.10 mg; povidone-K25 – 4.50 mg; potato starch – 6.00 mg; magnesium stearate – 3.00 mg.

Shell composition: hypromellose – 5.13 mg; macrogol-4000 – 1.26 mg; titanium dioxide – 2.61 mg.

Pregnancy

The drug is contraindicated for use during pregnancy and breastfeeding.
Reliable methods of contraception should be used during capecitabine therapy and for at least 3 months thereafter. If pregnancy occurs during therapy, the patient should be aware of the potential threat to the fetus.

Contraindications

Hypersensitivity to capecitabine and/or any other components of the drug.
Hypersensitivity to fluorouracil or with a history of reported cases 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).
Severe liver failure.
Severe leukopenia.
Initial neutrophil count <1.5×109/l and/or platelets <100×109/l. If there are contraindications to one of the combination therapy drugs, it should not be used. Pregnancy and lactation period. Children under 18 years of age (efficacy and safety of use have not been established). With caution

With coronary heart disease (CHD), arrhythmia and angina pectoris in history, moderate renal failure (creatinine clearance 30-50 ml/min) or liver failure, hypo- or hypercalcemia, diseases of the central and peripheral nervous system, diabetes mellitus and water-electrolyte balance disorders, age over 60 years, with simultaneous use with oral coumarin anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Interaction

Coumarin anticoagulants

In patients taking capecitabine concomitantly with coumarin anticoagulants (warfarin and phenprocoumon), coagulation abnormalities and/or bleeding have been reported several days to months after the start of capecitabine therapy, and in some cases within one month after its completion.

In a drug interaction study, following a single 20 mg dose of warfarin, capecitabine increased the AUC of S-warfarin by 57% and the international normalized ratio (INR) by 91%. In patients concomitantly taking capecitabine 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.

Cytochrome CYP2C9 substrates

No specific drug interaction studies have been conducted between capecitabine and other drugs metabolized by the CYP2C9 isoenzyme of the cytochrome P450 system. Caution should be exercised when administering capecitabine with these drugs.

Phenytoin

Increased plasma concentrations of capecitabine and phenytoin have been reported when administered concomitantly with capecitabine. Specific studies of drug-drug interactions between capecitabine 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 concomitant phenytoin and capecitabine, phenytoin plasma concentrations should be regularly monitored.

Antacids

When assessing the pharmacokinetic parameters of capecitabine 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, 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 capecitabine.

Sorivudin and its analogues

The literature describes a clinically significant drug interaction between sorivudine and 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, capecitabine should not be used concomitantly with sorivudine or its structural analogues such as brivudine. A minimum of four weeks should be maintained between the end of therapy with sorivudine or its structural analogs (including brivudine) and the start of treatment with capecitabine.

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.

Allopurinol

An interaction has been noted between allopurinol and FU with a possible decrease in the effectiveness of FU. In this regard, the simultaneous use of capecitabine and allopurinol should be avoided.

Interferon alpha

The maximum tolerated dose of capecitabine is 2000 mg/m² per day when co-administered with interferon 2-alpha (3 million IU/m² per day) compared to a capecitabine dose of 3000 mg/m² per day when administered alone.

Radiation therapy

The maximum tolerated dose of capecitabine in monotherapy with a standard dosing regimen is 3000 mg/m², when combined with radiation therapy in the treatment of colorectal cancer (with a continuous therapy regimen or 5-day courses from Monday to Friday for 6 weeks) – 2000 mg/m² per day.

Overdose

Symptoms: Symptoms of acute overdose include nausea, vomiting, diarrhea, inflammation of the mucous membrane (mucositis), gastrointestinal irritation and bleeding, and bone marrow suppression.

Treatment: treatment of overdose should include a standard set of therapeutic and supportive measures aimed at correcting clinical symptoms and preventing possible complications.

Storage conditions

At a temperature not exceeding 25 °C.
Keep out of the reach of children.

Shelf life

3 years.

Manufacturer

Veropharm LLC, Russia