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

Colorectal cancer

Gastric cancer

Active ingredient

Composition

How to take, the dosage

Ingestion with water, no later than 30 minutes after a meal.

The standard dosing regimen

Monotherapy

Colorectal cancer, colorectal cancer and breast cancer

br> 1250 mg/m² 2 times daily, morning and evening (2500 mg/m² daily), for 14 days, followed by a 7-day break.

Combination therapy

Breast cancer

Capecitabine is administered at 1250 mg/m²2 times daily for 14 days followed by a 7-day break, in combination with docetaxel at a dose of 75 mg/m² once every 3 weeks as an IV infusion for 1 hour.
Premedication is carried out prior to administration of docetaxel according to the instructions for its use.

Colorectal cancer and gastric cancer

In combination therapy, the dose of Capecitabine should be reduced to 800-1000 mg/m² 2 times daily for 14 days followed by a 7-day break or to 625 mg/m² 2 times daily with a continuous regimen.

In combination therapy with irinotecan (XELIRI regimen), the recommended dose of Capecitabine is 800 mg/m² 2 times daily for 14 days followed by a 7-day break.
Adding immunobiologic agents to combination therapy does not affect the dose of Capecitabine.

The anti-emetics and premedication to ensure adequate hydration are used prior to the administration of cisplatin and oxaliplatin according to the instructions for use of cisplatin and oxaliplatin when used in combination with capecitabine.

In adjuvant therapy for colorectal cancer, the recommended duration of therapy with Capecitabine is 6 months, which is 8 courses.

In combination with cisplatin

At 1000 mg/m² 2 times per day for 14 days followed by a 7-day break in combination with cisplatin (80 mg/m²1 every 3 weeks, IV infusion for 2 h, first infusion administered on the first day of the cycle). The first dose of Capecitabine is administered in the evening on day 1 of the therapy cycle; the last dose is administered in the morning on day 15.
In combination with oxaliplatin or oxaliplatin and bevacizumab

The dose is 1000 mg/m² 2 times daily for 14 days followed by a 7-day pause in combination with oxaliplatin or oxaliplatin and bevacizumab.

The first dose of Capecitabine is given in the evening on day 1 of the therapy cycle and the last dose on the morning of day 15. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, by IV infusion for 30-90 minutes, with the first infusion starting on day 1 of the cycle. After bevacizumab, oxaliplatin is given at a dose of 130 mg/m², IV infusion for 2 h.

In combination with epirubicin and platinum-based drug

At 625 mg/m² 2 times per day continuously in combination with epirubicin (50 mg/m² once every 3 weeks, by IV bolus, starting on day 1 of cycle) and platinum-based drug. The platinum-based drug (cisplatin at a dose of 60 mg/m² or oxaliplatin at a dose of 130 mg/m²) should be given on day 1 of the cycle as an IV infusion for 2 h, then once every 3 weeks.

In combination with irinotecan or irinotecan and bevacizumab

The recommended dose of Capecitabine is 800 mg/m² 2 times daily for 14 days followed by a 7-day break in combination with irinotecan or with irinotecan and bevacizumab.
Irinotecan is administered at a dose of 200 mg/m² once every 3 weeks, IV infusion for 30 minutes, first infusion on day 1 of the cycle.

Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, IV infusion for 30-90 min, first infusion beginning on cycle day 1.

The tables below show examples of standard and reduced dose calculations for Capecitabine for an initial dose of 1250 mg/m² or 1000 mg/m².

Table 1. Standard and reduced doses of Capecitabine for an initial dose of 1250 mg/m², calculated as a function of body surface area.

Table 2. Standard and reduced doses of Capecitabine for an initial dose of 1000 mg/m², calculated as a function of body surface area.

Dose adjustment during treatment

General guidelines

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The toxic effects of Capecitabine can be managed with symptomatic therapy and/or by adjusting the dose of the drug (by interrupting treatment or reducing the dose of the drug). If the dose has had to be reduced, it should not be increased subsequently.

If the treating physician’s assessment is that the drug’s toxic effects are not serious or life-threatening, treatment may continue at the initial dose without reduction or interruption of therapy.

In case of 1st degree toxicity, the dose is not changed. In case of grade 2 or 3 toxicity, therapy with Capecitabine should be discontinued.

If signs of toxicity disappear or are reduced to grade 1, therapy with Capecitabine may be resumed at the full dose or adjusted according to the recommendations in Table 3.

If signs of grade 4 toxicity develop, treatment should be stopped or temporarily interrupted until symptoms subside or decrease to grade 1, at which time therapy can be resumed at 50% of the starting dose.

The patient should immediately inform the physician about the development of adverse events. Capecitabine should be discontinued immediately in case of severe or moderate toxicity. If several doses of the drug have been missed due to toxicity, these doses are not replenished.

Hematologic toxicity

Capecitabine should not be used in patients with a baseline neutrophil count of less than 1.5×109/l and/or a baseline platelet count of less than 100×109/l. Capecitabine therapy should be discontinued if an unscheduled laboratory evaluation shows a neutrophil count of less than 1.0×109/l and a platelet count of less than 75×109/l (Grade 3 or 4 hematologic toxicity).

The table below provides recommendations for changing the dose of Capecitabine if toxic events associated with its use develop.

Table 3: Dose adjustment chart for Capecitabine.

General recommendations for combination therapy

If toxicity occurs during combination therapy, the recommendations for adjusting the dose of Capecitabine in Table 3 above and the corresponding recommendations in the instructions for use of other drugs should be followed.

At the beginning of a therapy cycle, if Capecitabine or other drug(s) are expected to be delayed, all drugs should be delayed until conditions are met to resume therapy with all drugs.

If, during the combination therapy cycle, toxicity does not appear to be related to Capecitabine, the therapy with Capecitabine should continue, and the dose of the other drug should be adjusted as recommended in the instructions for use.

If the other drug(s) have to be discontinued, treatment with Capecitabine can be continued if the requirements for resumption of Capecitabine therapy are met.

The guidelines apply for all indications and all special patient groups.

Dose adjustment in special cases

Hepatic impairment in patients with liver metastases

There is no need to change the starting dose in patients with liver metastases and mild to moderate hepatic impairment. However, these patients should be monitored closely. The use of the drug in patients with severe hepatic impairment has not been studied.

Renal dysfunction

A reduction of the starting dose to 75% of 1250 mg/m² is recommended in patients with baseline moderate renal impairment (CKR 30-50 ml/min, according to Cockroft-Gault formula), no dose adjustment is required at the starting dose of 1000 mg/m². In patients with mild renal impairment (CKR 51-80 ml/min), no adjustment of the initial dose is required.

If a patient has an adverse event of grade 2, 3 or 4, close monitoring is required and immediate discontinuation of therapy for subsequent dose adjustment according to the recommendations in Table 3.

If the calculated creatinine clearance decreases to less than 30 ml/min during therapy, therapy with the drug should be discontinued. Recommendations for adjustment of the drug dose in moderate renal failure apply to both monotherapy and combination therapy. Dose calculations are listed in Tables 1 and 2.

In children

The safety and effectiveness of capecitabine in children has not been studied.

Patients elderly and senile

There is no need to adjust the initial dose with Capecitabine monotherapy. However, severe treatment-related grade 3 and 4 adverse events developed more often in patients older than 80 years than in younger patients.

When using Capecitabine in combination with other anticancer drugs in elderly patients (aged ≥65 years) adverse reactions of 3rd and 4th degree severity, as well as adverse reactions that required withdrawal of therapy, were observed more often than in younger patients. Close monitoring of elderly patients is recommended.

When treated in combination with docetaxel, an increased incidence of grade 3 and 4 adverse events and serious adverse events associated with therapy was noted in patients aged 60 years and older. For patients 60 years of age and older who will receive a combination of Capecitabine with docetaxel, it is recommended that the starting dose of Capecitabine be reduced to 75% (950 mg/m² 2 times daily).

The dose calculation is shown in Table 1. If there are no signs of toxicity, the dose may be increased to 1250 mg/m² 2 times per day.

Interaction

Special Instructions

Dose-limiting side effects of the drug include diarrhea, abdominal pain, nausea, stomatitis, and palm dermal syndrome.

There should be close medical monitoring of the manifestations of toxicity in patients treated with Capecitabine.

The majority of adverse events are reversible and do not require complete withdrawal 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 monitored closely, and rehydration or compensation of electrolyte loss should be given if dehydration develops.

Standard anti-diarrheal medications (e.g., loperamide) should be given as soon as medically indicated.

The National Cancer Institute of Canada criteria (NCIC STS version 2) define grade 2 diarrhea as increased stools of 4-6 times per day or nighttime stools; grade 3 diarrhea as increased stools of 7-9 times per day or stool incontinence and malabsorption syndrome; grade 4 diarrhea as increased stools of 10 or more times per day, visible blood in stool, or a need for parenteral maintenance therapy. The dose of Capecitabine should be reduced if necessary.

Dehydration: dehydration should be prevented or corrected early. Dehydration can occur quickly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea.

Dehydration may cause acute renal failure, in some cases with fatal outcome, especially in patients with impaired renal function at therapy initiation or if the patient is taking capecitabine concomitantly with drugs that have nephrotoxic effects.

If dehydration of degree 2 or higher develops, treatment with Capecitabine should be stopped immediately and rehydration should be performed.

The treatment should not be resumed until rehydration has been completed and the factors causing it have been eliminated or corrected. The dose of the drug should be modified according to the recommendations for the adverse events that led to dehydration.

The spectrum of cardiotoxicity with treatment with capecitabine is similar to that with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, heart failure and ECG changes, including cases of QT interval prolongation.

These adverse events are more common in patients with CHD. Caution should be exercised in patients with a history of arrhythmias and angina pectoris.

The development of hypo- or hypercalcemia has been reported during therapy with capecitabine. Caution should be exercised when treating patients with previously diagnosed hypo- or hypercalcemia with capecitabine.

Patients with central and peripheral nervous system disorders (e.g., presence of brain metastases or neuropathy) as well as patients with diabetes mellitus and electrolyte and water balance disorders should be treated with capecitabine with caution since these diseases may be exacerbated during treatment with capecitabine.

In rare cases, unexpected severe toxicities (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with FP are due to insufficient activity of dihydropyrimidine dehydrogenase (DPD). Thus, a link between reduced DPD activity and the more pronounced, potentially lethal toxicity of FP cannot be ruled out.

Careful monitoring for ophthalmic complications such as keratitis and corneal lesions should be performed during treatment with capecitabine, especially in patients with a history of eye disease.

The treatment of detected pathology should be performed according to the clinical situation. A manifestation of cutaneous toxicity of Capecitabine is the development of palmar-todermal syndrome (synonyms: palmar-todermal erythrodisesthesia or acral erythema caused by chemotherapy).

The median time to development of manifestations of toxicity in patients receiving Capecitabine monotherapy is 79 days (ranging from 11 to 360 days), and severity ranges from grade 1 to grade 3.

Degree 1 palm-toech syndrome does not impair daily activities and is manifested by numbness, dysesthesias/paresthesias, tingling or redness of the palms and/or soles, and discomfort.

Degree 2 palm-soles syndrome is characterized by painful redness and swelling of the hands and/or feet, and the discomfort caused by these symptoms disrupts the patient’s daily activities.

Degree 3 palmar-subcutaneous syndrome is defined as moist desquamation, ulceration, blistering, and severe pain in the hands and/or feet as well as severe discomfort that makes it impossible for the patient to perform any activities of daily living.

In the event of grade 2 or 3 palmar-todermal syndrome, therapy with Capecitabine should be interrupted until symptoms disappear or are reduced to grade 1. If Grade 3 syndrome occurs, subsequent doses of Capecitabine should be reduced.

Vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of palm-tooth syndrome when Capecitabine is used in combination with cisplatin because it may reduce the effectiveness of cisplatin. There are data on the effectiveness of dexapanthenol in the prevention of palmar-todermal syndrome with Capecitabine therapy.

The drug capecitabine may cause hyperbilirubinemia. If in connection with treatment with Capecitabine hyperbilirubinemia >3.0×VGN (upper limit of normal) or increased “hepatic” aminotransferases activity (ALT, ACT) >2.5×VGN, treatment should be stopped.

The therapy can be resumed when bilirubin concentrations and “hepatic” aminotransferase activity decrease below these limits.

In patients receiving Capecitabine and coumarin-derived oral anticoagulants at the same time, coagulation parameters (prothrombin time or INR) should be monitored and the anticoagulant dose should be adjusted accordingly.

Capecitabine may cause serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome), including death. If severe skin reactions develop during the use of capecitabine the drug should be discontinued and not resumed.

The use of the drug in elderly and senile patients

The frequency of gastrointestinal toxic events in patients with colorectal cancer aged 60-79 years who received monotherapy with Capecitabine did not differ from that in general population of patients. Reversible gastrointestinal adverse events of grade 3 and 4, such as diarrhea, nausea and vomiting, developed more frequently in patients 80 years of age and older.

In patients ≥65 years of age who received combination therapy with capecitabine and other anticancer drugs, there was an increased incidence of grade 3 and 4 adverse reactions and adverse events that led to discontinuation of therapy compared to younger patients.

In an analysis of safety data in patients ≥60 years of age who received combination therapy with Capecitabine and docetaxel, there was an increased incidence of therapy-related Grade 3 and 4 adverse events, serious adverse events, and early therapy withdrawal due to adverse events compared to those in patients younger than 60 years.

Renal impairment

Patients with moderate renal impairment should be treated with caution when prescribing Capecitabine. As with treatment with fluorouracil, the incidence of therapy-associated adverse events of grade 3 and 4 was higher in patients with moderate renal impairment (CKD 30-50 ml/min).

Hepatic impairment

Patients with hepatic impairment should be under close medical supervision during therapy with Capecitabine. The effect of hepatic dysfunction not due to metastatic liver injury or severe hepatic impairment on the distribution of Capecitabine is unknown.

Influence on driving and operating ability

Some adverse reactions of the drug, such as dizziness, somnolence or nausea may adversely affect the ability to drive and perform potentially hazardous activities requiring increased concentration and rapid psychomotor reactions.

In case of the above-mentioned adverse events, you should refrain from performing the above activities.

Contraindications

. In ischemic heart disease (CHD), arrhythmia and angina pectoris history, moderate renal insufficiency (CK 30-50 ml/min) or hepatic insufficiency, hypo- or hypercalcemia, diseases of central and peripheral nervous system, diabetes and water-electrolyte balance disorders, age over 60 years, concomitant use with coumarin-type oral anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Overdose

Pregnancy use