anti-tumor agent, antimetabolite
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 predominantly in tumor tissue under the action of the tumor angiogenic factor, thymidine phosphorylase, which minimizes the systemic effects of FP on healthy body tissues. 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 FU in tumor tissue is 3.2 times higher than its concentration in adjacent healthy tissues (range, 0.9 to 8.0). The ratio of PV concentration in tumor tissue to plasma was 21.4 (range from 3.9 to 59.9), the ratio of PV concentration in healthy tissues to plasma was 8.9 (range from 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.
. 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 area under the curve “concentration-time” (AUC) of 5′-DFTCT and the following metabolite, FP, is not significantly affected. When the drug was administered 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-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 showed that for capecitabine, 5′-DFCT, 5′-DFUR and FU the binding to proteins (mainly to albumin) is 54%, 10%, 62% and 10%, respectively.
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, located mainly in the liver and tumor tissues. Further transformation to active cytotoxic metabolite of FP occurs mainly in tumor tissue under the action of tumor angiogenic factor – thymidine phosphorylase.
AUC for FP is 6-22 times less 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.
The PU is further catabolized to form the 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 rate of reaction.
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 range of therapeutic doses, pharmacokinetic parameters of capecitabine and its metabolites, except for 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.
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.
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.
The pharmacokinetics of capecitabine in patients of the Negro race are not different from those in patients of the Caucasian race.
- Combination therapy with docetaxel for locally advanced or metastatic breast cancer, if chemotherapy including an anthracycline drug is ineffective;
- monotherapy for locally advanced or metastatic breast cancer that is resistant to chemotherapy with taxanes or anthracycline-type drugs, or if there are contraindications to them.
- adjuvant therapy for stage III colorectal cancer after surgical treatment;
- the therapy of metastatic colorectal cancer.
- therapy of first-line advanced gastric cancer.
1 film-coated tablet 500 mg contains:
Active ingredient: capecitabine – 500.00 mg.
Excipients (core): microcrystalline cellulose – 260.00 mg; lactose monohydrate (milk sugar) – 198.00 mg; croscarmellose sodium – 30.00 mg; colloidal silica – 7.00 mg; povidon-K25 – 15.00 mg; potato starch – 20.00 mg; magnesium stearate – 10.00 mg.
Shell composition: hypromellose – 17.10 mg; macrogol-4000 – 4.20 mg; titanium dioxide – 8.70 mg.
How to take, the dosage
Orally, with water, no later than 30 minutes after a meal.
In patients who took capecitabine concomitantly with coumarin anticoagulants (warfarin and phenprocoumon), abnormal clotting and/or bleeding were reported days or months after the start of therapy with capecitabine, and in some cases – within one month after its completion.
In a drug interaction study, after a single administration of warfarin at a dose of 20 mg, 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, anticoagulant dose should be chosen according to these parameters.
Substrates of cytochrome CYP2C9
No special studies of drug interaction of capecitabine with other drugs metabolized by CYP2C9 isoenzyme of cytochrome P450 system were conducted. Caution should be exercised when prescribing Capecitabine together with these drugs.
An increase in plasma concentration of the latter was reported when concomitant administration of Capecitabine and phenytoin. Special studies of interdrug interaction between capecitabine and phenytoin have not been conducted, but it is assumed that the mechanism of interaction is based on inhibition of CYP2C9 isoenzyme under the influence of capecitabine (see “Coumarin-type anticoagulants” above). In patients receiving phenytoin and capecitabine concomitantly, plasma concentrations of phenytoin should be monitored regularly.
When assessing the pharmacokinetic parameters of capecitabine concomitantly with antacids containing aluminum hydroxide and magnesium hydroxide, a slight increase in plasma concentration of capecitabine and one of the metabolites (5′-DPCT) was noted. The three main metabolites of capecitabine (5′-DFCU, FU and FBAL) were not affected by the studied agents.
Calcium folinate (Leucovorin)
Calcium folinate has no effect on the pharmacokinetic properties of capecitabine and its metabolites. However, the toxic effect of capecitabine may be enhanced due to the effect of calcium folinate on the pharmacodynamics of capecitabine.
Sorivudine and its analogues
The literature describes a clinically significant drug interaction between sorivudine and FP, which is based on the inhibiting effect of sorivudine on DPD. This interaction can lead to a fatal increase in fluoropyrimidine toxicity. Therefore, capecitabine should not be used simultaneously with sorivudine or its structural analogues like brivudine. At least a four-week interval between the end of therapy with sorivudine or its structural analogues (including brivudine) and the beginning of treatment with capecitabine should be observed.
No clinically significant difference in exposure to capecitabine or oxaliplatin metabolites (free platinum or total platinum) was noted with the combined use of capecitabine and oxaliplatin, regardless of the presence of bevacizumab.
No clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites was noted.
An interaction between allopurinol and FP has been noted with a possible decrease in the effectiveness of FP. In this regard concomitant use of capecitabine and allopurinol should be avoided.
The maximum tolerated dose of capecitabine is 2000 mg/m² per day when concomitantly used with interferon 2-alpha (3 mI/m² per day) compared to the dose of capecitabine 3000 mg/m² per day on monotherapy.
Maximum tolerated dose of capecitabine in monotherapy in standard dosing regimen is 3000 mg/m², when combined with radiotherapy in the treatment of colorectal cancer (in continuous therapy or 5-day courses from Monday to Friday for 6 weeks) – 2000 mg/m² per day.
Dose-limiting adverse reactions 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. Most 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 early as medically advisable. The National Cancer Institute of Canada (NCIC STS version 2) defines grade 2 diarrhea as stools increased 4-6 times per day or bowel movements at night, grade 3 diarrhea as stools increased 7-9 times per day or stool incontinence and malabsorption syndrome, and grade 4 diarrhea as stools increased 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 may occur rapidly 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 the start of therapy or if the patient takes capecitabine concomitantly with drugs that have nephrotoxic effects.
In case of dehydration of grade 2 or higher, treatment with Capecitabine should be immediately interrupted and rehydration should be performed. Treatment should not be resumed until rehydration has been completed and the underlying factors have been eliminated or corrected. The dose of the drug should be modified in accordance with the recommendations for 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 QT interval prolongation. These adverse events are more typical for patients suffering from 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 used while capecitabine treatment in patients with earlier diagnosed hypo- or hypercalcemia.
Caution should be used while capecitabine treatment in patients with diseases of central and peripheral nervous system (for example, in presence of brain metastases or neuropathy) as well as in patients with diabetes and water-electrolyte balance disorders, because these diseases can worsen during capecitabine treatment.
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. Treatment of identified pathology should be according to the clinical situation.
The manifestation of cutaneous toxicity of Capecitabine is the development of palmar-todermal syndrome (synonyms: palmar-todermal erythrodisesthesia or chemotherapy-induced acral erythema). The median time to development of manifestations of toxicity in patients receiving Capecitabine monotherapy is 79 days (ranging from 11 to 360 days), and the severity ranges from grade 1 to grade 3.
Grade 1 palmar-todermal syndrome does not impair daily activities of the patient and is manifested by numbness, dysesthesia/paresthesias, tingling or redness of the palms and/or soles, and discomfort. Grade 2 palm plantar 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 and severe discomfort that makes it impossible for the patient to perform any activities of daily living. If palmar-todermal syndrome of grade 2 or 3 occurs, 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” aminotransferase 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. In patients aged 80 years and older reversible adverse gastrointestinal events of 3rd and 4th degree, such as diarrhea, nausea and vomiting, developed more frequently. Patients ≥65 years of age who received combination therapy with capecitabine and other antitumor drugs had an increased frequency 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.
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).
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 dangerous activities requiring increased concentration and rapid psychomotor reactions. In case of the above-mentioned adverse events, you should refrain from performing the specified activities.
- High sensitivity to capecitabine and/or any other drug components.
- High sensitivity to fluorouracil or a history of unexpected or severe adverse reactions to treatment with fluoropyrimidine derivatives.
- An established DPD (dihydropyrimidine dehydrogenase) deficiency as for other fluoropyrimidines.
- Simultaneous administration of sorivudine or its structural analogues, such as brivudine.
- Severe renal impairment (creatinine clearance below 30 ml/min).
- Severe hepatic insufficiency.
- Severe leukopenia.
- Basic neutrophil count <1.5×109/l and/or platelets <100×109/l.
- If one of the drugs in combination therapy is contraindicated, it should not be used.
- Pregnancy and lactation.
- Children under 18 years (effectiveness and safety of use not established).
. In coronary heart disease (CHD), history of arrhythmias and angina pectoris, moderate renal failure (CK 30-50 ml/min) or hepatic failure, hypo- or hypercalcemia, central and peripheral nervous system disorders, diabetes mellitus and water-electrolyte balance disorders, age over 60 years, concomitant use with coumarin-type oral anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
The most common side effects associated with capecitabine administration were gastrointestinal (GI) disorders (diarrhea, nausea, vomiting, abdominal pain, stomatitis), palmar-squamous syndrome, increased fatigue, asthenia, anorexia, cardiotoxicity, increased renal failure in patients with a history of impaired renal function, and thrombosis/embolism.
Symptoms: symptoms of acute overdose include nausea, vomiting, diarrhea, mucous membrane inflammation (mucositis), gastrointestinal tract irritation and bleeding, and suppression of bone marrow function.
Treatment: treatment of overdose should include a standard set of therapeutic and supportive measures aimed at correction of clinical symptoms and prevention of possible complications.
The drug is contraindicated in pregnancy and during breastfeeding.
During therapy with capecitabine and for at least 3 months after its completion, reliable contraceptive methods should be used. If pregnancy occurs during therapy, the patient should be aware of the potential threat to the fetus.
|Conditions of storage|
At a temperature not exceeding 25 ° C. Keep out of reach of children.
Buy Capecitabine, 500 mg 120 pcs with delivery to USA, UK, Europe and over 120 other countries.