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Xeloda (Сapecitabine) - cytostatic

The composition and the form of

One tablet, coated tablet contains:
Capecitabine 150 mg and 500 mg

Pharmacological actions

Capecitabine - derived ftorpirimidina carbamate, which was developed as oral cytostatic activated in tumor tissue and renders it not a selective cytotoxic effect. In vitro capecitabine has no cytotoxic effect. However, in vivo it turns into a cytotoxic compound - fluorouracil (5-FU), which undergoes further metabolism. The formation of 5-FU occurs in the tumor tissue under the influence of tumor angiogenic factors - thymidine (dTdFazy), which thus minimizes the systemic effects of 5-FU to healthy tissues. As a result of selective activation of the contents of 5-FU in the tumor significantly higher than the levels in healthy tissues.

To study the selective action of Сapecitabine in tumor was conducted pharmacokinetic study comparing capecitabine concentrations in the tumor, healthy tissue and plasma of patients with cancer poperechnoobodochnoy and rectum. Following oral administration of capecitabine (at a dose of 1,255 mg/m2 twice daily for 5-7 days before surgery), the concentrations of 5-FU in primary tumor were significantly higher than in surrounding healthy tissue (the ratio of geometric mean 2.5) and in plasma (ratio geometric mean 14). The activity of thymidine phosphorylase in the primary tumor 4 times higher than in healthy tissue. In human tumors such as breast cancer, stomach, poperechnoobodochnoy and rectum, cervix and ovary, contains much more thymidine that can convert 5'-DFUR (5'-deoxy-5-ftoruridin) in 5-FU than in healthy tissues.

Both healthy and tumor cells metabolize 5-FU in 5-fluoro-2-deoxyuridine monophosphate (FdUMF) and 5-ftoruridina triphosphate (FUTF). Those metabolites injure cells through two different mechanisms. First, FdUMF and folatny cofactor N5-10-methylenetetrahydrofolate timidilatsintazoy associated with the formation of covalently bound tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is a necessary precursor of thymidine triphosphate, which in turn is essential for DNA synthesis, so the lack of this substance can lead to inhibition of cell deleniya.Vo Second, during the synthesis of RNA transcription enzymes nucleus may mistakenly include the FUTF instead of uridine triphosphate (UTP). This metabolic "error" violates the processing of RNA and protein synthesis.

Antitumor activity of Xeloda was evaluated in patients with breast cancer stage IV. This category of patients who already received a massive therapy, has been refractory to previously administered treatment paclitaxel. In addition, 41% patients were resistant, while 26% absent the effect of the therapy before anthracycline, 82% of patients had received 5-FU. Primary endpoint of study was an objective decrease in tumor size (where they could be determined). Remission was considered a decrease of vzaimoperpendikulyarnyh tumor diameter not less than 50% for at least 1 month. Xeloda was administered at a daily dose of 2510 mg/m2 for 2 weeks, then did a week break and re-administered the drug in the form of a three-week cycles.

The total rate of objective remission in the analysis included all patients (135 men) was 20% (27 of remissions, including 3 full). The median time to disease progression was 93 days, median duration of remission - 241 days, median survival - 384 days.

To assess the effect of treatment using prospectively designed clinical response score (pain, need for analgesics and the general condition of Karnofsky). The overall clinical response was 20% (29 patients). Of those patients whose baseline pain syndrome was assessed by visual analogue scale as exceeding 20 mm in 47% was noted positive dynamics of the intensity of pain (decrease by 50% or more).

Pharmacokinetics

Absorption

After oral Сapecitabine is absorbed quickly and completely, then it is a vast transformation into metabolites, 5'-deoxy-5-ftortsitidin (5'-DFTST) and 5'-DFUR. Simultaneous food intake reduces the rate of absorption of capecitabine, but the value of the area under the curve "concentration-time" 5'-DFUR and the next metabolite, 5-FU, ingestion of affected slightly.

Distribution

Analysis of human plasma in vitro showed that Сapecitabine, 5'-DFTST, 5'-DFUR and 5-FU are associated with proteins (mainly albumin), respectively, at 54%, 10%, 62% and 10%.

Metabolism

Carboxylesterases liver carries out the first metabolic conversion of capecitabine to 5'-DFTST, which is then transformed into the 5'-DFUR under the influence tsitidindezaminazy, located mainly in the liver and tumor tissues.

The formation of 5-FU occurs in the tumor under the influence of tumor angiogenic factors - dTdFazy, which reduces the systemic impact of 5-FU to healthy tissues. After receiving the recommended therapeutic doses of Сapecitabine average area under the curve "in the plasma concentration - time» (AUC) of Сapecitabine Xeloda and its metabolites are as follows: capecitabine - 7.40 mg x hr / ml for 5'-DFTST - 5.21 mg x hr / ml, for 5'-DFUR - 21.7 mg x h / ml for 5-FU - 1.63 mg x hr / ml. The area under the curve "in the plasma concentration - time for 5-FU in 6 - 22 times less than that after intravenous administration of jet 5-FU in a dose of 600 mg/m2. Capecitabine metabolites are cytotoxic only after conversion into 5-FU and anabolity 5-FU.

Withdrawal

The pharmacokinetics of Capecitabine were studied in doses ranging from 502 to 3514 mg/m2 per day. Pharmacokinetic parameters of capecitabine, 5'-DFTST and 5'-DFUR at 1 st and 14 th days were similar. The area under the curve "concentration-time" 5-FU on day 14 was 30-35% higher, but later, on Day 22, no longer growing. In the range of therapeutic doses of pharmacokinetic parameters of Xeloda and its metabolites, except for 5-FU, is proportional to dose.

Maximum concentrations in plasma of Xeloda were reached in 1.5 hours (tmax), and 5'-DFTST and 5'-DFUR - 2 hours after admission. Then the concentration decreased exponentially with a half-life equal to 0.7-1.14 hours. Alpha-fluoro-beta-alanine (ABF), a decay product of 5-FU, reaches maximum concentration in plasma after 3 hours (tmax) after taking the drug and has a half-life equal to 3-4 hours.

After taking Xeloda into its metabolites are derived mainly from urine. Unchanged in the urine output 2.9% of applied dose in the form of 5'-DFTST - 7.2%, 5'-DFUR - 11.1%, 5-FU - 0.54%, FUN2 - 0.36%, Fufaev - 4.5%, ABF - 57% . In total, in the urine is detected 84% of applied dose, with the main metabolite (57%) is the ABF.

Pharmacokinetics in special cases

Patients with metastatic liver disease. In patients with cancer with light and moderate hepatic impairment, caused by metastases, clinically significant change bioactivation and pharmacokinetics of Capecitabine is not happening. Data on pharmacokinetics in patients with severe hepatic impairment are absent.

Patients with impaired renal function. Reduced creatinine clearance did not affect the pharmacokinetics 5'-DFUR and 5-FU, but changed the pharmacokinetics ABF: with a decrease in clearance creatinine 50% concentration of ABF rose by 45%. These findings were not unexpected, because urinary excretion is mainly through the elimination ABF and only a small inferential 5'-DFUR and 5-FU.

The data on pharmacokinetics in patients with severe renal insufficiency (creatinine clearance <30 ml / min) are absent.

Elderly patients. Age has no clinically significant effect on the pharmacokinetics of Capecitabine and its metabolites.

Statement

Locally advanced or metastatic breast cancer, with ineffective chemotherapy consisting of paclitaxel and anthracyclines medication, or if there are contraindications to therapy with anthracyclines.


Children. Safety and efficacy of Xeloda in children has not been studied.

Elderly patients may be more susceptible to the toxic effect of 5-FU, so they should be monitored carefully.

Contraindications

Hypersensitivity to Capecitabine. Heavy and unexpected reactions to treatment ftorpirimidinom or hypersensitivity to fluorouracil (metabolite of capecitabine) in history.


Precautionary measures

Application ftorpirimidinov may be accompanied by the phenomena of cardiotoxicity, including changes in the ECG, myocardial infarction, angina, arrhythmias, cardiogenic shock, sudden death. These undesirable phenomena are more typical for patients suffering from coronary heart disease.

In rare cases, the treatment of 5-fluorouracil observed unexpectedly severe toxic effects in the form of stomatitis, diarrhea, neutropenia and neurotoxicity caused by insufficient activity digidropirimidindegidrogenazy.

Patients taking Xeloda should be carefully observed for signs of toxicity. The frequency of toxic effects on the gastro-intestinal tract in patients aged 60-79 years was the same as in the general population of patients. In patients 80 years and older reversible gastrointestinal disorders grade 3 and 4, such as diarrhea, nausea and stomatitis, developed more frequently.

Treatment Xeloda can cause diarrhea, sometimes severe. The median time until the first signs of diarrhea was 2-4 degrees for 31 days. Patients with severe diarrhea should be carefully observed, holding them to replace fluids and electrolytes in the case of dehydration. Diarrhea grade 2 defined as increased stool up to 4-6 times per day or a chair at night, diarrhea grade 3 - a quickening of his chair up to 7-9 times a day or scatacratia and malabsorption syndrome, diarrhea, Grade 4 - as increased stool up to 10 or more times a day, or the appearance of blood in the stool makroprimesi, or the need for parenteral maintenance therapy. If you have diarrhea, 2, 3 and 4, the degree of therapy Xeloda should be interrupted until the disappearance of diarrhea or reduce its intensity to the degree 1. When diarrhea Grade 3 or 4 treatment Xeloda to be renewed with a decrease in dose. Recommend that you assign standard antidiarrhoeal drugs (eg loperamide).

Xeloda may cause the development of palmar-plantar syndrome, which is characterized by numbness, paresthesia, tingling, swelling, redness, peeling, blistering, and a sharp pain syndrome. Palmar-plantar syndrome of 2 degree reflected painful reddening and swelling of the hands and / or feet, and discomfort caused by these symptoms disrupt the daily activity of the patient. Palmar-plantar syndrome, grade 3 is defined as moist desquamation, ulceration, blistering and sharp pain in your hands and / or feet, as well as a strong discomfort that makes it impossible for the patient to any kind of daily activity. If you have 2 or 3 degrees of palmar-plantar syndrome, the use of Xeloda should be interrupted before the disappearance of symptoms or reduce them to a degree; syndrome grade 3 subsequent doses of Xeloda should be reduced.

When the bilirubin level in serum 2-4 degree receiving Xeloda should cease immediately until the disappearance of hyperbilirubinemia or decrease it by 1 degree. According to the criteria of the National Cancer Institute of Canada, hyperbilirubinemia grade 2 is defined as the increase in concentration to a level 1.5 times above the upper limit of normal, grade 3 - 1.5-3 times higher than the upper limit of normal, 4 degrees - more than 3 times the upper limit standards. Patients with mild and moderate hepatic impairment due to metastases should be carefully monitored. Experience of the drug in renal failure are few in the appointment of Xeloda in such patients should be careful.

In patients taking anticoagulants coumaric and Capecitabine should be regularly monitored parameters of coagulation.

Pregnancy and lactation

The drug belongs to the category D.

Studies on the treatment Xeloda in pregnant women do not, however, on the basis of pharmacological and toxicological characteristics of Xeloda, we can assume that the appointment pregnant women Xeloda can have a damaging effect on the fetus. In reproduction studies in animals appointment of capecitabine was accompanied by an increase in the death of embryos and the teratogenic effect, which is the expected effect of derivatives ftorpirimidina. Capecitabine should be considered a potential teratogen in humans. During pregnancy apply Xeloda should not be. If Xeloda prescribed during pregnancy or if pregnancy occurs in patients already receiving this drug, it should warn about the possible risk to the fetus. Women of childbearing age should be advised to avoid pregnancy during treatment with Xeloda.

We do not know whether the allocated Xeloda with breast milk. Because breast milk, many people fall into drugs, but also because of possible severe adverse reactions in infants, the prescription of a nursing mother should be avoided unless the benefits of therapy to the mother does not exceed the potential risk to the child.

Interactions

Xeloda has a low potential for pharmacokinetic interactions, because the weakly bound to proteins in serum, and neither capecitabine nor its metabolites do not inhibit or stimulate the activity of isoenzymes CYP450 in vitro and in vivo in animals.

Anticoagulants cumarine series: patients who received capecitabine concurrently with coumaric anticoagulants such as warfarin and fenprokumona, describes the violation of indicators of clotting and bleeding. They came within a few days - several months of therapy capecitabine, and in one case - a month after its completion.

Antacids: effects of antacids containing aluminum hydroxide and magnesium, was a small increase in the concentrations of Xeloda and one metabolite (5'-DFTSR) in plasma, three major metabolites (5'-DFUR, 5-FU and ABF) are not affected.

Leucovorin does not affect the pharmacokinetics of Capecitabine and its metabolites.

Paclitaxel: Capecitabine does not affect the pharmacokinetics of paclitaxel. Paclitaxel has no clinically significant effect on the pharmacokinetics kaeptsitabina.

Sorivudin and analogues: the literature describes clinically significant interaction between sorivudinom and 5-FU, arises because of the suppression digidropirimidindegidrogenazy sorivudinom. This leads to increased toxicity ftorpirimidinov, potentially fatal. Therefore, Xeloda should not be appointed to sorivudinom, or its chemical analogs, such as brivudin.

Overdose

In clinical studies, overdose Xeloda was not. However, considering the experience of the appointment of the maximum tolerated dose of man (3514 mg/m2/sutki), we can expect that acute overdosage would be manifested by nausea, vomiting, diarrhea, irritation of the gastrointestinal tract and hemorrhages, as well as bone marrow suppression. Treatment of overdose should include customary supportive measures aimed at addressing the symptoms. Although there is no experience in treating overdoses, reduce the concentration of 5'-DFUR, a low molecular weight metabolite of the drug source, could be using dialysis.

Storage life

Shelf life 2 years

The Xeloda drug should not be used after expiry date (EXP) stated on the package.

Store below 30 ° C

Packing

Coated tablets, po150 mg 60

Film-coated tablets, 500 mg 120

Keep out of reach from children.

On prescription.