Kapetsitabin

General characteristics. Structure:

Active ingredient: 150 mg or 500 mg of a kapetsitabin.

Excipients: lactose, cellulose microcrystallic, croscarmellose sodium, gipromelloza, magnesium stearate; a cover - a film covering (a gipromelloza (38.46%), talc (30,77%), titanium dioxide (Е 171) (29,41%), dye ferrous oxide red (Е 172) (0,68%), dye ferrous oxide yellow (Е 172) (0,68%).

Pharmacological properties:

Pharmacodynamics. Kapetsitabin - derivative a ftorpirimidina of a carbamate, peroral cytostatics, activated in fabric of a tumor and having the selection cytotoxic effect on it.
 
In vitro капецитабин has no cytotoxic effect, in vivo turns in ftoruratsit (FAUGH) which is exposed to further metabolism.
 
Education FAUGH happens preferential in tumor fabric under the influence of a tumoral angiogenic factor - thymidinephosphorylases that minimizes system impact FAUGH on healthy body tissues.

Consecutive fermental biotransformation of a kapetsitabin in FAUGH creates higher concentration of drug in tumor fabrics, than in surrounding healthy fabrics. After oral administration of a kapetsitabin a sick colorectal cancer (N=8) concentration FAUGH in fabric of a tumor is 3,2 times more than its concentration in adjacent healthy fabrics (range from 0,9 to 8,0).

Ratio of concentration FAUGH in fabric of a tumor and plasma-21,4 (range from 3.9 to 59,9), a ratio of its concentration in healthy fabrics and in plasma - 8,9 (range from 3,0 to 25,8). Activity of thymidinephosphorylase in primary colorectal tumor is also 4 times higher, than in adjacent healthy fabrics.
 
Tumor cells at patients with cancer of a mammary gland, stomach, a colorectal cancer, a neck of uterus and ovaries contain higher level of the thymidinephosphorylase capable to turn 5-DFUR (5-dezoksi-5-ftoruridin) in FAUGH, than in the corresponding healthy fabrics.
 
Both healthy, and tumor cells metabolize FAUGH in 5-ftor-2-дезоксиуридинмонофосфат (ФдУМФ) and 5-ftoruridintrifosfat (FUTF). These metabolites damage cells by means of two various mechanisms. First, FDUMF and a folatny cofactor of N5-10 - метилентетрагидрофолат contact with timidilatsintazy (CU) formation covalently of the connected tertiary complex. This binding suppresses formation of thymidylate from uracil. Thymidylate is a necessary predecessor of thymidinetriphosphate which, in turn, is extremely important for DNA synthesis so the lack of this substance can lead to oppression of cellular division.
 
Secondly, in the course of RNA synthesis transkriptsionny enzymes of a kernel can mistakenly include in it FUTF instead of uridinetriphosphate (UTF). This metabolic "mistake" breaks processing of RNA and synthesis of protein.

Pharmacokinetics. Absorption. After intake капецитабин it is soaked up quickly and completely then there is its transformation in metabolites of 5-dezoksi-5-ftortsitidin (5-DFTsT) and 5-DFUR. Food reduces the speed of absorption of a kapetsitabin, however under a curve "concentration time" (AUC) 5-DFUR and the following metabolite FAUGH influences area size slightly. At purpose of a kapetsitabin after reception write in a dose 1250 mg/sq.m for the 14th day the maximum concentration in plasma (Cmax) of a kapetsitabin, 5-DFTsT, 5-DFUR, FU and FBAL made respectively: 4,47, 3,05, 12,1, 0,95 and 5,46 mkg/ml. Time of achievement of the maximum concentration (Tmax) equaled 1,50, 2,00, 2,00, 2,00 and 3,34 h, AUC0-∞ made 7,75, 7,24, 24,6, 2,03 and 36,3 ¼¬úÕþ/ml respectively.

Distribution (linkng with proteins). The research in vitro to a blood plasma of the person showed that for a kapetsitabin, 5-DFTsT, 5-DFUR and FU communication with proteins (mainly, with albumine) makes 54%, 10%, 62% and 10%, respectively.

Metabolism. It is initially metabolized in a liver under the influence of a karboksilesteraza to a metabolite 5-DFTsT which then is transformed in 5-DFUR under the influence of the cytidinedeaminase which is in the basic in a liver and tumoral fabrics. Further transformation to an active cytotoxic metabolite FAUGH happens preferential in tumor fabric under the influence of a tumoral angiogenic factor - thymidinephosphorylases.

AUC for FAUGH in plasma is 6-22 times less, than after intravenous bolyusny administration FAUGH in a dose of 600 mg/sq.m. Metabolites of a kapetsitabin become cytotoxic only after transformation in FAUGH and metabolites FAUGH.
 
Further FAUGH catabolizes with formation of inactive metabolites: digidro-5-ftoruratsit (FUN2), 5-ftorureidopropionovy acid (FUPK) and a α-ftor-β-alanina (FBAL); this process happens under the influence of a dihydropyrimidindehydrogenase (DPD) which activity limits speed of response.
 
Removal. Biological half-life (t1/2) of a kapetsitabin, 5-DFTsR, 5-DFTsR, FU and FBAL makes 0,85, 1,11, 0,66, 0,76 and 3,23 hours respectively. Pharmacokinetics of a kapetsitabin studied in doses from 502 to 3514 mg/sq.m a day. Pharmacokinetic parameters of a kapetsitabin, 5-DFTsT and 5-DFUR for the 1st and 14th day were identical. AUC FAUGH increased by 14th day by 30-35% and did not increase any more (the 22nd day). In the range of therapeutic doses pharmacokinetic parameters of a kapetsitabin and its metabolites, behind an exception FAUGH, had dozozavisimy character. After reception of a kapetsitabin in its metabolites are removed mainly by kidneys. The most part (95%) of the accepted dose of a kapetsitabin is removed by kidneys. Removal with a stake is minimum (2,6%). The main metabolite in urine is FBAL of which 57% of the accepted dose are the share. About 3% of the accepted dose are removed by kidneys in not changed look.

Combination therapy. Any impact of a kapetsitabin on pharmacokinetics of a dotsetaksel or a paklitaksel (Cmax and AUC), and also or paklitakset influences of a dotsetaksel on pharmacokinetics 5-DFUR (the main metabolite of a kapetsitabin) it is not revealed.

Pharmacokinetics in special groups of patients. A floor, existence or lack of metastasises in a liver prior to treatment, the index of the general condition of the patient, concentration of the general bilirubin, seralbumin, activity of aspartate aminotransferase (ACT) and alaninaminotranspherase (ALT) did not render statistically significant effect on pharmacokinetic properties 5-DFUR, FU and FBAL.

Patients with the liver failure caused by metastatic damage of a liver

At patients with easy and average degree of the abnormal liver functions caused by metastasises, clinically significant change of bioactivation and pharmacokinetics of a kapetsitabin does not happen. Data on pharmacokinetics at patients with a heavy abnormal liver function are absent.

Patients with a renal failure. Results of a pharmacokinetic research show that at various degree (from easy to heavy) a renal failure the pharmacokinetics of not changed drug also FAUGH does not depend on the clearance of creatinine (CC). KK influences size of AUC 5-DFUR - the direct predecessor FAUGH (increase in AUC by 35% at decrease in KK by 50%) and FBAL (increase in AUC by 114% at decrease in KK by 50%). FBAL the metabolite which does not have aptiproliferativny activity; 5-DFUR direct predecessor FAUGH.

Patients of advanced age. The age does not influence pharmacokinetics 5-DFUR and FU. AUC FBAL increased with age (increase in age of patients by 20% was followed by increase in AUC FBAL by 15%) that is probably caused by change of function of kidneys.

Race. The pharmacokinetics of a kapetsitabin at patients of negroid race does not differ from that at patients of Caucasian race.

Indications to use:

Breast cancer:
 
- A combination therapy with dotsetaksely a locally-spread or metastatic breast cancer at inefficiency of the chemotherapy including drug of an anthracycline row;
 
- monotherapy of a locally-spread or metastatic breast cancer resistant to chemotherapy taxons or drugs of an anthracycline row or in the presence of contraindications to them.
 
Colorectal cancer:
 
- Adjuvant therapy of a colon cancer of the III stage after surgical treatment;
 
- therapy of a metastatic colorectal cancer.
 
Carcinoma of the stomach:

 - Therapy of the first line of a widespread carcinoma of the stomach.

Route of administration and doses:

Inside, washing down with water not later than in 30 min. after food.

Standard mode of dosing. Monotherapy. Colorectal cancer, colon cancer and breast cancer. On 1250 mg/sq.m 2 times a day - in the morning and in the evening (the general daily dose of 2500 mg/sq.m) within 14 days with the subsequent 7-day break.

Combination therapy. Breast cancer. On 1250 mg/sq.m 2 times a day within 14 days with the subsequent 7-day break, in a combination with dotsetaksely in a dose of 75 mg/sq.m once in 21 days in the form of intravenous infusion within 1 hour.

Premedication is carried out before introduction of a dotsetaksel according to the instruction for its use.

Colorectal cancer and carcinoma of the stomach. As a part of a combination therapy the dose of a kapetsitabin has to be lowered to 800-1000 mg/sq.m 2 times a day within 14 days with the subsequent 7-day break or to 625 mg/sq.m 2 times a day at the continuous mode. Addition of a bevatsizumab to a combination therapy does not influence an initial dose of a kapetsitabin.

Antiemetics and premedication for ensuring adequate hydration are appointed before introduction of Cisplatinum and oksaliplatin according to the application instruction of Cisplatinum and ksaliplatin at their use in a combination with kapetsitabiny.

In adjuvant therapy of a colon cancer the recommended therapy duration kapetsitabiny makes 6 months, i.e. 8 courses.

In a combination with Cisplatinum. On 1000 mg/sq.m 2 times a day within 14 days with the subsequent 7-day break in a combination with Cisplatinum (80 mg/sq.m of 1 times in 3 weeks, in/in infusion during 2 h, the first infusion are appointed in the 1st day of a cycle). The first dose of drug of a kapetsitabin is appointed in the evening in the 1st day of a cycle of therapy, the last - in the morning to the 15th day.

In a combination with oksaliplatiny or with oksaliplatiny and bevatsizumaby. On 1000 mg/sq.m 2 times a day within 14 days with the subsequent 7-day break in a combination with oksaliplatiny or with oksaliplatiny and bevatsizumaby. The first dose of a kapetsitabin is appointed in the evening in the 1st day of a cycle of therapy, the last - in the morning to the 15th day. Bevatsizumab is entered in a dose of 7,5 mg/kg of 1 times in 3 weeks, in/in infusion within 30-90 min., the first infusion begins in the 1st day of a cycle. After a bevatsizumab it is entered оксалиплатин in a dose of 130 mg/sq.m, in/in infusion during 2 h.

In a combination with epirubitsiny and drug on the basis of platinum. On 625 mg/sq.m 2 times a day in the continuous mode in a combination е epirubitsiny (50 mg/m of 1 times in 3 weeks, in/in bolyusno, since first day of a cycle) and drug on the basis of platinum. Drug on the basis of platinum (Cisplatinum in a dose of 60 mg/sq.m or оксалиплатин in a dose of 130 mg/sq.m) has to be entered in the 1st day of a cycle in a look into infusions during 2 h, further 1 time in 3 weeks.

In a combination with irinotekany or with irinotekany and bevatsizumaby. On 800 mg/sq.m 2 times a day within 14 days with the subsequent 7-day break in a combination with irinotekany or with irinotekany and bevatsizumaby. Irinotekan is entered in a dose of 200 mg/sq.m of 1 times in 3 weeks, in/in infusion within 30 min., the first infusion in the 1st day of a cycle. Bevatsizumab is entered in a dose of 7,5 mg/kg of 1 times in 3 weeks, in/in infusion within 30-90 min., the first infusion begins in the 1st day of a cycle.

The tables given below show examples of calculation of a standard and reduced dose of a kapetsitabin for an initial dose of 1250 mg/sq.m or 1000 mg/sq.m.

Table 1. The standard and reduced doses of a kapetsitabin for an initial dose of 1250 mg/sq.m calculated depending on body surface area.

Table 2. The standard and reduced doses of a kapetsitabin for an initial dose of 1000 mg/sq.m calculated depending on body surface area.

Correction of the mode of dosing. General recommendations. The toxic phenomena of a kapetsitabin can be eliminated with symptomatic therapy and/or dose adjustment of drug (having interrupted treatment or having reduced a drug dose). If the dose had to be lowered, it is impossible to increase it afterwards.

If according to the attending physician the toxic effect of a kapetsitabin has no serious or life-threatening sick character, treatment can be continued in an initial dose without its reduction or interruption of therapy.

At toxicity of the 1st degree the dose is not changed. At toxicity of the 2nd or 3rd degree therapy kapetsitabiny should be interrupted.

At disappearance of signs of toxicity or reduction of the last to the 1st degree, performing therapy kapetsitabiny can be resumed in a full dose or is corrected according to the recommendations specified in table 3.

At development of signs of toxicity of the 4th degree treatment should be stopped or to interrupt temporarily before stopping or reduction of symptoms to the 1st degree then use of drug can be resumed in the dose making 50% of initial. The patient has to report to the doctor about the undesirable phenomena which developed at him immediately. It is necessary to stop immediately reception of a kapetsitabin at emergence of toxicity heavy or moderate severity. If because of the toxic phenomena several receptions of a kapetsitabin were missed, then these doses are not filled.

Hematologic toxicity. It is not necessary to apply капецитабин at patients with the initial level of neutrophils less than 1,5Õ109/l and/or initial level of thrombocytes <100Õ109/l. It is necessary to interrupt therapy kapetsitabiny if during unplanned assessment of laboratory indicators quantity of neutrophils less than 1,0Õ109/l, and quantity of thrombocytes less than 75 x 109/l (hematologic toxicity of the 3rd or 4th degree).

In the table given below recommendations but to change of a dose of a kapetsitabin in case of development of the toxic phenomena connected with its use are specified.

Table 3. Scheme of dose adjustment of a kapetsitabin.

* According to the general criteria of toxicity of Group on conduct of clinical trials of National oncological institute of Canada (NCIC CTG, version 1) or the general terminological criteria of the undesirable phenomena of the Program for assessment of antineoplastic therapy of National oncological institute of the USA (CTCAE, version 4). Criteria of toxicity of a palmar and bottom syndrome and hyperbilirubinemia are in detail described in the section "Special Instructions".

The general recommendations at a combination therapy. In case of the phenomena of toxicity when carrying out a combination therapy it is necessary to adhere to the recommendations about dose adjustment of a kapetsitabin stated above in table 3 and the corresponding recommendations in application instructions of other drugs.

At the beginning of a therapy cycle if the delay with reception of a kapetsitabin or other drug(s) is expected, it is necessary to postpone reception of all drugs until conditions for therapy resuming are reached by all drugs.

If during a cycle of a combination therapy of the phenomenon of toxicity, according to the doctor, are not connected using a kapetsitabin, then therapy kapetsitabiny should be continued, and to adjust a dose of other drug according to recommendations of the instruction for its use.

If other drug(s) has to be cancelled, kapetsitabiny can continue treatment at satisfaction requirements for therapy resuming kapetsitabiny. These recommendations are applicable concerning all testimonies and all special groups of patients.

Use for special groups of patients. An abnormal liver function at patients with metastasises in a liver. Change of an initial dose is not required from patients with metastasises in a liver and to lungs or average degree with an abnormal liver function. However these patients should be observed carefully. Use of drug for patients with a heavy liver failure was not studied.

Renal failure. Reduction of an initial dose to 75% of 1250 mg/sq.m at patients from initial average degree is recommended by a renal failure (KK of 30-50 ml/min., on a formula Cockroft-Gault). With easy degree of a renal failure (KK of 51-80 ml/min.) correction of an initial dose is not required from patients.

In case of emergence at the patient of the undesirable phenomenon of the 2nd, 3rd or 4th severity, its careful monitoring and an immediate break of the carried-out therapy for the purpose of the subsequent dose adjustment of drug according to the recommendations specified in table 3 is necessary. If the calculated clearance of creatinine decreased during performing therapy to level less than 30 ml/min., therapy kapetsitabiny should be stopped. Recommendations about dose adjustment of drug at average degree of a renal failure belong both to monotherapy, and to a combination therapy.

Calculation of a dose is specified in tables 1 and 2.

Children. Safety and efficiency of a kapetsitabin at children was not studied.

Patients of advanced and senile age. Correction of an initial dose at monotherapy kapetsitabiny is not required. However the heavy undesirable phenomena of the 3rd and 4th degree connected with the carried-out therapy developed at patients 80 years are more senior more often than at more young people.

When using a kapetsitabin in a combination with other antineoplastic drugs at elderly patients (aged> 65 years) undesirable reactions of the 3rd and 4-oh of severity, and also the undesirable reactions which demanded therapy cancellation were noted more often than at more young people. Careful monitoring of a condition of patients of advanced age is recommended.

At treatment in a combination with dotsetaksely at patients at the age of 60 years is also more senior increase in frequency of the undesirable phenomena of the 3rd and 4th degree and the serious undesirable phenomena connected with therapy was noted. For patients at the age of 60 years is also more senior which will receive a combination of a kapetsitabin with dotsetaksely, it is recommended to lower an initial dose of a kapetsitabin to 75% (950 mg/sq.m 2 times a day). Calculation of a dose is given in table 1. In case of lack of manifestations of toxicity, the dose can be increased to 1250 mg/sq.m 2 times a day.

At treatment in a combination with irinotekany at patients at the age of 65 years is also more senior it is recommended to lower an initial dose of a kapetsitabin to 800 mg/sq.m two times a day.

Features of use:

Pregnancy and lactation. Drug is contraindicated to use at pregnancy and during breastfeeding.  During therapy kapetsitabiny and at least within 3 months after its termination it is necessary to use reliable methods of contraception. If pregnancy occurred during performing therapy, the patient has to be informed on potential threat for a fruit.

The side reactions limiting a drug dose are diarrhea, abdominal pains, nausea, stomatitis, a palmar and bottom syndrome.

It is necessary to carry out careful medical control of manifestations of toxicity at the patients receiving therapy kapetsitabiny.

The majority of the undesirable phenomena are reversible and do not demand full drug withdrawal though there can be a need for dose adjustment or temporary drug withdrawal.

Diarrhea: treatment kapetsitabiny can cause diarrhea, sometimes heavy. Patients with heavy diarrhea should be observed carefully, and at development of dehydration it is necessary to carry out a regidratation or compensation of loss of electrolytes. It is necessary to appoint standard antidiarrheal drugs (for example, loperamide) on medical indications as soon as possible. According to criteria of National oncological institute of Canada (NCIC of STS, version 2) diarrhea 2 degrees define as increase of a chair to 4-6 times a day or a chair at night, diarrhea 3 degrees - as increase of a chair to 7-9 times a day or an incontience a calla and a sprue, diarrhea 4 degrees - as increase of a chair to 10 and more times a day, emergence in a chair of visible blood or need of a parenteral maintenance therapy. If necessary it is necessary to reduce a dose of a kapetsitabin.

Dehydration: dehydration should be warned or eliminated at the very beginning of emergence. Dehydration can quickly develop at patients with anorexia, an adynamy, nausea, vomiting or diarrhea.

Dehydration can become the reason of development of an acute renal failure, in some cases with a lethal outcome, especially patients with a renal failure at the time of the beginning have therapies or if the patient accepts капецитабин along with the drugs possessing nephrotoxic action.

At development of dehydration 2 degrees or above, treatment kapetsitabiny it is necessary to interrupt and carry out a regidratation immediately. Treatment cannot be resumed before end of a regidratation and elimination or correction of the factors which caused it. The dose of drug should be modified according to recommendations for the undesirable phenomena which led to dehydration.

Cardiotoxicity: The cardiotoxicity range at treatment kapetsitabiny is similar to that when using other ftorpirimidin and includes a myocardial infarction, stenocardia, arrhythmias, a cardiac standstill, heart failure and changes on an ECG. These undesirable phenomena are more characteristic of the patients suffering from an ischemic heart disease.

It is necessary to be careful at treatment kapetsitabiny at patients with arrhythmia and stenocardia in the anamnesis.
Hypo - and a hypercalcemia: During therapy kapetsitabiny development hypo - or hypercalcemias was noted. It is necessary to be careful at patients with earlier diagnosed hypo - or a hypercalcemia.

Diseases of the central and peripheral nervous system: It is necessary to be careful at patients е diseases of the central and peripheral nervous system (for example, in the presence of metastasises in a brain and neuropathy).

Diabetes mellitus and disturbances of water and electrolytic balance: It is necessary to be careful at patients with a diabetes mellitus and disturbances of water and electrolytic balance as during treatment kapetsitabiny the exacerbation of these diseases is possible.

Insufficient activity of DPD: In rare instances the unexpected heavy phenomena of toxicity (for example, stomatitis, diarrhea, a neutropenia and a neurotoxicity) associated with FAUGH are caused by insufficient activity of a dihydropyrimidindehydrogenase (DPD). Thus, it is impossible to exclude communication between reduced activity of DPD and more expressed, potentially lethal toxicity FAUGH.

Ophthalmologic complications: It is necessary to observe patients regarding emergence of ophthalmologic complications, such as a keratitis or pathology of a cornea, especially in case of existence of disturbances from an organ of sight in the anamnesis. In case of development of complications from an organ of sight it is necessary to appoint the corresponding treatment.

Stephens-Johnson's syndrome and toxic epidermal necrolysis: Kapetsitabin can cause development of such serious skin reactions as Stephens-Johnson's syndrome and a toxic epidermal necrolysis. At development of heavy skin reactions against the background of use of a kapetsitabin administration of drug should stop and be not to resumed.

Palmar and bottom syndrome: Manifestation of skin toxicity of a kapetsitabin is development of a palmar and bottom syndrome (synonyms - the palmar and bottom eritrodizesteziya or an akralny erythema caused by chemotherapy). Time median before development of manifestations of toxicity in the patients receiving monotherapy kapetsitabiny makes 79 days (in the range from 11 to 360 days), and severity varies from the 1st degree to the 3rd degree. The palmar and bottom syndrome of the 1st degree does not break daily activity of the patient and is shown by numbness, дизестезиями / paresthesias, a pricking or reddening of palms and/or soles, discomfort. The palmar and bottom syndrome of the 2nd degree is characterized by painful reddening and hypostases of brushes and/or feet, and the discomfort caused by these symptoms breaks daily activity of the patient. The palmar and bottom syndrome 3-oh of degree is defined as wet desquamation, an ulceration, formation of bubbles and sharp pains in brushes and/or feet, and also the strong discomfort making impossible for the patient any kinds of daily activity. At emergence of a palmar and bottom syndrome of the 2nd or 3rd degree therapy of a kapetsitabin should be interrupted before disappearance of symptoms or their reduction to the 1st degree. At emergence of a syndrome of the 3rd degree the subsequent doses of a kapetsitabin have to be reduced.

B6 vitamin (pyridoxine) is not recommended to be applied to symptomatic or secondary preventive treatment of a palmar and bottom syndrome at use of a kapetsitabin in a combination with Cisplatinum as it can reduce efficiency of Cisplatinum. There are data on efficiency of a dekspantenol in prevention of development of a palmar and bottom syndrome at therapy kapetsitabiny

Hyperbilirubinemia, increase in activity of ALT, ACT: Kapetsitabin can cause a hyperbilirubinemia. If in connection with treatment kapetsitabiny the hyperbilirubinemia> 3,0 x UBN (upper bound of norm) or increase in activity of "hepatic" aminotransferases (ALT, ACT)> 2,5 x VGN is noted, treatment should be interrupted. Performing therapy can be resumed at decrease in concentration of bilirubin and activity of "hepatic" aminotransferases below the specified limits.

Joint reception with peroral anticoagulants: At the patients who are at the same time accepting капецитабин and peroral anticoagulants - coumarin derivatives, it is necessary to control coagulability indicators (a prothrombin time or MNO) and according to it to select an anticoagulant dose.

Patients of advanced and senile age: Frequency of the toxic phenomena from digestive tract at patients with a colorectal cancer at the age of 60 - 79 years receiving monotherapy kapetsitabiny did not differ from that in the general population of patients. Patients have 80 years and the reversible undesirable phenomena from digestive tract of the 3rd and 4th degree are more senior, such as diarrhea, nausea and vomiting, developed more often.

At patients aged> 65 years receiving a combination therapy kapetsitabiny and other antineoplastic drugs, were celebrated increase in frequency of the undesirable phenomena of the 3rd and 4th severity and the undesirable phenomena which led to the therapy termination, but comparison with patients of younger age. In the analysis of data of safety at patients> 60 years receiving a combination therapy kapetsitabiny and dotsetaksely, are celebrated increase in frequency of the connected е by therapy of the undesirable phenomena of the 3rd and 4th severity, serious undesirable phenomena and early cancellation of therapy because of the undesirable phenomena in comparison with those at patients 60 years are younger.
Renal failure: It is necessary to be careful at use of a kapetsitabin to patients е a renal failure of moderate severity. As well as at treatment ftoruratsily, the frequency of development connected with the carried-out therapy undesirable the phenomenon of the 3rd and 4th severity was higher at patients with a renal failure of moderate severity (KK of 30-50 ml/min.).

Liver failure: Patients with a liver failure during therapy kapetsitabiny have to be under careful medical observation. Influence of an abnormal liver function, the liver which is not caused by metastatic defeat or a heavy liver failure, on distribution of a kapetsitabin is unknown.

Influence on ability to manage vehicles and mechanisms. Some side reactions of drug, such as dizziness, drowsiness, can negatively influence ability of driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. At emergence of above-mentioned undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

Frequency of development of undesirable reactions is stated according to WHO recommendations: very often (> 10%), it is frequent (> 1% and <10%), infrequently (> 0,1% and <1%), is rare (> 0,01% and <0,1%), is very rare (<0,01%).
 
Disturbances from the digestive tract (DT) (diarrhea, nausea, vomiting, abdominal pains, stomatitis), a palmar and bottom syndrome, increased fatigue, an adynamy, anorexia, cardiotoxicity, increase of a renal failure at patients with a renal failure in the anamnesis, and also a fibrinferment/embolism were the most frequent side effects connected with reception of a kapetsitabin.
 
The side effects registered at the patients accepting капецитабин as monotherapy. Infectious and parasitic diseases: often - herpes a viral infection, a nasopharyngitis, a lower respiratory tract infection; infrequently - sepsis, an infection of urinary tract, cellulitis, tonsillitis, pharyngitis, candidiasis of a mucous membrane of an oral cavity, flu, a gastroenteritis, fungal infections, infections, tooth abscess.
 
The high-quality, malignant and not specified new growths: infrequently - a lipoma.
 
Disturbances from blood and lymphatic system: often - a neutropenia; infrequently - a febrile neutropenia, a granulocytopenia, thrombocytopenia, a leukopenia, hemolitic anemia, increase in the international normalized ratio, lengthening of a prothrombin time.
 
Disturbances from immune system: infrequently - hypersensitivity. Disturbances from a metabolism and food: very often - anorexia; often - dehydration, decrease in body weight; infrequently - a diabetes mellitus, a hypopotassemia, a digestive disturbance, a gipertriglitseridemiya.
 
Disturbances from mentality: infrequently - the panic attacks, the suppressed mood, decrease in a libido.
 
Disturbances from a nervous system: often - a headache, dizziness (except вертиго), slackness, paresthesias, a dysgeusia (food faddism): infrequently - aphasia, a dysmnesia, a syncope, balance disturbance, an anesthesia, peripheral neuropathy.
 
Disturbances from an organ of sight: often - the raised slezootdeleniye, conjunctivitis; infrequently - decrease in visual acuity, a diplopia.
 
Disturbances from an acoustic organ and labyrinth disturbances: infrequently - вертиго, ear pain.
 
Disturbances from heart: infrequently - stenocardia, including unstable, arrhythmia, sinus tachycardia, a heart consciousness.
 
Disturbances from vessels: often - thrombophlebitis; infrequently - a deep vein thrombosis, increase in arterial pressure, a petechia, lowering of arterial pressure, "inflows", a cold snap of distal departments of extremities.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum: often - nasal bleeding, a rhinorrhea; infrequently - pheumothorax, a pneumorrhagia, bronchial asthma, an asthma at an exercise stress.
 
Disturbances from digestive tract: very often - diarrhea, vomiting, nausea, stomatitis (including ulcer), abdominal pains; often - a lock, pains in epigastriums, dyspepsia; infrequently - intestinal impassability, ascites, enteritis, a dysphagy, pain in the bottom of a stomach, discomfort in a stomach, a gasgroezofagialny reflux disease, blood in a chair.
 Disturbances from a liver and biliary tract: often - change of functional tests of a liver; infrequently - jaundice.

Disturbances from skin and hypodermic fabrics: very often - a palmar and bottom syndrome (paresthesias, hypostasis, a hyperemia, a skin peeling, blistering), dermatitis; often - a skin hyperpegmentation, macular rash, rash, an alopecia, an erythema, a xeroderma; infrequently - a blister, skin ulcers, urticaria, a palmar erythema, a face edema, a purpura. At less than 2% of patients in 7 complete clinical trials (N=949) it was reported about skin cracks, at least, presumably connected with therapy kapetsitabiny.
 
Disturbances from musculoskeletal and connecting fabric: often - extremity pain, a dorsodynia; infrequently - swelling of joints, an ostealgia, front pain, constraint, muscular weakness.
 
Disturbances from kidneys and urinary tract: infrequently - a hydronephrosis, an urine incontience, a hamaturia, a nocturia, increase in creatinine in a blood plasma.

Disturbances from generative organs and a mammary gland: infrequently - vaginal bleedings.
 
The general frustration and disturbances in an injection site: very often - fatigue, drowsiness; often - peripheral hypostases, indispositions, a stethalgia, fever, weakness, an adynamy; infrequently - hypostases, a fever, flu on a similar syndrome, a shiver, fervescence.
 
Influence on results of laboratory and tool researches: often - a hyperbilirubinemia.
 
The following undesirable reactions are the toxicity manifestations known for therapy of a ftorpirimidinama; 5% of the patients participating in 7 complete clinical trials (N=949) were reported, at least, about indirect communication between development of such reactions and use of a kapetsitabin at less, than:

disturbances from digestive tract: dryness in a mouth, the meteorism, undesirable reactions connected with an inflammation/ulceration of mucous membranes such as esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding;

disturbances from cardiovascular system: hypostases of the lower extremities, a cardialgia, including stenocardia, a cardiomyopathy, myocardium ischemia, a myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including fibrillation of auricles, ventricular extrasystoles;

disturbances from a nervous system: taste disturbance, sleeplessness, confusion of consciousness, encephalopathy, symptoms of cerebellar disturbances (ataxy, dysarthtia, disturbance of balance and coordination).

Disturbances from mentality: depression; infectious and parasitic diseases: the infectious complications connected with a miyelosupressiya, easing of immunity and/or mukozity such as local and fatal system infections (bacterial, virus or fungal etiology) and sepsis.

Disturbances from blood and lymphatic system: anemia, миелосупрессия / pancytopenia.

Disturbances from skin and hypodermic fabrics: itch, focal peeling of skin, hyperpegmentation of skin, change of nails, reactions of a photosensitization, beam dermatitis.
 
Disturbances from an organ of sight: irritation of eyes.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: short wind, cough.
 
Disturbances from musculoskeletal and connecting fabric: arthralgia, mialgiya, dorsodynia.
 
The general frustration and disturbances in an injection site: stethalgia (not cardial etiology), extremity pain.
 
Use of a kapetsitabin in a combination therapy. The profile of safety did not differ at appointment according to various indications and at various combinations, however the undesirable reactions listed at monotherapy can be observed with a bigger frequency at use of a kapetsitabin in a combination therapy.
 
Undesirable reactions which were observed in addition to those at monotherapy are given below:
 
Infectious and parasitic diseases: often - the candidiasis of a mucous membrane of an oral cavity surrounding herpes, infections of urinary tract, upper respiratory tract infections, rhinitis, flu, an infection, oral cavity herpes.
 
Disturbances from blood and lymphatic system: very often - a neutropenia, anemia, thrombocytopenia, a leukopenia, a febrile neutropenia; often - a miyelosupressiya.

Disturbances from immune system: often - hypersensitivity.

Disturbances from a metabolism and food: very often - decrease in body weight, a loss of appetite; often - a hypopotassemia, a hyponatremia, a hypomagnesiemia, a hypocalcemia, a hyperglycemia;
 
Disturbances from mentality: often - frustration of a dream, alarm.

Disturbances from a nervous system: very often - paresthesia, a dysgeusia, a headache, peripheral neuropathy, peripheral touch neuropathy, a dizesteziya; often - a neurotoxicity, a tremor, neuralgia, a hypesthesia.

Disturbances from an organ of sight: very often - dacryagogue; often - vision disorders, a xerophthalmus, eye pain, an illegibility of visual perception.
 
Disturbances from an acoustic organ and labyrinth disturbances: often - a ring in ears, relative deafness.
 
Disturbances from heart: often - fibrillation of auricles.
 
Disturbances from vessels: very often - a fibrinferments/embolism, increase in the arterial pressure (AP), hypostasis of the lower extremities; often - a hyperemia, a lowering of arterial pressure, hypertensive crisis, "inflows", phlebitis.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often - a throat dizesteziya, a pharyngalgia; often - nasal bleeding, a dysphonia, a rhinorrhea, a hiccups, throat and throat pain.
 
Disturbances from digestive tract: very often - a lock, dyspepsia; often - bleeding from upper parts of digestive tract, an ulcer in oral cavities, gastritis, abdominal distention, a gastroesophageal reflux disease, a stomatalgia, a dysphagy, a proctorrhagia, pain in the bottom of a stomach, a dizesteziya, paresthesia and a hypesthesia in a mouth, discomfort in a stomach.
 
Disturbances from a liver and biliary tract: often - an abnormal liver function.
 
Disturbances from skin and hypodermic fabrics: very often - an alopecia, change of nails; often - a hyperhidrosis, erythematic rash, a small tortoiseshell, night perspiration.

Disturbances from musculoskeletal and connecting fabric: very often - a mialgiya, an arthralgia, extremity pain; often - a gnathalgia, muscular spasms, a lockjaw, muscular weakness.
 
Disturbances from kidneys and urinary tract: often - a hamaturia, a proteinuria, decrease in clearance of creatinine, a dysuria.
 
The general frustration and disturbances in an injection site: very often - weakness, slackness, hypersensitivity to high and low temperatures; often - fever, pain, an inflammation of a mucous membrane, a fever, a stethalgia, a grippopodobny syndrome, a contusion.
 
Both in clinical trials, and out of their framework cases of a liver failure and cholestatic hepatitis were registered. Relationship of cause and effect is not established with reception of a kapetsitabin.

At therapy kapetsitabiny in a combination with other chemotherapeutic drugs often (but less, than at 5% of patients) it was reported about cases of reactions of hypersensitivity (2%) and an ischemia/myocardial infarction (3%).

Laboratory and tool data. The changes of laboratory indicators observed within clinical trials at patients at adjuvant therapy of a colon cancer and at patients at therapy of a metastatic breast cancer and metastatic colorectal cancer regardless of their communication with reception of a kapetsitabin are given below: neutropenia, granulocytopenia, lymphocytopenia, thrombocytopenia, anemia, hyperbilirubinemia, increase in activity of ALT, nuclear heating plant, alkaline phosphatase, giperkreatininemiya, hyperglycemia, гипо-/hypercalcemia, hyponatremia, hypopotassemia.
 
Post-registration experience of use of a kapetsitabin. seldom - an acute renal failure as a result of dehydration, including with a lethal outcome, a dot keratitis, fibrillation of ventricles, lengthening of an interval of QT, arrhythmia ventricular takhisistolichesky pirouette ooze, bradycardia, a vasospasm; very seldom - a skin form of a lupus erythematosus, such heavy skin reactions as Stephens-Johnson's syndrome, a toxic epidermal necrolysis, a stenosis of the lacrimal tubule which is not specified, defeat of a cornea, including a keratitis; very seldom - clinical trials, and out of their framework cases of a liver failure and cholestatic hepatitis were registered.
 
Diarrhea. Diarrhea was observed at 50% of patients during therapy kapetsitabiny. As a result meta-Yoanaliza 14 clinical trials including more than 4700 patients receiving therapy kapetsitabiny were revealed kovariata which statistically were associated with increase in risk of development of diarrhea: increase in an initial dose of a kapetsitabin (in grams), increase in the studied treatment period (in weeks), increase in age of the patient (for each 10 years), a female. Kovariata, the development of diarrhea which is statistically associated with reduction of risk: increase in a cumulative dose of a kapetsitabin (0,1 - kg) and increase in relative intensity of a dose in the first 6 weeks of treatment.
 
Patients with heavy diarrhea should be observed carefully, carrying out by him a regidratation and recovering water and electrolytic balance at dehydration. According to indications it is as soon as possible recommended to accept standard antidiarrheal drugs (for example, loperamide).
 
Cardiotoxicity. Except side effects, predstavlesh1ykh in tables 4 and 5, at monotherapy kapetsitabiny the following undesirable reactions were noted with a frequency of emergence less than 0,1%: cardiomyopathy, heart failure, sudden death and ventricular premature ventricular contraction.

Encephalopathy. At monotherapy kapetsitabiny development of encephalopathy with a frequency of emergence less than 0,1% was noted.
 
Side reactions in special groups of patients. Patients of advanced age. At elderly patients aged> 60 years receiving капецитабин in the form of monotherapy or in a combination with dotsetaksely were celebrated increase in frequency of undesirable reactions 3 and 4 severity and serious undesirable reactions in comparison with patients aged <60 years. At most of patients aged> 60 years receiving a combination therapy with dotsetaksely revealed earlier termination of treatment as a result of side reactions in comparison with patients aged <60 years. As a result of meta-analysis of 14 clinical trials including more than 4700 patients receiving капецитабин it was revealed that with increase in age of the patient (for each 10 years) the risk of development of a palmar and bottom syndrome and diarrhea while the risk of development of a neutropenia, on the contrary, decreased increases.
 
Floor. At female patients statistically significant increase in risk of development of a palmar and bottom syndrome and diarrhea is noted, the risk of development of a neutropenia is reduced.

Patients with renal failures. At patients with a renal failure is prior to treatment, receiving monotherapy kapetsitabiny, the increase in frequency of side reactions 3 and 4 degrees connected with treatment in comparison with patients with normal function of kidneys is noted (36% - at patients without renal failure, 41% - with a slight renal failure and 54% - with a renal failure of average degree). Patients with a renal failure of average degree had a need for a dose decline (44%) in comparison with 33 and 32% of patients without renal failure with a slight renal failure respectively more often, and premature cancellation of treatment is more often noted.

Interaction with other medicines:

Anticoagulants of a coumarinic row. At the patients accepting капецитабин along with anticoagulants of a coumarinic row (warfarin and фенпрокумон), it was reported about disturbances of indicators of coagulation and/or bleedings in several days or months from the beginning of therapy kapetsitabiny, and in several cases - within one month after се end.
 
In a research of medicinal interaction after single administration of warfarin in a dose of 20 mg капецитабин increased AUC of S-warfarin by 57%, and the size of the international normalized relation (INR) - for 91%. At the patients who are at the same time accepting капецитабин and anticoagulants of a coumarinic row, it is necessary to watch carefully coagulation indicators (a prothrombin time or MNO), the dose of anticoagulant should be selected according to these to indicators.
 
CYP2C9 isoenzyme substrates. Special researches of medicinal interaction of a kapetsitabin with other drugs which are metabolized an isoenzyme of CYP2C9 of system of P450 cytochrome were not conducted. It is necessary to be careful at use of a kapetsitabin together with these drugs.
 
Phenytoinum. At a concomitant use of a kapetsitabin and Phenytoinum it was reported about increase in concentration of the last in plasma. Special researches of intermedicinal interaction of a kapetsitabin and Phenytoinum were not conducted, however it is supposed that suppression of an isoenzyme of CYP2C9 under the influence of a kapetsitabin is the cornerstone of the mechanism of interaction (see above "Anticoagulants of a coumarinic row"). At the patients receiving at the same time Phenytoinum and капецитабин it is regularly necessary to control concentration of Phenytoinum in plasma.
 
Antacids. At assessment of pharmacokinetic parameters of a kapetsitabin at a concomitant use with the antacids containing aluminum hydroxide and magnesium hydroxide small increase in concentration of a kapetsitabin and one of metabolites (5 ’-DFUR) in a blood plasma is noted. (5’ - DFUR, FU and FBAL) the studied means did not exert impact on three main metabolites of a kapetsitabin.
 
Calcium фолинат (Leykovorin). Calcium фолинат does not influence pharmacokinetic properties of a kapetsitabin and its metabolites. However, strengthening of toxic effect of a kapetsitabin due to influence of calcium of a folinat on a pharmacodynamics of a kapetsitabin is possible.
 
Sorivudin and his analogs. In references clinically significant medicinal interaction of a sorivudin and FAUGH which cornerstone the inhibiting effect of a sorivudin on DPD is is described. The specified interaction can lead to fatal strengthening of toxicity of ftorpirimidin. Therefore it is not necessary to appoint капецитабин along with sorivudiny or its structural analogs like brivudin. It is necessary to observe at least a four-week interval between the end of therapy sorivudiny or its structural analogs (including бривудин) and an initiation of treatment kapetsitabiny.

Oksaliplatin. Clinically significant difference in exposure of a kapetsitabin or metabolites of an oksaliplatin (free platinum or the general platinum) at the combined use of a kapetsitabin and oksaliplatin, irrespective of presence of a bevatsizumab, is noted.
 
Bevatsizumab. Clinically significant effect of a bevatsizumab on pharmacokinetics of a kapetsitabin, or its metabolites is noted.
 
Allopyrinolum. Interaction between Allopyrinolum and FAUGH with possible decrease in efficiency FAUGH is noted. In this regard it is necessary to avoid simultaneous use of a kapetsitabin and Allopyrinolum.
 
Interferon alpha. The most tolerable dose of a kapetsitabin - 2000 mg/sq.m a day at a concomitant use е interferon alpha 2 - an alpha (3 million ME/sq.m a day) in comparison with a dose of a kapetsitabin of 3000 mg/sq.m a day at monotherapy.
 
Radiation therapy. The most tolerable dose of a kapetsitabin in the monotherapy mode at the standard mode of dosing - 3000 mg/sq.m, at the combined use with radiation therapy of a colorectal cancer (at the continuous mode of therapy or 5-day courses Monday through Friday within 6 weeks) - 2000 mg/sq.m a day.

Contraindications:

- Hypersensitivity to a kapetsitabin or any other components of drug;
- hypersensitivity to a ftoruratsil or at the registered cases of development of unexpected or heavy side reactions on treatment by derivatives of a ftorpirimidin in the anamnesis;
- the established deficit of DPD (dihydropyrimidindehydrogenase), as well as for other ftorpirimidin;
- a concomitant use of a sorivudin or its structural analogs like brivudin;
- heavy liver failure;
- a heavy renal failure (the clearance of creatinine is lower than 30 ml/min.);
- heavy leukopenia;
- initial maintenance of neutrophils <1,5Õ109/l and/or thrombocytes <100Õ109/l;
- in the presence of contraindications to one of drugs of a combination therapy it should not be used;
- pregnancy and period of feeding by a breast;
- children's age (efficiency and safety of use are not established).

With care. At coronary heart disease, anemia and stenocardia in the anamnesis, a renal failure of moderate severity or a liver failure, hypo - or hypercalcemias, diseases of the central and peripheral nervous system, a diabetes mellitus and disturbances of water and electrolytic balance, age are more senior than 60 years, simultaneous use with peroral anticoagulants of a coumarinic row, hereditary deficit of lactase, a lactose intolerance, glyukozo-galaktozny malabsorption.

Overdose:

Symptoms of acute overdose include nausea, vomiting, diarrhea, the inflammation of a mucous membrane (mukozit), irritation of digestive tract and bleeding, and also oppression of function of marrow. Treatment of overdose has to include a standard complex of the therapeutic and supporting actions directed to correction of clinical symptoms and the prevention of possible complications.

Storage conditions:

In the dry, protected from light place at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in a blister strip packaging. 150 mg: on 6 blister strip packagings together with the application instruction in a pack from a cardboard. 500 mg: on 12 blister strip packagings together with the application instruction in a pack from a cardboard.