Kseloda

General characteristics. Structure:

One tablet, film coated, 150 mg contains:
Active agent: капецитабин - 150 mg;

Excipients: 15.6 mg, cellulose microcrystallic - 7.2 mg, croscarmellose sodium - 6.0 mg, a gipromelloza (3 мПа*с) - 4.5 mg, magnesium stearate - 2.7 mg;

Cover: Опадрай pink 03A14309 (a gipromelloza (6 мПа*с), talc, titanium dioxide (E171), dye ferrous oxide yellow (E172), dye ferrous oxide red (E172)) - 8.5 mg.

One tablet, film coated, 500 mg contains:
Active agent: капецитабин - 500 mg;

Excipients: lactose - 52.0 mg, cellulose microcrystallic - 24.0 mg, croscarmellose sodium - 20.0 mg, a gipromelloza (3 мПа.с) - 15.0 mg, magnesium stearate - 9.0 mg;

Cover: Опадрай pink 03A14380 (a gipromelloza (6 мПа.с), talc, titanium dioxide (E171), dye ferrous oxide yellow (E172), dye ferrous oxide red (E172)) - 18.0 mg.

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 5-ftoruratsit (5-FU) which is exposed to further metabolism.
Education 5-FU happens preferential in tumor fabric under the influence of a tumoral angiogenic factor - thymidinephosphorylases that minimizes system influence 5-FU on healthy body tissues.
Consecutive fermental biotransformation of a kapetsitabin in 5-FU creates higher concentration of drug in tumor fabrics, than in surrounding healthy fabrics. After peroral purpose of a kapetsitabin a sick colorectal cancer (N=8) concentration 5-FU 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 5-FU 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.
Tumoral 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 5-FU, than in the corresponding healthy fabrics.
Both healthy, and tumor cells metabolize 5-FU in 5-fluorine-2-dezoksiuridinmonofosfat (ФдУМФ) and 5-ftoruridintrifosfat (FUTF). These metabolites damage cells by means of two various mechanisms. First, FDUMF and a folatny cofactor N5-10-metilentetragidrofolat 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 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 5-FU influences area size slightly. At purpose of a kapetsitabin after meal in a dose of 1250 mg/sq.m; for the 14th day the maximum concentration in plasma (Cmax) of a kapetsitabin, 5 ’-DFTsT, 5’ - DFUR, 5-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 mkg x h/ml, respectively.

Distribution (linkng with proteins). The research in vitro in a blood plasma of the person showed that for a kapetsitabin, 5 ’-DFTsT, 5’ - DFUR and 5-FU communication with proteins (mainly, with albumine) make 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 5-FU happens preferential in tumor fabric under the influence of a tumoral angiogenic factor - thymidinephosphorylases.
AUC for 5-FU in plasma is 6-22 times less, than after intravenous bolyusny administration 5-FU in a dose of 600 mg/sq.m. Metabolites of a kapetsitabin become cytotoxic only after transformation in 5-FU and metabolites 5-FU.
Further 5-FU catabolizes with formation of inactive metabolites: dihydro-5-ftoruratsila (FUN2), 5-ftorureidopropionovy acid (FUPK) and 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’ - DFUR, 5-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 5-FU 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, except for 5-FU, had dozozavisimy character.
After reception of a kapetsitabin in its metabolites are removed mainly with urine. The most part (95%) of the accepted dose of a kapetsitabin is removed with urine. 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 with urine in not changed look.
Combination therapy
Any impact of the drug Kseloda® on pharmacokinetics of a dotsetaksel or paklitaksel (Cmax and AUC), and also or paklitakset influences of a dotsetaksel on pharmacokinetics 5’ - DFUR (the main metabolite of a kapetsitabin) is not revealed.

Pharmacokinetics in special clinical groups. 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 nuclear heating plant and ALT did not render statistically significant effect on pharmacokinetic properties 5 ’-DFUR, 5-FU and FBAL.
Patients with the liver failure caused by metastatic damage of a liver
At patients with easy and moderate 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 and 5-FU does not depend on the clearance of creatinine (CC). KK influences size of AUC 5’ - DFUR - the direct predecessor 5-FU (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 anti-proliferative activity; 5 ’-DFUR - the direct predecessor 5-FU.
Patients of advanced age
The age does not influence pharmacokinetics 5’ - DFUR and 5-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 the drug Kseloda®u of 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 two weeks with the subsequent seven-day break.
Combination therapy
Breast cancer
On 1250 mg/sq.m; 2 times a day within two weeks with the subsequent seven-day break, in a combination with dotsetaksely in a dose of 75 mg/sq.m; once in three weeks 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 the drug Kseloda® has to be lowered to 800-1000 mg/sq.m 2 times a day within two weeks with the subsequent seven-day break or to 625 mg/sq.m 2 times a day at the continuous mode. Addition of immunobiological drugs to a combination therapy does not influence a drug Kseloda® dose.
Antiemetics and premedication for ensuring adequate hydration are appointed before introduction of Cisplatinum and oksaliplatin according to application instructions of Cisplatinum and oksaliplatin at their use in a combination with the drug Kseloda®.
In adjuvant therapy of a colon cancer of the III stage the recommended therapy duration the drug Kseloda® makes 6 months, i.e. 8 courses.
In a combination with Cisplatinum
On 1000 mg/sq.m 2 times a day within two weeks with the subsequent seven-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 first day of a cycle). The first dose of the drug Kseloda® is appointed in the evening in the first day of a cycle of therapy, the last - in the morning to the 15th day.
In a combination with oksaliplatiny and/or bevatsizumaby
On 1000 mg/sq.m 2 times a day within two weeks with the subsequent seven-day break in a combination with oksaliplatiny and/or bevatsizumaby. The first dose of the drug Kseloda® is appointed in the evening in the first 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 first 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 with epirubitsiny (50 mg/sq.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 first day of a cycle in a look into infusions during 2 h, further 1 time in 3 weeks.
In a combination with irinotekany
On 1000 mg/sq.m 2 times a day within two weeks with the subsequent seven-day break in a combination with irinotekany (250 mg/sq.m of 1 times in 3 weeks, in/in infusion within 30 min., the first infusion are appointed in the first day of a cycle).
In a combination with irinotekany and bevatsizumaby
On 800 mg/sq.m 2 times a day within two weeks with the subsequent seven-day break in a combination 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 first 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 first day of a cycle.
The tables given below show examples of calculation of a standard and reduced dose of the drug Kseloda® for an initial dose of 1250 mg/sq.m or 1000 mg/sq.m.

Table 1. Standard and reduced doses of the drug Kseloda® for an initial dose of 1250 mg/sq.m; the bodies calculated depending on surface area.

	Dose - on 1250 mg/sq.m; two times a day
	Full dose 1250 mg/sq.m	Number of tablets of 150 mg and/or 500 mg on reception (on each reception two times a day - in the morning and in the evening)		Reduced dose (75% of an initial dose) 950 mg/sq.m	Reduced dose (50% of an initial dose) 625 mg/sq.m
Surface area of a body (sq.m)	Dose on reception (mg)	150 mg	500 mg	Dose on reception (mg)	Dose on reception (mg)
≤1.26	1500	-	3	1150	800
1.27 - 1.38	1650	1	3	1300	800
1.39 - 1.52	1800	2	3	1450	950
1.53 - 1.66	2000	-	4	1500	1000
1.67 - 1.78	2150	1	4	1650	1000
1.79 - 1.92	2300	2	4	1800	1150
1.93 - 2.06	2500	-	5	1950	1300
2.07 - 2.18	2650	1	5	2000	1300
≥2.19	2800	2	5	2150	1450

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

	Dose - on 1000 mg/m ² two times a day
	Full dose 1000 mg/sq.m	Number of tablets of 150 mg and/or 500 mg on reception (on each reception two times a day - in the morning and in the evening)		Reduced dose (75% of an initial dose) 750 mg/sq.m	Reduced dose (50% of an initial dose) 500 mg/sq.m
Surface area of a body (sq.m)	Dose on reception (mg)	150 mg	500 mg	Dose on reception (mg)	Dose on reception (mg)
≤1.26	1150	1	2	800	600
1.27 - 1.38	1300	2	2	1000	600
1.39 - 1.52	1450	3	2	1100	750
1.53 - 1.66	1600	4	2	1200	800
1.67 - 1.78	1750	5	2	1300	800
1.79 - 1.92	1800	2	3	1400	900
1.93 - 2.06	2000	-	4	1500	1000
2.07 - 2.18	2150	1	4	1600	1050
≥2.19	2300	2	4	1750	1100

Dose adjustment during treatment
General recommendations

The toxic phenomena of the drug Kseloda® 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 the drug Kseloda® 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 by the drug Kseloda® should be interrupted.
At disappearance of signs of toxicity or reduction of the last to the 1st degree, performing therapy by the drug Kseloda® 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 administration of drug of Kseloda® at emergence of toxicity heavy or moderate severity. If because of the toxic phenomena several administrations of drug of Kseloda® were missed, then these doses are not filled.
Hematologic toxicity
Therapy by the drug Kseloda® should be interrupted at detection of signs of hematologic toxicity of the 3rd or 4th degree.
In the table given below recommendations about change of a dose of the drug Kseloda® in case of development of the toxic phenomena connected with its use are specified.

Table 3. Scheme of dose adjustment of the drug Kseloda®.

Degree of toxicity of NCIC *	Change of a dose during a therapy cycle	Dose adjustment during the following cycle of therapy (% of an initial dose)
Degree 1	To continue in the same dose	To continue in the same dose
Degree 2
1st emergence	To interrupt therapy up to the permission to degree 0 - 1	100%
2nd emergence		75%
3rd emergence		50%
4th emergence	To completely stop therapy	It is not applicable
Degree 3
1st emergence	To interrupt therapy up to the permission to degree 0 - 1	75%
2nd emergence		50%
3rd emergence	To completely stop therapy	It is not applicable
Degree 4
1st emergence	To completely stop therapy OR if the doctor considers that for the benefit of the patient to continue treatment, to interrupt therapy up to the permission to degree 0 - 1	50%
2nd emergence	To completely stop therapy	It is not applicable

* 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 3). 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 the drug Kseloda® 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 administration of drug of Kseloda® 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 the drug Kseloda®, then therapy by the drug Kseloda® 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, the drug Kseloda® can continue treatment at satisfaction requirements for therapy resuming by the drug Kseloda®.
These recommendations are applicable concerning all testimonies and all special groups of patients.
Dose adjustment in special cases
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 an easy or moderate 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 with an initial moderate renal failure is recommended (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 by the drug Kseloda® should be stopped. Recommendations about dose adjustment of drug at a moderate 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 the drug Kseloda® at children was not studied.
Patients of advanced and senile age
Correction of an initial dose at monotherapy by the drug Kseloda® 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 the drug Kseloda® in a combination with other antineoplastic drugs at elderly patients (aged> 65 years) undesirable reactions of the 3rd and 4th 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 drug Kseloda® combination with dotsetaksely, it is recommended to lower an initial dose of the drug Kseloda® to 75% (950 mg/sq.m two times a day). Calculation of a dose is given in table 1.
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 the drug Kseloda® to 800 mg/sq.m two times a day.

Features of use:

It is necessary to carry out careful medical control of manifestations of toxicity at the patients receiving therapy by the drug Kseloda®.
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 by the drug Kseloda® 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 and compensation of loss of electrolytes. It is necessary to appoint standard antidiarrheal drugs (for example, loperamide) on medical indications as soon as possible. If necessary it is necessary to reduce a drug Kseloda® dose.
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.
At development of dehydration 2 degrees or above, treatment it is necessary to interrupt and carry out by the drug Kseloda® 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.
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 in the anamnesis.
In rare instances the unexpected heavy phenomena of toxicity (for example, stomatitis, diarrhea, a neutropenia and a neurotoxicity) associated with 5-FU 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 5-FU.
Manifestation of skin toxicity of the drug Kseloda® 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 by the drug Kseloda® 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 of the 3rd 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 by the drug Kseloda® 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 the drug Kseloda® 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 purpose of the drug Kseloda® in a combination with Cisplatinum as it can reduce efficiency of Cisplatinum.
The drug Kseloda® can cause a hyperbilirubinemia. If in connection with treatment the drug Kseloda® notes a hyperbilirubinemia> 3.0khvgn (the upper bound of norm) or increase in activity of "hepatic" aminotransferases (ALT, nuclear heating plant)> 2.5khvgn, treatment should be interrupted.
Performing therapy can be resumed at decrease in level of bilirubin and activity of "hepatic" aminotransferases below the specified limits.
At the patients who are at the same time accepting the drug Kseloda® 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.
Use of drug for 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 by the drug Kseloda® 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> 65 years receiving a combination therapy kapetsitabiny and other antineoplastic drugs, were celebrated increase in frequency of undesirable reactions of the 3rd and 4th severity and the undesirable phenomena which led to the termination of therapy in comparison with patients more young than 65 years.
In the analysis of data of safety at patients> 60 years receiving a combination therapy the drug Kseloda® and dotsetaksely are celebrated increase in frequency of the undesirable phenomena of the 3rd and 4th severity connected with therapy, because of the undesirable phenomena in comparison with those at patients 60 years are younger than the serious undesirable phenomena and early cancellation of therapy.
Renal failure
It is necessary to be careful at purpose of the drug Kseloda® to patients with a renal failure of moderate severity. As well as at treatment ftoruratsily, the frequency of development connected with the carried-out therapy of the undesirable phenomena 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 by the drug Kseloda® 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 the drug Kseloda® is unknown.
During therapy by the drug Kseloda® 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.
Treatment of unused drug and drug expired
Hit of medicine together with waste to the environment has to be minimized. It is not necessary to utilize drug by means of sewage or together with household waste. It is whenever possible necessary to use special systems for utilization of medicines.

Influence on ability to manage vehicles and mechanisms
The drug Kseloda® has small or moderate influence on ability to manage vehicles, mechanisms. To patients who had such undesirable phenomena as dizziness weakness or nausea, it is necessary to refrain from control of vehicles, mechanisms.

Side effects:

Frequency of development of undesirable reactions is stated according to the following gradation: very often> 1/10, it is frequent from> 1/100 to <1/10, infrequently from ≥1/1000 to <1/100.
Monotherapy by the drug Kseloda®
Disturbances from a metabolism and food: very often - anorexia; often - dehydration, a loss of appetite.
Disturbances from a nervous system: often - a headache, dizziness (except вертиго), paresthesias, a dysgeusia (food faddism).
Disturbances from an organ of sight: often - the raised slezootdeleniye, conjunctivitis.
Disturbances from digestive tract: very often - diarrhea, vomiting, nausea, stomatitis (including ulcer), abdominal pains; often - a lock, pains in epigastriums, dyspepsia.
Disturbances from skin and hypodermic fabrics: very often - a palmar and bottom syndrome (paresthesias, hypostasis, a hyperemia, a skin peeling, blistering), dermatitis; often - rash, an alopecia, an erythema, a xeroderma. 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 by the drug Kseloda®.
Influence on results of laboratory and tool researches: often - a hyperbilirubinemia.
The general frustration and disturbances in an injection site: very often - fatigue, drowsiness; often - fever, weakness, an adynamy.
The following undesirable reactions are the toxicity manifestations known for therapy of a ftorpirimidinama; it was reported, at least, about indirect communication between development of such reactions and use of the drug Kseloda® at less than 5% of the patients participating in 7 complete clinical trials (N=949):
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, cardialgias, 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 disturbances of integrity of mucous membranes such as local and fatal system infections (bacterial, virus or fungal etiology) and sepsis;
disturbances from blood and lymphatic system: anemia, miyelosupressiya/pancytopenia;
disturbances from skin and hypodermic fabrics: an itch, a focal peeling of skin, a hyperpegmentation of skin, change of nails, reactions of a photosensitization, the syndrome reminding 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 skeletal and muscular and connecting fabric: arthralgia, mialgiya, dorsodynia;
the general frustration and disturbances in an injection site: an adynamy, a stethalgia (not cardial etiology), extremity pain, the increased drowsiness.
Use of the drug Kseloda® 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 the drug Kseloda® in a combination therapy.
Some undesirable reactions are often observed at chemotherapy (for example, peripheral touch neuropathy at therapy dotsetaksely or oksaliplatiny, increase in the ABP at therapy bevatsizumaby), however at therapy by the drug Kseloda® it is impossible to exclude their deteriorations.
Undesirable reactions which were observed in addition to those at monotherapy are given below:
infectious and parasitic diseases: often - candidiasis of an oral cavity;
disturbances from blood and lymphatic system: very often - a leukopenia, a febrile neutropenia;
disturbances from a metabolism and food: very often - decrease in body weight;
disturbances from a nervous system: very often - peripheral neuropathy, peripheral touch neuropathy, a dizesteziya;
disturbances from vessels: very often - a fibrinferments/embolism, increase in the ABP;
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;
disturbances from skeletal and muscular and connecting fabric: very often - a gnathalgia;
the general frustration and disturbances in an injection site: very often - temperature intolerance; often - fever, pain.
In clinical trials and in the post-marketing period cases of a liver failure and cholestatic hepatitis were registered. Relationship of cause and effect is not established with administration of drug of Kseloda®.
At therapy by the drug Kseloda® 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%).
Changes from laboratory indicators
The changes of laboratory indicators observed at 995 patients at adjuvant therapy of a colon cancer and at 949 patients at therapy of a metastatic breast cancer and metastatic colorectal cancer regardless of their relationship of cause and effect with reception of a kapetsitabin are given below: decrease in number of neutrophils, decrease in number of granulocytes, decrease in number of lymphocytes, decrease in number of thrombocytes, decrease in hemoglobin, hyperbilirubinemia, increase in activity of ALT, nuclear heating plant, alkaline phosphatase, giperkreatininemiya, hyperglycemia, гипо-/hypercalcemia, hyponatremia, hypopotassemia.
Post-marketing observation
During post-marketing use of the drug Kseloda® the following undesirable reactions are found:
very seldom - the stenosis of the lacrimal tubule which is not specified;
very seldom - in clinical trials and in the post-marketing period cases of a liver failure and cholestatic hepatitis were registered.

Interaction with other medicines:

Anticoagulants of a coumarinic row
At the patients accepting the drug Kseloda® 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 its end.
In a research of medicinal interaction after single administration of warfarin in a dose of 20 mg the drug Kseloda® 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 the drug Kseloda® 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 indicators.
P4502C9 cytochrome substrates
Special researches of medicinal interaction of a kapetsitabin with other drugs which are metabolized an isoenzyme 2C9 of system of P450 cytochrome were not conducted. It is necessary to be careful at purpose of the drug Kseloda® together with these drugs.
Phenytoinum
At a concomitant use of the drug Kseloda® and Phenytoinum it was reported about increase in concentration of the last in plasma. Special researches of intermedicinal interaction of the drug Kseloda® 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 the drug Kseloda® it is regularly necessary to control concentration of Phenytoinum in plasma.
Antacids
At assessment of pharmacokinetic parameters of the drug Kseloda® 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 ’-DFTsT) in a blood plasma is noted. (5’ - DFUR, 5 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 drug Kseloda® pharmacodynamics is possible.
Sorivudin and his analogs
In references clinically significant medicinal interaction of a sorivudin and 5-FU 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 the drug Kseloda® along with sorivudiny or its structural analogs like brivudin. It is necessary to observe at least a four-weeks interval between the end of therapy sorivudiny or its structural analogs (including бривудин) and an initiation of treatment the drug Kseloda®.
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.

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.
Concomitant use of a sorivudin or its structural analogs like brivudin.
Heavy renal failure (the clearance of creatinine is lower than 30 ml/min.).
Initial maintenance of neutrophils <1.5 x 109/l and/or thrombocytes <100 x 109/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).

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:

To store at a temperature not above 30 °C.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 150 mg and 500 mg
On 10 tablets in the blister from a film of PVH/PVDH and aluminum foil.
On 6 (tablets of 150 mg) or 12 (tablets of 500 mg) blisters together with the application instruction place in a cardboard pack.