Capecitabine-TL - instructions for use, dose, side effects, contraindications

Composition of the film shell: opedraj II (white) [polyvinyl alcohol 46.9 %, titanium dioxide - 12,1%, talc - 17,4%, macrogol 4000 - 23,6%] - 10,5 mg.

500 mg:

active substance: capecitabine 500.00 mg;

Excipients: lactose 13.3 mg, microcrystalline cellulose 116.7 mg, croscarmellose sodium 49.0 mg, hypromellose 14.0 mg, magnesium stearate 7.0 mg.

Composition of the film shell: opedraj II (white) [polyvinyl alcohol 46.9 %, titanium dioxide - 12,1%, talc - 17,4%, macrogol 4000 - 23,6%] - 35,0 mg.

Description:

The tablets are round biconvex, covered with a film coat of white color. The core of the tablet is white or almost white.

Pharmacotherapeutic group:Antitumour agent, antimetabolite

ATX: & nbsp

L.01.B.C.06 Capecitabine

Pharmacodynamics:

Capecitabine is a derivative of fluoropyrimidine carbamate, an oral cytotoxic agent that activates in the tumor tissue and exerts a selective cytotoxic effect on it.

In vitro capecitabine does not have a cytotoxic effect, in vivo turns into fluorouracil (FU), which undergoes further metabolism. The formation of FU occurs predominantly in the tumor tissue under the action of the tumor angiogenic factor - thymidine phosphorylase, so the systemic effect of FU on healthy body tissues is minimized. Sequential enzymatic biotransformation of capecitabine in FU creates higher drug concentrations in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine, patients with colon cancer had a FU concentration in the tumor tissue higher by 3.2 times than in healthy tissues.The ratio of concentrations of FU in tumor tissue and plasma is 21.4, the ratio of its concentration in healthy tissues and in plasma is 8.9. The activity of thymidine phosphorylase in the primary colorectal tumor is also 4 times higher than in the adjacent healthy tissues.

In tumor cells in patients with breast, stomach, colon, cervical and ovarian cancer, there is more thymidine phosphorylase, which is capable of converting 5'-deoxy-5-fluorouridine (5'-DFUR) to FU than in the corresponding healthy tissues. Both healthy and tumor cells metabolize FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMF) and 5-fluorouridine triphosphate (FUTF). These metabolites damage cells by two different mechanisms. First, FUUM and the folate cofactor N^5-10-methylenetetrahydrofolate bind to thymidylate synthase (TC) to form a 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 extremely important for DNA synthesis, so the lack of this substance can lead to inhibition of cell division.Secondly, during the synthesis of RNA, the transcriptional enzymes of the nucleus can erroneously include FUTP in it instead of uridine triphosphate (UTP). This metabolic "error" disrupts RNA processing and protein synthesis.

Pharmacokinetics:

Suction

After oral administration capecitabine quickly and completely absorbed in the intestine in an unchanged form, after which its biotransformation takes place with the formation of metabolites: 5'-deoxy-5-fluorocytidine (5'-DFTST) and 5'-DFUR. Simultaneous food intake reduces the rate of absorption of capecitabine, but the area under the concentration-time curve (AUC) 5'-DFUR food intake affects slightly. When using capecitabine after meals at a dose of 1250 mg / m² on the 14th day the maximum concentrations (FROM_max) capecitabine, 5'-DFTST, 5'-DFUR, FU, and α-fluoro-β-alanine (FBAL) were respectively 4.47; 3.05; 12.1; 0.95 and 5.46 μg / ml. Time achievements FROM_maxis 1.50; 2.00; 2.00; 2.00 and 3.34 hours, and the value AUC - 7.75; 7.24; 24.6; 2.03 and 36.3 μg / hr / ml respectively.

Interval values of the main pharmacokinetic parameters for capecitabine FROM_max, AUC_0-t, FROM_max / AUC_0-t for the drug Capecitabine-TL were 0.64-1.21 μg / ml; 1.85-3.91 μg / hr / ml; 0.375-0.543 h^-1 respectively, the coefficients of variation of the main pharmacokinetic parameters C_max, AUC_0-t, C_max/AUC_0-t were 93.94%, 84.78% and 39.67%, respectively.

Interval values of the main pharmacokinetic parameters according to FU C_max, AUC_0-t, C_max / AUC_0-t for the drug Capecitabine-TL were 0.64-1.21 μg / ml; 1.85-3.91 μg / hr / ml; 0.375-0.543 h^-1 respectively, the coefficients of variation of the main pharmacokinetic parameters C_max, AUC_0-t, C_max/ AUC_0-t amounted to 91.30%, 106.68% and 54.55% respectively.

Distribution (binding with proteins)

Capecitabine, 5'-DFTST, 5'-DFUR and FU bind to plasma proteins (mainly albumin) by 54, respectively; 10; 62 and 10%.

Metabolism

Metabolised in the liver under the action of carboxyl esterase to the metabolite 5'-DFTST, which is then transformed into 5'-DFUR under the action of cytidine deaminase, localized mainly in the liver and tumor tissues. The concentration of FU and its active phosphorylated anabolites in the tumor is much higher than in healthy tissues, thereby ensuring a relative selectivity of the cytotoxic effect. Value AUC for FU in 6-22 times less than after intravenous fluid administration FU in a dose of 600 mg / m². Metabolites capecitabine become cytotoxic only after conversion to FU and anabolite FU. Then FU is catabolized with the formation of inactive metabolites of dihydrofluorouracil (FUN₂), 5-fluoroureidopropionic acid (PUPC) and FBAL; this process is influenced by dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.

Excretion

Half-life (T_1/2) capecitabine, 5'-DPCT; 5'-DFUR; FU and FBAL are respectively 0.85; 1.11; 0.66; 0.76 and 3.23 h. The pharmacokinetics of capecitabine was studied for range of doses 502-3514 mg / m²/ day. The pharmacokinetic parameters of capecitabine, 5'-DFTST and 5'-DFUR in the 1 st and 14 th days are the same. AUC FU increases by the 14th day by 30-35% and after the 22nd day does not increase. In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of FU, are dose-dependent.

After taking capecitabine, its metabolites are excreted mainly by the kidneys - 95.5%, the intestine - 2.6%. The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose of capecitabine is excreted by the kidneys unchanged.

Combination Therapy

In studies, no effect of capecitabine on the pharmacokinetics of docetaxel and paclitaxel (C_max and AUC) and the effects of docetaxel and paclitaxel on the pharmacokinetics of capecitabine and 5'-DFUR as the most important metabolite of capecitabine.

Pharmacokinetics in special clinical groups

Sex, the presence or absence of metastases in the liver before the start of treatment, the index of the general condition of the patient, the concentration of total bilirubin, serum albumin, the activity of alanine aminotransferase (ALT) and aspartate aminotransferaseACT) in patients with colon cancer did not have a significant effect on the pharmacokinetics of 5'-DFUR, FU, and FBAL.

Patients with hepatic failure due to metastatic liver damage

In patients with impaired liver function caused by metastases, mild to moderate severity of clinically significant changes in the pharmacokinetics of capecitabine does not occur. Data on the pharmacokinetics in patients with severe impairment of liver function are absent.

Patients with renal insufficiency

The pharmacokinetics of capecitabine and FU for renal failure of varying severity (from mild to severe) does not depend on creatinine clearance (CK). QC affects the magnitude AUC 5'-DFUR, the immediate precursor of FU (AUC increases by approximately 35% with a decrease in CK by 50%) and FBAL, a metabolite that does not have antiproliferative activity (increase AUC by 114% with a decrease in QC by 50%).

Elderly patients

Age does not affect the pharmacokinetics of 5'-DFUR and FU. AUC FBAL increased in patients aged 65 years and older (an increase in age by 20% was accompanied by an increase AUC FBAL by 15%), which is probably due to changes in kidney function.

The pharmacokinetics in patients of the Negroid race did not differ from that in patients of the Caucasian race. Pharmacokinetic studies have shown that in Japanese patients the values of C_max and AUC capecitabine by 36% and 24% and FBAL by 25% and 34%, respectively, were lower than in patients of the Caucasoid race. The clinical significance of these differences is unknown. There were no significant differences in the values of other metabolites (5'-DFTST, 5'-DFUR and FU).

Indications:

Mammary cancer

- Combination therapy with docetaxel of locally advanced or metastatic breast cancer with ineffective chemotherapy, including an anthracycline-based drug;

- mitotherapy of locally advanced or metastatic breast cancer, chemotherapy-resistant taxanes or anthracycline-based drugs, or in the presence of contraindications to them.

Colorectal cancer

- Adjuvant therapy for colon cancer III stage after surgical treatment;

- tTherapy of metastatic colorectal cancer.

Stomach cancer

- Therapy of the first line of common stomach cancer.

Contraindications:

- Hypersensitivity to capecitabine or any other components of the drug;

- Pincreased sensitivity to FU, or when there are reported cases of unexpected or severe adverse reactions to fluoropyrimidine derivatives in history;

- thea deficit of DPD (as for other fluoropyrimidines);

- aboutsimultaneous administration of sorivudine or its structural analogues of brivudine type;

- tsevere renal failure (CC below 30 ml / min);

- initial content of neutrophils <1.5х10⁹/ l and / or platelets <100x10⁹/ l;

- PIn the presence of contraindications to one of the drugs of combination therapy, it should not be used;

- bVariability and the period of breastfeeding;

- Children's age (effectiveness and safety of use are not established);

- tsevere hepatic impairment;

- letikopenia.

Carefully:

Caution should be exercised in appointing capecitabine in coronary heart disease, renal failure of moderate severity or liver failure,over 60 years of age, concomitant use with coumarinic oral anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption, anemia and angina pectoris, hypo- and hypercalcemia, central and peripheral nervous system diseases, diabetes mellitus and water- electrolyte balance.

Pregnancy and lactation:

The drug is contraindicated for use during pregnancy and during breastfeeding. During the therapy with capecitabine and at least 3 months after the end, reliable methods of contraception should be used. If the pregnancy occurred during the period of therapy, the patient should be aware of the potential threat to the fetus. During treatment with capecitabine, breastfeeding should be discontinued.

Dosing and Administration:

Inside, with water, not later than 30 minutes after eating.

Standard dosing regimen

Monotherapy

Colorectal cancer, breast cancer

The recommended daily dose of capecitabine-TL is 2500 mg / m² in the form of 3-week cycles: the drug is taken every day for 14 days, after which make a 7-day break.The total daily dose of the drug Capecitabine-TL is divided into 2 doses - in the morning and in the evening at 1250 mg / m body surface.

Combination Therapy

Mammary cancer

At 1250 mg / m² 2 times a day for 14 days, followed by a 7-day break in combination with docetaxel in the form of intravenous infusion for 1 hour at a dose of 75 mg / m² 1 time in 3 weeks. Premedication is performed before docetaxel is administered in accordance with the instructions for its use.

Colorectal cancer, stomach cancer

As part of combination therapy, the dose of capecitabine-TL should be reduced to 800-1000 mg / m² 2 times a day for 14 days followed by a 7-day break or up to 625 mg / m² 2 times a day in continuous mode.

In combination with cisplatin: 1000 mg / m² 2 times a day for 14 days followed by a 7-day break in combination with cisplatin (80 mg / mg once every 3 weeks, intravenous infusion for 2 hours, the first infusion is given on the first day of the cycle). The first dose of the drug Capecitabine-TL is appointed in the evening on the first day of the therapy cycle, the last one in the morning on day 15.

In combination with oxaliplagin and / or bevacizumab: 1000 mg / m² 2 times a day for two weeks followed by a seven-day break in combination with oxaliplagin and / or bevacizumab.The first dose of the drug Capecitabine-TL is appointed in the evening on the first day of the therapy cycle, the last one in the morning on day 15. Bevacizumab is administered at a dose of 7.5 mg / kg every 3 weeks, intravenous infusion for 30-90 minutes, the first infusion begins on the first day of the cycle. After bevacizumab is introduced oxaliplatinum in a dose of 130 mg / m², intravenous infusion for 2 hours.

In combination with epirubicin: 625 mg / m² 2 times a day in a continuous mode in combination with epirubicin (50 mg / m² 1 every 3 weeks, iv bolus starting from the first day of the cycle).

In combination with irinotecan: at 1000 mg / m² 2 times a day for 14 days followed by a 7-day break in combination with irinotecan (250 mg / m² 1 every 3 weeks, IV infusion for 30 minutes, the first infusion is given on the first day of the cycle).

In combination with irinotecan and bevacizumab: 800 mg / m² 2 times a day for 14 days followed by a 7-day break in combination with irinotecan and bevacizumab. Irynotekan is administered at a dose of 200 mg / m² 1 every 3 weeks, IV infusion for 30 minutes, the first infusion on the first day of the cycle. Bevacizumab is administered at a dose of 7.5 mg / kg every 3 weeks, intravenous infusion for 30-90 minutes, the first infusion begins on the first day of the cycle.

The addition of bevacizumab to combination therapy does not affect the dose of the drug Capecitabine-TL. In adjuvant therapy for colon cancer of Stage III, the recommended duration of therapy with the drug Capecitabine-TL is 6 months, that is, 8 courses.

Antiemetics and premedication to ensure adequate hydration are prescribed before the administration of cisplatin according to the instructions for use of cisplatin and oxaliplatin.

The following tables show examples of calculating the standard and reduced dose of capecitabine-TL for an initial dose of 1250 mg / m² or 1000 mg / m².

Table 1. Standard and reduced doses of capecitabine-TL for the initial dose of 1,250 mg / m², calculated depending on the surface area of the body.

Body surface area (m²)	Dose - at 1250 mg / m² twice a day
	The total dose of 1250 mg / m²	The number of tablets 150 mg and / or 500 mg per reception (for each appointment twice a day - in the morning and in the evening)		Reduced dose (75% of initial dose) 950 mg / m²	Reduced dose (50% of initial dose) 625 mg / m²
	Dose for admission (mg)	150 mg	500 mg	Dose for admission (mg)	Dose for admission (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. Standard and reduced doses of capecitabine-TL for the initial dose of 1000 mg / m², calculated depending on the surface area of the body.

Body surface area (m²)	The dose of 1000 mg / m² twice a day
	The total dose of 1000 mg / m²	The number of tablets 150 mg and / or 500 mg per reception (for each appointment twice a day - in the morning and in the evening)		Reduced dose (75% of initial dose) 750 mg / m²	Reduced dose (50% of initial dose) 500 mg / m²
	Dose for admission (mg)	150 mg	500 mg	Dose for admission (mg)	Dose for admission (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

Correction of dose during treatment

General recommendations

Toxic effects of the drug Capecitabine-TL can be eliminated by symptomatic therapy and / or dose adjustment (interrupting treatment or reducing the dose of the drug). If the dose had to be reduced, you can not increase it later. If the toxic effect of the drug Capecitabine-TL is not a serious or life-threatening patient by the assessment of the attending physician, the treatment can be continued at the initial dose without reducing it or interrupting the therapy. With toxicity of the 1st degree, the dose is not changed. With toxicity of the 2nd or 3rd degree, therapy with capecitabine-TL should be discontinued. With the disappearance of signs of toxicity or a reduction in the latter to grade 1, treatment with the drug Capecitabine-TL can be resumed in a full dose or adjusted according to the recommendations in Table 3.

With the development of signs of toxicity of the 4th degree, treatment should be stopped or temporarily interrupted until the symptoms are reduced or reduced to 1 degree, after which the use of the drug can be resumed at a dose equal to 50% of the initial level. The patient should immediately inform the doctor about the unwanted events that develop in him. It should immediately stop taking the drug Capecitabine-TL in the event of severe or moderate toxicity. If several methods of the drug Capecitabine-TL were missed due to toxic effects, these doses are not replenished.

Hematological toxicity

Therapy with capecitabine-TL should be discontinued if signs of grade 3 or 4 hematologic toxicity are found. The table below shows recommendations for changing the dose of capecitabine-TL in case of development of toxic phenomena associated with its use.

Table 3. Schedule of dose reduction (3-week cycle or prolonged treatment) of the drug Capecitabine-TL.

The degree of toxicity according to the criteria * NCIC*	Dose variation during the course of therapy	Correction of dose during the next cycle of therapy (% of the initial dose)
Degree 1	Continue in the same dose	Continue in the same dose
Degree 2
1st appearance	Interrupt therapy before resolution to grade 0-1	100%
2nd appearance		75%
3rd appearance		50%
4th appearance	Completely stop therapy	Not applicable
Degree 3
1st appearance	Interrupt therapy before resolution to grade 0-1	75%
2nd appearance	Interrupt therapy before resolution to grade 0-1	50%
3rd appearance	Completely stop therapy	Not applicable
Degree 4
1st appearance	Completely discontinue therapy OR, if the doctor believes that it is in the patient's interest to continue treatment, discontinue therapy until resolution to grade 0-1	50%
2nd appearance	Completely stop therapy	Not applicable

* In accordance with the general toxicity criteria of the Clinical Research Unit of the National Cancer Institute of Canada (NCIC CTG, version 1) or the common terminology criteria for adverse events of the Antitumor Evaluation Program of the National Cancer Institute (USACA, version 3).

General recommendations for combination therapy

In case of occurrence of toxicity in combination therapy should follow the recommendations for dose adjustment of the drug Capecitabine-TL, listed above in Table 3,and the corresponding recommendations in the instructions for the use of other drugs.

At the beginning of the therapy cycle, if a delay is expected with the admission of capecitabine-TL or another drug (s), all drugs should be deferred until all the drugs are restored.

If, during the combination therapy cycle, toxic effects are not associated with the use of the drug Capecitabine-TL in the opinion of the doctor, then therapy with capecitabine-TL should be continued, and the dose of the other drug should be adjusted in accordance with the recommendations of the instructions for its use.

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

These recommendations are applicable to all indications and all special patient groups.

Correction of the dose in special cases

Impaired liver function in patients with liver metastases

In patients with impaired liver function caused by metastases to the liver, mild to moderate severity, it is not necessary to change the initial dose.However, such patients should be monitored. Data on the use of capecitabine in individuals with severe hepatic insufficiency do not.

Impaired renal function

Patients with initial moderate renal insufficiency (CK 30-50 ml / min) are recommended to reduce the initial dose to 75% of the standard 1250 mg / m². Patients with mild renal insufficiency (KK 51-80 ml / min) do not need dose adjustment. If there are manifestations of toxicity of the 2nd, 3rd or 4th degree, it is recommended to cancel treatment, change the dose according to Table 3 and carry out detailed monitoring. With a decrease in creatinine <30 ml / min, treatment with capecitabine-TL should be discontinued. Recommendations for correcting the dose for renal insufficiency of moderate severity are the same both with monotherapy with capecitabine, and with combined therapy. Recommendations for calculating the dose are given in Tables 1 and 2.

Children

The safety and effectiveness of capecitabine-TL in children are not established.

Patients of elderly and senile age

Correction of the initial dose with monotherapy drug Capecitabine-TL is not required.However, severe adverse events of 3rd and 4th degree associated with ongoing therapy developed in patients older than 80 years more often than in younger patients.

When using the drug Capecitabine-TL in combination with other antineoplastic agents in elderly patients (aged> 65 years), adverse reactions of the 3rd and 4th degree of severity, as well as undesirable reactions requiring discontinuation of therapy, were noted more often than in younger patients. A thorough monitoring of the condition of elderly patients is recommended.

In the treatment in combination with docetaxel in patients aged 60 years and older there was an increase in the incidence of adverse events 3rd and 4th degree and serious adverse events associated with therapy. For patients aged 60 years and older who will receive a combination of the drug Capecitabine-TL with docetaxel, it is recommended to reduce the initial dose of the drug Capecitabine-TL to 75% (950 mg / m² twice a day). Calculation of the dose is given in Table 1.

In the treatment in combination with irinotecan in patients aged 65 years and older it is recommended to reduce the initial dose of the drug Capecitabine-TL to 800 mg / m² twice a day.

Side effects:

The frequency of development of unwanted reactions is stated in accordance with the following gradation: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1/100). Undesirable reactions with monotherapy with capecitabine.

Disorders from the metabolism and nutrition: very often - anorexia; often - dehydration, decreased appetite, weight loss; infrequently - diabetes, hypokalemia, hypertriglyceridemia, digestive disorders.

Infectious diseases: often - herpesvirus infection, nasopharyngitis, lower respiratory infections; infrequently - sepsis, urinary tract infections, tonsillitis, pharyngitis, candidiasis of the oral mucosa, inflammation of the subcutaneous tissue, gastroenteritis, fungal infections, influenza, tooth abscess.

Benign, malignant and unspecified neoplasms: infrequently - a lipoma. Disturbances from the nervous system: often - headache, dizziness (except vertigo), paresthesia, dysgeusia (perversion of taste), drowsiness; infrequently - aphasia, memory impairment, ataxia, syncope, imbalance and coordination, loss of sensitivity, peripheral neuropathy.

Disorders of the psyche: often - insomnia, depression; infrequently - confused consciousness, panic attacks, depressed mood, decreased libido.

Disturbances on the part of the organ of sight: often - increased tear, conjunctivitis, irritation of the mucous membrane of the eyes; infrequent - reduced visual acuity, diplopia.

Hearing disorders: infrequently - vertigo, pain in the ear.

Disorders from the gastrointestinal tract: very often - diarrhea, vomiting, nausea, stomatitis (including ulcerative), abdominal pain; often - constipation, pain in the upper abdomen, dyspepsia, dry mouth, flatulence, gastrointestinal bleeding; infrequently - dysphagia, pain in the lower abdomen, gastroesophageal reflux, gastritis, enteritis, colitis, ascites, discomfort in the abdominal cavity, bloody stool, esophagitis, intestinal obstruction.

Violations from the heart and blood vessels: often - thrombophlebitis; infrequently, unstable angina, angina pectoris, myocardial ischemia, atrial fibrillation, arrhythmias, tachycardia, including sinus, palpitations, increased blood pressure, lower blood pressure, cold extremities, deep vein thrombosis, petechiae,"hot flashes", cardiomyopathy, myocardial infarction, heart failure, sudden death, ventricular extrasystoles.

Disturbances from the skin and subcutaneous tissues: very often - palmar-plantar syndrome (paresthesia, edema, hyperemia, skin peeling, blistering); often - rash, dermatitis, alopecia, erythema, macular rash, dry skin, pigmentation disorders, nail damage, hyperpigmentation, itching, desquamation of the skin; infrequently - purpura, skin ulceration, urticaria, photosensitivity reactions, palmar erythema, facial edema.

Violations of the blood and lymphatic system: often - anemia, neutropenia; infrequently - pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased international normalized ratio (INR) / prolonged prothrombin time, febrile neutropenia.

Immune system disorders: infrequently, hypersensitivity reactions. Disorders from the liver and biliary tract: often - violations of the liver, hyperbilirubinemia; infrequently, jaundice.

Disturbances from musculoskeletal and connective tissue: often - pain in the limbs, back pain, arthralgia; infrequently - pain in the bones, stiffness of muscles and joints, muscle weakness, swelling of the joints.

Violations of the genitals: infrequently - menorrhagia.

Disturbances from the respiratory system: often - shortness of breath, epistaxis, cough, rhinorrhea; infrequently - pulmonary embolism, pneumothorax, bronchospasm, hemoptysis, shortness of breath with physical exertion, bronchial asthma.

Disorders from the kidneys and urinary tract: infrequently - hydronephrosis, involuntary urination, hematuria, nocturia, increased concentration creatinine in the blood.

General disorders and disorders at the site of administration: very often - asthenia, increased fatigue; often - fever, pain in the chest, peripheral edema, anxiety, drowsiness; rarely - swelling, fever, shaking, chills, flu-like conditions, lethargy, weakness, malaise.

Impact on laboratory and instrumental data: regardless of their causal relationship with the administration of capecitabine: a decrease in the number of neutrophils, a decrease in the number of granulocytes, a decrease in the number of lymphocytes, a decrease in the number of platelets,reduction of hemoglobin, hyperbilirubinemia, increased activity of ALT, ACT, alkaline phosphatase, hypercreatininaemia, hyperglycemia, hypo- / hypercalcemia, hyponatremia, hypokalemia.

The following adverse events were noted with the use of capecitabine in combination therapy and in the postmarketing period:

Disorders from the gastrointestinal tract: dry mouth, flatulence, undesirable reactions associated with inflammation / ulceration of the mucous membranes, such as: esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding;

Violations from the heart and blood vessels: edema of the lower extremities, cardialgia, including angina, cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including atrial fibrillation, ventricular extrasystoles;

Disturbances from the nervous system: a taste disorder, insomnia, confusion, encephalopathy, symptoms of cerebellar disorders (dysarthria);

Disorders of the psyche: depression;

Infectious diseases: infectious complications associated with myelosuppression,weakening the immune system and / or impaired mucosal integrity, such as local and fatal systemic infections (bacterial, viral or fungal etiology), and sepsis;

Violations from the organs of the blood: anemia, myelosuppression / pancytopenia;

Disturbances from the skin and subcutaneous tissues: pruritus, focal skin peeling, skin hyperpigmentation, nail changes, photosensitization reactions, a syndrome resembling radiation dermatitis;

Disturbances on the part of the organ of sight: eye irritation;

Disturbances from the respiratory system: shortness of breath, cough;

Disturbances from musculoskeletal and connective tissue: arthralgia, myalgia, back pain;

General disorders: asthenia, chest pain (non-cardial etiology), pain in the extremities, increased drowsiness.

In the clinical practice of the drug capecitabine, as well as in clinical trials and in the postmarketing period, very rarely individual cases of stenosis of the tear duct, liver failure and cholestatic hepatitis were recorded. The causal relationship with the administration of capecitabine has not been established.

When capecitabine was used in combination with other chemotherapeutic drugs, cases of hypersensitivity reactions (2%) and myocardial ischemia / myocardial infarction (3%) were often reported (but less than 5% of patients).

Overdose:

Symptoms acute overdose - nausea, vomiting, diarrhea, inflammation of the mucous membrane (mucositis), irritation of the gastrointestinal tract and bleeding, as well as suppression of bone marrow function.

Treatment overdose should include a standard set of therapeutic and supportive measures aimed at correcting clinical symptoms and preventing possible complications.

Interaction:

Coumarin anticoagulants

In patients who took capecitabine simultaneously with anticoagulants coumarinic series (warfarin and fenprokumone), reports of coagulation and / or bleeding disorders were reported in a few days or months after initiation of capecitabine therapy, and in several cases within one month after its completion.

In the study of drug interaction after a single administration of warfarin in a dose of 20 mg capecitabine increased the AUC S-warfarin by 57%, and the value of MNO - by 91%. In patients who simultaneously take capecitabine and anticoagulants of the coumarin series, it is necessary to carefully monitor the clotting indices (prothrombin time or INR), the dose of anticoagulant should be selected in accordance with these indices.

Substrates of cytochrome P4502S9

Special studies of the drug interaction between capecitabine and other drugs metabolized by the 2S9 isoenzyme of the cytochrome P450 system were not carried out.

Caution should be used when administering capecitabine-TL together with these drugs.

Phenytoin

With concomitant administration of capecitabine and phenytoin, an increase in plasma concentration in plasma was reported. Special studies of the inter-drug interaction between capecitabine and phenytoin have not been conducted, but it is assumed that the basis of the mechanism of interaction is the suppression of the isoenzyme CYP2C9 under the influence of capecitabine (see "Coumarin anticoagulants" above), in patients receiving concomitantly phenytoin and capecitabine, it is necessary to regularly monitor the concentration of phenytoin in the plasma.

Antacids

When assessing the pharmacokinetic parameters of capecitabine with simultaneous administration of antacids containing aluminum hydroxide and magnesium hydroxide, a slight increase in the concentration of capecitabine and one of the metabolites (5'-DFTST) in blood plasma was noted. The three major metabolites of capecitabine (5'-FUS, FU and FBAL) did not exert any influence on the agents studied.

Calcium folinate

Calcium folinate does not affect the pharmacokinetic properties of capecitabine and its metabolites. However, it is possible to increase the toxic effect of capecitabine due to the influence of calcium folinate on the pharmaco-dynamics of capecitabine.

Sorivudine and its analogs

Clinically significant drug interaction between sorivudine and FU is described, which is based on the inhibitory effect of sorivudine on DPD. This interaction can lead to a fatal increase in the toxicity of fluoropyrimidines. Therefore, do not prescribe the drug Capecitabine-TL simultaneously with sorivudine or its structural analogues such as brivudine. It should be observed at least a four-week interval between the end of therapy with sorivudine or its structural analogues (including brivudine) and the beginning of treatment with the drugCapecitabine-TL.

Allopurinol

There was observed an interaction between allopurinol and 5-FU with a possible decrease in the efficacy of 5-FU. In this regard, the simultaneous use of capecitabine and allopurinol should be avoided.

Oxaliplatin

There was no clinically significant difference in the exposure of capecitabine or metabolites of oxaliplatin (free platinum or total platinum) with the combined use of capecitabine and oxaliplatin, regardless of the presence of bevacizumab.

Bevacizumab

Clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites was not observed.

Interferon alfa

The maximum tolerated dose (MTD) of capecitabine when taken concomitantly with interferon alfa-2a (at a dose of 3 million IU / m² per day) decreased from 3000 mg / m²per day up to 2000 mg / m²per day compared with monotherapy with capecitabine.

Radiation therapy

When monotherapy with capecitabine using the standard dosing regimen, MTD was 3000 mg / m² per day. When combined with radiotherapy in the treatment of colorectal cancer (from Monday to Friday for 6 weeks) led to a decrease in the MTD to 2000 mg / m².

Special instructions:

It is necessary to carry out thorough medical control over the manifestations of toxicity in patients receiving therapy with capecitabine-TL.

Most of the undesirable phenomena are reversible and do not require complete discontinuation of the drug, although there may be a need for dose adjustment or temporary withdrawal of the drug. Diarrhea: treatment with capecitabine-TL can cause diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored, and with the development of dehydration it is necessary to rehydrate and compensate for the loss of electrolytes. Standard antidiarrheal drugs (for example, loperamide) should be prescribed as soon as possible on medical grounds. If necessary, reduce the dose of the drug Capecitabine-TL.

Dehydration: dehydration should be prevented or eliminated at the outset of the occurrence. Dehydration can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea. With the development of dehydration of 2 degrees or higher, treatment with capecitabine-TL should be immediately interrupted and rehydrated. Treatment can not be resumed until the completion of rehydration and elimination or correction of the factors that caused it.The dose of the drug should be modified in accordance with the recommendations for adverse events leading to dehydration.

Dehydration can lead to the development of acute renal failure, in some cases with a fatal outcome: especially in patients with impaired renal function at the time of initiation of therapy or in the case of a patient taking capecitabine simultaneously with drugs that have a nephrotoxic effect.

Range cardiotoxicity when treated with capecitabine is similar to that with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, heart failure and changes in the electrocardiogram (ECG). These undesirable phenomena are more typical for patients with coronary heart disease (CHD) in history.

In rare cases, unexpected severe toxic effects (for example, stomatitis, diarrhea, neutropenia and neurotoxicity), in the treatment of fluoropyrimidines, are due to insufficient activity of DPD. Thus, the relationship between reduced activity of DPD and a more pronounced, potentially lethal toxicity of fluoropyrimidines can not be ruled out.

Manifestation skin toxicity drug Kapecitabine-TL is the development of the palmar dyspnea syndrome (synonyms - palmar-plantar erythrodysesthesia or erythema acryl erythema caused by chemotherapy). The median time to development of manifestations of toxicity in patients receiving capecitabine monotherapy was 11 to 360 days, and the degree of severity ranged from grade 1 to grade 3. Palmar-plantar syndrome of the 1st degree does not disturb the daily activity of the patient and is manifested by numbness, dysesthesia / paresthesia, pricking or redness of the palms and / or soles, discomfort. Palmar-plantar syndrome of the 2nd degree is characterized by painful reddening and swelling of the hands and / or feet, and the discomfort caused by these symptoms disrupts the daily activity of the patient. Paladno-plantar syndrome of the third degree is defined as wet desquamation, ulceration, blistering and sharp pains in hands and / or feet, and also severe discomfort, making it impossible for the patient to any kinds of daily activities. If palmar-plantar syndrome occurs 2nd or 3rd degree, therapy with capecitabine-TL should be discontinued until symptoms disappear or decrease to 1 degree.If there is a syndrome of 3rd degree, subsequent doses of capecitabine-TL should be reduced.

Vitamin B₆ (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of the palmar-plantar syndrome in the appointment of the drug Capecitabine-TL in combination with cisplatin, as it can reduce the effectiveness of cisplatin.

The drug Capecitabine-TL can cause hyperbilirubinemia. If in connection with treatment with the drug Capecitabine-TL hyperbilirubinemia> 3.0 x VGN (upper limit of the norm) or an increase in the activity of "hepatic" aminotransferases (ALT, ACT)> 2.5 x VGN, treatment should be interrupted.

The therapy can be resumed with a decrease in the concentration of bilirubin and the activity of "hepatic" aminotransferases below these limits.

In patients concurrently taking capecitabine-TL and oral anticoagulants-coumarin derivatives, coagulation factors (prothrombin time or INR) should be monitored and, accordingly, a dose of anticoagulant should be selected.

The use of the drug in elderly and senile patients

The incidence of toxic effects from the gastrointestinal tract in patients with colorectal cancer aged 60-79 years who received monotherapy with capecitabine-TL did not differ from that in the general population of patients. In patients 80 years and older reversible adverse events from the gastrointestinal tract of the 3rd and 4th degree, such as diarrhea, nausea and vomiting, developed more often. In patients older than 65 years who received combined therapy with capecitabine and other antitumor drugs, there was an increase in the incidence of adverse reactions of 3rd and 4th severity and adverse events that led to discontinuation of therapy compared with patients younger than 65 years of age. In the analysis of safety data in patients over 60 years of age who received combination therapy with capecitabine and docetaxel, there was an increase in the incidence of third- and fourth-degree adverse events associated with therapy, serious adverse events and early discontinuation of therapy due to adverse events compared to with those in patients younger than 60 years.

Renal insufficiency

Caution should be exercised when administering capecitabine-TL to patients with moderate renal insufficiency.As with the treatment of FU, the frequency of development of adverse events of the 3rd and 4th degree of severity associated with the therapy was higher in patients with moderate renal insufficiency (CK 30-50 ml / min).

Liver failure

Patients with hepatic insufficiency during therapy with the drug Capecitabine-TL should be under close medical supervision. Impact of violation function of the liver, not due to metastatic liver damage or severe hepatic insufficiency, is not known for the distribution of the drug Capecitabine-TL.

According to the clinical application of capecitabine, the development of severe skin reactions such as Stephen-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), in some cases with a fatal outcome, has been revealed. When developing severe skin reactions with capecitabine, taking the drug should be stopped and not restarted.

When capecitabine was used, cases of hypo- and hypercalcemia were reported. Caution should be exercised in patients with hypo- and hypercalcemia.

Diseases of the central or peripheral nervous system

Caution should be exercised when using capecitabine in patients with diseases of the central or peripheral nor- mal system, for example, metastases in the brain or neuropathy.

Diabetes mellitus or violation of water-electrolyte balance

When capecitabine is used in patients with diabetes mellitus or a disturbance of the electrolyte balance, caution should be exercised, since capecitabine can lead to a worsening of their course.

Ophthalmologic complications

Careful observation of patients with eye diseases in history should be ensured in order to monitor ophthalmologic complications (corneal lesions, including keratitis, spot keratitis).

Handling of an unused product and an expired product

The ingestion of the medicinal product together with the waste in the environment must be minimized. Do not dispose of the product with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

Effect on the ability to drive transp. cf. and fur:The drug Capecitabine-TL can have an undesirable effect on the ability to drive a car and work with mechanisms, as this drug can cause confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, imbalance and coordination), increased drowsiness. If the above symptoms occur, you should refrain from driving and practicing potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets, 150 mg and 500 mg.

Packaging:

For 60 tablets (for a dosage of 150 mg) or 120 tablets (for a dosage of 500 mg) in a polymer canister for medicines or a bottle for medicines made of plastic.

Free space in the jar, bottle is filled with cotton wool hygroscopic. Each can, a bottle together with the instruction for use is placed in a pack of cardboard.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002628

Date of registration:22.09.2014

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp22.09.2014

Illustrated instructions

Instructions

Capecitabine-TL (Capecitabine-TL)