Cabecin - instructions for use, dose, side effects, contraindications

Composition of the film shell: Opaprai II light blue - polyvinyl alcohol, partially hydrolyzed, - 40%, titanium dioxide - 22.41%, macrogol-3350 - 20.2%, talcum - 14.8%, aluminum varnish based on indigo carmine (3-5% p-p) - 2.19%, aluminum lacquer based on indigo carmine (30-36% rr) - 0.4%.

500 mg:

active substance: Capecitabine 500.00 mg;

Excipients: microcrystalline cellulose 95.00 mg, starch 37.0 mg, crospovidone 16.0 mg, magnesium stearate 5.0 mg.

The tablet core weight is 653.0 mg.

Film shell: to obtain a tablet coated with a film coating, 680 mg.

Composition of the film shell: Opaprai II blue - polyvinyl alcohol, partially hydrolyzed, - 40%, titanium dioxide - 20%, macrogol-3350 - 20.2%, talc - 14.8%, aluminum varnish based on indigo carmine (11-14% rr) - 5%.

Description:

Dosage of 150 mg: Oblong biconvex tablets covered with a film shell of light blue color with an engraving "150" on one side and a stylized company logo on the other side.

Dosage 500 mg: Oblong biconvex tablets covered with a film shell of blue color with engraving "500" on one side and a stylized company logo on the other side.

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 has no cytotoxic effect, in vivo it is converted into fluorouracil (FU), which undergoes further metabolism.

The formation of FU occurs predominantly in the tumor tissue under the action of a tumor angiogenic factor - thymidine phosphorylase, which minimizes the systemic effect of FU on healthy body tissues.

Sequential enzymatic biotransformation of capecitabine in FU creates higher drug concentrations in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine to patients with colorectal cancer (N = 8), the concentration of FU in the tumor tissue is 3.2 times greater than its concentration in the adjacent healthy tissues (range from 0.9 to 8.0).

The ratio of FU concentrations in the tumor and plasma tissues is -21.4 (range from 3.9 to 59.9), the ratio of its concentration in healthy tissues and in plasma is 8.9 (range from 3.0 to 25.8). 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, colorectal cancer, cervical and ovarian cancer, there is a higher level of thymidine phosphorylase, capable of converting 5'-DFUR (5'-deoxy-5-fluorouridine) to FU than in the corresponding healthy tissues.

Both healthy and tumor cells metabolize FU to 5-fluoro-2-deoxyuridine monophosphate (FUDF) and 5-fluorouridine triphosphate (FUTF). These metabolites damage the cells through 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 absorbed rapidly and completely, after which it is transformed into the metabolites of 5'-deoxy-5-fluorocytidine (5-DFTST) and 5'-DFUR. Food decreases the rate of absorption of capecitabine, however, the magnitude of the area under the concentration-time curve (AUC) of the 5'-DFUR and the next metabolite of FU does not significantly influence. With the appointment of capecitabine after taking a dose of 1250 mg / m² on the 14th day the maximum concentrations in plasma (C_max) capecitabine, 5'-DFTST, 5'-DFUR, FU, and FBAL were 4.47, 3.05, 12.1, 0.95, and 5.46 μg / ml, respectively. The time to reach the maximum concentration (T_max) were 1.50, 2.00, 2.00, 2.00 and 3.34 hours, AUC_0-∞ was 7.75, 7.24, 24.6, 2.03 and 36.3 μg h / h, respectively.

Distribution (binding with proteins)

An in vitro study of human plasma showed that for capecitabine, 5'-DFTST, 5'-DFUR and FU, the association with proteins (mainly with albumin) is 54%, 10%, 62% and 10%, respectively.

Metabolism

Primarily metabolized in the liver under the influence of carboxyl esterase to the metabolite 5'-DFTST, which is then transformed into 5'-DFUR under the action of cytidine deaminase, located mainly in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite FU occurs predominantly in the tumor tissue under the action of tumor angiogenic factor - thymidine phosphorylase.

AUC for FU in plasma is 6-22 times less than after intravenous bolus administration of FU at a dose of 600 mg / m². Metabolites of capecitabine become cytotoxic only after conversion to FU and metabolites of FU.

Further FU is catabolized with the formation of inactive metabolites: dihydro-5-fluorouracil (FUN₂), 5-fluoroureidopropionic acid (FCCC) and α-fluoro-β-alanine (FAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.

Excretion

Half-life from the body (t_1/2) capecitabine, 5'-DFCR, 5'-DFCR, FU and FBAL are 0.85, 1.11, 0.66, 0.76 and 3.23 hours, respectively. The pharmacokinetics of capecitabine were studied in doses ranging from 502 to 3514 mg / m² per day. The pharmacokinetic parameters of capecitabine, 5'-DFTST and 5'-DFUR were the same at day 1 and day 14. AUC FU increased by day 30 to 30% by the 14th day and did not increase (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of FU, were dose-dependent.

After taking capecitabine, its metabolites are excreted mainly by the kidneys. Most (95%) of the accepted dose of capecitabine is excreted by the kidneys. Excretion with feces is minimal (2.6%). The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose is excreted by the kidneys unchanged.

Combination Therapy

No effect of capecitabine on the pharmacokinetics of docetaxel or paclitaxel (C_max and AUC), as well as the effects of docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the main metabolite of capecitabine) was not detected.

Pharmacokinetics in special patient groups

Sex, the presence or absence of metastases in the liver prior to treatment, the general patient status index, the concentration of total bilirubin, serum albumin, the activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT) did not have a statistically significant effect on the pharmacokinetic properties of 5'-DFUR, FU and FBAL .

Patients with hepatic insufficiency due to metastatic liver damage

In patients with mild to moderate liver function disorders caused by metastases, there is no clinically significant change in bioactivation and pharmacokinetics of capecitabine. Data on pharmacokinetics in patients with severe impairment of liver function are absent.

Patients with impaired renal function

The results of the pharmacokinetic study show that at varying degrees (from mild to severe) of renal failure, the pharmacokinetics of the unchanged drug and FU does not depend on creatinine clearance (CC).QA affects the AUC value of 5'-DFUR, the immediate precursor of FU (35% increase in AUC with 50% decrease in CK) and FBAL (114% increase in AUC with 50% decrease in CK). FBAL metabolite, not having aptyproliferative activity; 5'-DFUR is the immediate precursor of FU.

Elderly patients

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

Race

The pharmacokinetics of capecitabine in patients of the Negroid race does not differ from that of the patients of the Caucasoid race.

Indications:

Mammary cancer

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

- monotherapy of locally advanced or metastatic breast cancer chemically resistant to 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;

- Therapy 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;

- hypersensitivity to fluorouracil or when there are reported cases of unexpected or severe adverse reactions to fluoropyrimidine derivatives in the history;

- established deficiency of DPD (dihydropyrimidine dehydrogenase), as well as for other fluoropyrimidines;

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

severe hepatic impairment;

- severe renal failure (creatinine clearance below 30 ml / min);

- severe leukopenia;

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

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

- pregnancy and the period of breastfeeding;

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

Carefully:With ischemic heart disease, anemia and angina in history, renal failure of moderate severity or liver failure, hypo- or hypercalcemia, diseases of the central and peripheral nervous system,diabetes mellitus and violations of water-electrolyte balance, age over 60 years, simultaneous application with oral anticoagulants coumarinic series, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Pregnancy and lactation:

Contraindicated in the use of capecitabine during pregnancy and during breastfeeding.

Dosing and Administration:

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

Standard dosing regimen

Monotherapy

Colorectal cancer, colon cancer and breast cancer

At 1250 mg / m² 2 times a day - morning and evening (total daily dose of 2500 mg / m²) for 14 days followed by a 7-day break.

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 at a dose of 75 mg / m²once every 21 days as an intravenous infusion for 1 hour.

Premedication is performed before docetaxel is administered in accordance with the instructions for its use.

Colorectal cancer and stomach cancer

In the combination therapy, the dose of Cabecin 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. The addition of bevacizumab to combination therapy does not affect the initial dose of the drug Cabecin.

Antiemetics and premedication to ensure adequate hydration are prescribed before the administration of cisplatin and oxaliplatin in accordance with the instruction for the use of cisplatin and oxaliplatin when used in combination with the Cabecine drug.

In adjuvant therapy for colon cancer, the recommended duration of therapy with the drug Kabetsin is 6 months, i.e. 8 courses.

In combination with cisplatin

By 1000 mg / m² 2 times a day for 14 days followed by a 7-day break in combination with cisplatin (80 mg / m² 1 every 3 weeks, IV infusion for 2 hours, the first infusion is given on the 1st day of the cycle). The first dose of the drug Cabecin is prescribed on the evening of the first day of the therapy cycle, the last one on the morning of the 15th day.

In combination with oxaliplatin or with oxaliplatin and bevacizumab

By 1000 mg / m² 2 times a day for 14 days followed by a 7-day break in combination with oxaliplatin or with oxaliplatin and bevacizumab. The first dose of the drug Cabecin is prescribed in the evening on the 1st day of the therapy cycle, the last one on the morning of the 15th day. 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 1st 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 and a platinum-based drug

At 625 mg / m² 2 times a day in a continuous mode in combination with epirubicin (50 mg / m 1 every 3 weeks, iv bolus, starting from the first day of the cycle) and a preparation based on platinum. The drug is based on platinum (cisplatin in a dose of 60 mg / m² or oxaliplatinum in a dose of 130 mg / m²) should be administered on the 1st day of the cycle as an IV infusion for 2 hours, then 1 every 3 weeks.

In combination with irinotecan or with irinotecan and bevacizumab

The recommended dose of Cabecin is 800 mg / m² 2 times a day for 14 days followed by a 7-day break in combination with irinotecan or with irinotecan and bevacizumab.

Irinotecan is administered at a dose of 200 mg / m² 1 every 3 weeks, IV infusion for 30 minutes, the first infusion on the 1st day of the cycle. Bevacizumab is administered in a dose of 7.5 mg / kg every 3 weeks, intravenous infusion for 30-90 minutes, the first infusion begins on the 1st day of the cycle.

The following tables show examples of calculating the standard and reduced dose of Cabecine for the initial dose1250 mg / m² or 1000 mg / m².

Table 1. Standard and reduced doses of the drug Cabecin for the initial dose of 1250 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 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 the initial dose) 950 mg / m²	Reduced dose (50% of the 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 Cabecine for an 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 the initial dose) 750 mg / m²	Reduced dose (50% of the 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 the dosing regimen

General recommendations

The toxic effects of the drug Cabecin 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 afterwards.

If, according to the attending physician, the toxic effect of Cabecin is not a serious or life-threatening patient, treatment can be continued at the initial dose without reducing it or interrupting therapy.

With toxicity of the 1st degree, the dose is not changed. With toxicity of the 2nd or 3rd degree, therapy with Cabecin should be discontinued.

With the disappearance of signs of toxicity or a reduction in the latter to the 1 st degree, the administration of therapy with Cabecin can be resumed in full dose or adjusted according to the recommendations indicated 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 Cabecin if serious or moderate toxicity occurs. If due to toxic effects several passes of the drug Cabecin have been missed, these doses are not replenished.

Hematological toxicity

Do not administer capecitabine therapy in patients with a baseline neutrophil count of less than 1.5x10⁹/ l and / or baseline platelet count <100x10⁹/ l. The treatment with capecitabine should be discontinued if, in the course of an unscheduled evaluation of laboratory parameters, the number of neutrophils is less than 1.0 × 10⁹/ l, and the number of platelets is less than 75 x 10^9/l (hematological toxicity 3rd or 4th degree).

The table below shows recommendations for a change in the dose of the drug Cabecin in the event of the development of toxic effects associated with its use.

Table 3. Scheme of dose adjustment of the drug

Power toxicity *	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
2-oc 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 before resolution to 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 the undesirable phenomena of the Evaluation Program antitumor therapy of the National Cancer Institute of the USA (STAAE, version 3). The criteria for toxicity of the palmar-plantar syndrome and hyperbilirubinemia are described in detail in the "Special instructions" section.

General recommendations for combination therapy

In the event of occurrence of toxicity in combination therapy, the recommendations for dose adjustment of the Cabecine drug listed above should be followed 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 taking Cabecin or another drug (s), all drugs should be deferred until the conditions for resumption of therapy with all drugs are reached.

If, during a cycle of combination therapy, toxic effects, according to the doctor,are not associated with the use of the drug Kabetsin, then the drug Kabatsin should be continued, and the dose of another drug should be adjusted in accordance with the recommendations of the instructions for its use.

If the other drug (s) have to be canceled, the Cabecin drug treatment can be continued if the requirements for the renewal of the Cabecine drug are met. These recommendations are applicable to all indications and all special patient groups.

Correction of the dose in special cases

Violation of liver function in patients with liver metastases

It is not required to change the initial dose in patients with liver metastases and with mild or moderate degree of impaired hepatic function. However, these patients should be carefully monitored. The use of the drug in patients with severe hepatic insufficiency has not been studied.

Impaired renal function

It is recommended that the initial dose be reduced to 75% from 1250 mg / m² in patients with an initial mean degree of renal insufficiency (CK 30-50 ml / min, according to the formula Cockroft- Gault). In patients with mild renal insufficiency (KK 51-80 ml / min) correction of the initial dose is not required.

In case the patient develops an undesirable phenomenon of the 2nd, 3rd or 4th degree of severity, careful monitoring and immediate interruption of the therapy should be carried out in order to subsequently correct the dose of the drug in accordance with the recommendations indicated in Table 3. If the calculated creatinine clearance decreased during the therapy to less than 30 ml / min, therapy with Cabecin should be discontinued. Recommendations for correcting the dose of the medication with an average degree of renal failure refer both to monotherapy and to combination therapy.

Calculation of the dose is indicated in Tables 1 and 2.

Children

The safety and efficacy of Cabecin in children have not been studied.

Patients of elderly and senile age

Correction of the initial dose with monotherapy with the drug Cabecin 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 Cablezin in combination with other antineoplastic agents the elderly patients (≥65 years of age), unwanted reactions of the 3rd and 4th degree of severity, as well as undesirable reactions that required discontinuation of therapy were noted more often than in younger patients.A careful 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 Cabecine with docetaxel, it is recommended to reduce the initial dose of the drug Cabecin up to 75% (950 mg / m² 2 times a day). Calculation of the dose is given in Table 1. In the absence of manifestations of toxicity, the dose may be increased to 1,250 mg / m² 2 times a day.

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 Cabecin up to 800 mg / m² twice a day.

Side effects:

The following categories are used to describe the frequency of unwanted reactions: very often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and <1/1000), very rarely (<1/10000, including individual cases). The undesirable reactions listed below are listed in order of clinical significance.

The most common and / or clinically relevant adverse reactions during the treatment with the drug Cabecin were disorders bygastrointestinal (diarrhea, nausea, vomiting, abdominal pain, stomatitis), ladonnopodoshvenny syndrome, fatigue, somnolence, asthenia, anorexia, cardiotoxicity, renal failure, thrombosis / embolism.

Monotherapy with capsicine

Infectious and parasitic diseases: often - herpes viral infection, nasopharyngitis, lower respiratory tract infection; infrequently - sepsis, urinary tract infection, cellulitis, tonsillitis, pharyngitis, candidiasis of the oral mucosa, influenza, gastroenteritis, fungal infection, infection, abscess tooth.

Benign, malignant and unspecified neoplasms: infrequently - a lipoma.

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

Immune system disorders: infrequently - increased sensitivity.

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

Disorders of the psyche: infrequently - panic attacks, depressed mood, decreased libido.

Disturbances from the nervous system: often - headache, dizziness (except vertigo), lethargy, paresthesia, dysgeusia (perversion of taste); infrequently - aphasia, memory disorder, ataxia, syncope, imbalance, loss of sensitivity, peripheral neuropathy.

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

Hearing disorders and labyrinthine disorders: infrequently - vertigo, pain in the ears.

Heart Disease: infrequently - angina, including unstable, arrhythmia, sinus tachycardia, palpitation.

Violations from the side of the vesselat: often - thrombophlebitis; infrequently - deep vein thrombosis, increased blood pressure (BP), petechiae, lowering of blood pressure, "hot flashes", cooling of the distal limbs.

Disturbance of the respiratory system, chest and mediastinum: often - epistaxis, rhinorrhea; infrequently - pneumothorax, hemoptysis, bronchial asthma, dyspnoea with physical exertion.

Disorders from the gastrointestinal tract: very often - diarrhea, vomiting, nausea, stomatitis (including ulcer), abdominal pain; often - constipation, epigastric pain, dyspepsia; infrequent - intestinal obstruction, ascites, enteritis, gastritis, dysphagia, abdominal pain, abdominal discomfort, gastroesophageal reflux disease, colitis, blood in the stool.

Disturbances from the liver and bile ducts: often - Hyperbilirubinemia, changes in functional liver tests; infrequently, jaundice.

Disturbances from the skin and subcutaneous tissues: very often - palmar dyspnea syndrome (paresthesia, edema, flushing, skin peeling, blistering), dermatitis; often - hyperpigmentation of the skin, macular rash, skin pigmentation disorder, rash, alopecia, erythema, dry skin; infrequently - blisters, skin ulcers, urticaria, palmar erythema, swelling of the face, purpura; rarely - cracked skin.

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

Disorders from the kidneys and urinary tract: infrequently - hydronephrosis, urinary incontinence, hematuria, nocturia, an increase in creatinine in the blood plasma.

Violations of the genitals and mammary gland: infrequently - vaginal bleeding.

General disorders and disorders at the site of administration: very often fatigue, drowsiness; often - peripheral edema, malaise, chest pain, fever, weakness, asthenia; infrequently - edema, chills, flu-like syndrome, trembling, fever.

Impact on the results of laboratory and instrumental studies: often - hyperbilirubinemia.

The following undesirable reactions are manifestations of toxicity known for the treatment of fluoropyrimidines; reported at least an indirect link between the development of such reactions and the use of capecitabine in less than 5% of patients participating in 7 completed clinical trials (N=949):

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

disorders of the cardiovascular system: Lower extremity edema, cardialgia including angina pectoris, cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including atrial fibrillation, ventricular extrasystoles;

disorders of the nervous system: impaired taste, insomnia, confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, imbalance and coordination); disorders of the psyche: depression;

infectious and parasitic diseases: infectious complications associated with myelosuppression, immunosuppression and / or mucositis, such as local and fatal systemic infections (bacterial, viral or fungal etiology) and sepsis;

disorders of the blood and lymphatic system: anemia, myelosuppression / pancytopenia;

disorders of the skin and subcutaneous tissue: itching, focal skin peeling, skin hyperpigmentation, nail changes, photosensitization reaction, radiation dermatitis;

impairment of sight: eye irritation;

disorders of the respiratory system, chest and mediastinum: shortness of breath, cough;

disorders of musculoskeletal and connective tissue: myalgia, arthralgia, back pain;

General disorders and disorders at the site of administration: pain in the chest (non-cardial etiology), pain in the limbs.

Use of the drug Cabecin in combination therapy

The safety profile did not differ with the appointment for different indications and with different combinations, however, undesirable reactions listed with monotherapy can be observed with a greater frequency with the use of the drug Cabecin in combination therapy.

Below are the undesirable reactions that were observed in addition to those with monotherapy:

infectious and parasitic diseases: often - candidiasis of the oral mucosa, herpes zoster, urinary tract infections, upper respiratory tract infections, rhinitis, influenza, infection, herpes of the oral cavity;

disorders of the blood and lymphatic system: very often - neutropenia, anemia, thrombocytopenia, leukopenia, neutropenia (including neutropenia of 3-4 degrees,associated with an increase in body temperature above 38 ° C); often - myelosuppression, febrile neutropenia;

disorders of the immune system: often - hypersensitivity; disorders of metabolism and nutrition: very often - weight loss, decreased appetite; often - hypokalemia, hyponatremia, hypomagnesemia, hypo / hypercalcemia, hyperglycemia;

mental disorders: often - sleep disorder, anxiety; disorders of the nervous system: very often - paresthesia, dysesthesia, dysgeusia, headache, peripheral neuropathy, peripheral sensory neuropathy; often - neurotoxicity, tremor, neuralgia, hypoesthesia;

impairment of the organ of vision: very often - increased tear; often - visual impairment, dry eyes, pain in the eyes, blurred vision; disorders of the hearing organ and labyrinthine disorders: often - ringing in the ears, hearing loss;

cardiac disorders: often - atrial fibrillation, ischemia / myocardial infarction;

vascular disorders: very often - thrombosis / embolism, increased blood pressure, swelling of the lower extremities; often - hyperemia, decreased blood pressure, hypertensive crisis, "hot flashes", phlebitis;

disorders of the respiratory system, chest and mediastinal organs: very often - dysesthesia of the pharynx, sore throat; often - nosebleeds, dysphonia, rhinorrhea, pain in the pharynx and larynx;

disorders of the gastrointestinal tract: very often - constipation, indigestion; often - hiccups, bleeding from the upper gastrointestinal tract, mouth ulcers, gastritis, bloating, gastroesophageal reflux disease, oral pain, dysphagia, rectal bleeding, abdominal pain, dysesthesia, paresthesia and hypoesthesia in the mouth , discomfort in the abdomen;

disorders of the liver and bile ducts: often - a violation of liver function;

abnormality of the skin and subcutaneous tissues: very often - alopecia, nail change; often - hyperhidrosis, erythematous rash, hives, night sweats; violation of musculoskeletal and connective tissue: very often - myalgia, arthralgia, pain in the limbs; often - pain in the jaw, muscle spasms, trismus, muscle weakness;

disorders of the kidneys and urinary tract: often - hematuria, proteinuria, decreased creatinine clearance, dysuria;

General disorders and disorders at the site of administration: very often - temperature intolerance, fever, weakness, lethargy; often - pain, inflammation of the mucous membrane, chills, chest pain, flu-like syndrome, bruising.

In clinical practice, cases of hepatic insufficiency 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).

Below you will find information on individual adverse reactions.

Diarrhea

Diarrhea was observed in 50% of patients during therapy with capecitabine. A meta-analysis of 14 clinical trials involving more than 4,700 patients receiving capecitabine therapy revealed covariates that were statistically associated with an increased risk of diarrhea: an increase in the initial dose of capecitabine (in grams), an elongation of the study period of therapy (in weeks), an increase age (for every 10 years) and female sex.Covariates statistically associated with a reduced risk of diarrhea: an increase in the cumulative dose of capecitabine (0.1 * kg), an increase in the relative intensity of the dose in the first 6 weeks of therapy (see section "Special instructions").

Cardiotoxicity

As a result of the analysis of the safety profile of seven clinical trials with the participation of 949 patients who received capecitabine as a monotherapy, the following undesirable reactions (frequency less than 0.1%) were detected: cardiomyopathy, heart failure, sudden cardiac arrest and ventricular extrasystole (see section "Special instructions").

Encephalopathy

Encephalopathy was also associated with the administration of capecitabine as monotherapy (frequency less than 0.1%).

Undesirable reactions in specific clinical groups

Elderly patients

In the analysis of the safety profile in patients aged> 60 years who received capecitabine in combination with docetaxel, as well as as monotherapy, an increase in the number of serious adverse reactions and undesired reactions of grade 3 and 4 toxicity associated with treatment was found compared with patients <60 years of age.Patients aged ≥60 years who received capecitabine in combination with docetaxel, were also previously withdrawn from the study due to the development of unwanted reactions, compared with patients <60 years of age. As a result of meta-analysis, 14 clinical trials involving more than 4,700 patients who received capecitabine, it was found that with increasing patient's age (for every 10 years), the risk of palmar-plantar syndrome and diarrhea increased, while the risk of developing neutropenia, on the contrary, declined (see section "Methods of administration and dose").

Floor

As a result of meta-analysis, 14 clinical trials involving more than 4,700 patients who received capecitabine, it was found that in female patients the risk of developing the palmar-plantar syndrome and diarrhea was higher, while the risk of developing neutropenia, on the contrary, decreased.

Patients with renal insufficiency (see sections "Method of administration and dose", "Special instructions")

In the analysis of the safety profile in patients with renal insufficiency who received capecitabine as monotherapy (colorectal cancer), an increase in the frequency of development(36% (n = 268) of patients with normal renal function, compared with 41% (n = 257) of patients with mild renal insufficiency and 54% (n = 59) patients with moderate renal insufficiency) (see section "Pharmacological properties"). Among patients with moderate renal insufficiency, the most frequent occurrence was a reduction in the dose of capecitabine (44%) compared with patients with normal renal function (33%) and patients with mild renal insufficiency (32%). There was also an increase in the number of patients who left the study at an early stage (21% of patients who left the study during the first two cycles) compared with patients with normal renal function (5%) and patients with mild renal insufficiency (8%).

Laboratory and instrumental data

Decreased number of neutrophils, decreased number of granulocytes, decreased number of lymphocytes, decreased platelet count, decreased hemoglobin, hyperbilirubinemia, increased activity of alanine aminotransferase (ATL), aspartate aminotransferase (ACT), alkaline phosphatase, hypercreatininaemia, hyperglycemia, hypo- / hypercalcemia, hyponatremia, hypokalemia.

Post-Business Monitoring

During the post-marketing application of capecitabine, the following undesirable reactions were detected:

rarely - acute renal failure as a consequence of dehydration, including fatal, corneal damage, including keratitis, ventricular fibrillation, lengthening of the interval QT, arrhythmia ventricular tachysystolic type "pirouette", bradycardia, vasospasm;

very rarely - dermal form of lupus erythematosus, such severe skin reactions as Stevens-Johnson syndrome and toxic epidermal necrolysis, stenosis of the tear duct, unspecified, corneal involvement, including keratitis;

very rarely - cases of hepatic insufficiency and cholestatic hepatitis were recorded in clinical trials and post-marketing period.

Overdose:

Symptoms Acute overdoses include nausea, vomiting, diarrhea, 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:

Anticoagulants of the coumarin series. In patients taking 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 the international normalized ratio (INR) - 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 the isoenzyme CYP2C9. Special studies of the drug interaction of capecitabine with other drugs metabolized by isoenzyme CYP2C9 system of cytochrome P450, was not performed.Caution should be exercised when administering capecitabine 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 main metabolites of capecitabine (5'-DFUR, FU and FBAL) did not exert any influence on the agents studied.

Allopurinol. It should avoid simultaneous reception of allopurinol and capecitabine, since it is possible to reduce the effectiveness of fluorouracil due to the interaction of fluorouracil with allopurinol.

Interferon alfa. The maximum tolerated dose of capecitabine in combination with interferon 2-alpha (3 international million units / m per day) was 2000 mg / m² per day, while the maximum tolerated dose of capecitabine as a monotherapy was 3000 mg / m² per day.

Radiation therapy. The maximum tolerated dose of capecitabine in combination with radiotherapy in the treatment of patients with rectal cancer was 2000 mg / m² per day (with a continuous regimen of therapy or in the regime of therapy from Monday to Friday and a 6-day course of radiotherapy), while the maximum tolerated dose of capecitabine as monotherapy was 3000 mg / m² per day (intermittent mode).

Calcium folinate (Leucovorin). 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 pharmacodynamics of capecitabine.

Sorivudine and its analogs. The literature sources describe the clinically significant drug interaction between sorivudine and FU, 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, one should not appoint capecitabine 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 capecitabine.

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.

Special instructions:

Adverse reactions that limit the dose of the drug are diarrhea, abdominal pain, nausea, stomatitis and palmar-plantar syndrome.

It is necessary to carefully monitor the manifestations of toxicity in patients receiving capecitabine therapy.

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 Cabecin 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. According to the criteria of the National Cancer Institute of Canada (NCIC, STS, version 2), grade 2 diarrhea is defined as the increase in stool to 4-6 times a day or stool at night; diarrhea 3 degrees - as a stool up to 7-9 times a day or incontinence and malabsorption syndrome; diarrhea 4 degrees - as the increase in stool to 10 times or more per day, the appearance of visible blood in the stool or the need for parenteral maintenance therapy. If necessary, reduce the dose of capecitabine.

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.

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

With the development of dehydration of 2 nd degree or higher, treatment with capecitabine 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.

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 ECG changes. These undesirable phenomena are more typical for patients suffering from coronary artery disease in the anamnesis. Care must be taken in patients with arrhythmia and angina in history.

During the therapy with capecitabine, development of hypo- or hypercalcemia was noted. Caution should be exercised in patients with previously diagnosed hypo- or hypercalcemia.

Care must be taken in patients with diseases of the central and peripheral nervous system (for example,in the presence of metastases in the brain and neuropathy), as well as in patients with diabetes mellitus and violations of water-electrolyte balance, as during the treatment with capecitabine, possible aggravation of these diseases.

In rare cases, unexpected severe toxicity events (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with FU are due to inadequate dihydropyrimidine dehydrogenase (DPD) activity. Thus, it is impossible to exclude the connection between the decreased activity of DPD and the more pronounced, potentially lethal toxicity of FU.

Patients should be observed for ocular complications, such as keratitis or corneal pathology, especially if there is a history of visual impairment. In case of development of complications from the side of the eye, appropriate treatment should be prescribed.

The drug Cabetin can cause the development of such serious skin reactions as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). When developing severe skin reactions with capecitabine, taking the drug should be stopped and not restarted.

Manifestation skin toxicity capecitabine is the development of the palmar-plantar syndrome (synonyms - palmar-plantar erythrodysesthesia or erythema acroma caused by chemotherapy). The median time to development of toxicity in patients receiving capecitabine monotherapy is 79 days (range 11 to 360 days), and the severity varies 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, tingling 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, capecitabine therapy should be discontinued until symptoms disappear or decrease to 1 degree.If there is a syndrome of 3rd degree, subsequent doses of capecitabine should be reduced.

Vitamin AT₆ (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of the palmar-plantar syndrome with the administration of the drug Cabecin in combination with cisplatin, as it can reduce the effectiveness of cisplatin. There are data on the effectiveness of dexpanthenol in the prevention of the development of the palmar-plantar syndrome in the treatment with the drug Cabecin.

Capecitabine can cause hyperbilirubinemia. If in connection with the treatment with Cabecin, 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 the "hepatic" aminotransferases of the following limits.

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

Application of the drug the patients of elderly and senile age

The incidence of toxic effects from the gastrointestinal tract in patients with colorectal cancer aged 60-79 years who received capecitabine monotherapy 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 ≥65 years of age who received combination 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.

When analyzing safety data in patients ≥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 with with those in patients younger than 60 years.

Renal insufficiency

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

Liver failure

Patients with hepatic insufficiency during therapy with Cabecin should be under close medical supervision. The effect of a violation of liver function, not due to metastatic liver damage or severe hepatic insufficiency, on the distribution of the drug Cabecin is unknown.

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.

Handling of unused and expired drugs

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 Cabetin has a slight or moderate influence on the ability to drive vehicles, mechanisms. Patients who have experienced such undesirable effects as dizziness, weakness, or nausea should refrain from managing vehicles, mechanisms.

Form release / dosage:Pills, film-coated, 150 mg and 500 mg.

Packaging:

60 tablets (150 mg) or 120 tablets (500 mg) are placed in vials of polymeric materials for medicines sealed with a plastic lid, with or without a first opening. 1 bottle is placed together with instructions for medical use in a cardboard box.

10 tablets are placed in a contour mesh box made of a polyvinylchloride film and foil printed lacquered. For 6 (150 mg dosage) or 12 (500 mg dosage) of contiguous cell packs are placed along with the instruction for medical use in a cardboard pack.

Storage conditions:

The drug should be stored in a dry, protected from light at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

The drug should not be used after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002755

Date of registration:11.12.2014 / 28.11.2016

Expiration Date:11.12.2019

The owner of the registration certificate:FARM-SYNTHESIS, CJSC FARM-SYNTHESIS, CJSC Russia

Manufacturer: & nbsp

RAFARMA, JSC Russia

Representation: & nbspFARMSINTEZ, PAO FARMSINTEZ, PAO Russia

Information update date: & nbsp29.11.2017

Illustrated instructions

Instructions

Cablezin (Cabecibine)