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

Excipients: lactose 27.33 mg, microcrystalline cellulose 27.33 mg, croscarmellose sodium 9.84 mg, hypromellose 0.87 mg, magnesium stearate 3.28 mg; Sheath - film coating 6.56 mg (hypromellose (38.46%), talc (30.77%), titanium dioxide (E 171) (29.41%), ferric oxide red oxide (E 172) (0.68%) , the iron dye oxide is yellow (E 172) (0.68%).

500 mg:

active substance: capecitabine 500.00 mg;

Excipients: lactose 91.11 mg, cellulose microcrystalline 91.11 mg, croscarmellose sodium 32.80 mg, hypromellose 2.92 mg,magnesium stearate 10.93 mg; Sheath - film coating 6.56 mg (hypromellose (38.46%), talc (30.77%), titanium dioxide (E 171) (29.41%), iron dye red oxide (E 172) (0.68 %), the iron dye oxide is yellow (E 172) (0.68%).

Description:

150 mg: oval, biconvex tablets, covered with a film coating of light-peach color, with engraving "150" on one side. On the transverse section, the tablets are white.

500 mg: oval, biconvex tablets, covered with a film shell of light peach color, with engraving "500" on one side. On the transverse section, the tablets are 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 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 tumor tissue and plasma 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 / hr, respectively.

Distribution (binding with proteins)

Study in vitro to human blood 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 action cytidine deaminase, found 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 on the 1 st and 14 th day were the same. AUC FU increased by the 14th day by 30-35% and did not increase (22nd day). 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) And docetaxel or paclitaxel impact on the pharmacokinetics of 5'-DFUR (a metabolite of capecitabine ground) is detected.

Pharmacokinetics in special patient 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, 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). QC affects the magnitude AUC 5'-DFUR is the immediate precursor of FU (increase AUC by 35% with a decrease in CK by 50%) and FBAL (increase AUC by 114% with a decrease in QC by 50%). 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 patient's age by 20% was accompanied by an increase AUC FBAL by 15%), which is probably due to changes in kidney 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;

- mitotherapy 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;

- 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;

- gand hypersensitivity to fluorouracil or with reported cases of developmentunexpected or severe adverse reactions to treatment with fluoropyrimidine derivatives in the anamnesis;

- theBecoming deficit DPD (dihydropyrimidine dehydrogenase), as well as for other fluoropyrimidine;

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

- tsevere hepatic impairment;

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

- tsevere leukopenia;

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

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

- bPregnancy and period of breastfeeding;

- d(effectiveness and safety of use are not established).

Carefully:

In ischemic heart disease, anemia and a history of angina, renal insufficiency of moderate severity or liver failure, hypo- or hypercalcemia, diseases of the central and peripheral nervous system, diabetes and disorders of water and electrolyte balance, the age of 60, simultaneous use of oral coumarin anticoagulants, hereditary deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

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.

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 / m² once 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 capecitabine 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 capecitabine.

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 xaliplatin when applied in combination with capecitabine.

In adjuvant therapy for colon cancer, the recommended duration of therapy with capecitabine 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 capecitabine is prescribed in the evening on the first day of the therapy cycle, the latter 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 capecitabine is prescribed in the evening on the first day of the therapy cycle, the latter 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

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. Irynotekan 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 capecitabine for an initial dose of 1250 mg / m² or 1000 mg / m².

Table 1.Standard and reduced doses of capecitabine for an 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
	Full 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 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 capecitabine 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 capecitabine 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, according to the attending physician, the toxic effect of capecitabine is not of a serious or life threatening character, 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 capecitabine should be discontinued.

With the disappearance of signs of toxicity or a decrease in the last to 1 degree, the administration of capecitabine therapy 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 capecitabine when severe or moderate toxicity occurs. If several methods of capecitabine were missed due to toxic effects, these doses are not replenished.

Hematological toxicity

Do not use capecitabine in patients with a baseline neutrophil count of less than 1.5x10⁹/ l and / or baseline platelet count <100x10⁹/ l. Capecitabine therapy should be interrupted if, during unscheduled laboratory evaluation indicators neutrophil count less 1,0h10⁹/ l, and the number of platelets is less than 75 x 10⁹/ l (haematological toxicity 3rd or 4th degree).

The following table shows the recommendations but change the dose of capecitabine in the case of toxic effects associated with its use.

Table 3. Correction of dose of capecitabine.

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
1appearance	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 4). 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 capecitabine mentioned 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 with taking capecitabine or another drug (s) is expected, all drugs should be deferred until all the drugs are restored.

If, during a cycle of combination therapy, toxic effects, according to the doctor,are not associated with the use of capecitabine, then therapy with capecitabine 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) has to be canceled, capecitabine treatment can be continued if the requirements for the renewal of capecitabine therapy are met. These recommendations are applicable to all indications and all special patient groups.

Use in special patient groups

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 the event that the patient develops an undesirable phenomenon of the 2nd, 3rd or 4th degree of severity,it requires careful monitoring and immediate interruption of therapy for subsequent correction of the dose according to the recommendations set forth in Table 3. If the calculated creatinine clearance decreased during therapy, to a level less than 30 ml / min, capecitabine therapy should be discontinued. Recommendations for correcting the dose of the drug at an average degree of renal failure apply both to monotherapy and to combination therapy.

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

Children

The safety and efficacy of capecitabine in children has not been studied.

Patients of elderly and senile age

Correction of the initial dose with monotherapy capecitabine 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 capecitabine in combination with other antineoplastic agents the elderly patients (aged> 65 years), adverse reactions of 3rd and 4th degree of severity, as well as undesirable reactions requiring 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 capecitabine and docetaxel, it is recommended that the initial dose of capecitabine be reduced 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 capecitabine to 800 mg / m² twice a day.

Side effects:

The frequency of unwanted reactions is set out in accordance with WHO recommendations: very often (> 10%), often (> 1% and <10%), infrequently (> 0.1% and <1%), rarely (> 0.01% and < 0.1%), very rarely (<0.01%).

The most frequent side effects associated with taking capecitabine were gastrointestinal (GI) disorders (diarrhea, nausea, vomiting, abdominal pain, stomatitis), palmar-plantar syndrome, increased fatigue, asthenia, anorexia, cardiotoxicity,the increase in renal failure in patients with a history of renal dysfunction, as well as thrombosis / embolism.

Side effects, registered in patients, who took capecitabine as a monotherapy

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 of the blood and lymphatic system: often - neutropenia; infrequently - febrile neutropenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, an increase in the international normalized ratio, prolongation of prothrombin time.

Immune system disorders: infrequently - hypersensitivity. Disorders from the metabolism and nutrition: very often - anorexia; often - dehydration, weight loss; infrequently - diabetes, hypokalemia, indigestion, hypertriglyceridemia.

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

Disturbances from the nervous system: often - headache, dizziness (except vertigo), lethargy, paresthesia, dysgeusia (distortion of taste): infrequently - aphasia, memory disorder, fainting, 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.

Vascular disorders: often - thrombophlebitis; infrequently - thrombosis of deep veins, increase in blood pressure, petechiae, lowering of arterial pressure, "hot flashes", cooling of the distal limbs.

Disturbances from the respiratory system, chest and mediastinal organs: 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, dysphagia, lower abdominal pain, abdominal discomfort, gastroesophageal reflux disease, blood in the stool.

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

Disturbances from the skin and subcutaneous tissues: very often - palmar-plantar syndrome (paresthesia, edema, flushing, skin peeling, blistering), dermatitis; often - hyperpigmentation of the skin, macular rash, rash, alopecia, erythema, dry skin; infrequently - a blister, skin ulcers, hives, palmar erythema, swelling of the face, purpura. In less than 2% of patients, 7 of the completed clinical trials (N = 949) reported skin cracks, at least presumably associated with capecitabine therapy.

Disturbances of 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, increased creatinine in 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 - swelling, chills, flu for a similar syndrome, trembling, fever.

Impact on laboratory and instrumental research results: often - hyperbilirubinemia.

The following undesirable reactions are manifestations of toxicity known for the treatment of fluoropyrimidines; there has been 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: violation of taste, insomnia, confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, imbalance and coordination);

mental disorders: 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, hyperpigmentation of the skin, nail changes, photosensitization reactions, radiation dermatitis;

impairment of the organ of vision: eye irritation;

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

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

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

The use of capecitabine in combination therapy

The safety profile did not differ with the appointment for different indications and with different combinations, however, undesirable reactions listed under monotherapy can be observed with a higher frequency with capecitabine 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;

Violations of the blood and lymphatic system: very often - neutropenia, anemia, thrombocytopenia, leukopenia, febrile neutropenia; often - myelosuppression;

Immune system disorders: often - hypersensitivity;

Disorders from the metabolism and nutrition: very often - weight loss, decreased appetite; often - hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia;

Disorders from the psyche: often - sleep disorders, anxiety;

Disturbances from the nervous system: very often - paresthesia, dysgeusia, headache, peripheral neuropathy, peripheral sensory neuropathy, dysesthesia; often - neurotoxicity, tremor, neuralgia, hypoesthesia;

Disturbances on the part of the organ of sight: very often - lacrimation; often - visual impairment, dry eyes, pain in the eyes, blurred vision;

Hearing disorders and labyrinthine disorders: often - ringing in the ears, hearing loss;

Heart Disease: often - atrial fibrillation;

Vascular disorders: very often - thrombosis / embolism, increased blood pressure (BP), swelling of the lower limbs; often - hyperemia, lowering blood pressure, hypertensive crisis, "hot flashes", phlebitis;

Disturbances from the respiratory system, chest and mediastinum: very often - dysesthesia of the pharynx, sore throat; often - nosebleeds, dysphonia, rhinorrhea, hiccough, pain in the pharynx and larynx;

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

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

Disturbances from the skin and subcutaneous tissues: very often - alopecia, nail change; often - hyperhidrosis, erythematous rash, hives, night sweats;

Disturbances of musculoskeletal and connective tissue: very often - myalgia, arthralgia, pain in the limbs; often - pain in the jaw, muscle spasms, trismus, muscle weakness;

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

General disorders and disorders at the site of administration: very often - weakness, lethargy, hypersensitivity to high and low temperatures; often - fever, pain, inflammation of the mucous membrane, chills, chest pain, flu-like syndrome, contusion.

Both in clinical studies and outside their framework, 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).

Laboratory and instrumental data:

Below are the changes in laboratory indicators observed in clinical trials in patients with adjuvant therapy for colon cancer and the patients with metastatic breast cancer and metastatic colorectal cancer, regardless of their association with capecitabine: neutropenia, granulocytopenia, lymphocytopenia, thrombocytopenia, anemia, hyperbilirubinemia, increased activity of ALT, AST, alkaline phosphatase, hypercreatininemia, hyperglycemia, hypo- / hypercalcemia , hyponatremia, hypokalemia.

Post-registration experience of capecitabine application

rarely - acute renal failure as a consequence of dehydration, including fatal, point keratitis, ventricular fibrillation, lengthening of the interval QT, arrhythmia ventricular tachysystolic type "pirouette", bradycardia, vasospasm; very rarely - cutaneous form of lupus erythematosus, such severe skin reactions as Stevens-Johnson syndrome, toxic epidermal necrolysis, stenosis of the tear duct, unspecified, corneal involvement, including keratitis; very rarely - clinical studies, and outside their framework, cases of hepatic insufficiency and cholestatic hepatitis were recorded.

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 increase in the study period of treatment (in weeks), an increase age of the patient (for every 10 years), female sex. Covariates statistically associated with a reduced risk of diarrhea: an increase in the cumulative dose of capecitabine (0.1 kg) and an increase in the relative intensity of the dose in the first 6 weeks of treatment.

Patients with severe diarrhea should be carefully monitored, by rehydrating them and restoring the water-electrolyte balance during dehydration. According to the indications as soon as possible, it is recommended to take standard antidiarrhoeal preparations (for example, loperamide).

Cardiotoxicity

In addition to side effects, presented1the following adverse events were noted with capecitabine monotherapy with a frequency of less than 0.1%: cardiomyopathy, heart failure, sudden death, and ventricular extrasystoles.

Encephalopathy

With monotherapy with capecitabine, there was a development of encephalopathy with a frequency of less than 0.1%.

Adverse reactions in special groups of patients

Elderly patients

In elderly patients aged> 60 years who received capecitabine in the form of monotherapy or in combination with docetaxel, there was an increase in the incidence of adverse reactions of 3 and 4 severity and serious adverse reactions compared with patients <60 years of age. Most patients aged> 60 years who received combination therapy with docetaxel showed earlier cessation of treatment as a result of adverse reactions compared with patients <60 years of age.A meta-analysis of 14 clinical trials involving more than 4,700 patients receiving 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, decreased.

Floor

In female patients, a statistically significant increase in the risk of developing the palmar-plantar syndrome and diarrhea, a risk of developing neutropenia is reduced.

Patients with impaired renal function

In patients with impaired renal function prior to initiating treatment who received capecitabine monotherapy, an increase in the incidence of grade 3 and 4 adverse reactions was noted compared to patients with normal renal function (36% in patients without renal dysfunction, 41% with mild renal insufficiency and 54% - with renal insufficiency of an average degree). In patients with moderate-to-moderate renal insufficiency, there was a greater need for dose reduction (44%) compared with 33 and 32% of patients without renal failure with mild renal failure, respectively, and premature withdrawal of treatment was more often noted.

Overdose:

Symptoms of acute overdose include nausea, vomiting, diarrhea, mucositis, irritation of the gastrointestinal tract and bleeding, as well as suppression of bone marrow function. Treatment of 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 fenprocumone), violations of coagulation rates and / or bleeding were reported in a few days or months after initiation of capecitabine therapy, and in several cases within one month after 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 coumarinovogo number, you must carefully monitor the coagulation indicators (prothrombintime or INR), the dose of anticoagulant should be selected in accordance with these indicators.

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 using capecitabine 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 above "Anticoagulants coumarin series"). 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'-DFUR) in blood plasma was noted.The three major metabolites of capecitabine (5'-DFUR, FU and FBAL) did not exert any influence.

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 effect 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

The clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine, or its metabolites, has not been observed.

Allopurinol

The interaction between allopurinol and FU with a possible decrease in the efficacy of FU has been noted. In this regard, the simultaneous use of capecitabine and allopurinol should be avoided.

Interferon alfa

The maximum tolerated dose of capecitabine is 2000 mg / m² per day with the simultaneous administration of interferon alpha-2-alpha (3 million IU / m² per day) compared with the dose of capecitabine 3000 mg / m² per day with monotherapy.

Radiation therapy

The maximum tolerated dose of capecitabine in monotherapy with a standard dosage regimen is 3000 mg / m², combined with radiotherapy of colorectal cancer (with continuous treatment or 5-day courses from Monday to Friday for 6 weeks) - 2000 mg / m² per day.

Special instructions:

Adverse reactions that limit the dose of the drug are diarrhea, abdominal pain, nausea, stomatitis, 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 capecitabine can cause diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored, and with the development of dehydration it is necessary to rehydrate or 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, grade 3 diarrhea - like stooling up to 7-9 times a day or stool incontinence and malabsorption syndrome, grade 4 diarrhea - like stool up to 10 or more times a 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 degrees 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.

Cardiotoxicity: The spectrum of cardiotoxicity in the treatment with capecitabine is similar to that of other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, heart failure and changes in the ECG. These adverse events are more common in patients with IHD.

Caution should be exercised when treating capecitabine in patients with a history of an arrhythmia and angina.

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

Diseases of the central and peripheral nervous system: 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).

Diabetes mellitus and violations of water-electrolyte balance: Care must be taken in patients with diabetes mellitus and violations of water-electrolyte balance, as during the treatment with capecitabine, possible aggravation of these diseases.

Insufficient activity of DAP: In rare cases, unexpected severe toxic effects (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.

Ophthalmologic complications: Patients should be observed for ocular complications,such as keratitis or corneal pathology, especially if there is an abnormality on the part of the eye in the history. In case of development of complications from the side of the eye, appropriate treatment should be prescribed.

Stevens-Johnson syndrome and toxic epidermal necrolysis: Capecitabine can cause the development of such serious skin reactions as Stevens-Johnson syndrome and toxic epidermal necrolysis. When developing severe skin reactions with capecitabine, taking the drug should be stopped and not restarted.

Palmar-plantar syndrome: The manifestation of skin toxicity of 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, as well as severe discomfort, making it impossible for the patient to any kinds of daily activities. If palmar-plantar syndrome occurs 2nd or 3rd degree, capecitabine 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 B₆ (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of the palmar-plantar syndrome with capecitabine in combination with cisplatin, as it may reduce the effectiveness of cisplatin. There are data on the effectiveness of dexpanthenol in the prevention of the development of palmar-plantar syndrome in the therapy with capecitabine

Hyperbilirubinemia, increased activity of ALT, ACT: Capecitabine can cause hyperbilirubinemia. If in connection with treatment with capecitabine, 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 discontinued. The therapy can be resumed with a decrease in the concentration of bilirubin and the activity of "hepatic" aminotransferases below these limits.

Joint reception with oral anticoagulants: 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.

Patients of elderly and senile age: The incidence of toxic effects from the gastrointestinal tract in patients with colorectal cancer aged 60 to 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 aged> 65 years who received combination therapy with capecitabine and other antitumor drugs, there was an increase in the incidence of adverse events of the 3rd and 4th degree of severity and adverse events that led to discontinuation of therapy, but compared with younger patients. When analyzing safety data, patients> 60 years of age who received combination therapy with capecitabine and docetaxel experienced an increase in the incidence of third-degree and fourth-degree adverse events, serious adverse events and early discontinuation of therapy due to adverse events compared with those in patients younger than 60 years.

Renal insufficiency: Caution should be exercised when using capecitabine in 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 the therapy was higher in patients with moderate renal insufficiency (QA 30-50 ml / min).

Liver failure: Patients with hepatic insufficiency during therapy with capecitabine 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 capecitabine is unknown.

Effect on the ability to drive transp. cf. and fur:

Some adverse drug reactions, such as dizziness, drowsiness, can adversely affect the ability to drive and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. If the above undesirable phenomena occur, you should refrain from performing these activities.

Form release / dosage:

Film-coated tablets, 150 mg and 500 mg.

Packaging:

10 tablets per contour cell pack.

150 mg: 6 contour packs with instructions for use in a pack of cardboard.

500 mg: 12 contour packs with instructions for use in a pack of cardboard.

Storage conditions:

In dry, the dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002866

Date of registration:19.02.2015

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp19.02.2015

Illustrated instructions

Instructions

Capecitabine (Capecitabine)