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

auxiliary substances for the production of a core of a ballet with a mass of 190 mg: lactose anhydrous 17.6 mg, microcrystalline cellulose 9.5 mg, croscarmellose sodium 9.5 mg, hypromellose 1.5 mg, magnesium stearate 1.9 mg.

Composition of the film shell: opedrai II (light orange) 5.0 mg [hypromellose 28%, lactose monohydrate 36%, titanium dioxide 23.72%, talc 17.4%, macrogol (polyethylene glycol 4000) 10.0%, aluminum varnish based on solar sunset yellow 2.25%, iron oxide black 0.03%].

500 mg:

active substance: capecitabine 500.00 mg;

auxiliary substances for the preparation of a core of a ballet with a mass of 620 mg:lactose anhydrous 41.9 mg, microcrystalline cellulose 31.0 mg, croscarmellose sodium 31.0 mg, hypromellose 9.9 mg, magnesium stearate 6.2 mg.

Composition of the film shell: opedrai II (orange) 18.0 mg [hypromellose 18%, lactose monohydrate 28%, titanium dioxide 10.0%, talc 17.4%, macrogol (polyethylene glycol 4000) 36.0%, aluminum varnish based on sunset yellow 6.56%, Aluminum lacquer based on ponso 4R 0.02%].

Description:

Oblong biconvex tablets, covered with a film coating of light orange color (dosage of 150 mg) and orange (500 mg dosage). On the cross section, the core of the tablet is white or almost white in color.

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, the concentration of FU in the tumor tissue is 3.2 times greater 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 (3.9 - 59.9), the ratio of its concentration in healthy tissues and in plasma is 8.9 (3.0 - 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 (FdUMF) 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 It absorbed rapidly and completely, after which the transformation occurs in its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Food reduces the absorption rate of capecitabine, but the area under the concentration-time curve (AUC) 5'-DFUR and the next metabolite FU affects slightly. When using the drug after meals at a dose of 1250 mg / m on the 14th day, the maximum concentrations FROM_m_Oh capecitabine, 5'-DFTST, 5'-DFUR, FU and FBAL were, respectively, 4.47; 3.05; 12.1; 0.95 and 5.46 μg / ml. Time to reach the maximum concentration TFROM_m_Oh was 1.50; 2.00; 2.00; 2.00 and 3.34 hours, a AUC_0-∞ - 7.75; 7.24; 24.6; 2.03 and 36.3 μg x h / ml, respectively.

Distribution

For capecitabine, 5'-DFTST, 5'-DFUR and FU, the association with proteins (mainly albumin) is 54%, 10%, 62% and 10%, respectively.

Metabolism

Metabolised 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 of FU occurs predominantly in tumor tissue under the action of tumor angiogenic factor - thymidine phosphorylase. AUC for FU 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 T_1/2 capecitabine, 5'-DFTST, 5'-DFUR, FU and FBAL is 0.85; 1.11; 0.66; 0.76 and 3.23 hours, respectively. The pharmacokinetic parameters of capecitabine, 5'-DFTST and 5'-DFUR on the 1 st and 14 th day are the same. AUC FU increases by the 14th day by 30-35% and does not increase (22 days). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of FU, are dose-dependent. Excretion through the kidneys - 95%, intestine - 2.6%. The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose is excreted unchanged in the urine.

Combination Therapy

No effect of capecitabine on the pharmacokinetics of docetaxel or paclitaxel (FROM_m_Oh and AUC) And docetaxel or paclitaxel impact on the pharmacokinetics of 5'-DFUR (a metabolite of capecitabine ground) is detected.

Pharmacokinetics in special clinical groups

Sex, the presence or absence of liver metastases prior to treatment, the patient's general condition index, the concentration of total bilirubin, serum albumin, ALT activity and ACT in patients with colon cancer did not have a significant effect on the pharmacokinetics 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, no clinically significant change in the pharmacokinetics of capecitabine occurs. Data on the pharmacokinetics in patients with severe impairment of liver function are absent.

Patients with impaired renal function

At different (from mild to severe) degree of renal failure, the pharmacokinetics of the unchanged drug and FU does not depend on the creatinine clearance (CK). QC affects the magnitude AUC 5'-DFUR (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 is a metabolite that does not possess antiproliferative activity; 5'-DFUR is the immediate precursor of FU.

Elderly age

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

Race

The pharmacokinetics of capecitabine does not depend on the 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, chemotherapy-resistant taxanes or anthracycline-based drugs, or in the presence of contraindications to them.

Colorectal cancer

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

- tTherapy of metastatic colorectal cancer.

Stomach cancer

- Therapy of the first line of common stomach cancer.

Contraindications:

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

- ghypersensitivity to fluorouracil or fluoropyrimidine derivative in history;

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

- aboutsimultaneous administration of sorivudine or its structural analogs, such as brivudine;

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

- andsimilar content of neutrophils less than 1.5 x 10⁹/ l and / or platelets less than 100x10⁹/ l;

- lhaykopenia;

- tsevere hepatic impairment;

- bPregnancy and period of breastfeeding;

- dEthnic age (efficacy and safety of use not established);

- if there are contraindications to one of the drugs that make up the combination therapy, such a drug should not be used.

Carefully:

- With ischemic heart disease (CHD), renal failure of moderate severity or liver failure, age over 60;

- Pwhen combined with oral anticoagulants coumarinic;

- Pin the absence of lactase, lactose intolerance, glucose-galactose malabsorption;

- Panemia and angina in history;

- Pin hypo- or hypercalcemia;

- with diseases of the central and peripheral nervous system;

- Pin diabetes mellitus and violations of water-electrolyte balance.

Pregnancy and lactation:

The drug is contraindicated for use during pregnancy and during breastfeeding.

During the therapy with capecitabine and at least 3 months after the end, reliable contraceptive methods 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, breast cancer

At 1250 mg /m² 2 times a day - in the morning and in the evening (2500 mg /m² per day), during 14 days followed by a 7-day break.

Combined therapy

Mammary cancer

At 1250 mg / m² 2 times a day for 14 days followed by a 7-day break in combination with docetaxel 75 mg / m² 1 every 3 weeks as an intravenous infusion for 1 hour. Premedication is performed prior to docetaxel administration in accordance with instruction on the use of docetaxel.

Colorectal cancer and stomach cancer

In the combination therapy, the dose of the drug Capecitover 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 Capecitover. 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 applied in combination with the drug Capecitover.

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

In combination with cisplatin

For 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 Capecitover is prescribed in the evening on the 1st day of the therapy cycle, the latter on the morning of the 15th day.

In combination with oxaliplatin or with oxaliplatin and bevacizumab

For 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 Capecitover is prescribed in the evening on the 1st day of the therapy cycle, the latter on the morning of the 15th day. 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. 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 / m² 1 every 3 weeks, iv bolus starting from the first day of the cycle) and a platinum-based drug. 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 entered on the 1st day of the cycle in the form of IV infusion for 2 hours, then 1 every 3 weeks.

In combination with irinotecan or with irinotecan and bevacizumab

At 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.

Calculation of the standard and reduced dose of capecitabine for the initial dose 1250 mg /m²or 1000 mg / m² (tables 1 and 2).

Table 1. Standard and reduced doses of capecitabine for the initial dose of 1250 mg / m², calculated depending on the surface area of the body

	Dose - at 1250 mg / m² twice a day
	The total dose of 1250 mg / m²	The number of tablets is 150 mg or 500 mg per session (twice a day, morning and evening)		Reduced dose (75% of initial dose) 950 mg / m²	Reduced dose (50% of initial dose) 625 mg / m²
Body surface area (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

	The dose of 1000 mg / m² twice a day
	The total dose of 1000 mg / m²	The number of tablets is 150 mg or 500 mg per session (twice a day, morning and evening)		Reduced dose (75% of initial dose) 750 mg /m²	Reduced dose (50% of the initial dose) 500 mg / m²
Body surface area (m²)	Dose for admission (mg)	150 mg	500 mg	Dose for admission, mg	Dose for admission, mg
≤ 1.26	1150	1	2	800	600
1.27-1.38	1300	2	2	1000	600
1.39-1.52	1450	3	2	1100	750
1.53-1.66	1600	4	2	1200	800
1.67-1.78	1750	5	2	1300	800
1.79-1.92	1800	2	3	1400	900
1.93-2.06	2000	-	4	1500	1000
2.07-2.18	2150	1	4	1600	1050
≥2.19	2300	2	4	1750	1100

Correction of dose during treatment

General recommendations

Toxic effects in the treatment with the drug Capecitover can be eliminated by symptomatic therapy and / or correction of the dose of the drug Capecitover (interrupting treatment or reducing the dose of the drug). If the dose had to be reduced, you can not increase her later. If, according to the attending physician, the toxic effect of Capecitover is not a serious or life threatening patient, treatment can be continued at the initial dose without reducing or interrupting the therapy.

With toxicity of the 1st degree, the dose is not changed.With toxicity of the 2nd and 3rd degree, the drug should be discontinued. With the disappearance of signs of toxicity or a decrease in the latter to the 1 st degree, the therapy can be resumed in a 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 drug can be used at a dose equal to 50% of the previous one.

Immediately stop taking the medication if severe or moderate toxicity occurs. If several methods of the drug were missed due to toxic effects, these doses are not replenished.

Hematological toxicity

Therapy with capecitabine should be discontinued if signs of hematologic toxicity of 3rd or 4th degree are found.

The following are recommendations for changing the dose in case of development of toxic phenomena associated with its use.

Table 3. Scheme of correction of the dose of the drug Capecitover

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

* Criteria used by the National Cancer Institute of Canada (NCIC CTC, version 1). The criteria for toxicity of the palmar-plantar syndrome and hyperbilirubinemia are described in detail in the "Precautions for Use" section.

Table 4. Criteria for degrees of hematological toxicity CTC-NCIC (Clinical Trial Center, National Cancer Institute, Canada)

	Degree 0	Degree I	Degree II	Degree III	Degree IV
Hemoglobin	Norm	10.0 g / dL - Norm	8.0 -10.0 g / dL	6.5 to 7.9 g / dL	<6.5 g / dL
Leukocytes - 10⁹/ l	> 4,0	3,0 -3,9	2,0 -2,9	1,0 -1,9	<1,0
Granulocytes - 10⁹/ l	> 2,0	1,5 -1,9	1,0 -1,4	0,5 -0,9	<0,5
Platelets - 10%	Norm	75.0 - Normal	50,0 - 74,9	25,0-49,9	<25,0
Blood loss	Absent	Moderate, not requiring transfusion	Significant, requiring up to 1 -2 transfusion	Significant, requiring up to 3-4 transfusions	Massive, requiring more than 4 transfusions

General recommendations for combination therapy

In case of occurrence of toxicity in combination therapy, the recommendations for dose adjustment of Capecitover as specified in Table 3 and the corresponding recommendations in the instructions for the use of other drugs should be followed. At the beginning of the therapy cycle, if a delay is expected with the use of the drug Capecitover or another drug, all drugs should be deferred until the conditions for the resumption of therapy with all drugs have been reached. If, during the cycle of combination therapy, toxic effects, according to the doctor, are not associated with the use of the drug Capecitover, then therapy with Capecitover should be continued, and the dose of another drug should be adjusted in accordance with the recommendations of the instructions for its use. If another drug has to be discontinued, the treatment with Capecitover can be continued if the requirements for the renewal of therapy with Capecitover 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 necessary to change the initial dose in patients with liver metastases and with mild or moderate liver function impairment. 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 initial renal insufficiency of medium degree (KK 30-50 ml / min, according to the formula Cockroft- Gault), do not require dose adjustment at an initial dose of 1000 mg / m². 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 discontinuation of the therapy should be performed in order to subsequently correct the dose of the drug in accordance with the recommendations indicated in Table 3.

If the calculated clearance of creatinine decreased during the treatment to less than 30 ml / min, therapy with Capecitover should be discontinued.Recommendations for correcting the dose of the drug for renal insufficiency of an average degree apply to both monotherapy and combination therapy. Calculation of the dose is indicated in Tables 1 and 2.

Children

Safety and efficacy of the drug Capecitover in children have 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 antitumor drugs elderly patients (≥65 years of age), adverse reactions of the 3rd and 4th degree of severity, as well as undesirable reactions requiring discontinuation of therapy, were more frequent than in younger patients. A thorough monitoring of the condition of elderly patients is recommended.

In the treatment in combination with docetaxel in patients aged 60 years and older there was an increase in the incidence of adverse events 3rd and 4th degree and serious adverse events associated with therapy. For patients aged 60 years and over,which 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. If there is no manifestation of toxicity, the dose may be raised to 1250 mg / m² 2 times a day.

Side effects:The most frequent and / or clinically significant adverse events (AEs) associated with taking the drug were AEs from the gastrointestinal tract (diarrhea, nausea, vomiting, pain in the abdomen, stomatitis), palmar-plantar syndrome, increased fatigue, asthenia, anorexia, cardiotoxicity, impaired renal function, thrombosis / embolism.

The incidence of adverse reactions is described in accordance with the following gradation: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely from ≥1 / 10000 to <1/1000), very rarely (<1/10000), including individual messages.

Monotherapy with capecitabine

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 - lipoma.

Violations of 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 - hypersensitivity. 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: often - insomnia, depression; infrequently - confusion, panic attacks, depressed mood, decreased libido.

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

Disorders from the side of the organ of vision: often - increased tear, conjunctivitis, eye irritation; infrequent - reduced visual acuity, diplopia.

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

Heart Disease: infrequently - angina pectoris, including unstable, myocardial ischemia, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitation; frequency unknown - cardiomyopathy, myocardial infarction, heart failure, sudden death, ventricular extrasystoles.

Vascular disorders: often - thrombophlebitis, infrequently - deep vein thrombosis, increased blood pressure (BP), petechiae, lowering of blood pressure, "hot flashes", cooling of the distal limbs.

Disturbances from the respiratory system, chest and mediastinal organs: often - dyspnea, epistaxis, cough, rhinorrhea, infrequently - pulmonary embolism, pneumothorax, hemoptysis, bronchial asthma, dyspnoea with physical exertion.

Disorders from the gastrointestinal tract: very often - diarrhea, vomiting, nausea, stomatitis (including ulcer), abdominal pain; often - gastrointestinal bleeding,constipation, epigastric pain, dyspepsia, flatulence, dry mouth; infrequent - intestinal obstruction, ascites, enteritis, gastritis, dysphagia, abdominal pain, abdominal discomfort, gastroesophageal reflux disease, colitis, blood in the stool. Disorders 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-plantar syndrome (paresthesia, edema, hyperemia, skin peeling, blistering); often - skin rash, alopecia, erythema, dry skin, itching, hyperpigmentation of the skin, macular rash, skin peeling, dermatitis, skin pigmentation, changes in nails; infrequent - blister, skin ulcers, photosensitization reactions, urticaria, palmar erythema, face swelling, purpura, radiation dermatitis; rarely - cracked skin.

Disturbances from musculoskeletal and connective tissue: often - pain in the limbs, back pain, arthralgia; 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 the concentration of 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 - increased fatigue, asthenia, increased drowsiness; often - fever, weakness, peripheral edema, malaise, chest pain; infrequently - edema, chills, flu-like syndrome, trembling, fever.

The use of capecitabine in combination therapy

Undesirable reactions listed with monotherapy can be observed with a greater frequency when using 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 infection, upper respiratory tract infection, rhinitis, influenza, infections, herpes of the oral cavity.

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

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

Disorders of the psyche: often - sleep disorders, anxiety.

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

Disturbances on the part of the organ of sight: very often - increased tear, often - visual impairment, dry eyes, pain in the eyes, blurred vision. Hearing disorders and labyrinthine disturbances: often - ringing in the ears, deafness.

Violations from the hearta: often - atrial fibrillation, ischemia / myocardial infarction.

Vascular disorders: very often - edema of the lower extremities, thrombosis / embolism, increased blood pressure; often - hyperemia, lowering blood pressure, hypertensive crisis, "hot flashes", phlebitis.

Disturbances from 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 from 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.

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

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

Disturbances from 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 - temperature intolerance, fever, weakness, lethargy; often - pain, inflammation of the mucous membrane, chills, chest pain, flu-like syndrome, bruising.

Laboratory and instrumental data:

hyperbilirubinemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase, hypercreatininaemia.

In clinical studies and with the use of capecitabine, 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).

Postmarketing experience with capecitabine

During clinical use of capecitabine, the following AEs were found, rarely found:

Disturbances on the part of the organ of sight: rarely - corneal damage, including keratitis, acupuncture, stenosis of the lacrimal tubule, unspecified.

Violations from the hearta: rarely - ventricular fibrillation, lengthening of the interval QT, arrhythmia ventricular tachysystolic type "pirouette", bradycardia.

Vascular disorders: rarely - vasospasm.

Disturbances from the liver and bile ducts: rarely - hepatic insufficiency and cholestatic hepatitis.

Disturbances from the skin and subcutaneous tissues: rarely - cutaneous form of lupus erythematosus; very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis.

Disorders from the kidneys and urinary tract: rarely - acute renal failure as a consequence of dehydration, including fatal.

Description of selected unwanted medicinal products reactions

Diarrhea

Treatment with capecitabine can cause the development of diarrhea, sometimes severe. The occurrence of diarrhea during treatment with capecitabine was noted in 50% of patients.

With the increased risk of diarrhea, the following covariates are statistically significantly associated: an increase in the initial dose of capecitabine (in grams), an increase in the duration of treatment (weeks), an increase in the patient's age (10 years), female sex. With a decrease in the risk of diarrhea, it is statistically significantThe following covariates are associated: 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

The spectrum of cardiotoxicity in the treatment with capecitabine is similar to that of other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiogenic shock, sudden death, cardiac arrest, heart failure and ECG changes (including, very rarely, lengthening QT). These side effects are more common in patients with ischemic heart disease. Heart rhythm disturbances (including ventricular fibrillation, ventricular tachysystolic type arrhythmia, pirouette, bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathies were recorded in patients receiving capecitabine. Caecitabine should be used with caecitabine in patients with clinically significant heart disease, arrhythmias and angina.

Encephalopathy

In addition to these adverse reactions, capecitabine monotherapy was associated with the occurrence of encephalopathy with a frequency of <0.1%.

Adverse reactions in special patient groups

Elderly patients

Patients aged ≥60 years who received capecitabine monotherapy and combination therapy with docetaxel had an increased risk of serious adverse events 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.

Floor

Female gender is statistically significantly associated with an increased risk of palmar-plantar syndrome and diarrhea, as well as a reduced risk of developing neutropenia.

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 III and IV related 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-level renal insufficiency, there was a greater need for dose reduction (44%) compared with 33 and 32% of patients without renal failure and with mild renal failure, respectively, and premature withdrawal of treatment was more often noted.

Overdose:

Symptoms: nausea, vomiting, diarrhea, mucositis, irritation of the gastrointestinal tract and bleeding, as well as suppression of bone marrow function.

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

Interaction:Coumarin anticoagulants: capecitabine intensifies the effects of coumarinic anticoagulants (warfarin and fenprokumone), which can lead to disruption of the coagulation and bleeding after a few days or months from the beginning of therapy with capecitabine, and in several cases - within 1 month after its completion. After a single administration of 20 mg of warfarin capecitabine increased the AUC S-warfarin by 57% and the magnitude of the international normalized ratio (INR) by 91%.With the simultaneous administration of capecitabine and anticoagulants coumarinovogo series should carefully monitor the prothrombin time or INR, the dose of coagulant should be selected in accordance with these indicators.

Substrates of the isoenzyme CYP2C9: studies on the interaction of capecitabine and other drugs metabolized by the CYP2C9 isoenzyme of the cytochrome P450 system have not been conducted. Caution should be exercised when administering capecitabine with these drugs.

Phenytoin: capecitabine increases the concentration of phenytoin in the plasma.

It is assumed that it is based on suppression of the isoenzyme CYP2C9 under the influence of capecitabine. In patients receiving capecitabine simultaneously with phenytoin, it is recommended to regularly monitor the concentration of phenytoin in the plasma.

Antacids, containing aluminum and magnesium hydroxide: slightly increase the concentration of capecitabine and one metabolite (5'-DFTST) in blood plasma; it does not affect the three main metabolites (5'-DFUR, FU and FAA) of capecitabine.

Calcium folinate (Leucovorin) does not affect the pharmacokinetics of capecitabine and its metabolites, but may enhance the toxic effect of capecitabine.

Sorivudine and its analogs: a clinically significant drug interaction between sorivudine and FU is described, which is based on the inhibitory effect of sorivudine on DPD (dihydropyrimidine dehydrogenase). This interaction can potentially lead to a fatal increase in the toxicity of fluoropyrimidines. 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: a significant difference in the exposure of capecitabine and metabolites of oxaliplatin (free platinum or total platinum), regardless of the presence of bevacizumab, was not noted.

Bevacizumab: no clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites was noted.

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 simultaneous admission with interferon alfa-2a (3 million IU / m² per day) compared with the dose of capecitabine 3000 mg / m² per day with monotherapy.

Radiation therapy: the maximum tolerable dose of capecitabine in the monotherapy regimen at the standard dosage regimen is 3000 mg / m²per day, when combined with radiation therapy of colorectal cancer (from Monday to Friday for 6 weeks) - 2000 mg / m² per day.

Special instructions:

Therapy with capecitabine is carried out under careful medical supervision. 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.

Side effects limiting the dose of capecitabine: diarrhea, abdominal pain, nausea, stomatitis, palmar-plantar syndrome.

Treatment with capecitabine may cause diarrhea, sometimes heavy. Patients with severe diarrhea should be closely monitored by rehydration and compensation for electrolyte loss in case of dehydration. According to indications, as soon as possible, it is recommended to use standard antidiarrheal drugs (for example, loperamide). Diarrhea II degree according to the criteria of the National Cancer Institute of Canada (NCIC STS,version 2) is defined as an increase in the number of defecations up to 4-6 times a day or defecation at night; diarrhea III degree - as an increase in the number of bowel movements up to 7-9 times a day, or stool incontinence and malabsorption. Diarrhea IV degree is defined as an increase in the number of defecations ≥10 times a day or massive diarrhea with blood impurities, or the need to prescribe parenteral infusions. If necessary, the dose of capecitabine should be reduced.

Dehydration should be prevented or eliminated at the outset of the occurrence. Dehydration can develop 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, capecitabine should be immediately discontinued 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 capecitabine should be adjusted in accordance with the recommendations.

Range cardiotoxicity when treated with capecitabine is similar to that of other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, heart failure, and ECG changes. These adverse events are more common in patients with IHD. Care should be taken in patients with clinically significant heart disease, arrhythmia and angina in history.

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

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

Diseases of the central or peripheral nervous system: caution should be exercised when using capecitabine in patients with a diseasecentral or peripheral nervous system, for example, metastases in the brain or neuropathy.

Diabetes mellitus or violation of water-electrolyte balance: when using capecitabine in patients with diabetes mellitus or a violation of the water-electrolyte balance, caution is necessary, since the use of capecitabine can lead to a worsening of their course.

Ophthalmologic complications: close monitoring of patients with eye diseases should be ensured in order to monitor ophthalmologic complications (corneal lesions, including keratitis, spot keratitis).

In rare cases, severe toxicity associated with FU is noted in the form of stomatitis, diarrhea, neutropenia and neurotoxicity due to inadequate dihydropyrimidine dehydrogenase (DPD) activity. It is impossible to exclude the connection between the decreased activity of DPD and the more pronounced potentially lethal toxicity of FU.

Development of skin toxicity is development palmar-plantar syndrome 1-3 degrees of severity (synonyms - palmar-plantar erythrodysesthesia or erythema arthritis, caused by chemotherapy).The time to development with monotherapy is 79 days on average (in the range of 11 to 360 days). Palmar-plantar syndrome of the 1st degree does not disturb the daily activity of the patient and is manifested by numbness, dysesthesia and paresthesia, tingling or redness of the palms and / or soles, discomfort. Palmar-plantar syndrome of the 2nd degree is manifested 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. Palmar-plantar syndrome of the third degree is defined as wet desquamation, ulceration, blistering and sharp pains in the hands and / or feet, as well as severe discomfort, making it impossible for the patient to any kinds of daily activity. If palmar-plantar syndrome occurs, grade 2 or grade 3, capecitabine should be discontinued until symptoms disappear or decrease to 1 degree; At the next occurrence of the syndrome of the 3rd degree, the dose of capecitabine should be reduced. There are data on the effectiveness of dexpanthenol in the prevention of the development of palmar-plantar syndrome in the therapy with capecitabine.

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.

If, in connection with the treatment with capecitabine, there is hyperbilirubinemia exceeding the upper limit of the norm by more than 3 times, or an increase in the activity of "hepatic" aminotransferases (ALT, ACT), exceeding the upper limit of the norm by more than 2.5 times, the use of capecitabine should be interrupted. It can be resumed by lowering the concentration of bilirubin and the activity of "liver" transaminases below these limits.

In patients who simultaneously take capecitabine and oral anticoagulants - coumarin derivatives, it is necessary to carefully monitor the coagulability (prothrombin time or MEU) and select the dose of anticoagulant.

The use of the drug in elderly and senile patients

The incidence of toxic phenomena 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 gastrointestinal disorders of grade 3 and 4, such as diarrhea, nausea and stomatitis, 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 treatment-related adverse events of grade 3 and 4, serious adverse events and early discontinuation of therapy due to adverse events compared with those in 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 those in patients younger than 60 years.

Renal insufficiency

Caution should be exercised when using capecitabine in patients with moderate renal insufficiency. As in the treatment of FU, the frequency of development of adverse events associated with the treatment of 3rd and 4th degree of severity 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.

Handling of an unused product and an expired product

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

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

Capecitabine has little or moderate influence on the ability to drive vehicles, mechanisms. Patients who experience such undesirable effects as dizziness, weakness, or nausea should refrain from controlling vehicles and mechanisms.

Form release / dosage:

Film-coated tablets, 150 mg and 500 mg.

Packaging:

10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

60 tablets (for a dosage of 150 mg) and 60 or 120 tablets (for a dosage of 500 mg) in a jar of polypropylene or low pressure polyethylene with a screw cap.

Each jar or 6 contour mesh packages (for a dosage of 150 mg), or 12 contour mesh packages (for a dosage of 500 mg) together with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 30 ° C. Keep out of the reach of children.

Shelf life:

3 years. The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002605

Date of registration:29.08.2014 / 05.10.2015

Expiration Date:29.08.2019

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Representation: & nbspVEROPHARM, AO VEROPHARM, AO Russia

Information update date: & nbsp03.12.2017

Illustrated instructions

Instructions

Capecitover (Capecitover)