Capametin FS - instructions for use, dose, side effects, contraindications

	Amount, mg
	Dosage of 150 mg	Dosage 500 mg
Active substance:
Capecitabine	150,0	500,0
Excipients:
Microcrystalline cellulose	26,0	95,0
Corn sweet corn starch	10,5	37,0
Crospovidone	4,0	16,0
Magnesium stearate	1,5	5,0
Film Sheath:
Fallen II yellow 85F32771 (polyvinyl alcohol 40.00%, talcum 14.80%, macrogol 3350-20.20%, titanium dioxide 23.70%, iron oxide yellow 1.30%)	8,0	-
Fallen II yellow 85F32733 (polyvinyl alcohol 40.00%, talcum 14.80%, macrogol 3350-20.20%, titanium dioxide 21.65%, iron oxide yellow 3.35%)	-	27,0
Theoretical tablet weight	200,0	680,0

Description:

Dosage of 150 mg: oval, biconvex tablets, covered with a film coating of light yellow color. On the cross-section the nucleus is white.

Dosage 500 mg: oval, biconcave tablets with a risk on one side, covered with a film coating of yellow color. On the cross-section the nucleus is white.

Pharmacotherapeutic group:Antitumor 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.

Capecitabine in vitro has no cytotoxic effect, whereas in vivo turns into fluorouracil (FU), which undergoes further metabolism. The formation of FU occurs predominantly in tumor tissue under the action of tumor angiogenic factor - thymidine phosphorylase and, thus, 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.

In patients with colon cancer after taking capecitabine, the concentration of FU in the tumor tissue is more than its concentration in the adjacent healthy tissues 3.2 times. The ratio of the concentration of FU in tumor tissue and plasma is 21.4, the ratio of its concentration in healthy tissues and plasma is 8.9.

The activity of thymidine phosphorylase in the primary colorectal tumor is 4 times higher than in the adjacent healthy tissues.

In tumor cells in patients with breast, stomach, colon, cervical and ovarian cancer, there is more thymidine phosphorylase involved in the conversion of the metabolite capecitabine-5'-deoxy-5-fluorouridine (5'-DFUR) to FU than in the corresponding healthy tissues.

Both healthy and tumor cells metabolize FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMF) and 5-fluorouridine triphosphate (FUTF). Metabolites FU damage cells through two different mechanisms. First, FUUM and the folate cofactor N^5-10-methylenetetrahydrofolate covalently bind to thymidylate synthetase to form a tertiary complex, which disrupts the formation of thymidylate, the precursor thymidine triphosphate, necessary for DNA synthesis, from uracil, its deficiency leads to inhibition of cell division.Secondly, in the process of RNA synthesis, the transcriptional enzymes of the nucleus can erroneously include FUT instead of uridine triphosphate (UTP), and this metabolic "error" disrupts RNA processing and protein synthesis.

Pharmacokinetics:

Suction. After oral administration capecitabine quickly and completely absorbed from the gastrointestinal tract (GIT), after which it is transformed into the metabolites of 5'-deoxy-5-fluorocytidine (5'-DFTST) and 5'-DFUR. Simultaneous food intake reduces the rate of absorption of capecitabine, but the area under the concentration-time curve (AUC) 5'-DFUR and the next metabolite FU affects slightly. When using the drug after meals at a dose of 1250 mg / m² on the 14th day the maximum concentration (C_mOh) capecitabine, 5'-DFTST, 5'-DFUR, FU and α-fluoro-β-alanine (FBAL) were 4.47, 3.05, 12.1, 0.95 and 5.46 μg / ml. The time to reach the maximum concentration (T_mOh) is 1.50, 2.00, 2.00, 2.00 and 3.34 hours, and AUC_0-∞ - 7.75, 7.24, 24.6, 2.03 and 36.3 μg * h / ml, respectively.

Distribution. According to research in vitro in human blood plasma, the association with proteins (mainly albumin) of capecitabine, 5'-DFTST, 5'-DFUR and FU is 54%, 10%, 62% and 10%, respectively.

Metabolism. In the liver capecitabine is initially hydrolyzed by carboxyl esterase to the metabolite 5'-DFTST, which is converted to 5'-DFUR by cytidine deaminase of the liver and tumor tissues. Later on, the transformation mainly takes place in tumor tissue under the action of tumor angiogenic factor - thymidine phosphorylase to the active metabolite of FU.

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

Further FU is metabolized to inactive metabolites - dihydro-5-fluorouracil (FUN₂), 5-fluoroureidopropionic acid (FCCC) and FBAL under the influence of dihydropyrimidine dehydrogenase (DPD), whose activity limits the rate of reaction.

Excretion. The half-life (T_1/2) capecitabine, 5'-DFCR, 5'-DFUR, FU and FBAL are 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 days do not differ and are dose-dependent in the range of therapeutic doses. The equilibrium concentration of 5-FU is reached by the 14th day from the start of administration and then remains unchanged.

Upon receiving capecitabine inside its metabolites are excreted mainly by the kidneys - 95.5%, intestines - 2.6%, about 3% of the administered dose excreted by the kidneys in unchanged form. The main metabolite in urine is FBAL, which accounts for 57% the accepted dose.

Combination Therapy

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

Pharmacokinetics in specific patient groups

Paul, presence or absence of metastases in the liver before treatment, the patient's general condition index of Karnofsky, the concentration of total bilirubin, serum albumin, alanine aminotransferase activity (ALT) and aspartate aminotransferase (ACT) had no significant effect on the pharmacokinetics of 5'-DFUR, FU, and FBAL.

Patients with hepatic insufficiency due to metastatic liver damage

Have patients with violations of liver function of mild and moderate severity caused by metastatic lesion, pharmacokinetic parameters and processes of bioactivation of capecitabineclinically significant do not change. Data on the pharmacokinetics in patients with severe impairment of liver function are absent.

Patients with impaired renal function

With varying degrees of renal failure (from mild to severe), the pharmacokinetics of the unchanged drug and FU does not depend on creatinine clearance (CK). QC affects the magnitude AUC 5'-DFUR (increase AUC by 35% - with a decrease in the CK by 50%) and FBAL (increase AUC by 114% with a decrease in QC by 50%). FBAL-metabolite, which does not possess antiproliferative activity; 5'-DFUR is the immediate precursor of 5-FU.

Elderly patients

Age does not affect the pharmacokinetics of 5'-DFUR and FU. AUC FBAL increases with age (an increase in age by 20% is 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.

- Monotherapy of locally advanced or metastatic breast cancer with resistance to chemotherapy with taxanes or anthracycline drugs or in the presence of contraindications to them.

Colorectal cancer

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

- Therapy of metastatic colorectal cancer.

Stomach cancer

- Therapy of the first line of common stomach cancer.

Contraindications:

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

- Hypersensitivity to fluorouracil or in case of unexpected or severe adverse reactions to fluoropyrimidine derivatives in the history.

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

- Severe hepatic insufficiency, leukopenia.

- Severe renal insufficiency (creatinine clearance below 30 ml / min).

- The initial content of neutrophils <1.5 x 10⁹/ l and / or platelets <100 x 10⁹/ l.

- Simultaneous administration of sorivudine or its structural analogues (for example, brivudine).

- Presence of contraindications for other drugs of combination therapy.

- Age to 18 years (efficacy and safety of use not established).

- Pregnancy and lactation.

Carefully:

At moderate renal failure (creatinine klierens 30-50 ml / min) or hepatic failure, ischemic heart disease (IHD), angina and arrhythmia history, hypo- or hypercalcemia, diseases of the central and peripheral nervous system, diabetes and disorders water -elektrolitnogo balance over the age of 60 years, concomitant use with oral anticoagulants coumarin.

Pregnancy and lactation:

Currently, there are no data on the use of capecitabine in pregnant women.

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

Dosing and Administration:

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

Standard dosing regimen

Monotherapy

Colorectal cancer, colon cancer and breast cancer

The recommended dose of the drug is 1250 mg / m² 2 times a day (corresponding to a total daily dose of 2500 mg / m²) for 14 days followed by a 7-day break.

Combination Therapy

Mammary cancer

The recommended dose for capecitabine is 1250 mg / m² 2 times a day (corresponding to a total daily dose of 2500 mg / m²) 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 before docetaxel is administered in accordance with the instructions for its use.

Colorectal cancer and stomach cancer

In the combination therapy (with the exception of therapy in combination with irinotecan), the dose of the drug Capametine® FS is up to 800-1000 mg / m² 2 times a day for 14 days followed by a 7-day break or up to 625 mg / m² 2 times a day in continuous mode.

In the combination therapy with irinotecan (regimen XELIRI) the recommended dose of the drug Capametine® FS is 800 mg / m² 2 times a day for 14 days followed by a 7-day break. The addition of bevacizumab to combination therapy does not affect the initial dose of the drug Capametin FS.

Antiemetic drugs and premedication to ensure adequate hydration are prescribed prior to administration of cisplatin andoxaliplatin in accordance with the instructions for the use of cisplatin and oxaliplatin when used in combination with capecitabine. In adjuvant therapy for colon cancer, stage III, the recommended duration of drug therapy Capamethin® FS is 6 months, i.е. 8 courses.

Combination therapy with cisplatin

The recommended dose for capecitabine is 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, intravenous infusion within 2 hours, the first infusion is administered on the first day of the cycle). The first dose of capecitabine is in the evening on the first day of the therapy cycle, the last one in the morning on day 15.

Combination therapy with oxaliplatin or with oxaliplatin and bevacizumab

The recommended dose for capecitabine is 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 injected in the evening on the first day of the therapy cycle, the latter on the morning of 15 days. Bevacizumab is administered at a dose of 7.5 mg / kg every 3 weeks, intravenous infusion for 30-90 minutes, the first infusion is administered on the first day of the cycle. After bevacizumab is introduced oxaliplatinum in a dose of 130 mg / m², intravenous infusion for 2 hours.

Combination therapy with epirubicin and a preparation based on platinum

The recommended dose for capecitabine is 625 mg / m² 2 times a day in a continuous mode in combination with epirubicin (50 mg / m² 1 every 3 weeks, intravenously, 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 / kg² or oxaliplatinum in a dose of 130 mg / m²) should be administered on the first day of the therapy cycle, intravenous infusion for 2 hours, then 1 every 3 weeks.

Combination therapy with irinotecan or with irinotecan and bevacizumab

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

Irinotecan is administered at a dose of 200 mg / m² 1 every 3 weeks, IV infusion for 30 minutes, the first infusion is performed on the first day of the cycle.

Bevacizumab is administered at a dose of 7.5 mg / kg every 3 weeks, intravenous infusion for 30-90 minutes, the first infusion is performed on the first day of the cycle.

The following tables (Tables 1, 2) show examples of calculating the standard and reduced dose of the drug Capametine® FS for an initial dose of 1250 mg / m² or 1000 mg / m².

Table 1.Standard and reduced doses of the drug Capamethin® FS for an initial dose of 1250 mg / m², calculated depending on the surface area of the body.

	Dose - at 1250 mg / m² 2 times a day
	The total dose of 1250 mg / m²	The number of tablets 150 mg and / or 500 mg per reception (for each intake 2 times a day - in the morning and in the evening)		Reduced dose (75% of the initial dose) 950 mg / m²	Reduced dose (50% of the initial dose) 625 mg / m²
Body surface area (m²)	Single dose per reception (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 the drug Kapametin® FS for an initial dose of 1000 mg / m², calculated depending on the surface area of the body.

	The dose of 1000 mg / m² 2 times a day
	The total dose of 1000 mg / m²	The number of tablets 150 mg and / or 500 mg per reception (for each intake 2 times 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
Body surface area (m²)	Single dose per reception (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 of capecitabine during treatment

General recommendations

The toxicity phenomena in the treatment with capecitabine can be eliminated by symptomatic therapy and / or correcting the dose of the drug (interrupting treatment or reducing the dose).If the dose had to be reduced, then it can not be increased.

If the toxic effect of the drug is estimated by the attending physician Capamethin® FS does not carry a serious or life threatening patient character, treatment can be continued at the initial dose without reducing it or interrupting treatment.

With a toxicity of 1 degree, do not adjust the dose. For toxicity levels 2 and 3, the drug should be discontinued. With the disappearance of signs of toxicity or its reduction to the 1st degree, therapy with capecitabine can be resumed in a full dose or adjusted in accordance with the recommendations indicated in Table 3.

With the development of signs of toxicity of the 4th degree, treatment should be discontinued or temporarily interrupted until the symptomatology is reduced or reduced to 1 degree, after which the drug should be resumed at a dose equal to 50% of the initial dose. The patient should immediately inform the doctor about the unwanted events that develop in him.

Immediately stop taking the drug Capamethin® FS when severe and moderate toxicity occurs. If several methods of the drug were missed due to toxic effects, these doses are not replenished.

Hematological toxicity

Patients with baseline neutrophil count <1.5 x 10⁹/ l or platelets <100 x 10⁹/ l should not be prescribed capecitabine therapy.

The treatment with capecitabine should be interrupted if, in the course of an unscheduled evaluation of laboratory parameters, the number of neutrophils decreased below 1.0 x 10⁹/ l, and the number of platelets decreased below 75 x 10⁹/ l (haematological toxicity 3rd or 4th degree).

The following are recommendations for changing the dose of capecitabine in the event of the development of toxic effects associated with its use (Table 3).

Table 3. Scheme of correction of the dose of the drug Kapametin® FS

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

* The toxicity criteria of the Clinical Research Unit of the National Cancer Institute of CanadaNCIC CTC, version 1) or the common terminology criteria for adverse events of the Antitumor Evaluation Program of the National Cancer Institute (STAAE, version 3). The criteria for toxicity of the palmar-plantar syndrome are described in detail in the "Special instructions" section.

General recommendations for combination therapy

In case of occurrence of toxicity in combination therapy, the recommendations for dose adjustment should be followed Kanamethin® FSmentioned in table 3 above, and the corresponding recommendations in the instructions for the use of other drugs.

At the beginning of the therapy cycle, if a delay in taking the drug is expected Kanametin® FS or other drug (s), all drugs should be deferred until the conditions for resumption of therapy with all drugs have been reached.

If, during the combination therapy cycle, the toxicity phenomena, according to the doctor, are not related to the use of the drug Kanametin® FS, then drug therapy Kanamethin® FS should be continued, and the dose of another drug should be adjusted in accordance with the recommendations of the instructions for its use.

If the other drug (s) have to be canceled, treatment with the drug Kapametin FS can be continued when meeting the requirements for the resumption of therapy with the drug Capametine® FS.

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

Correction of the dose in special cases

Impaired renal function

In patients with initial renal insufficiency of medium degree (KK 30-50 ml / min), it is recommended to reduce the initial dose to 75% from 1,250 mg / m². At an initial dose of 1000 mg / m² no dose adjustment is required.

In patients with mild renal insufficiency (QC 51-80 ml / min) correction of the initial dose is not required.

If the patient develops an undesirable phenomenon of 2, 3 or 4 severity, careful observation and immediate discontinuation of the therapy should be carried out with a view to correcting the dose of the drug in accordance with the recommendations in Table 3. If during the treatment the calculated CC decreased to less than 30 ml / min with drug therapy Capametine® FS should be discontinued.

Recommendations for correcting the dose of the drug for renal insufficiency of moderate severity apply both to monotherapy and to combination therapy.

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

Impaired liver function in patients with liver metastases

In patients with liver metastases and a mild or moderate liver function disorder, an initial dose of capecitabine is not required. Such patients should be carefully observed. The use of capecitabine in patients with severe hepatic insufficiency has not been studied.

Use in elderly patients

Correction of the initial dose with monotherapy with the drug Capametine® FS not required. There is evidence that severe adverse events of 3rd and 4th degree of severity associated with capecitabine therapy developed in patients older than 80 years more often than in younger patients.

When capecitabine was used in combination with other antitumor drugs in elderly patients (≥65 years of age), adverse reactions of the 3rd and 4th degree of severity, as well as undesirable reactions requiring the withdrawal of therapy, were noted more often than in younger patients.

A thorough monitoring of the condition of elderly patients is recommended.

When treated 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 combination therapy with capecitabine and docetaxel, it is recommended to lower the initial dose of the drug Capametip® FS up to 75% (950 mg / m² 2 times a day).

Calculation of the dose is given in Table 1.

In the absence of toxicity, the dose may be increased to 1250 mg / m² 2 times a day.

Use in children

Safety and efficacy of capecitabine in children not installed.

Side effects:

Side effects recorded more often than single observations are listed below for organs and systems, indicating the frequency of their occurrence.

The frequency of adverse reactions that may occur during therapy is given in the following gradation: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100 ), rarely (> 1/10000, <1/1000), very rarely (<1/10000, including individual messages) and the frequency is not known (the frequency can not be calculated from the available data).

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, build-up renal failure in patients with a history of renal dysfunction, as well as thrombosis / embolism.

Table 4. Adverse effects observed in patients taking capecitabine as a monotherapy.

Systems of organs	Very often (all degrees)	Often (all degrees)	Infrequently (severe and / or life-threatening (3-4 degrees), or considered clinically relevant)	Rarely / very rare
Infectious and parasitic diseases		Herpesvirus infections, nasopharyngitis, lower respiratory infections	Sepsis, urinary tract infections, cellulitis, tonsillitis, pharyngitis, candidiasis of the oral mucosa, influenza,gastroenteritis, fungal infections, infections, tooth abscess
Benign, malignant and unspecified neoplasms			Lipoma
On the part of the blood and lymphatic system		Neutropenia, anemia	Febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, an increase in the international normalized ratio, prolongation of prothrombin time
From the side immune system			Hypersensitivity
From the side of metabolism and nutrition	Anorexia	Dehydration, weight loss	Diabetes mellitus, hypokalemia, decreased appetite, indigestion, hypertriglyceridemia
Disorders of the psyche		Insomnia, depression	Confusion, panic attacks, decreased libido, depressed mood
From the nervous system		Headache, lethargy, dizziness (except vertigo), paresthesia, dysgeusia	Aphasia, memory impairment, ataxia, syncope, imbalance, loss of sensitivity, peripheral neuropathy
From the side of the organ of vision		Increased lacrimation, conjunctivitis, eye irritation	Decreased visual acuity, diplopia
From the side of the hearing organ and labyrinthine disorders			Vertigo, pain in the ears
From the heart			Angina pectoris, incl. unstable, myocardial ischemia, arrhythmia, supraventricular arrhythmia (including atrial fibrillation), tachycardia, sinus tachycardia, palpitation
From the side of the vessels		Thrombophlebitis	Deep vein thrombosis, elevation / lowering of arterial pressure, petechiae, "hot flashes", cooling of the distal limbs
On the part of the respiratory system, the organs of the thorax and the mediastinum		Shortness of breath, epistaxis, cough, rhinorrhea	Embolism of the pulmonary artery, pneumothorax, hemoptysis, bronchial asthma, dyspnoea with physical exertion
From the side gastro- intestinal tract	Diarrhea, vomiting, nausea, stomatitis (including ulceration), abdominal pain	Gastrointestinal bleeding, constipation, pain in the upper abdomen, dyspepsia, flatulence, dry mouth	Intestinal obstruction, ascites, enteritis, gastritis, dysphagia, abdominal pain, esophagitis, abdominal discomfort, gastroesophageal reflux, colitis, blood in stools	-
From the liver and biliary tract		Hyperbilirubinemia, changes in functional liver tests	Jaundice
From the rut and subcutaneous tissues	Syndrome of palmar-plantar erythrodysesthesia	Skin rash, alopecia, erythema, dry skin, macular rash, itching, skin hyperpigmentation, skin peeling, dermatitis, nail changes, skin pigmentation disorder	Cutaneous ulcers, blisters, radiation dermatitis, hives, photosensitivity reactions, palmar erythema, facial edema, purpura	Cracks in the skin
From the musculoskeletal and connective tissue		Pain in the extremities, back pain, arthralgia	Swelling of the joints, bone pain, facial pain, stiffness of the joints, muscle weakness
From the side of the kidneys and urinary tract			Hydronephrosis, urinary incontinence, hematuria, nocturia, increased creatinine concentration in the blood plasma
From the side genital organs and mammary gland	-	-	Vaginal bleeding	-
Are common disorders and disorders at the site of administration	Increased fatigue, asthenia, drowsiness	Fever, peripheral edema, malaise, weakness, chest pain	Edema, chills, flu-like syndrome, fever, trembling.

Table 5. Adverse effects observed in patients taking capecitabine as part of combination therapy in addition to the reactions recorded with monotherapy with capecitabine, or observed with a higher frequency in comparison with monotherapy with capecitabine.

System of organs	Very often (all degrees)	Often (all degrees)
Infectious and parasitic diseases		Herpes zoster, infection, urinary tract infection, candidiasis of the oral mucosa, upper respiratory tract infection, rhinitis, influenza, infections, oral cavity herpes
On the part of the blood and lymphatic system	Neutropenia (including grade 3-4 neutropenia associated with fever above 38 ° C), leukopenia, anemia, thrombocytopenia	Myelosuppression, febrile neutropenia
From the side of the immune system		Hypersensitivity
From the side of metabolism and nutrition	Decreased body weight, decreased appetite	Hypokalemia, hyponatremia, hypomagnesemia, hypo / hypercalcemia, hyperglycemia
Mental disorders		Sleep disorders, anxiety
From the nervous system	Paresthesia, dysesthesia, peripheral neuropathy, peripheral sensory neuropathy, dysgeusia, headache	Neurotoxicity, tremor, neuralgia, hypoesthesia
From the side of the organ of vision	Increased lacrimation	Visual disturbances, blurred vision, dry eyes, pain in the eyes,
From the side of the hearing organ and labyrinthine disorders	-	Ringing in the ears, hearing loss
From the heart		Atrial fibrillation, myocardial ischemia (including myocardial infarction)
From the side of the vessels	Edema of the lower limbs, increased blood pressure, thrombosis / embolism	Hyperemia, lowering of arterial pressure, hypertensive crisis, "hot flashes", phlebitis
On the part of the respiratory system, the organs of the thorax and the mediastinum	Sore throat, laryngeal dysaesthesia	Hiccups, pain in the pharynx and larynx, dysphonia
From the gastrointestinal tract	Constipation, indigestion	Bleeding from the upper gastrointestinal tract, ulcers of the oral mucosa, gastritis, bloating, gastroesophageal reflux, oral pain, dysphagia, rectal bleeding, abdominal pain, dysesthesia, paresthesia and hypoesthesia, abdominal discomfort
From the liver and biliary tract		Dysfunction of the liver
From the skin and subcutaneous tissues	Alopecia, nail change	Hyperhidrosis, erythematous rash, hives, night sweats
From the musculoskeletal and connective tissue	Myalgia, arthralgia, pain in the extremities	Pain in the jaw, muscle spasms, trismus, muscle weakness
From the side of the kidneys and urinary tract		Hematuria, proteinuria, decreased creatinine clearance, dysuria
General disorders and disorders at the site of administration	Fever, weakness, lethargy (3-4 degrees), intolerance to high temperatures	Pain, inflammation of the mucous membrane, pain in the extremities, chills, chest pain, flu-like syndrome, bruising
Other	-	Contusion

Other side effects reported with capecitabine therapy

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

Disturbances from the nervous system: very rarely - toxic leukoencephalopathy.

From the liver and biliary tract: rarely - liver failure, cholestatic hepatitis.

Heart Disease: rarely - ventricular fibrillation, lengthening of the interval QT, arrhythmia ventricular tachysystolic type "pirouette", bradycardia.

Vascular disorders: rarely - vasospasm.

From the skin and subcutaneous fat: rarely - systemic lupus erythematosus (cutaneous form); very rarely - Stevens-Johnson syndrome and toxic epidermal necrolysis.

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

Description of individual unwanted drug reactions

Diarrhea

Diarrhea was observed in 50% of patients during therapy with capecitabine. As a result of meta-analysis of 14 clinical studies involving more than 4700 patients receiving capecitabine therapy were identified covariates are statistically associated with an increased risk of diarrhea: increase the initial dose of capecitabine (in grams), the increase in the study treatment period (weeks), increasing 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

As a result of the analysis of the safety profile, 7 clinical trials with the participation of 949 patients who received capecitabine as monotherapy, the following adverse reactions were identified with a incidence 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%.

Unwanted reactions in specific patient groups

Elderly patients

In elderly patients ≥60 years of age who received capecitabine in the form of monotherapy or in combination with docetaxel, there was an increase in the incidence of undesired reactions of 3-4 grade 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 developing the palmar-plantar syndrome and diarrhea increases, while the risk of developing neutropenia, on the contrary, declined (see section "Dosing and Administration").

Floor

In female patients, the risk of developing the palmar-plantar syndrome and diarrhea is higher, while the risk of developing neutropenia, on the contrary, decreases.

Patients with renal insufficiency (see also sections "Dosage and administration", "Special instructions")

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-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 of acute overdose include nausea, vomiting, diarrhea, mucositis, irritation of the gastrointestinal tract and bleeding, 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:

With the simultaneous use of capecitabine with anticoagulants coumarinic series (warfarin and fenprokumone), there may be a violation of the coagulation and bleeding indicators, due to the intensification of their effects. Bleeding can occur after a few days or months from the start of treatment with capecitabine.

In studies of drug interaction after taking warfarin in a dose of 20 mg capecitabine increased AUC S-isomer of warfarin by 57%, with an increase in the international standardized ratio (INR) by 91%. Since the R-isomer was not affected, the results of the study show that capecitabine inhibits isoenzyme CYP 2C9, but does not affect isoenzymes CYP1A2 and CYP 3A4.

In patients taking the drug simultaneously Capamethin® FS and anticoagulants coumarinovogo number, you need to carefully monitor the coagulation indicators (prothrombin time and INR), the dose of anticoagulant should be selected in accordance with these indicators.

Phenytoin

With the simultaneous use of capecitabine and phenytoin increases the concentration of phenytoin in the blood plasma, due to suppression of the isoenzyme CYP2C9. Regular monitoring of the concentration of phenytoin in plasma is recommended.

Antacids

When co-administered capecitabine with antacids (containing aluminum and magnesium hydroxide) there was a slight increase in the concentration of capecitabine and 5'-DPPC in blood plasma; on the metabolites of 5'-DFUR, FU and FBAL they do not affect.

Calcium folinate

Calcium folinate does not affect the pharmacokinetics of capecitabine and its metabolites. The toxic effect of capecitabine may increase due to the influence of calcium folinate on its pharmacodynamics.

Sorivudine and its analogs

Clinically significant drug interaction between sorivudine and FU is described. This interaction can lead to a fatal increase in the toxicity of fluoropyrimidines, due to the suppression of dihydropyrimidine dehydrogenase. Therefore, one should not appoint capecitabine simultaneously with sorivudine or its structural analogues such as brivudine. It should be observed at least a four-week interval between the end of therapy with sorivudine or its structural analogues (including brivudine) and the beginning of treatment with capecitabine.

Oxaliplatin

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

Bevacizumab

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

Substrates of cytochrome P4502S9

Special studies of the drug interaction between capecitabine and other drugs metabolized by the 2C9 isoenzyme of the cytochrome P450 system were not performed except for warfarin. Caution should be exercised when administering capecitabine with cytochrome P4502C9 substrates.

Allopurinol

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

Interferon alfa

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

Radiation therapy

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

Special instructions:

Therapy capecitabine is carried out under the supervision of a doctor who has experience with antitumor chemotherapeutic drugs.

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

It is necessary to carry out thorough medical monitoring of manifestations of toxicity in patients receiving drug therapy Capametine® FS.

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 and compensate for the loss of electrolytes.

Standard antidiarrheal drugs (for example, loperamide) should be prescribed as soon as possible on medical grounds. According to the criteria of the National Cancer Institute of Canada (NCIC STS, version 2), diarrhea of the 2nd degree is defined as the increase in stool to 4-6 times a day or stool at night; diarrhea 3rd degree - as a stool up to 7-9 times a day or incontinence and malabsorption syndrome; diarrhea of the 4th degree - as a 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, 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 should be modified in accordance with the recommendations for adverse events leading to dehydration.

Range cardiotoxicity when treated with capecitabine is similar to that with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, heart failure, and ECG changes. These undesirable phenomena are more typical for patients suffering from coronary artery disease in the anamnesis. Care must be taken in patients with arrhythmia and angina in history.

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

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

In rare cases, unexpected severe toxic effects (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-FU are due to inadequate dihydropyrimidine dehydrogenase (DPD) activity. Thus, it is impossible to exclude the connection between the decreased activity of DPD and the more pronounced, potentially lethal toxicity of FU.

Patients should be monitored for ophthalmologic 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.

Capecitabine can cause the development of such serious skin reactions as Stevens-Johnson syndrome and toxic epidermal necrolysis. With the development of severe skin reactions against the background of the drug Capamethin® FS The drug should be discontinued and not restarted.

The manifestation of skin toxicity of capecitabine is the development of palmar dyspnea syndrome (synonyms - palmar-plantar erythrodysesthesia or erythema acroma caused by chemotherapy). The severity of the development of toxicity varies from the 1st degree to the 3rd degree. Palmar-plantar syndrome of the 1st degree does not disturb the daily activity of the patient and is manifested by numbness, dysesthesia / paresthesia, tingling or redness of the palms and / or soles, discomfort. Palmar-plantar syndrome of the 2nd degree is characterized by painful reddening and swelling of the hands and / or feet, and the discomfort caused by these symptoms disrupts the daily activity of the patient. Paladno-plantar syndrome of the third degree is defined as wet desquamation, ulceration, blistering and sharp pains in hands and / or feet, and also severe discomfort, making it impossible for the patient to any kinds of daily activities. If palmar-plantar syndrome occurs 2nd or 3rd degree, therapy with Kapametin® FS should be discontinued until symptoms disappear or decrease to 1-stdegree. If there is a syndrome of 3rd degree, subsequent doses of the drug Kapametin® FS should be reduced.

Vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of palmar-plantar syndrome in the appointment of 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.

Capecitabine may cause hyperbilirubinemia. If in connection with treatment with the drug, hyperbilirubinemia> 3.0 x VGN (upper limit of the norm) or an increase in the activity of "hepatic" aminotransferases (ALT, ACT)> 2,5хVGN, treatment should be interrupted. The therapy can be resumed with a decrease in the concentration of bilirubin and the activity of "hepatic" aminotransferases below these limits.

In patients 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.

The use of the drug in elderly patients

The incidence of toxic effects from the gastrointestinal tract in patients with colorectal cancer aged 60-79 years receiving capecitabine monotherapy did not differ from that in the general population by the patient.

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, can develop more often.

In patients ≥65 years of age receiving combination therapy with capecitabine and other drugs may increase the incidence of adverse reactions of third and fourth degree and adverse events compared to patients younger than 65 years.

In patients ≥60 years of age who are receiving combination therapy with capecitabine and docetaxel, the incidence of third- and fourth-degree adverse events associated with therapy, serious adverse events and early withdrawal of therapy due to adverse events may increase as compared with that in patients younger 60 years.

Renal insufficiency

Care should be taken when prescribing the drug Capamethin® FS patients with moderate renal insufficiency. As with treatment with fluorouracil, the incidence of development of adverse events associated with the treatment of the 3rd and 4th degree of severity is higher in patients with moderate renal insufficiency (QA 30-50 ml / min).

Liver failure

Patients with hepatic impairment during drug therapy Capamethin® FS 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.

The use of the drug in patients with preserved reproductive potential

During drug therapy Capamethin® FS and at least within 3 months after its end, reliable methods of contraception should be used. If the pregnancy occurred during the period of therapy, the patient should be aware of the potential threat to the fetus.

Handling of 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:

When using the drug Capamethin® FS may develop side effects such as dizziness, reduced visual acuity, weakness, nausea, etc. When these undesirable phenomena appear, one should refrain from managing vehicles and working with mechanisms, as well as from engaging in other potentially hazardous activities requiring increased concentration and speed psychomotor reactions.

Form release / dosage:

Film-coated tablets, 150 mg and 500 mg.

Packaging:

Tablets, film-coated, 150 mg

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

For 60 tablets in bottles of polyethylene or polyethylene terephthalate, sealed with polyethylene lids. A self-adhesive label is attached to the vial.

For 6 contour packagings or one bottle together with the instruction for use are placed in a cardboard box.

Film coated tablets 500 mg

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

For 120 tablets in bottles of polyethylene or polyethylene terephthalate, sealed with polyethylene caps. A self-adhesive label is attached to the vial.

For 12 contour packagings or one bottle together with the instructions for use are placed in a cardboard box.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003440

Date of registration:02.02.2016 / 23.03.2016

Expiration Date:02.02.2021

The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia

Manufacturer: & nbsp

NATIVA, LLC Russia

FARMSTANDART-UFAVITA, JSC Russia

Representation: & nbspPHARMSTANDART-Ufa-VITA, JSCPHARMSTANDART-Ufa-VITA, JSC

Information update date: & nbsp30.11.2017

Illustrated instructions

Instructions

Capamethin® FS (Capamethin® FS)