Tutabin - instructions for use, doses, side effects, contraindications

Excipients: lactose, corn starch, cellulose microcrystalline, croscarmellose, povidone, silicon dioxide colloid, magnesium stearate, opadrai II orange (polyvinyl alcohol, titanium dioxide, macrogol, aluminum aluminum lacquer (dye quinoline yellow), lacquer aluminum red (dye red charming).

Description:Biconvex tablets covered with a film coat of orange-pink 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 is converted into 5-fluorouracil (5-FU), which, undergoes further metabolism. The formation of 5- FU occurs in the tumor tissue under the action of a tumor angiogenic factor - thymidine phosphorylase, which minimizes the systemic effect of 5-FU on healthy body tissues.

Sequential enzymatic biotransformation of capecitabine in 5-FU creates higher drug concentrations in tumor tissues than in surrounding healthy tissues. 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, cervical and ovarian cancer, there is a higher concentration of thymidine phosphorylase, capable of converting 5'-DFUR (5'-deoxy-5-fluorouridine) to 5-FU than in the corresponding healthy tissues.

Both healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FUDF) and 5-fluorourea 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 an essential precursor of thymidine triphosphate, which, in turn, is extremely is important for the synthesis of DNA, 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 FUTM 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) Of 5'-DFUR and the next metabolite of 5-FU affects slightly. With a single dose of capecitabine in patients with solid tumors (Cmah) capecitabine was 2.96 μg / ml, 5'-DFUR - 5.73 μg / ml. The time to reach the maximum concentration (Tmah) capecitabine - 2 h (0.27-4.05 h), 5'-DFUR -2h (0.5-4.13 h). AUC0-24 h for capecitabine was 3.97 μg x h / ml, for 5'-DFUR - 10.87 μg x h / ml; AUC_inf capecitabine - 5.12 μg x h / ml, 5'-DFUR - 12.1 μg x h / ml.

Distribution (binding with proteins)

In vitro capecitabine, 5'-DFTST, 5'-DFUR and 5-FU bind to proteins (mainly serum albumin) by 54%, 10%, 62% and 10%, respectively.

Metabolism

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

Metabolites of capecitabine become cytotoxic only after conversion to 5-FU and metabolites of 5-FU.

5-FU is further catabolized with the formation of inactive metabolites - dihydro-5-fluorouracil (FUN₂), 5-fluoroureidopropionic acid (FCCA) and α-fluoro-β-alanine (FBAAL) under the action of dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.

Excretion

The half-life (T1 / 2) of capecitabine, 5'-DFUR was about 0.8 and 0.6 hours, respectively. In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, except for 5-FU, are dose-dependent.

After taking capecitabine, its metabolites are excreted mainly in the urine. Most (about 95%) of the dose of capecitabine taken is excreted in the urine (the main metabolite in the urine is FBAL (about 57% of the dose taken), about 3% of the dose taken is unchanged). With feces about 2.6% are excreted.

Pharmacokinetics in various 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, the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) did not significantly affect the pharmacokinetic properties of 5'-DFUR, 5-FU, and FBAL.

Patients with metastatic liver damage: in patients with mild to moderate liver function disorders caused by metastases, there is no clinically significant change in the pharmacokinetics of capecitabine.Data on pharmacokinetics in patients with severe impairment of liver function are absent.

Patients with impaired renal function: the pharmacokinetics of capecitabine and 5-FU does not depend on creatinine clearance (CC). QC affects the magnitude AUC 5'-DFUR is the immediate precursor of 5-FU (AUC increases by approximately 35% with a decrease in the CK by 50%).

Elderly patients: age did not affect the pharmacokinetics of 5'-DFUR and 5-FU.

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

Indications:

Mammary cancer

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

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

Colorectal cancer

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

- tTherapy of metastatic colorectal cancer.

Stomach cancer

- Therapy of the first line of common stomach cancer.

Contraindications:

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

- ghypersensitivity to fluorouracil or when there are reported cases of unexpected or severe adverse reactions to treatment with fluoropyrimidine derivatives in the anamnesis;

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

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

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

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

- PIn the presence of contraindications to one of the drugs of combination therapy;

- bPregnancy and period of breastfeeding;

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

Carefully:

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

Pregnancy and lactation:

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

Dosing and Administration:

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

Standard dosing regimen

Monotherapy

Colorectal cancer, colon cancer and breast cancer

At 1250 mg / m² 2 times a day - morning and evening (total daily dose of 2500 mg / m²) within 14 days from the next 7-day break.

Combination Therapy

In case of breast cancer, 1,250 mg / m² 2 times a day for two weeks followed by a seven-day break, in combination with docetaxel at a dose of 75 mg / m² once every three weeks as an intravenous infusion for 1 hour.

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

With colorectal cancer and stomach cancer, Tutabin® as part of combination therapy is prescribed in a dose reduced to 800-1000 mg / m² 2 times a day for two weeks followed by a seven-day break or up to 625 mg / m² 2 times a day in continuous mode.The addition of immunobiological drugs to combination therapy does not affect the dose of Tutabin®.

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

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

The following tables show examples of calculating the standard and reduced dose of Tutabin® for an initial dose of 1250 mg / m² or 1000 mg / m²

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

Body surface area (m²)	Dose - at 1250 mg / m² twice a day
	Full dose 1250 mg / m²	The number of tablets 150 mg and / or 500 mg per reception (for each appointment twice a day - in the morning and in the evening)		Reduced dose (75% of initial dose) 950 mg / m²	Reduced dose (50% of the initial dose) 625 mg / m²
	Dose for admission (mg)	150 mg	500 mg	Dose for admission (mg)	Dose for admission (mg)
<1,26	1500	-	3	1150	800
1,27- 1,38	1650	1	3	1300	800
1,39- 1,52	1800	2	3	1450	950
1,53- 1,66	2000	-	4	1500	1000
1,67- 1,78	2150	1	4	1650	1000
1,79- 1,92	2300	2	4	1800	1150
1,93 -2,06	2500	-	5	1950	1300
2,07-2,18	2650	1	5	2000	1300
>2,19	2800	2	5	2150	1450

Table 2. Standard and reduced doses of Tutabin® for the initial dose of 1000 mg / m², calculated depending on the surface area of the body.

Body surface area (m²)	The dose of 1000 mg / m² twice a day
	The total dose of 1000 mg / m²	The number of tablets 150 mg and / or 500 mg per reception (for each appointment twice a day - in the morning and in the evening)		Reduced dose (75% of the initial dose) 750 mg / m²	Reduced dose (50% of the initial dose) 500 mg / m²
	Dose for admission (mg)	150 mg	500 mg	Dose for admission (mg)	Dose for admission (mg)
<1,26	1150	1	2	800	600
1,27- 1,38	1300	2	2	1000	600
1,39-1,52	1450	3	2	1100	750
1,53 - 1,66	1600	4	2	1200	800
1,67 -1,78	1750	5	2	1300	800
1,79-1,92	1800	2	3	1400	900
1,93-2,06	2000	-	4	1500	1000
2,07-2,18	2150	1	4	1600	1050
>2,19	2300	2	4	1750	1100

Correction of dose during treatment

General recommendations

Toxic effects of Tutabin® can be eliminated by symptomatic therapy and / or dose adjustment (interrupting treatment or reducing the dose of the drug). If the dose had to be reduced, you can not increase it later.

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

With toxicity of the 1st degree, the dose is not changed. With toxicity of the second or third degree, therapy with Tutabin® should be discontinued.

With the disappearance of signs of toxicity or a reduction in the latter to grade 1, treatment with Tutabin® can be resumed in a full dose or adjusted according to the recommendations in Table 3.

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

Hematological toxicity

Therapy with Tutabin® should be discontinued if signs of hematological toxicity of 3rd or 4th degree are found.

The table below shows recommendations for changing the dose of Tutabin® in case of development of toxic effects associated with its use.

Table 3. Scheme of correction of Tutabin®

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

* According to Societyandthe Group's clinical toxicity criteria. Research of the National Cancer Institute of Canada (NCIC SRT, version 1) or the common terminology criteria for adverse events of the Program for the Evaluation of Antitumor Therapy of the National Cancer Institute (STAAE, version 3). The criteria for toxicity of the palmar-plantar syndrome and hyperbilirubinemia are described in detail in the "Special instructions" section.

General recommendations for combination therapy

In the event of occurrence of toxicity in combination therapy, the recommendations for dose adjustment of Tutabin® indicated in Table 3 above should be followed,and the corresponding recommendations in the instructions for the use of other drugs. At the beginning of the therapy cycle, if a delay is expected with the taking of Tutabin® or another 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, toxic effects, according to the doctor, are not associated with Tutabin®, then drug therapy Tutabin® 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 Tutabin® can be continued if the Tutabin® drug regimen is approved. 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 mild or moderate impairment of liver function. However, these patients should be carefully monitored.The use of the drug in patients with severe hepatic insufficiency has not been studied.

Impaired renal function

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

In case the patient develops an undesirable phenomenon of the 2nd, 3rd or 4th degree of severity, careful monitoring and immediate interruption of the therapy should be carried out in order to subsequently correct the dose of the drug in accordance with the recommendations indicated in Table 3. If the calculated creatinine clearance decreased during the therapy to less than 30 ml / min, therapy with Tutabin® should be discontinued. Recommendations for correcting the dose of the drug in case of moderate renal failure refer both to monotherapy and to combination therapy. Calculation of the dose is indicated in Tables 1 and 2.

Children

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

Patients of elderly and senile age

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

When Tutabin® was used in combination with other antitumor drugs in elderly patients (aged> 65 years), undesirable reactions of the 3rd and 4th degree of severity, as well as undesirable reactions requiring the abolition of therapy, were noted more often than in younger patients. A careful monitoring of the condition of elderly patients is recommended.

When treated in combination with docetaxel in patients aged 60 years and older, there is 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 receive a combination of Tutabin® with docetaxel, it is recommended that the initial dose of Tutabin® be reduced to 75% (950 mg / m² twice a day). Calculation of the dose is given in Table 2. In combination with irinotecan in patients 65 years of age and older, it is recommended that the initial dose of Tutabin® be reduced to 800 mg / m² 2 times a day.

Side effects:

The frequency of development of undesired 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.

The undesirable reactions with monotherapy with capecitabine are listed below.

From the side of metabolism: very often - anorexia; often - dehydration, decreased appetite, weight loss; infrequently - diabetes, hypokalemia, hypertriglyceridemia, digestive disorders.

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

Malignant, benign and other unknown neoplasms: infrequently - a lipoma.

From the nervous system: often - headache, dizziness (except vertigo), paresthesia, dysgeusia (perversion of taste), drowsiness; infrequently - aphasia, memory impairment, ataxia, syncope, imbalance and coordination, loss of sensitivity, peripheral neuropathy.

From the psychic sphere: often - insomnia, depression; infrequently - confused consciousness, panic attacks, depressed mood, decreased libido.

From the side of the organ of vision: often - increased tear, conjunctivitis, irritation of the mucous membrane of the eyes; infrequent - reduced visual acuity, diplopia.

From the side of the hearing organ: infrequently - vertigo, pain in the ear.

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

From the side of the cardiovascular system: often - thrombophlebitis; infrequently - unstable angina, angina pectoris, myocardial ischemia, atrial fibrillation, arrhythmia, tachycardia, incl. sinus, palpitation, increased blood pressure, lower blood pressure, cold extremities, deep vein thrombosis, petechiae, "hot flashes".

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

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

From the immune system: infrequently, hypersensitivity reactions.

From the liver and bile ducts: often - violations of the liver, hyperbilirubinemia; infrequently, jaundice.

From the side of the musculoskeletal system: often - pain in the limbs, back pain, arthralgia; infrequently - pain in the bones, stiffness of muscles and joints, muscle weakness, swelling of the joints.

From the side of reproductive systemss: infrequently - menorrhagia.

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

From the urinary system: infrequently - hydronephrosis, involuntary urination, hematuria, nocturia, an increase in the concentration of creatinine in the blood.

From the body as a whole: very often - asthenia, increased fatigue; often - fever, pain in the chest, peripheral edema, anxiety, drowsiness; rarely - swelling, fever, shaking, chills, flu-like conditions.

The following undesirable reactions are manifestations of toxicity known in the treatment of fluoropyrimidines; reported at least on the indirect link between the development of such reactions and the use of capecitabine:

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

from the cardiovascular system: swelling of the lower extremities, cardialgia, including angina pectoris,cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including atrial fibrillation, ventricular extrasystoles;

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

on the part of the psychic sphere: Depression;

infection: infectious complications associated with myelosuppression, immunosuppression and / or mucosal integrity disorders, such as local and fatal systemic infections (bacterial, viral or fungal etiology) and sepsis;

from the hematopoietic system: anemia, myelosuppression / pancytopenia; from the side of the skin: itching, frontal skin peeling, hyperpigmentation of the skin, nail changes, photosensitization reactions, a syndrome resembling radiation dermatitis;

sensory organs: eye irritation; from the respiratory system: shortness of breath, cough;

from the musculoskeletal system: arthralgia, myalgia, back pain; Other: asthenia, chest pain (non-cardial etiology), pain in the extremities, increased drowsiness.

Individual cases (very rarely) of stenosis of the lacrimal tubule, liver failure and cholestatic hepatitis were also recorded. The causal relationship with the administration of capecitabine has not been established.

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

Overdose:

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

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

Interaction:

Coumarin anticoagulants

The patients who took capecitabine simultaneously with anticoagulants coumarinic series (warfarin and fenprocumone), violations of coagulation factors and / or bleeding in a few days or months from the beginning of therapy with capecitabine,and in several cases - within one month after its completion.

After a single administration of warfarin in a dose of 20 mg capecitabine increased AUC S- warfarin by 57%, and MNO - by 91%. In patients who simultaneously take capecitabine and anticoagulants coumarinovogo number, you must carefully monitor the coagulation indicators (prothrombin time or INR); The dose of anticoagulant should be selected in accordance with these indicators.

Substrates of cytochrome P4502S9

Special studies of the drug interaction between capecitabine and other drugs metabolized by the 2S9 isoenzyme of the cytochrome P450 system were not carried out. Care should be taken when prescribing Tutabin® concomitantly with such medications.

Phenytoin

With the simultaneous administration of capecitabine and phenytoin, an increase in the concentration of the latter in plasma was reported. Special studies of the inter-drug interaction between capecitabine and phenytoin have not been conducted, but it is assumed that the basis of the mechanism of interaction is the suppression of the isoenzyme CYP2C9 under the influence of capecitabine (see Fig.above "Anticoagulants coumarinovogo number"). Patients receiving concomitantly phenytoin and drug Tutabin®, it is necessary to regularly monitor the concentration of phenytoin in the plasma.

Antacids

When assessing the pharmacokinetic parameters of capecitabine with simultaneous administration of antacids containing aluminum hydroxide and magnesium hydroxide, there was a slight increase in the concentration of capecitabine and one of the metabolites (5-DPPC) in blood plasma. Three study metabolites of capecitabine (5-DFUR, 5-FU and FBAL) did not affect the investigational drugs.

Calcium folinate

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

Sorivudine and its analogs

In the literature, a clinically significant drug interaction between sorivudine and fluorouracil is described, which is based on the inhibitory effect of sorivudine on the fatal increase in the toxicity of fluoropyrimidines. Therefore, do not prescribe Tutabin® concurrently with sorivudine or its structural analogues such as brivudine.Observe at least a 4-week interval between the end of therapy with sorivudine or its structural analogues (including brivudine) and initiation of treatment with Tutabin®.

Allopurinol

There was an interaction of allopurinol and fluorouracil with a possible decrease in the effectiveness of fluorouracil, therefore simultaneous administration of capecitabine and allopurinol should be avoided.

Interferon alfa

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

Oxaliplatin

A clinically significant difference in the exposure of capecitabine or its metabolites, unbound platinum and total platinum in the combined use of capecitabine and oxaliplatin, regardless of the presence of bevacizumab, has not been observed.

Bevacizumab

The clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites was not observed in the presence of oxaliplatin.

Radiation therapy

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

Special instructions:

It is necessary to conduct thorough medical control of toxicity manifestations in patients receiving therapy with Tutabin®.

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 Tutabin® can cause diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored, and with the development of dehydration it is necessary to rehydrate or compensate for the loss of electrolytes. Standard antidiarrheal drugs (for example, loperamide) should be prescribed as soon as possible on medical grounds. If necessary, reduce the dose of Tutabin®.

Dehydration: dehydration should be prevented or eliminated at the outset of the occurrence. Dehydration can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea.

With the development of dehydration of 2 degrees or higher, treatment with Tutabin® should be immediately interrupted and rehydrated. Treatment can not be resumed until the completion of rehydration and elimination or correction of the factors that caused it. The dose of the drug should be modified in accordance with the recommendations for adverse events leading to dehydration.

Range cardiotoxicity when treated with capecitabine is similar to that with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiogenic shock, sudden death and changes in the ECG. These adverse events are more common in patients with concomitant IHD. In cases of capecitabine, there have been reports of arrhythmias, myocardial infarction, heart failure, and cardiomyopathy. Care must be taken when using the drug in patients with a history of severe heart disease, arrhythmia, angina.

In rare cases, unexpected severe toxicity phenomena (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with fluoropyrimidine treatment are due to inadequate activity of DPD.Thus, the relationship between reduced activity of DPD and a more pronounced, potentially lethal toxicity of fluoropyrimidines can not be ruled out.

Manifestation skin toxicity Tutabin® is the development of the palmar-plantar syndrome (synonyms - palmar-plantar erythrodysesthesia or erythema acroma caused by chemotherapy). The median time to development of manifestations of toxicity in patients receiving capecitabine monotherapy was 11 to 360 days, and the degree of severity ranged from grade 1 to grade 3. Palmar-plantar syndrome of the 1st degree does not disturb the daily activity of the patient and is manifested by numbness, dysesthesia / paresthesia, tingling or flushing 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 Tutabin® should be discontinued until symptoms disappear or decrease to 1 degree. If there is a syndrome of 3rd degree, subsequent doses of Tutabin® should be reduced.

Vitamin B (pyridoxine) is not recommended for symptomatic or secondary preventive treatment of palmar-plantar syndrome with Tutabin® in combination with cisplatin, as it may reduce the effectiveness of cisplatin.

Tutabin® can cause hyperbilirubinemia. If in connection with treatment with Tutabin®, hyperbilirubinemia> 3.0xVGN (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 bilirubin and the activity of "hepatic" aminotransferases below these limits.

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

The use of the drug in elderly and senile patients

The incidence of toxic effects from the gastrointestinal tract in patients with colorectal cancer aged 60-79 years who received capecitabine monotherapy did not differ from that in the general population of patients. In patients 80 years and older reversible adverse events from the gastrointestinal tract of the 3rd and 4th degree, such as diarrhea, nausea and vomiting, developed more often. In patients> 65 years of age who received combination therapy with capecitabine and other antitumor drugs, there was an increase in the incidence of adverse reactions of 3rd and 4th severity and adverse events that led to discontinuation of therapy compared to younger patients. 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 prescribing Tutabin® to patients with moderate renal insufficiency. As with treatment with fluorouracil, the incidence of adverse events of the 3rd and 4th degree of severity associated with the therapy was higher in patients with concomitant renal insufficiency of moderate severity (CK 30-50 ml / min).

Liver failureь

Patients with hepatic insufficiency during therapy with Tutabin® should be under close medical supervision. The effect of a violation of liver function, not due to metastatic liver damage or severe hepatic insufficiency, is not known for the distribution of Tutabin®.

During therapy with Tutabin® and at least 3 months after its 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.

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

It is likely that Tutabin® can have an undesirable effect on the ability to drive a car and work with mechanisms,since this drug can cause confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, imbalance and coordination), increased drowsiness.

Form release / dosage:

Tablets, film-coated, 500 mg.

Packaging:

For 10 tablets in a blister of PVC / Al.

For 12 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-008789/10

Date of registration:26.08.2010

The owner of the registration certificate:Laboratory Tutor SAASIFAALaboratory Tutor SAASIFAA Argentina

Manufacturer: & nbsp

Laboratorio TUTEUR S.A.C.I.F.I.A. Argentina

Representation: & nbspHEAD OF MEDICA SAHEAD OF MEDICA SASwitzerland

Information update date: & nbsp11.07.2012

Illustrated instructions

Instructions

Tutabin® (Tutabin®)