–Adjuvant therapy for colon cancer III stage after surgical treatment.
–Therapy of the first line of general stomach cancer.
–Therapy of metastatic colorectal cancer
Xeloda– An antineoplastic drug associated with antimetabolites and having in its composition a component that is capable of activating in the tumor tissue and exerts selective cytotoxic effects on it.
Antineoplastic agents. Antimetabolites. Analogs of pyrimidine.Capecitabine.
After oral administration, capecitabine is absorbed rapidly and completely, after which it is converted into metabolites-5'-deoxy-5-fluorocytidine (5'-DFTST) and 5'-deoxy-5-fluorouridine (5'-DFUR). The food slows the rate of absorption of capecitabine, but the effect on the AUC value of 5'-DFUR and the next metabolite, 5-fluorouracil (5-FU), is insignificant. When the drug was administered after meals at a dose of 1250 mg / m2 on the 14th day, Cmax capecitabine, 5'-DFTST, 5'-DFUR, 5-FU and α-fluoro-β-alanine (FBAL) were 4.47, respectively;3.05; 12.1; 0.95 and 5.46 μg / ml. The time to reach the maximum concentration (Tmax) was 1.50; 2.00; 2.00; 2.00 and 3.34 hours, and the AUC is 7.75; 7.24; 24.6; 2.03 and 36.3 μg × h / ml, respectively.
Research invitro showed that 54%, 10%, 62% and 10%, respectively, for capecitabine, 5'-DFTST, 5'-DFUR and 5-FU, respectively, with proteins (mainly albumin).
Capecitabine is metabolized in the liver under the influence of carboxyl esterase to the metabolite 5'-DFTST, which is then transformed into 5'-DFUR under the action of cytidine deaminase, located mainly in the liver and tumor tissues.
Further transformation to the active cytotoxic metabolite of 5-FU occurs predominantly in tumor tissue under the action of tumor angiogenic factor-thymidine phosphorylase (dTdPase);while the systemic effect of 5-FU on healthy tissues is minimized.
AUC for 5-FU is 6-22 times less than after intravenous (in / in) jet administration of 5-FU in a dose of 600 mg / m2. Metabolites capecitabine become cytotoxic only after conversion to 5-FU and anabolite 5-FU (see section "Mechanism of action").
Further, 5-FU is catabolized with the formation of inactive metabolites - dihydro-5-fluorouracil (FUNH2), 5-fluoroureidopropionic acid (FCCC) and α-fluoro-β-alanine (FBAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.
The half-life (T1 / 2) of capecitabine, 5'-DFTST, 5'-DFUR, 5-FU and FBAL is 0.85; 1.11; 0.66; 0.76 and 3.23 hours, respectively. The pharmacokinetics of capecitabine was determined in the dose range from 502 to 3514 mg / m2 / day. The pharmacokinetic parameters of capecitabine, 5'-DFTST and 5'-DFUR on the 1 st and 14 th day are the same. AUC 5-FU increases by the 14th day by 30-35%, and no longer increases (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, except for 5-FU, are dose-dependent.
After oral administration, metabolites of capecitabine are excreted mainly with urine (95.5%). Excretion with feces is minimal (2.6%). The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose is excreted unchanged in the urine.
Phase 1 studies of the effect of capecitabine on the pharmacokinetics of docetaxel and paxitaxel and inverse dependence showed no effect of capecitabine on the pharmacokinetic parameters of docetaxel and paxitaxel (Cmax and AUC) or the effects of docetaxel and paxitaxel on the pharmacokinetics of 5'-DFUR (the main metabolite of capecitabine).
Pharmacokinetics in specific patient categories
Based on the data of capecitabine in 505 patients with colorectal cancer (1250 mg / m2 twice a day), a population pharmacokinetic analysis was performed. Sex, the presence or absence of liver metastases before the start of treatment, the index of the general condition of the patient (Carnofsky index), the concentration of total bilirubin, serum albumin, the activity of ALT and AST did not have a statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.
Patients with metastatic liver disease
In patients with mild to moderate liver failure due to metastases, there is no clinically significant change in the pharmacokinetics of capecitabine and its biological activity (see the section on dosing for specific patient categories).
Data on the pharmacokinetics in patients with severe liver dysfunction are absent.
Patients with renal insufficiency
According to the pharmacokinetic study at varying degrees (from mild to severe) of renal failure, the pharmacokinetics of the unchanged drug and 5-FU does not depend on the creatinine clearance. Creatinine clearance affects the AUC value of 5'-DFUR (35% increase in AUC with 50% decrease in creatinine clearance) and FBAL (114% increase in AUC with 50% decrease in creatinine clearance). FBAL is a metabolite that does not possess antiproliferative activity; 5'-DFUR is the immediate precursor of 5-FU (see section on dosing for specific patient categories).
Population pharmacokinetic analysis, which encompassed patients of various ages (27 to 86 years), including 234 (46%) patients aged ≥65 years, showed that age does not affect the pharmacokinetics of 5'-DFUR and 5-FU. AUC FBAL increased in patients aged 65 years and older (an increase in age by 20% was accompanied by an increase in FUC AUC by 15%), which is probably due to a change in renal function (see the section on dosing for specific patient categories and the section " Pharmacokinetics for special categories of patients ", subsection" Patients with renal insufficiency ").
Population pharmacokinetic analysis, which covered 455 patients of the Caucasoid race (90.1%), 22 patients of Negroid race (4.4%) and 28 patients of other races and ethnic groups (5.5%), showed that the pharmacokinetics in patients of the Negroid race did not differ from that in Caucasoid patients race.
Mechanism of action
Xeloda is a derivative of fluoropyrimidine carbamate, an oral cytotoxic agent that activates in the tumor tissue and exerts a selective cytotoxic effect on it. In vitro, capecitabine has no cytotoxic effect, whereas in vivo it is converted to 5-FU, which undergoes further metabolism. The formation of 5-FU occurs in tumor tissue under the action of tumor angiogenic factor - thymidine phosphorylase (dTdPase), 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. After oral administration of Xeloda to patients with colon cancer, the concentration of 5-FU in the tumor tissue was 3.2 times higher than in the adjacent healthy tissues. The ratio of concentrations of 5-FU in tumor tissue and plasma - an average of 21.4 (3.9-59.9), the ratio of its concentration in healthy tissues and in plasma - 8.9 (3.0 - 25.8). 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, 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-fluorouridine tri-phosphate (FUTF). These metabolites damage the cells through two different mechanisms. First, FUUM and the folate cofactor N5-10-methylenetetrahydrofolate bind to thymidylate synthetase to form a covalently bound tertiary complex. This binding inhibits the formation of thymidylate from uracil. Timidylate 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 FUTM in it instead of uridine triphosphate (UTP). This metabolic "error" disrupts RNA reproduction and protein synthesis.
Indications for use
in combination with docetaxel is used to treat patients with locally advanced or metastatic breast cancer (BC) after ineffective chemotherapy involving anthracyclines
in the form of monotherapy for the treatment of patients with locally advanced or metastatic breast cancer (MMR) after ineffective chemotherapy involving taxanes and anthracyclines, or those who are contraindicated with anthracyclines
as an adjuvant therapy for patients with colon cancer
for the treatment of patients with metastatic colorectal cancer (mCRC)
as the first line of therapy for patients with advanced gastrointestinal cancer.
in combination with oxaliplatinum is used as an adjuvant therapy for patients with stage II and III adenocarcinoma of stomach after complete resection
Dosing and Administration
Xeloda tablets are taken orally, 30 minutes after eating, with water.
Breast cancer, colon and colorectal cancer:
The recommended initial dose of Xeloda for monotherapy is 1250 mg / m2 twice a day (morning and evening), equivalent to a total daily dose of 2500 mg / m2 for two weeks followed by a break of 7 days.
In combination with docetaxel, Xeloda is administered at a dose of 1250 mg / m2 twice a day for 2 weeks, followed by a break of 7 days. Docetaxel is administered at a dose of 75 mg / m2 as a one-hour intravenous infusion once every 3 weeks. Before the introduction of docetaxel with Xeloda, premedication is performed in accordance with the instructions for the use of docetaxel.
Esophageal-gastric cancer, stomach, colon and colorectal cancer :
With combined therapy (with the exception of irinotecan), the recommended initial dose of Xeloda is reduced to 800-1000 mg / m2 twice a day for two weeks, followed by a break of 7 days, or up to 625 mg / m2 twice a day with continuous therapy (see section Clinical studies / Efficacy studies).
In combined therapy with irinotecan (XELIRI), the recommended initial dose of Xeloda is 800 mg / m2 twice a day for 2 weeks, followed by a break of 7 days. Irinotecan is administered 200 mg / m2 on the first day of each three-week cycle (see Clinical Studies / Efficacy studies).
Inclusion in the combination therapy of bevacizumab does not affect the initial dose of Xeloda. Adjuvant therapy for patients with colorectal cancer of grade III is recommended for a total of 6 months.
Antiemetics and premedication to ensure adequate hydration are prescribed before the administration of cisplatin or oxaliplatin in accordance with the instructions for their use.
Correction of dose during treatment
The toxicity phenomena in the treatment of Xeloda can be eliminated by symptomatic therapy and / or changing the dose of Xeloda (interrupting treatment or reducing the dose of the drug). If once I had to reduce the dose of Xeloda, then in the future it should not be increased. In situations where the attending physician believes that the symptoms of toxicity do not pose a threat to the life of the patient, or their severity is not severe, Xeloda treatment can be continued at the initial dose without lowering the dose and without interrupting treatment.
With a toxicity of 1 degree, do not adjust the dose. At toxicity of 2 and 3 degrees reception of Xeloda should be suspended. After resolving undesirable phenomena or reducing their severity to 1 degree, Xeloda reception can be resumed in a full dose, or by adjusting it according to the recommendations given in Table 7. In developing signs of toxicity of the 4th degree, treatment should be discontinued or temporarily interrupted until the severity is reduced or reduced symptomatology up to 1 degree, after which the use of the drug can be resumed in a dose equal to 50% of the previous one. Patients taking Xeloda should be informed of the need to immediately stop treatment if severe or moderate toxicity occurs. Missed because of the toxicity of several techniques Xeloda is not replenished, but simply continue the planned cycles of therapy.
Patients with baseline neutrophils <1.5 x 109 / l and / or platelets <100 x 109 / l should not be treated with Xeloda. If the results of unscheduled laboratory tests conducted during treatment indicate hematological toxicity of the 3rd and 4th degree, Xeloda should be discontinued.
Special recommendations for dosing
Patients with hepatic insufficiency due to metastasis in the liver
In patients with mild or moderate hepatic insufficiency, there is no need to reduce the dose at the beginning of treatment. However, they need careful observation during treatment.Patients with severe hepatic impairment were not included in the study.
Patients with renal insufficiency
Patients with renal insufficiency of moderate severity (creatinine clearance 30-50 ml / min) at the beginning of treatment should reduce the dose to 75% of 1250 mg / m2. Patients with mild renal insufficiency (KK 51-80 ml / min) do not need a dose reduction.
If there is an undesirable phenomenon of 2-4 degree, immediate measures should be taken to carefully monitor its condition, if necessary, to cancel treatment and further dose adjustment in accordance with the recommendations in Table 3. If during the treatment the QC fell below 30 ml / min, reception of Xeloda should be discontinued. Recommendations for dose adjustment in patients with moderate renal insufficiency are for both Xeloda monotherapy and combined regimens. To calculate the daily dose, see tables 1 and 2.
Safety and efficacy of Xeloda in children is not established.
With Xeloda monotherapy, there is no need for dose adjustment. However, in patients older than 80 years, side effects of grade 3 and 4 are more common than in younger patients. With combined treatment in elderly people (over 65 years old), adverse reactions of grade 3 and 4 requiring Xeloda cancellation occur more often than in younger patients. Careful observation of elderly patients is recommended. In the treatment of Xeloda in combination with docetaxel, a higher incidence of adverse reactions of grade 3 and 4 and serious adverse events significantly associated with treatment was noted in the group of patients older than 60 years, compared with younger ones. Therefore, individuals over 60 years of age, with a combination of xeloda and docetaxel, require a reduction in the initial dose to 75% (950 mg / m2 twice a day). To calculate the dose, refer to Table 2.
The possible, probable and long-term relationship between Xeloda's intake and unwanted drug reactions (NLR) has been found in clinical studies of Xeloda's monotherapy (adjuvant therapy for colon cancer, metastatic colorectal cancer and metastatic breast cancer), as well as in studies of combined Xeloda and other preparations of chemotherapy of various diseases. In the tables below, NLRs are based on the frequency of their occurrence, as determined by a comprehensive analysis of seven clinical trials. Within each frequency category, NLRs are listed in descending order of severity. The frequency of undesired reactions is determined as follows: very often ≥ 1/10, often ≥ 5/100 - <1/10 and rarely ≥ 1/1000 and <1/100.
Monotherapy with Xeloda
Data on the safety of Xeloda monotherapy were obtained for patients receiving adjuvant treatment for colon cancer and patients treated for metastatic breast cancer and metastatic colorectal cancer. The safety information includes Phase III studies of adjuvant colon cancer therapy (995 patients received Xeloda and 974 patients received intravenously 5-FU / leucovorin), 4 phase II studies of patients with breast cancer (N = 319) and data 3 studies (Phase I study and 2 study III) in both sexes with colorectal cancer (N = 630). The safety profile of Xeloda in patients receiving adjuvant therapy for colon cancer, who received the drug for the treatment of metastatic breast cancer and metastatic colorectal cancer, is similar. The intensity of NLR was classified according to the NCIC CTC toxicity categories.* stomatitis, inflammation of the mucosa, ulceration of the mucosa, ulceration of the oral cavity.
A distant relationship between skin lesion and Xeloda was found in less than 2% of patients participating in 7 clinical trials (N = 949).
The following NLRs refer to toxic reactions to fluoropyrimidines and were at least remotely related to Xeloda intake in less than 5% of patients participating in seven clinical trials (N = 949):
Disorders from the gastrointestinal tract: dry mouth, flatulence, NLR associated with inflammation / ulceration of mucous membranes, including esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding.
Heart disorders: swelling of the lower extremities, chest pains, including angina pectoris, cardiomyopathy, ischemia / myocardial infarction, heart failure, sudden death, tachycardia, atrial arrhythmias, including atrial fibrillation and ventricular extrasystoles.
Disturbances from the nervous system: distortion of taste sensations, insomnia, confusion, encephalopathy, cerebellar symptoms (ataxia, dysarthria, imbalance and coordination).
Infectious and parasitic diseases: NLR associated with the suppression of bone marrow activity, weakened immunity and / or disruption of mucosal integrity, local and systemic infections (bacterial, viral, fungal), possibly fatal, sepsis.
Violations from the blood and lymphatic system: anemia, suppression of bone marrow / pancytopenia.
Disorders from the skin and subcutaneous tissues: pruritus, focal peeling, hyperpigmentation of the skin, dysfunction and discoloration of the nails, photosensitivity reactions, relapse of side effects of radiation therapy.
General disorders and reactions at the site of administration: asthenia, pain in the limbs, lethargy, chest pain (not associated with the heart).
Spotting disorders: eye irritation
Disturbances from the respiratory system: shortness of breath, cough
Disorders from the musculoskeletal system: back pain, myalgia, arthralgia
Mental disorders: depression
During clinical trials and during post-registration follow-up, cases of hepatic insufficiency and cholestatic hepatitis were documented. The causal relationship of these pathologies with Xeloda is not established.
known hypersensitivity to capecitabine or other components of the drug
known hypersensitivity to fluorouracil or serious and unforeseen reactions to fluoropyrimidine therapy
deficiency of dihydropyrimidine dehydrogenase (DPD)
simultaneous administration with sorivudine or its chemical analogs, for example, brivudine
severe renal failure (CC below 30 ml / min)
children under 18 years of age (efficacy and safety not studied)
If there are contraindications to any other drug combination therapy, then this drug can not be used.
Anticoagulants - coumarin derivatives
In patients who took Xeloda in conjunction with anticoagulants from the group of coumarin derivatives, such as warfarin or phenoprocumone, there were changes in coagulation and / or bleeding parameters. They arose from a few days to several months after the start of Xeloda (in one case - a month after its completion). When studying the drug interaction Xeloda, it was shown that the simultaneous administration of a single dose of warfarin 20 mg resulted in an increase in exposure to warfarin (AUC) by 57% and an increase in INR (the international normalizing ratio) by 91%. In patients taking capecitabine and oral anticoagulants - coumarin derivatives simultaneously, it is necessary to carefully monitor the clotting parameters (prothrombin time) and adjust the dose of anticoagulant accordingly.
Substrates of cytochrome P450 2C9
Special studies to study the interaction of capecitabine and drugs that are metabolized by isoenzyme 2C9 cytochrome P450 have not been performed. Therefore, joint appointment with Xeloda requires caution.
With the simultaneous use of Xeloda with phenytoin, an increase in its concentration in the blood plasma is observed. The mechanism of this interaction can be explained by the fact that capecitabine suppresses the system of 2C9 isoenzymes of cytochrome P450. If the patient takes phenethylin simultaneously with Xeloda, they need to monitor the concentration of phenytoin in the blood plasma.
Interaction with food
In all clinical trials, patients took Xeloda for 30 minutes after a meal. Since all safety and efficacy data are from study participants taking Xeloda after a meal, this is also recommended for other patients.
The effect of antacids containing aluminum and magnesium hydroxides was a slight increase in the concentration of capecitabine and one metabolite (5'-DPPC) in plasma; on three major metabolites (5'-DFUR, 5-FU and FBAL) they did not affect.
Leucovorin does not affect the pharmacokinetics of Xeloda and its metabolites, which is confirmed in the study of the pharmacokinetics of capecitabine when taken concomitantly with leucovorin in cancer patients. However, leucovorin affects the pharmacodynamics of Xeloda, and its toxicity may be enhanced in the presence of leucovorin.
Sorivudine and analogues
The clinically significant interaction between sorivudine and 5-FU, due to the suppression of DPD with sorivudine, leads to a potentially fatal increase in the toxicity of fluoropyrimidines. Therefore, Xeloda should not be taken concomitantly with sorivudine or its chemical analogues, such as brivudine.
With combined treatment with capecitabine and oxaliplatin with bevacizumab, or without it, there was no change in the pharmacokinetics of capecitabine and its metabolites, free or bound platinum.
There is no clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine and its metabolites.
Xeloda can cause diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored, in case of dehydration, to perform replacement therapy to restore the water and electrolyte balance. As early as possible, prescribe the appropriate medication (loperamide). If necessary, reduce the dose.
You should prevent dehydration, or treat as early as possible, if any. Patients with anorexia, asthenia, nausea and vomiting or diarrhea are more prone to dehydration. Admission Xeloda should immediately stop when dehydrating 2 degrees (or higher). Until the water balance is restored and any causes of thrombosis are resolved, treatment should not be resumed. If necessary, adjust the dose for side effects associated with increased blood coagulability.
The spectrum of cardiotoxicity of Xeloda is similar to other fluoropyrimidines. It includes changes in the ECG, myocardial infarction, angina pectoris, arrhythmias, cardiac arrest and heart failure. These undesirable phenomena are more typical for patients suffering from ischemic heart disease.
In rare cases, severe unintended manifestations of toxicity characteristic of 5-FU (such as stomatitis, diarrhea, neutropenia and neurotoxicity) are attributed to inadequate activity of DPD. It is impossible to exclude the connection between low DPD level and more pronounced, potentially fatal, toxicity of 5-FU.
Xeloda can cause severe skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) (see section Post-registration experience, Adverse events). When severe skin reactions, possibly associated with the use of Xeloda, appear, it is necessary to completely stop taking the drug.
The manifestation of skin toxicity is the development of palmar-plantar syndrome of 1-3 degrees of severity (synonyms: palmar-plantar erythrodysesthesia or erythema acroma caused by chemotherapy). The time to development is from 11 to 360 days, an average of 79 days.
Paladno-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 reddening 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.
The third degree of palmar-plantar syndrome is characterized by moist desquamation, ulceration, the formation of blisters and sharp pain in the hands and / or feet, causing severe discomfort in the patient, in which any kind of daily activity is impossible.
With the development of palm-plantar syndrome of 2 or 3 degrees, the use of Xeloda should be stopped until the symptoms disappear or reduce to 1 degree; with the initial 3 degrees of the syndrome, subsequent doses of capecitabine should be reduced (Table 3). When Xeloda is combined with cisplatin, in the case of palmar-plantar syndrome, the appointment of vitamin B6 (pyridoxine) for its symptomatic treatment or prevention is not recommended, as this may affect the effectiveness of cisplatin.
When treating Xeloda, the level of bilirubin in the blood can increase. If the level of bilirubin is more than 3 times, and the activity of hepatic aminotransferases (ALT, AST) is more than 2.5 times higher than the upper limit of the norm, Xeloda intake should be suspended. It can be resumed with a decrease in the level of bilirubin and the activity of hepatic transaminases below these limits.
When studying the drug interaction Xeloda, it was shown that the simultaneous administration of a single dose of warfarin leads to an increase in exposure to warfarin (AUC + 57%). This is attributed to the suppression of the cytochrome P450 2C9 isoenzyme system by capecitabine. In patients taking capecitabine and oral anticoagulants - coumarin derivatives simultaneously, it is necessary to carefully monitor the clotting parameters (prothrombin time) and adjust the dose of anticoagulant accordingly.
Patients taking Xeloda need to be closely monitored for signs of toxicity. Most adverse events are reversible and do not require withdrawal of treatment, but a dose reduction may be required.
Among the mCRC patients aged 60-79 years who received Xeloda as a monotherapy, the incidence of side effects from the gastrointestinal tract was the same as in the general population. In the group of patients 80 years and older, the incidence of reversible gastrointestinal side effects of grade 3 and 4, such as diarrhea, nausea and vomiting, was more frequent. With combined treatment in elderly people (over 65 years), adverse reactions of grade 3 and 4 requiring Xeloda withdrawal occur more often than in younger patients. In the treatment of Xeloda in combination with docetaxel, a higher incidence of adverse reactions of grade 3 and 4 and serious adverse events significantly associated with treatment was noted in the group of patients older than 60 years, compared with younger ones.
Doctors should be careful when prescribing Xeloda to patients with impaired renal function. The experience with the use of 5-FU shows that treatment-related adverse reactions of grade 3 and 4 are more likely to occur in patients with moderate renal insufficiency (CK 30-5 ml / min).
Patients with hepatic insufficiency need careful monitoring in the treatment of Xeloda. The effect of liver function abnormalities not associated with cancer metastases in the liver, or severe hepatic insufficiency on the pharmacodynamics of Xeloda is not known.
If Xeloda is used during pregnancy, or the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Women of childbearing age should be protected from pregnancy during treatment with Xeloda.
During treatment, Xeloda should stop breastfeeding.
Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms
Consider the possibility of developing side effects that can disrupt the ability to perform work that requires concentration and speed of the psychomotor reaction.
Symptoms of acute overdose: nausea, vomiting, diarrhea, mucositis, gastrointestinal disorders and bleeding, bone marrow depression.
Treatment: standard medical and supporting medical measures aimed at correcting clinical symptoms and preventing possible complications.
Form of production and packaging
10 tablets are placed in a contour mesh box made of PVC / PVDC film and aluminum foil.
Store at a temperature not exceeding 30°C.
Keep out of the reach of children!
3 years Do not use after the expiry date printed on the package