Universal reference book for medicines
Product name: TEYSUNO (TEYSUNO)

Active substance: tegafur

Type: Antitumor preparation

Manufacturer: NORDIC GROUP (Netherlands) manufactured by TAIHO PHARMACEUTICAL (Japan)
Composition, form of production and packaging
Capsules
hard gelatinous, opaque, size 4, cylindrical, with brown lid and white body, labeled "TC448" with gray ink on the capsule (lid and casing);
the contents of the capsules are a mixture of white powder and white granules.
1 caps.

tegafur 15 mg

gimeracil 4.53 mg

oteracil potassium 14.7 mg,

which corresponds to the content of oteracil 11.8 mg

[PRING] lactose monohydrate - 70.2 mg, magnesium stearate - 0.3 mg.

The composition of the shell: body: gelatin - 19.7752 mg, titanium dioxide - 0.84 mg, sodium lauryl sulfate - 0.0248 mg, talc *;
cap: gelatin - 13.4155 mg, titanium dioxide - 0.24 mg, iron oxide red - 0.088 mg, sodium lauryl sulfate - 0.0165 mg, talc *.
Ink composition: iron oxide red *, FD & C blue No. 2 aluminum lacquer (E132) *, carnauba wax *, shellac bleached *, glyceryl monooleate *.

* - contained in trace amounts.

14 pcs.
- blisters (3) - packs of cardboard.
14 pcs.
- blisters (6) - packs of cardboard.
14 pcs.
- blisters (9) - packs of cardboard.
Capsules hard gelatinous, opaque, size 4, cylindrical, with brown lid and white body, labeled "TC448" with gray ink on the capsule (lid and casing);
the contents of the capsules are a mixture of white powder and white granules.
1 caps.

tegafur 20 mg

gimeracil 5.8 mg

oteracil potassium 19.6 mg,

which corresponds to the content of oteracil 15.8 mg

[PRING] lactose monohydrate - 93.6 mg, titanium dioxide - 0.4 mg.

The composition of the shell: body: gelatin - 19.7752 mg, titanium dioxide - 0.84 mg, sodium lauryl sulfate - 0.0248 mg, talc *;
lid: gelatin - 13.1835 mg, titanium dioxide - 0.56 mg, sodium lauryl sulfate - 0.0165 mg, talc *.
Ingredients of ink: iron oxide red *, iron oxide yellow *, FD & C blue No. 2 aluminum varnish (E132) *, carnauba wax *, shellac bleached *, glyceryl monooleate *.

* - contained in trace amounts.

14 pcs.
- blisters (3) - packs of cardboard.
14 pcs.
- blisters (6) - packs of cardboard.
14 pcs.
- blisters (9) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

Teisuno is a combined oral fluoropyrimidine antitumor drug that includes a fixed combination of 3 active substances - tegafur, gimeracil and oteracil.

After absorption in the gastrointestinal tract tegafur transformed and active form of fluorouracil (FU), which has a pronounced antitumor activity, without enhancing the toxic effect of FU.

Gimeracil is a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), its action is to inhibit the destruction of FU in the human body.

Oteracil - an inhibitor of orotate phosphoribosyltransferase (OPF), reduces the local irritant effect of FU on the unchanged gastrointestinal mucosa and the severity of the inflammatory reactions caused by FU.

Combined drug Teisuno containing a fixed combination of tegafur, gimeracil and oteracil potassium in a molar ratio of 1: 0.4: 1, while retaining the antitumor activity of FU, has a less pronounced toxic effect, compared with monotherapy of FU.

Tegafur is a prodrug of FU.
When ingested, tegafur has a high bioavailability. In studies in vivo under the influence of cytochrome P450 isoenzyme CYP2A6, tegafur is gradually transformed into FU. Under the action of dihydropyrimidine dehydrogenase of the liver, FU is metabolized, and activation of FU and the formation of an active metabolite, 5-fluoro-deoxyuridip-monophosphate (FUMF), takes place inside the tumor cell during phosphorylation. In turn, FUMF and the folic acid derivative bind to thymidylate synthetase, the formed tertiary complex breaks down the synthesis of DNA. Also, 5-fluoro-deoxyuridine-triphosphate (FdUTP) is inserted into the structure of RNA, causing a disruption of the function of the latter.
Gimeracil prevents the destruction of FU by selective and reversible inhibition of DPD, the main enzyme of FU metabolism, thus, when taking a low dose of tegafur, a higher level of FU concentration in the blood plasma is achieved.
In preclinical studies, it has been shown that after oral administration oteracil is detected in high concentrations in the gastrointestinal tract, while its concentration in the blood plasma and in the tumor remains relatively low.
The preparation of Teysuno does not have cardiotoxic effect (does not affect the process of myocardial repolarization) in patients with advanced stomach cancer.
The relationship between QTc interval dynamics was not established when compared with the baseline values ​​and maximum plasma concentrations of the active substances that make up Teisuno's preparation.
The overall survival with Teysuno in combination with cisplatin was comparable with the combination of FU and cisplatin.
At the time of the assessment, the median of the period of overall survival of patients was 18.3 months.
PHARMACOKINETICS

Suction

After receiving the preparation Teisuno in a dose of 50 mg (determined by the content of tegafur) in patients (at a dose of 30 mg / m 2 , determined by the surface area of ​​the body 1.56-2.10 m 2 in patients n = 14), the average time to reach the maximum concentration in The blood plasma ( Tmax ) of the components of the Teisuno preparation, including tegafur, gimeracil and oteracil, was 0.5 h, 1 h and 2 h, respectively.
Mean and standard deviations of AUC and C max were 14595 ± 4340 ng / hr and 1762 ± 279 ng / ml in tegafur, 1884 ± 640 ng / hr and 452 ± 102 ng / ml in gimeracil, 556 ± 281 ng h / ml and 112 ± 52 ng / ml in oteracil. T max FU is 2 h, and the mean values ​​of AUC 0-inf and C max are 842 ± 252 ng · h / ml and 174 ± 58 ng / ml.
Concentrations of tegafur, gimeracil and oteracil, as well as FU in the blood are determined within 10 hours. After using Teisuno 30 mg / m 2, the equilibrium concentrations of tegafur, gimeracil and oteracil are reached no later than 8 days.
After repeated administration of Teisuno (at a dose of 30 mg / m 2 2 times / day for 14 days, n = 10), the median time T max of tegafur, gimeracil and oteracil is 0.8 h, 1 h and 2 h, respectively, and the average standard the deviation of the values ​​of AUC (0-12h) and C max - 19967 ± 6027 ng · h / ml and 2970 ± 852 ng / ml in tegafur, 1483 ± 527 ng · h / ml and 305 ± 116 ng / ml in gimeracil, 692 ± 529 ng h / ml and 122 ± 82 ng / ml in oteracil, respectively. The median time T max FU is 2 h, and the mean values ​​of AUC (0-12h) and C max are 870 ± 405 ng · h / ml and 165 ± 62 ng / ml, respectively.
The use of Teisuno after a meal is accompanied by a decrease in AUC 0-inf oteracil by approximately 71% and gimeracil by 25% compared with the administration of the drug on an empty stomach.
Simultaneous administration of proton pump inhibitor drugs reduces the effect of food intake on the pharmacokinetic profile of oteracil, although it does not completely neutralize it. It is noted that AUC 0-inf FU after meals decreases by 15%, however, the concentration in the blood plasma of tegafur does not change after eating (no effect of food on the concentration of tegafur).
The mean values ​​of AUC 0-inf and C max FU were almost 3-fold higher when taking Teisuno (50 mg in tegafur) compared with tegafur monotherapy (800 mg), while AUC 0-inf and C metabolite alpha-fluoro-beta-alanine (FAA) FU about 15-22 times lower after taking the drug Teisuno compared with the use of tegafur.

Oteracil, which is part of the drug Teisuno.
does not affect the pharmacokinetic profiles of FU, tegafur, gimeracil, FAA and uracil. Gimeracil does not change the pharmacokinetic profiles of tegafur.
Linearity / Nonlinearity of Pharmacokinetics

In a study on the dose selection of Teisuno, it was shown that plasma concentrations of tegafur, gimeracil, and oteracil increased in direct proportion to the dose in the range of 25 to 200 mg / kg.
The tendency of a more significant increase in the concentration of FU compared with the increase in the concentration of tegafur in blood plasma was noted.
Distribution

Oteracil, gimeracil, FU and tegafur bind to plasma proteins by 8.4%, 32.2%, 18.4% and 52.3%, respectively.
The association with blood plasma proteins does not depend on the concentration when applied in the dose range above 0.1-1.0 μg / ml oteracil, gimeracil and FU and 1.2-11.8 μg / ml - tegafur.
Despite the lack of data on intravenous administration of Teisuno in clinical trials, the V d components of the preparation, 16 l / m 2 , 17 l / m 2 and 23 l / m 2 in tegafur, gimeracil and oteracil, respectively, can be estimated approximately by the expected V d and the rate of renal excretion.

Metabolism

Tegafur is metabolized in the liver under the influence of cytochrome P450 isoenzyme CYP2A6, transforming into FU.
Gimeracil was stable when homogenizing (fraction S9) with a lithium salt of adenosine-3'-phosphate-5'-phosphosulfate (AFFS; cofactor sulfotransferase) or nicotinamide adenine dinucleotide phosphate (NADP). In vitro study found that oteracil under the influence of gastric juice and without the participation of enzymes is partially converted into 5-azauracil (5-AMU), and then - into cyanuric acid (CA) in the gastrointestinal tract. Both metabolites of oteracil do not decrease the activity of the enzyme orotate-phosphoribosyltransferase (OPF). Metabolism in the liver undergoes only a small amount of oteracil, which is due to its low penetrating ability. In an in vitro study on human liver microsome, it was shown that tegafur, gimeracil and oteracil did not inhibit the enzymatic activity of the cytochrome P450 isoenzymes studied (for example, CYP1A1 / 2, CYP2A6, CYP2C8 / 9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4). In vitro studies (0.7-70 μmol), gimeracil (0.2-25 μmol) and oteracil (0.04-4 μmol) have a weak ability to induce the metabolic activity of the listed isoenzymes CYP1A1 / 2, CYP2A6 and CYP3A4 / 5 or do not have this ability at all.The concentration of uracil in blood plasma was determined in order to evaluate the activity of dehydropyridine dehydrogenase (DPD) without significant changes in uracil plasma concentration after taking 800 mg of tegafur; however, after taking 50 mg of Teisuno, the concentration of uracil in the blood plasma increased significantly (due to the inhibitory DPD action of gimeracil). C max of uracil, corresponding to the inhibition of DPD, is observed approximately 4 hours after the start of the drug administration, either after a single dose of Teysuno (50 mg) and repeated (30 mg / m 2 2 times / day). In both variants of drug administration, a comparable inhibitory effect is observed. The concentration of uracil in the blood returns to baseline values ​​approximately 48 hours after taking the drug, which indicates the reversibility of inhibition of DPD by gimeracil.
Excretion

T 1/2 FU after receiving the drug Teisuno (containing tegafur, prodrug FU) was more prolonged (about 1.6-1.9 h) compared with T 1/2 after intravenous administration of FU (10-20 min).
After a single intake of Teisuno preparation, T 1/2 tegafur is 6.7-11.3 h, gimeracil is 3.1-4.1 h and oteracil is 1.8-9.5 h.
After a single dose of Teisuno in unchanged form, 3.8-4.2% of the administered dose of tegafur, 65-72% of gimeracil and 3.5-3.9% of oteracil are excreted by the kidneys.

About 9.5-9.7% of the administered dose of tegafur is excreted by the kidney in the form of FU and 70-77% - in the form of FAA, 83-91% of the injected dose of Teisuno (together tegafur + FU + FBA) is summarized by the kidneys.
When compared with tegafur's clearance in monotherapy, it is shown that gimeracil does not change the renal clearance of tegafur, FBA and FU when taking Teisuno.
Pharmacokinistry in special groups of patients

Studies in specific populations

The concentration in the blood plasma of gimeracil and FU has the most significant effect such a factor as a decrease in kidney function, which is determined by the magnitude of QC.
The tendency of influence on the pharmacokinetics of Teisuno's preparation of the age of patients is noted, as the kidney function decreases with age, which is also determined by the QC value.
In patients with impaired renal function

In a comparative study of the pharmacokinetics of the active substances of the Teisuno preparation and their metabolites in patients with normal and reduced renal function, it was shown that in patients with mild renal impairment (CK 51-80 ml / min) and receiving the same dose of the drug as patients with normal function in monotherapy 30 mg / m 2 2 times / day (the maximum tolerated dose in monotherapy), as well as in patients with normal renal function (KK> 80 ml / min) there is an increase in the value of AUC 0-inf FU compared with patients with stored function by
nuts. In patients with moderate renal impairment (QA 30-50 ml / min) and receiving a dose of Teisuno 2 times / day reduced to 20 mg / m 2 , there was no increase in the value of AUC 0-inf 5-FU compared to patients , which have no renal dysfunction.
An increase in the concentration of FU in the blood plasma in patients with mild renal impairment and the results of population pharmacokinetic analysis suggest that close plasma concentrations of FU can be achieved both in patients with mild renal impairment when using Teisuno in dose 25 mg / m 2 dose 2 times / day, and in patients without disturbances of kidney function when taking Teisuno in a dose of 30 mg / m 2 dose 2 times / day, as well as in patients with a moderate degree ofkidney dysfunction, which receive a dose of 20 mg / m 2 .

After applying a dose of Teisuno 1 time / day in patients with severe renal dysfunction (CC <30 ml / min), AUC 0-infF FU after a single dose and AUC 0-t FU after repeated application of the preparation of Teysuno increased 2-fold compared with the values ​​in the group of patients with normal renal function who received the drug Teisuno in a dose of 30 mg / m 2 2 times / day.
In this regard, the daily exposure of FU should be comparable in both groups, as the daily exposure in patients with severe renal impairment is based on the use of Teysuno 1 time / day, while the daily exposure of FU in patients with normal renal function is based on admission preparation Teisuno 2 times / day. It should be noted that exposure to FU may vary and may be unexpectedly higher in patients with severe renal dysfunction due to decreased renal function in these patients.
In patients with impaired hepatic function

With a single or repeated administration of Teisuno 30 mg / m 2 2 times / day in patients with mild, moderate and severe liver function disorders, there was no significant difference in the concentrations of tegafur, gimeracil, and oteracil in plasma compared with patients in which have no liver function disorders.

In patients with severe liver function impairment compared with patients with normal liver function, a single administration of the drug was accompanied by a statistically significant decrease in C max FU and gimeracil, but no further differences were observed with the repeated use of the drug.

In patients of different ethnic groups

In a comparative study of the pharmacokinism of Teisuno in monotherapy in patients from Asia (China, Malaysia) and Europeans (US patients), it was shown that in Asian patients, due to the lower activity of the isoenzyme CYP2A6, AUC 0-12 tegafur is higher, and T 1/2 - longer than in Europeans.
AUC 0-12 gimeracil and uracil in both groups were comparable, which may indicate that the inhibitory effects on PDD of the liver in the studied groups of patients are similar. Exposure of FU was not statistically different in both groups. AUC 0-12 oteracil - 2 times lower in Asian patients than in Europeans, but this difference was statistically unreliable, probably due to high interindividual variability.
The pharmacokinetics of Teisuno in children were not studied.

INDICATIONS

- treatment of advanced stomach cancer in adults in combination with cisplatin.

DOSING MODE

Inside, washed down with water, 1 hour before or 1 hour after meals (as part of a combination therapy with cisplatin).

Treatment with Teisuno should be prescribed and monitored by an oncologist who has experience in diagnosing and treating patients with gastric neoplasms.

In the combination therapy with cisplatin, the recommended standard dose of Teisuno is 25 mg / m 2 (indicated by the dose of tegafur) 2 times / day, in the morning and in the evening, for 21 days, followed by a break for 7 days.
The total duration of one course of treatment is 28 days. Treatment is repeated every 4 weeks.
Standard and reduced doses of Teisuno and cisplatin preparations are calculated from the patient's body surface area (PPT) (see tables 1 and 2).

If the patient's body weight changes by 10% or more, and if the change is not associated with pronounced swelling, the body surface area is determined repeatedly, and the cause of the Teisuno drug is increased or decreased.

Cisplatin is administered as an IV infusion at the recommended dose of 75 mg / m 2 once every 4 weeks.
The use of cisplatin is discontinued after 6 courses of therapy, the drug Teisuno continues. If the use of cisplatin is stopped before 6, the Teysuno drug is resumed if the criteria necessary to continue treatment are met.
During the period of treatment, one should closely monitor the patient's general condition, regularly monitor the peripheral blood levels, the activity of "liver" transaminases, QA, the content of electrolytes.
Treatment is stopped in case of progression of the disease and with the development of symptoms of toxicity that can not be eliminated.
The patient should consume a sufficient amount of fluid (see instructions for the use of cisplatin).

It may be necessary to carry out therapy aimed at the treatment of anemia and diarrhea.
The applied dose Teysuno
Table 1. Standard and reduced dose Teysuno and cisplatin
Drug Name Standard Dose (mg / m 2 ) Reduced Dose 1 (mg / m 2 ) Reduced Dose 2 (mg / m 2 )
Teysuno 25 *> 20 *> 15 *
and / or
Cisplatin 75> 60> 45
* expressed in content tegafur
Selection dose Teysuno
Table 2. calculation of standard and low dose drug Teysuno depending on the body surface area (m 2 )
dose preparation Teysuno Single dose mg (single dosing) Daily dose in mg The number of capsules each dose (2 doses / day)
Standard dose *: 25 mg / m 2 Capsules * 15 mg (brownish white) Capsules * 20 mg (white)
BSA 2.30 m? 2 60 120 0 3
BHE = 2.10- 2.29 m 2 55110 1 February
TIC = 1.90-2.09 m 2 50 100 1 February
TIC = 1.70-1.89 m 2 45 90 3 0
PPT = 1.50-1.69 m 2 40 80 0 2
BHE 1.30-1.49 m = 2 35 70 1 January
PPT <1.29 m 2 30 60 2 0
The first dose reduction of up to 20 mg / m 2
BSA 2.13 m? 245 90 3 0
PPT = 1.88-2.12 m 2 40 80 0 2
TIC = 1.30-1.87 m 2 35 1 1 70
BSA = 1.30- 1.62 m 2 30 60 2 0
PPT 1.29 m? 2 20 40 0 1
Second dose reduction: to 15 mg / m 2
BSA? 2.17 m 2 35 1 1 70
BSA = 1.67-2.16 m 2 30 60 2 0
PPT = 1.30-1.66 m 2 20 40 0 1
TIC? 1.29 m 2 15 30 0 1
The values determined to PPT * Specifies hundredths of a dose of tegafur
dose adjustment of the drug during treatment
general information

Intensity of toxic effects associated with the use of Teysuno drug can be reduced during the symptomatic therapy, as well as at lower dose or a transient cancellation. In the case of moderate or severe symptoms of toxic action of the drug, patients should immediately inform your doctor.
If, in connection with the development of toxic reactions interrupted treatment, the missed dose not take Teysuno. Also, the drug is not re-used, and after vomiting. If the drug dose was reduced Teysuno, then it does not increase.
The criteria for dose reduction
Dose Teysuno reduced in accordance with the information provided in Tables 1, 3, 4 and 5. In the case of reactions toxicity dose of each drug combination treatment (preparation Teysuno and cisplatin) are successively reduced, the maximum - 2 times (see table 1.). Each reduction in the dose is reduced by about 20-25%. Details of the number of Teysuno capsules of the drug per dose reduction is shown in Table 2. The criteria on which the possible resumption of treatment is indicated and in Table 6.
Changes in dose Teysuno in part of combination therapy with cisplatin, is necessary in the event of toxic reactions may be carried out by two ways.
- During the 4-week treatment
Teysuno patients take the drug every day from 1 to 21 days of each treatment and do not take from 22 to 28 days. Days of the course, when the drug was skipped due to toxicity reactions are not repeated.
During the course of treatment carried out correction of the dose of the drug which causes toxicity observed response if such determination is possible. If toxicity reaction could be caused by the use of both drugs or it is impossible to determine the relationship with one of them, it recommended reduction in dose of both drugs.
- At the beginning of the next course of treatment
If treatment preparayum Teysuno or cisplatin should be delayed for a time following the beginning of treatment is transferred to the point where treatment with each of the preparations would be possible or to when one of the drugs is completely overturned.
Changing dose Teysuno in connection with the emergence of general toxic reactions, except The case of hematological toxicity and nephrological
Table 3. Scheme dose reduction during the development of general toxic reactions in non-hematologic toxicity nephrology and
severity of symptoms of toxicity as changes vines Teysuno drug within 21 -day treatment Teysuno dose correction at reception of next dose / next course
degree 1
Occurrence of symptoms at any time continue treatment at the same dose not carried
Degree 1 b, c
of symptoms at any time temporarily cancel treatment to reduce the severity of symptoms to 0 or 1 degree is not carried out
degree 3 or higher
Symptoms identified first temporarily cancel treatment to reduce the severity of w0 or 1 degree of symptoms dose is reduced by 1 level, compared to the prior
symptoms detected again temporarily cancel treatment to reduce the severity of symptoms or 1 degree w0 dose reduced 1 level CPA vneny to the prior
symptoms revealed the third time Cancel Cancel drug treatment
and- According to the criteria of severity of adverse reactions by the National Institute CTCAE classification of malignant tumors. US (version 3). b - In case of nausea and vomiting 2 severity antiemetics optimum dose should be chosen to cancel Teysuno preparation. with - At the discretion of the treatment of the treating physician may be continued without interruption or reduction in dose (irrespective of severity) during the development of toxic reactions, since low probability that they become serious or zhizpeugrozhayuschimi (e.g., alopecia, decreased libido / erectile dysfunction, dry the skin).
Reduced doses of drugs with nephrotoxic reactions occur
before each course of treatment and before the first taking the drug in Teysuno Day 1 should identify QC.
Table 4. Scheme dose reduction preparayuv Teysuno and cisplatin in reducing CK (development of nephrotoxic reactions) in the beginning of treatment
Creatinine clearance Changing Teysuno dose at the beginning of treatment Change cisplatin dose at the beginning of treatment
? 50 ml / min Dose Dose not reduced not reduced
30-49 ml / min Post treatment at a dose reduced to one level Post treatment with cisplatin at a dose reduced by 50% compared with those of the previous course of treatment
<30 ml / INN andStop drug treatment to restore kidney function (? 30 ml / INN), then start treatment at a dose reduced by one level from the previous stop treatment drug to recovery of renal function (? 30 ml / INN), then start the treatment with cisplatin at a dose reduced to 50% compared with those of the previous course of treatment
but - not recommended for CC <30 ml / INN treatment. See "Changing the dose patients in special groups / Renal dysfunction"
Reduced dose Teysuno at occurrence of toxic reactions in the hematopoietic organs
Table 5. hematological toxicity at which to discontinue Teysuno
hematological Hematologic
The observed baseline values or 1 degree platelets? 100 × 10 9 / l
QA> 30 ml / min and Neutrophils? 1.5 × 10 9 / L
Hemoglobin? 6.2 mg / dL
QC should be determined at the beginning of each cycle prior to the treatment with Teysuno on Day 1 .
and When CC <30 ml / min treatment is not recommended. See "Changing dose in patients in special groups / Renal Function."
Changing the dose of the drug in a specific patient groups
Renal dysfunction
- Patients with impaired renal mild severity function (CC 5 1-80 ml / min) is required correction a standard dose of the drug.
- Patients with impaired renal function moderate severity (CC 30-50 ml / min), the recommended dose reduced 1 Teysuno drug is 20 mg / m 2 2 times / day (tegafur dose).
- Patients with severe renal impairment severity function (creatinine clearance <30 mL / min) using the product is not recommended.
Use in elderly patients
In patients 70 years and older are not required to carry out correction of the standard dose.
If abnormal liver function
carrying out the correction in patients with impaired hepatic function does not require the standard dose (see. "Pharmacokinetics" section).
Ethnic peculiarities of the
patients of Asian origin correction of the standard dose is not required (see. Section "Pharmacokinetics").
Children
Effektivnosg and safety of the drug Teysuno in children under 18 years of age have not been studied.
SIDE EFFECT

Safety profile features
among 593 patients receiving the drug and Teysuno combination with cisplatin, the most commonly observed adverse reactions following severe (Grade 3 with at least 10%), neutropenia, anemia, and fatigue.
The list of adverse reactions
The frequency of adverse reactions often (> 1/10); often (> 1/100 <1/10.);
infrequently (> 1/1000, <1/100); rare (> 1/10 000. <1/1000) very rare (<1/10 000); frequency is not set (the currently available data on the prevalence of adverse reactions are absent).
The system-organ class Very often Often Infrequent Seldom / Rarely
Infectious and parasitic diseases of septic shock, sepsis, infections of the upper and lower respiratory tract infections, acute pyelonephritis, infection, urinary tract infection and oral candidiasis, herpetic lesions of the oral mucosa, paronychia, furunculosis
benign, malignant neoplasm undiagnosed (including cysts and polyps) from tumor bleeding, severe pain
from the hematopoietic and lymphatic system with Istemineutropenia, leukopenia, anemia, thrombocytopenia, febrile neutropenia, lymphopenia pancytopenia, increase in prothrombin time, an increase in the INR (international normalized ratio), hypoprothrombinemia, shortening of prothrombin time, granulocytopenia, leukocytosis, lymphocytopenia, increased numbers of monocytes, thrombocythemia disseminated intravascular coagulation syndrome (DIC )
immune system hypersensitivity reaction
endocrine system bleeding in the adrenal
From Storo us Metabolism and nutrition systemanorexia, dehydration, hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, hypoalbuminemia, hyperkalemia hyperglycemia, elevated alkaline phosphatase, lactate dehydrogenase, hypophosphatemia, gipermagniemiya, gout, hypoproteinemia, hyperglobulinaemia, hyperlipidemia, reduced food intake
mental disorders insomnia confusion, restlessness, personality disorder, hallucinations , depression, anxiety, loss of libido, impotence
of the nervous systemperipheral neuropathy, paresthesia, hypersthesia, polyneuropathy, neurotoxicity, dysesthesia dizziness, headache, dysgeusia acute cerebrovascular accident, stroke, cerebrovascular disorders, seizures, ischemic stroke, syncope, hemiparesis, aphasia, ataxia, encephalopathy caused by metabolic disorders, loss of consciousness, optic neuritis of the auditory nerve, loss of memory, impaired balance, drowsiness, tremor, loss of taste sensitivity, distortion of the sense of smell, burning sensation, feeling of "pins and needles"
part of the visiondisorders of the visual perception, dysfunction of the lacrimal apparatus (increase tear production, "dry eye" syndrome, stenosis nasolacrimal canal), conjunctivitis, corneal alterations (defect corneal epithelium, corneal erosion, corneal injury, corneal opacity, corneal perforation, keratitis, punctate keratitis, ulcerative keratitis, reduced visual acuity, blurred vision, diplopia, photopsia, violation of clarity of vision), allergic conjunctivitis, ptosis of the eyelids, redness, conjunctival century
part of the organ of hearing and labyrinth dysregulation hearing loss, deafness vertigo, a feeling of "stuffiness in your ears", discomfort in the ears of
the part of the cardiovascular systemlowering blood pressure, thrombosis of deep veins of the extremities, increased blood pressure heart failure, acute myocardial infarction, exudative pericarditis, atrial fibrillation, angina pectoris, ventricular fibrillation, tachycardia, palpitations, thrombosis iliac artery, hypovolemic shock, thrombosis of arteries, sensation of heat, thrombosis pelvic veins thrombophlebitis, phlebitis, superficial phlebitis, orthostatic hypotension, hematoma, redness of the skin, "tides" of blood to the skin
part of the respiratory system, organs, thoracic and mediastinal disorders shortness of breath, nosebleed, hiccups, cough, pulmonary embolism, pulmonary bleeding, shortness of breath with exertion, sore throat, runny nose, throat congestion, rhinitis allerichesky, dysphonia, .produktivny cough, nasal congestion, interstitial lung disease
Digestive system diarrhea, vomiting, nausea, constipation, gastrointestinal bleeding, stomatitis, inflammatory disease of the gastrointestinal tract, flatulence, abdominal pain, dysphagia, feeling of abdominal discomfort, indigestion, mucosal dryness oral perforation GIT izofagit, infectious gastrointestinal lesion , ileitis (inflammation of the ileum), ileus, ascites, edema of the lips, a spasm of the esophagus, ulcerative lesion of the gastric mucosa, reflux esophagitis, reflux gastritis, retroperitoneal fibrosis, functional violated Nia gastrointestinal tract, bleeding from the expanded hemorrhoidal veins of the rectum, hypersecretion salivary glands, the urge to vomit, decreased salivary gland function, cheilitis, aerophagia, belching, glossodiniya, pain in the mouth, increased fragility of teeth acute pancreatitis
From the hepatobiliary system hyperbilirubinemia, increased ALT, AST change of biochemical parameters of liver, increased gamma-glutamate transferase (GGT), acute liver failure
the part of the skin and subcutaneous tissuepalmar-plantar eritrodizesterii syndrome, skin rash, skin pigmentation, dry skin, skin pruritus, alopecia Exfoliative rash, skin exfoliation, necrolytic migratory erythema, subcutaneous hemorrhage, allergic dermatitis, skin reactions, akneformny dermatosis, erythema, increased tendency to form subcutaneous hematomas purpura, rash, excessive sweating at night, atroficheskne change the nail plate, depigmentation of the skin, skin discoloration, hypertrichosis toxic epidermal necrolysis, Sindh rum Stevens-Johnson syndrome, photosensitivity, nail damage
the part of the musculoskeletal system and connective tissuebone pain and muscle spasms, arthralgia, pain in extremity, back pain, neck pain, bone pain, swelling in the joints, discomfort, pressure, and muscle weakness in the limbs rhabdomyolysis
From the urinary system kidney failure, increasing the concentration creatinine in blood plasma, reduction of renal glomerular filtration rate, increasing concentrations of urea in blood plasma, toxic nephropathy, oliguria, hematuria, decreased kidney function, pollakiuria, increased creatine, creatine reduction on
the part of the reproductive organs and breast cancer , erectile dysfunction, feeling of heaviness in the breast, pain in the breast nipple
Alphabetical index of medicines:
A  B  V  G  D  E  J
Z  I  Y  K  L  M  N
O  P  R  S  T  U  F
H  C  CH  SH  E  U  Y
Rambler's Top100
Privacy policy:
Copyright 2009 - 2017. Universal reference book of medicines. All rights reserved.
When using site materials, an active hyperlink is required!