Theisuno (Teysuno)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTegafur + Gimeracil + OteracilTegafur + Gimeracil + Oteracil
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  • Theisuno
    capsules inwards 
    Nordic Group BV    
    • Dosage form: & nbspcapsules
    Composition:

    Ha 1 capsule 15 mg / 4.35 mg / 11.8 mg:

    Active substances: tegafur - 15.00 mg, gimeracil - 4.35 mg, potassium sulfate (in terms of polysulfide) - 14.70 mg (11.80 mg);

    Excipients: lactose monohydrate - 70.2 mg, magnesium stearate-0.3 mg;

    Capsule shell: body: gelatin - 19.7752 mg, titanium dioxide - 0.8400 mg, sodium lauryl sulfate - 0.0248 mg, talc *; lid: gelatin - 13.4155 mg. titanium dioxide - 0.2400 mg, iron oxide red - 0.0880 *, sodium lauryl sulfate - 0.0165 mg. talc*; ink: iron oxide yellow *, FD&C blue # 2 aluminum varnish (E132) *, carpuba wax *, bleached shellac *, glyceryl monooleate *

    For 1 capsule 20 mg / 5.8 mg / 15.8 mg:

    Active substances: tegafur - 20.00 mg, gimeracil - 5.80 mg, potassium sulfate (in terms of polysulfyl) - 19.60 mg (15.80 mg);

    Excipients: lactose monohydrate - 93.6 mg, magnesium stearate-0.4 mg;

    Capsule shell: body: gelatin - 19.7752 mg, titanium dioxide - 0.8400 mg, sodium lauryl sulfate - 0.0248 mg, talc *; lid: gelatin - 13.1835 mg, titanium dioxide - 0.5600 mg, sodium lauryl sulfate - 0.0165 mg, talc *; ink: iron oxide red *, iron oxide yellow *, FD&C blue №2 aluminum varnish (IE 132) *, carpuba wax *, bleached shellac *, glyceryl monooleate *

    * - contained in trace amounts

    Description:

    Capsules with tegafur content 15 mg:

    opaque hard gelatin capsules No. 4 cylindrical, consisting of a brown lid and a white body, marked with "TS448" with gray ink on the capsule (cap and body); the content of the capsules is a mixture of powder and white granules.

    Capsules with tegafur sodaugicum 20 mg:

    opaque hard gelatin capsules No. 4 cylindrical, consisting of a white lid and a white body, marked with "TS442" with gray ink on the capsule (cap and casing); contents of capsules - a mixture of powder and white granules .
    Pharmacotherapeutic group:antitumour agent - antimetabolite
    Pharmacodynamics:

    Mechanism of action

    Teisuno is a combined oral fluoropyrimidipic antitumor drug that includes a fixed combination of 3 active ingredients - tegafur, gimeracipe and oteracil.

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

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

    Oteracil - inhibitor of orotate phosphoribosyltransferase (OPF). reduces the severity of the local irritant effect of FU on the unchanged mucous membrane of the gastrointestinal tract (GI tract) and the severity of the inflammatory reactions caused by FU. Combined drug Teysuno, containing a fixed combination of tegafur, gimeracil and oteracil potassium in a molar ratio 1:0, 4: 1, while preserving the antitumor activity of FU. has a less pronounced toxic effect, in comparison with monotherapy of FU.

    Tegafur is a prodrug of FU. When administered orally tegafur has a high bioavailability. In studies in vivo under the influence of isoenzyme CYP2A6 cytochrome P450 tegafur gradually transformed into FU. Under the action of dihydropyrimidine dehydrogenase, liver FU is metabolized, and inside the tumor cell, phosphorylation activates FU and forms an active metabolite. 5-fluoro-deoxyuridip-monophosphate (FdUMF). 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 incorporated into the structure of RNA.causing a violation of the function of the latter.

    Hyssratsil 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 was shown that after ingestion 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 Teysuno ns has a cardiotoxic effect (does not affect the process of repolarization of the myocardium) in patients with advanced stomach cancer. The relationship between the dynamics of the interval QTcF when compared with the initial values ​​and maximum concentrations in the blood plasma of the active substances that make up the preparation of Teisuno.

    The overall survival with Teysuno in combination with cisplatin was comparable with the combination of FU and cisplatin. At the time of the evaluation, the median of the period of overall survival of patients was 18.3 months.

    Pharmacokinetics:

    Suction

    After receiving the drug Teisuno in a dose of 50 mg (determined by the content of tegafur) in patients (at a dose of 30 mg / m2, determined by the surface area of ​​the body 1.56-2.10 m2 in patients n = 14), the average time to reach the maximum concentration in blood plasma T max) of the components of the preparation of Teysuno, including tegafur, gimeracil and oteracil, was 0.5 hours, 1h and 2h, respectively. Mean values ​​and standard deviations AUC and Cmax were 14595 ± 4340 ng * h / ml and 1762 ± 279 ng / ml in tegafur, 1884 ± 640 ng * h / ml and

    452 ± Ю2 ng / ml in gimeracil, 556 ± 281 ng * h / ml and 112 ± 52 mg / ml in oteracil. Tmax The FU is 2 h, and the mean values AUCQ.jnf and Cmax - 842 ± 252 pg * 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 in a dose of 30 mg / m, the equilibrium concentrations of tegafur, gimeracil and oteracil are reached no later than 8 day.

    After repeated intake of the preparation of Teisuno (at a dose of 30 mg / m 2 per day for 14 days, n = 10), the median time Tmax tegafur, gimeracil and oteracil is 0.8 hours, 1 h and 2 h, respectively, and the mean standard deviation of the values AUC(0-12 h) and Cmax - 19967 ± 6027 ng * h / ml and 2970 ± 852 ng / ml in tegafur, 1483 ± 527 ig / h / ml and 305 ± 116 ng / ml in gimeracil, 692 ± 529 ng * h / ml and 122 ± 82 ng / ml in oteracil, respectively. Median of time Tmax The FU is 2 h, and the mean values AUC(0-12 h) and Cmax - 870 ± 405 ng * h / ml and 165 ± 62 ng / ml, respectively.

    The use of Teisuno after eating is accompanied by a decrease AUC0-inf Oteracil by approximately 71% and gimeracil - by 25%, but compared with taking the drug on an empty stomach. Simultaneous intake 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 AUCo-inf FU after meals decreases by 15%, however, the concentration in the plasma of tegafur does not change after eating (no effect of food on the concentration of tegafur).

    Mean values AUC 0-jnf and Cmax FU were almost 3 times higher when taking Teisuno (at a dose of 50 mg in tegafur) but compared with monotherapy with tegafur (800 mg), while AUCo-jnf and FROMmax 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 blood 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 mcg / ml - tegafur.

    In spite of the lack of data on the intravenous administration of Teisuno in clinical trials, the volume distribution of the components of the preparation, 16 lm / m, 17 l / m and 23 l / m in tegafur, gimeracil and oteracil, respectively, can be estimated approximately by the expected volume of distribution and the rate of renal excretion.

    Metabolism

    Tegafur metabolite is produced from the liver under the influence of isoenzyme CYP2A6 cytochrome P450.transforming into FU. Ginsratsil was stable at homogenization (fractions S9) with lithium salt of adenosine-3 '-phosphate-5'-phosphosulfate (AFPS; cofactor of sulfotransferase) or nicotinamide adenine dinucleotide phosphate (11ADP). In the study in vitro It has been established that oteracil iodine is partially converted into 5-azauracil (5-amin) by the influence of gastric juice and without the participation of enzymes, and then to 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 the study in vitro on microsomes of the human liver showed that tegafur, gimsracil and oteracil did not inhibit the enzymatic activity of the studied isoenzymes of cytochrome P450 (eg, CYP1A1 / 2. CYP2A6, CYP2C8 / 9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4).

    In studies in vitro on the basic cell cultures of the human liver, it is established that tegafur (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 these isozymes 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 dehydrohepase (DH1D) 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). The maximum concentration of uracil, corresponding to 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 daily). 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

    The half-life (T 1/2) FU after taking the drug Teisuno (containing tegafur, the proliferation of FU) turned out to be more prolonged (about 1.6-1.9 hours) compared with T1/2 after intravenous administration of FU (10-20 minutes).After a single intake of the drug Teisuno T1/2 tegafur is 6.7-11.3 hours, gimeracil is 3.1-4.1 hours and oteracil is 1.8-9.5 hours.

    After a single dose of Teysuno 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 kidneys 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). When compared with tegafur's clearance in monotherapy, it is shown that gimeracil does not change the renal clearance of tegafur, FAA and FU when taking Teisuno.

    Pharmacokinetics in special patient groups Studies conducted in special populations

    The concentration in the blood plasma of gimeracil and FU has the most significant effect such a factor as a decrease in renal function, which is determined by the magnitude of creatinine clearance (CC). The tendency of influence on the pharmacokinetics of Teisuno's drug of the age of patients was noted, as the kidney function decreases with age, which is also determined by the magnitude of creatinine clearance.

    In patients with impaired renal function

    In a comparative study of the pharmacokinetics of the active substances of Teisuno and their metabolites in patients with normal and reduced renal function,that in patients with mild renal impairment (KK 51-80 ml / min) and receiving the same dose of the drug, patients with normal function in monotherapy of 30 mg / m 2 (the maximum tolerated dose in monotherapy), as well as in patients with normal renal function (CC> 80 ml / min), an increase in the value AUCo-inf FU compared with patients who have a preserved kidney function. In patients with moderate renal impairment (KK 30-50 ml / min) and receiving a dose of Teisuno reduced to 20 mg / m 2 times a day, no increase in the value AUC0-inf -FU compared with patients who have impaired renal function.

    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 of 25 mg / m2 dose twice a day, and in patients without disturbances of kidney function when taking Teisuno in a dose of 30 mg / m2 dose 2 once a day, as well as in patients with a moderate degree of renal dysfunction that receive a dose of the drug 20 mg / m.

    After applying a dose of Teisuno I reduced to 20 mg / m once a day in patients with severe renal dysfunction (CK <30 ml / min), AUC0-inf FU after a single and AUC0-ῖ FU after repeated application of the drug Teisuno increase in 2 times in comparison with the values ​​in the troupe of patients with normal renal function receiving a preparation of Teisuno in a dose of 30 mg / m2 2 times a day. In this regard, the daily exposure of FU should be comparable in both groups, since the daily exposure in patients with severe disorders of the night is based on the use of Teysuno 1 time per day, while the daily exposure of FU in patients with normal renal function is based on taking the drug Teisuno 2 times a 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 multiple administration of Teisuno in a dose of 30 mg / m 2 per day in patients with mild,moderate and severe degree of liver function abnormalities, there were no significant differences in the concentrations of tegafur, gimeracil and oteracil in blood plasma, but compared with patients with no liver function impairment.

    In patients with severe liver function impairment but compared with patients with normal liver function, a single dose of the drug was accompanied by a statistically significant decrease Cmax FU and gimeracil, but with repeated use of the drug, these differences were observed.

    Have patients of different ethnic groups

    In a comparative study of the pharmacokinetics of Tsisuno in monotherapy in patients from Asia (China, Malaysia) and Europeans (US patients), it was shown that in Asian patients due to a lower isoenzyme activity CYP2A6, AUC0-12 tegafur higher, and T1/2 - longer than in the case of the Naziite-Europeans. AUCo-12 gimeracil and uracil in both groups were comparable, which may indicate that the inhibitory effects on the PDD of the liver in the studied patient groups are similar. Exposure of FU was not statistically different in both groups. AUC0-12 oteracil - in 2 times lower in Asian patients than in Europeans, but this difference was statistically unreliable, probably due to high inter-individual variability.

    Have children

    The pharmacokinetics of Teisuno in children were not studied.

    Indications:Treatment of advanced stomach cancer in adults in combination with cisplatin.
    Contraindications:

    - Hypersensitivity to tegafur, gimeracil, scoracil and other components of the drug;

    - Hypersensitivity to fluoroureimidine derivatives;

    - Simultaneous and previous (4 weeks before the current treatment) intake of inhibitors of DPD, including sorivudine and its structural analogues such as brivudine:

    - Established deficiency of dihydropyrimidine dehydrohease;

    - Oppression of bone marrow hematopoiesis (severe leukopenia, neutropenia or thrombonitis);

    - In patients with impaired renal function of severe severity (CK <30 ml / min);

    - Simultaneous application with alluourinol;

    - Simultaneous use with fluoroorimidine derivatives;

    - Contraindications for the use of cisplatin;

    - Pregnancy and the period of breastfeeding;

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

    Carefully:

    Renal failure of moderate severity, liver failure, age over 70 years, concomitant use with indirect anticoagulants coumarinic series, folic acid and its derivatives, derivatives of 5-nitroimidazole, including metronidazole and misonidazole, with methotrexate, clozapine, cimetidine, phenytoin; rare hereditary diseases, such as glucose-galactose intolerance, hereditary lactase deficiency, lactose intolerance or glucose-galactose malabsorption.

    Pregnancy and lactation:

    The use of Teisuno is contraindicated in pregnancy and during breastfeeding (there is no clinical experience in this group of patients). According to the data of the preclinical study, the preparation of Teisuno has embryotoxic and teratogenic effects. In case of pregnancy in the period of treatment with Teisuno drug should be canceled, and the patient should be sent for genetic counseling. During treatment with Teysuno, breastfeeding should be discontinued, as the drug can penetrate into breast milk.

    Dosing and Administration:

    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 / m2 (indicated by the dose of tegafur) 2 times a 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 body surface area (1IIIT) patient (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 edema, the surface area of ​​the body is determined repeatedly, and the dose of Teisuno is increased or decreased.

    The cisplatin is administered as an intravenous infusion at a recommended dose of 75 mg / m2 every 4 weeks. The use of cisilatype is discontinued through 6 courses of therapy, taking the drug Teisuno continue.If the use of cisilatype is stopped before 6 course, reception of the drug Teisuno is renewed if the criteria necessary for continuing treatment are met.

    During the treatment should closely monitor the overall condition of the patient, regularly monitor the peripheral blood, the activity of "liver" transaminases. clearance of creatinine, 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 the instructions for using cisilatype).

    It may be necessary to conduct therapy aimed at the treatment of anemia and diarrhea.

    The dose of Teisuno

    Table I. Standard and reduced doses of Teisuno and cisilatin

    Name

    preparation

    The standard dose (mg / m)

    Reduced

    dose 1 (mg / m2)

    Reduced dose 2 (mg / m2 )

    Theisuno

    25*

    -

    20*

    -

    15*

    and / or

    Cisplatin

    75

    -

    60

    -

    45

    ^ Expressed by the content of tegafur

    Selecting a dose of Teisuno

    Table 2. Calculation of the standard and reduced dose of Teisuno, depending on the body surface area (m2 )

    Dose of Teisuno

    Single dose in mg

    (single entry

    dosing)

    *

    The daily dose in mg

    The number of capsules of each dose (2 doses / day)

    Standard


    dose *: 25 mg / m2

    Capsules * 15 mg (brownish white)

    Capsules * 20 mg

    (white)

    PPT> = 2.30 m2

    60

    120

    0

    3

    PPT = 2.10 - 2.29 m2

    55

    110

    1

    2

    PPT = 1.90 - 2.09 m2

    50

    100

    2

    1

    П ПТ-1,70- 1,89 m2

    45

    90

    3

    0

    11 PT = 1.50 - 1.69 m2

    40

    80

    0

    2

    PPT = 1.30-1.49 m2

    35

    70

    1

    1

    PPT <1.29 m2

    30

    60

    2

    0


    First dose reduction: up to 20 mg / m

    PPT> = 2.13 m2

    45

    90

    3

    0

    PPT = 1.88-2.12 m2

    40

    80

    0

    2

    PPT = 1.63-1.87 m2

    35

    70

    1

    1

    11111 = 1.30-1.62 m2

    30

    60

    2

    0

    PPT <1.29 m2

    20

    40

    0

    1


    Second dose reduction: up to 15 mg / m

    PPT> = 2.17 m2

    35

    70

    1

    1

    ППТ = 1.67-2.16м2

    30

    60

    2

    0

    PPT = 1.30-1.66 m2

    20

    40

    0

    1

    PPT <1.29 m2

    15

    30

    1

    0

    The PPT values ​​are determined up to hundredths.

    * - Indicated but dose of tegafur

    Correction of the dose of the drug during treatment

    general information

    The severity of toxic symptoms associated with the use of the drug Teisuno, can be reduced in the conduct of symptomatic therapy, as well as reducing the dose of the drug or its short-term cancellation. In the case of moderate or severe symptoms of the toxic effect of the drug, patients should immediately inform the attending physician.

    If the treatment is interrupted due to the development of toxic reactions, the missed dose of Teysuno is not taken. Also, the drug is re-used after vomiting. Nelya dose of the drug Teisuno was reduced, subsequently it is not increased.

    Criteria for dose reduction

    The dose of Teisuno is reduced according to the information presented in Tables 1. 3. 4 and 5. In the case of dose toxicity reactions, each of the combined treatment medications (Teisuno and cisplatin) are successively reduced, a maximum of 2 times (see Table I). At each decrease, the dose of the drug decreases by approximately 20-25%. Details of the number of Teisuno capsules for each dose reduction are shown in Table 2. The criteria based on which the resumption of treatment is possible are indicated in the table 6.

    Change in the dose of the preparation of Teysuno as a part of the combined treatment with cisplatin, which is necessary for the occurrence of toxic reactions, can be carried out in two ways.

    - During the 4-week course of treatment

    The preparation of Teysuno patients is taken daily from 1 to 21 days of each course of treatment and is not taken from 22 to 28 days. The days of this course, when the drug was missed because of toxicity reactions, are not repeated.

    During the course of treatment, dose adjustment of the drug that causes the observed toxicity reaction is performed, if such a determination is possible. If the toxicity reaction can be caused by the use of both drugs or the relationship with one of them can not be determined,a reduction in the dose of both drugs is recommended.

    - At the beginning of the next course of treatment

    If treatment with Teisuno or cisplatin should be delayed for a while, the beginning of the next course of treatment is postponed until the moment when treatment with each drug is possible or until one of the drugs is completely canceled.

    The change in the dose of Teisuno's preexis due to the occurrence of common toxic reactions, with the exception of cases of hematological and nephrologic toxicity

    Table 3. Scheme of dose reduction in the development of general toxic reactions not associated with hematologic and nephrologic toxicity

    The severity of symptoms of toxicity a

    Changes in the dose of Teisuno during the 21-day course of treatment

    Correction of the dose of Teisuno with the next dose / in the next course

    Degree 1

    The onset of symptoms at any time

    Continue treatment at the same dose

    11e is conducted

    Degree 2 b, c

    The onset of symptoms at any time

    Temporarily discontinue treatment until the severity of symptoms decreases to 0 or 1 degree

    Not conducted

    Degree 3 or higher

    Symptoms were revealed for the first time

    Temporarily discontinue treatment until the severity of symptoms decreases to 0 or 1 degree

    The dose is reduced by 1 level in comparison with the previous level

    With it,

    Temporarily discontinue treatment until the severity of symptoms decreases to 0 or 1 degree

    The dose is reduced by 1 level in comparison with the previous level

    Symptoms revealed a third time

    Cancel treatment

    Cancel the drug

    a 'According to the criteria for the severity of adverse reactions according to the classification of STAAE of the National Institute of Malignant neoplasms, USA (version 3).

    B - In case of nausea and vomiting of 2 degrees of severity, the optimal dose of antiemetic drugs should be matched prior to the discontinuation of Teisuno

    from_ At the discretion of the attending physician, treatment can be continued without interruption or dose reduction in the development of toxic reactions (regardless of their severity), since the likelihood that they will become serious or life-threatening (such as alopecia, decreased libido / erectile dysfunction, dry skin) .

    Before the beginning of each course of treatment and before the first reception of preparation Teisupo on Day I should be determined the clearance of creatinine (CC).

    Table 4.Scheme of decrease in the dosage of Teisupo and cisplatin preparations with a decrease in creatinine clearance (development of nephrotoxic reactions) at the beginning of the course of treatment

    Creatinine clearance

    Change in the dose of Teieuno at the beginning of the course of treatment

    Changing the dose of cisplatin at the beginning of the course of treatment

    > 50 ml / min

    The dose does not decrease

    The dose of ns decreases

    30-49 ml / min

    Start treatment in a dose reduced by one level

    Start treatment with ciplatin in a dose that is reduced by 50% compared with the one used in the previous course of treatment

    <30 ml / mina

    Stop treatment with the drug until the kidney function is restored (> 30 ml / min), then start treatment at a dose reduced one level from the previous one

    Discontinue cisplatin treatment before restoring renal function (> 30 mL / min), then begin cisplatin treatment at a dose reduced by 50% compared to the one used in the previous treatment course

    aWith QC <30 ml / min, treatment is not recommended. See section "A change in the dose of the drug in patients in special groups / Impaired renal function."

    Reduction of the dose of Teeyeuno in case of toxic reactions from the hematopoiesis

    Table 5. Hematologic toxicity indices for which treatment should ceaseTeisuno

    Units

    measurement

    Neutrophils

    Platelets

    Hemoglobin

    Change in the dose of the drug Teisuno

    ME

    <0.5 x 10%

    <25 x 10%

    4.0 mmol / l

    Discontinue treatment until hematological parameters are restored (see table 6). then start treatment in a dose reduced by one level from the previous one

    Criteria for the resumption of treatment with Teysuno

    Table 6. Minimum criteria for the resumption of treatment with Teysuno after its cancellation due to toxic reactions

    Non-hematological

    Hematological

    Observed initial values ​​or 1 degree

    Thrombocytes> 100.x 10%

    CK> 30 ml / mina

    Neutrophils> 1.5 x 10%

    Hemoglobin> 6.2 mmol / l

    QC should be determined at the beginning of each cycle before treatment with Teisuno on day 1.

    aPROM KK <30 ml / min treatment is not recommended. See section "A change in the dose of the drug in patients in special groups / Impaired renal function."

    Change in the dose of the drug in patients in special groups Impairment of kidney function

    - In patients with disorders of the function of light-colored nights (CK 51-80 ml / min), no correction of the standard dose of the drug is required.

    - In patients with impaired renal function of moderate severity (KK 30-50 ml / min), the recommended reduced dose of the I drug Teisuno is 20 mg / m- 2 once a day (but a dose of tegafur).

    - In patients with impaired renal function with a severe degree of severity (CK <30 ml / min), the use of the drug is not recommended.

    PPatients in elderly patients

    Patients 70 years of age and older do not need a standard dose adjustment.

    With violations of liver function

    Patients with hepatic impairment do not need a standard dose adjustment (see the section "Pharmacokinetics").

    Ethnic Features

    In patients of Asian origin, a standard dose adjustment is not required (see the section "Pharmacokinetics").

    Children

    The effectiveness and safety of the use of Teisuno in children under 18 years of age have not been studied.

    Side effects:

    Characteristics of the security profile

    Among the 593 patients receiving the drug in combination with Tsysuno tsnenlatinom most frequently observed following severe adverse reactions (Grade 3 with at least 10%): neutropenia, anemia and fatigue.

    Peadverse reactions

    Frequency of adverse reactions: very often (> = 1/10); often (> = 1/100, <1/10); infrequently (> = 1/1000, <1/100); rarely (> =1/10 000, <1/1000): very rarely (<1/10 000), the frequency is not established (there is currently no data on the prevalence of adverse reactions).

    System-Organ Class

    Often

    Often

    Infrequently

    Rarely / Very rare

    Infectious and parasitic diseases

    septic shock, sepsis, upper and lower respiratory tract infections. acute pyelonephritis, urinary tract infections

    ways, infections and candidiasis of the oral cavity, herpetic lesions of the oral mucosa. iarooichii, furunculosis

    Benign, malignant and undocumented

    neoplasms (including cysts and polyps)

    bleeding from the tumor, expressed by pain syndrome

    From the hemopoietic system and

    lymphatic

    systems

    neutropenia.

    leukopenia,

    anemia,

    thrombocytosis

    the

    febrile

    neutropenia,

    lymphopenia

    pancytopenia.

    enlargement

    prothrombin

    time,

    enlargement MHO (International Normalized Relationship),

    hypoprothrombinemiashortening

    prothrombin

    time,

    granulocytosis,

    leukocytosis.

    eosinophilia.

    lymphocytosis.

    reduction and

    increase in the number

    monocytes,

    thrombocythemia

    syndrome

    dissemini

    the

    in-pump

    a

    coagulation

    (DVS-siidrom)

    From the side

    immune

    systems

    reactions

    gierschuvstvitel-

    of the

    From the endocrine system

    adrenal hemorrhage

    From the side of metabolism and nutrition

    anorexia

    dehydration, hypokalemia, hypopatremia, hypocalcemia. hypomagnesium,

    hyperglycemia,

    rise

    activity

    alkaline

    phosphatase.

    hypoalbuminemia,

    hyperkalemia

    lactate dehydro-

    genase,

    hypophosphatemia.

    hypermagnesia,

    gout,

    hypoproteinemia.

    hyperglobulin-

    The empire.

    hyperlipidemia, reduced food intake

    Violations

    psyche

    insomnia

    confusion

    consciousness,

    impellent

    anxiety,

    disorder

    personality,

    hallucinations,

    depression.

    anxiety,

    decreased libido,

    impotence

    From the side

    nervous

    systems

    periphery

    the

    Neuropathy.

    paresthesia,

    hyperstress.

    polypyrope

    AND I.

    neurotoxicity,

    dysesthesia

    dizziness, headache, taste perversion

    acute disorders of cerebral circulation, cerebral hemorrhage,

    cerebrovascular disorders, convulsions, ischemic stroke, syncope, hemiparesis, aphasia, ataxia, encephalopathy caused by metabolic disorders, loss of consciousness, auditory nerve neuritis, memory loss, imbalance, drowsiness, tremor, loss of taste

    sensitivity.

    perversion

    the sense of smell.

    leukoencepha-

    shovels.

    anosmia

    feeling of burning, sensation of "crawling creepy"

    From the side of the organ of vision

    violations

    visual

    perception.

    violation of

    lacrimal function

    apparatus

    (increase

    produce tears,

    syndrome of dry

    eyes ", stenosis

    nasolacrimal

    dripping),

    conjunctivitis,

    change

    cornea (defect

    epithelium

    cornea, erosion

    cornea,

    damage

    cornea,

    clouding

    cornea,

    perforation

    cornea,

    keratitis

    keratitis, ulcerative

    keratitis, decrease

    visual acuity,

    impaired vision,

    diplopia,

    photopsy,

    violation of

    clarity

    visual

    perception).

    allergic conjunctivitis, ptosis of the eyelids. conjunctival hyperemia of the eyelids

    From the side of the hearing organ and labyrinthine disorders

    hearing loss, deafness

    vertigo, a feeling of "stuffiness in the ears," discomfort in the ears.

    From the side of the cardiovascular system

    lowering blood pressure (BP), deep vein thrombosis of limbs, increasing LD

    cardiac

    failure,

    acute myocardial infarction

    myocardium.

    exudate

    pericarditis,

    fibrillation

    of the atria.

    angina pectoris.

    fibrillation

    ventricles.

    tachycardia.

    sensation

    palpitation.

    thrombosis

    iliac

    arteries,

    gynovolemic shock, arterial thrombosis of the extremities, sensation of heat, thrombosis of pelvic veins, thrombophlebitis, phlebitis, superficial phlebitis,

    orthostatic

    hypotension.

    hematoma,

    redness of the skin, "tides" of blood to the skin of the face

    On the part of the respiratory system, the organs of the thorax and the mediastinum

    shortness of breath, nosebleeds, hiccough, cough

    thromboembolism of the pulmonary artery, pulmonary hemorrhage, dyspnea with exertion, sore throat, riporea, hyperemia of the throat, allergic rhinitis, dysphonia. productive cough,

    nasal congestion

    interstitial lung disease

    From the digestive system

    diarrhea, vomiting,

    nausea.

    constipation

    gastro-

    intestinal

    bleeding,

    stomatitis.

    inflammatory

    disease

    gastro-

    perforation of the gastrointestinal tract. esophagitis, gastrointestinal infections. ileitis (inflammation of the ileum), intestinal

    acute

    pancreatitis

    intestinal tract, flatulence, abdominal pain, dysphagia. feeling of discomfort in the abdomen, dyspepsia, dryness of the oral mucosa

    obstruction, ascites, edema of the lips. spasm of the esophagus, ulcerative lesions of the gastric mucosa, reflux esophagitis, reflux gastritis,

    retroperitoneal fibrosis, functional disorders of CT, rectal bleeding, bleeding from the enlarged hemorrhoidal veins of the rectum, hypersecretion of the salivary glands, a call for vomiting, a decrease in the salivary gland function of cheilitis, and aerophagia. eructation, glossodia. pain in the mouth. increased brittleness of teeth

    From the hepatibiliary side systems

    gperbilirubin

    Miya. rise

    activity

    alaninamino-

    transferases

    (ALT),

    asparagypamino-

    transfsrazy

    (ACT)

    Change in liver biochemical parameters, increase in activity of gamma-glutamate-

    transferase (GGT)

    acute

    hepatic

    inadequate

    the

    From the skin and subcutaneous tissues

    syndrome of palmar-plantar erythrodysesthesia. skin rash, hyperpigmentation of the skin, dry skin, itching of the skin, alopecia

    exfoliative rash, exfoliation of the skin,

    necrotic

    migratory

    erythema,

    subcutaneous

    hemorrhage,

    toxic

    epidermal

    necrolysis,

    syndrome

    Stevens-

    Johnson.

    photosensitive

    Awareness.

    allergic

    dermatitisth

    reaction,

    acneform

    dermatosis, erythema,

    increased

    inclination to

    education

    subcutaneous

    hematoma, purpura,

    hyperhidrosis,

    increased

    sweating in

    night time,

    atrophic

    change

    nail

    plates,

    depigmentation

    skin, change

    color,

    hypertrichosis

    defeat

    nails

    From the side

    osteo-

    muscular

    systems and

    connective

    fabrics

    pain in bones and muscles

    muscular spasms, arthralgia, pain in the limbs, back pain, neck pain. pain in the bones, swelling in the joints, feelings of discomfort, pressure and muscle weakness in the limbs

    rhabdomyolysis

    From the urinary system

    renal

    failure.

    rise

    concentrations

    creatinine in

    blood plasma,

    decline

    speeds

    tlomerular

    filtration of nights,

    rise

    concentrations

    urea in

    blood plasma

    toxic

    nephropathy,

    oliguria.

    hematuria,

    reduced function

    kidney,

    pollakiuria,

    rise

    creatine,

    decline

    creatinine

    From the genitals and breast

    erectile dysfunction, a feeling of heaviness in the mammary gland, pain in the nipple region of the breast

    Are common

    disorders and disorders at the site of administration

    increased

    fatigue.

    asthenia

    fungal lesions of the mucous membranes, increased temperature of the green, weight loss,

    peripheral edema, colds

    polygonal failure, general condition worsening, pain, swelling, chest pain, chest discomfort, generalized swelling, swelling of the face, local edema, weight gain, feeling of "rapid saturation", chills, reactions at the injection site, general malaise

    Injuries.

    intoxication and

    complications

    manipulation

    bruises, medical errors

    aSide effects were distributed according to the classification of organo-organic classes depending on the target organ. The close terms used in the enumeration of the reactions were grouped into one term.
    Overdose:

    There is information about that. that when Tsysuno was used in a dose of 1400 mg, the patient experienced leukopenia (3 degrees of severity).

    Symptoms of acute overdose include nausea, vomiting, diarrhea, mucositis, irritation of the gastrointestinal tract, bleeding, oppression of bone marrow hematopoiesis, respiratory failure.

    Treatment of symptoms of overdose includes symptomatic therapy - the implementation of conventional therapeutic and supportive measures aimed at correcting the arising disorders, as well as the prevention of possible complications. There is no specific antidote.
    Interaction:

    Studies on the interaction of the drug in adults and children have not been conducted.

    Other fluoropyrimidines

    The simultaneous use of other fluoropyrimidines, in particular capecitabine, fluorouracil, tegafur or flucytosine, is contraindicated because of the combined intensification of toxic effects. The period before the possible start of taking Teisuno after the withdrawal of the fluoropyrnmidine group should be at least 7 days. It is necessary to take into account the elimination period, which is specified in the instructions for medical use, the preparation of the fluoropyrnmidine group. if the preparation of Teysuno is prescribed after the application of another preparation of the group of fluoropyrnmidine.

    Sorivudine and Brivudine

    Sorivudine and its chemical analogue brivudin irreversibly inhibits DPD. as a result, the effect of FU is enhanced. The ego can lead to an increase in the clinically significant toxic effects of fluoroprimidines, including the risk of legal outcomes. The preparation of Teysuno can not be used simultaneously with sorivudip or brivudine. as well as within 4 weeks after the abolition of these drugs.

    Toffeefert inhibitors СУР2А6

    Because the CYP2A6 is the main isoenzyme of cytochrome P450, responsible for the conversion of tegafur into FU. It is necessary to avoid simultaneous application of the preparation of Teysuno and inhibitors CYP2A6, since it is possible to decrease the expected efficacy of Teisupo (see "Pharmacological properties").

    Folic acid and its derivatives

    The simultaneous use of folic acid and Teisuno in combination with cisplatin has not been studied. However, it is known that metabolites of folic acid form a triple structure with thymidylglysingase and fluorine deoxyuridine monophosphate (FUMF). potentially increasing the cytotoxicity of FU. Care should be taken, as combined use may increase the toxicity of the preparation of Teysuno.

    Derivatives of 5-nitroimidazole, including metronidazole and misonidazole Simultaneous use of 5-nigroimndazole derivatives with Teisuno in combination with cisplatin has not been studied. Nevertheless, it is known that 5-pentomidazole preparations can reduce the clearance of FU and, consequently, increase the concentration of FU in the blood plasma. Therefore, simultaneously use Teisuno with cisplatin and derivatives of 5-nitroimidazole with caution.

    Methotrexate

    Simultaneous use of methotrexate and combined treatment with Teisuno and cisplatinum has not been studied. Nevertheless, it is known that methotrexate polyglutamate inhibits thymidate synthase and dihydrofolate reductase potentially increasing the cytotoxicity of FU. Therefore, simultaneously use a combination of Teisuno with cisplatin and methotrexate, be careful.

    Clozapine

    The simultaneous use of clozapine and combined treatment with Teisuno and cisplatinum has not been studied. However, due to the possible pharmacodynamic interaction (myelotoxicity), when used simultaneously with clozapip, caution is necessary, since the risk and severity of the hematologic toxicity of Teisuno may be increased.

    Cimetibin

    Simultaneous use of cimetidine with Teisuno in combination with cisplatin has not been studied. With joint application, care should be taken, since it is possible to reduce renal clearance and increase the concentration of FU in the blood plasma.

    Indirect anticoagulants - coumarin derivatives

    Teisuno increases the activity of indirect anticoagulants of the coumarin series.With simultaneous use with the drug Teisuno should be careful, because with combined use may increase the risk of bleeding (see section "Special instructions").

    Phenytoin

    Fluoropyrimidine derivatives can increase the concentration of phenytoin in the blood plasma in the case of simultaneous use with fepitoinom. thereby increasing the toxic effect of phenytoin. With the simultaneous use of phenytoin with Teisuno, regular and frequent monitoring of the concentration of phenytoin in the blood plasma is recommended. Correction of the dose of phenytoin should be carried out on the basis of information provided in the instructions for phyengoin. In the development of toxic reactions of phenytoin, appropriate measures must be taken.

    Other drugs

    Based on preclinical data, due to inhibition of phosphorylation of FU, allopurinol can reduce the antitumor activity of the drug. therefore

    The simultaneous use of allopuprimol and Teisuno is not recommended.

    Other forms of interaction

    Food intake

    With simultaneous reception with food, a decrease in the concentration of oteracil and gimeracil in the blood plasma is possible, with a more pronounced decrease in the concentration of the otercil (see section "Pharmacokinetics").The drug should be taken 1 hour before or 1 hour after meals, washed down with water (see section "Method of administration and dose").

    Special instructions:

    Clinical symptoms requiring correction of doses of the drug include diarrhea and symptoms of dehydration. Most of the side affects are reversible and can be eliminated in the course of symptomatic therapy, there may also be a need for dose adjustment or temporary cancellation.

    Inhibition of bone marrow hematopoiesis

    In patients receiving combined therapy with Teisuno and cisilatin preparations, oppression of bone marrow hematopoiesis, including neutropneumonia, leukopenia, thrombocytosis, anemia and pancytopenia, can be observed. Due to the increased risk of infectious diseases and the development of other complications, patients with leukopenia and peitropenia should be observed regularly by the attending physician, if necessary, appropriate therapy should be conducted (antibacterial drugs and preparations related to factors that stimulate colony formation of grapulocytes | G-CSF). . Patients with a low platelet count increase the risk of bleeding, they should regularly monitor platelet counts and a clinical blood test.In some cases, you may need to reduce the dose of Teisuno, (see the section "Method of administration and dose").

    Diarrhea

    Patients with diarrhea need careful clinical observation and replenishment of fluid and electrolyte losses when symptoms of dehydration appear. If necessary, anti-diarrheal drugs should be used. Initiate treatment with antidiarrhoeal drugs (eg, loperamide). should be as early as possible from the onset of diarrhea, while ensuring sufficient fluid and / or electrolyte administration. Correction of the dose of Teysuno is carried out with diarrhea of ​​2 degrees of severity or higher, and also in cases when diarrhea continues, despite the treatment being performed.

    Dehydration

    Dehydration and any electrolyte disturbances associated with it must be corrected before the beginning of treatment or eliminated at the very beginning of development. Particular attention should be paid to the symptoms of dehydration and to monitor the condition of those patients who have anorexia, asthenia, nausea, vomiting, diarrhea, stomatitis and intestinal obstruction. In such patients correction of dehydration and electrolyte disturbances should be more active.When dehydrating 2 degrees of severity or higher, stop treatment immediately and eliminate dehydration. It is not permissible to resume treatment until dehydration is eliminated and the causes that caused it. If necessary, a dose adjustment of Teisupo can be used to reduce side effects (see section "Dosage and Administration").

    Nephrotoxicity

    The use of Teisupo in combination with cisplatin may be accompanied by a transient decrease in the rate of glomerular filtration, which can be caused by primary prerenal factors (such as dehydration, electrolyte disturbances, etc.). In patients receiving combination therapy with Teisupo and cisplatin. side effects of grade 3 and above were observed, including an increase in the concentration of creatinine in the blood, a decrease in creatinine clearance, toxic nephropathy, and acute renal failure. In order to identify the initial manifestations of nsprotoxic action during the period of treatment with Teisupo, it is recommended to regularly monitor the kidney function (in particular, to determine the concentration of creatinine plasma, creatinine clearance).When the glomerular filtration rate decreases, the dose / s of Teisupo and / or cienlatin preparation (s) should be adjusted in accordance with the data in Table 4 and maintenance therapy should be prescribed (see the "Application and Dosage" section). Dehydration and diarrhea may increase the risk of an nfrotoxic effect of cyanenate. Hyperhydration (forced diuresis) is necessary to reduce the risk of an nfrotoxic effect, which is associated with the use of cyenlatine. as indicated in the instructions on cisplatin.

    Gimeracil increases the concentration of FU in the blood by inhibiting DPD, the main enzyme involved in the metabolism of FU. Gimeracil is mainly excreted by the kidneys, so in patients with renal insufficiency, the rate of removal of gimeracil decreases, and the concentration of FU in the blood rises. During the treatment, one can expect an increase in the toxic effects due to the increase in FU, (see the section "Pharmacokinetics").

    Severe renal insufficiency

    In patients with severe renal insufficiency, the use of Teisuio is not recommended because of the increased side effects from the hematopoiesis system and the lymphatic system and an unpredictable increase in the concentration of FU due to impaired renal function in such patients.sections "Pharmacokinetics", "Method of administration and dose" and "Pobochpae action ").

    Disturbances on the part of the organ of sight

    In patients with combined treatment with Teisuio and cisilatium, the most frequent reactions on the part of the visual organ were disorders of the function of the tear apparatus (8.8%). including increased lacrimation, dry eye syndrome, stenosis of nasolacrimal canals (see section "Pobochnos action ").

    The expression of the greater part of the symptoms on the part of the visual organ is corrected or reduced upon discontinuation of the drug and proper treatment (artificial tear preparations, antibacterial drugs, implantation of glass or silicone tubes in tear points or tubules, and it is also recommended that patients use eyeglasses rather than contact lenses more often). It is necessary to diagnose these disorders in a timely manner, you should seek advice from an ophthalmologist with the first persistent symptoms of impairment with the visual organs, in particular, with increased lachrymation or symptoms of dysfunction of the cornea.

    Read the instructions for cisilatin to take into account possible visual impairment,which can be caused by the use of cisplatin.

    Indirect anticoagulants of coumarin

    Patients receiving orally indirect am and coumarin coagulants, it is recommended to regularly monitor the effectiveness of treatment (Ml 10 and thrombin time), and correct the dose of anticoagulant (see section "Interaction with Other Drugs"). In clinical studies, it was shown that with simultaneous application of Teisuio and indirect anticoagulants, there was an increase Ml 10 and the development of bleeding from the gastrointestinal tract, hemorrhagic disorders, hematuria, anemia.

    DPD inductors

    At simultaneous application of preparation Teisuio and inductors DPD concentration FU

    may not reach an effective level. However, since DPD inducers are not known at present, it is difficult to assess the interaction between these drugs.

    Microsatellite instability

    Teisuno was not studied in patients with gastric cancer who underwent a microsatellite instability (MCS) test. The relationship between sensitivity to FU and the presence of SMEs in Nazi patients with gastric cancer has not been determined, and between Teisuno and MSN between Nazis and stomach cancer has not been studied. Glucose-galactose intolerance / malabsorption syndrome

    The preparation of Teisuno contains lactose in its composition. Patients with rare hereditary diseases, such as glucose-galactose intolerance, hereditary lactase deficiency, lactose intolerance or glucose-galactose malabsorption should take the drug with caution.

    Other fluoropyrimidine preparations

    There were no comparative clinical studies of the preparation of Teysuno and other oral derivatives of FU. In this regard, Teisuno should not be used in place of other drugs containing FU.

    Use in women of childbearing age

    Before starting treatment with Teisuno, a check should be made to confirm the absence of pregnancy.

    Women of reproductive age and their husbands should apply reliable contraceptive methods during therapy with Teysuno and for at least 6 months after completion of therapy.

    Possible effects on spermatogenesis in adults

    Data on the violation of spermatogenesis with the use of Teisuno is not available, however, there have been cases of a decrease in the total amount of sperm and azoospermia in men who use the drug cisplatin (a drug that is used as part of a combination therapy with Teisuno).

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

    During the period of treatment with Teisuno, a number of symptoms associated with the use of the drug (including from the side of the organ of vision, the central nervous system), which may have an adverse effect on the ability to drive and complex mechanisms, may occur. Therefore, patients should refrain from performing activities that require concentration and high speed psychomotor reactions.

    Form release / dosage:

    Capsules. 15 mg / 4.35 mg / 1 1.8 mg and 20 mg / 5.8 mg / 15.8 mg.

    For 14 capsules in a blister of PVC / 1 GGFHE / aluminum foil. By 3. 6 or 9 blisters with instructions for use in a pack of cardboard.

    Packaging:(14) - blisters (3) - packs cardboard
    (14) - blisters (6) - packs cardboard
    (14) - blisters (9) - packs cardboard
    Storage conditions:Store at a temperature not higher than 30 ° C. Keep out of the reach of children.
    Shelf life:

    3 of the year

    Not Use at the expiration date indicated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002935
    Date of registration:31.03.2015
    The owner of the registration certificate:Nordic Group BVNordic Group BV
    Manufacturer: & nbsp
    Representation: & nbspCompany FARMSTOR, LLCCompany FARMSTOR, LLC
    Information update date: & nbsp06.09.2015
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