Gikamtin

General characteristics. Structure:

Lyophilisate for preparation of solution for infusions in the form of porous weight from light yellow till greenish color; the recovered solution transparent, from yellow till flavovirent color.

Active ingredient: топотекан (in the form of a hydrochloride) 4 mg

Excipients: tartaric acid - 20 mg, Mannitolum - 48 mg, sodium hydroxide - q.s. to pH 3.0, Acidum hydrochloricum - q.s. to pH 3.0.

Pharmacological properties:

Antineoplastic drug, inhibitor of topoisomerase-I, the enzyme which is directly participating in DNA replication. Topotekan suppresses activity of topoisomerase-I, stabilizing a covalent complex of enzyme and the spiral split DNA which is an intermediate link of the catalytic mechanism.

The inhibition of topoisomerase-I leads to a rupture of one-spiral DNA and a stop of DNA replication.

Pharmacokinetics. Distribution

Topotekan is characterized by big Vd (about 132 l), approximately by 3 times exceeding the total amount of liquid in an organism, and rather short T1/2 (2–3 h). When comparing pharmacokinetic parameters no changes of pharmacokinetics during a 5-day course of therapy are revealed.

Linkng of a topotekan with proteins of a blood plasma makes 35%, and distribution between blood cells and plasma uniform.

Values of clearance of a blood plasma and volume of distribution were slightly higher at men, than at women. However these distinctions corresponded to distinctions in body surface area.

Metabolism

The main way of metabolism of a topotekan is a reversible pH-dependent hydrolysis of a lactonic ring with formation of an inactive carboxyl form.

Is exposed to metabolism <10% of the entered topotekan. N-demetilirovanny the metabolite of a topotekan possessing similar or smaller, than топотекан activity, is found in urine, a blood plasma and fecal masses. Later in/in introductions average value of a ratio of AUC of a metabolite of a topotekan and topotekan made less than 10% and for the general topotekan, and for a topotekan in the form of a lactone. In urine O is found? glucuronide of a topotekan and N-demetilirovanny топотекан.

In vitro топотекан does not suppress activity of isoenzymes of CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A and CYP4A of system of P450 cytochrome, and also cytosolic enzymes a dihydropyrimidine dioxidase and a xanthineoxidase.

Removal

Later in/in introductions the curve of decrease in concentration of a topotekan in a blood plasma has bieksponentsialny character. The pharmacokinetics of a topotekan at in introduction is approximately proportional to the entered dose. At repeated daily in introduction топотекан in an organism collects in the minimum quantities or does not collect in general, and there are no data on change of pharmacokinetics at repeated introduction.

The clearance of a topotekan later in/in introductions in doses from 0.5 mg/sq.m to 1.5 mg/sq.m (30-minute daily infusions within 5 days in a row) was high (64 l/h, i.e. about 2/3 hepatic blood-grooves).

After a 5-day course of a topotekan the total quantity of the topotekan brought out of an organism and its metabolites made from 71% to 76% entered into doses. About 51% are removed through kidneys in the form of a topotekan, 2.5% - in the form of N-demetilirovannogo of a metabolite of a topotekan, through intestines 18% of a topotekan and 1.5% of N-demetilirovannogo of a metabolite of a topotekan are removed. In general, in the form of a metabolite (N-demetilirovannogo of a metabolite of a topotekan) through kidneys and intestines less than 7% of a topotekan are removed (an interval from 4% to 9%). Concentration the O-glucuronide of a topotekan and N-demetilirovannogo the O-glucuronide of a topotekan in urine make ≤ 2% of the entered dose.

At introduction to combinations with Cisplatinum (Cisplatinum in the 1st day, топотекан in days 1–5) the clearance of a topotekan for the 5th day was lower, than in the 1st day (19.1 l/h/sq.m and 21.3 l/h/sq.m, respectively). In population researches joint introduction of a granisetron, ondansetron, morphine or glucocorticosteroids did not render significant effect on pharmacokinetics of a topotekan.

Pharmacokinetics at special groups of patients

In a population research in/in a topotekan a number of factors, including age, body weight and existence of ascites, did not exert significant impact on clearance.

Children

Features of pharmacokinetics of a topotekan at children studied after 24-hour infusion of a topotekan in a dose from 2 mg/sq.m to 7.5 mg/sq.m or 72-hour infusion from 0.75 mg/sq.m / to 1.95 mg/sq.m / In both researches the clearance of a topotekan was equal to clearance at the adult patients receiving drug according to similar schemes in a dose.

Renal failure

At patients with a renal failure (KK from 40 ml/min. to 60 ml/min.) the clearance in/in the entered topotekan was reduced approximately to 67% of value in control group. Vd was a little reduced, and, thus, time of semi-removal is increased by 14%. At patients with a moderate renal failure (KK from 20 ml/min. to 39 ml/min.) the clearance of a topotekan from a blood plasma was reduced to 34% of control value. Vd was also reduced approximately by 25% that led to increase in time of semi-removal from 1.9 h to 4.9 h.

Abnormal liver function

At patients with an abnormal liver function (serumal bilirubin from 1.5 mg/dl to 10 mg/dl) the clearance of a topotekan in the form of a lactone from a blood plasma in/in introductions is reduced later approximately to 67% of value in control group. Time of semi-removal of a topotekan is increased approximately by 30%, but explicit increase in Vd was not observed. The clearance of a topotekan at patients with an abnormal liver function decreased only by 10% in comparison with control.

Indications to use:

— small-celled cancer of a lung;

— ovary cancer;

— the recurrent or persistent cancer of a neck of uterus which is not giving in to surgical treatment and/or radiation therapy (a stage of IV B) as a part of a combination therapy with Cisplatinum.

Route of administration and doses:

Gikamtin enter in the form of 30-minute in/in infusions.

Before purpose of the first course of therapy by drug Gikamtin the quantity of neutrophils has to be 1500/mkl, thrombocytes ≥ 100 000/mkl, hemoglobin level ≥ 9 g/dl (after a transfusion if it is necessary).

Drug is appointed to adults and patients of advanced age.

At small-celled lung cancer and ovarian cancer appoint 1.5 mg/sq.m daily within 5 consecutive days at an interval of 3 weeks (21 days) before each course.

For achievement of effect it is recommended to conduct at least 4 courses of therapy (in clinical trials the average time of approach of effect at suffering from cancer ovaries made 7.6-11.7 weeks, at patients with small-celled cancer of a lung - 6.1 weeks. Approximately at 18% of patients with cancer of an ovary the effect was reached after carrying out 5 and more courses of therapy).

Repeated courses of therapy by drug Gikamtin can be conducted only at the following indicators: neutrophils 1000/mkl, thrombocytes ≥100 000/mkl, hemoglobin of ≥9 g/dl (including after a transfusion if it is necessary).

At the expressed neutropenia (quantity of neutrophils <500/mkl) within 7 days or more, or a febrile neutropenia, or in case of a treatment delay because of a neutropenia, it is necessary or to lower a drug dose to 1:25 mg/sq.m/days (or is up to 1 mg/sq.m later/), or to conduct the subsequent courses with purpose of preventive introduction of G-KSF. If the neutropenia against the background of G-KSF remains, doses of drug have to be reduced.

At decrease in number of thrombocytes at the previous course of chemotherapy <25 000/mkl doses have to be reduced similarly.

In clinical trials therapy topotekany was stopped if it was necessary to lower a dose lower than 1 mg/sq.m.

At cancer of a neck of uterus the recommended drug dose Gikamtin makes 0.75 mg/sq.m in the 1st, 2nd and 3rd days. In the 1st day of therapy after administration of drug Gikamtin is carried out infusion of Cisplatinum in a dose of 50 mg/sq.m. This scheme repeats each 21 day, only 6 courses. At emergence of signs of progressing of a disease Gikamtin it is necessary to cancel.

Repeated courses of therapy by drug Gikamtin can be conducted only at the following indicators: quantity of neutrophils 1500/mkl, thrombocytes - ≥100 000/mkl, hemoglobin - ≥9 g/dl (after a transfusion if it is necessary).

At the expressed neutropenia (quantity of neutrophils less 500/mkl) within 7 or more days, or a febrile neutropenia, or in case of a treatment delay because of a neutropenia it is necessary or to lower a drug dose for the subsequent courses by 20% to 600 mkg/sq.m / (or is up to 450 mkg/sq.m later/), or to conduct the subsequent courses with purpose of preventive introduction of G-KSF. If the neutropenia against the background of G-KSF remains, doses of drug have to be reduced.

At decrease in number of thrombocytes less than 25 000/mkl doses should be reduced similarly.

Gikamtin's appointment for treatment of children is contraindicated since the available experience of use of drug for this category of patients is insufficient.

With a renal failure at monotherapy at KK ≥ 40 ml/min. of correction of the mode of dosing are not required from patients. At KK from 20 to 39 ml/min. the recommended dose makes 750 mkg/sq.m/; recommendations are based on the researches including of patients with widespread cancer. At KK <20 ml/min. of the recommendation are absent.

At a combination therapy Gikamtin with Cisplatinum for cancer therapy of a neck of uterus is recommended to begin with drug therapy only to patients at whom concentration of creatinine in plasma does not exceed 1.5 mg/dl. If during treatment creatinine level in plasma exceeds 1.5 mg/dl, it is necessary to implement recommendations of the application instruction of Cisplatinum about reduction of its dose or cancellation. In case of cancellation of Cisplatinum there are no sufficient data concerning monotherapy continuation by drug Gikamtin at patients with cancer of a neck of uterus.

For patients with abnormal liver functions (level of bilirubin from 1.5 to 10 mg/dl) at monotherapy dose adjustment is not required. At a combination therapy with other cytotoxic drugs dose adjustment can be required.

Rules of preparation of solution

Contents of a bottle should be dissolved in 4 ml of sterile water for injections to concentration 1 mg/ml. The received solution it is necessary to dilute 0.9% with solution of sodium of chloride or 5% dextrose solution to concentration of 25-50 mkg/ml.

To use the recovered solution right after preparation or to store in the refrigerator at a temperature from 2 ° to 8 °C during 24 h.

To use the prepared solution right after preparation or to store in the refrigerator at a temperature from 2 ° to 8 °C during 24 h.

Features of use:

Treatment topotekany has to be carried out under observation of the specialist having experience with antineoplastic drugs.

Hematologic toxicity of a topotekan depends on its dose, it is necessary to carry out regularly developed blood tests with determination of level of hemoglobin, a hematocrit, calculation of quantity of leukocytes, neutrophils and thrombocytes.

At a combination of a topotekan to other cytotoxic drugs it is necessary to adjust its dose.

At development of the expressed neutropenia careful observation is necessary for timely diagnosis of infectious complications.

As well as at use of other cytotoxic drugs, топотекан can cause the heavy miyelosupressiya leading in certain cases to heavy infectious complications, including to sepsis and the related lethal outcome.

The neutropenia induced by treatment topotekany can serve as the reason of development of neytropenichesky colitis. During clinical trials cases of this complication with a lethal outcome were registered. At patients with fever, a neutropenia in combination with an abdominal pain in a projection of a large intestine it is necessary to consider a possibility of development of neytropenichesky colitis.

Cases of an intersticial pulmonary disease were registered against the background of treatment topotekany, some with a lethal outcome. Patients with an intersticial pulmonary disease, lung fibrosis, lung cancer in the anamnesis, and also the patients who underwent radiation of a thorax, accepting pneumotoxic drugs and/or colony stimulating factors are in group of high risk of development of this complication. Patients need observation regarding emergence of symptoms of an intersticial pulmonary disease (for example, cough, fever, short wind and/or a hypoxia). At confirmation of again revealed intersticial pulmonary disease топотекан it is necessary to cancel.

When developing of the expressed thrombocytopenia are necessary extreme care at implementation of invasive procedures, regular survey of integuments and mucous membranes, and also allocations for identification of symptoms of bleeding.

During the work with drug it is necessary to follow the standard rules of the treatment of cytotoxic drugs. At accidental hit of drug on skin or in eyes it is necessary to wash out their large number waters.

Influence on ability to driving of motor transport and to control of mechanisms

It is necessary to consider the general clinical condition of the patient and possible development of the undesirable phenomena (especially increased fatigue and weakness) at assessment of ability to driving and the work with mechanisms demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Prolonged use does not cause increase in toxic effect of drug. Serious manifestations of cardiotoxicity, a neurotoxicity, organ toxicity are noted.

The undesirable phenomena given below are listed according to defeat of bodies and systems of bodies and occurrence frequency. Frequency of occurrence is defined as follows: very often (≥1/10), it is frequent (≥1/100, <1/10), infrequently (≥1/1000, <1/100), is rare (≥1/10 000, <1/1000), is very rare (<1/10 000, including separate cases). Categories of frequency were created on the basis of clinical trials of drug.

From system of a hemopoiesis: very often - a neutropenia, a febrile neutropenia, a leukopenia, thrombocytopenia, anemiya1, change of indicators krovi2; often - a pancytopenia; very seldom - the side effects influencing results of blood tests; frequency is unknown - bleeding, the expressed and concealed hemorrhages caused by thrombocytopenia.

From a musculoskeletal system: often - a mialgiya.

From the alimentary system: very often - diareya3, nausea, vomiting (including heavy degree), pain in zhivote4, a lock, stomatitis, anorexia (including heavy degree); often - a hyperbilirubinemia; very seldom - an intestines inflammation (colitis); frequency is unknown - intestinal impassability.

From immune system: often - hypersensitivity reactions, including rash.

From respiratory system: seldom - an intersticial pulmonary disease.

From skin and a hypodermic fatty tissue: very often - an alopecia.

Allergic reactions: very often - anaphylactoid reactions; seldom - a small tortoiseshell, the complicated breath; very seldom - a Quincke's disease; frequency is unknown - skin rash (including erythematic, makulopapulezny rash, a small tortoiseshell, dermatitis, a violent erythema).

The general frustration and disturbances in an injection site: very often - fervescence, increased fatigue, an adynamy, infections; often - weakness, sepsis; very seldom - an ekstravazation: a hematoma or a dermahemia in an injection site (at an ekstravazation) (the reactions connected with an ekstravazation were poorly expressed and, as a rule, did not demand specific treatment); frequency is unknown - short wind, infections.

1 Cases from moderated to heavy anemia (3 and 4 degrees - Hb <8 g/dl) met in 25% of cases (12% of courses). Time median prior to the beginning of average and heavy degree of anemia - the 12th day with an average duration of 7 days. In 46% of courses with moderate and heavy degree of anemia - duration is more than 7 days. Packed red cells transfusions received 30% of patients (13% of courses). Erythropoetin was entered by 10% of patients into 8% of courses.

2 Low quantity of the cells necessary for a blood coagulation that can cause bruises, bleedings and, seldom, severe bleeding (hemorrhage).

3 At in introduction of a topotekan diarrhea at patients is aged more senior than 65 years met in 10% of cases.

4 Cases of neytropenichesky colitis, including cases with a lethal outcome, were regarded as a complication lekarstvenno of the caused neutropenia.

Interaction with other medicines:

As well as in case of other myelosuppressive cytotoxic drugs, the miyelosupressiya increases at use of a topotekan in a combination with other cytotoxic substances (for example, paklitaksely or etopozidy) that demands a dose decline. However at use of a topotekan in combinations with platinum drugs (for example, Cisplatinum or карбоплатин) accurate dependence of interaction between drugs on the sequence of their introduction, i.e. on is traced whether the platinum drug on the 1st or for the 5th day of use of a topotekan is administered. If the patient receives platinum drug for the 1st day of introduction of a topotekan, both drugs have to be appointed in smaller doses than if the drug of platinum is administered for the 5th day.

At in introduction of a topotekan (than 750 mkg/sq.m / 5 days in a row) and Cisplatinum (60 mg/sq.m / in the 1st day) average values of clearance of a topotekan in a blood plasma for the 5th day can be slightly lower, than in the 1st day. Thus, system exposure of the general topotekan (AUC and Cmax) for the 5th day can be 12% higher (95% of the confidence interval (CI): from 2% to 24%) and 23% (95% of DI: from 7% to 63%) respectively. Patients have no data on pharmacokinetic interaction after introduction of a topotekan (750 mkg/sq.m / 3 days in a row) and Cisplatinum (50 mg/sq.m / in the 1st day) with cancer of a neck of uterus.

Doses and schemes of use of a topotekan and drugs of platinum are included below:

— Cisplatinum in the 1st day in a dose of 60 mg/sq.m and топотекан in a dose of 750 mkg/sq.m from 1st to the 5th day.

— Cisplatinum in the 5th day in a dose of 50 mg/sq.m and топотекан in a dose of 1.25 mg/sq.m from 1st to the 5th day.

Topotekan does not suppress activity of isoenzymes of system of P450 cytochrome. In population researches joint introduction of a granisetron, ondansetron, morphine or GKS (infusions were carried out through different systems or other way of introduction was used) did not render significant effect on pharmacokinetics in/in the entered topotekan.

Topotekan is substrate both for protein of resistance of a breast cancer of BCRP (ABCG2), and for ABCB1 (R-glycoprotein). Elakridar vlit on pharmacokinetics of the topotekan entered in/in, than accepted orally much less.

Contraindications:

— the expressed oppression of function of marrow (quantity of neutrophils less 1500/mkl, thrombocytes — less than 100 000/mkl);

— anemia (Hb <9 g/dl);

— pregnancy;

— lactation (breastfeeding);

— children's age (lack of sufficient experience);

— hypersensitivity in the anamnesis to the topotekan or other components which are a part of drug.

Use of drug GIKAMTIN at pregnancy and feeding by a breast
Drug is contraindicated to use at pregnancy and in the period of a lactation (breastfeeding).

The woman of childbearing age and the man in the period of reception Gikamtin have to use well-tried remedies of contraception. At approach of pregnancy it is necessary to report about it to the attending physician immediately.

Use at abnormal liver functions
For patients with abnormal liver functions (bilirubin of plasma from 1.5 to 10 mg/dl) of special selection of a dose it is not required. At Gikamtin's use in a dose of 1.5 mg/sq.m within 5 days each 3 weeks small decrease in clearance of a topotekan was observed.

Use at renal failures
At renal failures for patients with KK40 the ml/min. of dose adjustment is not required. The recommended dose for patients with KK of 20-39 ml/min. makes 750 mkg/sq.m / For recommendations concerning a drug dose for patients with KK <20 ml/min. of the available data are not enough.

 

Use for children
Contraindication: children's age (lack of sufficient experience).

Overdose:

Symptoms: oppression of function of marrow, stomatitis.

Treatment: the antidote of a topotekan is unknown. Carry out symptomatic therapy.

Storage conditions:

Not opened bottle should be stored in the unavailable to children, protected from light place at a temperature not above 30 °C. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

Bottles glass of 17 ml (1) - packs cardboard.
Bottles glass of 17 ml (5) - packs cardboard with the built-in cardboard divider.