Gemita

General characteristics. Structure:

Active ingredient: 1138,6 mg of gemcitabine of a hydrochloride that corresponds to 1000 mg of gemcitabine.

Excipients: Mannitolum, acetate sodium trihydrate, Acidum hydrochloricum - q.s. for correction of pH, sodium hydroxide - q.s. for correction of pH.

Pharmacological properties:

Pharmacodynamics. Antineoplastic drug, an antimetabolite of group of analogs of a pyrimidine, suppresses DNA synthesis. Shows cyclospecificity, affecting cells in a phase S and on border of the phases G1 and S. It is metabolized in a cell under action нуклеозидкиназ to active diphosphatic and trifosfatny nucleosides. Diphosphatic nucleosides inhibit action of a ribonukleotidreduktaza (the only enzyme catalyzing formation of the dezoksinukleozidtrifosfat necessary for DNA synthesis). Trifosfatny nucleosides are capable to be built in DNA chain (to a lesser extent by RNA) that leads to the termination of further synthesis of DNA and the programmed lysis of a cell (apoptosis).

Gemcitabine is also strong radio sensibilizing means even in concentration lower, than cytotoxic.

Pharmacokinetics. Cmax of gemcitabine (from 3.2 mkg/ml to 45.5 mkg/ml) is reached in 5 minutes after the end of infusion. The pharmacokinetic analysis of researches with single and repeated introduction of doses shows that Vd substantially depends on a floor. Linkng of gemcitabine with proteins of plasma insignificant.

In an organism gemcitabine is quickly metabolized under the influence of a cytidinedeaminase in a liver, kidneys, blood and other fabrics therefore are formed gemcitabine mono - di - and triphosphates from which are considered active di's gemcitabine - and triphosphates.

Gemcitabine is quickly removed from an organism by kidneys generally in the form of an inactive metabolite 2-dezoksi-2, a 2-diftoruridin. Less than 10% entered into doses are found in urine in the form of not changed gemcitabine. The system clearance which fluctuates approximately from 30 l/h/sq.m to 90 l/h/sq.m depends on age and a floor.

T1/2 fluctuates from 42 min. to 94 min. At observance of the recommended dosing mode full removal of gemcitabine comes during 5-11 h from the beginning of infusion. At introduction once a week gemcitabine does not collect in an organism.

Combination therapy gemcitabine and paklitaksely. At joint administration of gemcitabine and a paklitaksel the pharmacokinetics of drugs does not change.

Combination therapy gemcitabine and karboplatiny. At joint administration of gemcitabine and a karboplatin the pharmacokinetics of gemcitabine does not change.

Renal failure. The renal failure of easy and moderate degree (clearance of creatinine of 30-80 ml/min.) has no significant effect on gemcitabine pharmacokinetics.

Indications to use:

— locally-spread or metastatic not small-celled cancer of a lung as therapy of the first line in a combination with Cisplatinum and in monotherapy at elderly patients with the functional status equal 2 (on ECOG-BOZ scale);

— an inoperable, local and recurrent or metastatic breast cancer after performing neoadjuvant and/or adjuvant therapy with inclusion of anthracyclines in the absence of contraindications to their appointment as a part of a combination therapy with paklitaksely;

— locally-spread or metastatic urothelial cancer (cancer of a bladder, renal pelvis, ureters, urethras);

— locally-spread or metastatic ovarian cancer as monotherapy or in combination with karboplatiny at patients with progressing of a disease after carrying out the first line of therapy on the basis of platiniferous drugs;

— locally-spread or metastatic pancreatic cancer;

— locally-spread or metastatic cancer of a neck of uterus.

Route of administration and doses:

Gemit's drug is administered in/in kapelno within 30 minutes.

Not small-celled cancer of a lung. At monotherapy the recommended dose of drug makes 1000 ^mg/sq.m in the 1st, 8th and 15th days of each 28-day cycle.

At a combination therapy with Cisplatinum the recommended drug dose - 1250 ^mg/sq.m in the 1st and 8th day of each 21-day cycle or 1000 ^mg/sq.m in the 1st, 8th and 15th days of each 28-day cycle. Cisplatinum is entered in a dose of 70 ^mg/sq.m in the 1st day of a cycle against the background of water loading after infusion of drug of Gemit.

At a combination therapy with karboplatiny the recommended drug dose - 1000 ^mg/sq.m or 1200 ^mg/sq.m in the 1st and 8th day of each 21-day cycle. Karboplatin is entered in a dose of AUC of 5.0 mg/ml/min. in the 1st day of a cycle after infusion of drug of Gemit.

Breast cancer. At a combination therapy as therapy of the 1st line when progressing a disease after the neoadjuvant therapy including anthracyclines, the recommended drug dose - 1250 ^mg/sq.m in the 1st and 8th days in combination with paklitaksely which is entered after administration of drug of Gemit in a dose of 175 ^mg/sq.m in the 1st day of each 21-day cycle in/in kapelno approximately during 3 h.

Urothelial cancer. At monotherapy the recommended dose of drug makes 1250 ^mg/sq.m in the 1st, 8th and 15th days of each 28-day cycle.

At a combination therapy the recommended dose of drug of-1000 ^mg/sq.m in the 1st, 8th and 15th days in combination with Cisplatinum which is entered in a dose of 70 ^mg/sq.m right after infusion of drug of Gemit into the 1st or in the 2nd day of each 28-day cycle.

Ovarian cancer. At monotherapy the recommended drug dose - 800-1250 ^mg/sq.m in the 1st, 8th and 15th days of each 28-day cycle.

Pancreatic cancer. At monotherapy the recommended drug dose - 1000 ^mg/sq.m once a week within 7 weeks with the subsequent week break. Then the drug is administered in the 1st, 8th and 15th days of each 28-day cycle.

Cancer of a neck of uterus (locally-spread or metastatic). Combination therapy: at locally-spread cancer (neoadjyuvantno) and at metastatic cancer gemcitabine is entered in a dose of 1250 ^mg/sq.m in the 1st and 8th days of each 21-day cycle. Cisplatinum is entered after administration of drug of Gemit in a dose of 70 ^mg/sq.m in the 1st day of a cycle against the background of an overhydratation.

At locally-spread cancer at simultaneous radiation therapy Gemit's drug is administered once a week within 6 weeks in a dose of 125 ^mg/sq.m with the subsequent (directly after administration of drug of Gemit) introduction of Cisplatinum in a dose of 40 ^mg/sq.m for 1-2 h prior to radiation therapy. Radiation therapy is carried out for 28 fractions, in a single focal dose of 1.8 g, 5 days in a week to a total focal dose of 50.4 g.

Change of a dose of drug in connection with the phenomenon of hematologic toxicity. Beginning of a cycle of treatment. Irrespective of indications, before each administration of drug it is necessary to estimate number of thrombocytes and granulocytes. A condition of an initiation of treatment is the absolute quantity of neutrophils not less 1500/mkl and quantity of thrombocytes not less than 100 000/mkl.

In case of development of hematologic toxicity during a cycle of therapy the dose of drug of Gemit can be reduced, or its introduction is postponed according to the following recommendations.

Modification of a dose of Gemit's drug used in monotherapy or in a combination with Cisplatinum at cancer therapy of a bladder, not small-celled cancer of a lung and a pancreatic cancer.

Absolute quantity of neutrophils (in 1 мкл)		Quantity of thrombocytes (in 1 мкл)	% of the previous dose
> 1000	and	> 100 000	100
500-1000	or	50 000-100 000	75
<500	or	<50 000	To postpone introduction *

* At increase in quantity of neutrophils to 500/mkl and thrombocytes to 50 000/mkl administration of drug of Gemit it can be continued within a cycle.

Modification of a dose of Gemit's drug used in a combination with paklitaksely at cancer therapy of a mammary gland.

Absolute quantity of neutrophils (in 1 мкл)		Quantity of thrombocytes (in 1 мкл)	% of a standard dose
≥ 1200	and	> 75 000	100
1000-1200	or	50 000-75 000	75
700-1000	and	≥ 50 000	50
<700	or	<50 000	To postpone introduction *

* Treatment within a cycle is not resumed. The next administration of drug of Gemit is carried out in the 1st day of the next cycle at achievement of quantity of neutrophils at least to 1500/mkl and thrombocytes to 100 000/mkl.

Modification of a dose of Gemit's drug used in a combination with karboplatiny at cancer therapy of ovaries.

Absolute quantity of neutrophils (in 1 мкл)		Quantity of thrombocytes (in 1 мкл)	% of a standard dose
> 1500	and	≥ 100 000	100
1000-<1500	or	75 000-100 000	50
<1000	or	<75 000	To postpone introduction *

* Treatment within a cycle is not resumed. The next administration of drug of Gemit is carried out in 1 day of the next cycle at achievement of quantity of neutrophils at least to 1500/mkl and thrombocytes to 100 000/mkl.

The drug dose Gemita on the next cycle has to be reduced by 25% at all indications in cases if at the previous cycle it was observed:

— decrease in absolute number of neutrophils <500/mkl, proceeding more than 5 days;

— decrease in absolute number of neutrophils <100/mkl, proceeding more than 3 days;

— febrile neutropenia;

— decrease in number of thrombocytes <25 000/mkl;

— the cycle was postponed more than for 1 week because of hematologic toxicity.

Way of introduction. Infusional administration of drug of Gemit it is usually well transferred by patients and it can be carried out in out-patient conditions. In case of an ekstravazation infusion is stopped and resume administration of drug in other vein. After administration of drug of Gemit the patient has to be observed for some time.

It is necessary to use Gemit's drug at patients with a liver failure or with an impaired renal function with care since there are no sufficient data on use of drug for this category of patients. The renal failure moderate or moderately severe (a glomerular filtration rate from 30 ml/min. to 80 ml/min.) does not exert noticeable impact on gemcitabine pharmacokinetics.

Gemit's drug is well transferred by elderly patients 65 years are more senior. Specific recommendations about change of a dose of drug for this population are absent.

Children are not recommended to appoint Gemit's drug aged up to 18 years in connection with insufficient information on safety and efficiency of drug in this population.

Rules of preparation of solution for infusions. As solvent only 0.9% chloride sodium solution without preservatives are used.

For preparation of solution for infusions contents of a bottle of 200 mg are dissolved not less than in 5 ml, 1000 mg — not less than in 25 ml, and 1400 mg — not less than in 35 ml of 0.9% of solution of sodium of chloride for injections. Each bottle is accurately shaken up before full dissolution of lyophilisate. The received solution has to be transparent.

The maximum concentration of gemcitabine should not exceed 40 mg/ml. The solutions prepared with concentration above than 40 mg/ml, can be followed by incomplete dissolution.

The prepared solution of drug of Gemit containing the necessary dose of drug before introduction is diluted by 0.9% with chloride sodium solution for injections in the quantity sufficient for 30-minute in/in infusions.

Before parenteral administration it is necessary to control visually prepared solution on presence of mechanical impurities and discoloration.

The prepared solution of drug of Gemit is stable from the physical and chemical point of view during 24 h provided that it was stored at the controlled room temperature (from 20 °C to 25 °C). From the microbiological point of view the prepared solution has to be used immediately. If the prepared solution was not used at once and its preparation was carried out in controlled and validirovanny aseptic conditions, storage time usually makes no more than 24 h at the room temperature (from 20 ° to 25 °C).

Features of use:

Use at pregnancy and feeding by a breast. Use of drug at pregnancy and the period of a lactation (breastfeeding) is contraindicated.

Use at abnormal liver functions. With care: at an abnormal liver function, at metastatic damage of a liver, hepatitis. During treatment it is necessary to carry out regular assessment of function of a liver. Administration of drug of Gemit at metastasises in a liver, at hepatitis and alcoholism in the anamnesis, and also at cirrhosis increases risk of development of a liver failure.

Use at renal failures. With care: at a renal failure. During treatment it is necessary to carry out regular assessment of function of kidneys.

Use for children. It is contraindicated to children up to 18 years (lack of sufficient data by efficiency and safety).

Use for elderly patients. Drug is well transferred by patients 65 years are more senior. Specific recommendations about change of a dose of drug for this population are absent.

Special instructions. Treatment by Gemit's drug can be carried out only under observation of the doctor having experience of carrying out antineoplastic chemotherapy.

Before each administration of drug of Gemit it is necessary to define a leukocytic formula and quantity of thrombocytes in blood. At signs of oppression of function of the marrow caused by drug it is necessary to suspend treatment or to correct a dose.

It is necessary to conduct regular examination of the patient and assessment of function of kidneys and a liver.

Administration of drug of Gemit at metastasises in a liver, at hepatitis and alcoholism in the anamnesis, and also at cirrhosis increases risk of development of a liver failure.

At emergence of signs of development of the undesirable phenomena from respiratory system (for example, a fluid lungs, an intersticial pneumonitis or a respiratory distress syndrome at adults) against the background of treatment Gemit's drug treatment it is necessary to stop and appoint the corresponding therapy.

At emergence of the first symptoms of mikroangiopatichesky hemolitic anemia, such as bystry decrease in hemoglobin with the accompanying thrombocytopenia, increase in serumal concentration of bilirubin, creatinine, nitrogen, urea or increase in activity of LDG, drug should be cancelled. Increase in duration of infusion and frequency of introductions leads to toxicity increase.

Depending on toxicity degree the dose can be reduced during each cycle or from the beginning of a new cycle in steps.

During treatment and within 6 months after the end of therapy by Gemit's drug it is necessary to use reliable methods of contraception. The men receiving Gemit's drug are recommended to resort to a sperm cryopreservation prior to treatment in connection with the risk of infertility caused by use of this drug.

Gemcitabine can begin to be entered after permission of acute beam reactions or not earlier than in 7 days after the end of radiation therapy.

Gemcitabine in monotherapy or in a combination with other antineoplastic means shows activity at the progressing small-celled cancer of a lung, the progressing cancer of a small egg and a bile duct carcinoma.

Influence on ability to driving of motor transport and to control of mechanisms. Data on influence of therapy of drug of Gemit on ability to manage the vehicle and to work with mechanisms are absent, however, some side effects of drug, such as the increased drowsiness, can negatively influence ability of driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions that demands respect for care.

Side effects:

The side reactions which were found more often than in isolated cases are listed according to the following gradation: very often (> 10%); often (> 1% to <10%); infrequently (> 0.1% to <1%); seldom (> 0.01% to <0.1%); very seldom (<0.01%).

From bodies of a hemopoiesis: very often - a leukopenia, a neutropenia, thrombocytopenia, anemia; often - a febrile neutropenia; very seldom - a thrombocytosis.

From the alimentary system: very often - nausea, vomiting, increase in activity of hepatic transaminases (nuclear heating plant, ALT), ShchF; often - anorexia, diarrhea, a lock, stomatitis, increase in concentration of bilirubin; seldom - increase in activity of GGT.

From an urinary system: very often - a hamaturia and a proteinuria of easy degree; seldom - the renal failure, clinical signs and symptoms similar to a gemolitiko-uraemic syndrome (decrease in hemoglobin, thrombocytopenia, increase in concentration of bilirubin, creatinine, urea and/or activity of LDG in blood serum).

From skin and hypodermic fabrics: very often - the skin rashes which are followed by an itch, an alopecia; often - a skin itch, the increased perspiration; seldom - skin ulcerations, formation of bubbles; very seldom - the expressed skin reactions, including desquamation and violent rashes.

From respiratory system: very often - an asthma; often - cough, rhinitis; infrequently - a bronchospasm, an intersticial pneumonitis, lung hypostasis; seldom - an acute respiratory distress syndrome.

From cardiovascular system: seldom - decrease in the ABP, a myocardial infarction, heart failure, arrhythmia.

From a nervous system: often - a headache, the increased drowsiness, sleeplessness.

Others: very often - a grippopodobny syndrome, peripheral hypostases; often - fervescence, a fever, an adynamy, dorsodynias, a mialgiya; infrequently - puffiness of the person; very seldom - anaphylactic reactions.

Interaction with other medicines:

Radiation therapy. The accompanying radiation therapy (along with administration of drug of Gemit or with an interval <7 days prior to treatment): in this situation toxicity of treatment depends on many factors, including a dose of gemcitabine and frequency of its introduction, a radiation dose, a method of radiation therapy, character of the irradiated fabric and its volume. It was shown that gemcitabine possesses radio sensitizing power. In one research where patients with not small-celled cancer of a lung received gemcitabine in a dose of 1000 mg/sq.m for 6 consecutive weeks in combination with therapeutic radiation on area of a thorax, considerable toxicity in the form of heavy and potentially life-threatening inflammation of mucous membranes, mainly an esophagitis and a pneumonitis was noted, especially patients with large volume have radiations of fabrics (a median of volume of the irradiated cm3 fabric 4795). In the subsequent researches it was shown that the combination of lower doses of gemcitabine and radiation therapy is better transferred by patients and is characterized by a predictable profile of toxicity. So, in one of phase researches II to patients with not small-celled cancer of a lung radiation therapy in a dose of 60 Gr together with administration of gemcitabine (600 mg/sq.m 4 times) and Cisplatinum (80 mg/sq.m 2 times) for 6 weeks was carried out.

Consecutive therapy (break> of 7 days): according to the existing data, administration of gemcitabine more than in 7 days prior to radiation therapy or more than in 7 days after its end is not followed by increase in toxicity, except for the damage of skin connected with introduction of a himiopreparat after radiation. Treatment by gemcitabine can be begun in 7 days after radiation or after permission of all acute beam reactions.

Both at accompanying, and at consecutive use of gemcitabine and radiation therapy perhaps radiation injury of the irradiated fabrics (for example, an esophagitis, colitis and a pneumonitis).

Other types of interaction. At simultaneous use with live attenuirovanny vaccines the intensification of process of replication of a vaccinal virus, strengthening of its side/adverse effects and/or decrease in development of antibodies in the patient's organism in response to introduction of a vaccine is possible.

Immunodepressants (including Azathioprinum, hlorambutsit, GKS, cyclophosphamide, cyclosporine, Mercaptopurinum) increase risk of developing of infections.

Researches of compatibility of drug of Gemit were not conducted. It is not recommended to mix Gemit's drug with other medicines.

Contraindications:

— pregnancy;

— breastfeeding period;

— children's age up to 18 years (lack of sufficient data by efficiency and safety);

— hypersensitivity to active agent or to any of excipients.

With care it is necessary to appoint drug at an abnormal liver function and/or kidneys, oppression of a marrowy hemopoiesis (including against the background of accompanying beam or chemotherapy), cardiovascular diseases, at metastatic damage of a liver, hepatitis, alcoholism, at at the same time carried out radiation therapy, acute infectious diseases of the virus, fungal or bacterial nature (including chicken pox, shingles).

Overdose:

The antidote for gemcitabine is unknown. At administration of drug of Gemit in doses to 5700 mg/sq.m in/in kapelno in 30 min. each 2 weeks the level of toxicity of treatment remained acceptable.

At suspicion on overdose of gemcitabine it is necessary to control degree of a cytopenia and if necessary to appoint a maintenance therapy.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 25 °C. Not to freeze. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

Bottles glass (1) - packs cardboard.