Ongetsin

General characteristics. Structure:

Active ingredient: 228 mg or 1140 mg of gemcitabine of a hydrochloride that 200 mg or 1000 mg of gemcitabine are equivalent.

Excipients: Mannitolum, acetate sodium trihydrate, Acidum hydrochloricum, sodium hydroxide.

Pharmacological properties:

Pharmacodynamics. Antineoplastic means, an antimetabolite of group of analogs of a pyrimidine, suppresses DNA synthesis. Shows cyclospecificity, affecting cells in the phases S and G1/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. The maximum plasma concentration 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 distribution volume 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 (dTdCMP, dFdCDP and dFdCTP) from which dFdCDP and dFdCTP are considered active.

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

The elimination half-life fluctuates from 42 minutes to 94 minutes. 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 or 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.
• The Nerezektabelny, mestnoretsidiviruyushchy 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 epithelial 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.

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

Route of administration and doses:

Gemcitabine is entered intravenously kapelno within 30 minutes.

Not small-celled cancer of a lung. Monotherapy: the recommended drug dose - 1000 mg/sq.m in 1, 8 and 15 days of each 28-day cycle. A combination therapy with Cisplatinum: the recommended drug dose - 1250 mg/sq.m in the 1 and 8 day of each 21-day cycle or 1000 mg/sq.m in 1, 8 and 15 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 gemcitabine infusion. A combination therapy with karboplatiny: the recommended drug dose – 1000 mg/sq.m or 1200 mg/sq.m in the 1 and 8 day of each 21-day cycle. Karboplatin is entered in AUC dose (the area under a curve "concentration time") 5,0 mg / мл*мин in the 1st day of a cycle after gemcitabine infusion.

Breast cancer. 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 gemcitabine in a dose of 175 mg/sq.m in the 1st day of each 21-day cycle intravenously kapelno approximately during 3 h.

Urothelial cancer. Monotherapy: the recommended drug dose – 1250 mg/sq.m in 1, 8 and 15 days of each 28-day cycle. Combination therapy: the recommended drug dose - 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 gemcitabine into the 1st or in the 2nd day of each 28-day cycle.

Epithelial ovarian cancer. Monotherapy: the recommended drug dose – 800-1250 mg/sq.m in the 1st, 8th and 15th days of each 28-day cycle. Combination therapy: the recommended drug dose - 1000 mg/sq.m in the 1st and 8th days in combination with karboplatiny in a dose of AUC of 4,0 mg / мл*мин which is entered right after infusion of gemcitabine in the 1st day of each 21-day cycle.

Pancreatic cancer. 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 gemcitabine 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 gemcitabine is entered once a week within 6 weeks in a dose of 125 mg/sq.m with the subsequent (directly after administration of gemcitabine) 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 Gr, 5 days in a week to a total focal dose of 50.4 Gr.

Change of a dose of drug in connection with the phenomena 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 100000/mkl. In case of development of hematologic toxicity during a cycle of therapy the dose of gemcitabine can be reduced, or its introduction is postponed according to the following recommendations:

Modification of a dose of the gemcitabine applied 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 a standard dose
> 1 000	and	> 100 000	100
500 - 1 000	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 50000/mkl administration of gemcitabine can be continued within a cycle

Modification of a dose of the hemoglobin applied 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
1 000 <1200	or	50 000 - 75 000	75
700 <1 000	and	> =50 000	50
<700	or	<50 000	To postpone introduction *
* Treatment within a cycle is not resumed. The next administration of gemcitabine is carried out in the 1st day of the next cycle at achievement of quantity of neutrophils at least to 1 500/mkl and thrombocytes to 100 000/mkl

Modification of a dose of the gemcitabine applied 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
> 1 500	and	> = 100 000	100
1 000 <1 500	or	75 000 - 100 000	50
<1 000	or	<75 000	To postpone introduction *
* Treatment within a cycle is not resumed. The next administration of gemcitabine is carried out in the 1st day of the next cycle at achievement of quantity of neutrophils at least to 1 500/mkl and thrombocytes to 100 000/mkl

The gemcitabine dose 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 <25000/mkl;
• the cycle was postponed more than for 1 week because of hematologic toxicity.

Way of introduction. Infusional administration of gemcitabine is usually well transferred by patients and 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 gemcitabine the patient has to be observed for some time.

Special groups of patients. Patients with an abnormal liver function and kidneys: it is necessary to apply gemcitabine at patients with a liver failure or with an impaired renal function with care as 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.

Elderly patients (> 65 years): gemcitabine is well transferred by patients 65 years are more senior. Specific recommendations about change of a dose of drug for this population are absent.

Children (<18 years): children are not recommended to appoint gemcitabine aged up to 18 years in connection with insufficient information on safety and efficiency of drug in this population.

Recommendations about preparation of solution for infusions:
1. As solvent only 0,9% chloride sodium solution without preservatives are used.
2. For preparation of solution for infusions contents of a bottle of 200 mg are dissolved not less than in 5 ml, and 1 g – not less than in 25 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.
3. 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.
4. The prepared gemcitabine solution 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 intravenous infusion.
5. Before parenteral administration it is necessary to control visually prepared solution on presence of mechanical impurities and discoloration.

Features of use:

Treatment by gemcitabine can be carried out only under observation of the doctor having experience of use of antineoplastic chemotherapy.

Before each administration of gemcitabine it is necessary to control quantity of thrombocytes, leukocytes and granulocytes 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 gemcitabine 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 gemcitabine 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, an urea nitrogen or increase in activity of a lactate dehydrogenase, gemcitabine it has to 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 gemcitabine it is necessary to use reliable methods of contraception. The men receiving gemcitabine are recommended to resort to a sperm cryopreservation prior to treatment in connection with the risk of infertility caused by use of this drug.

Influence on ability to manage the vehicle and to work with mechanisms. The therapies given about influence by gemcitabine 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.

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: often - a leukopenia, a neutropenia, thrombocytopenia, anemia; often – a febrile neutropenia; very seldom – a thrombocytosis.

From system of digestion: very often - nausea, vomiting, increase in activity of "hepatic" transaminases (aspartate aminotransferase, alaninaminotranspherase), an alkaline phosphatase; often - anorexia, diarrhea, a lock, stomatitis, increase in concentration of bilirubin; seldom – increase in activity gamma глутамилтрансферазы.

From urinogenital 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 levels of bilirubin, creatinine, urea and/or lactate dehydrogenase in blood serum).

From skin and skin appendages: very often - the skin rashes which are followed by an itch, an alopecia; often - a skin itch, the increased perspiration;
seldom – 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, intersticial pneumonia, lung hypostasis; seldom - an acute respiratory distress syndrome.

From cardiovascular system: seldom – a lowering of arterial pressure, 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; sometimes – puffiness of the person; very seldom – anaphylactic reactions.

Interaction with other medicines:

Specific researches of interactions of gemcitabine were not conducted.

Radiation therapy. The accompanying radiation therapy (along with administration of gemcitabine 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 a mucous membrane, mainly an esophagitis and a pneumonitis, especially at patients, with the large volume of radiation of fabrics (a median of volume of the irradiated cm3 fabric 4795) was noted. 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 (e.g., an esophagitis, colitis and a pneumonitis).

Other types of interaction. At a concomitant use with live virus 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.

Incompatibility. Researches of compatibility of gemcitabine were not conducted. It is not recommended to mix gemcitabine with other medicines.

Contraindications:

• hypersensitivity to active agent or to any of excipients,
• pregnancy and period of feeding by a breast,
• children's age up to 18 years (lack of sufficient data by efficiency and safety).

With care: 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 gemcitabine in doses to 5700 mg/sq.m intravenously kapelno in 30 minutes 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:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to use drug after the expiry date specified on packaging.
 
Note: after cultivation drug keeps chemical and physical stability within 28 days at a temperature of 2 - 8 °C and at the room temperature in solution of glucose of 5% or solution of sodium of chloride of 0,9% (0,1 mg/ml and 7,5 mg/ml). From the microbiological point of view the prepared drug has to be used immediately. Drug can be stored in other cases during no more than 24 h at a temperature of 2-8 °C if only its cultivation was not made in the approved aseptic conditions.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for infusions, 200 mg, 1000 mg. On 200 or 1000 mg of gemcitabine, in the bottle from glass with a capacity of 10 or 50 ml corked by a stopper from brombutilovy rubber and a cap like "flip-off". On 1 bottle together with the application instruction place in a cardboard pack. On 5, 10 or 48 bottles with the equal number of instructions on a medical use in a cardboard box (for hospitals).