Gemtsitar

General characteristics. Structure:

Active ingredient: 200 mg or 1000 mg of gemcitabine (in the form of a hydrochloride).

Excipients: Mannitolum, sodium acetate.

Pharmacological properties:

Pharmacodynamics. Gemcitabine represents an antimetabolite of group of analogs of a pyrimidine. Suppresses synthesis of deoxyribonucleic acid (DNA). 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 with formation of active diphosphatic and trifosfatny nucleosides. Diphosphatic nucleosides inhibit the ribonukleotidreduktaza which is the only enzyme catalyzing formation of the dezoksinukleozidtrifosfat necessary for DNA synthesis. Trifosfatny nucleosides actively compete with dezoksitsitidintrifosfaty for embedding in molecules DNA and RNA. After embedding of intracellular metabolites of gemcitabine one more additional nucleotide is added to DNA chain to its growing threads that leads to complete inhibition of further synthesis of DNA and apoptosis of a cell.

Pharmacokinetics. The maximum concentration of gemcitabine in plasma after single 30-minute infusion in a dose of 1 g/m2 exceeds 5 mkg/ml within about 30 min. after completion of infusion. Within the next hour it exceeds 0,4 mkg/ml.
 
The elimination half-life fluctuates from 42 to 94 minutes. At elderly patients the elimination half-life is increased. Gemcitabine is completely removed from an organism in 5-11 hours. At weekly introduction the cumulative effect is not observed. Linkng of gemcitabine with proteins of plasma insignificant.
 
Gemcitabine quickly is exposed to metabolism in a liver, kidneys, blood and other fabrics. Active intracellular metabolites are not found in blood and urine. The inactive metabolite 2-dezoksi-2,2-diftoruridin is brought out of an organism with urine.
 
The system clearance which fluctuates approximately from 30 l/h/sq.m to 92 l/h/sq.m depends on age and a floor. At women the clearance is 25% less, than at W men; with age the clearance of gemcitabine decreases. About 90% of drug are removed with urine in the form of an inactive metabolite, less than 10% of the dose entered intravenously are found in urine in the form of not changed drug, less than 1% are removed with a fecal masses.

At purpose of gemcitabine as a part of a combination therapy its pharmacokinetics does not undergo significant changes.

The renal failure easy or moderate severity (a glomerular filtration rate from 30 to 80 ml/min.) does not exert noticeable impact on gemcitabine pharmacokinetics.

Indications to use:

- Not small-celled cancer of a lung
- Breast cancer
- Bladder cancer
- Ovarian cancer
- Pancreatic cancer
- Cancer necks of uterus

Gemcitabine in monotherapy or in a combination with other antineoplastic means also shows activity at locally-spread small-celled cancer of a lung, locally-spread refractory cancer of a small egg, cancer of biliary tract.

Route of administration and doses:

Gemcitabine is entered intravenously kapelno within 30 minutes.

Gemcitabine is a part of many chemotherapeutic modes in this connection at selection of doses and the mode of administration of drug in each individual case it is necessary to address special literature.

Not small-celled cancer of a lung (locally-spread or disseminated). Monotherapy. As monotherapy the recommended dose makes 1000 mg/sq.m within 3 weeks with the subsequent week break, each 28 days once a week.
 
Combination therapy. With a cisplug-in gemcitabine is entered into combinations in a dose of 1250 mg/sq.m in the 1 and 8 days of each 21-day cycle or in a dose of 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 first day of a cycle after infusion of gemcitabine against the background of an overhydratation.
 
Breast cancer (locally-spread or disseminated). Monotherapy. When progressing a disease after the first line of the therapy including anthracyclines or without them (at a contraindication to use of anthracyclines), gemcitabine is applied in a dose of 1000-1200 mg/sq.m in 1, 8 and 15 days each 28 days.
 
Combination therapy. As therapy of the first line, when progressing neoadjuvant therapy, with inclusion of anthracyclines. The recommended drug dose - 1250 mg/sq.m in the 1 and 8 days in combination with paklitaksely in a dose of 175 mg/sq.m approximately in 3 hours after administration of gemcitabine in 1 day of each 21 day cycle.
 
Bladder cancer (locally-spread, disseminated or superficial). Monotherapy. The recommended drug dose - 1250 mg/sq.m in 1, 8 and 15 days each 28 days.
 
Combination therapy. The recommended drug dose - 1000 mg/sq.m in 1, 8 and 15 days in combination with Cisplatinum which is entered in a dose of 70 mg/sq.m right after infusion of gemcitabine in 1 or in the 2nd day of each 28-day cycle.
 
Intravesical chemotherapy. The recommended drug dose - 2000 mg. For receiving solution for instillations drug dissolve in 100 or 50 ml 0,9% of solution of sodium of chloride to concentration from 20 to 40 mg/ml.
 
Exposure of drug makes 60 minutes. It is entered once a week within 6 weeks. Concentration of solution should not exceed 40 mg/ml.
 
Ovarian cancer (locally-spread or disseminated). Monotherapy. The recommended drug dose - 800-1250 mg/sq.m in 1, 8 and 15 days each 28 days.
 
Combination therapy. The recommended drug dose - 1000 mg/sq.m in the 1 and 8 days in combination with karboplatiny which is entered right after infusion of gemcitabine in 1 day of each 21-day cycle.
 
Pancreatic cancer (locally-spread or disseminated). Monotherapy. The recommended drug dose - 1000 mg/sq.m once a week within 7 weeks with the subsequent week break. The subsequent cycles have to consist of the infusions which are carried out once a week within 3 weeks with the subsequent week break.
 
Cancer of a neck of uterus (locally-spread or disseminated). Combination therapy. At locally-spread cancer at consecutive himioluchevy therapy (neoadjyuvantno) and at the disseminated cancer gemcitabine is entered in a dose of 1250 mg/sq.m in the 1 and 8 day of a 21-day cycle. Cisplatinum is entered after administration of gemcitabine in a dose of 70 mg/sq.m in 1 day of a cycle each 21 day against the background of an overhydratation.
 
At locally-spread cancer at simultaneous himioluchevy therapy once a week in 1-2 hours prior to radiation therapy gemcitabine 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 is entered.
 
In case of development of hematologic toxicity a dose of the drug Gemtsitar® it is possible to reduce or postpone its introduction.
 
At use of the drug Gemtsitar® for patients with cancer of a bladder in the mode of monotherapy or in a combination with Cisplatinum in case of development of hematologic toxicity change of the mode of dosing is made according to the following scheme:  At use of the drug Gemtsitar® for patients with cancer of a mammary gland in a combination with paklitaksely in case of development of hematologic toxicity change of the mode of dosing is made according to the following scheme:

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

At use of the drug Gemtsitar® for suffering from cancer ovaries in a combination with karboplatiny in case of development of hematologic toxicity change of the mode of dosing is made according to the following scheme: 

Absolute quantity of neutrophils (in 1 мкл)		Quantity of thrombocytes (in 1 мкл)	% of the previous dose
≥1200	and	> 75 000	100
1000-1200	and/or	50 000-75 000	75
700-1000	and/or	≥50 000	50
<700	and/or	<50 000	to postpone introduction

The dose of gemcitabine has to be lowered to 75% of initial chemotherapy in all subsequent cycles in the following cases:

Absolute quantity of neutrophils (in 1 мкл)		Quantity of thrombocytes (in 1 мкл)	% of the previous dose
> 1500	and	> 100 000	100
1000-1500	and/or	75 000-100 000	50
<1000	and/or	<75 000	To postpone introduction

• decrease in absolute number of granulocytes less than 500 on мкл during more than 5 days
 
• decrease in absolute number of granulocytes less than 100 on мкл during more than 3 days
 
• development of a febrile neutropenia
 
• quantity of thrombocytes less than 25000 on мкл
 
• a delay of the next cycle of chemotherapy more than for 1 week in view of toxicity
 
For detection of not hematologic toxicity it is necessary to conduct regular examination of the patient and to control functions of a liver and kidneys. Depending on toxicity degree the dose can be reduced during each cycle or from the beginning of a new cycle in steps. The decision on a delay of the next administration of drug has to be based on clinical assessment by the doctor of dynamics of toxic manifestations.

Special groups of patients. Elderly patients: the proofs allowing to assume that at elderly patients it is necessary to adjust a dose are not available though the clearance of gemcitabine decreases with age, and the elimination half-life increases.
 
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. Easy or moderate severity the renal failure (clearance of creatinine from 30 ml/min. to 80 ml/min.) does not exert noticeable impact on gemcitabine pharmacokinetics. Children: use of gemcitabine for children was not studied.
 
Rules of preparation of infusion solution. As solvent only 0,9% chloride sodium solution are used (without preservatives). For preparation of solution for infusions contents of a bottle of 200 mg are dissolved not less than in 5 ml, and 1000 mg - not less than in 25 ml of 0,9% of solution of sodium of chloride for injections. The bottle is accurately shaken up before full dissolution of lyophilisate. The prepared solution of drug has to be transparent.

The maximum concentration of gemcitabine should not exceed 40 mg/ml. At preparation of solutions with concentration higher than 40 mg/ml can be observed incomplete dissolution of drug.

The prepared drug Gemtsitar® solution containing the necessary dose of drug before introduction is diluted with enough by 0,9% of solution of sodium of chloride for injections for performing the 30th minute intravenous infusion.

Before parenteral administration direct vision of the prepared infusion solution on presence of mechanical impurities and discoloration is necessary.

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 drug it is necessary to define leukocytic

formula and quantity of thrombocytes in blood. At signs of oppression of function of marrow it is necessary to suspend treatment or to correct a dose.

It is periodically necessary to carry out assessment of function of kidneys and a liver. Increase in duration of infusion and frequency of infusions leads to toxicity increase.

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 the first signs of a gemolitiko-uraemic syndrome treatment by gemcitabine should be stopped.

At patients with cancer of a lung or metastasises in lungs the risk of emergence of side effects from system of breath is increased.

At emergence of the first symptoms of a pneumonitis or emergence of infiltrates in lungs treatment by gemcitabine should be stopped.

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. Women and men during treatment by gemcitabine and at least within 6 months later should use reliable ways of contraception.

Influence on ability to manage vehicles and mechanisms. During treatment it is necessary to be careful at control of vehicles and occupation 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%, <10%); sometimes (> 0,1%, <1%); seldom (> 0,01%, <0,1%); very seldom (<0,01%).

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

From system of digestion: very often - nausea, vomiting, increase in activity of hepatic transaminases, an alkaline phosphatase; often - anorexia, diarrhea, a lock, stomatitis, a hyperbilirubinemia; seldom - increase in the GGT level; very seldom - a liver failure, ischemic colitis

From an urinary system: very often - a proteinuria and a hamaturia, it is very rare - a gemolitiko-uraemic syndrome and/or a renal failure.

From skin and skin appendages: often - skin rashes, a skin itch, an alopecia, the increased perspiration; seldom - ulcerations, vesicular and inflammatory rash, a peeling; very seldom - heavy skin reactions, including a Lyell's disease, Stephen-Johnson's syndrome.

From respiratory system: very often - an asthma; often - cough, rhinitis; sometimes - a bronchospasm, intersticial pneumonia, lung hypostasis; very seldom - an acute respiratory distress syndrome (at emergence of these symptoms treatment should be stopped).

From cardiovascular system: seldom - the lowering of arterial pressure, a myocardial infarction, heart failure, arrhythmia, is very rare - disturbances of cerebral circulation, clinical symptoms of a peripheral vasculitis and gangrene;

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

Allergic reactions: very seldom - anaphylactic reactions.

Others: very often - a grippopodobny syndrome, peripheral hypostases; often - fervescence, a fever, an adynamy, dorsodynias, a mialgiya; sometimes - local reactions in an injection zone; very seldom - the radio sensitization phenomena.

At use of gemcitabine in a combination with paklitaksely increase in frequency of development of hematologic and not hematologic toxicity 3-4 degrees in comparison with monotherapy paklitaksely was observed, namely: increase in frequency of development of anemia, thrombocytopenia, neutropenia, and also febrile neutropenia, weakness, diarrhea, motive and touch neuropathy.

At use of gemcitabine in a combination with Cisplatinum increase in frequency of development of hematologic and not hematologic toxicity 3-4 degrees in comparison with the combined chemotherapy under the MVAC protocol, including increase in frequency of development of anemia, thrombocytopenia, nausea and vomiting, stomatitis and infectious complications was observed.

At use of gemcitabine in a combination with karboplatiny in comparison with monotherapy karboplatiny increase in frequency of development of hematologic and not hematologic toxicity 3-4 degrees was observed, namely: increase in frequency of development of anemia, a neutropenia, thrombocytopenia, a leukopenia, hemorrhagic syndrome, febrile neutropenia, infectious complications without neutropenia and touch neuropathy.

Interaction with other medicines:

Gemcitabine possesses the radio sensibilizing action therefore at use of drug against the background of performing radiation therapy it is possible to expect strengthening of beam reactions, including life-threatening mukozita, especially an esophagitis and a pneumonitis. It is necessary to consider the possibility of a dose decline of gemcitabine against the background of performing radiation therapy.

Use of attenuirovanny live vaccines against the background of an immunodeficiency is not recommended because of risk of general diseases with a possibility of a lethal outcome. The interval between use of gemcitabine and vaccination has to make not less than 3 months. Against the background of gemcitabine use efficiency of use of any vaccines decreases. Immunodepressants (including Azathioprinum, hlorambutsit, glucocorticosteroids, cyclophosphamide, cyclosporine, Mercaptopurinum) increase risk of developing of infections.

Contraindications:

- hypersensitivity to gemcitabine or other components of drug;
- pregnancy and period of feeding by a breast;
- Children's age up to 18 years (lack of sufficient experience of use)

From an ostorozhnostyyu:pra an abnormal liver function and/or kidneys, oppression of a marrowy hemopoiesis (including against the background of accompanying beam or chemotherapy), at at the same time carried out radiation therapy, acute infectious diseases of the virus, fungal or bacterial nature (including chicken pox, shingles).

Overdose:

Symptoms: a miyelosupressiya, paresthesias, the expressed skin rash, a hemorrhagic syndrome.

Treatment: there is no specific antidote. At suspicion on overdose the patient has to be under the constant medical control including performing the general blood test with definition of a leukocytic formula; if necessary the symptomatic treatment is carried out.

Storage conditions:

To store in the place protected from light, at a temperature not above 30 °C. To store the prepared solution of drug at a temperature not above 30 °C no more than 24 watch. To store in the place, unavailable to children. A period of validity - 3 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 200 mg, 1000 mg in the bottles from neutral glass I of a hydrolytic class corked by rubber bungs and which are pressed out by aluminum caps. On 1 bottle with the application instruction in a pack - from a cardboard.