Gemcitabine

General characteristics. Structure:

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

Excipients: a mannitol, sodium acetate (in the form of trihydrate acetate sodium).

Pharmacological properties:

Pharmacodynamics. Cytotoxic activity concerning cultures of cells. Gemcitabine shows the expressed cytotoxic effect against a number of the cultivated mouse and human cancer cells. Gemcitabine works fazospetsifichno, first of all, killing the cells which are in a stage of synthesis of DNA (S-phase) and, under certain conditions, stops transition of cells through border of G1/S of phases. The cytotoxic effect of in vitro gemcitabine depends on concentration and time.

Antineoplastic activity on preclinical models. On animal models of cancer, dependence of antineoplastic activity of gemcitabine on use frequency was shown. Daily purpose of drug caused the high frequency of lethal cases among animals at low antineoplastic activity. However, at purpose of gemcitabine every third or fourth day in doses is lower lethal, drug showed considerable antineoplastic activity of rather wide range of tumors at mice.

Action mechanism. Intracellular metabolism and mechanism of action: gemcitabine (dFdC), being a pyrimidine antimetabolite, it is metabolized in a cell nukleozidkinazy with formation of active diphosphatic (dFdCDP) and trifosfatny (dFdCTP) nucleosides. The cytotoxic effect of drug is reached thanks to suppression of synthesis of DNA on two mechanisms: by means of dFdCDP and dFdCTP. In the first case, dFdCDP inhibits a ribonukleotidreduktaza which is the only catalyst of reactions of formation of dezoksinukleozidtrifosfat (dCTP) necessary for DNA synthesis. It leads to decrease in dezoksinukleozid in general and, in particular, dCTP. In the second case, dFdCTP competes with dCTP for embedding in DNA (self-potentiation).

Also small amounts of gemcitabine can be built in also RNA. Thus, reduced intracellular concentration of dCTP strengthens embedding of dFdCTP in DNA. The DNA polymerase an epsilon is not capable to remove gemcitabine and to reparirovat threads of the growing DNA. After embedding of gemcitabine in DNA one more nucleotide joins the growing chain that leads to complete inhibition of further synthesis of DNA (screened break of a chain) and the programmed death of a cell (apoptosis).

Clinical data. Bladder cancer. In clinical testing on patients with a widespread or metastatic urothelial Schmincke's tumor lack of distinctions of the line of therapy gemcitabine / Cisplatinum concerning methotrexates / vinblastines / adriamycins/cisplates of therapy (MVAC) in survival median terms (12,8 and 14,8 months respectively, р =0,547) was shown, to time before progressing of a disease (7,4 and 7,6 months respectively, р =0,842) and answer frequency (49,4% and 45,7% respectively, р =0,512). However the toxic profile at a combination of gemcitabine and Cisplatinum was better, than at MVAC.

Pancreatic cancer. In randomized clinical testing on patients with a widespread or metastatic pancreatic cancer gemcitabine showed higher statistically significant frequency of the answer, than 5-ftoruratsit (23,8% and 4,8% respectively, р =0,0002). The statistical importance had also increase in time up to progressing from 0,9 to 2,3 months (a log - rank р <0,0002) and at the patients receiving therapy by gemcitabine in comparison with the patients receiving 5-ftoruratsit increase in a median of survival from 4,4 to 5,7 months (a log - rank р <0,0024).

Not small-celled cancer of a lung. In randomized clinical testing on patients with locally widespread or metastatic not small-celled cancer of easy (NMRL) gemcitabine in a combination with Cisplatinum showed higher statistically significant frequency of the answer, than monotherapy by Cisplatinum (31,0% and 12,0% respectively, р <0,0001). The statistical importance had also increase in time up to progressing from 3,7 to 5,6 months (a log - rank р <0,0012) and increase in average survival from 7,6 to 9,1 months (a log - rank р <0,004) at the patients receiving therapy by a combination gemcitabine / Cisplatinum in comparison with the patients receiving monotherapy by Cisplatinum.

In other randomized clinical testing on patients with IIIB or the IV stage of NMRL gemcitabine in a combination with Cisplatinum showed higher statistically significant frequency of the answer, than Cisplatinum combination with etopozidy (40,6% and 21,2% with responsibly, р =0,025). Statistically significant increase in time up to progressing from 4,3 to 6,9 months (р =0,014) at the patients receiving gemcitabine / Cisplatinum in comparison with therapy этопозид / Cisplatinum was revealed. In both tests portability of the main and control lines of therapy was comparable.

Ovary cancer. In randomized clinical testing patients with widespread epithelial ovarian cancer, with a recurrence of at least 6 months after completion of platinum therapy, were randomizirovana for treatment gemcitabine and karboplatiny (GKB) or karboplatiny (KB). Statistically significant increase in time up to a disease progression from 5,8 to 8,6 months (a log - rank р =0,0038) was revealed at patients of the GKB group in comparison with the KB group. The difference in the frequency of the answer made 47,2% in GKB in comparison with 30,9% in KB (р =0,0016) and a survival median - 18 months (GKB) against 17,3 (KB) (р =0,73).

Breast cancer. In randomized clinical testing on patients with inoperable, locally widespread or metastatic breast cancer with a recurrence after adjuvant/not adjuvant chemotherapy, gemcitabine in a combination with paklitaksely showed higher statistically significant increase in time up to documentary progressing of a disease from 3,98 to 6,14 months (a log - rank р =0,0002), than mono therapy paklitaksely. Absolute survival made 18,6 months against 15,8 months (a log - rank р =0,0489, HR 0,82) at patients of group gemcitabine / paklitakset in comparison with patients of group paklitakset also with an absolute frequency of answer of 41,1% and 26,2% respectively (р =0,0002).

Pharmacokinetics. The peak of plasma concentration (within 5 minutes after the end of infusion) makes 3,2-45,5 mkg/ml. Concentration of initial connection in plasma after introduction of 1000 mg/sq.m / 30 exceeds minutes 5 mkg/ml within 30 minutes after the end of infusion and within an hour there is higher than the level of 0,4 mkg/ml.

Distribution. The volume of distribution of gemcitabine in the central kompartment makes from 12,4 l/sq.m at women and men have 17,5 l/sq.m (individual variability is equal to 91,1%). Distribution volume in a peripheral kompartment makes 47,41 l/sq.m. The volume of a peripheral kompartment does not depend on a floor. Gemcitabine slightly contacts proteins of plasma.

The elimination half-life fluctuates from 42 to 94 minutes depending on age and a floor. For the recommended dose the period of elimination of gemcitabine has to make from 5 to 11 hours from the moment of the beginning of infusion. Gemcitabine does not accumulate at introduction of once to week.

Metabolism. Gemcitabine is quickly metabolized by a cytidinedeaminase in a liver, kidneys, blood and other fabrics. As a result of intracellular metabolism of gemcitabine are formed gemcitabine mono - di - and triphosphates (dFdCMP, dFdCDP and dFdCTP) from which dFdCDP and dFdCTP are considered as active. These intracellular metabolites are not found in plasma and urine. Primary metabolite 2-dezoksi-2, 2-diftoruridin is not active (dFdU) and it is found in plasma and urine.

Excretion. The system clearance fluctuates from 29,2 l/h/sq.m to 92,2 l/h/sq.m depending on gender and age (individual variability is equal to 52,2%). The clearance at women is about 25% lower, than at men. With age the clearance of gemcitabine decreases at men and women. At low value of clearance, both at men, and from women minute infusion does not need decrease in the recommended dose of gemcitabine of 1000 mg/sq.m during 30.

Less than 10% of the dose entered intravenously are found in urine in the form of not changed drug. The renal clearance makes from 2 to 7 l/h/m.

Within a week after administration of gemcitabine, it is removed from 92% to 98% of a dose of drug: 99% with urine (it is preferential in the form of dFdU) and 1% with excrements.

dFdCTP kinetics. This metabolite is found in mononuclear cells of peripheral blood and the data given below belong to the specified cells. Intracellular concentration increases in proportion to the entered gemcitabine dose. At introduction from 35 to 350 mg/sq.m / 30 minutes, stationary concentration makes 0,4-5 mkg/ml. At exceeding of plasma concentration of gemcitabine of 5 mkg/ml, the intracellular dFdCTP level ceases to increase that speaks about its saturability in these cells. The elimination half-life is equal 0,7-12 hours.

dFdU kinetics. The peak of plasma concentration (3-5 minutes after the termination 30 minute infusion, 1000 mg/sq.m): 28-52 mkg/ml. The minimum concentration after administration of drug once a week: 0,07-1,12 mkg/ml without visible accumulation.

Three-phase concentration curve in plasma in time, the average period to a removal floor in a final phase - 65 hours (range of 33-84 hours).

Formation of dFdU from initial substance: 91-98%.

The average volume of distribution in the central kompartment: 18 l/sq.m (range of 11-22 l/sq.m). Average value of volume of distribution in an equilibrium phase (Vss): 150 l/sq.m (range of 11-22 l/sq.m). Distribution in fabrics: wide. The average seeming clearance: 2,5 l/h/sq.m (range of 1-4 l/h/sq.m). All metabolite is removed with urine.

Combination therapy gemcitabine and paklitaksely. The combination therapy does not exert impact on pharmacokinetics of gemcitabine and a paklitaksel.

Combination therapy gemcitabine with karboplatiny. The combination therapy with karboplatiny does not exert impact on gemcitabine pharmacokinetics.

Renal failure. Easy and average degree of a renal failure (GFR from 30 ml/min. to 80 ml/min.) does not make considerable impact on gemcitabine pharmacokinetics.

Indications to use:

Ø  treatment of locally widespread or metastatic cancer of bladder in a combination with Cisplatinum.

Ø  treatment of locally widespread or metastatic adenocarcinoma of a pancreas.

Ø  the first line of therapy of locally widespread or metastatic not small-celled cancer of easy (NMRL) in a combination with Cisplatinum. Monotherapy by gemcitabine is possible at elderly patients or patients with the functional status 2.

Ø  treatment of locally widespread or metastatic epithelial cancer of ovary in a combination with karboplatiny at patients with a recurrence at least 6 months of the bezretsidivny period later after end of the first line of platinum therapy.

Ø  complex treatment with paklitaksely nerezektabelny locally widespread or metastatic breast cancer at patients with a recurrence after adjuvant / not adjuvant chemotherapy. Primary therapy has to include anthracycline, in the absence of contraindications.

Route of administration and doses:

Gemcitabine can be appointed only by the doctor of chemotherapeutic department specializing in antineoplastic therapy.

Gemcitabine is entered intravenously kapelno within 30 minutes.

Bladder cancer. Combination therapy. The recommended dose of 1000 ^mg/sq.m within 30 minutes. The drug is administered for 1, 8 and 15 days of each 28-day cycle in a combination with Cisplatinum. The recommended dose of Cisplatinum of 70 ^mg/sq.m for the 1 or 2 day after gemcitabine of each 28-day cycle. Then the week cycle given 4-ekh is repeated. Reduction of a dose with each new cycle is possible or during a cycle proceeding from the level of toxicity of drug at the patient.

Pancreatic cancer. The recommended dose of 1000 mg/m within 30 minutes. The drug is administered once a week within 7 weeks, with the subsequent week break. Further cycles have to consist of 4 weeks in which the drug is administered once a week within the first 3 weeks in a row. Reduction of a dose with each new cycle is possible or during a cycle proceeding from the level of toxicity of drug at the patient.

Not small-celled cancer of a lung. Monotherapy. The recommended dose of 1000 ^mg/sq.m within 30 minutes. The drug is administered once a week within 3 weeks, with the subsequent week break. Then this 4-week cycle is repeated. Reduction of a dose with each new cycle is possible or during a cycle proceeding from the level of toxicity of drug at the patient.

Combination therapy. The recommended dose of 1250 ^mg/sq.m within 30 minutes. The drug is administered for the 1 and 8 day of a 21-day cycle. Reduction of a dose with each new cycle is possible or during a cycle proceeding from the level of toxicity of drug at the patient. A dose of Cisplatinum of 75-100 ^mg/sq.m once within 3 weeks.

Breast cancer. Combination therapy. The recommended drug dose - 1250 ^mg/sq.m in the 1 and 8 days (a cycle 21 days) in combination with paklitaksely which is entered to gemcitabine in a dose of 175 ^mg/sq.m in 1 day of each 21-day cycle intravenously kapelno approximately within 3 hours. Reduction of a dose with each new cycle is possible or during a cycle proceeding from the level of toxicity of drug at the patient. Gemcitabine / paklitakset absolute quantity of granulocytes at the patient before therapy has to make ^{not less than 1500x106/l}.

Ovarian cancer. Combination therapy. The recommended drug dose - 1000 ^mg/sq.m in the 1 and 8 days (a cycle 21 days) in combination with karboplatiny in the dose corresponding to AUC of 4,0 mg/ml/min. which is entered right after infusion of gemcitabine in the 1st day of each 21-day cycle. Reduction of a dose with each new cycle is possible or during a cycle proceeding from the level of toxicity of drug at the patient.

Monitoring of toxicity and change of a dose because of toxicity. Dose adjustment because of not hematologic toxicity. It is necessary to perform periodic medical examination, and also control of hepatic and renal function for definition of not hematologic toxicity. Reduction of a dose with each new cycle is possible or during a cycle proceeding from the level of toxicity of drug at the patient. In case of emergence heavy (degree 3 or 4) not hematologic toxicity, except for nausea/vomiting, the attending physician has to postpone treatment or lower a drug dose.

Correction of a dose of Cisplatinum, karboplatin and paklitaksel is carried out according to application instructions of the specified drugs.

Dose adjustment because of hematologic toxicity. Beginning of a cycle. Before each administration of gemcitabine according to any indication at patients it is necessary to carry out control of level of thrombocytes and granulocytes. Before a cycle the absolute quantity of granulocytes has to make ^{not less than 1500x106/l} and thrombocytes – ^{100000Õ106/l}.

During a cycle. Dose adjustment of gemcitabine during a cycle it is necessary to carry out according to the following tables:

Dose adjustment of gemcitabine during a cycle at cancer of a bladder, NMRL and a pancreatic cancer, monotherapy or in a combination with Cisplatinum
Absolute quantity of granulocytes (h106/l)	Quantity of thrombocytes (h106/l)	Percent from a standard dose of gemcitabine (%)
> 1000                         and	> 100000	100
500-1000                       or	50000-100000	75
<500                         or	<50000	to postpone introduction *

* The cancelled dose should not be entered during a cycle until the absolute quantity of granulocytes reaches ^{at least 500Õ106/l} and quantity of thrombocytes ^50000x106/l.

Dose adjustment of gemcitabine during a cycle at a breast cancer, monotherapy or combinations with paklitaksely
Absolute quantity of granulocytes (h106/l)	Quantity of thrombocytes (h106/l)	Percent from a standard dose of gemcitabine (%)
≥1200                         and	> 75000	100
1000-<1200                 or	50000-75000	75
700-<1000                     and	≥50000	50
<700                         or	<50000	to postpone introduction *

* The cancelled dose should not be entered during a cycle until the absolute quantity of granulocytes reaches ^{at least 1500Õ106/l} and quantity of thrombocytes ^100000x106/l.

Dose adjustment of gemcitabine during a cycle at ovarian cancer, monotherapy or in a combination with karboplatiny
Absolute quantity of granulocytes (h106/l)	Quantity of thrombocytes (h106/l)	Percent from a standard dose of gemcitabine (%)
> 1500                         and	≥100000	100
1000-1500                  or	75000-100000	50
<1000                      or	<75000	to postpone introduction *

* The cancelled dose should not be entered during a cycle until the absolute quantity of granulocytes reaches ^{at least 1500Õ106/l} and quantity of thrombocytes ^100000x106/l.

Dose adjustment because of hematologic toxicity in the subsequent cycles for all indications.

It is necessary to reduce a dose of gemcitabine to 75% of an initial dose of a cycle in case of the following types of hematologic toxicity:

Ø absolute quantity of granulocytes <^{500 x 106/l} more than 5 days;

Ø absolute quantity of granulocytes <100 x ^10b/l more than 3 days;

Ø feverish neutropenia;

Ø thrombocytes <^{25000 x 106/l};

Ø a cycle delay more than for 1 week because of toxicity.

Route of administration. Gemcitabine is well transferred to time of infusion and can be appointed on an outpatient basis. In case of developing of bleeding, usually at once stop infusion and continue infusion in other blood vessel. It is necessary to watch carefully the patient after administration of drug.

Special groups of patients. Patients with a renal or liver failure. To apply with care at patients with a renal or liver failure, in connection with small amount of information, received in clinical tests.

Elderly patients (> 65 years). Gemcitabine is well transferred by patients 65 years are more senior. Proofs of need of dose adjustment are not available for elderly patients.

Children (<18 years) are not recommended to be applied at children 18 years because of lack of data on efficiency and safety are younger.

Instruction for dissolution (and to further cultivation, if necessary). The only admissible solvent for sterile powder of gemcitabine is solution of sodium chloride 9mgml (0,9%) for injections (without preservatives). Because of limited solubility, the most admissible concentration at dissolution of gemcitabine makes 40mg/ml. Gemcitabine solution preparation with concentration above 40mg/ml because of probability of its incomplete dissolution is forbidden.

1. Dissolution and any subsequent cultivation of gemcitabine for intravenous administration need to be carried out with use of aseptik.

2. For dissolution of 200 mg of gemcitabine to add 5 ml of sterile solution of sodium chloride 9mgml (0,9%) for injections (without preservatives) to a bottle. For dissolution of 1000 mg of gemcitabine to add 25 ml of sterile solution of sodium chloride 9mgml (0,9%) for injections (without preservatives) to a bottle. Final volume after dissolution 5,26ml (200 mg) or 26,3ml (1000 mg). The received concentration makes 38 mg/ml, taking into account the working volume of the lyophilized powder. To shake up before dissolution. Further solution can be diluted with sterile solution of sodium chloride 9mgml (0,9%) for injections (without preservatives). The received solution has to be transparent, colourless or light-straw color.

3. Before introduction it is necessary to check solution for lack of solid particles and dullness. Not to use in the presence of solid particles.

Features of use:

At increase in time of infusion and frequency of introduction toxicity of gemcitabine increases.

Hematologic toxicity. Gemcitabine is capable to suppress function of marrow that is shown by a leukopenia, thrombocytopenia and anemia.

At the patients receiving treatment by gemcitabine it is necessary to define quantity of thrombocytes, leukocytes and granulocytes before each purpose of drug. At detection of the suppression of function of marrow connected with therapy, it is necessary to postpone treatment or to modify a drug dose. However the miyelosupressiya has short terms and, usually, does not demand a dose decline and seldom causes the treatment termination.

The amount of peripheral blood can continue to decrease also after the gemcitabine reception termination. At patients with dysfunction of marrow it is necessary to begin treatment with care. At simultaneous use of gemcitabine with other chemotherapy it is necessary to consider possible risk of cumulative overwhelming action on marrow.

Liver failure. Purpose of gemcitabine at patients with the accompanying metastasises in a liver or with the hepatitis taking earlier place, alcoholism or cirrhosis, can lead to an exacerbation of a liver failure.

It is periodically necessary to carry out assessment of renal and hepatic functions (including virologic tests).

Gemcitabine should be applied with care at patients with a renal and liver failure since in clinical tests sufficient information for selection of a special dose at this category of patients was not obtained.

The accompanying radiation therapy. It was reported about emergence of toxicity at radiation therapy together with gemcitabine or with an interval of ≤7 days.

Live vaccines. Vaccination against yellow fever or administration of other live attenuated vaccines is not recommended to the patients receiving treatment by gemcitabine.

Cardiovascular diseases. Patients in the history need to be careful with cases of cardiovascular diseases at treatment of gemcitabine because of risk of development of cordial and/or vascular frustration.

Respiratory system. At treatment by gemcitabine it was reported about adverse reactions from respiratory system, sometimes to heavy degree (a fluid lungs, an intersticial pneumonitis or the respiratory distress syndrome of adults (RDSA)). At emergence of the above-stated reactions it is necessary to consider a question of the therapy termination. Early use of a maintenance therapy can improve a condition of the patient.

Urinary system. In clinical tests several cases of emergence of the hemolitic uraemic syndrome (HUS) at the patients receiving gemcitabine were described. It is necessary to stop immediately treatment by gemcitabine at detection of the first symptoms of mikroangiopatichesky hemolitic anemia (sharp decrease in level of hemoglobin with the accompanying thrombocytopenia, increase in bilirubin in blood serum, serumal creatinine, an urea nitrogen of blood or a lactate dehydrogenase). In case of preservation of a renal failure at therapy cancellation, dialysis can be required.

Sodium. Gemcitabine of 200 mg contains 3,5 mg (<1 mmol) sodium on a bottle. It should be considered at purpose of drug to the patients keeping to a sodium diet.

Use at pregnancy and in the period of a lactation. Pregnancy. There are no sufficient data about use of gemcitabine for pregnant women. In researches on animals reproductive toxicity was shown. Being based on the data of preclinical tests and the mechanism of effect of gemcitabine, it is not recommended to use drug during pregnancy, except for special need. Women of childbearing age have to use reliable methods of contraception during treatment by gemcitabine and immediately warn the attending physician in case of pregnancy approach.

Lactation period. There are no data on a possibility of penetration of gemcitabine into breast milk. It is also unknown what side reactions drug can cause, at hit in the child's organism with mother's milk. Breastfeeding has to be stopped during treatment by gemcitabine.

Influence on reproductibility. In tests administration of gemcitabine caused a hypospermatogenesis in males of mice. For this reason, the men receiving treatment by gemcitabine it is necessary to use effective methods of contraception during therapy and within 6 months after the therapy termination. Also the request for additional consultation on a sperm cryopreservation prior to treatment as there is a probability of infertility because of treatment by gemcitabine is recommended to patients.

Influence on ability to control of vehicles or potentially dangerous mechanisms. Influence of gemcitabine on ability to control of vehicles or potentially dangerous mechanisms not, was studied. However, proceeding from data on ability of gemcitabine to cause small drowsiness (especially at joint alcohol intake), the patient should refrain from control of vehicles or potentially dangerous mechanisms for treatment by gemcitabine.

Side effects:

The most frequent messages on side reactions connected with gemcitabine include: nausea with/without vomiting, increase in level of hepatic transaminases (AST/ALT) and alkaline phosphatase (60% of patients); proteinuria and hamaturia (about 50% of patients); an asthma at 10-40% of patients (the largest frequency at patients with lung cancer); allergic rashes of skin (about 25% of patients) and with the accompanying itch at 10% of patients.

Frequency and weight of side reactions depends on a dose, the frequency of infusion and intervals between introductions.

Results of clinical tests. Frequency of development of side effects is specified in the following gradation: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000), including separate messages.

From bodies of a hemopoiesis: very often - a leukopenia (a neutropenia 3 degrees = 19,3%; 4 degrees = 6%) - suppression of marrow usually carry easy or average expressiveness and most often influences quantity of granulocytes; thrombocytopenia; anemia; often - a feverish neutropenia; very seldom - a thrombocytosis.

From immune system: very seldom - anaphylactoid reaction.

From a metabolism: often - anorexia.

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

From cardiovascular system: seldom - a myocardial infarction, a lowering of arterial pressure.

From respiratory system: very often - an asthma (usually easy, quickly passing without treatment); often - cough, rhinitis; infrequently - intersticial pneumonia, a bronchospasm (usually easy and temporary, but parenteral treatment can be required).

From the alimentary system: very often - nausea, vomiting; often - diarrhea, stomatitis and an ulceration of an oral cavity, a lock.

From gepatobiliarny system: very often - increase in the ACT and ALT level, and also an alkaline phosphatase; often - increase in bilirubin; seldom - increase in GGT.

From integuments: very often - the allergic skin rash which is often connected with an itch an alopecia; often - an itch, perspiration; seldom - an ulceration, vesicles and erosion, a peeling; very seldom - the acute skin reactions including desquamation and violent skin rash.

From a musculoskeletal system: often - dorsodynias, a mialgiya.

From urinogenital system: very often - a hamaturia, an easy proteinuria.

Others: very often - grippopodobny symptoms (the most frequent symptoms: heat, headache, fever, mialgiya, adynamy and anorexia; also it was reported about cough, rhinitis, an indisposition, perspiration and sleeplessness), hypostasis / peripheral hypostasis, including a face edema (hypostasis usually passes after therapy cancellation); often - heat, an adynamy, a fever; seldom-seater reaction to introduction (usually easy degree).

Poisoning and complications of therapy: side effect of radiation therapy at the subsequent chemotherapy.

Post-clinical experience of use (message on by-effects). Frequency is not established (it is impossible to estimate from the available data)

From a nervous system: disturbance of cerebral circulation.

From cardiovascular system: arrhythmia, heart failure, preferential supraventricular nature, clinical symptoms of a peripheral vasculitis and gangrene.

From respiratory system: fluid lungs, respiratory distress syndrome of adults.

From digestive tract: ischemic colitis.

From gepatobiliarny system: an acute hepatotoxic, including a liver failure and death.

From integuments: the acute skin reactions including desquamation and violent skin rash, a Lyell's disease, Stephens-Johnson's syndrome.

From urinogenital system: renal failure, gemolitiko-uraemic syndrome.

Poisoning and complications of therapy: side effect of radiation therapy at the subsequent chemotherapy.

Combination therapy at a breast cancer. Frequency of hematologic toxicity 3 and 4 degrees, especially a neutropenia, increases at purpose of gemcitabine with paklitaksely. Nevertheless, increase in cases of these side reactions is not connected with increase in cases of an infection or hemorrhagic complications. Fatigue and a feverish neutropenia are shown more often at combined use of gemcitabine with paklitaksely. The fatigue which is not connected with anemia usually disappears after the first cycle.

3 and 4 degrees at therapy paklitaksely against a combination gemcitabine / paklitakset by-effects
Number (%) of patients
Paklitaksel		Gemcitabine / палкитаксел
Degree 3	Degree 4	Degree 3	Degree 4
Laboratory indicators
Anemia	5 (1,9)	1 (0,4)	15 (5,7)	3(1,1)
Thrombocytopenia	0	0	14 (5,3)	1 (0,4)
Neutropenia	11 (4,2)	17 (6,6) *	82 (31,3)	45 (17,2) *
General symptoms
Feverish neutropenia	3 (1,2)	0	12 (4,6)	1 (0,4)
Fatigue	3 (1,2)	1 (0,4)	15 (5,7)	2 (0,8)
Diarrhea	5 (1,9)	0	8 (3,1)	0
Motor neuropathy	2 (0,8)	0	6 (2,3)	1 (0,4)
Touch neuropathy	9 (3,5)	0	14 (5,3)	1 (0,4)

* Neurosinging 4 degrees within 7 days took place at 12,6% of the patients receiving a combination therapy and at 5% of the patients receiving paklitakset.

Combination therapy at bladder cancer

By-effects 3 and 4 degrees at therapy of MVAC against a combination gemcitabine/Cisplatinum
Number (%) of patients
MVAC (methotrexate, vinblastine, doxorubicine and Cisplatinum)		Gemcitabine/Cisplatinum
Degree 3	Degree 4	Degree 3	Degree 4
Laboratory indicators
Anemia	30 (16)	4 (2)	47 (24)	7 (4)
Thrombocytopenia	15 (8)	25 (13)	57 (29)	57 (29)
General symptoms
Nausea and vomiting	37 (19)	3 (2)	44 (22)	0 (0)
Diarrhea	15 (8)	1 (1)	6 (3)	0 (0)
Infection	19 (10)	10 (5)	4 (2)	1 (1)
Stomatitis	34 (18)	8 (4)	2 (1)	0 (0)

Combination therapy at ovarian cancer

By-effects 3 and 4 degrees at therapy karboplatiny against a combination gemcitabine / карбоплатин
	Number (%) of patients
	Karboplatin		Gemcitabine / карбоплатин
	Degree 3	Degree 4	Degree 3	Degree 4
Laboratory indicators
Anemia	10 (5,7)	4 (2,3)	39 (22,3)	9 (5,1)
Neutropenia	19 (10,9)	2 (1,1)	73 (41,7)	50 (28,6)
Thrombocytopenia	18 (10,3)	2 (1,1)	53 (30,3)	8 (4,6)
Leukopenia	11 (6,3)	1 (0,6)	84 (48,0)	9 (5,1)
General symptoms
Bleeding	0 (0,0)	0 (0,0)	3 (1,8)	0 (0)
Feverish neutropenia	0 (0,0)	0 (0,0)	2 (1,1)	0 (0)
Infection without neutropenia	0 (0)	0 (0,0)	(0,0)	1 (0,6)

Cases of touch neuropathy were also more frequent at a combination therapy, than at therapy karboplatiny.

Interaction with other medicines:

Radiation therapy. Accompanying (at the same time or with an interval of ≤7 days) – the toxicity connected with multimodal therapy depends on the following factors: gemcitabine dose, frequency of purpose of gemcitabine, dose of radiation, technology of planning of radiation therapy, target organ and target volume of radiation. In preclinical and clinical tests of display but that gemcitabine possesses the radio sensibilizing action. In clinical testing where gemcitabine was appointed within 6 weeks in a row along with radiation therapy of a thorax to patients with NMRL, the toxicity which is shown in the form of acute, potentially life-threatening mukozit, in particular, an esophagitis and pneumonia, especially at patients with the large volume of radiation (the average volume of 4795 cm3) was shown. In the subsequent tests of NMRL it was established that gemcitabine in smaller doses can be applied together with radiation therapy. Radiation of a thorax in a dose 66 Gray was carried out together with purpose of gemcitabine (600 mg/sq.m 4 times) and Cisplatinum (80 mg/sq.m twice) within 6 weeks. For today the optimum mode of gemcitabine for safe combined use with therapeutic doses of radiation therapy for all types of a tumor is not picked up.

Separate (an interval> 7 days) - it is not established to hypertoxity at purpose of gemcitabine with an interval more than 7 days to or after radiation therapy, except the effect of radiation. Use of gemcitabine can be begun after disappearance of acute side reactions from radiation therapy or, at least a week later after radiation therapy.

Radiation injury of target organs (for example, esophagites, colitis and pneumonia) took place both at the accompanying gemcitabine use, and at separate radiation therapy.

Others. Vaccination against yellow fever or administration of other live attenuated vaccines because of risk system, with probability of a lethal outcome, diseases is not recommended to the patients receiving treatment by gemcitabine (especially at immunosuppressive patients).

Contraindications:

Ø hypersensitivity to gemcitabine or other components of drug;

Ø pregnancy and period of a lactation.

Overdose:

The antidote of gemcitabine is absent. At intravenous administration within 30 minutes of the doses exceeding 5700 mg/sq.m each two weeks clinically admissible toxicity was shown.

In case of the suspected overdose the patient has to be under the constant medical control including calculation of a blood count. If necessary the maintenance therapy is carried out.

Storage conditions:

In the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

On 200 mg in bottles on 10 ml or on 1000 mg in bottles the glass 50 ml (light glass) corked by rubber bungs and rolled by caps aluminum or alyumoplastikovy. Each bottle together with the application instruction is placed in a pack from a cardboard.

Packaging for hospitals: on 40 bottles - for a dosage of 200 mg and on 20 bottles for a dosage of 1000 mg with the corresponding number of application instructions in a group container.