Gemcitabine is a pyrimidine analog antimetabolite group. Inhibits the synthesis of deoxyribonucleic acid (DNA). Exhibits tsiklospetsifichnost, acting on cells in the S phase and at the interface G1 and S. metabolized intracellularly by the action of nucleoside kinases to active diphosphate and form a nucleoside triphosphate. Nucleoside diphosphate inhibits ribonucleotide reductase, which is the only enzyme that catalyzes the formation of deoxynucleoside triphosphates required to synthesize DNA. Triphosphate nucleosides actively compete with dezoksitsitidintrifosfatom for incorporation into the DNA and RNA molecules. After insertion of the intracellular metabolites gemcitabine in a DNA strand to its growing filaments is added one more additional nucleotide that results in complete inhibition of further DNA synthesis and cell apoptosis.
The maximum concentration of Gemcitabine in plasma after a single 30-minute infusion at a dose of 1 g / m2 exceed 5 ug / ml for about 30 minutes after completing the infusion. Over the next hour it exceeds 0.4 g / ml.
The half-life ranges from 32 to 94 minutes. In elderly patients the half-life is increased. Gemcitabine is completely eliminated from the body through the 5-11 hours. At weekly administration is not observed a cumulative effect. Gemcitabine plasma protein binding is negligible.
Gemcitabine is rapidly metabolized in the liver, kidneys, blood and other tissues. Active intracellular metabolites are not found in blood and urine. The inactive metabolite of 2′-deoxy-2 ‘, 2’-diftoruridin excreted in the urine.
Systemic clearance, which ranges from about 30L / h / m2 to 90l / h / m2, depending on the age and gender. In women, the ride height by 25% less than men; with age decreases clearance of gemcitabine. About 90% of the drug excreted in the urine as an inactive metabolite, less than 10% of the introduced i.v. dose is found in urine in an unmodified form of the drug is less than 1% excreted in feces.
In the appointment of gemcitabine in combination therapy the pharmacokinetics does not undergo significant changes.
Renal failure mild or moderate severity (glomerular filtration rate from 30 to 80 ml / min), has no marked effect on the pharmacokinetics of Gemcitabine.
1 vial contains
active substance: Gemcitabine hydrochloride (equivalent to 1000 mg gemcitabine);
Excipients: Mannitol 1000 mg, 62.5 mg sodium acetate.
– Locally advanced or metastatic non-small cell lung cancer, as first line therapy in combination with cisplatin and carboplatin, as well as monotherapy in elderly patients with performance status of 2.
– unresectable, mestnoretsidiviruyuschy or metastatic breast cancer in a combination therapy with paclitaxel after neoadjuvant and / or adjuvant therapy including anthracyclines, in the absence of contraindications for their intended purpose.
– Locally advanced or metastatic urothelial carcinoma (bladder cancer, renal pelvis, ureter, urethra).
– Locally advanced or metastatic epithelial ovarian cancer as a monotherapy or in combination with carboplatin in patients with progressive disease after the first line on the basis of derivatives of platinum therapy.
– Locally advanced or metastatic pancreatic cancer.
– Locally advanced or metastatic cancer of the cervix.
– biliary tract cancer.
The effectiveness of gemcitabine in advanced small cell lung cancer and refractory testicular cancer spread.
– Increased sensitivity to gemcitabine or other components of the formulation;
– Pregnancy and lactation;
– Children under 18 years of age (lack of sufficient experience in the application)
If abnormal liver function and / or kidney disease, inhibition of bone marrow hematopoiesis (including with concurrent radiotherapy or chemotherapy), acute infectious diseases, viral, fungal or bacterial origin (including chickenpox, shingles) in patients with cardiovascular diseases (including in the anamnesis).
Adverse reactions occur more frequently than in rare cases are listed according to the following gradation: very often (> 10%); often (> 1%, < 10%); times (> 0,1%, < 1%); rarely (> 0,01%, < 0,1%); very rare (< 0,01%).
From the blood system and lymphatic system: very often – anemia, leukopenia, and thrombocytopenia; often – febrile neutropenia; very rarely – thrombocytosis.
Immune system: very rarely – anaphylactic reaction.
On the part of metabolism and nutrition: often – anorexia.
From the nervous system: often – headache, insomnia, somnolence; seldom – cerebrovascular accident; very rarely – reversible posterior encephalopathy syndrome.
Of the heart: rarely – heart failure; arrhythmia, supraventricular advantageously; rare – myocardial infarction.
On the part of the vessels: very often – edema, peripheral edema; rare – blood pressure, peripheral vascular vasculitis, gangrene; rarely – increased capillary permeability syndrome.
The respiratory system: very often – shortness of breath; often – cough, rhinitis, rarely – bronchospasm, interstitial pneumonitis; rarely – pulmonary edema, respiratory distress syndrome of adults.
Gastro-intestinal system: very often – nausea, vomiting, increased activity of “liver” enzymes aspartate aminotransferase (the ACT), alanine aminotransferase (ALT) and alkaline phosphatase; often – diarrhea, stomatitis, ulcerative lesion of oral mucous membrane, constipation, increased bilirubin concentration, infrequently – severe hepatotoxicity, including liver failure, in some cases fatal; rarely – increased concentration gammaglutamiltransferazy (GGT); very rarely – ischemic colitis.
Skin and skin appendages: very often – allergic skin rashes of mild, accompanied by itching; alopecia (hair loss is usually minimal); often itching, sweating; rarely – ulcers, the formation of vesicles, scaling, skin reactions to severe, including desquamation and bullous skin lesions; very seldom – toxic epidermal necrolysis, Stevens-Johnson syndrome.
The kidneys and the urinary tract: very often – mild proteinuria and hematuria, infrequently – renal failure; rarely – increased creatinine concentration, urea and lactate dehydrogenase (LDH) with hemolytic uremic syndrome.
On the part of the musculoskeletal system and connective tissue disorders: often – back pain, myalgia.
Other: very often – flu-like symptoms. Also cases of malaise, sweating have been reported; often – fever, fatigue, chills; rarely – injection site reactions predominantly mild.
Anaphylactoid reactions were recorded very rarely.
Radiation toxicity rarely recorded.
The use of gemcitabine in combination with paclitaxel in breast cancer
Adverse events severity III
anemia – 5.7%, thrombocytopenia – 5.3% -31.3% neutropenia.
febrile neutropenia – 4.6%, fatigue – 5.7%, diarrhea – 3.1%, motor neuropathy – 2.3%, sensory neuropathy – 5.3%.
Adverse events severity IV
anemia – 1.1%, and thrombocytopenia – 0.4%, neutropenia – 17.2% (degree IV neutropenia lasting more than 7 days was recorded in 12.6% of patients).
febrile neutropenia – 0.4%, fatigue – 0.8%, motor neuropathy – 0.4%, sensory neuropathy – 0.4%.
The use of gemcitabine in combination with cisplatin in bladder cancer
Adverse events severity III
anemia – 24%, thrombocytopenia – 29%.
nausea and vomiting – 22%, diarrhea – 3%, infection – 2%, stomatitis – 1%.
Adverse events severity IV
anemia – 4%, thrombocytopenia – 29%.
Infection – 1%.
The use of gemcitabine in combination with carboplatin in ovarian cancer
Adverse events severity III
Anemia – 22.3%, neutropenia – 41.7%, thrombocytopenia – 30.3%, leukopenia – 48.0%
bleeding – 1.8%, febrile neutropenia – 1.1%.
Adverse events severity IV
anemia – 5.1%, neutropenia – 28.6%, thrombocytopenia – 4.6%, leukopenia – 5.1%.
infection without neutropenia – 0.6%
How to accept, acceptance rate and dosage
Gemcitabine is administered intravenously kapslno for 30 minutes.
Before each administration of gemcitabine is necessary to control the number of platelets, leukocytes and granulocytes in the blood. When signs of bone marrow function oppression caused by the drug, it is necessary to suspend the treatment or adjust the dose.
Non-small cell lung cancer (locally advanced or metastatic), the first line therapy
The recommended dose – 1000 mg / m2 at 1, 8 and 15 days of each 28-day cycle.
Combined with cisplatin therapy
The recommended dose of 1250 mg / m2 of the drug in days 1 and 8 of each 21-day cycle, or 1000 mg / m2 of 1, 8 and 15 days of each 28-day cycle. Cisplatin was administered at a dose of 70 mg / m2 on the first day of the cycle after the infusion of gemcitabine on the background overhydration.
Combination therapy with carbo-platin: recommended dose – 1000 mg / m2 or 1250 mg / m2 day 1 and 8 of each 21-day cycle. Carboplatin AUC is inputted from the calculation (the area under the curve “concentration-time”) 5.0 mg / ml / min on Day 1 after the infusion of gemcitabine cycle.
Breast cancer (non-resectable, metastatic or mestnoretsidiviruyuschy)
Combination therapy with paclitaxel: As a first-line therapy with disease progression after neoadjuvant and / or adjuvant consisting of anthracyclines in the absence of contraindications thereto. Paclitaxel is administered at a dose of 175 mg / m2 intravenous infusion over 3 hours in a 1 21-day cycle, followed by administration of gemcitabine. The recommended dose – 1250 mg / m2 day 1 and 8 of each 21-day cycle.
Before the start of combination therapy (gemcitabine + paclitaxel) the absolute number of granulocytes in the blood of patients should be at least 1500 / ml.
Urothelial cancer (cancer of the bladder (locally advanced, and metastatic surface), renal pelvis, ureter, urethra)
The recommended dose – 1250 mg / m2 of 1, 8 and 15 days of each 28-day cycle.
Combined with cisplatin therapy
The recommended dose is 1000 mg / m2 of 1, 8 and 15 days in combination with cisplatin, which is administered in a dose of 70 mg / m2 immediately after the infusion of gemcitabine of 1 or 2 day during each 28-day cycle. Clinical studies have shown that at doses of cisplatin 100 mg / m2 is observed more severe myelosuppression.
Epithelial ovarian cancer (locally advanced or metastatic resistant to platinum derivative)
The recommended dose – 800-1250 mg / m2 to 1, 8 and 15 days of each 28-day cycle.
Combination therapy with carboplatin
The recommended dose – 1000 mg / m2 day 1 and 8 in combination with carboplatin calculation of AUC 4,0 mg / ml / min, which is input immediately after the infusion of gemcitabine on day 1 of each 21-day cycle.
Pancreatic cancer (locally advanced or metastatic, including fluorouracil resistant to therapy)
The recommended dose – 1000 mg / m2 once weekly for seven weeks followed by one week apart. The preparation was then injected into the 1, 8 and 15 days of each 28-day cycle.
Cervical cancer (locally advanced or metastatic)
Combined with cisplatin therapy
When the sequential mestnorasprostranonnom cancer chemoradiotherapy (neoadyovantno) and metastatic cancer cisplatin is administered at a dose of 70 mg / m2 on day 1 of the cycle on the background of hydration followed by administration of gemcitabine. Gemcitabine is administered in a dose of 1250 mg / m2 day 1 and 8 of each 21-day cycle.
When mestnorasprostranonnom cancer with cisplatin concurrent chemoradiotherapy is administered at a dose of 40 mg / m2, followed by (directly after cisplatin) administration of gemcitabine. Gemcitabine is administered 1 time per week for 1-2 hours prior to radiotherapy in a dose of 125 mg / m2.
Biliary tract cancer
Combined with cisplatin therapy
Cisplatin was administered at a dose of 70 mg / m2 on day 1 of the cycle on the background of hydration followed by administration of gemcitabine. Gemcitabine is administered in a dose of 1250 mg / m2 day 1 and 8 of each 21-day cycle.
In the case of hematological toxicity Gemtsitar® dose of drug may be reduced or delayed its introduction.
To identify hematological toxicity should be carried out regular examination of the patient and monitoring of liver and kidney function. Depending on the degree of toxicity the dose may be reduced during each cycle or to start a new cycle steps. The introduction of the drug should be postponed until such time as, in the opinion of the physician, the toxicity is not resolved.
Special patient groups
There is no evidence to suggest that elderly patients need to adjust the dose.
Patients with impaired liver function and kidney
Apply gemcitabine in patients with hepatic insufficiency or with impaired renal function, care should be taken as sufficient data on the use of the drug in this category of patients there.
Mild to moderate renal impairment (glomerular filtration rate from 30 ml / min to 80 mL / minute) has no marked effect on the pharmacokinetics of Gemcitabine.
Gemcitabine was studied in limited studies I and phase II in children with various types of neoplasms. Data from these studies is not sufficient to prove the efficacy and safety of gemcitabine in children.
Rules of drug infusion solution
As the solvent used only 0.9% sodium chloride (without preservatives).
To prepare the solution for infusion contents of the vial were dissolved 200 mg of not less than 5 ml, and 1000 mg – not less than 25 ml 0.9% sodium chloride solution for injection. The vial was gently shaken until complete dissolution of the lyophilizate. The prepared drug solution should be clear.
The maximum concentration of gemcitabine should not exceed 40 mg / ml. In preparing solutions with concentration higher than 40 mg / ml can be observed incomplete dissolution of the drug.
Gemtsitar® prepared solution preparation containing the desired dose of the drug, before administration diluted with a sufficient amount of 0.9% sodium chloride solution for injection for 30 minute intravenous infusion.
Prior to parenteral administration requires visual inspection of the prepared infusion solution for mechanical impurities and color variation.
Store in a dark place at a temperature not higher than 30 ° C.
The prepared solution formulation stored at temperatures not above 30 ° C is not more than 24 hours.
Keep out of the reach of children.
Simultaneous application (joint or with an interval less than 7 days): the toxicity of the conjugate with multimodal treatment depends on many different factors: gemcitabine dose, frequency of administration of gemcitabine dose radiation therapy, radiation therapy planning technique, the type and amount of the irradiated tissue.
Preclinical and clinical studies have shown that gemcitabine has radiosensitizing effect. In the only study in which gemcitabine was administered at a dose of 1000 mg / m2. for 6 weeks in conjunction with radiation therapy of the chest in patients with non-small cell lung cancer, significant toxicity was recorded in the form of severe and potentially life-threatening inflammation of the mucous membranes, especially esophagitis; and pneumonitis, especially in patients with a large volume of tissue irradiation (irradiation median volume 4795 cm3).
Conducted later study (study II phase with non-small cell lung cancer) indicate the advisability of administration of gemcitabine at lower doses with concomitant radiotherapy with predicted toxicity. Radiation therapy to the chest (ODS 66 Gy) was performed simultaneously with gemcitabine chemotherapy in a dose of 600 mg / m2 (4 injections) and cisplatin at a dose of 80 mg / m2 (2 injection) for 6 weeks.
Several studies phases I and II showed that for non-small cell lung cancer and pancreatic cancer expedient gemcitabine monotherapy (at a dose of 300 mg / m2 / week) in parallel with radiotherapy.
Optimal for safe administration of gemcitabine with therapeutic doses of radiation therapy is not yet set for all types of tumors.
Sequential use (more than 7 days interval): a radiation reaction with gemcitabine administered more than 7 days before or after radiation therapy, increased toxicity have been reported. These data suggest that gemcitabine can be administered one week after radiation therapy or after will be resolved acute effects of radiation therapy.
And at the same time, and consistent application of gemcitabine with radiation therapy have been reported ray irradiated tissue damage (e.g., esophagitis, colitis and pneumonia).
We do not recommend joint application with live yellow fever vaccine and other live vaccines, due to the risk of systemic disease which can be fatal, particularly in immunosuppressed patients.
Gemcitabine treatment can be carried out only under the supervision of a physician who is experienced in the use of anticancer chemotherapy.
Gemcitabine can suppress bone marrow function, as manifested by leukopenia, thrombocytopenia or anemia. Before each administration of the drug to determine the number of platelets, leukocytes and granulocytes in the blood. When signs of bone marrow suppression necessary to stop treatment or adjust the dose.
Kidney and liver function
It is necessary to carry out regular examination of the patient and assess the nochek and liver function. Gemcitabine with metastases in the liver, hepatitis and alcoholism in history, as well as in liver cirrhosis increases the risk of liver failure.
Patients treated with gemcitabine, hemolytic uremic syndrome was detected in rare cases. Gemcitabine therapy should be discontinued at the first sign of microangiopathic hemolytic anemia, such as a rapid decline in hemoglobin, thrombocytopenia, increased serum bilirubin concentrations.
Renal failure may be irreversible after discontinuing therapy with gemcitabine, and therefore may require hemodialysis.
increased capillary permeability syndrome, adult respiratory distress syndrome, adult reversible rear encephalopathy syndrome with potentially serious consequences observed in patients treated with gemcitabine as a single agent or in combination with other chemotherapeutic agents. These syndromes may be associated with damage to the vascular endothelium, perhaps induced by gemcitabine. In the case of their development during therapy should be discontinued treatment with gemcitabine and to take the necessary measures.
Furthermore respiratory distress syndrome, adult other dysfunction of the lung, sometimes severe degree (e.g., pulmonary edema, interstitial pneumonitis), have been reported in patients treated with gemcitabine as a single agent or in combination with other cytostatics. The etiology of these disorders is not known. With the development of such side effects should stop gemcitabine therapy and take appropriate action. Early use of symptomatic treatment may improve the situation.
In fertility studies, gemcitabine caused gipospermatogenez in male mice. Therefore, men treated with gemcitabine therapy is not recommended paternity during treatment and for 6 months after graduation. Prior to treatment should seek further advice in relation to semen cryopreservation because of possible infertility due to therapy with gemcitabine.
Gemtsitar® preparation contains 200 mg of 2.11 mg (0.092 mmol) Gemtsitar® formulation contains 1000 mg 10.56 mg (0.46 mmol) of sodium per vial. This should be considered when administering the drug to patients on a diet with a controlled sodium diet. Increasing the duration and frequency of administrations infusion leads to an increase in toxicity.
Depending on the degree of toxicity the dose may be reduced during each cycle or to start a new cycle steps.
gemcitabine studies on the ability to drive vehicles and other mechanisms not conducted. Nevertheless, it is known that gemcitabine can cause drowsiness mild to moderate severity, especially in conjunction with alcohol.
Patients should warn against the mechanisms of control in cases where they feel sleepy.
Clinically acceptable toxicity was observed upon administration of single doses of up to 5.7 g / m2 intravenously over 30 minutes every 2 weeks.
Symptoms: Myelosuppression, paresthesias, severe skin rash, hemorrhagic syndrome.
Treatment: No specific antidote. If overdose is suspected, the patient should be under constant medical supervision, including holding blood count with differential count; if necessary symptomatic treatment.
Do not use beyond the expiration date printed on the package.