Description
Release form
lyophilisate
Packaging
1 bottle per pack.
Pharmacological action
Gemcitabine is an antimetabolite group of pyrimidine analogues. Suppresses synthesis of deoxyribonucleic acid (DNA). It shows cyclospecificity, acting on cells in phase S and at the boundary of phases G1 and S. Metabolized inside the cell under the action of nucleoside kinases with the formation of active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit ribonucleotide reductase, which is the only enzyme that catalyzes the formation of deoxynucleoside triphosphates necessary for DNA synthesis. Triphosphate nucleosides actively compete with deoxycytidine triphosphate for incorporation into DNA and RNA molecules. After the intracellular metabolites of gemcitabine are inserted into the DNA chain, another additional nucleotide is added to its growing strands, which leads to complete inhibition of further DNA synthesis and cell apoptosis.
Pharmacokinetics:
The maximum concentration of gemcitabine in plasma after a single 30-minute infusion at a dose of 1 g / m2 exceeds 5 μg / ml for about 30 minutes after completion of the infusion. Over the next hour, it exceeds 0.4 μg / ml.
The elimination half-life ranges from 32 to 94 minutes. In elderly patients, the half-life is increased. Gemcitabine is completely excreted in 5-11 hours. With weekly administration, no cumulative effect is observed. The binding of gemcitabine to plasma proteins is negligible.
Gemcitabine is rapidly metabolized in the liver, kidneys, blood and other tissues. Active intracellular metabolites are not found in blood and urine. Inactive metabolite 2′-deoxy-2 ‘, 2’-difluoruridine is excreted in the urine.
System clearance, which ranges from approximately 30l / h / m2 to 90l / h / m2, depends on age and gender. In women, the clearance is 25% less than in men with age, the clearance of gemcitabine decreases. About 90% of the drug is excreted in the urine as an inactive metabolite, less than 10% of the intravenous dose is found in the urine in the form of an unchanged drug, less than 1% is excreted in feces.
When prescribing gemcitabine as part of combination therapy, its pharmacokinetics does not undergo significant changes.
Renal failure of mild or moderate severity (glomerular filtration rate from 30 to 80 ml / min) does not significantly affect the pharmacokinetics of gemcitabine.
Indications
– Locally advanced or metastatic non-small cell lung cancer as a first-line therapy in combination with cisplatin and carboplatin, and also in monotherapy in elderly patients with a functional status of 2.
– Unresectable, locally recurrent or metastatic breast cancer as part of combination therapy with paclitaxel after neoadjuvant and / or adjuvant therapy, including anthracyclines, in the absence of contraindications to their appointment.
– Locally advanced or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureter, urethra).
– Locally or metastatic epithelial ovarian cancer as monotherapy or in combination with carboplatin in patients with disease progression after the first line of therapy based on platinum derivatives.
– Locally advanced or metastatic pancreatic cancer.
– Locally advanced or metastatic cervical cancer.
– Cancer of the biliary tract.
Gemcitabine has been shown to be effective in advanced small cell lung cancer and advanced refractory testicular cancer.
Contraindications
– Hypersensitivity to gemcitabine or other components of the
preparation – pregnancy and lactation period
– children under 18 years of age (lack of sufficient experience of use)
Caution: In case of impaired liver and / or kidney function, inhibition of bone marrow hematopoiesis (including against the background of concomitant radiation or chemotherapy), acute infectious diseases of a viral, fungal or bacterial nature (including chicken pox, shingles), in patients with cardiovascular diseases (including a history).
Pregnancy and lactation
Pregnancy and lactation are contraindicated.
Composition
1 bottle contains
active ingredient: gemcitabine hydrochloride (equivalent to 1000 mg of gemcitabine)
excipients: mannitol 1000 mg, sodium acetate 62.5 mg.
Dosage and administration of
Gemcitabine is administered intravenously dropwise for 30 minutes.
Before each administration of gemcitabine, it is necessary to control the number of platelets, white blood cells and granulocytes in the blood. With signs of inhibition of bone marrow function caused by the drug, it is necessary to suspend treatment or adjust the dose.
Non-small cell lung cancer (locally or metastatic), first line of therapy
Monotherapy
The recommended dose is 1000 mg / m2 on days 1, 8 and 15 of each 28-day cycle.
Combination therapy with cisplatin
The recommended dose of the drug is 1250 mg / m2 on days 1 and 8 of each 21-day cycle or 1000 mg / m2 on days 1, 8 and 15 of each 28-day cycle. Cisplatin is administered at a dose of 70 mg / m2 on the first day of the cycle after the infusion of gemcitabine against a background of hyperhydration.
Combination therapy with carboplatin: the recommended dose is 1000 mg / m2 or 1250 mg / m2 on days 1 and 8 of each 21-day cycle. Carboplatin is introduced from the calculation of AUC (area under the concentration-time curve) 5.0 mg / ml / min on day 1 of the cycle after gemcitabine infusion.
Breast cancer (unresectable, locally recurrent or metastatic)
Combination therapy with paclitaxel: as a first-line therapy for disease progression after neoadjuvant and / or adjuvant therapy, including anthracyclines in the absence of contraindications. Paclitaxel is administered at a dose of 175 mg / m2 intravenously for 3 hours on the 1st day of the 21-day cycle, followed by the introduction of gemcitabine. The recommended dose of the drug is 1250 mg / m2 on the 1st and 8th day of each 21-day cycle.
Before starting combination therapy (gemcitabine + paclitaxel), the absolute number of granulocytes in the blood of patients should be at least 1500 / μl.
Urothelial cancer (bladder cancer (locally advanced, metastatic and superficial), renal pelvis, ureter, urethra)
Monotherapy
The recommended dose is 1250 mg / m2 on days 1, 8 and 15 of each 28-day cycle.
Combined therapy with cisplatin
The recommended dose of the drug is 1000 mg / m2 on days 1, 8 and 15, combined with cisplatin, which is administered at a dose of 70 mg / m2 immediately after infusion of gemcitabine on 1 or 2 days of each 28-day cycle. Clinical studies have shown that at doses of cisplatin 100 mg / m2, more pronounced myelosuppression is observed.
Epithelial ovarian cancer (locally or metastatic, resistant to platinum derivatives)
Monotherapy
The recommended dose is 800-1250 mg / m2 on days 1, 8 and 15 of each 28-day cycle.
Combined therapy with carboplatin
The recommended dose is 1000 mg / m2 on days 1 and 8 in combination with carboplatin at AUC 4.0 mg / ml / min, which is administered immediately after gemcitabine infusion on day 1 of every 21-day cycle.
Pancreatic cancer (locally or metastatic, including resistant to fluorouracil therapy)
Monotherapy
The recommended dose is 1000 mg / m2 once a week for 7 weeks, followed by a weekly break. Then the drug is administered on the 1st, 8th and 15th days of each 28-day cycle.
Cervical cancer (locally or metastatic)
Combination therapy with cisplatin
For locally advanced cancer with sequential chemoradiotherapy (neoadadovant) and for metastatic cancer, cisplatin is administered at a dose of 70 mg / m2 after 1 day of hemodization against the background. Gemcitabine is administered at a dose of 1250 mg / m2 on the 1st and 8th day of each 21-day cycle.
For locally advanced cancer with simultaneous chemoradiotherapy, cisplatin is administered at a dose of 40 mg / m2 followed by (immediately after cisplatin) gemcitabine. Gemcitabine is administered once a week 1-2 hours before the start of radiation therapy at a dose of 125 mg / m2.
Cancer of the biliary tract
Combination therapy with cisplatin
Cisplatin is administered at a dose of 70 mg / m2 on the 1st day of the cycle amid hyperhydration followed by gemcitabine. Gemcitabine is administered at a dose of 1250 mg / m2 on the 1st and 8th day of each 21-day cycle.
Dose adjustment
If hematologic toxicity develops, the dose of Gemcitar ® may be reduced or its administration delayed.
To detect non-hematologic toxicity, it is necessary to conduct a regular examination of the patient and monitor liver and kidney function. Depending on the degree of toxicity, the dose can be reduced stepwise during each cycle or with the start of a new cycle. The introduction of the drug should be delayed until, in the opinion of the doctor, toxicity is resolved.
Special patient groups
Elderly patients
There is no data suggesting that elderly patients need to adjust the dose.
Patients with impaired liver and kidney function
Use gemcitabine in patients with hepatic impairment or impaired renal function with caution, since there are no sufficient data on the use of the drug in this category of patients.
Mild or moderate renal failure (glomerular filtration rate from 30 ml / min to 80 ml / min) does not significantly affect the pharmacokinetics of gemcitabine.
Children
Gemcitabine has been studied in limited studies of phase I and II in children with various types of neoplasms. The data from these studies are insufficient to prove the efficacy and safety of gemcitabine in children.
Rules for the preparation of
infusion solution. Only 0.9% sodium chloride solution (without preservatives) is used as a solvent.
To prepare an infusion solution, the contents of a 200 mg vial are dissolved in at least 5 ml, and 1000 mg in at least 25 ml of a 0.9% sodium chloride solution for injection. The vial is gently shaken until the lyophilisate is completely dissolved. The prepared solution of the drug should be transparent.
The maximum concentration of gemcitabine should not exceed 40 mg / ml. When preparing solutions with a concentration above 40 mg / ml, incomplete dissolution of the drug may be observed.
The prepared solution of the drug Gemcitar ® containing the desired dose of the drug is diluted with a sufficient amount of 0 before administration, 9% sodium chloride solution for injection for a 30 minute intravenous infusion.
Prior to parenteral administration, visual monitoring of the prepared infusion solution for mechanical impurities and discoloration is necessary.
Side effects
Side reactions that occurred more often than in single cases are listed according to the following gradation: very often (> 10%) often (> 1%, <10%) sometimes (> 0.1%, <1 %) rarely (> 0.01%, <0.1%) very rarely (<0.01%). From the blood and lymphatic system: very often – anemia, leukopenia and thrombocytopenia often – febrile neutropenia is very rare – thrombocytosis. From the side of the immune system: very rarely – anaphylactic reaction. From the side of metabolism and nutrition: often – anorexia. From the nervous system: often – headache, insomnia, drowsiness infrequently – cerebrovascular accident very rarely – reversible posterior encephalopathy syndrome. From the side of the heart: infrequently – heart failure, arrhythmia, mainly supraventricular rarely – myocardial infarction. From the vascular side: very often – edema, peripheral edema rarely – lowering blood pressure, peripheral vasculitis, gangrene very rarely – syndrome of increased permeability of capillaries. From the respiratory system: very often – shortness of breath often – cough, rhinitis, infrequently – bronchospasm, rarely interstitial pneumonitis – pulmonary edema, adult respiratory distress syndrome. From the gastrointestinal tract: very often – nausea, vomiting, increased activity of the liver enzymes aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and alkaline phosphatase often – diarrhea, stomatitis, ulcerative lesions of the oral mucosa, constipation, increased bilirubin concentration , infrequently – severe hepatotoxicity, including liver failure, in some cases with a fatal outcome rarely – increased concentration of gammaglutamyl transferase (GGT) is very rare – ischemic colitis. On the part of the skin and skin appendages: very often – allergic skin rashes of a mild degree, accompanied by itching, alopecia (usually minimal hair loss), often itching, sweating rarely – ulcers, vesicle formation, peeling, severe skin reactions, including desquamation and bullous skin damage, very rarely – toxic epidermal necrolysis, Stevens-Johnson syndrome. On the part of the kidneys and urinary tract: very often – mild proteinuria and hematuria, infrequently – renal failure rarely – increased concentrations of creatinine, urea and lactate dehydrogenase (LDH) in hemolytic-uremic syndrome. From the side of the musculoskeletal system and connective tissue: often – back pain, myalgia. Other: very common – flu-like syndrome. Cases of malaise have also been reported, sweating often – fever, asthenia, chills rarely – reactions at the injection site are mostly mild. Hypersensitivity: Anaphylactoid reactions were reported very rarely. Radiation toxicity has been reported rarely. The use of gemcitabine in combination with paclitaxel for breast cancer Adverse events of III severity Hematological toxicity: anemia – 5.7%, thrombocytopenia – 5.3%, neutropenia -31.3%. Non-hematologic toxicity: febrile neutropenia – 4.6%, increased fatigue – 5.7%, diarrhea – 3.1%, motor neuropathy – 2.3%, sensory neuropathy – 5.3%. Adverse events of the IV severity Hematological toxicity: anemia – 1.1%, thrombocytopenia – 0.4%, neutropenia – 17.2% (grade IV neutropenia lasting more than 7 days was recorded in 12.6% of patients). Non-hematologic toxicity: febrile neutropenia – 0.4%, increased fatigue – 0.8%, motor neuropathy – 0.4%, sensory neuropathy – 0.4%. The use of gemcitabine in combination with cisplatin for bladder cancer Adverse events III severity Hematological toxicity: anemia – 24%, thrombocytopenia – 29%. Non-hematologic toxicity: nausea and vomiting – 22%, diarrhea – 3%, infection – 2%, stomatitis – 1%. Adverse events of the IV severity Hematological toxicity: anemia – 4%, thrombocytopenia – 29%. Non-hematologic toxicity: infection – 1%. The use of gemcitabine in combination with carboplatin in ovarian cancer Adverse events III severity Hematological toxicity: anemia – 22.3%, neutropenia – 41.7%, thrombocytopenia – 30.3%, leukopenia – 48, 0% Non-hematologic toxicity: bleeding – 1.8%, febrile neutropenia – 1.1%. Adverse events of the IV severity Hematological toxicity: anemia – 5.1%, neutropenia – 28.6%, thrombocytopenia – 4.6%, leukopenia – 5.1%. Non-hematologic toxicity: infection without neutropenia – 0.6% Drug interaction Radiation therapy Concomitant use (concomitant or with an interval of less than 7 days): toxicity, associated with such multimodal treatment depends on many different factors: dose of gemcitabine, frequency of administration of gemcitabine, dose of radiation therapy, radiation therapy planning technique, type and volume of irradiated tissue. Preclinical and clinical studies have shown that gemcitabine has a radiosensitizing effect. In a single study in which gemcitabine was administered at a dose of 1000 mg / m2. during 6 weeks, simultaneously with therapeutic chest irradiation 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, mainly esophagitis and pneumonitis, especially in patients with a large volume of tissue irradiation (median irradiation volume 4795 cm3). Later studies (phase II studies in non-small cell lung cancer) indicate the advisability of administering lower doses of gemcitabine with concomitant radiation therapy with predictable toxicity. Radiation therapy to the chest area (SOD 66 Gy) was carried out simultaneously with chemotherapy with gemcitabine at a dose of 600 mg / m2 (4 administrations) and cisplatin at a dose of 80 mg / m2 (2 administrations) for 6 weeks. Several phase I and II studies have shown that for non-small cell lung cancer and pancreatic cancer, it is more advisable to conduct gemcitabine monotherapy (at a dose of up to 300 mg / m2 / week) in parallel with radiation therapy. The optimal regimen for the safe administration of gemcitabine with therapeutic doses of radiation therapy has not yet been established for all types of neoplasms. Sequential use (interval of more than 7 days): in addition to the radiation reaction with the introduction of gemcitabine more than 7 days before or after radiation therapy, no increase in toxicity was recorded. These data suggest that gemcitabine can be administered one week after radiation therapy or after the acute effects of radiation therapy are resolved. In both the simultaneous and sequential use of gemcitabine with radiation therapy, radiation injuries of irradiated tissues (for example, esophagitis, colitis and pneumonitis) have been reported. Others: Co-administration with live yellow fever vaccines and other live vaccines is not recommended due to the risk of a systemic disease with possible death, especially in immunosuppressed patients. Overdose Clinically acceptable toxicity was observed with single doses up to 5.7 g / m2 intravenously for 30 minutes every 2 weeks. Symptoms: myelosuppression, paresthesia, severe skin rash, hemorrhagic syndrome. Treatment: There is no specific antidote. If an overdose is suspected, the patient should be under constant medical supervision, including a general blood test with the determination of a leukocyte formula, if necessary, symptomatic treatment. Storage conditions Store in a dark place at a temperature not exceeding 30 ° C. Store the prepared solution of the drug at a temperature not exceeding 30 ° C for no more than 24 hours. Keep out of the reach and sight of children. Shelf life 3 years. Do not use after the expiration date printed on the package. Active ingredient Gemcitabine Dosage form solution for infusion Possible product names Gemcitar 1g 1fl
