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Composition:


active ingredient: gemcitabine hydrochloride;


1 bottle contains gemcitabine hydrochloride in terms of gemcitabine 200 mg or 1.0 g;


excipients: mannitol (E 421); sodium acetate, trihydrate.


Dosage form. Lyophilizate for infusion solution.


Basic physical and chemical properties: white or almost white lyophilizate in colorless glass vials.


Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Structural analogues of pyrimidine. ATX code L01B C05.


Pharmacological properties.


Pharmacodynamics.


Gemcitabine exhibits cyclospecificity, mainly leading to cell death during DNA synthesis (s-phase), as well as blocking cell growth in the G1-/s-phase of the cycle.


Gemcitabine (dFdC) undergoes intracellular metabolism under the action of nucleoside kinases to form diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is due to the combined action of diphosphate and triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, diphosphate nucleoside inhibits ribonucleotide reductase, which catalyzes the formation reactions of deoxynucleoside triphosphates necessary for DNA synthesis. Inhibition of this enzyme by diphosphatnucleoside causes a decrease in the concentration of deoxynucleotides, including dCTP. Second, dFdCTP competes with dCTP in DNA construction (self-potentiation).


Thus, a decrease in the intracellular concentration of dCTP makes it possible to attach triphosphate nucleosides to the DNA chain. Epsilon-DNA polymerases are unable to eliminate gemcitabine and restore synthesized DNA strands. After the intracellular metabolites of gemcitabine are attached to the DNA, one additional nucleotide is attached to the synthesized DNA strands, which leads to complete inhibition of subsequent DNA synthesis (hidden end of the chain) and programmed cell death, known as apoptosis.


Pharmacokinetics.


Distribution. The maximum concentration in blood plasma (within 5 minutes after the end of the infusion) is 3.2-45.5 mcg/ml.


The volume of distribution in the central part of the body in women is 12.4 L/m2, in men – 17.5 L/m2. The volume of distribution in the peripheral part of the body is 47.4 L/M2 (the same in women and men). Women have approximately 25% lower clearance than men.


The elimination half-life is 42-94 minutes, depending on the gender and age of patients. For the recommended administration regimen, gemcitabine withdrawal should be completed within 5-11 hours after the start of the infusion. When administered every week, there is no accumulation of gemcitabine.


Metabolism. Gemcitabine is rapidly metabolized in the liver, kidneys, blood and other tissues with the participation of cytidine deaminase.


During intracellular metabolism, gemcitabine mono -, Di -, and triphosphates (dFdCMP, dFdCDP, and dFdCTP) are formed, of which dFdCDP and dFdCTP have pharmacological activity. These intracellular metabolites are not detected in blood plasma or urine.


The primary metabolite 2’-deoxy-2’, 2 ' - difluoruridine (dFdU) is inactive and is found in the blood and urine.


Output. The systemic clearance of gemcitabine ranged from 29.2 to 92.2 L/H/M2, depending on the patient's gender and age (interindividual variability of 52.2 %). The clearance of the drug in women is approximately 25% lower than in men. Gemcitabine clearance decreases with age in both women and men, although it remains rapid. When gemcitabine is administered at the recommended dose of 1000 mg/m2 of body surface area by 30-minute intravenous infusions, there is no need to reduce the dose for women and men with lower clearance.


Urinary excretion. Less than 10% of the dose is excreted in the urine as unchanged gemcitabine. Renal clearance varies from 2 to 7 L/H/M2.


Within a week after gemcitabine administration, 92 to 98% of the dose is excreted from the body, 99 % – in the urine, mainly in the form of dFdU, and 1 % – in the feces.


Dfdctp Kinetics. This metabolite is found in peripheral blood mononuclears, so the following information applies to these cells. When gemcitabine is administered at doses from 35 to 350 mg/m2 of body surface area by 30-minute intravenous infusions, the steady-state intracellular concentration of dfdctp increases proportionally from 0.4 to 5 mcg/ml. When the concentration of Gemcitabine in blood plasma exceeds 5 mcg/ml, the concentration of dFdCTP in mononuclear cells does not increase, which indicates the saturation of the process of formation of this metabolite.


The terminal Half-Life of dFdCTP is 0.7-12 hours.


Dfdu Kinetics


The maximum concentration of dfdu in blood plasma is reached 3-15 minutes after the end of a 30-minute infusion at a dose of 1000 mg/m2 of body surface area and is 28-52 mcg/ml.


The minimum concentration of dfdu in blood plasma when gemcitabine is administered once a week is 0.07-1.12 mcg/ml without signs of accumulation.


The process of reducing the concentration of dFdU in blood plasma is three-phase, the average half-life in the terminal phase is 65 hours (range 33-84 hours).


91-98% of gemcitabine is converted to dFdU.


The average volume of dfdu distribution in the central chamber is 18 L/m2 (range 11-22 L/M2).


The average volume of dFdU distribution at steady state (VSS) is 150 L/m2 (range 96-228 L/M2).


Tissue distribution is extensive.


The average ground clearance of dFdU is 2.5 L/H/m2 (range 1-4 L/H/M2).


Urinary excretion-completely.


Combination therapy with gemcitabine and paclitaxel


With the combined use of gemcitabine and paclitaxel, the pharmacokinetics of both drugs do not change.


Combination therapy with gemcitabine and carboplatin


With the combined use of gemcitabine and carboplatin, the pharmacokinetics of gemcitabine do not change.


Impaired renal function


Mild to moderate renal failure (GFR 30-80 mL/min) does not significantly affect the pharmacokinetics of gemcitabine.


Clinical characteristics.


Indications.


Bladder cancer. Gemcitabine is prescribed for the treatment of locally advanced or metastatic bladder cancer in combination with cisplatin.


Pancreatic cancer. Gemcitabine is prescribed for the treatment of locally advanced pancreatic adenocarcinoma.


Non-small cell lung cancer. Gemcitabine is prescribed in combination with cisplatin as a first-line therapy for patients with locally advanced or metastatic non-small cell lung cancer. The possibility of using gemcitabine as monotherapy can be considered for elderly patients or patients with functional status 2 on the ECOG scale.


Ovarian cancer. Gemcitabine in combination with carboplatin is prescribed for the treatment of locally advanced or metastatic epithelial ovarian cancer in patients with recurrent disease after a relapse-free period of at least 6 months after first-line therapy with platinum preparations.


Breast cancer. Gemcitabine in combination with paclitaxel is prescribed for the treatment of patients with inoperable locally recurrent or metastatic breast cancer who have relapsed after previous adjuvant/non-adjuvant chemotherapy. Previous chemotherapy in the absence of clinical contraindications should include anthracyclines.


Contraindications.


Hypersensitivity to gemcitabine or other components of the drug; breast-feeding period.


Special security measures.


Features of preparation of the infusion solution


As with other cytostatics, great attention should be paid to the preparation and use of the infusion solution. Preparation of the infusion solution should be carried out in a protective box and using gloves and protective raincoats. If it is not possible to work in a protective box, you must use a mask and safety glasses.


Contact with the solution in the eyes can cause severe irritation. In this case, you should immediately rinse your eyes thoroughly with water. If the irritation persists, you should consult a doctor. If the solution gets on the skin, immediately flush the skin with water.

Overdose.


There is no known antidote for gemcitabine overdose. Clinically acceptable toxicity was observed when a dose of up to 5.7 g/m2 was administered by a 30-minute intravenous infusion every 2 weeks. In case of suspected overdose, the patient should be monitored, including an appropriate calculation of the blood formula, and if necessary, he should be prescribed maintenance therapy.


Adverse reactions.


Adverse reactions associated with gemcitabine treatment, which were most often reported: nausea, both with and without vomiting, increased levels of hepatic transaminases (Alt and ASAT), as well as alkaline phosphatase were observed in approximately 60% of patients; proteinuria and hematuria were observed in approximately 50% of patients; shortness of breath was observed in 10-40% of patients (the highest frequency is in patients with lung cancer); allergic skin rashes were observed in 25% of patients, and in 10% they were accompanied by pruritus.


The frequency of occurrence and strength of adverse reactions depend on the dose, rate of administration, and intervals between doses. Dose-dependent adverse reactions include decreased platelet, white blood cell, and granulocyte counts.


Tags: Gemcitabine