Gemcitabine "ebewe"
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GEMCITABINE «EBEWE»
Composition:
Active substance: gemcitabine;
1 ml of concentrate for infusion solution contains 40 mg of gemcitabine (in the form of gemcitabine hydrochloride);
Excipients: hydrochloric acid diluted, water for injections.
Pharmaceutical form. Concentrate for solution for infusion.
Main physicochemical properties: clear, colorless or pale yellow solution.
Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01B C05.
Pharmacological properties.
Pharmacodynamics.
Gemcitabine exhibits significant cytotoxic activity against various tumor cell lines in mice and humans. The action of gemcitabine is cell cycle phase-dependent; the drug primarily affects cells undergoing DNA synthesis (S-phase) and, under certain conditions, blocks the transition from G1-phase to S-phase of the cell cycle. The cytotoxic effect of gemcitabine in vitro depends on its concentration and duration of exposure.
Gemcitabine (dFdC), a pyrimidine antimetabolite, undergoes intracellular metabolic activation by deoxycytidine kinase to form the active metabolites gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). The cytotoxic effect of gemcitabine is mediated by inhibition of DNA synthesis through a dual mechanism of action of the metabolites dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, the sole enzyme catalyzing the formation of deoxynucleoside triphosphates (dCTP), which are essential for DNA synthesis. Inhibition of this enzyme by dFdCDP leads to decreased intracellular concentrations of deoxynucleosides in general and of dCTP in particular. Second, dFdCTP competes with dCTP for incorporation into the DNA chain (self-potentiation).
In addition, gemcitabine may be incorporated to a minor extent into RNA chains. Thus, the reduction in intracellular dCTP concentration promotes more efficient incorporation of dFdCTP into DNA. DNA polymerase epsilon is unable to excise incorporated gemcitabine or repair the elongating DNA chain. After gemcitabine is incorporated into the growing DNA chain, one additional nucleotide is added. Subsequently, further DNA synthesis is completely blocked (masked chain termination). Following incorporation into DNA, gemcitabine induces programmed cell death, known as apoptosis.
Pharmacokinetics.
Pharmacokinetic characteristics of gemcitabine were determined in 353 patients (121 women and 232 men) aged 29 to 79 years, enrolled in 7 clinical studies. Approximately 45% of these patients were treated for non-small cell lung cancer and 35% for pancreatic cancer. Following intravenous infusions of gemcitabine at doses ranging from 500 to 2592 mg/m² body surface area administered over 0.4 to 1.2 hours, the following pharmacokinetic parameters were observed.
Maximum plasma concentration of gemcitabine (reached within 5 minutes after the end of infusion) ranged from 3.2 to 45.5 µg/mL. After administration of 1000 mg/m² body surface area via 30-minute intravenous infusions, the concentration of the parent compound in plasma exceeded 5 µg/mL for approximately 30 minutes after the end of infusion and remained above 0.4 µg/mL for an additional hour.
Distribution.
The volume of distribution of gemcitabine in the central compartment was 12.4 L/m² for women and 17.5 L/m² for men (interindividual variability: 91.9%). The volume of distribution in the peripheral compartment was 47.4 L/m². The volume of distribution of gemcitabine in the peripheral compartment is independent of sex.
Plasma protein binding of gemcitabine is negligible.
Elimination half-life ranges from 42 to 94 minutes, depending on patient age and sex. With the recommended dosing schedule, complete elimination of gemcitabine occurs within 5–11 hours after the start of infusion. When administered once weekly, gemcitabine does not accumulate in the body.
Metabolic transformation.
Gemcitabine undergoes rapid metabolism catalyzed by cytidine deaminase in the liver, kidneys, blood, and other tissues. Intracellular metabolism of gemcitabine produces gemcitabine mono-, di-, and triphosphate (dFdCMP, dFdCDP, and dFdCTP), among which dFdCDP and dFdCTP are considered active metabolites. These intracellular metabolites have not been detected in plasma or urine. The primary metabolite of gemcitabine, 2′-deoxy-2′,2′-difluorouridine (dFdU), is inactive and is detectable in plasma and urine.
Elimination.
Systemic clearance of gemcitabine ranges from 29.2 to 92.2 L/h/m², depending on patient age and sex (interindividual variability: 52.2%). Clearance values in women are approximately 25% lower than in men. Gemcitabine clearance decreases with age in both women and men, although elimination remains relatively rapid. Following administration of the recommended dose of 1000 mg/m² body surface area via 30-minute intravenous infusions, reduced clearance in both women and men does not warrant dose reduction of gemcitabine.
Renal excretion: less than 10% of the administered dose is excreted unchanged in urine.
Renal clearance values range from 2 to 7 L/h/m².
Within one week after gemcitabine administration, 92% to 98% of the administered dose is eliminated from the body, with 99% excreted in urine (primarily as dFdU) and 1% in feces.
Kinetics of dFdCTP.
This metabolite is detected in peripheral blood mononuclear cells; therefore, the information below refers specifically to these cells. Following administration of gemcitabine at doses ranging from 35 to 350 mg/m² body surface area via 30-minute intravenous infusions, steady-state intracellular concentrations of dFdCTP increase proportionally from 0.4 to 5 µg/mL. When plasma gemcitabine concentration exceeds 5 µg/mL, dFdCTP concentration in mononuclear cells does not increase further, indicating saturation of these cells.
Terminal half-life of dFdCTP ranges from 0.7 to 12 hours.
Kinetics of dFdU.
Maximum plasma concentration of dFdU (reached 3–15 minutes after the end of a 30-minute infusion of 1000 mg/m² body surface area) ranges from 28 to 52 µg/mL.
Trough plasma concentrations of dFdU following weekly administration of gemcitabine range from 0.07 to 1.12 µg/mL, with no evidence of accumulation.
The decline in plasma dFdU concentration follows a triphasic pattern, with a mean terminal half-life of 65 hours (range: 33–84 hours).
Conversion of parent compound to dFdU: 91–98%.
Mean volume of distribution of dFdU in the central compartment: 18 L/m² (range: 11–22 L/m²).
Mean volume of distribution at steady state (Vss) for dFdU: 150 L/m² (range: 96–228 L/m²).
Tissue distribution: extensive.
Mean clearance of dFdU: 2.5 L/h/m² (range: 1–4 L/h/m²).
Urinary excretion: complete.
Combination therapy with gemcitabine and paclitaxel.
When gemcitabine and paclitaxel are administered in combination, the pharmacokinetic characteristics of both drugs remain unchanged.
Combination therapy with gemcitabine and carboplatin.
When gemcitabine and carboplatin are administered in combination, the pharmacokinetic characteristics of both drugs remain unchanged.
Renal impairment.
Mild to moderate renal impairment (glomerular filtration rate: 30–80 mL/min) does not have a consistent, clinically significant effect on the pharmacokinetic characteristics of gemcitabine.
Clinical characteristics.
Indications.
Cholangiocarcinoma. Gemcitabine is indicated for the treatment of patients with cholangiocarcinoma.
Bladder cancer. Gemcitabine "Ebewe" in combination with cisplatin is indicated for the treatment of patients with locally recurrent or metastatic bladder cancer.
Breast cancer. Gemcitabine "Ebewe" in combination with paclitaxel is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer after prior adjuvant/neoadjuvant chemotherapy. An anthracycline should be administered prior to chemotherapy, if there are no contraindications.
Non-small cell lung cancer. Gemcitabine "Ebewe" in combination with cisplatin is indicated as a first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer. Gemcitabine "Ebewe" as monotherapy is indicated for the treatment of elderly patients and patients with a performance status of 2.
Ovarian cancer. Gemcitabine "Ebewe" in combination with carboplatin is indicated for the treatment of patients with locally advanced or metastatic epithelial ovarian carcinoma. Gemcitabine "Ebewe" is indicated for the treatment of patients with recurrent epithelial ovarian carcinoma after a remission period of at least 6 months following prior first-line platinum-based therapy.
Pancreatic cancer. Gemcitabine "Ebewe" is indicated for the treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Breastfeeding period.
Special precautions.
When preparing or disposing of the infusion solution, general safety rules for handling cytotoxic substances must be observed. The solution for infusion should be prepared in an isolated cabinet or a biological safety cabinet designated for handling cytostatic agents. Protective clothing (gown, gloves, mask, protective goggles) must be used.
If the solution comes into contact with the eyes, severe irritation may occur. In such a case, the eyes should be immediately and thoroughly rinsed with water. If irritation persists, medical advice should be sought. If the solution contacts the skin, it should be thoroughly washed off with water.
Unused residues of the medicinal product, as well as all instruments and materials used in the preparation of infusion solutions and administration of gemcitabine, must be destroyed in accordance with approved procedures for disposal of cytotoxic waste and in compliance with local regulations regarding hazardous waste disposal.
Interaction with other medicinal products and other forms of interaction.
No specific interaction studies have been conducted.
Radiotherapy.
Concurrent radiotherapy (administered together or ≤ 7 days after). Toxicity resulting from combined modality therapy depends on multiple factors, including the dose of gemcitabine, frequency of infusions, radiation dose, technique used, and the volume and site of irradiation.
Preclinical and clinical studies have shown that gemcitabine has radiosensitizing activity. In one trial, gemcitabine at a dose of 1000 mg/m² was administered over a period of up to 6 weeks concurrently with thoracic radiotherapy to patients with non-small cell lung cancer, and significant toxicity was observed in the form of severe and potentially life-threatening mucositis, particularly esophagitis and pneumonitis, especially in patients who received high-dose radiotherapy (median treatment volume of 4,795 cm³). Subsequent studies suggested that lower doses of gemcitabine should be used when administered concurrently with radiotherapy to reduce expected toxicity, as demonstrated in a phase II trial in non-small cell lung cancer, where thoracic irradiation at 66 Gy was combined with gemcitabine (600 mg/m² 4 times) and cisplatin (80 mg/m² 2 times) over 6 weeks. The optimal regimen for safe use of gemcitabine with therapeutic radiation doses has not yet been established for all tumor types.
Non-concurrent radiotherapy (> 7 days). Analysis of data has not shown increased toxicity when gemcitabine is administered more than 7 days before or after radiation, except in cases of "radiation recall." Data indicate that gemcitabine may be initiated after acute radiation effects have subsided, at least one week after radiotherapy.
Tissue damage in previously irradiated areas (e.g., esophagitis, colitis, pneumonitis) has been reported with both concurrent and non-concurrent administration of gemcitabine.
Others.
Concomitant use of live attenuated vaccines, including yellow fever vaccine, is not recommended due to the risk of systemic, potentially fatal disease, particularly in immunosuppressed patients.
Special precautions for use.
Treatment with gemcitabine must be administered under the supervision of an oncologist.
Prolonged infusion duration and increased frequency of gemcitabine administration enhance the drug's toxic effects.
Gemcitabine Ebewe, concentrate for solution for infusion, must be diluted before use. The solution should be administered into large veins to avoid vascular damage and prevent subcutaneous hemorrhage.
Hematological toxicity.
Gemcitabine may suppress bone marrow function, manifesting as leukopenia, thrombocytopenia, and anemia.
Patients receiving gemcitabine must have platelet, white blood cell, and granulocyte counts assessed before each dose. The dose of gemcitabine may be reduced or administration delayed in case of bone marrow suppression (myelosuppression). However, myelosuppression is usually transient and most often does not require dose reduction or discontinuation of therapy.
Peripheral blood cell counts may continue to decline even after discontinuation of gemcitabine therapy. Gemcitabine should be administered with caution in patients with impaired bone marrow function. As with other cytotoxic agents, the risk of cumulative bone marrow suppression should be considered when gemcitabine is used in combination with other chemotherapeutic agents.
Hepatic impairment. The drug should be used with caution in patients with hepatic or renal impairment, as clinical studies have not provided sufficient data to recommend precise dosing for such patients. Administration of gemcitabine in the presence of liver metastases, hepatitis, history of alcoholism, or hepatic cirrhosis may lead to worsening hepatic insufficiency. Laboratory evaluation of renal and hepatic parameters (including virological testing) should be performed periodically.
Concomitant radiotherapy.
Toxicity has been reported during concomitant radiotherapy (administered together or ≤ 7 days after gemcitabine).
Live vaccines.
Administration of the yellow fever vaccine and other live attenuated vaccines is not recommended in patients receiving gemcitabine therapy.
Posterior reversible encephalopathy syndrome (PRES).
Cases of posterior reversible encephalopathy syndrome (PRES), potentially with severe outcomes, have been reported in patients receiving gemcitabine either as monotherapy or in combination with other chemotherapeutic agents. Most patients who developed PRES while receiving gemcitabine experienced acute hypertension and epileptic seizures; other symptoms may also occur, such as headache, lethargy, confusion, and visual loss.
This condition (syndrome) is diagnosed by magnetic resonance imaging (MRI). Posterior reversible encephalopathy syndrome (PRES) is reversible with appropriate supportive therapy. If PRES develops during gemcitabine therapy, treatment should be discontinued and supportive measures initiated, including blood pressure control and anticonvulsant therapy.
Cardiovascular system.
Due to the risk of cardiac or vascular disorders associated with gemcitabine use, special caution is required when prescribing gemcitabine to patients with a history of cardiovascular disease.
Capillary leak syndrome.
Capillary leak syndrome has been reported in patients receiving gemcitabine as monotherapy or in combination with other chemotherapeutic agents. With early detection and appropriate treatment, capillary leak syndrome is usually treatable, but fatal outcomes have been reported. This condition arises from increased systemic vascular permeability, allowing fluid and proteins to leak from the intravascular space into the interstitium. Reported clinical signs include generalized edema, weight gain, hypoalbuminemia, severe hypotension, acute renal failure, and pulmonary edema. Administration of the drug should be discontinued at the first signs of capillary leak syndrome, and appropriate therapy initiated. Capillary leak syndrome may occur in later treatment cycles and is often associated with adult respiratory distress syndrome.
Respiratory system.
Pulmonary effects have been reported, sometimes severe (such as pulmonary edema, interstitial pneumonitis, or adult respiratory distress syndrome (ARDS)). If such events occur, discontinuation of gemcitabine therapy should be considered. The condition may improve with early symptomatic treatment.
Urinary and reproductive system.
Hemolytic-uremic syndrome (HUS).
Clinical data related to hemolytic-uremic syndrome (HUS) have been rarely reported in post-marketing data from patients receiving gemcitabine. Hemolytic-uremic syndrome (HUS) is potentially life-threatening. Drug administration should be discontinued at the first signs of microangiopathic hemolytic anemia, such as rapid decline in hemoglobin levels accompanied by thrombocytopenia, elevated serum bilirubin, elevated serum creatinine, elevated blood urea, or elevated lactate dehydrogenase. Renal failure may be irreversible even after discontinuation of therapy, and dialysis may become necessary.
There is evidence that concomitant medications used with gemcitabine, particularly other chemotherapeutic agents, may contribute to the development of disseminated intravascular coagulation (DIC) or thrombotic microangiopathy (TMA). Additionally, patients receiving gemcitabine may have an inherent thrombotic risk due to their underlying malignancy. However, in some cases, clinical improvement has been observed after discontinuation of gemcitabine, leading physicians to consider a possible causal relationship between gemcitabine use and DIC/TMA. Although gemcitabine-induced DIC/TMA is rare, healthcare providers should remain aware of these potentially life-threatening complications.
Carcinogenesis. Long-term animal studies did not reveal any carcinogenic potential of gemcitabine.
Mutagenesis. In in vivo biological testing, gemcitabine induced cytogenetic changes. In in vitro studies on mouse lymphoma (L51778Y), gemcitabine caused direct mutagenesis.
Solutions containing visible particles must not be used.
Severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been observed during gemcitabine treatment. Patients should be informed about the signs and symptoms of cutaneous adverse reactions and closely monitored for their occurrence. Gemcitabine should be discontinued immediately upon the appearance of signs or symptoms suggestive of these reactions.
Use during pregnancy or breastfeeding.
Pregnancy. There are no adequate data on the use of gemcitabine in pregnant women. Animal studies have shown reproductive toxicity. Given the results of animal studies and the mechanism of action, gemcitabine should not be used during pregnancy unless clearly necessary. Women should be advised to avoid pregnancy during treatment with gemcitabine and to inform their physician if they become pregnant while receiving gemcitabine.
Breastfeeding. It is unknown whether gemcitabine is excreted in human milk, and adverse reactions in breastfed infants cannot be excluded. Therefore, breastfeeding should be discontinued during gemcitabine therapy.
Fertility. Fertility studies in mice showed that gemcitabine caused hypospermatogenesis in male animals. Therefore, men receiving gemcitabine therapy should not plan fathering children during treatment and for 6 months after therapy. Due to the potential for infertility caused by gemcitabine therapy, men are advised to consider sperm preservation before starting treatment.
Ability to affect reaction speed when driving or operating machinery.
Studies on the effect of gemcitabine on the ability to drive or operate machinery have not been conducted. However, gemcitabine is known to cause mild to moderate drowsiness, particularly when combined with alcohol. Therefore, patients should refrain from driving or operating machinery until they are certain they are not affected by drowsiness.
Method of Administration and Dosage.
Treatment with gemcitabine must be prescribed exclusively by an oncologist qualified to administer antineoplastic chemotherapy.
Bladder cancer.
Combination therapy. Adults. The recommended dose of Gemcitabine "Ebewe" is 1000 mg/m² administered as a 30-minute intravenous infusion. This dose should be given on days 1, 8, and 15 of each 28-day cycle in combination with cisplatin. Cisplatin is administered at the recommended dose of 70 mg/m² on day 1 after Gemcitabine "Ebewe" or on day 2 of each 28-day cycle. This 4-week cycle should then be repeated. Dose reduction between cycles or within a cycle may be applied depending on the degree of toxicity experienced by the patient.
Pancreatic cancer.
The recommended dose of Gemcitabine "Ebewe" is 1000 mg/m² administered via intravenous infusion over 30 minutes once weekly for 7 weeks, followed by a one-week break. Subsequent cycles consist of weekly infusions for three consecutive weeks followed by a one-week break in the fourth week. Dose reduction between cycles or within a cycle may occur depending on the degree of toxicity experienced by the patient.
Non-small cell lung cancer.
Monotherapy. Elderly patients. The recommended dose is 1000 mg/m² administered as a 30-minute intravenous infusion once weekly for three weeks, followed by a one-week break. This four-week cycle should be repeated. Dose reduction between cycles or within a cycle may be performed depending on the degree of toxicity experienced by the patient.
Combination therapy. Adults. The recommended dose is 1250 mg/m² body surface area, administered as a 30-minute intravenous infusion on days 1 and 8 of each 21-day cycle. The dose may be reduced between cycles or within a cycle depending on the degree of toxicity experienced by the patient. Cisplatin should be administered at the recommended dose of 75–100 mg/m² once every 3 weeks of the cycle.
Breast cancer.
Combination therapy. Adults. Gemcitabine "Ebewe" in combination with paclitaxel is recommended to be administered as follows: paclitaxel (175 mg/m²) is administered on day 1 via a 3-hour intravenous infusion, followed by gemcitabine (1250 mg/m²) via a 30-minute intravenous infusion on days 1 and 8 of each 21-day cycle. The dose may be reduced between cycles or within a cycle depending on the degree of toxicity experienced by the patient. Prior to the first administration of the combination of gemcitabine and paclitaxel, patients must have an absolute granulocyte count of at least 1,500 (×10⁶/L).
Ovarian cancer.
Combination therapy. Adults. Gemcitabine "Ebewe" in combination with carboplatin is recommended to be administered at the following doses: gemcitabine 1000 mg/m² via 30-minute intravenous infusion on days 1 and 8 of a 21-day cycle. On day 1 of the cycle, after administration of Gemcitabine "Ebewe", carboplatin should be administered at a dose providing an AUC of 4 mg/mL·min. The dose may be reduced between cycles or within a cycle depending on the degree of toxicity experienced by the patient.
Biliary tract cancer.
Monotherapy. Adults. The recommended dose of Gemcitabine "Ebewe" is 1000 mg/m² administered intravenously over 30 minutes. Infusion should be given once weekly for three consecutive weeks, followed by a one-week break. This four-week cycle should be repeated. Dose reduction between cycles or within a cycle may occur depending on the extent of toxicity experienced by the patient.
Combination therapy. Adults. Gemcitabine "Ebewe" in combination with cisplatin: cisplatin 70 mg/m² is recommended to be administered on day 1 of the cycle via intravenous infusion, followed by Gemcitabine "Ebewe" at a dose of 1250 mg/m². Gemcitabine "Ebewe" should be administered on days 1 and 8 of each 21-day cycle via a 30-minute intravenous infusion. This 3-week cycle is repeated. Dose reduction between cycles or within a cycle may be applied depending on the degree of toxicity experienced by the patient.
Toxicity monitoring, individual dose adjustment, and methods of treatment discontinuation.
Dose modification related to non-hematological toxicity.
Periodic clinical evaluations and monitoring of renal and liver function are required to detect non-hematological toxicity. Dose reduction between cycles or within a cycle may be performed depending on the degree of toxicity experienced by the patient.
In general, in the event of severe non-hematological toxicity (Grade III or IV), except for nausea or vomiting, the dose of Gemcitabine "Ebewe" may be reduced or administration delayed in the presence of hematological toxicity according to the following grading. (Treatment should be withheld until toxicity has been resolved.)
Dose modification related to hematological toxicity.
At the beginning of the treatment cycle.
In patients receiving Gemcitabine "Ebewe", platelet, leukocyte, and granulocyte counts should be checked before each dose. The absolute granulocyte count prior to the start of a cycle should be at least 1,500 (×10⁶/L), and platelets should be at least 100,000 (×10⁶/L).
During the treatment cycle.
If necessary, the dose of Gemcitabine "Ebewe" may be reduced or administration delayed in the presence of hematological toxicity according to the following grading:
| Dose modification of Gemcitabine "Ebewe" during the treatment cycle for indications: bladder cancer, non-small cell lung cancer, pancreatic cancer when used as monotherapy or in combination therapy |
|||
| Absolute granulocyte count (×10⁶/L) |
Platelet count (×10⁶/L) |
Percentage of full dose |
|
| > 1000 500–1000 < 500 |
and or or |
> 100000 50000–100000 < 50000 |
100 75 delay dose administration* |
*Dose administration during the cycle should be withheld until the absolute granulocyte count reaches at least 500 (×10⁶/L) and platelets reach 50,000 (×10⁶/L).
| Dose modification of Gemcitabine "Ebewe" during the treatment cycle for indications: breast cancer when used in combination with paclitaxel |
|||
| Absolute granulocyte count (×10⁶/L) |
Platelet count (×10⁶/L) |
Percentage of full dose |
|
| > 1200 1000–1200 700–1000 < 700 |
and or and or |
> 75000 50000–75000 ≥ 50000 < 50000 |
100 75 50 delay dose administration* |
*Dose administration will not be resumed during the cycle. Treatment will be restarted on the first day of the next cycle, once the absolute neutrophil count reaches at least 1,500 (×10⁶/L) and platelets reach 100,000 (×10⁶/L).
| Dose modification of Gemcitabine "Ebewe" during the treatment cycle as indicated: ovarian cancer in combination with carboplatin |
|||
| Absolute granulocyte count (×10⁶/L) |
Platelet count (×10⁶/L) |
Percentage of full dose |
|
| > 1500 1000–1500 < 1000 |
and or or |
≥ 100,000 75,000–100,000 < 75,000 |
100 50 delay dose* |
*The administered dose will not be resumed during the cycle. Treatment will be restarted on the first day of the next cycle, as soon as the absolute neutrophil count reaches at least 1500 (×10⁶/L) and platelet count reaches 100,000 (×10⁶/L).
Dose modification due to hematological toxicity during subsequent cycles, for all indications.
The dose of Gemcitabine "Ebewe" must be reduced to 75% of the full initial dose in case of the following manifestations of hematological toxicity:
- Absolute neutrophil count < 500 × 10⁶/L for more than 5 days.
- Absolute neutrophil count < 100 × 10⁶/L for more than 3 days.
- Febrile neutropenia.
- Platelet count < 25,000 × 10⁶/L.
- Delay of the cycle due to toxicity by more than 1 week.
Special patient groups.
Patients with hepatic and renal impairment. The drug should be administered with caution in patients with hepatic and renal impairment, as insufficient data from clinical studies are available to recommend precise dosing for such patients.
Elderly patients (˃ 65 years). The drug is well tolerated in patients aged 65 years and older. There are no grounds to assume that dose adjustments are required for elderly patients, except those already recommended for all patients.
Method of administration.
The drug must be reconstituted before use. Large veins should be selected for administration to prevent vascular damage and extravasation.
The required volume should be transferred into an infusion bag or bottle under aseptic conditions. The drug may be administered at the prepared concentration or further diluted with 0.9% sodium chloride solution or 5% glucose solution. The solution should be mixed thoroughly by gentle shaking of the bag or bottle.
Gemcitabine "Ebewe" is well tolerated during infusion and can be administered on an outpatient basis. In case of hematoma formation, infusion must be stopped immediately and administration continued into another vein. The patient's condition should be carefully monitored after infusion.
Children.
Gemcitabine is not recommended for use in children due to insufficient data on safety and efficacy in this patient group.
Overdose.
There is no known antidote for gemcitabine overdose.
Clinically tolerable toxicity has been observed with doses up to 5700 mg/m² administered as a 30-minute intravenous infusion every 2 weeks.
In case of suspected overdose, patient monitoring and appropriate blood tests should be performed, and symptomatic therapy should be administered as necessary.
Adverse Reactions
The most commonly reported adverse reactions associated with gemcitabine treatment are nausea and vomiting, elevated levels of liver transaminases (AST/ALT) and alkaline phosphatase (in approximately 60% of patients); proteinuria and hematuria (in approximately 50% of patients); dyspnea (in 10–40% of patients, most frequently in patients with lung cancer); and allergic skin reactions (in approximately 25% of patients, including pruritus in 10% of patients).
The frequency and severity of adverse reactions depend on the dose of gemcitabine, the rate of infusion, and the intervals between administrations. Dose-limiting toxicities include thrombocytopenia, leukopenia, and granulocytopenia.
When gemcitabine is used in combination chemotherapy, the frequency and severity of adverse effects increase.
Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not known (frequency cannot be estimated from available data).
Infections and infestations. Common: infections. Not known: sepsis.
Blood and lymphatic system disorders. Very common: leukopenia (grade III neutropenia in 19.3% of patients; grade IV in 6%). Bone marrow suppression is usually mild to moderate and primarily affects granulocyte counts. Thrombocytopenia, anemia. Common: febrile neutropenia. Rare: thrombocytosis, thrombotic microangiopathy, disseminated intravascular coagulation.
Immune system disorders. Rare: anaphylactoid reactions.
Metabolism and nutrition disorders. Common: anorexia.
Nervous system disorders. Common: headache, insomnia, somnolence. Uncommon: cerebrovascular disorders. Rare: reversible posterior leukoencephalopathy syndrome.
Cardiac disorders. Uncommon: arrhythmias (predominantly supraventricular arrhythmias), heart failure. Rare: myocardial infarction; clinical manifestations of peripheral vasculitis and gangrene; arterial hypotension. Very rare: capillary leak syndrome.
Respiratory, thoracic and mediastinal disorders. Very common: dyspnea (in most cases mild, transient, and resolving without treatment). Common: cough, rhinitis. Uncommon: interstitial pneumonitis, bronchospasm (usually transient and mild, but in some cases parenteral therapy may be required). Rare: pulmonary edema, adult respiratory distress syndrome.
Gastrointestinal disorders. Very common: vomiting, nausea. Common: diarrhea, stomatitis and oral ulcers, constipation. Rare: ischemic colitis.
Hepatobiliary disorders. Very common: increased activity of liver transaminases (AST and ALT) and alkaline phosphatase. Common: increased bilirubin levels. Uncommon: severe hepatotoxicity, including renal dysfunction and fatal outcomes. Rare: increased gamma-glutamyl transferase (GGT) activity.
Skin and subcutaneous tissue disorders. Very common: allergic skin rashes, often with pruritus, alopecia. Common: skin pruritus, hyperhidrosis. Rare: severe skin reactions, including desquamation, bullous eruptions, skin ulcers, vesicle formation, skin lesions, and skin peeling. Very rare: toxic epidermal necrolysis, Stevens-Johnson syndrome. Not known: pseudo-cellulitis, acute generalized exanthematous pustulosis.
Musculoskeletal and connective tissue disorders. Common: back pain, myalgia.
Renal and urinary disorders. Very common: hematuria, mild proteinuria. Uncommon: renal failure, hemolytic-uremic syndrome.
Administration of the drug should be discontinued at the first sign of microangiopathic hemolytic anemia, such as a rapid decrease in hemoglobin levels accompanied by thrombocytopenia, increased serum bilirubin, serum creatinine, blood urea, or lactate dehydrogenase levels. Renal failure may be irreversible even after discontinuation of therapy, and dialysis may become necessary.
General disorders and administration site conditions. Very common: flu-like symptoms (most commonly fever, headache, chills, myalgia, asthenia, and anorexia; cough, rhinitis, malaise, hyperhidrosis, and sleep disturbances have also been reported); edema/peripheral edema, including facial edema (in most cases, edema resolves after discontinuation of treatment). Common: fever, asthenia, chills. Rare: infusion site reactions (mostly mild in severity).
Injury, poisoning and procedural complications. Rare: re-emergence of toxic effects caused by radiation therapy.
Use in combination therapy for breast cancer treatment.
An increased incidence of grade III–IV adverse reactions, particularly neutropenia, has been observed when gemcitabine is used in combination with paclitaxel. However, this increased frequency of adverse reactions is not associated with a higher incidence of infections or hemorrhagic events. Fatigue and febrile neutropenia occur more frequently with the combination of gemcitabine and paclitaxel. Fatigue not related to anemia usually resolves after the first cycle of therapy.
| Grade III and IV adverse events with paclitaxel monotherapy compared to combination therapy with gemcitabine and paclitaxel |
||||
| Number of patients (%) |
||||
| Paclitaxel monotherapy |
Combination therapy with gemcitabine and paclitaxel (N=262) |
|||
| Grade III |
Grade IV |
Grade III |
Grade IV |
|
| Laboratory parameters |
||||
| 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)* |
| Non-laboratory parameters |
||||
| Febrile neutropenia |
3 (1.2) |
0 |
12 (4.6) |
1 (0.4) |
| Weakness |
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) |
| Sensory neuropathy |
9 (3.5) |
0 |
14 (5.3) |
1 (0.4) |
* Grade IV neutropenia lasting more than 7 days was observed in 12.6% of patients receiving the combination therapy and in 5% of patients receiving paclitaxel alone.
Use in combination therapy for the treatment of bladder cancer.
Grade III-IV adverse reactions, including anemia, thrombocytopenia, nausea, and vomiting, occur more frequently with the gemcitabine-cisplatin combination than with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen.
| Grade III and IV adverse events with M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) compared to combination therapy with gemcitabine and cisplatin |
||||
| Number of patients (%) |
||||
| M-VAC combination (N=196) |
Combination therapy with gemcitabine and cisplatin (N=200) |
|||
| Grade III |
Grade IV |
Grade III |
Grade IV |
|
| Laboratory parameters |
||||
| Anemia |
30 (16) |
4 (2) |
47 (24) |
7 (4) |
| Thrombocytopenia |
15 (8) |
25 (13) |
57 (29) |
57 (29) |
| Non-laboratory parameters |
||||
| 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) |
Use in combination therapy for the treatment of ovarian cancer
When gemcitabine is combined with carboplatin, adverse reactions of grade III-IV severity occur more frequently, including anemia, neutropenia, thrombocytopenia, leukopenia, as well as isolated cases of bleeding and febrile neutropenia, compared to carboplatin monotherapy. Sensory neuropathy was also observed more frequently in patients receiving combination therapy compared to those receiving monotherapy (carboplatin).
| Grade III and IV adverse events with carboplatin monotherapy compared to combination therapy of gemcitabine with carboplatin |
||||
| Number of patients (%) |
||||
| Carboplatin (N=174) |
Combination therapy of gemcitabine with carboplatin (N=175) |
|||
| Grade III |
Grade IV |
Grade III |
Grade IV |
|
| Laboratory parameters |
||||
| 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) |
| Non-laboratory parameters |
||||
| Bleeding |
0 (0) |
0 (0) |
3 (1.8) |
0 (0) |
| Febrile neutropenia |
0 (0) |
0 (0) |
2 (1.1) |
0 (0) |
| Infection without neutropenia |
0 (0) |
0 (0) |
0 (0) |
1 (0.6) |
Shelf life.
Sealed vial – 2 years.
Data on stability after first opening of the vial:
Chemical and physical stability have been demonstrated for 28 days at 2–8 °C and at room temperature (15–25 °C).
From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the duration and storage conditions are the responsibility of the user; generally, the storage period should not exceed 24 hours at 2–8 °C, unless the vial has been opened under controlled and validated sterile conditions.
Shelf life after dilution:
Chemical and physical stability of the prepared solution, diluted with 5% glucose solution or 0.9% sodium chloride solution, have been demonstrated for 28 days at 2–8 °C and at room temperature.
From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the duration and storage conditions are the responsibility of the user; generally, the storage period should not exceed 24 hours at 2–8 °C, unless the solution preparation was carried out under controlled and validated sterile conditions.
Storage conditions.
Store at 2–8 °C. Do not freeze.
Keep out of reach of children.
Incompatibilities.
The product should not be mixed with other medicinal products except 0.9% sodium chloride solution or 5% glucose solution.
Packaging.
5 ml (200 mg) or 25 ml (1000 mg) or 50 ml (2000 mg) in a vial with a package leaflet, 1 vial in a carton.
Prescription category. Prescription only.
Manufacturer.
Fresenius Kabi Austria GmbH
or
EBEWE Pharma Ges.m.b.H. Nfg. KG
Address of manufacturer and location of its business operation.
Mondseestrasse 11, 4866 Unterach am Attersee, Austria
Mondseestrasse 11, 4866 Unterach am Attersee, Austria