Gemcitabine-pharmex
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GEMCITABINE-PHARMEX (GEMCITABINE-PHARMEX)
Composition:
Active substance: gemcitabine (gemcitabine);
1 vial contains gemcitabine hydrochloride equivalent to 200 mg or
1000 mg of gemcitabine;
Excipients: mannitol (E 421); sodium acetate, trihydrate; hydrochloric acid, diluted and/or sodium hydroxide.
Pharmaceutical form. Lyophilisate for solution for infusion.
Main physicochemical properties: lyophilized porous mass or white powder.
Pharmacotherapeutic group.
Antineoplastic medicinal products. Pyrimidine analogues. ATC code L01B C05.
Pharmacological Properties.
Pharmacodynamics.
Cytotoxic activity in cell cultures.
Gemcitabine demonstrates significant cytotoxic activity against various types of human cancer cells and cultured mouse cancer cells. Gemcitabine is cell-cycle phase-specific, primarily killing cells undergoing DNA synthesis (S-phase), and under certain conditions blocks progression through the G1/S phase boundary.
Antitumor activity in preclinical models.
In animal tumor models, the antitumor activity of gemcitabine depends on the administration schedule. Daily administration of gemcitabine resulted in high lethality among animals and minimal antitumor activity. However, when administered every third or fourth day at non-lethal doses, gemcitabine demonstrated significant antitumor activity against a broad spectrum of tumors in mice.
Mechanism of action.
Intracellular metabolism and mechanism of action.
Gemcitabine (dFdC) is a pyrimidine antimetabolite that is intracellularly metabolized by nucleoside kinase into active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to the inhibition of DNA synthesis by two active metabolites—diphosphate and triphosphate nucleosides. First, the diphosphate nucleoside inhibits ribonucleotide reductase, the enzyme responsible for catalyzing reactions that produce deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme leads to a reduction in the overall concentration of deoxynucleosides, particularly deoxynucleoside triphosphates. Second, dFdCTP competes with dCTP during DNA synthesis (self-potentiation).
Additionally, a small amount of gemcitabine may incorporate into RNA. Thus, the reduction in intracellular dCTP concentration facilitates the incorporation of triphosphate nucleosides into the DNA strand. The epsilon DNA polymerase is unable to remove gemcitabine and repair the synthesizing DNA strands. After incorporation of intracellular gemcitabine metabolites into the growing DNA chains, one additional nucleotide is added, leading to complete inhibition of further DNA synthesis (masked chain termination) and programmed cell death known as apoptosis.
Pharmacokinetics.
Pharmacokinetics of gemcitabine were studied in seven trials involving 353 patients. The studies included 121 women and 232 men aged from 29 to 79 years. Approximately 45% of these patients had non-small cell lung cancer, and 35% had pancreatic cancer. The following pharmacokinetic parameters were obtained after administration of doses ranging from 500 to 2592 mg/m² infused over 0.4 to 1.2 hours.
Peak plasma concentrations (measured 5 minutes before the end of infusion) ranged from 3.2 to 45.5 µg/mL. Plasma concentrations of the main component after a 1000 mg/m² dose administered over 30 minutes exceeded 5 µg/mL approximately 30 minutes after the end of infusion and remained above 0.4 µg/mL for another hour.
Distribution.
The volume of distribution in the central compartment is 12.4 L/m² in women and 17.5 L/m² in men (interindividual variability is 91.9%). The volume of distribution in the peripheral compartment was 47.4 L/m² and did not depend on sex. Plasma protein binding is negligible and can be disregarded.
Half-life.
Depending on age and sex, the half-life ranges from 42 to 94 minutes. After administration at recommended doses, elimination of gemcitabine is almost complete within 5–11 hours after the start of infusion. When administered once weekly, gemcitabine does not accumulate.
Metabolism.
Gemcitabine is rapidly metabolized by cytidine deaminase in the liver, kidneys, blood, and other tissues. Intracellular metabolism of gemcitabine produces gemcitabine mono-, di-, and triphosphates (dFdCMP, dFdCDP, and dFdCTP, respectively), with dFdCDP and dFdCTP considered the active metabolites. These intracellular metabolites are not detectable in plasma or urine. The primary metabolite, 2'-deoxy-2',2'-difluorouridine (dFdU), is inactive and is found in plasma and urine.
Excretion.
Systemic clearance ranges from 29.2 L/h/m² to 92.2 L/h/m², depending on age and sex (interindividual variability is 52.2%). Clearance in women is approximately 25% lower than in men. Despite the rate of clearance, it decreases with age in both men and women. When gemcitabine is administered at the recommended dose of 1000 mg/m² as a 30-minute infusion, the lower clearance in women and men is not a reason to reduce the gemcitabine dose.
Renal excretion. Less than 10% of the drug is excreted unchanged.
Renal clearance was 2–7 L/h/m².
Within one week after administration, 92% to 98% of the administered dose is excreted, with 99% eliminated in urine, primarily as dFdU, and 1% of the administered dose excreted in feces.
Combination therapy with gemcitabine and paclitaxel.
Combination therapy with gemcitabine and paclitaxel does not affect the pharmacokinetics of either drug.
Combination therapy with gemcitabine and carboplatin.
Combination therapy with gemcitabine and carboplatin does not affect the pharmacokinetics of gemcitabine.
Renal impairment.
Mild to moderate renal impairment (glomerular filtration rate from 30 mL/min to 80 mL/min) does not have a prolonged significant effect on the pharmacokinetics of gemcitabine.
Preclinical safety data.
In studies conducted in mice and dogs lasting up to 6 months, dose-dependent, reversible bone marrow suppression was observed. Gemcitabine showed mutagenic activity in in vitro mutation assays and in in vivo bone marrow micronucleus tests. Long-term animal studies to assess carcinogenic potential have not been conducted. In fertility studies, gemcitabine caused reversible hypospermatogenesis in male mice. No effect on female fertility was observed. Evaluation of experimental animal studies indicated reproductive toxicity, such as congenital malformations and other adverse effects on embryonic or fetal development, gestation, or peri- and postnatal development.
Clinical Characteristics.
Indications.
Bladder cancer. Gemcitabine in combination with cisplatin is indicated for the treatment of locally recurrent or metastatic bladder cancer.
Pancreatic cancer. Gemcitabine is indicated for the treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.
Non-small cell lung cancer. Gemcitabine in combination with cisplatin is indicated as first-line therapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer. Monotherapy with gemcitabine may be considered in elderly patients and in patients with a performance status of 2.
Ovarian cancer. Gemcitabine in combination with carboplatin is indicated for the treatment of patients with persistent or recurrent epithelial ovarian carcinoma following a disease-free interval of at least 6 months after prior platinum-based first-line therapy.
Breast cancer. Gemcitabine in combination with paclitaxel is indicated for the treatment of patients with metastatic or locally recurrent, unresectable breast cancer who have received prior adjuvant or neoadjuvant chemotherapy containing an anthracycline, unless contraindicated for clinical reasons.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Breast-feeding period.
Safety precautions.
Special instructions for the preparation of infusion solution.
As with other cytotoxic agents, great care should be taken in the handling and preparation of the infusion solution. The solution should be prepared in a safety cabinet using gloves and protective gowns. If work in a safety cabinet is not possible, a mask and protective goggles must be used.
Contact of the solution with the eyes may cause severe irritation. In such a case, the eyes should be immediately and thoroughly rinsed with water. If irritation persists, medical advice should be sought. In case of skin contact, the skin should be immediately washed with water.
Interaction with other medicinal products and other forms of interaction.
Specific interaction studies have not been conducted.
Radiotherapy.
Concurrent radiotherapy. The toxicity associated with combined modality therapy (concurrent or ≤ 7 days apart) 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 demonstrated that gemcitabine has radiosensitizing activity. In one trial, where gemcitabine at a dose of 1000 mg/m² was administered over a period of up to 6 weeks concurrently with thoracic radiotherapy in patients with non-small cell lung cancer, significant toxicity was observed in the form of severe and potentially life-threatening mucositis, esophagitis, and pneumonitis, particularly in patients who received high-dose radiotherapy (median treatment volume of 4,795 cm³). Subsequent studies have suggested that lower doses of gemcitabine should be used when administered concurrently with radiotherapy, with anticipated toxicity, as demonstrated in a phase II trial in non-small cell lung cancer, where thoracic irradiation at a dose of 66 Gy was combined with gemcitabine (600 mg/m², four doses) and cisplatin (80 mg/m², two doses) over 6 weeks. The optimal regimen for safe administration 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" reactions. Data suggest that gemcitabine may be initiated after acute radiation effects have resolved, at least one week after radiotherapy.
Tissue injury following radiotherapy (e.g., esophagitis, colitis, and pneumonitis) has been reported both with concurrent and non-concurrent administration of gemcitabine.
Concomitant use of live attenuated vaccines, including yellow fever vaccine, is not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.
Special precautions for use.
Prolonged duration and increased frequency of dosing increase toxicity.
Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), have been observed during gemcitabine therapy, which may be life-threatening or lead to fatal outcomes. Patients should be informed about the signs and symptoms and should be closely monitored for skin reactions. Gemcitabine should be discontinued immediately upon the appearance of signs or symptoms suggestive of these reactions.
Hematologic toxicity.
Gemcitabine may cause myelosuppression, leading to leukopenia, thrombocytopenia, and anemia.
Patients receiving gemcitabine should have platelet, white blood cell, and granulocyte counts assessed before each dose.
Consideration should be given to interrupting or modifying treatment whenever drug-induced bone marrow toxicity is detected (see section "Dosage and administration"). However, myelosuppression is usually transient and most often does not require dose reduction or discontinuation of therapy. Blood cell counts may continue to decline even after discontinuation of gemcitabine therapy. Caution should be exercised when administering treatment to patients with pre-existing bone marrow dysfunction. As with other cytotoxic agents, the risk of cumulative bone marrow suppression should be considered when gemcitabine is administered in combination with other chemotherapeutic agents.
Hepatic and renal impairment. Gemcitabine should be administered with caution in patients with impaired liver or kidney function, as there are insufficient clinical data to recommend specific dosing regimens for such patients (see section "Special precautions for use"). Administration of gemcitabine in the presence of liver metastases, hepatitis, history of alcoholism, or hepatic cirrhosis may lead to increased hepatic insufficiency. Renal and hepatic function tests (including virological testing) should be performed periodically.
Concomitant radiotherapy.
Toxicity has been reported during concomitant radiotherapy (administered concurrently or ≤ 7 days after gemcitabine) (see section "Interaction with other medicinal products and other forms of interaction").
Live vaccines.
Administration of the yellow fever vaccine and other live attenuated vaccines is not recommended in patients receiving gemcitabine therapy (see section "Interaction with other medicinal products and other forms of interaction").
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 a reversible condition if appropriate supportive measures are promptly initiated. 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 should be exercised when prescribing gemcitabine to patients with a history of cardiovascular disease.
Capillary leak syndrome.
Capillary leak syndrome has been reported in patients receiving gemcitabine either 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 due to increased systemic vascular permeability, resulting in leakage of fluid and proteins from the intravascular space into the interstitium. Clinical manifestations include generalized edema, weight gain, hypoalbuminemia, severe arterial 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 should be initiated. Capillary leak syndrome may occur during later treatment cycles and is often associated with adult respiratory distress syndrome.
Respiratory system.
Pulmonary toxicity, sometimes severe (such as pulmonary edema, interstitial pneumonitis, or adult respiratory distress syndrome (ARDS)), has been reported. If such events occur, discontinuation of gemcitabine therapy should be considered. Early symptomatic intervention may improve the clinical outcome.
Urinary and reproductive system.
Hemolytic uremic syndrome (HUS).
Clinical data related to HUS have been rarely reported in post-marketing data from patients receiving gemcitabine. 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, serum creatinine, blood urea nitrogen, or lactate dehydrogenase. Renal failure may be irreversible even after discontinuation of therapy, and dialysis may become necessary.
Fertility.
Fertility studies in mice showed that gemcitabine caused hypospermatogenesis in males. Therefore, men receiving gemcitabine therapy should avoid planning pregnancy during treatment and for at least 6 months after therapy. Due to the potential for loss of fertility associated with gemcitabine therapy, men are advised to consider sperm preservation prior to initiating treatment.
Sodium.
One vial of Gemcitabine-Farmeks 200 mg contains 3.5 mg (<1 mmol) of sodium, i.e., sodium content is negligible.
One vial of Gemcitabine-Farmeks 1000 mg contains 17.5 mg (<1 mmol) of sodium, i.e., sodium content is negligible.
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. Considering the animal study results and the mechanism of action, gemcitabine should not be used during pregnancy except in cases of clear necessity.
Women should be advised to avoid pregnancy during gemcitabine therapy and to inform their physician immediately if they become pregnant.
Breastfeeding.
It is unknown whether gemcitabine is excreted in human milk, and adverse reactions in breastfed infants cannot be excluded. Breastfeeding should be discontinued during gemcitabine therapy.
Fertility.
Fertility studies in mice showed that gemcitabine caused hypospermatogenesis in males. Therefore, men receiving gemcitabine therapy should avoid planning pregnancy during treatment and for at least 6 months after therapy. Due to the potential for loss of fertility associated with gemcitabine therapy, men are advised to consider sperm preservation prior to initiating treatment.
Ability to affect reaction speed when driving or operating machinery.
No studies have been conducted to evaluate the effect of gemcitabine on the ability to drive or operate machinery. Since gemcitabine may cause mild to moderate somnolence, particularly when combined with alcohol, patients should avoid driving or operating machinery until this adverse effect resolves.
Method of Administration and Dosage
Gemcitabine should only be administered by a physician experienced in anticancer chemotherapy.
Recommended Doses
Bladder Cancer
Combination therapy. Adults. The recommended dose is 1000 mg/m² administered as a 30-minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle, in combination with cisplatin. Cisplatin should be administered at the recommended dose of 70 mg/m² on day 1 after Gemcitabine-Farmex or on day 2 of each 28-day cycle. This 4-week cycle should then be repeated. Dose reduction in each cycle or during any single cycle may be considered depending on the degree of toxicity experienced by the patient.
Pancreatic Cancer
The recommended dose of Gemcitabine-Farmex is 1000 mg/m² administered as a 30-minute intravenous infusion once weekly for 7 weeks, followed by a one-week rest period. Subsequent cycles consist of weekly infusions for 3 consecutive weeks followed by a one-week rest in the fourth week. Dose reduction in each cycle or during any single cycle may be considered depending on the degree of toxicity experienced by the patient.
Non-Small Cell Lung Cancer
Monotherapy. The recommended dose is 1000 mg/m² administered as a 30-minute intravenous infusion once weekly for 3 weeks, followed by a one-week rest. This 4-week cycle should be repeated. Dose reduction in each cycle or during any single cycle may be performed depending on the degree of toxicity experienced by the patient.
Combination therapy. 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 in each cycle or during any single 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. The drug in combination with paclitaxel is recommended to be administered according to the following regimen: paclitaxel (175 mg/m²) should be 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 in each cycle or during any single 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 1500 (×10⁶/L).
Ovarian Cancer
Combination therapy. The drug in combination with carboplatin is recommended to be administered at the following doses: gemcitabine 1000 mg/m² via a 30-minute intravenous infusion on days 1 and 8 of a 21-day cycle. On day 1 of the cycle, following Gemcitabine-Farmex, carboplatin should be administered at a dose providing an AUC of 4.0 mg/mL/min. The dose may be reduced in each cycle or during any single cycle 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 physical examinations and assessments of renal and liver function are required to detect non-hematological toxicity. Dose reduction in each cycle or during any single cycle may be considered depending on the degree of toxicity experienced by the patient. In general, in the presence of severe non-hematological toxicity (Grade III or IV), except for nausea or vomiting, the dose of Gemcitabine-Farmex may be reduced or administration delayed at the physician’s discretion in the presence of hematological toxicity. Treatment should be withheld until toxicity is resolved. Dose adjustments for cisplatin, carboplatin, and paclitaxel used in combination therapy should be performed according to the instructions for medical use of these medicinal products.
Dose Modification Related to Hematological Toxicity
At the Beginning of a Treatment Cycle
Patients receiving Gemcitabine-Farmex should have platelet, white blood cell, and granulocyte counts checked before each dose. The absolute granulocyte count prior to the start of a cycle should be at least 1500 (×10⁶/L), and platelet count should be at least 100,000 (×10⁶/L).
During the Treatment Cycle
If necessary, the dose of Gemcitabine-Farmex may be reduced or administration delayed in the presence of hematological toxicity according to the following grading:
| Dose modifications of Gemcitabine-Pharmex when used as monotherapy or in combination with cisplatin during treatment cycles for bladder cancer, non-small cell lung cancer, pancreatic cancer |
|||
| Absolute granulocyte count (x10⁶/L) |
Platelet count (x10⁶/L) |
Percentage of standard dose of Gemcitabine-Pharmex |
|
| > 1000 500–1000 < 500 |
and or or |
> 100000 50000–100000 < 50000 |
100 75 delay dose administration* |
*Avoid administering the dose during the cycle until the absolute granulocyte count reaches at least 500 (x10⁶/L) and platelets reach 50,000 (x10⁶/L).
| Dose modification of Gemcitabine-Pharmex during the treatment cycle for the indication: breast cancer when used in combination with paclitaxel |
|||
| Absolute granulocyte count (x10⁶/L) |
Platelet count (x10⁶/L) |
Percentage of standard dose of Gemcitabine-Pharmex |
|
| > 1200 1000–1200 700–1000 < 700 |
and or and or |
> 75,000 50,000–75,000 ≥ 50,000 < 50,000 |
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, as soon as the absolute granulocyte count reaches at least 1500 (x10⁶/L) and platelet count reaches 100,000 (x10⁶/L).
| Dose modification of Gemcitabine-Pharmex during the treatment cycle for the indication: ovarian cancer in combination with carboplatin |
|||
| Absolute granulocyte count (x10⁶/L) |
Platelet count (x10⁶/L) |
Percentage of standard dose of Gemcitabine-Pharmex |
|
| > 1500 1000–1500 < 1000 |
and or or |
≥ 100000 75000–100000 < 75000 |
100 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, as soon as the absolute granulocyte count reaches at least 1500 (x10^6/L) and platelet count reaches 100,000 (x10^6/L).
Dose modification related to hematological toxicity during subsequent cycles, for all indications.
The dose of Gemcitabine-Farmex must be reduced to 75% of the full dose administered at the beginning of treatment in case of the following manifestations of hematological toxicity:
absolute granulocyte count < 500 x10^6/L for more than 5 days;
absolute granulocyte count < 100 x10^6/L for more than 3 days;
febrile neutropenia;
platelet count < 25,000 x10^6/L;
delay of cycle due to toxicity manifestations for more than 1 week.
Method of administration.
Gemcitabine is well tolerated during infusion and can be administered on an outpatient basis. In case of hematoma development, infusion must be stopped immediately and administration continued into another vein. The patient's condition must be carefully monitored after infusion.
Special patient groups.
Patients with hepatic and renal impairment. The medicinal product should be administered with caution to patients with hepatic and renal impairment, as there is insufficient data to recommend precise dosing for such patients.
Elderly patients (˃65 years). The medicinal product 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.
Instructions for solution preparation (and further dilution if necessary). The only tested solvent for reconstituting the sterile powder of Gemcitabine-Farmex is
0.9% sodium chloride solution for injection without preservatives.
According to solubility data, the maximum concentration of Gemcitabine-Farmex after solution preparation should not exceed 40 mg/mL. Concentrations above 40 mg/mL may result in incomplete dissolution of the drug, and this should be avoided.
-
Solution preparation and further dilution, if necessary, must be performed under aseptic conditions.
-
To prepare the solution, add not less than 5 mL of 0.9% sodium chloride solution for injection to the vial containing 200 mg of gemcitabine powder, or not less than 25 mL of 0.9% sodium chloride solution for injection to the vial containing 1000 mg of gemcitabine powder. The total volume after reconstitution will be 5.26 mL (vials containing 200 mg gemcitabine) and 26.3 mL (vials containing 1000 mg gemcitabine). This provides a gemcitabine concentration of 38 mg/mL, which also accounts for the lyophilizate displacement volume. Shake to dissolve. The prepared solution may be further diluted with 0.9% sodium chloride solution for injection without preservatives. The appropriate amount of the medicinal product can be administered immediately after preparation or further diluted with 0.9% sodium chloride solution for injection. The resulting solution may be clear or slightly yellowish.
-
Parenteral preparations must be visually inspected for the presence of foreign particles and discoloration prior to administration. If foreign particles are present, the solution must not be used. Any unused medicinal product or waste material must be destroyed in accordance with current legislation.
Children. Gemcitabine is not recommended for children under 18 years of age due to lack of sufficient data on safety and efficacy.
Overdose.
There is no known antidote for gemcitabine overdose.
Clinically tolerable toxicity was observed when administering doses up to 5.7 g/m^2 via 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 if necessary.
Adverse Reactions
The most commonly reported adverse reactions associated with gemcitabine therapy are nausea, with or without vomiting, elevated levels of liver transaminases (ALT and AST) and alkaline phosphatase (in 60% of patients), proteinuria and hematuria (in 50% of patients), dyspnea (in 10–40% of patients, most frequently in patients with lung cancer), and allergic skin rashes (observed in 25% of patients), of which 10% were accompanied by pruritus.
The frequency and severity of adverse reactions depend on the dose, rate of administration, and intervals between doses. Dose-dependent adverse reactions include thrombocytopenia, leukopenia, and granulocytopenia.
Data from Clinical Trials
The adverse reactions listed in the table below are ranked in decreasing order of severity by frequency: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).
The adverse reactions and their frequencies in the table below are based on data from clinical trials. Within each frequency category, adverse reactions are listed in decreasing order of severity.
| Organs and systems |
Frequency |
| Infections and infestations |
Common:
Frequency unknown:
|
| Blood and lymphatic system disorders |
Very common:
(grade III neutropenia = 19.3%; grade IV = 6%) bone marrow suppression is usually mild to moderate in severity and most prominently affects granulocyte counts.
Common:
Very rare:
|
| Immune system disorders |
Very rare:
|
| Metabolism and nutrition disorders |
Common:
|
| Nervous system disorders |
Common:
Uncommon:
Very rare:
|
| Cardiac disorders |
Uncommon:
Rare:
|
| Vascular disorders |
Rare:
Very rare: capillary leak syndrome (see section "Special precautions") |
| Respiratory, thoracic and mediastinal disorders |
Very common:
Common:
Uncommon:
Rare:
|
| Gastrointestinal disorders |
Very common:
Common:
Very rare:
|
| Hepatobiliary disorders |
Very common:
Common:
Uncommon:
Rare:
|
| Skin and subcutaneous tissue disorders |
Very common:
Common:
Rare:
Very rare:
Unknown:
|
| Musculoskeletal and connective tissue disorders |
Common:
|
| Renal and urinary disorders |
Common:
Uncommon:
|
| General disorders |
Very common:
Common:
Rare:
|
| Injury, poisoning and procedural complications |
Rare:
|
Combination use in breast cancer.
The frequency of grade III and IV hematological toxicity events, particularly neutropenia, increases with the combination of gemcitabine and paclitaxel, although the increased frequency of these adverse reactions is not associated with a higher incidence of infections or hemorrhagic events. Weakness and febrile neutropenia are observed more frequently with the combination of gemcitabine and paclitaxel. Weakness, not associated with anemia, usually resolves after the first cycle of therapy.
| Grade III and IV adverse events with paclitaxel monotherapy compared to combination therapy with gemcitabine plus paclitaxel |
||||
| Number of patients (%) |
||||
| Paclitaxel monotherapy |
Combination therapy with gemcitabine plus 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 combination therapy and in 5% of patients receiving paclitaxel alone.
Combination therapy in bladder cancer.
| Adverse events of grade III and IV with MBDTS (methotrexate, vinblastine, doxorubicin, cisplatin) compared to combination therapy of gemcitabine with cisplatin |
||||
| Number of patients (%) |
||||
| MBDTS combination (N=196) |
Combination therapy of gemcitabine with 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) |
Combination therapy in ovarian cancer.
| Adverse events of grade III and IV during carboplatin monotherapy compared to combination therapy with gemcitabine and carboplatin |
||||
| Number of patients (%) |
||||
| Carboplatin (N=174) |
Combination therapy with gemcitabine and 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) |
Sensory neuropathy phenomena were observed more frequently with combination therapy compared to monotherapy with carboplatin.
Reporting of adverse reactions following marketing authorization of the medicinal product is of significant importance. This enables continuous monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach and sight of children.
Incompatibilities.
The only tested solvent for reconstitution of the sterile powder Gemcitabine-Pharmex is 0.9% sodium chloride injection solution without preservatives.
Packaging.
200 mg or 1000 mg per vial, 1 vial in a blister pack, 1 blister pack in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
LLC "FARMEKS GROUP".
Manufacturer's address and location of its business operations.
100, Shevchenka Street, Boryspil, Kyiv region, Ukraine, 08301.