Gemcitabine fares
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INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Gemcitabine PhaRes (Gemcitabine PhaRes)
Composition:
Active substance: gemcitabine;
One vial contains gemcitabine hydrochloride equivalent to 200 mg or 1000 mg of gemcitabine;
Excipients: mannite (E 421), sodium acetate trihydrate, hydrochloric acid, sodium hydroxide.
Pharmaceutical form. Powder for solution for infusion.
Main physicochemical properties: white or almost white powder.
Pharmacotherapeutic group. Antineoplastic agents. Pyrimidine analogues. ATC code L01B C05.
Pharmacological Properties.
Pharmacodynamics.
Cytotoxic activity in cell cultures
Gemcitabine exerts significant cytotoxic activity against various types of human cancer cells and cultured murine cancer cells. Gemcitabine demonstrates cell-cycle phase specificity, primarily affecting cells undergoing DNA synthesis (S-phase), and under certain conditions, blocks cell progression through the G1/S boundary. In vitro, the cytotoxic effect of gemcitabine is dependent on both concentration and duration of exposure.
Antitumor activity in preclinical models
In animal tumor models, the antitumor activity of gemcitabine depends on the dosing schedule. Daily administration of gemcitabine resulted in high animal mortality and minimal antitumor activity. However, when administered every 3rd or 4th day at non-lethal doses, gemcitabine demonstrated significant antitumor activity against a broad spectrum of tumors in mice.
Mechanism of action
Gemcitabine (dFdC) is a pyrimidine antimetabolite that is intracellularly metabolized by deoxycytidine kinase into active difluorodeoxyuridine diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic activity of gemcitabine is mediated by two active metabolites—dFdCDP and dFdCTP—through inhibition of DNA synthesis.
First, the diphosphate metabolite (dFdCDP) inhibits ribonucleotide reductase, the enzyme responsible for the conversion of ribonucleotides into deoxyribonucleotides required for DNA synthesis. This inhibition leads to a reduction in deoxynucleotide pools, particularly deoxycytidine triphosphate (dCTP). Second, dFdCTP competes with dCTP and is incorporated into DNA.
Additionally, small amounts of gemcitabine may also be incorporated into RNA. The reduction in intracellular dCTP concentration facilitates the incorporation of dFdCTP into the DNA chain. The epsilon-DNA polymerases are unable to remove gemcitabine or repair the growing DNA strand. After incorporation of gemcitabine metabolites into the elongating DNA chain, one additional nucleotide is added, which results in complete inhibition of further DNA synthesis and programmed cell death known as apoptosis.
Pharmacokinetics.
The pharmacokinetics of gemcitabine were studied in seven clinical trials involving 353 patients. The study included 121 women and 232 men aged 29 to 79 years. Approximately 45% of these patients had non-small cell lung cancer, and 35% had pancreatic cancer. Pharmacokinetic parameters were obtained following intravenous infusions of gemcitabine at doses ranging from 500 to 2592 mg/m² over 0.4–1.2 hours.
Absorption
Maximum plasma concentration (measured within 5 minutes after the end of infusion) ranged from 3.2 to 45.5 µg/mL. Following a dose of 1000 mg/m² administered over 30 minutes, plasma concentrations of the parent compound exceeded 5 µg/mL approximately 30 minutes after the end of infusion and remained above 0.4 µg/mL for an additional hour.
Distribution
The volume of distribution in the central compartment is 12.4 L/m² in women and 17.5 L/m² in men (inter-individual variability: 91.9%).
The volume of distribution in the peripheral compartment is 47.4 L/m² (independent of sex). Plasma protein binding is negligible and clinically insignificant.
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), of which dFdCDP and dFdCTP are considered active. 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.
Elimination
Systemic clearance ranges from 29.2 to 92.2 L/h/m², depending on sex and age (inter-individual variability: 52.2%). Clearance in women is approximately 25% lower than in men. Despite this, clearance in both men and women decreases with age. When gemcitabine is administered at the recommended dose of 1000 mg/m² over 30 minutes, the lower clearance in women and men does not necessitate dose reduction.
Renal excretion: less than 10% of the administered dose is excreted unchanged. Renal clearance ranges from 2 to 7 L/h/m².
The elimination half-life ranges from 42 to 94 minutes, depending on age and sex. After administration at recommended doses, elimination of gemcitabine is nearly complete within 5–11 hours after the start of infusion. When administered once weekly, gemcitabine does not accumulate. The total amount excreted within one week is 92–98%, of which 99% is excreted in urine (mainly as dFdU) and 1% in feces.
Pharmacokinetics of dFdCTP
This metabolite is detectable in peripheral blood mononuclear cells.
Terminal elimination half-life: 0.7–12 hours.
Intracellular concentrations increase proportionally with gemcitabine dose (35–350 mg/m²/30 min), achieving steady-state concentrations of 0.4–5 µg/mL. At plasma gemcitabine concentrations above 5 µg/mL, dFdCTP concentrations in mononuclear cells do not increase further, indicating saturation of metabolite formation. Initial plasma concentrations after administration of 1000 mg/m²/30 min exceed 5 µg/mL approximately 30 minutes after the end of infusion and remain above 0.4 µg/mL for the subsequent hour.
Pharmacokinetics of dFdU
Maximum plasma concentration (measured 3–15 minutes after the end of a 30-minute infusion of 1000 mg/m²) ranges from 28 to 52 µg/mL.
Plasma concentrations after weekly administration 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). Formation of dFdU from the parent compound accounts for 91–98%.
Mean volume of distribution in the central compartment: 18 L/m² (range: 11–22 L/m²).
Mean steady-state volume of distribution (Vss): 150 L/m² (range: 96–228 L/m²). Extensive tissue distribution occurs.
Mean clearance: 2.5 L/h/m² (range: 1–4 L/h/m²).
Urinary excretion is complete.
Combination of gemcitabine with carboplatin
When administered in combination with carboplatin, the pharmacokinetics of gemcitabine are not altered.
Combination of gemcitabine with paclitaxel
Pharmacokinetic analysis has shown that the pharmacokinetics of both gemcitabine and paclitaxel are unchanged when administered in combination.
Renal impairment
Moderate to severe renal impairment (glomerular filtration rate from 30 mL/min to 80 mL/min) does not have a clinically significant prolonged effect on the pharmacokinetics of gemcitabine.
Clinical characteristics.
Indications.
Bladder cancer. The medicinal product Gemcitabine FaRes in combination with cisplatin is indicated for the treatment of patients with locally advanced or metastatic bladder cancer.
Pancreatic cancer. Gemcitabine FaRes is indicated for the treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.
Non-small cell lung cancer. Gemcitabine FaRes 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. Gemcitabine FaRes as monotherapy is indicated for the treatment of elderly patients and patients with a performance status of 2.
Ovarian cancer. Gemcitabine FaRes in combination with carboplatin is indicated for the treatment of patients with locally advanced or metastatic epithelial ovarian carcinoma. This medicinal product is indicated for the treatment of patients with recurrent epithelial ovarian carcinoma following a remission period of at least 6 months after prior first-line platinum-based therapy.
Breast cancer. The medicinal product Gemcitabine FaRes in combination with paclitaxel is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer after prior adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should have included an anthracycline, unless contraindicated.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Breastfeeding period.
Special precautions.
Preparation of infusion solution
As with other cytotoxic agents, great care should be taken in the preparation and handling of the infusion solution. Pregnant personnel should not handle cytotoxic drugs. Reconstitution of the drug should be performed by trained personnel. Preparation of the infusion solution must be carried out 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 contact with the skin, the skin should be immediately washed with water.
Interaction with other medicinal products and other forms of interaction.
Specific studies on gemcitabine interactions have not been conducted.
Radiotherapy
Concurrent radiotherapy. Concurrent toxicity (administered simultaneously or ≤ 7 days apart) resulting from combined therapy depends on multiple factors, including the dose of gemcitabine, frequency of infusions, radiation dose, technique used, and the area and volume irradiated. Preclinical and clinical studies have shown 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, life-threatening mucositis, particularly esophagitis and pneumonitis, especially in patients treated with high-dose radiation (median treatment volume of 4.795 cm³). Subsequent studies have suggested that lower doses of gemcitabine should be used when combined with concurrent radiotherapy to achieve expected toxicity, as demonstrated in a phase II study of non-small cell lung cancer, where thoracic irradiation at a dose of 66 Gy was administered concurrently 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 did not reveal increased toxicity when gemcitabine was administered more than 7 days before or after radiation, except in cases of "radiation recall" reactions. Data indicate that gemcitabine can be initiated after acute radiation effects have subsided, i.e., at least one week after completion of radiotherapy.
Tissue injury in irradiated areas (e.g., esophagitis, colitis, and pneumonitis) has been reported both with concurrent and non-concurrent use of gemcitabine.
Other
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.
Prolonging the duration of infusion and increasing the frequency of dosing may increase toxicity. Hematologic toxicity. The use of the medicinal product Gemcitabine FaRes may cause myelosuppression, manifested as leukopenia, thrombocytopenia, and anemia, which in some cases may require discontinuation of treatment. Treatment should be initiated with caution in patients with impaired bone marrow function. As with other cytotoxic therapies, when using Gemcitabine FaRes in combination with other chemotherapy methods, the possibility of cumulative myelosuppression should be considered.
Patients receiving Gemcitabine FaRes must be closely monitored. Prior to each treatment cycle, platelet, leukocyte, and granulocyte counts must be assessed. The dose of Gemcitabine FaRes may be reduced or administration delayed in case of bone marrow suppression (myelosuppression). However, myelosuppression is usually transient and most often does not lead to dose reduction or discontinuation of therapy.
Peripheral blood cell counts may decrease even after discontinuation of gemcitabine therapy. This medicinal product should be administered with caution to patients with impaired bone marrow function. As with treatment using other cytotoxic agents, the risk of cumulative bone marrow suppression should be considered when gemcitabine is administered in combination with other chemotherapy drugs.
Hepatic and renal impairment. Administration of Gemcitabine FaRes to patients with concomitant liver metastases, hepatitis, or a history of alcoholism or liver cirrhosis may lead to increased hepatic insufficiency. Renal and hepatic laboratory parameters (including virological tests) should be periodically evaluated.
Gemcitabine FaRes should be administered with caution to patients with hepatic or renal impairment, as insufficient data from clinical studies are available to recommend precise dosing for such patients.
Concomitant radiotherapy
Toxicity has been reported during concomitant radiotherapy (either concurrently or within ≤ 7 days after administration).
Live vaccines
Administration of the yellow fever vaccine and other live attenuated vaccines is not recommended in patients receiving gemcitabine.
Posterior reversible encephalopathy syndrome (PRES)
Cases of posterior reversible encephalopathy syndrome (PRES), potentially with severe outcomes, have been reported in patients receiving gemcitabine as monotherapy or in combination with other chemotherapeutic agents. Most patients receiving gemcitabine who developed PRES 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 implemented. 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, particular caution should be exercised when prescribing Gemcitabine FaRes 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 chemotherapy agents. With early detection and appropriate therapy, this syndrome is usually treatable, but fatal outcomes have been reported. This condition arises due to increased systemic vascular permeability, leading to leakage of fluid and proteins from the intravascular space into the interstitium. 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 toxicity has 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. Early symptomatic intervention may improve the clinical condition.
Urinary and reproductive system
Hemolytic-uremic syndrome (HUS)
Clinical data related to HUS have rarely been reported in post-marketing data from patients receiving Gemcitabine FaRes. 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, increased serum bilirubin, serum creatinine, blood urea, or lactate dehydrogenase. Renal failure may be irreversible even after discontinuation of therapy, and dialysis may become necessary.
Severe skin reactions
Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), have been observed during treatment with gemcitabine, which may be life-threatening or fatal. Patients should be informed about the signs and symptoms and closely monitored for skin reactions. Gemcitabine should be immediately discontinued upon the appearance of signs or symptoms suggestive of these reactions.
Sodium
Patients on a controlled sodium diet should consider the sodium content as follows:
1 vial of Gemcitabine FaRes, 200 mg dose, contains < 1 mmol sodium, i.e., sodium is practically absent.
1 vial of Gemcitabine FaRes, 1000 mg dose, contains < 1 mmol sodium, i.e., sodium is practically absent.
Reconstituted solutions of Gemcitabine FaRes remain chemically and physically stable for 24 hours when stored at temperatures not exceeding 25 °C.
From a microbiological standpoint, the diluted solution should be used immediately. Reconstituted gemcitabine solutions must not be refrigerated, as crystallization may occur.
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 results of animal studies 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 treatment with gemcitabine and to inform their physician if they become pregnant while receiving gemcitabine.
Breastfeeding period
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 treatment with gemcitabine.
Fertility
In fertility studies, gemcitabine caused hypospermatogenesis in male mice. Therefore, men receiving gemcitabine should not plan fathering children during treatment and for 6 months after therapy. Due to the potential for loss of fertility following gemcitabine therapy, men are advised to consider sperm preservation prior to starting treatment.
Ability to affect reaction speed when driving or operating machinery.
No studies have been conducted to evaluate the effect of Gemcitabine FaRes on the ability to drive or operate machinery. Since Gemcitabine FaRes may cause mild to moderate somnolence, particularly when combined with alcohol, patients should avoid operating machinery or driving vehicles until this effect subsides.
Administration and Dosage
Gemcitabine must be administered only in departments specialized in cytotoxic chemotherapy, under the supervision of a physician experienced in anticancer chemotherapy.
Recommended Doses
Non-small cell lung cancer
Monotherapy. Adults. 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 period. This four-week cycle is repeated. Dose reduction from cycle to cycle or within a single 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 from cycle to cycle or within a 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.
Pancreatic cancer
Adults. The recommended dose of Gemcitabine Pharos 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 three consecutive weeks followed by a one-week rest every fourth week. Dose reduction from cycle to cycle or within a single cycle may occur depending on the degree of toxicity experienced by the patient.
Bladder cancer
Combination therapy. Adults. The recommended dose of Gemcitabine Pharos 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 should be administered at the recommended dose of 70 mg/m² on day 1 after Gemcitabine Pharos administration or on day 2 of each 28-day cycle. This four-week cycle is then repeated. Dose reduction from cycle to cycle or within a single cycle is possible depending on the degree of toxicity experienced by the patient.
Breast cancer
Combination therapy. Adults. Gemcitabine Pharos in combination with paclitaxel is recommended to be administered as follows: paclitaxel (175 mg/m²) is administered on day 1 as a 3-hour intravenous infusion, followed by gemcitabine (1250 mg/m²) as a 30-minute intravenous infusion on days 1 and 8 of each 21-day cycle. The dose may be reduced from cycle to cycle or within a single cycle depending on the degree of toxicity experienced by the patient. Prior to the first administration of the gemcitabine and paclitaxel combination, patients must have an absolute granulocyte count of at least 1500 (×10⁶/L).
Ovarian cancer
Combination therapy. Adults. Gemcitabine Pharos in combination with carboplatin is recommended to be administered at the following doses: gemcitabine 1000 mg/m² as a 30-minute intravenous infusion on days 1 and 8 of a 21-day cycle. On day 1 of the cycle, after administration of Gemcitabine Pharos, carboplatin should be administered at a dose providing an area under the pharmacokinetic concentration-time curve (AUC) of 4 mg/mL*min. The dose may be reduced from cycle to cycle or within a single cycle depending on the degree of toxicity experienced by the patient.
Toxicity monitoring and toxicity-related dose modification
Toxicity-related dose modification for non-hematological toxicity
To detect non-hematological toxicity, periodic physical examinations and assessments of renal and liver function should be performed. Dose reduction from cycle to cycle or within a single cycle may be performed depending on the degree of toxicity experienced by the patient.
In general, in case of severe non-hematological toxicity (grade III or IV), except for nausea or vomiting, the dose of Gemcitabine Pharos may be reduced or administration delayed, at the physician’s discretion, particularly if hematological toxicity is present. Treatment should be withheld until, in the physician’s opinion, the toxicity has resolved. For dose adjustments of cisplatin, carboplatin, and paclitaxel in combination therapy, refer to the respective product’s instructions for medical use.
Toxicity-related dose modification for hematological toxicity
At the beginning of a treatment cycle
In patients receiving Gemcitabine Pharos, platelet and granulocyte counts should be determined before administration of 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 Pharos may be reduced or administration delayed in the presence of hematological toxicity, as described below:
| Dose modification of Gemcitabine FaRes during the treatment cycle for indications: bladder cancer, non-small cell lung cancer, pancreatic cancer when used as monotherapy or in combination with cisplatin |
|||
| Absolute neutrophil count (×106/L) |
Platelet count (×106/L) |
Percentage of standard dose of Gemcitabine FaRes (%) |
|
| > 1000 500–1000 < 500 |
and or or |
> 100000 50000–100000 < 50000 |
100 75 Withhold dose* |
*Dosing should be withheld during the cycle until the absolute neutrophil count reaches at least 500 (×106/L) and platelets reach 50,000 (×106/L).
| Dose modification of Gemcitabine FaRes during the treatment cycle for indications: breast cancer in combination with paclitaxel |
|||
| Absolute neutrophil count (x10⁶/L) |
Platelet count (x10⁶/L) |
Percentage of standard dose of Gemcitabine FaRes (%) |
|
| > 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, as soon as the absolute neutrophil count reaches at least 1,500 (x10⁶/L) and platelet count reaches 100,000 (x10⁶/L).
| Dose modification of Gemcitabine Pharos during the treatment cycle for ovarian cancer indications when used in combination with carboplatin |
|||
| Absolute neutrophil count (x10⁶/L) |
Platelet count (x10⁶/L) |
Percentage of standard dose of Gemcitabine Pharos (%) |
|
| > 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 day 1 of the next cycle, once the absolute neutrophil count reaches at least 1500 (x10^6/L) and platelet count reaches 100,000 (x10^6/L).
Dose modifications due to hematological toxicity during subsequent cycles, for all indications
The dose of Gemcitabine FaRes should be reduced to 75% of the initial dose administered at the beginning of treatment in the event of the following manifestations of hematological toxicity:
- Absolute neutrophil count < 500 × 10^6/L for more than 5 days.
- Absolute neutrophil count < 100 × 10^6/L for more than 3 days.
- Febrile neutropenia.
- Platelet count < 25,000 × 10^6/L.
- Delay of the cycle due to toxicity for more than 1 week.
Administration methods
Gemcitabine is well tolerated during infusion and may therefore be administered on an outpatient basis. In case of extravasation, infusion must be stopped immediately and administration continued into another vein. Careful monitoring of the patient is required after infusion.
Special patient groups
Elderly patients (aged 65 years and older). The drug is well tolerated in elderly patients. Therefore, dose adjustment is not necessary for elderly patients, except as already recommended for all patients.
Children. Gemcitabine is not recommended for use in children due to insufficient data on efficacy and safety in this patient group.
Patients with hepatic or renal impairment
Gemcitabine should be administered with caution in patients with hepatic or renal impairment, as clinical studies have not provided sufficient data to recommend specific doses for such patients.
Instructions for solution preparation (and further dilution, if necessary). The only tested diluent for the sterile powder of Gemcitabine FaRes is 0.9% sodium chloride injection solution without preservatives.
According to solubility data, the maximum concentration of Gemcitabine FaRes after reconstitution should not exceed 40 mg/mL. Concentrations above 40 mg/mL may result in incomplete dissolution of the drug; therefore, such concentrations should be avoided.
- Solution preparation and further dilution, if necessary, must be performed under aseptic conditions.
- To prepare the solution, add at least 5 mL of 0.9% sodium chloride injection solution to the vial containing 200 mg of gemcitabine powder, or 25 mL of 0.9% sodium chloride injection solution to the vial containing 1000 mg of gemcitabine powder. The total volume after reconstitution will be 5.26 mL (for vials containing 200 mg of gemcitabine) and 26.3 mL (for vials containing 1000 mg of gemcitabine). Shake well to dissolve. Each of these dilutions provides a gemcitabine concentration of 38 mg/mL, accounting for the volume of displacement of the lyophilisate. Further dilution of the prepared solution may be performed using 0.9% sodium chloride injection solution without preservatives. The resulting solution may be clear or slightly yellowish.
- Parenteral preparations should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present, the solution must not be used.
Any unused solution or waste material should be disposed of in accordance with applicable regulations.
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 was observed with doses up to 5700 mg/m^2 administered as a 30-minute intravenous infusion every 2 weeks. In case of suspected overdose, patient monitoring with appropriate blood tests should be performed, and symptomatic treatment should be administered if necessary.
Adverse reactions
The most commonly reported adverse reactions associated with gemcitabine treatment were nausea, with or without vomiting, and elevated liver transaminase (AST/ALT) and alkaline phosphatase activities, observed in approximately 60% of patients; proteinuria and hematuria were reported in approximately 50% of patients; dyspnea was observed in 10–40% of patients (the highest frequency was observed in patients with lung cancer); allergic skin reactions occurred in 25% of patients, and in 10% of cases were accompanied by pruritus.
The frequency and severity of adverse reactions depend on the dose of gemcitabine, the rate of infusion, and the intervals between administrations. Dose-dependent adverse reactions include decreased levels of platelets, leukocytes, and granulocytes (see section "Dosage and administration").
Data obtained from clinical studies
Classification of frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from available data).
The table below lists adverse reactions and their frequencies observed during clinical studies. Within each group, adverse reactions are listed in order of decreasing 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 neutropenia = 6%). Suppression of bone marrow function is usually mild to moderate and most commonly affects granulocyte counts (see sections "Special precautions" and "Dosage and administration").
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:
|
| 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:
Frequency unknown:
|
| Musculoskeletal and connective tissue disorders |
Common:
|
| Renal and urinary disorders |
Very common:
Uncommon:
|
| General disorders |
Very common:
Common:
Rare:
|
| Injury, poisoning and procedural complications |
Rare:
|
Combination use in breast cancer
The incidence of hematological toxicity of grade III and IV, 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. Fatigue and febrile neutropenia occur more frequently with the combination of gemcitabine and paclitaxel. Fatigue not associated with anemia usually resolves after the first cycle of therapy.
| Incidence of Grade III and IV adverse events with paclitaxel monotherapy compared to combination therapy with gemcitabine and paclitaxel |
||||
| Number of patients (%) |
||||
| Paclitaxel monotherapy (N=259) |
Gemcitabine and paclitaxel combination therapy (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
| Grade III and IV adverse events with MVD (methotrexate, vinblastine, doxorubicin, cisplatin) compared to combination therapy of gemcitabine with cisplatin |
||||
| Number of patients (%) |
||||
| MVD 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 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 |
||||
| Hemorrhage |
0 (0.0) |
0 (0.0) |
3 (1.8) |
0 (0.0) |
| Febrile neutropenia |
0 (0.0) |
0 (0.0) |
2 (1.1) |
0 (0.0) |
| Infection without neutropenia |
0 (0) |
0 (0.0) |
0 (0.0) |
1 (0.6) |
The phenomenon of sensory neuropathy was also observed more frequently with combination therapy compared to carboplatin use alone.
Shelf life. 3 years.
Reconstituted solutions of Gemcitabine FaRes remain chemically and physically stable for 24 hours when stored at a temperature not exceeding 25°C.
Storage conditions.
Keep out of reach of children. Do not store in the refrigerator and do not freeze.
Incompatibilities.
The only tested diluent for reconstitution of the sterile powder Gemcitabine FaRes is 0.9% sodium chloride injection solution without preservatives.
Packaging.
200 mg or 1000 mg of gemcitabine per vial; 1 vial per cardboard box.
Prescription category. Prescription only.
Manufacturer.
Timoorgan Pharma GmbH.
Manufacturer's address and location of business activity.
Schiffgraben 23, Goslar, Niedersachsen, 38690, Germany.