Gemcitabine accord
UkraineTable of Contents
I N S T R U C T I O N for medical use of the medicinal product GEMCITABINE ACCORD
Composition:
active substance: gemcitabine hydrochloride;
1 ml of concentrate for solution for infusion contains 113.85 mg of gemcitabine hydrochloride, equivalent to 100 mg of gemcitabine;
excipients: macrogol 300, propylene glycol, sodium hydroxide, hydrochloric acid, anhydrous ethanol.
Pharmaceutical form. Concentrate for solution for infusion.
Main physicochemical properties: clear, colorless or slightly yellow solution in a transparent glass vial. When examined under favorable viewing conditions, it should be practically free from particles.
Pharmacotherapeutic group. Antineoplastic agents. Pyrimidine analogues. ATC code L01B C05.
Pharmacological Properties.
Pharmacodynamics.
Cytotoxic activity in cell cultures
Gemcitabine exhibits significant cytotoxic activity against various human cancer cell lines and murine cultured cancer cells. Gemcitabine is cell-cycle phase-specific, primarily targeting cells undergoing DNA synthesis (S-phase), and under certain conditions, it blocks progression through the G1/S phase boundary. The cytotoxic effect of gemcitabine in vitro is dependent on both concentration and exposure time.
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 animal mortality and minimal antitumor activity. However, when administered every third or fourth day at non-lethal doses, gemcitabine demonstrated substantial antitumor activity against a broad spectrum of murine tumors.
Mechanism of action
Intracellular metabolism and 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 effect of gemcitabine is mediated by two active metabolites—dFdCDP and dFdCTP—through inhibition of DNA synthesis. First, dFdCDP inhibits ribonucleotide reductase, the enzyme responsible for catalyzing the conversion of ribonucleotides into deoxyribonucleotides (including dCTP) required for DNA synthesis.
Inhibition of this enzyme leads to a reduction in the overall concentration of deoxyribonucleotides, particularly deoxycytidine triphosphate (dCTP). Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation).
Additionally, a small amount of gemcitabine may be incorporated into RNA. The reduction in intracellular dCTP concentration enhances the incorporation of gemcitabine triphosphate into the DNA chain. DNA polymerases, particularly epsilon DNA polymerase, 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, after which further DNA synthesis is completely halted ("masked chain termination"), ultimately leading to programmed cell death known as apoptosis.
Pharmacokinetics.
Following intravenous infusion of gemcitabine at doses ranging from 500 to 2592 mg/m² over durations of 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. After administration of a 1000 mg/m² dose 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 up to 1 hour post-infusion.
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: 91.9%). The volume of distribution in the peripheral compartment is 47.4 L/m² and is independent of sex. Plasma protein binding is negligible and clinically insignificant. The elimination half-life ranges from 42 to 94 minutes, depending on patient age and sex. With the recommended dosing regimen, complete elimination of gemcitabine occurs within 5 to 11 hours after the start of infusion. When administered once weekly, gemcitabine does not accumulate in the body.
Metabolism
Gemcitabine is rapidly metabolized by cytidine deaminase in the liver, kidneys, blood, and other tissues. Intracellular metabolism of gemcitabine produces mono-, di-, and triphosphate metabolites (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 detectable in plasma and urine.
Excretion
Systemic clearance ranges from 29.2 to 92.2 L/h/m², depending on age and sex (interindividual variability: 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. However, the lower clearance observed in women and men following administration of the recommended dose of 1000 mg/m² over 30 minutes does not necessitate dose reduction.
Renal excretion: Less than 10% of the drug is excreted unchanged.
Renal clearance ranges from 2 to 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% 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 between 30 mL/min and 80 mL/min) does not have a clinically significant or prolonged effect on the pharmacokinetics of gemcitabine.
Clinical characteristics.
Indications.
Bladder cancer. Gemcitabine Accord in combination with cisplatin is indicated for the treatment of patients with locally recurrent or metastatic bladder cancer.
Pancreatic cancer. Gemcitabine Accord is indicated for the treatment of patients with locally advanced or metastatic adenocarcinomas of the pancreas.
Non-small cell lung cancer. Gemcitabine Accord in combination with cisplatin is indicated as first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer. Gemcitabine Accord as monotherapy is indicated for the treatment of elderly patients and patients with a performance status of 2.
Ovarian cancer. Gemcitabine Accord in combination with carboplatin is indicated for the treatment of patients with locally advanced or metastatic epithelial ovarian carcinoma. Gemcitabine Accord 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.
Breast cancer. Gemcitabine Accord 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.
Breastfeeding period.
Special precautions.
Handling of the medicinal product
As with other cytotoxic agents, great care should be taken in the preparation and administration of the infusion solution. The preparation of the infusion solution should 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.
No specific interaction studies have been conducted.
Radiotherapy
Concurrent radiotherapy (together or ≤ 7 days after). Toxicity resulting from combined 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. Studies in which gemcitabine was administered at a dose of 1000 mg/m² for up to 6 weeks concurrently with thoracic radiotherapy in patients with non-small cell lung cancer have demonstrated significant toxicity, including severe and potentially life-threatening mucositis, particularly esophagitis and pneumonitis, especially in patients treated with high-dose radiotherapy (median treated 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, four times) and cisplatin (80 mg/m², twice) 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 revealed increased toxicity when gemcitabine is administered more than 7 days before or after radiotherapy, except in cases of "radiation recall." Data indicate that gemcitabine may be initiated after acute radiation effects have resolved or at least one week after radiotherapy.
Tissue damage in previously irradiated areas (e.g., esophagitis, colitis, and pneumonitis) has been reported following radiotherapy, both with concurrent and non-concurrent administration of gemcitabine.
Others
The 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.
Prolonging the infusion duration and increasing the dosing frequency increases toxicity.
Skin and subcutaneous tissues
Severe skin adverse reactions (SSARs) have been observed during gemcitabine therapy, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or lead to fatal outcomes. Patients should be informed about the signs and symptoms and closely monitored for skin reactions. Gemcitabine should be discontinued immediately upon the appearance of signs and symptoms suggestive of these reactions.
Hematological toxicity
Gemcitabine may suppress bone marrow function, manifesting as 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 withholding treatment or modifying the dose in the event of myelosuppression (see section "Dosage and administration"). 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 administered in combination with other chemotherapeutic agents.
Hepatic and renal function impairment
The drug should be used with caution in patients with hepatic or renal function impairment, as insufficient clinical data are available to recommend specific dosing for such patients (see section "Dosage and administration"). Administration of gemcitabine in cases of liver metastases, hepatitis, or history of alcoholism or hepatic cirrhosis may lead to increased hepatic dysfunction. Laboratory monitoring of renal and hepatic parameters (including virological testing) should be performed periodically.
Concomitant radiotherapy
Cases of toxicity have been reported during concomitant radiotherapy (administered simultaneously 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 as monotherapy or in combination with chemotherapeutic agents. Most patients who developed PRES while receiving gemcitabine experienced acute hypertension and epileptic seizures; other symptoms such as headache, lethargy, confusion, and visual loss may also occur. This condition (syndrome) is diagnosed by magnetic resonance imaging (MRI). Posterior reversible encephalopathy syndrome (PRES) is a reversible condition if detected promptly and managed with 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 should be exercised when administering 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 (see section "Adverse reactions"). With early detection and appropriate treatment, capillary leak syndrome is usually manageable, but fatal outcomes have been reported. This condition arises from increased systemic vascular permeability, leading to leakage of fluid and proteins from the intravascular space into the interstitium. Clinical manifestations 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, 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 symptoms associated with hemolytic-uremic syndrome (HUS) have been rarely observed in patients receiving gemcitabine (post-marketing data) (see section "Adverse reactions"). HUS is a potentially life-threatening condition. 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 levels. Renal failure may become irreversible even after discontinuation of therapy, and dialysis may be required.
Fertility
Fertility studies showed that gemcitabine caused hypospermatogenesis in male mice. Therefore, men receiving gemcitabine therapy should not plan to father children during and for at least 3 months after treatment. Due to the potential for loss of fertility associated with gemcitabine therapy, men are advised to consider sperm preservation before starting treatment (see section "Use during pregnancy or breastfeeding").
Sodium
Gemcitabine Accord, concentrate for solution for infusion, 100 mg/mL, contains 206 mg (9 mmol) of sodium per maximum daily dose (2250 mg). This should be taken into account when prescribing the drug to patients on a sodium-controlled diet.
Ethanol
Gemcitabine Accord, concentrate for solution for infusion, 100 mg/mL, contains 440 mg of anhydrous ethanol per 1 mL of concentrate. It may be harmful to patients with alcoholism. Caution should be exercised when administering to patients at risk, such as those with liver disease or epilepsy.
Potential effects on the central nervous system and other effects should also be considered.
Use during pregnancy or breastfeeding.
Women of reproductive potential / Contraception in men and women
Due to the genotoxic potential of gemcitabine, women of reproductive potential should use effective contraceptive methods during treatment and for at least 6 months after discontinuation of therapy.
Men should be advised to use effective contraception and refrain from fathering children during gemcitabine therapy and for at least 3 months after its discontinuation.
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. Patients should be made aware of the risks associated with gemcitabine therapy during pregnancy and should 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 animals showed that gemcitabine caused hypospermatogenesis. Therefore, men receiving gemcitabine therapy should not plan to father children during and for at least 3 months after treatment. Due to the potential for loss of fertility associated with gemcitabine therapy, men are advised to consider sperm preservation before starting treatment.
Ability to affect performance of skilled tasks such as 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 effect subsides.
Method of Administration and Dosage
Gemcitabine should be prescribed only by a physician experienced in the use of anticancer chemotherapeutic agents.
Recommended Doses
Bladder Cancer
Combination Therapy. Adults. The recommended dose of Gemcitabine Accord 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 recommended at a dose of 70 mg/m² on Day 1 after gemcitabine or on Day 2 of each 28-day cycle. This 4-week cycle is then repeated. Dose reduction from cycle to cycle or within a single cycle may be applied depending on the degree of toxicity experienced by the patient.
Pancreatic Cancer
Adults. The recommended dose of Gemcitabine Accord is 1000 mg/m² administered via intravenous infusion over 30 minutes. Administration should be repeated once weekly for 7 weeks, followed by a one-week break. Subsequent cycles consist of weekly infusions for 3 consecutive weeks, followed by a one-week break in the 4th week. Dose reduction from cycle to cycle or within a single cycle may occur depending on the degree of toxicity experienced by the patient.
Non-Small Cell Lung Cancer
Monotherapy. Adults. The recommended dose is 1000 mg/m² administered as a 30-minute intravenous infusion. Administration should be repeated once weekly for 3 weeks, followed by a one-week break. This 4-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 a recommended dose of 75–100 mg/m² once every 3 weeks of the cycle.
Breast Cancer
Combination Therapy. Adults. Gemcitabine Accord 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 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 combination of gemcitabine and paclitaxel, patients must have an absolute granulocyte count of at least 1500 (×10⁶/L).
Ovarian Cancer
Combination Therapy. Adults. Gemcitabine Accord in combination with carboplatin is recommended to be administered as follows: 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, after gemcitabine, carboplatin should be administered at a dose providing an 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 Dose Modification Due to Toxicity
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 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 the event of severe non-hematological toxicity (Grade III or IV), excluding nausea or vomiting, the dose of gemcitabine may be reduced or administration may be delayed in the presence of hematological toxicity at the physician’s discretion. Treatment should be withheld until, in the physician’s opinion, the toxicity has been resolved.
For dose modification of cisplatin, carboplatin, and paclitaxel in combination, refer to the respective Instructions for Medical Use of these medicinal products.
Dose Modification Related to Hematological Toxicity
At the Beginning of a Treatment Cycle
In patients receiving Gemcitabine Accord, platelet and granulocyte counts should be checked before each dose. The absolute granulocyte count prior to the start of a cycle must be at least 1500 (×10⁶/L), and platelet count must be at least 100,000 (×10⁶/L).
During the Treatment Cycle
If necessary, the dose of gemcitabine may be reduced or administration delayed in the presence of hematological toxicity according to the following grading:
| Dose modification of gemcitabine during the treatment cycle as indicated: 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 Accord (%) |
|
| > 1000 500–1000 < 500 |
and or or |
> 100000 50000–100000 < 50000 |
100 75 delay dose administration* |
*Avoid administration of the dose throughout the cycle until the absolute granulocyte count reaches at least 500 (×106/l) and platelets reach 50000 (×106/l).
| Dose modification of Gemcitabine Accord during the treatment cycle for indications: breast cancer in combination with paclitaxel |
|||
| Absolute neutrophil count (×10⁶/L) |
Platelet count (×10⁶/L) |
Percentage of standard dose of Gemcitabine Accord (%) |
|
| ≥ 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 granulocyte count reaches at least 1,500 (×10⁶/L) and platelet count reaches 100,000 (×10⁶/L).
| Dose modifications of Gemcitabine Accord during the treatment cycle for indications: ovarian cancer when used in combination with carboplatin |
|||
| Absolute neutrophil count (×10⁶/L) |
Platelet count (×10⁶/L) |
Percentage of standard dose of Gemcitabine Accord (%) |
|
| > 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 (×10^6/L) and platelets reach 100,000 (×10^6/L).
Dose modification due to hematological toxicity during subsequent cycles for all indications
The dose of Gemcitabine Accord must be reduced to 75% of the initial dose administered at the start of treatment in the event of the following manifestations of hematological toxicity:
- Absolute granulocyte count < 500×10^6/L for more than 5 days.
- Absolute granulocyte count < 100×10^6/L for more than 3 days.
- Febrile neutropenia.
- Platelet count < 25,000×10^6/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 resumed into another vein. The patient's condition must be carefully monitored after infusion.
Special patient groups
Patients with hepatic and renal impairment. Gemcitabine Accord should be administered with caution to patients with hepatic and renal impairment, as insufficient data from clinical studies are available to recommend precise dosing for such patients (see section "Special precautions for use").
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 necessary for elderly patients beyond those already recommended for all patients.
Instructions for solution preparation (and further dilution if necessary)
The concentrate for infusion solution of gemcitabine requires appropriate dilution before use. The concentration of gemcitabine in the concentrate for infusion solution differs from other gemcitabine products.
The concentrate must be diluted (100 mg/mL); otherwise, life-threatening overdose may occur.
The concentrate for infusion solution of gemcitabine must be diluted. The total amount of gemcitabine concentrate required for an individual patient should be diluted with sterile 0.9% sodium chloride solution to a final concentration of 0.1 to 9 mg/mL.
Dilution
The only approved diluent for diluting the sterile gemcitabine concentrate is 0.9% sodium chloride solution for injection (without preservatives).
- Aseptic techniques must be used when preparing gemcitabine for intravenous administration.
- The gemcitabine concentrate for infusion solution is a clear, colorless or slightly yellow solution with a gemcitabine concentration of 100 mg/mL. The total amount of gemcitabine concentrate required for an individual patient should be diluted with sterile 0.9% sodium chloride solution. The final diluted solution concentration, prepared using the maximum gemcitabine dose (~2.25 g), should be approximately 0.1 to 9 mg/mL. Concentrations of 4.5 mg/mL (achieved with a diluent volume of 500 mL) to 9 mg/mL (achieved with a diluent volume of 250 mL) correspond to an osmolarity of approximately 1000 mOsmol/kg to 1700 mOsmol/kg. The diluted solution is a clear, colorless or slightly yellowish solution.
- Preparation, storage, and administration of the diluted solution must be performed only with equipment and instruments that do not contain polyvinyl chloride (PVC).
Preparation of infusion solution
Gemcitabine, concentrate for infusion solution, contains 100 mg of gemcitabine per 1 mL of concentrate. The concentrate for solution must be diluted before use.
If vials have been stored at low temperatures, the required number of gemcitabine concentrate vials should be allowed to reach room temperature (up to 25°C) for 5 minutes before use. More than one vial of concentrate may be required to achieve the necessary patient dose.
The required amount of gemcitabine concentrate should be aseptically withdrawn using a calibrated syringe.
The required volume of gemcitabine concentrate must be added to an infusion bag containing 0.9% sodium chloride solution for infusion.
The contents of the infusion bag should be mixed by gentle agitation. Further dilution with the same diluent may be performed to achieve a final concentration of 0.1 to 9 mg/mL.
As with all parenteral medicinal products, the gemcitabine infusion solution should be visually inspected for particulate matter and discoloration prior to administration. The product must not be administered if particulate matter is observed (see section "Shelf life").
The gemcitabine infusion solution is intended for single use only. Unused product or waste material must be disposed of in accordance with current legislation.
Children.
Gemcitabine is not recommended for use in 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 5700 mg/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 treatment are nausea, with or without vomiting, elevated levels of liver transaminases (ALT and AST), as well as alkaline phosphatase, observed in approximately 60% of patients; proteinuria and hematuria were reported in approximately 50% of patients; dyspnea occurred in 10–40% of patients (the highest frequency was observed in patients with lung cancer); allergic skin rashes were observed in 25% of patients, and in 10% of cases they were accompanied by pruritus.
The frequency and severity of adverse reactions depend on the dose, rate of administration, and intervals between doses (see section "Special Instructions"). Dose-dependent adverse reactions include decreased levels of thrombocytes, leukocytes, and granulocytes (see section "Dosage and Administration").
Data from Clinical Studies
The table below lists adverse reactions observed during clinical trials. Within each frequency group, adverse reactions are listed in order of decreasing frequency.
Classification of adverse reaction frequencies: 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 determined from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.
| Organs and systems |
Frequency |
| Blood and lymphatic system disorders |
Very common
(Grade III neutropenia = 19.3%; Grade IV neutropenia = 6%) Bone marrow suppression is most commonly mild to moderate in severity and primarily affects granulocyte counts
Common
Very rare
|
| Immune system disorders |
Very rare
|
| Infections and infestations |
Common
Frequency unknown
|
| 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 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 and paclitaxel |
||||
| Number of patients (%) |
||||
| Paclitaxel monotherapy |
Combination therapy with gemcitabine and paclitaxel |
|||
| 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 4 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.
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 |
Combination therapy of gemcitabine with cisplatin |
|||
| 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) |
Combined use in ovarian cancer
| Grade III and IV adverse events with carboplatin monotherapy compared to combination therapy of gemcitabine with carboplatin |
||||
| Number of patients (%) |
||||
| Carboplatin |
Combination therapy of gemcitabine with carboplatin |
|||
| 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) |
The phenomenon of sensory neuropathy was also observed more frequently with combination therapy compared to carboplatin alone.
Reporting of suspected adverse reactions
Reporting of adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all cases of suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua.
Shelf life
3 years.
After solution preparation
Chemical and physical stability after opening the container and after dilution in 0.9% sodium chloride solution has been demonstrated for 3 days at 25°C and at 2–8°C.
From a microbiological standpoint, the infusion solution should be used immediately. If not used immediately, responsibility for the storage conditions and duration after opening the container and prior to use lies with the user, and under normal circumstances should not exceed 24 hours at 2–8°C, unless dilution has been carried out under controlled and validated aseptic conditions.
Storage conditions
Store in the original packaging in a light-protected place at a temperature not exceeding 25°C. Keep out of the reach of children.
After opening the vial prior to solution preparation
Each vial is intended for single use and should be used immediately after opening. If not used immediately, the storage duration and conditions are the responsibility of the user.
Incompatibilities
The medicinal product must not be mixed with other medicinal substances except 0.9% sodium chloride solution.
Packaging
2 ml (200 mg), 10 ml (1000 mg), 15 ml (1500 mg), 20 ml (2000 mg) in clear type I glass vials closed with grey rubber stoppers sealed with aluminium flip-off caps, № 1 in a cardboard box.
Prescription status Prescription only.
Manufacturer
Accord Healthcare Limited; Accord Healthcare Limited. Or Accord Healthcare Polska Sp. z o.o. Importer's Site / Accord Healthcare Polska Sp. z o.o. Magazyn Importera.
Manufacturer's address and location of its operations
Ground Floor, Sage House, 319 Pinner Road, Harrow, HA1 4HF, United Kingdom; Ground Floor, Sage house, 319 Pinner road, Harrow, HA1 4HF, United Kingdom. Or ul. Lutomierska 50, Pabianice, 95-200, Poland / ul. Lutomierska 50, Pabianice, 95-200, Poland.
Marketing Authorization Holder
Accord Healthcare Polska Sp. z o.o., Poland / Accord Healthcare Polska Sp. z o.o., Poland.
Complaints regarding poor quality of the medicinal product; issues relating to safety of use, improper use of the medicinal product, or complaints are accepted 24/7 via phone: +380993100335 or by email at: [email protected].
Address of the Marketing Authorization Holder 7 Tasmowa St., Warsaw, 02-677, Poland / 7 Tasmowa St., Warsaw, 02-677, Poland.