Vizgem
UkraineTable of Contents
INSTRUCTIONS for medical use of the medicinal product VIZGEM (VISGEM)
Composition:
Active substance: gemcitabine;
1 vial contains gemcitabine hydrochloride equivalent to gemcitabine 200 mg or 1000 mg;
Excipients: mannitol (E 421), sodium acetate, sodium hydroxide.
Pharmaceutical form. Lyophilisate for solution for infusion.
Main physicochemical properties: white lyophilized mass.
Pharmacotherapeutic group. Antineoplastic agents. Pyrimidine analogues. ATC code L01BC05.
Pharmacological Properties.
Pharmacodynamics.
Cytotoxic activity in cell cultures.
Gemcitabine demonstrates significant cytotoxic activity against various types of human cancer cells and cultured murine cancer cells. Gemcitabine exhibits cell-cycle phase specificity, primarily killing cells undergoing DNA synthesis (S-phase), and under certain conditions, blocks cell progression through the G1/S phase 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 administration schedule. Daily administration of gemcitabine resulted in high animal lethality 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.
Gemcitabine (dFdC) is a pyrimidine antimetabolite that is intracellularly metabolized by deoxycytidine kinase into active difluorodeoxycytidine diphosphate (dFdCDP) and trifluorodeoxycytidine 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 catalyzing the formation of deoxyribonucleotide triphosphates (dCTP) required for DNA synthesis. This leads to a reduction in the overall concentration of deoxyribonucleosides, particularly dCTP. Second, dFdCTP competes with dCTP and incorporates into DNA.
Additionally, small amounts of gemcitabine may be incorporated into RNA. The reduction in intracellular dCTP concentration facilitates the incorporation of dFdCTP into the growing DNA chain. The epsilon-DNA polymerases are unable to remove gemcitabine or repair the DNA chain. After one additional nucleotide is added to the DNA strand following the incorporation of gemcitabine metabolites, further DNA synthesis is completely inhibited, leading to programmed cell death known as apoptosis.
Pharmacokinetics.
The pharmacokinetics of gemcitabine have been studied in seven clinical trials involving 353 patients, including 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.
Peak plasma concentrations (measured within 5 minutes after 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 an additional hour.
Distribution.
The volume of distribution in central circulation was 12.4 L/m² in women and 17.5 L/m² in men (inter-individual variability: 91.9%).
The volume of distribution in peripheral circulation was 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 pharmacologically 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 both 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 difference, clearance in both sexes decreases with age. At the recommended dose of 1000 mg/m² administered as a 30-minute infusion, 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: 2–7 L/h/m².
Elimination half-life ranges from 42 to 94 minutes, depending on age and sex. After administration at the recommended dose, elimination of gemcitabine is practically complete within 5–11 hours after the start of infusion. When administered once weekly, gemcitabine does not accumulate.
The total amount of drug excreted within one week is 92–98%, of which 99% is excreted in urine, primarily as dFdU, and 1% of the dose is excreted in feces.
Kinetics of dFdCTP.
This metabolite is detectable in peripheral blood mononuclear cells.
The terminal elimination half-life ranges from 0.7 to 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. When plasma gemcitabine concentrations exceed 5 µg/mL, dFdCTP concentrations in mononuclear cells do not increase further, indicating saturation of the metabolic pathway. After administration of 1000 mg/m² over 30 minutes, initial plasma concentrations exceed 5 µg/mL approximately 30 minutes after the end of infusion and remain above 0.4 µg/mL for the subsequent hour.
Kinetics of dFdU.
Peak plasma concentrations (measured 3–15 minutes after completion of a 1000 mg/m² dose over 30 minutes) range 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 is triphasic, 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 central circulation: 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).
Renal 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 indicates that the pharmacokinetics of both gemcitabine and paclitaxel remain 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 or prolonged effect on the pharmacokinetics of gemcitabine.
Clinical characteristics.
Indications.
Cholangiocarcinoma. Gemcitabine is indicated for the treatment of patients with cholangiocarcinoma.
Bladder cancer. Gemcitabine in combination with cisplatin is indicated for the treatment of patients with locally advanced or metastatic bladder cancer.
Breast cancer. Gemcitabine in combination with paclitaxel is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer after prior adjuvant/neoadjuvant chemotherapy. An anthracycline should be administered prior to chemotherapy, unless contraindicated.
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. Gemcitabine as monotherapy is indicated for the treatment of elderly patients and patients with a performance status of 2.
Ovarian cancer. Gemcitabine in combination with carboplatin is indicated for the treatment of patients with locally advanced or metastatic epithelial ovarian carcinoma. Gemcitabine is indicated for the treatment of patients with recurrent epithelial ovarian carcinoma after a remission period of at least 6 months following prior first-line platinum-based therapy.
Pancreatic cancer. Gemcitabine is indicated for the treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Breast-feeding period.
Safety precautions.
Preparation of infusion solution.
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 types of interactions.
Radiotherapy.
Concomitant radiotherapy (within or ≤ 7 days). Toxicity associated with combined modality therapy depends on multiple factors, including the dose of gemcitabine, frequency of infusions, radiation dose, technique used, and volume and site of irradiation.
Gemcitabine has radiosensitizing activity. When gemcitabine was administered at a dose of 1000 mg/m² 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, particularly esophagitis and pneumonitis, especially in patients treated with high-dose radiotherapy (median treatment volume of 4,795 cm³). Subsequent studies have suggested that lower doses of gemcitabine should be used with concomitant 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, 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-concomitant 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." Data indicate that gemcitabine may be initiated after acute radiation effects have subsided or at least one week after radiotherapy.
Tissue damage in previously irradiated areas (e.g., esophagitis, colitis, and pneumonitis) has been reported with both concomitant and non-concomitant administration of gemcitabine.
Others.
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 infusion duration and increased dosing frequency may enhance toxicity.
Hematologic toxicity.
Gemcitabine can suppress bone marrow function, manifesting as leukopenia, thrombocytopenia, and anemia.
Patients receiving gemcitabine require monitoring of platelet, white blood cell, and granulocyte counts prior to each dose. The dose of Vizgem may be reduced or administration delayed in case of bone marrow suppression (myelosuppression). However, myelosuppression is usually transient and most often does not require dose reduction or discontinuation of therapy.
Peripheral blood cell counts may continue to decrease even after discontinuation of gemcitabine therapy. Treatment 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 drugs.
Hepatic impairment. The drug should be used with caution in patients with hepatic or renal impairment, as insufficient clinical data are available to recommend specific dosing for such patients. Administration of gemcitabine in the presence of liver metastases, hepatitis, history of alcoholism, or hepatic cirrhosis may lead to worsening of hepatic insufficiency. Periodic laboratory assessment of renal and hepatic function (including virological testing) should be performed.
Concomitant radiotherapy.
Toxicity has been reported during concomitant radiotherapy (administered together or ≤7 days after gemcitabine).
Live vaccines.
Administration of the yellow fever vaccine and other live attenuated vaccines is not recommended in patients receiving gemcitabine therapy.
Posterior reversible encephalopathy syndrome (PRES).
Cases of posterior reversible encephalopathy syndrome (PRES), potentially with severe consequences, have been reported in patients receiving gemcitabine 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 included headache, lethargy, confusion, and visual disturbances.
This condition (syndrome) is diagnosed by magnetic resonance imaging (MRI). Posterior reversible encephalopathy syndrome (PRES) is a reversible condition with appropriate supportive therapy. If PRES develops during gemcitabine therapy, treatment should be discontinued and supportive measures initiated, including blood pressure control and anticonvulsant therapy.
Cardiovascular system.
Due to the risk of cardiac or vascular disorders associated with gemcitabine use, special caution is required when prescribing Vizgem to patients with a history of cardiovascular disease.
Capillary leak syndrome.
Capillary leak syndrome has been reported in patients receiving gemcitabine as monotherapy or in combination with other chemotherapeutic agents. With early detection and appropriate therapy, capillary leak syndrome is usually treatable, but fatal outcomes have been reported. This condition arises from increased systemic vascular permeability, resulting in leakage of fluid and proteins from the intravascular space into the interstitium. Reported clinical signs include generalized edema, weight gain, hypoalbuminemia, severe hypotension, acute renal failure, and pulmonary edema. Drug administration 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 Vizgem therapy should be considered. Prompt symptomatic intervention may improve the condition.
Urinary and reproductive system.
Clinical data related to hemolytic-uremic syndrome (HUS) have been rarely reported in patients receiving gemcitabine. Drug administration should be discontinued at the first signs of microangiopathic hemolytic anemia, such as rapid decline in hemoglobin 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.
Fertility.
Fertility studies in mice showed that gemcitabine causes hypospermatogenesis in males. Therefore, men receiving gemcitabine therapy should avoid planning conception during treatment and for 6 months after therapy. Due to the potential for fertility loss associated with gemcitabine therapy, men are advised to consult specialists regarding sperm cryopreservation prior to starting treatment.
Preclinical data indicate that gemcitabine is mutagenic in in vitro mutagenicity tests and in vivo micronucleus tests in bone marrow cells.
Sodium.
The medicinal product contains sodium. This should be taken into account for patients on a sodium-restricted diet.
Severe cutaneous adverse reactions (SCARs), 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 fatal. Patients should be informed about the signs and symptoms and closely monitored for skin reactions. Gemcitabine should be discontinued immediately upon appearance of signs or symptoms suggestive of these reactions.
Use during pregnancy or breastfeeding.
Pregnancy.
There are no adequate data on the use of gemcitabine in pregnant women. Animal studies have shown reproductive toxicity. Considering the animal study results and the mechanism of action, gemcitabine should not be used during pregnancy unless clearly necessary. Women should be advised not to become pregnant during gemcitabine therapy and to inform their physician if they become pregnant while receiving gemcitabine.
Breastfeeding.
It is unknown whether gemcitabine is excreted in human milk, and adverse reactions in breastfed infants cannot be excluded. Therefore, breastfeeding should be discontinued during gemcitabine therapy.
Fertility.
Fertility studies in mice showed that gemcitabine causes hypospermatogenesis in males. Therefore, men receiving gemcitabine therapy should avoid planning conception during treatment and for 6 months after therapy. Due to the potential for fertility loss associated with gemcitabine therapy, men are advised to consult specialists regarding sperm cryopreservation 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 on the ability to drive or operate machinery. Since Vizgem may cause mild to moderate drowsiness, particularly when combined with alcohol, patients should avoid operating technical equipment or driving until this effect subsides.
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 of Vizgem 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 given at the recommended dose of 70 mg/m² on day 1 after Vizgem or on day 2 of each 28-day cycle. This 4-week cycle is then repeated. Dose reduction within or between cycles may be applied depending on the degree of toxicity experienced by the patient.
Pancreatic cancer.
Adults. The recommended dose of Vizgem is 1000 mg/m² administered as a 30-minute intravenous infusion once weekly for 7 weeks, followed by a one-week break. Subsequent cycles consist of weekly infusions for 3 consecutive weeks with a one-week break every 4th week. Dose reduction within or between cycles 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 once weekly for 3 weeks, followed by a one-week break. This 4-week cycle is repeated. Dose reduction within or between cycles 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 drug dose may be reduced within or between cycles depending on the degree of toxicity experienced by the patient. Cisplatin should be administered at the recommended dose of 75–100 mg/m² once every 3 weeks of the cycle.
Breast cancer.
Combination therapy. Adults. Vizgem 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 of the drug may be reduced within or between cycles 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 1,500 (×10⁶/L).
Ovarian cancer.
Combination therapy. Adults. Vizgem 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 Vizgem, carboplatin should be administered at a dose providing an AUC of 4 mg/mL*min. The drug dose may be reduced within or between cycles depending on the degree of toxicity experienced by the patient.
Bile duct cancer.
Monotherapy. Adults. The recommended dose of Vizgem is 1000 mg/m² to be administered intravenously over 30 minutes. Infusion should be given once weekly for 3 consecutive weeks, followed by a one-week break. This 4-week cycle should be repeated. Dose reduction within or between cycles may occur depending on the extent of toxicity experienced by the patient.
Combination therapy. Adults. Vizgem in combination with cisplatin: cisplatin 70 mg/m² is recommended to be administered on day 1 of the cycle via intravenous infusion, followed by Vizgem at a dose of 1250 mg/m². Vizgem should be administered on days 1 and 8 of each 21-day cycle via a 30-minute intravenous infusion. This 3-week cycle should be repeated. Dose reduction within or between cycles may be applied depending on the degree of toxicity experienced by the patient.
Toxicity Monitoring and Dose Modification Related to Toxicity.
Dose modification related to non-hematological toxicity.
Periodic physical examinations and monitoring of kidney and liver function are required to detect non-hematological toxicity. Dose reduction within or between cycles may be performed depending on the degree of toxicity experienced by the patient.
In general, in the event of severe non-hematological toxicity (Grade III or IV), except for nausea or vomiting, the dose of Vizgem 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.
Dose modification related to hematological toxicity.
At the beginning of a treatment cycle.
In patients receiving Vizgem, 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 1,500 (×10⁶/L), and platelet count must be at least 100,000 (×10⁶/L).
During the treatment cycle.
If necessary, the dose of Vizgem may be reduced or administration delayed in the presence of hematological toxicity according to the following grading:
| Dose modification of Vyzgeim 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 (x106/L) |
Platelet count (x106/L) |
Percentage of standard Vyzgeim dose (%) |
|
| > 1000 500–1000 < 500 |
and or or |
> 100000 50000–100000 < 50000 |
100 75 delay dose* |
*Dosing should be withheld during the cycle until the absolute granulocyte count reaches at least 500 (x10⁶/L) and platelets reach 50,000 (x10⁶/L).
| Dose modification of Vizhem 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 Vizhem (%) |
|
| > 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 initiated on day 1 of the next cycle, as soon as the absolute granulocyte count reaches at least 1500 (x10⁶/L) and platelets reach 100,000 (x10⁶/L).
| Dose modification of Vyzgeim 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 Vyzgeim dose (%) |
|
| > 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, once the absolute neutrophil count reaches at least 1500 (x106/L) and platelet count reaches 100,000 (x106/L).
Dose modification due to hematological toxicity during subsequent cycles, for all indications.
The dose of Vizgem must 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 x 106/L for more than 5 days.
- Absolute neutrophil count < 100 x 106/L for more than 3 days.
- Febrile neutropenia.
- Platelet count < 25,000 x 106/L.
- Delay of cycle due to toxicity for more than 1 week.
Method of administration.
Vizgem 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. Careful monitoring of the patient is required after infusion.
Special patient groups.
Patients with hepatic and renal impairment. The drug should be administered with caution in patients with hepatic and renal impairment.
Elderly patients (˃65 years). The drug is well tolerated in patients aged 65 years and older. There is no reason to assume that dose adjustments are required for elderly patients beyond those 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.
Instructions for solution preparation (and further dilution, if necessary). The only tested solvent for reconstitution of the drug is 0.9% sodium chloride injection solution without preservatives.
According to solubility data, the maximum concentration of Vizgem after solution preparation is 40 mg/mL. Reconstitution at concentrations exceeding 40 mg/mL may result in incomplete dissolution of the drug and 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 at least 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 (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 volume of lyophilisate displacement. Shake to dissolve. The prepared solution may be further diluted with 0.9% sodium chloride injection solution without preservatives. The appropriate amount of the medicinal product can be administered immediately after preparation or further diluted with 0.9% sodium chloride injection solution. The resulting solution may be clear or slightly yellowish.
- Parenteral preparations must be visually inspected for particulate matter and discoloration prior to administration. If particulate matter is present, the solution must not be used. Any unused portions of the medicinal product or waste must be destroyed in accordance with applicable legislation.
Children.
Gemcitabine is not recommended for use in children (age < 18 years) due to insufficient information on safety and efficacy of treatment in this patient group.
Overdose.
There is no known antidote for gemcitabine overdose.
Clinically tolerable toxicity was observed with doses up to 5700 mg/m2 administered as a 30-minute intravenous infusion every 2 weeks.
In case of suspected overdose, patient monitoring and appropriate blood tests should be performed, and symptomatic therapy should be administered if necessary.
Adverse reactions.
The most commonly reported adverse reactions associated with gemcitabine therapy include nausea, with or without vomiting, and 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 (with the highest frequency observed in patients with lung cancer); allergic skin rashes were observed in 25% of patients, and in 10% of cases were accompanied by pruritus.
The frequency and severity of adverse reactions depend on the dose, rate of infusion, and intervals between doses. Dose-dependent adverse reactions include decreased levels of platelets, leukocytes, and granulocytes.
The following table of adverse reactions and their frequencies was obtained from clinical studies of gemcitabine. Within each category, adverse reactions are listed in decreasing order of frequency according to the following classification: 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).
| Organs and systems |
Frequency |
| 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
|
| Infections and infestations |
Common
Unknown
|
| Immune system disorders |
Very rare
|
| Metabolism and nutrition disorders |
Common
|
| Nervous system disorders |
Common
Uncommon
Very rare
|
| Cardiac and vascular disorders |
Uncommon
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
Unknown
|
| Musculoskeletal and connective tissue disorders |
Common
|
| Renal and urinary disorders |
Very common
Uncommon
|
| General disorders and administration site conditions |
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. Fatigue and febrile neutropenia are observed more frequently with the combination of gemcitabine and paclitaxel. Fatigue, not associated with anemia, usually resolves after the first cycle of therapy.
| Adverse events of Grade III and IV with paclitaxel monotherapy compared to combination therapy of gemcitabine with paclitaxel |
||||
| Number of patients (%) |
||||
| Paclitaxel monotherapy (N=259) |
Combination therapy of gemcitabine with 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.
| Grade III and IV adverse events with MVB (methotrexate, vinblastine, doxorubicin, cisplatin) compared to combination therapy of gemcitabine with cisplatin |
||||
| Number of patients (%) |
||||
| MVB 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 |
||||
| 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 used alone.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children. Do not freeze.
Incompatibilities.
Vizgem must be reconstituted only using sterile 0.9% sodium chloride injection solution without preservatives. Compatibility with other medicinal products has not been studied.
Packaging.
1 vial of lyophilisate per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Venus Remedies Limited.
Manufacturer's address and location of operations.
Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh 173205, India.