Gemita RTU

Gemcitabine.

Each mL contains Gemcitabine Hydrochloride USP equivalent to Gemcitabine base 38 mg.
Gemcitabine HCl is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in alcohol and in polar organic solvents.
The chemical name for gemcitabine HCl is 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer). The empirical formula for gemcitabine HCl is C₉H₁₁F₂N₃O₄·HCl. It has a molecular weight of 299.66. The formulation is supplied in a sterile form for intravenous use only. Vials contain either 200 mg, 1 g, 1.4 g and 2.0 g of gemcitabine HCl (expressed as free base) as a sterile solution.
Excipients/Inactive Ingredients: Also contains Propylene Glycol, Polyethylene Glycol 400, Hydrochloric acid, Sodium hydroxide and Water for Injection.

PHARMACOLOGY: Mechanism of action: Gemcitabine, a pyrimidine analog, has a wide spectrum of antitumor activity. It is cell-cycle phase specific and kills the cells undergoing DNA synthesis in the S-phase. It also blocks the progression of cells through the G1/S-phases. Gemcitabine is metabolized intracellularly to two active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). The diphosphate of gemcitabine appears to be an effective inhibitor of ribonucleotide reductase and this may be irreversible. Ribonucleotide reductase inhibition results in depletion of cellular deoxyribo-nucleotide triphosphate pools. The effect of cellular depletion of deoxycytidine triphosphate is a self-potentiation of the cytotoxicity of gemcitabine as gemcitabine triphosphate (dFdCTP) competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine needs to be activated by deoxycytidine kinase and other kinases to its triphosphate, gemcitabine triphosphate, which can be incorporated into RNA and DNA. The latter effect is considered to be responsible for its antitumor effect and causes masked chain termination and inhibition of DNA repair. This effect may be of importance for combination with DNA interacting agents.
Pharmacokinetics: Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. In a radiolabeled study on gemcitabine in five patients who received a single 1000 mg/m²/30 minute infusion of drug, ninety two to ninety eight percent of the dose was recovered, almost entirely in the urine within one week's time. The inactive uracil metabolite, 2'-deoxy-2', 2'-difluorouridine (dFdU) and gemcitabine accounted for 99% of the excreted dose. The plasma protein binding is negligible for gemcitabine. Pharmacokinetic study of gemcitabine was carried out in 353 patients, with various solid tumors. The total gemcitabine dose varied from 500 to 3600 mg/m². Using the data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes) the pharmaco-kinetic parameters were derived. Combined single and multiple dose studies showed that duration of infusion, age and gender significantly influenced the volume of distribution and drug clearance of gemcitabine. Base on patient characteristics or the duration of infusion the differences in either clearance or volume of distribution result in changes in half-life and plasma concentrations. The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have not been assessed. In mononuclear cells, the half-life of the terminal phase for gemcitabine triphosphate ranges from 1.7 to 19.4 hours. The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells.

Non-Small Cell Lung Cancer: Gemcitabine is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung cancer.
Pancreatic Cancer: Gemcitabine is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine is indicated in patients previously treated with 5-FU.
Breast Cancer: Gemcitabine in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.
Bladder Cancer: Gemcitabine in combination with cisplatin is indicated for treatment of patients with bladder cancer.
Ovarian Cancer: Gemcitabine, alone or in combination with carboplatin, is indicated for the treatment of patients with recurrent epithelial ovarian carcinoma who have relapsed following platinum-based therapy.
Biliary Tract Cancer: Gemcitabine is indicated for treatment of patients with biliary tract cancer.
Cervical Cancer: Gemcitabine is indicated for treatment of patients with locally advanced cervical cancer in combination therapy with radiation and cisplatin.

Standard Dosing: Non small cell lung cancer: Single-agent use: Adults: The recommended dose of gemcitabine is 1,000 mg/m², given by 30 minutes intravenous infusion. This should be repeated once weekly for three weeks, followed by a one-week rest period. This four-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
Combination use with Cisplatin: Adults: Gemcitabine in combination with cisplatin has been investigated using two dosing regimens. One regimen used a three-week schedule and the other used a four-week schedule. The three-week schedule used gemcitabine 1,250 mg/m², given by 30 minutes intravenous infusion, on days 1 and 8 of each 21-day cycle. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
The four-week schedule used gemcitabine 1,000 mg/m², given by 30 minutes intravenous infusion, on days 1, 8, 15 of each 28 days cycle. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
Pancreatic Cancer: Adults: The recommended dose of gemcitabine is 1,000 mg/m², given by 30 minutes intravenous infusion. This should be repeated once weekly for up to 7 weeks followed by a week of rest. Subsequent cycles should consist of injections once weekly for 3 consecutive weeks out of every 4 weeks. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patients.
Breast Cancer: Combination use: Adults: Gemcitabine in combination with paclitaxel: paclitaxel (175 mg/m²) administered on Day 1 over approximately 3 hours as an intravenous infusion, followed by gemcitabine (1250 mg/m²) as a 30-minute intravenous infusion on Days 1 and 8 of each 21-day cycle. Dose reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient. Patients should have an absolute granulocyte count of at least 1,500 (x 10⁶/L) prior to initiation of gemcitabine+paclitaxel combination.
Bladder Cancer: Combination use: Adults: The recommended dose of gemcitabine is 1,000 mg/m², given by 30-minutes intravenous infusion. The dose should be given on Days 1, 8 and 15 of each 28-day cycle in combination with cisplatin. Cisplatin is given at a recommended dose of 70 mg/m² on Day 1 following gemcitabine or Day 2 of each 28-day cycle. This four-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patients. A clinical trial showed more myelosupression when cisplatin was used in doses of 100 mg/m².
Ovarian Cancer: Single-agent use: Adults: The recommended dose of gemcitabine is 800-1250 mg/m², given by a 30-minute intravenous infusion. The dose should be given on Days 1, 8 and 15 of each 28-day cycle. This four-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
Combination use: Adults: Gemcitabine in combination with carboplatin is recommended using gemcitabine 1000 mg/m² administered on Days 1 and 8 of each 21-day cycle as a 30-minute intravenous infusion.
After gemcitabine, carboplatin will be given on Day 1 consistent with a target AUC of 4.0 mg/ml·min. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
Biliary Tract Cancer: Single-agent use: Adults: The recommended dose of gemcitabine is 1000 mg/m², given by 30-minute intravenous infusion. This should be repeated once weekly for three weeks, followed by a one-week rest period. This four-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
Combination use: Adults: Gemcitabine in combination with cisplatin is recommended using cisplatin 70 mg/m² on Day 1 as an intravenous infusion, followed by gemcitabine 1250 mg/m² administered on Days 1 and 8 of each 21-day cycle, given as a 30-minute intravenous infusion. This three-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
Cervical Cancer: Combination therapy using radiation and cisplatin: Gemcitabine in combination with cisplatin is recommended using 40 mg/m² followed immediately by gemcitabine 125 mg/m² by IV infusion once weekly for 6 weeks (days 1, 8, 15, 22, 29 and 36), 1 to 2 hr before concurrent pelvic radiation therapy. Radiation therapy should be 50.4 Gy external beam radiation delivered to the entire field of radiation in 28 fractions, i.e. 1.8 Gy/day, 5 days/week over the 6 weeks of chemotherapy, followed by 2 adjuvant 21-day cycles of gemcitabine (1000 mg/m² on day 1 and day 8) plus cisplatin (50 mg/m² on day 1 of each cycle).
Dose Modification: Recommended gemcitabine dose modifications for myelosuppression are described in the following tables. (See Tables 1-4.)

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Dose Modifications for Non-Hematologic Adverse Reactions: Permanently discontinue gemcitabine for any of the following: Unexplained dyspnea or other evidence of severe pulmonary toxicity; Severe hepatic toxicity; Hemolytic-Uremic Syndrome or severe renal impairment; Capillary Leak Syndrome; Posterior reversible encephalopathy syndrome.
Withhold gemcitabine or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological adverse reactions until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.
Preparation and Administration Precautions: Exercise caution and wear gloves when preparing Gemcitabine solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.
Instructions for dilution: The approved diluent for dilution of Gemcitabine Injection 38 mg/ml is sodium chloride 9 mg/ml (0.9%) solution for injection (without preservative).
Total quantity of Gemcitabine Injection required for an individual patient must be diluted, before use, to at least 500 ml of sodium chloride 9 mg/ml solution for injection to obtain clinically relevant concentrations. Further dilution with the same diluent can be done.
Based on the recommended dose (1000 mg/m² and 1250 mg/m²) and body surface area (between 1.0 m² to 2.0 m²) a concentration range of 2 mg/ml to 5 mg/ml is obtained.
The osmolality and pH range of the diluted injection is also provided for reference. (See Table 5.)

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The following instructions for dilution should be strictly followed in order to avoid adverse events.
1. Use aseptic technique during dilution of gemcitabine for intravenous infusion administration.
2. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer.
Shelf life after dilution: Chemical and physical in use stability after dilution in 0.9%w/v sodium chloride solution at concentration of 0.1 mg/ml, 1 mg/ml and 25 mg/ml has been demonstrated for 7 days at 2°C to 8°C or at 25°C.
Additional in use stability after dilution in 0.9%w/v sodium chloride solution at concentration of 0.1 mg/ml and 5 mg/ml has been demonstrated for 7 days at 2°C to 8°C or at 30°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

There is no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m² was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study. In the event of suspected overdose, monitor with appropriate blood counts and provide supportive therapy, as necessary.

Gemcitabine is contraindicated in patients hypersensitive to the drug.

Schedule-dependent Toxicity: In clinical trials evaluating the maximum tolerated dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is influenced by the length of the infusion.
Myelosuppression: Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with gemcitabine as a single agent and the risks are increased when gemcitabine is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving gemcitabine in combination with another drug.
Pulmonary Toxicity and Respiratory Failure: Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine. Permanently discontinue gemcitabine in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe pulmonary toxicity.
Hemolytic Uremic Syndrome: Hemolytic Uremic Syndrome to include fatalities from renal failure or the requirement for dialysis can occur in patients treated with gemcitabine. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS. Serious cases of thrombotic microangiopathy other than HUS have been reported with gemcitabine.
Assess renal function prior to initiation of gemcitabine and periodically during treatment. Consider the diagnosis of HUS in patients who develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN). Permanently discontinue gemcitabine in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy.
Hepatic Toxicity: Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs. Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of gemcitabine and periodically during treatment. Discontinue gemcitabine in patients that develop severe liver injury.
Exacerbation of Radiation Therapy Toxicity: Gemcitabine is not indicated for use in combination with radiation therapy.
Concurrent (given together or ≤7 days apart): Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which gemcitabine was administered at a dose of 1000 mg/m² to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation.
Non-concurrent (given >7 days apart): Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who received gemcitabine after prior radiation.
Capillary Leak Syndrome: Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents. Discontinue gemcitabine if CLS develops during therapy.
Posterior Reversible Encephalopathy Syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI) and discontinue gemcitabine if PRES develops during therapy.
Carcinogenicity, Mutagenicity and Impairment of Fertility: Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay.
Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m² basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the human dose on a mg/m² basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m² basis).
Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (approximately 0.005 times the recommended human dose on a mg/m² basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 0.002 times the recommended human dose on a mg/m² basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays.
Renal Impairment: No clinical studies have been conducted with gemcitabine in patients with decreased renal function. Use with caution in patients with preexisting renal impairment.
Hepatic Impairment: No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function. Use with caution in patients with preexisting hepatic impairment.
Administration to patients with concurrent liver metastases or a history of alcoholism, hepatitis, or liver cirrhosis may lead to exacerbation of the underlying hepatic function impairment.
Gender: Gemcitabine clearance is affected by gender. The lower clearance in women results in higher concentrations of gemcitabine for any given dose.
Use in Pregnancy & Lactation: Embryofetal Toxicity: Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months following the final dose.
Pregnancy: Category D: Gemcitabine can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking gemcitabine, the patient should be apprised of the potential hazard to a fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from gemcitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating gemcitabine.
Contraception: Gemcitabine can cause fetal harm when administered to a pregnant woman.
Females: Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose of gemcitabine.
Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months after the final dose.
Infertility: Males: Based on animal studies, gemcitabine may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.
Use in Children: The safety and effectiveness of gemcitabine have not been established in pediatric patients.
Use in the Elderly: Gemcitabine clearance is affected by age, however there are no recommended dose adjustments based on patients' age.

Embryofetal Toxicity: Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months following the final dose.
Pregnancy: Category D: Gemcitabine can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking gemcitabine, the patient should be apprised of the potential hazard to a fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from gemcitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating gemcitabine.
Contraception: Gemcitabine can cause fetal harm when administered to a pregnant woman.
Females: Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose of gemcitabine.
Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months after the final dose.
Infertility: Males: Based on animal studies, gemcitabine may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.

Gemcitabine has been used in a wide variety of malignancies, both as a single-agent and in combination with other cytotoxic drugs.
The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity; Schedule-Dependent Toxicity; Myelosuppression; Pulmonary Toxicity and Respiratory Failure; Hemolytic Uremic Syndrome; Hepatic Toxicity; Exacerbation of Radiation Therapy Toxicity; Capillary Leak Syndrome; Posterior Reversible Encephalopathy Syndrome.
Single-Agent Use: Gemcitabine as a single agent administered at doses between 800 mg/m² to 1250 mg/m² over 30 minutes intravenously, once weekly, in patients with a variety of malignancies. The most common adverse reactions of single-agent gemcitabine are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Adverse reactions resulting in discontinuation of gemcitabine in patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension), anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.
Additional adverse reactions include the following: Transfusion requirements: Red blood cell transfusions; platelet transfusions.
Edema: Edema, peripheral edema, generalized edema.
Flu-like Symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia, insomnia, rhinitis, sweating, and/or malaise.
Infection: Sepsis.
Extravasation: Injection-site reactions.
Allergic: Bronchospasm; anaphylactoid reactions.
Other Adverse Reactions: These events have occurred after gemcitabine single-agent use and gemcitabine in combination with other cytotoxic agents.
Cardiovascular: Congestive heart failure and myocardial infarction have been observed very rarely with the use of gemcitabine. Arrhythmias, predominantly supraventricular in nature, have been observed very rarely.
Vascular Disorders: Clinical signs of peripheral vasculitis and gangrene have been observed very rarely, capillary leak syndrome has also been observed.
Nervous System Disorders: Posterior reversible encephalopathy syndrome (PRES) has been observed.
Skin: Allergic skin rash frequently associated with pruritus and alopecia are commonly occurred.
Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely observed. Severe skin reactions, including desquamation and bullous skin eruptions, ulceration, vesicle and sore formation have also been observed rarely. Toxic epidermal necrolysis, Stevens-Johnson Syndrome have been observed very rarely.
Hepatic: Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been observed rarely. Serious hepatotoxicity including liver failure and death has been observed very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs.
Pulmonary: Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been observed rarely following one or more doses of gemcitabine administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last gemcitabine dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy.
Renal: Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been observed following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely observed. The majority of the cases of renal failure leading to death are due to HUS.
Injury, Poisoning, and Procedural Complications: Radiation recall reactions and radiation toxicity have been observed.
Stomatitis and ulceration of the mouth has also been commonly observed.
The following adverse reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and lymphatic system: Thrombotic microangiopathy (TMA).
Cardiovascular: Congestive heart failure, myocardial infarction, Arrhythmias, supraventricular arrhythmias.
Vascular Disorders: Peripheral vasculitis, gangrene, and capillary leak syndrome.
Skin: Cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skin eruptions.
Hepatic: Hepatic failure, hepatic veno-occlusive disease.
Pulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), pulmonary eosinophilia.
Nervous System: Posterior reversible encephalopathy syndrome (PRES).

No drug interaction studies have been conducted.

HANDLING AND DISPOSAL: The normal safety precautions for cytostatic agents must be observed when preparing and disposing of the infusion solution. Pregnant personnel should not handle the product. Handling of the Injection should be done in a safety box and protective coats and gloves should be used. If no safety box is available, the equipment should be supplemented with a mask and protective glasses.
If the preparation comes into contact with the eyes, this may cause serious irritation. The eyes should be rinsed immediately and thoroughly with water. If there is lasting irritation, a doctor should be consulted. If the solution is spilled on the skin, rinse thoroughly with water.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store below 30°C. Do not refrigerate or freeze.

Cytotoxic Chemotherapy

L01BC05 - gemcitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

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