Gemtabin

Gemcitabine hydrochloride.

Each vial contains Gemcitabine Hydrochloride equivalent to: Gemcitabine, USP 200 mg or 1 g.

Pharmacology: Pharmacodynamics: Cytotoxic Activity in Cell Culture Models: Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells through the G1/S-phase boundary.
Cellular Metabolism and Mechanism of Action: Gemcitabine (dFdC) is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides.
The cytotoxic action of gemcitabine appears to be due to inhibition of DNA synthesis by 2 actions of dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase which is uniquely responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by dFdCDP causes a reduction in the concentrations of deoxynucleosides in general and especially in that of dCTP. Secondly, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation). Thus, the reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. Deoxyribonucleic acid polymerase epsilon is essentially unable to remove gemcitabine and repair the growing DNA strands. After gemcitabine is incorporated into DNA, 1 additional nucleotide is added to the growing DNA strands. After this addition, there is essentially a complete inhibition in further DNA synthesis (masked chain termination). After incorporation into DNA, gemcitabine then appears to induce the programmed cellular death process known as apoptosis.
Pharmacokinetics: Gemcitabine is rapidly cleared from plasma, principally by metabolism to the inactive metabolite, 2'-deoxy-2',2'-diflurouradine (dFdU). Less than 10% of an IV dose is recovered in urine as unchanged gemcitabine.
Gemcitabine and dFdU are the only compounds found in plasma and comprise 99% of the drug-related material recovered in urine. Gemcitabine plasma protein-binding is negligible. Population pharmacokinetic analyses of single- and multiple-dose studies show that the volume of distribution is significantly influenced by gender.
Systemic clearance is affected by age and gender. These effects result in differences in plasma gemcitabine concentration and in rate of elimination (t_1/2) from the systemic circulation. Systemic clearance ranged from approximately 30 L/hr/m² to approximately 90 L/hr/m². With recommended infusion time, t_1/2 ranged from 32-94 min, depending on age and gender.

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.
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.

Adults: Non-Small Cell Lung Cancer: Single-Agent Use: Gemcitabine HCl should be administered by intravenous infusion at a dose of 1000 mg/m² over 30 minutes once weekly for up to 3 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.
Combination Treatment: Two schedules have been investigated and the optimum schedule has not been determined. With the 4-week schedule, gemcitabine HCl should be administered intravenously at 1000 mg/m² over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered intravenously at 100 mg/m² on Day 1 after the infusion of gemcitabine HCl. With the 3-week schedule, gemcitabine HCl should be administered intravenously at 1250 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m² should be administered intravenously after the infusion of gemcitabine HCl on Day 1.
Pancreatic Cancer: Gemcitabine HCl should be administered by intravenous infusion at a dose of 1000 mg/m² over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.
Breast Cancer: Gemcitabine should be administered intravenously at a dose of 1,250 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m² on Day 1 as a 3-hour intravenous infusion before gemcitabine administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count 1500 x 10⁶/L and a platelet count ≥100,000 x 10⁶/L prior to each cycle.
Bladder Cancer: In combination treatment with cisplatin, gemcitabine HCl should be administered intravenously at 1000 mg/m² over 30 minutes on Days 1, 8, and 15 of each 28-day cycle, followed by a week of rest from treatment. In 28-day cycle, Cisplatin should be administered intravenously at 70 mg/m² on Day 1 after the infusion of gemcitabine HCl or Day 2. The 4- week cycle could be repeated. Before the chemotherapy, reduction of dosage and delay of prescription should be considered by the degree of patients' side effect. At the result of clinical test, combination treatment with 100 mg/m² of cisplatin may induce remarkable myelosuppression.
Patients receiving gemcitabine HCl should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines as follows. (See table.)

Click on icon to see table/diagram/image

Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine HCl should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.
Direction for Reconstitution: The recommended diluent for reconstitution of gemcitabine HCl is 0.9% Sodium Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration for gemcitabine HCl upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided.
To reconstitute, add 5 mL, 25 mL and 50 mL of 0.9% Sodium Chloride Injection to the 200 mg, 1 g and 2 g vials, respectively. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200-mg vial, 1.3 mL for the 1-g vial and 2.6 mL for the 2 g vial). The total volume upon reconstitution will be 5.26 mL, 26.3 mL and 52.6 mL respectively. Complete withdrawal of the vial contents will provide 200 mg, 1 g or 2 g of gemcitabine HCl. The appropriate amount of drug may be administered as prepared or further diluted with 0.9% Sodium Chloride Injection to concentrations as low as 0.1 mg/mL. Reconstituted gemcitabine HCl is a clear, colorless solution and is stable for 24 hours at controlled room temperature 20°C to 25°C. Discard unused portion. Solutions of reconstituted gemcitabine HCl should not be refrigerated, as crystallization may occur.
Caution should be exercised in handling and preparing gemcitabine HCl solutions. The use of gloves is recommended. If gemcitabine HCl solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug-related systemic toxicities (death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption.
Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

There is no known antidote for overdoses of gemcitabine HCl. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5.7 g/m² was administered by I.V. infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.

Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity.
This preparation is for intravenous use only. Patients receiving therapy with gemcitabine should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Gemcitabine can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia, and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy.
Gemcitabine should be used with caution in patients with preexisting renal impairment or hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency.
The patient should be cautioned that driving automobile, operating hazardous machinery or engaging in hazardous activities should not be undertaken during receiving the drug.
Use in Pregnancy: Gemcitabine HCl can cause fetal harm when administered to a pregnant woman.
Gemcitabine HCl has been shown to cause malformations and embryotoxicity in mice and rabbits. Pregnant women or women of childbearing potential should be advised to avoid becoming pregnant during therapy with gemcitabine HCl.
Use in Nursing Mothers: It is not known whether gemcitabine HCl or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from gemcitabine HCl in nursing infants, the mother should be warned and 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 and the potential risk to the infant.
Use in Children: The effectiveness of gemcitabine in pediatric patients has not been demonstrated. Gemcitabine was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m²/min for 360 minutes three times weekly followed by a one week rest period. Gemcitabine was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m²/min for 360 minutes three times weekly followed by a one week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial.
Use in Elderly: Gemcitabine clearance is affected by age. There is no evidence, however, that unusual dose adjustments are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly. In the randomized clinical trial of Gemcitabine in combination with carboplatin for recurrent ovarian cancer, 125 women treated with gemcitabine plus carboplatin were <65 years and 50 were ≥65 years. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. Overall, there were no substantial differences in toxicity profile of gemcitabine plus carboplatin based on age.

Use in Pregnancy: Gemcitabine HCl can cause fetal harm when administered to a pregnant woman.
Gemcitabine HCl has been shown to cause malformations and embryotoxicity in mice and rabbits.
Pregnant women or women of childbearing potential should be advised to avoid becoming pregnant during therapy with gemcitabine HCl.
Use in Nursing Mothers: It is not known whether gemcitabine HCl or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from gemcitabine HCl in nursing infants, the mother should be warned and 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 and the potential risk to the infant.

Hematologic: In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with gemcitabine, but <1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during gemcitabine therapy and dosage modified or suspended according to the degree of hematologic toxicity.
Hepatic: In clinical trials, gemcitabine HCl was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of exposure to gemcitabine HCl or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving gemcitabine HCl alone or in combination with other potentially hepatotoxic drugs.
Gastrointestinal: Nausea and vomiting were commonly reported (69%) but were usually of mild to moderate severity. Severe nausea and vomiting occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.
Respiratory: In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with gemcitabine HCl therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of gemcitabine HCl. The etiology of these effects is unknown. If such effects develop, gemcitabine HCl should be discontinued. Early use of supportive care measures may help ameliorate these conditions.
Renal: In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving Gemcitabine HCl in clinical trials. Four patients developed HUS on Gemcitabine HCl therapy, 2 immediately post-therapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine or BUN). Gemcitabine HCl therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required.
Allergic: Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemcitabine HCl should not be administered to patients with a known hypersensitivity to this drug.
Cardiovascular: During clinical trials, 2% of patients discontinued therapy with gemcitabine HCl due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease.
Others: Flu-like Symptoms: "Flu syndrome" was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms.
Infection: Infections were reported for 16% of patients. Sepsis was rarely reported (<1%).
Alopecia: Hair loss, usually minimal, was reported by 15% of patients.
Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported.
Less than 1% of patients discontinued due to edema.
Extravasation: Injection-site related events were reported for 4% of patients. There were no reports of injection site necrosis. Gemcitabine is not a vesicant.
Neurotoxicity: There was a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias.

Preserve in hermetic containers.
Store at temperatures not exceeding 30°C.

Cytotoxic Chemotherapy

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

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