Gemita

Gemcitabine hydrochloride.

Gemcitabine HCL is a nucleoside analogue 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 ethanol and polar organic solvents.
Gemcitabine for Injection USP 200 mg: Each vial contains: Gemcitabine hydrochloride USP equivalent to gemcitabine 200 mg, mannitol USP 200 mg, sodium acetate trihydrate USP 12.5 mg, hydrochloric acid USNF and/or sodium hydroxide USNF to adjust pH.
Gemcitabine for Injection USP 1 g: Each vial contains: Gemcitabine hydrochloride USP equivalent to gemcitabine 1.0 gm, mannitol USP 1.0 gm, sodium acetate trihydrate USP 62.5 mg, hydrochloric acid USNF and/or sodium hydroxide USNF to adjust pH.
Gemcitabine for Injection USP 1.4 g: Each vial contains: Gemcitabine hydrochloride USP equivalent to gemcitabine 1.4 gm, mannitol USP 1.4 gm, sodium acetate trihydrate USP 87.5 mg, hydrochloric acid USNF and/or sodium hydroxide USNF to adjust pH.
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 and 1.4 g of gemcitabine HCl (expressed as free base) as a sterile lyophilized powder.
Excipients/Inactive Ingredients: Mannitol, sodium acetate trihydrate, hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

Pharmacology: Pharmacodynamics: 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 deoxyribonucleotide 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 infusion (<70 minutes) and long infusions (70 to 285 minutes) the pharmacokinetic 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.
Clinical Studies: Non-Small Cell Lung Cancer (NSCLC): The use of gemcitabine in combination with cisplatin as first line treatment was established by two randomized clinical studies in patients with locally advanced or metastatic NSCLC having a sample size of 657 patients.
Sandler AB et al carried out a randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in 522 chemotherapy-naive patients with inoperable Stage IIIA, IIIB, or IV advanced NSCLC who had not received prior chemotherapy. Gemcitabine 1000 mg/m² was administered on days 1, 8, and 15 of a twenty-eight day cycle with cisplatin 100 mg/m² administered on day 1 of each cycle. Single-agent cisplatin 100 mg/m² was administered on day 1 of each 28-day cycle. The primary end point was survival. Gemcitabine plus cisplatin arm had a median survival time of 9.0 months compared to 7.6 months for single-agent cisplatin arm. Gemcitabine plus cisplatin arm had a median time to disease progression of 5.2 months compared to cisplatin arm with 3.7 months. In the gemcitabine plus cisplatin arm the objective response rate was 26% compared to 10% for cisplatin. With regard to duration of response there was no difference observed between treatment arms.
Cardenal F et al conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). In a multicentric study 135 patients with Stage IIIB or IV NSCLC were randomized to gemcitabine 1250 mg/m² on days 1 and 8, and cisplatin 100 mg/m² on day 1 of a 21-day cycle or to etoposide 100 mg/m² I.V. on days 1, 2, and 3 and cisplatin 100 mg/m² on day 1 on a 21-day cycle. There was no significant difference in survival between the two treatment arms. Gemcitabine plus cisplatin arm showed an objective response rate of 33% compared to 14% on the etoposide plus cisplatin arm. Gemcitabine plus cisplatin arm had median time to disease progression of 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm. Gemcitabine plus cisplatin arm had a median survival of 8.7 months versus 7.0 months for the etoposide plus cisplatin arm.
Pancreatic Cancer: A trial compared gemcitabine to 5-fluorouracil (5-FU) in patients who had received no prior chemotherapy. One hundred and twenty six chemo-naive patients with (measurable or evaluable) confirmed advanced or metastatic pancreas cancer were randomized to gemcitabine, 1000 mg/m² over 30 min once weekly for up to 7 weeks, followed by weekly x 3 every 4 weeks thereafter, or to 5-FU 600 mg/m² over 30 min once weekly. Gemcitabine treated patients had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to 5-FU. With either treatment, no confirmed objective tumor responses were observed. A second trial studied the use of gemcitabine in 63 patients (32F, 31M) with 5-FU-refractory pancreas cancer. The first cycle of gemcitabine was administered intravenously at a dose of 1000 mg/m² over 30 minutes once weekly for up to 7 weekly (or until toxicity necessitated holding a dose) followed by a week of rest from treatment with gemcitabine. Subsequent cycles consisted of injections once weekly for 3 consecutive weeks out of every 4 weeks. The median survival was 3.9 months and the clinical benefit response rate was 27%.
Breast cancer: Data from a multi-national, randomized Phase 3 study of 529 patients support the use of gemcitabine in combination with paclitaxel for treatment of breast cancer patients who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated.
Gemcitabine 1250 mg/m² was administered on Days 1 and 8 of a 21-day cycle with paclitaxel 175 mg/m² administered prior to gemcitabine on Day 1 of each cycle. Single-agent paclitaxel 175 mg/m² was administered on Day 1 of each 21-day cycle as the control arm. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in time to documented disease progression (5.2 months, 2.9 months) and overall response rate (40.8%, 22.1%) compared to monotherapy with Paclitaxel. Further, there was a strong trend toward improved survival for the group given gemcitabine based on an interim survival analysis.

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.

1. 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, follows 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 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 (1,250 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 (x10⁶/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 does 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 myelosuppression when cisplatin was used in doses of 100 mg/m².
Ovarian Cancer: Single-agent use: Adults: The recommended dose of gemcitabine is 800-1,250 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 1,000 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 1,000 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 1,250 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: In combination therapy using radiation plus cisplatin 40 mg/m² followed immediately by gemcitabine 125 mg/m² IV infusion once weekly for 6 weekly (days 1, 8, 15, 22, 29 and 36) at 1-2 hr before concurrent pelvic radiation therapy of 50.4 Gy external beam radiation delivered to entire field of radiation in 28 fractions, i.e. 1.8 Gy/day, 5 days/week over the 6 week of chemotherapy, followed by 2 adjuvant 21-day cycles of gemcitabine (1,000 mg/m² on day 1 and day 8) plus cisplatin (50 mg/m² on day 1 of each cycle).
2. Monitoring, Dose Adjustments or Titration, Method of Terminating Treatment: Patients receiving gemcitabine should be monitored prior to each dose for platelet, leucocyte and granulocyte count and, if necessary, the dose of gemcitabine may be either reduced or withheld in the presence of haematological toxicity, according to the following scale: See table.

Click on icon to see table/diagram/image

Periodic physical examination and checks of renal and hepatic function should be made to detect non-haematologic toxicity. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
Doses should be withheld until toxicity has resolved in the opinion of the physician.
Gemcitabine is well tolerated during the infusion, with only a few cases of injection site reaction reported. There have been no reports of injection site necrosis. Gemcitabine can be easily administered on an outpatient basis.
Elderly patients: Gemcitabine has been well tolerated in patients over the age of 65. There is no evidence to suggest that dose adjustments are necessary in the elderly, although gemcitabine clearance and half-life are affected by age.
Hepatic and renal impairment: Gemcitabine should be used with caution in patients with hepatic insufficiency or with impaired renal function as there is insufficient information from clinical studies to allow clear dose recommendation for this patient population.
Mild to moderate renal insufficiency (GFR from 30 mL/min to 80 mL/min) has no consistent, significant effect on gemcitabine pharmacokinetics.
Children: Gemcitabine has been studied in limited Phase I and II trials in children in a variety of tumor types. These studies did not provide sufficient data to establish the efficacy and safety of gemcitabine in children.

Antidote for overdoses of gemcitabine is unknown. When a single dose as high as 5700 mg/m² was administered by I.V. infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study the principle toxicities seen were myelosuppression, paresthesia and severe rash. Monitoring of appropriate blood counts and supportive therapy for patient, as necessary should be given if overdose is suspected.

Gemcitabine is contraindicated in those patients with a known hypersensitivity to the drug.

General: A physician experienced in the use of cancer chemotherapeutic agents should do close monitoring of patients receiving therapy with gemcitabine. There is no need for discontinuation of gemcitabine therapy as most adverse events are reversible, although doses may need to be withheld or reduced. Women, especially older women had a tendency, not to proceed to the next cycle.
Caution: If the infusion time is prolonged beyond 60 minutes and frequency is more than weekly dosing then there is an increase in toxicity.
Laboratory Test: Complete blood count (CBC), including differential and platelet count should be monitored prior to each dose for patients receiving gemcitabine. When marrow suppression is detected therapy should be suspended or modified. Prior to initiation of therapy and periodically thereafter the Laboratory evaluation of renal and hepatic function should be performed.
Hematology: Gemcitabine suppresses bone marrow function. Manifestations of bone marrow suppression are leucopenia, thrombocytopenia and anemia Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy.
Renal: With the use of gemcitabine (HUS) Hemolytic-Uremic Syndrome and/or renal failure have been reported rarely.
Pulmonary: Pulmonary toxicity has been reported with the use of gemcitabine. In cases of severe lung toxicity, gemcitabine therapy should be discontinued immediately and appropriate supportive measures instituted.
Hepatic: Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs.
Gender: Gemcitabine clearance is affected by gender. Older women were more likely not to proceed to a subsequent cycle and to experience grade 3/4 neutropenia and thrombocytopenia. In single agent studies of gemcitabine adverse reaction rates were similar in men and women.
Radiation Therapy: A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of gemcitabine.
Patients with Renal or Hepatic Impairment: Caution should be exercised for use of gemcitabine in patients with preexisting renal impairment or hepatic insufficiency. Gemcitabine has not been studied in patients with significant renal or hepatic impairment. Administration of gemcitabine in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency.
Carcinogenesis, Mutagenesis, Impairment of Fertility: To evaluate the carcinogenic potential of gemcitabine, long-term animal studies have not been conducted. In a mouse lymphoma (L5178Y) assay, gemcitabine induced forward mutations in vitro and was clastogenic. In an in vivo mouse micronucleus assay, gemcitabine was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assay, and did not cause unscheduled DNA synthesis in vitro. In male mice fertility was affected at gemcitabine doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m² basis) 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 I.V. (about 1/200 the human dose on a mg/m² basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day I.V. (about 1/1300 the human dose on a mg/m² basis).
Use in Children: Gemcitabine has not been studied in pediatric patients. Safety and effectiveness in pediatric patients have not been established.
Use in the Elderly: Age affects the clearance of gemcitabine. There is no evidence, that unusual dose adjustments are necessary in patients over 65. In the elderly, Grade 3/4 thrombocytopenia is more common.

Pregnancy: Pregnancy Category D.
Gemcitabine is cautiously administered to a pregnant woman. There are no studies of gemcitabine in pregnant women. Gemcitabine at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m² basis) is embryotoxic causing fetal malformations (cleft palate, incomplete ossification). Gemcitabine at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m² basis) is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. The patient should be apprised of the potential hazard to the fetus if gemcitabine is used during pregnancy, or if the patient becomes pregnant while taking gemcitabine.
Nursing Mothers: The excretion kinetics of gemcitabine or its metabolites in human milk is unknown. Because of the potential for serious adverse reactions from gemcitabine 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.

Gemcitabine has been used in a wide variety of malignancies, both as a single-agent and in combination with other cytotoxic drugs.
Single-Agent Use: Myelosuppression is the principle dose-limiting toxicity with gemcitabine therapy.
Hematologic: In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with gemcitabine, but <1% of patients discontinues therapy for either anemia, leucopenia, or thrombocytopenia. Red blood cell transfusions have been required by 19% of patients. The incidence of sepsis is less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, has been reported in 16% of patients; less than 1% of patients require platelet transfusions.
Gastrointestinal: Nausea and vomiting have been commonly reported (69%) but are usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) have occurred in <15% of patients. Diarrhea has been reported by 19% of patients, and stomatitis by 11% of patients.
Hepatic: In clinical studies, gemcitabine have been associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there is no evidence of increasing hepatic toxicity with either longer duration of exposure to gemcitabine or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs.
Renal: In clinical studies, mild proteinuria and hematuria have been commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) have been reported in 6 of 2429 patients (0.25%) receiving gemcitabine in clinical studies. Four patients developed HUS on gemcitabine therapy, 2 immediately post-therapy.
Fever: The overall incidence of fever is 41%. This is in contrast to the incidence of infection (16%) and indicates that gemcitabine may cause fever in the absence of clinical infection. Fever is frequently associated with other flu-like symptoms and is usually mild and clinically manageable.
Rash: Rash has been reported in 30% of patients. The rash is typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus has been reported for 13% of patients.
Pulmonary: In clinical studies, dyspnea, unrelated to underlying disease, has been reported in association with gemcitabine therapy. Dyspnea is occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of gemcitabine.
Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%) have been reported. Less than 1% of patients discontinued due to edema.
Flu-like Symptoms: "Flu syndrome" has been reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia have been commonly reported. Fever and asthenia have been 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 have been reported for 16% of patients. Sepsis is rarely reported (<1%).
Alopecia: Hair loss, usually minimal, has been reported by 15% of patients.
Neurotoxicity: There is a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias.
Extravasation: Injection-site related events have been reported for 4% of patients. There are no reports of injection site necrosis.
Allergic: Bronchospasm has been reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely.
Cardiovascular: In clinical studies, 2% of patients discontinued therapy with gemcitabine due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension.
Combination Use in Non-small Cell Lung Cancer: In the gemcitabine plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of gemcitabine injections and 17% of cisplatin injections on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations for possibly drug-related adverse events occurred in 15% of patients on the combination arm and 8% of patients on the cisplatin arm. With a median of 4 cycles of gemcitabine plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse events. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse events.
The safety data from the gemcitabine plus cisplatin versus cisplatin study in non-small cell lung cancer represented the two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppressive with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Nine cases of febrile neutropenia were reported on the combination therapy arm compared to 2 on the cisplatin arm. More patients required RBC and platelet transfusions on the gemcitabine plus cisplatin arm. Myelosuppression occurred more frequently on the combination arm, and in 4 possibly treatment-related deaths myelosuppression was observed. Sepsis was reported in 4% of patients on the gemcitabine plus cisplatin arm compared to 1% on the cisplatin arm. Platelet transfusions were required in 21% of patients on the combination arm and <1% of patients on the cisplatin arm. Hemorrhagic events occurred in 14% of patients on the combination arm and 4% on the cisplatin arm. However, severe hemorrhagic events were rare. Red blood cell transfusions were required in 39% of the patients on the gemcitabine plus cisplatin arm, versus 13% on the cisplatin arm. Nausea and vomiting despite the use of antiemetics occurred slightly more often with gemcitabine plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent gemcitabine, a lower incidence of nausea and vomiting (58% to 69%) was reported. Renal function abnormalities, hypomagnesemia, neuromotor, neurocortical and neurocerebellar toxicity occurred more often with gemcitabine plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity was similar on both arms. Cardiac dysrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with gemcitabine plus cisplatin compared to one (<1%) Grade 3 dysrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the Gemcitabine plus cisplatin combination arm.
In the gemcitabine plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of gemcitabine injections and 16% of cisplatin injections in the gemcitabine plus cisplatin arm compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a median of 5 cycles of gemcitabine plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse events. With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%) experienced 22 hospitalizations due to possibly treatment-related adverse events. In patients who completed more than one cycle, dose adjustments were reported in 81% of the gemcitabine plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related adverse events occurred in 14% of patients on the gemcitabine plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with gemcitabine plus cisplatin treatment (~90%) compared to that with the gemcitabine monotherapy (~60%). With combination therapy gemcitabine dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required.
In this randomized study of gemcitabine plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC, one death (1.5%) was reported on the gemcitabine plus cisplatin arm due to febrile neutropenia associated with renal failure which was possibly treatment-related. No deaths related to treatment occurred on the etoposide plus cisplatin arm. The overall incidence of Grade 4 neutropenia on the gemcitabine plus cisplatin arm was less than on the etoposide plus cisplatin arm (28% versus 56%). Sepsis was experienced by 2% of patients on both treatment arms. Grade 3 anemia and Grade 3/4 thrombocytopenia were more common on the gemcitabine plus cisplatin arm. RBC transfusions were given to 29% of the patients who received gemcitabine plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received gemcitabine plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the gemcitabine plus cisplatin arm. On the gemcitabine plus cisplatin arm, 7% of participants were hospitalized due to febrile neutropenia compared to 12% on the etoposide plus cisplatin arm. More than twice as many patients had dose reductions or omissions of a scheduled dose of gemcitabine as compared to etoposide, which may explain the differences in the incidence of neutropenia and febrile neutropenia between treatment arms. Flu syndrome was reported by 3% of patients on the gemcitabine plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the gemcitabine plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm.
Combination Use in Breast Cancer: In the gemcitabine plus paclitaxel versus paclitaxel study, dose reductions occurred with 8% of gemcitabine injections and 5% of paclitaxel injections on the combination arm, versus 2% on the paclitaxel arm. On the combination arm, 7% of gemcitabine dose were omitted and <1% of paclitaxel doses were omitted, compared to <1% of paclitaxel doses on the paclitaxel arm. A total of 18 patients (7%) on the gemcitabine plus paclitaxel arm and (5%) on the paclitaxel arm discontinued the study because of adverse events. There were two deaths on study or within 30 days after study drug discontinuation that were possibly drug-related, one on each arm.
The incidences of Grade 3 and 4 adverse events of gemcitabine plus paclitaxel versus paclitaxel arm are febrile neutropenia (5.0% versus 1.2%), infection (0.8% versus 0.8%), dyspnea (1.9% versus 0) and allergic reaction/hypersensitivity (0 versus 0.8%). All these adverse events are clinically relevant and have occurred in >1% and <10% (all grades) of patients on either arm.
Post-marketing experience: The following adverse events have been identified during post-approval use of gemcitabine. 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 reported very rarely with the use of gemcitabine. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely.
Vascular Disorders: Clinical signs of peripheral vasculitis and gangrene have been reported very rarely.
Skin: Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported 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 reported rarely. Serious hepatotoxicity including liver failure and death has been reported 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 reported 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 reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death are due to HUS.
Injury, Poisoning, and Procedural Complications: Radiation recall reactions have been reported.

In NSCLC patients a combination of gemcitabine (1250 mg/m² on Days 1 and 8) and Cisplatin was administered as (75 mg/m² on Day 1). The clearance of gemcitabine on Day 1 was 128 L/hr/m² and on Day 8 was 107 L/hr/m². The clearance of cisplatin was reported to be 3.94 mL/min/m² with a corresponding half-life of 134 hours.

Handling and Disposal: Use of 0.5M sulphuric acid and 0.1M potassium permanganate solution/two hours is recommended as neutralizing agent in cases of spills or leak of this solution.
Reconstitution: Reconstitute Gemcitabine for Injection USP 200 mg with 5 ml of Sterile 0.9% w/v Sodium Chloride Injection, Gemcitabine for Injection USP 1 g with 25 ml of Sterile 0.9% w/v Sodium Chloride Injection, Gemcitabine for Injection USP 1.4 g with 35 ml of Sterile 0.9% w/v Sodium Chloride Injection. Shake gently to make a clear solution. 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 200 mg vial or 1.3 ml for 1 g vial or 1.82 ml for 1.4 g vial). The total volume upon reconstitution will be 5.26 ml or 26.3 ml or 36.82 ml respectively. Complete withdrawal of vial contents will provide 200 mg or 1 g or 1.4 g of gemcitabine, respectively. It may further be diluted with 0.9% Sodium Chloride Injection to concentration as low as 0.1 mg/ml. Due to solubility consideration, the maximum concentration for gemcitabine upon reconstitution is 40 mg/ml. Reconstitution at concentration greater than 40 mg/ml may result in incomplete dissolution and should be avoided. The reconstituted solutions should be used immediately or may be used within 24 hours if stored at controlled room temperature (30°C).
Discard unused portion.
Solution of reconstituted gemcitabine should not be refrigerated, as crystallization may occur.
Inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is found, do not administer.
The compatibility of gemcitabine with other drug has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Proper procedures for handling and disposal of cytotoxics should be followed for injection USP.
Incompatibilities: None Identified.

Store below 30°C. Do not refrigerate.
Shelf life: 2 years.

Cytotoxic Chemotherapy

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

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