Gemtero

Gemcitabine hydrochloride.

GEMTERO (Gemcitabine for Injection 200 mg): Each vial contains Gemcitabine Hydrochloride 227.6 mg Ph.Eur. equivalent to Gemcitabine 200 mg.
GEMTERO (Gemcitabine for Injection 1 g): Each vial contains Gemcitabine Hydrochloride 1138 mg Ph.Eur. equivalent to Gemcitabine 1 g.
Gemcitabine for injection is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer).
The empirical formula for gemcitabine HCl is C₉H₁₁F₂N₃O₄·HCl. 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.
The clinical formulation is supplied in a sterile form for intravenous use only. Vials of gemcitabine for injection contain either 200 mg or 1 g of gemcitabine HCl (expressed as free base) and the excipients are Mannitol, Sodium Acetate Trihydrate, Sodium Hydroxide, Hydrochloric Acid & water for injection.

Pharmacology: Pharmacodynamics: Mechanism of Action: Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the concentrations of deoxynucleotides, including dCTP. Second, gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands. After this addition, there is inhibition of further DNA synthesis. DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strands (masked chain termination). In CEM T lymphoblastoid cells, gemcitabine induces internucleosomal DNA fragmentation, one of the characteristics of programmed cell death.
Pharmacokinetics: Absorption and Distribution: The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using 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 total gemcitabine for injection dose varied from 500 to 3600 mg/m².
The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m² following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m². Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible.
Metabolism: Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m²/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2'-deoxy-2',2'-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.
The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.
Excretion: Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 1 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender. (See Table 1.)

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Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions.
Drug Interactions: When gemcitabine for injection (1250 mg/m² on Days 1 and 8) and cisplatin (75 mg/m² on Day 1) were administered in NSCLC patients, 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 in the same study was reported to be 3.94 mL/min/m² with a corresponding half-life of 134 hours [see Interactions]. Analysis of data from metastatic breast cancer patients shows that, on average, gemcitabine for injection has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine for injection. Data from NSCLC patients demonstrate that gemcitabine for injection and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine for injection or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

Breast Cancer: Gemcitabine for injection 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.
Non-Small Cell Lung Cancer: Gemcitabine for injection 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 for injection is indicated for the treatment of adult patients with locally advanced or metastatic adenocarcinoma of the pancreas. Gemcitabine for injection is indicated for patients with 5-FU refractory pancreatic cancer.

Gemcitabine for injection is for intravenous use only. Gemcitabine for injection may be administered on an outpatient basis.
Breast Cancer: Gemcitabine for injection should be administered by intravenous infusion at a dose of 1250 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 for injection 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.
Dose Modifications: Gemcitabine for injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine for injection dosage should be modified according to the guidelines in Table 2. (See Table 2.)

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In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine for injection should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer's prescribing information.
Non-Small Cell Lung Cancer: Two schedules have been investigated and the optimum schedule has not been determined. With the 4-week schedule, gemcitabine for injection should be administered by intravenous infusion 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 for injection. With the 3-week schedule, gemcitabine for injection should be administered by intravenous infusion 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 for injection on Day 1. See prescribing information for cisplatin administration and hydration guidelines.
Dose Modifications: Dosage adjustments for hematologic toxicity may be required for gemcitabine for injection and for cisplatin. Gemcitabine for injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving gemcitabine for injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer's prescribing information.
In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine for injection plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for gemcitabine for injection plus cisplatin was 5% versus 2% for cisplatin alone).
Pancreatic Cancer: Gemcitabine for injection 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.
Dose Modifications: Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Precautions]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Precautions and Pharmacology: Pharmacodynamics under Actions].
Patients receiving gemcitabine for injection 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 in Table 3. (See Table 3.)

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Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine for injection 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. Dose reduction is recommended in patients with elevated serum bilirubin concentration because such patients are at increased risk of toxicity. The dose modifications are based on a Phase 1 study of cancer patients with elevated serum bilirubin concentrations (median 50 µmol/L, range 30-100 µmol/L), who were administered gemcitabine monotherapy, 8 out of 10 patients experienced toxicity at a gemcitabine dose of 950 mg/m² compared with 3 out of 8 at 800 mg/m². The toxicity was mostly related to the liver. In the same study, patients with elevated serum creatinine concentration appeared to experience increased sensitivity to gemcitabine. However, the data based on 15 patients was not sufficient to make dosing recommendation.
Preparation and Administration Precautions: Caution should be exercised in handling and preparing gemcitabine for injection solutions. The use of gloves is recommended. If gemcitabine for injection 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.
Preparation for Intravenous Infusion Administration: The recommended diluent for reconstitution of gemcitabine for injection is 0.9% Sodium Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration for gemcitabine for injection 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 of 0.9% Sodium Chloride Injection to the 200-mg vial or 25 mL of 0.9% Sodium Chloride Injection to the 1-g vial. 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 or 1.3 mL for the 1-g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine, respectively. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.
Reconstituted gemcitabine for injection is a clear, colorless to light straw-colored solution. After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3. The solution should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. If particulate matter or discoloration is found, do not administer.
When prepared as directed the reconstituted solution is stable for 24 hours when stored at 20-25°C. Discard unused portion. Solutions of reconstituted gemcitabine for injection should not be refrigerated, as crystallization may occur.
The compatibility of gemcitabine for injection with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

There is no known antidote for overdoses of gemcitabine for injection. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m² was administered by IV 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.

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

Patients receiving therapy with gemcitabine for injection should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.
Infusion Time: Caution - Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity.
Hematology: Gemcitabine for injection can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia [see Adverse Reactions], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage & Administration].
Pulmonary: Pulmonary toxicity has been reported with the use of gemcitabine for injection. In cases of severe lung toxicity, gemcitabine for injection therapy should be discontinued immediately and appropriate supportive care measures instituted [see Adverse Reactions].
Laboratory Tests: Patients receiving gemcitabine for injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected [see Dosage & Administration]. Peripheral blood counts may continue to fall after the drug is stopped. As with other oncolytics, the possibility of cumulative bone marrow suppression when using combination or sequential chemotherapy should be considered.
Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter [see Dosage & Administration].
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 for injection.
Non-concurrent (given >7 days apart): Analysis of the data does not indicate enhanced toxicity when gemcitabine for injection is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that gemcitabine for injection can be started after the acute effects of radiation have resolved or at least one week after radiation.
Concurrent (given together or ≤7 days apart): Preclinical and clinical studies have shown that gemcitabine for injection has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of gemcitabine for injection, frequency of gemcitabine for injection administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where gemcitabine for injection at a dose of 1000 mg/m² was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm²]. The optimum regimen for safe administration of gemcitabine for injection with therapeutic doses of radiation has not yet been determined in all tumor types.
Effects on ability to drive and use machines: Gemcitabine has been reported to cause mild to moderate somnolence. Patients should be cautioned against driving or operating machinery until it is established that they do not become somnolent.
Renal: Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine for injection. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS. Gemcitabine for injection should be discontinued at the first signs of any evidence of microangiopathic hemolytic anemia such as rapidly falling hemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH, which may indicate development of hemolytic uremic syndrome. Gemcitabine for injection should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.
Hepatic: Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving gemcitabine for injection alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions]. Gemcitabine for injection should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of gemcitabine for injection 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.
Gender: Gemcitabine for injection clearance is affected by gender [see Pharmacology under Actions]. In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments [see Dosage & Administration] are necessary in women. In general, in single-agent studies of gemcitabine for injection, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. There was a greater tendency in women, especially older women, not to proceed to the next cycle.
Use in pregnancy: Pregnancy Category D.
Gemcitabine for injection can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, gemcitabine for injection is expected to result in adverse reproductive effects. There are no adequate and well-controlled studies of gemcitabine for injection in pregnant women. Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 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 1/600 the recommended human dose on a mg/m² basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Use in lactation: 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 for injection, 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.
Use in 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.
Use in the elderly: Gemcitabine for injection clearance is affected by age [see Pharmacology under Actions]. There is no evidence, however, that unusual dose adjustments [see Dosage & Administration] 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.

Pregnancy: Pregnancy Category D.
Gemcitabine for injection can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, gemcitabine for injection is expected to result in adverse reproductive effects. There are no adequate and well-controlled studies of gemcitabine for injection in pregnant women. Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 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 1/600 the recommended human dose on a mg/m² basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Precautions].
Lactation: 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 for injection, 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.

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.
Gemcitabine for injection 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 principal dose-limiting toxicity with gemcitabine for injection therapy. Dosage adjustments for hematologic toxicity are frequently needed [see Dosage & Administration].
The data in Table 4 are based on 979 patients receiving gemcitabine for injection as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The gemcitabine for injection starting doses ranged from 800 to 1250 mg/m². Data are also shown for the subset of patients with pancreatic cancer treated in 5 clinical studies. The frequency of all grades and severe (WHO Grade 3 or 4) adverse reactions were generally similar in the single-agent safety database of 979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the single-agent safety database resulted in discontinuation of gemcitabine for injection therapy in about 10% of patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the gemcitabine for injection arm and 4.8% for the 5-FU arm. All WHO-graded laboratory adverse reactions are listed in Table 4, regardless of causality. Non-laboratory adverse reactions listed in Table 4 or discussed as follows were those reported, regardless of causality, for at least 10% of all patients, except the categories of Extravasation, Allergic, and Cardiovascular and certain specific adverse reactions under the Renal, Pulmonary, and Infection categories. (See Table 4.)

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Hematologic: In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with gemcitabine for injection, 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 for injection therapy and dosage modified or suspended according to the degree of hematologic toxicity [see Dosage & Administration].
Gastrointestinal: Nausea and vomiting were commonly reported (69%) but were usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.
Hepatic: In clinical trials, gemcitabine for injection 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 for injection or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving gemcitabine for injection alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions].
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 for injection in clinical trials. Four patients developed HUS on gemcitabine for injection therapy, 2 immediately posttherapy. 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 for injection therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required [see Adverse Reactions].
Fever: The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that gemcitabine for injection may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable.
Rash: Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus was reported for 13% of patients.
Pulmonary: In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with gemcitabine for injection therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of gemcitabine for injection [see Adverse Reactions]. The etiology of these effects is unknown. If such effects develop, gemcitabine for injection should be discontinued. Early use of supportive care measures may help ameliorate these conditions.
Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less than 1% of patients discontinued due to edema.
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.
Neurotoxicity: There was a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias.
Extravasation: Injection-site related events were reported for 4% of patients. There were no reports of injection site necrosis. Gemcitabine for injection is not a vesicant.
Allergic: Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemcitabine for injection should not be administered to patients with a known hypersensitivity to this drug [see Contraindications].
Cardiovascular: During clinical trials, 2% of patients discontinued therapy with gemcitabine for injection due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease [see Adverse Reactions].
Combination Use in Non-Small Cell Lung Cancer: In the gemcitabine for injection plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of gemcitabine for injection 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 reactions 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 for injection plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse reactions. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse reactions.
In the gemcitabine for injection plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of gemcitabine for injection injections and 16% of cisplatin injections in the gemcitabine for injection 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 for injection plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse reactions. 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 reactions. In patients who completed more than one cycle, dose adjustments were reported in 81% of the gemcitabine for injection plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related adverse reactions occurred in 14% of patients on the gemcitabine for injection plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with gemcitabine for injection plus cisplatin treatment (~90%) compared to that with the gemcitabine for injection monotherapy (~60%). With combination therapy gemcitabine for injection dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required.
Table 5 presents the safety data from the gemcitabine for injection plus cisplatin versus cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression 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 for injection 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 for injection 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 for injection plus cisplatin arm, versus 13% on the cisplatin arm. The data suggest cumulative anemia with continued gemcitabine for injection plus cisplatin use.
Nausea and vomiting despite the use of antiemetics occurred more often with gemcitabine for injection plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent gemcitabine for injection, 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 for injection plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity was similar on both arms.
Cardiac dysrrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with gemcitabine for injection plus cisplatin compared to one (<1%) Grade 3 dysrrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the gemcitabine for injection plus cisplatin combination arm.
Table 6 presents data from the randomized study of gemcitabine for injection plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC. One death (1.5%) was reported on the gemcitabine for injection 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 for injection 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 for injection plus cisplatin arm. RBC transfusions were given to 29% of the patients who received gemcitabine for injection plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received gemcitabine for injection plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the gemcitabine for injection plus cisplatin arm. On the gemcitabine for injection 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 for injection 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 for injection plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the gemcitabine for injection plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm. (See Tables 5 and 6.)

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Combination Use in Breast Cancer: In the gemcitabine for injection plus paclitaxel versus paclitaxel study, dose reductions occurred with 8% of gemcitabine for injection injections and 5% of paclitaxel injections on the combination arm, versus 2% on the paclitaxel arm. On the combination arm, 7% of gemcitabine for injection doses 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 for injection plus paclitaxel arm and 12 (5%) on the paclitaxel arm discontinued the study because of adverse reactions. There were two deaths on study or within 30 days after study drug discontinuation that were possibly drug-related, one on each arm.
Table 7 presents the safety data occurrences of ≥10% (all grades) from the gemcitabine for injection plus paclitaxel versus paclitaxel study in breast cancer. (See Table 7.)

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The following are the clinically relevant adverse reactions that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine for injection plus paclitaxel versus paclitaxel): 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%).
No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

No specific drug interaction studies have been conducted. Information is available on the pharmacodynamics and pharmacokinetics of gemcitabine for injection in combination with cisplatin, paclitaxel, or carboplatin [see Pharmacology under Actions].

To reconstitute: GEMTERO (Gemcitabine for Injection 200 mg): Add 5 mL of 0.9% Sodium Chloride injection (without preservatives) to make a solution containing 38 mg/mL. Shake to dissolve. Administer solution within 24 hours. Discard unused portion.
GEMTERO (Gemcitabine for Injection 1 g): Add 25 mL of 0.9% Sodium Chloride injection (without preservatives) to make a solution containing 38 mg/mL. Shake to dissolve. Administer solution within 24 hours. Discard unused portion.

Prior to reconstitution store below 30°C and after reconstitution store at 20-25°C.

Cytotoxic Chemotherapy

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

POM