Gemzar (Gemcitabine)

GEMZAR®

Lilly

Gemcitabine HCl

Antineoplastic Agent

Caution: Gemcitabine is a cytotoxic drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity. The dosage should be reduced, omitted, or the drug discontinued upon evidence of abnormal suppression of the bone marrow. Acute shortness of breath with a temporal relationship to gemcitabine administration may occur. Some reports of parenchymal lung toxicity were consistent with drug-induced pneumonitis in association with the use of gemcitabine.

This preparation is for i.v. administration only.

Action And Clinical Pharmacology: Gemcitabine is a cell-cycle dependent oncolytic agent of the antimetabolite class. It is a deoxycytidine analog (difluoro-deoxycytidine; dFdC) that is metabolized intracellularly to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effects of gemcitabine are exerted through dFdCDP-assisted incorporation of dFdCTP into DNA, resulting in inhibition of DNA synthesis and induction of apoptosis.

Pharmacokinetics: Gemcitabine disposition was studied in 5 patients who received a single 1 000 mg/m30 min infusion of radiolabeled drug. Within 1 week, 92 to 98% of the dose was recovered, almost entirely in the urine.

The pharmacokinetics of gemcitabine were examined in 353 patients, about 2/3 men, 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.

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. Clearance was affected by age and gender. 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.

Gemcitabine half-life for short infusions ranged from 32 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. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose.

The maximum plasma concentrations of dFdU (inactive metabolite) were achieved up to 30 minutes after discontinuation of the infusions. The metabolite was excreted in urine without undergoing further biotransformation and did not accumulate with weekly dosing. Its elimination is dependent on renal excretion and the metabolite could accumulate with decreased renal function.

The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have not been assessed.

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.

Indications And Clinical Uses: For the treatment of patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas to achieve a Clinical Benefit Response (a composite measure of clinical improvement).

Gemcitabine is also indicated for the palliative treatment of patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC).

Contra-Indications: Patients with a known hypersensitivity to the drug (see Adverse Effects, Allergic).

Manufacturers’ Warnings In Clinical States: Gemcitabine is a cytotoxic drug and should be used only by physicians experienced with cancer chemotherapeutic agents. Blood counts should be taken prior to each dose. Reduce, omit or discontinue the dosage upon evidence of abnormal suppression of the bone marrow (see Dosage).

Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity (see Dosage).

Acute shortness of breath in association with gemcitabine administration may occur. There have been reports of parenchymal lung toxicity consistent with drug induced pneumonitis in association with the use of gemcitabine (see Adverse Effects, Pulmonary and Dosage).

There have been cases of histologically confirmed Hemolytic Uremic Syndrome (HUS) reported in patients treated with gemcitabine (see Adverse Effects, Renal). Patients with pre-existing renal dysfunction should be followed closely while being treated with gemcitabine.

Pregnancy: Gemcitabine has been shown to be embryotoxic and/or fetotoxic in animals. Therefore gemcitabine should be used in pregnancy only following the careful consideration of the benefits vs the risks.

Lactation: It is not known whether the 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, it is recommended that nursing be discontinued.

Children: Safety and effectiveness in children have not been established.

Precautions: Selection of Patients: In all instances where the use of gemcitabine is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events. If severe adverse events occur, the drug should be reduced in dosage, omitted, or discontinued and appropriate corrective measures should be taken based on the clinical judgment of the physician (see Dosage).

Gemcitabine should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from previous chemotherapy.

Most drug-related adverse reactions are reversible.

Hematologic: See Warnings.

Fever and Flu-like Symptoms: Gemcitabine may cause fever, with or without flu-like symptoms, in the absence of clinical infection (see Adverse Effects). The administration of acetaminophen may provide symptomatic relief.

Rash: Gemcitabine administration has been associated with rash (see Adverse Effects). Topical corticosteroids may provide symptomatic relief.

Pulmonary: Acute shortness of breath in association with gemcitabine administration may occur (see Warnings). Bronchodilators, corticosteroids and/or oxygen produce symptomatic relief.

Pregnancy and Lactation: See Warnings.

Gender: Gemcitabine clearance is affected by gender (see Pharmacology). There is no evidence, however, that further dose adjustments (i.e., other than those already recommended in Dosage) are necessary in women.

Geriatrics: Gemcitabine has been well tolerated in patients over the age of 65. Although clearance is affected by age (see Pharmacology), there is no evidence that further dose adjustments, (i.e., other than those already recommended in Dosage) are necessary in patients over the age of 65.

Children: See Warnings.

Patients with Renal or Hepatic Impairment: Gemcitabine should be used with caution in patients with renal or hepatic insufficiency. No data are available in patients with significant renal or hepatic impairment (see Adverse Effects).

Radiosensitizing Effect: In a single trial where gemcitabine at a dose of 1 000 mg/mwas administered for up to 6 consecutive weeks concurrently with therapeutic thoracic radiation to patients with NSCLC, significant toxicity was observed in the form of severe, and potentially life-threatening, esophagitis and pneumonitis, particularly in patients receiving large volumes of radiotherapy. No clinical studies have been carried out to date to elucidate the optimum regimen that may be used for the safe administration of gemcitabine with therapeutic doses of radiation.

Drug Interactions: No confirmed interactions have been reported with the use of gemcitabine. No specific drug interaction studies have been conducted.

Information for the Patient: Patients should be informed that the major acute toxicities of gemcitabine are related to bone marrow toxicity, specifically myelosuppression, with increased susceptibility to infection. They should also be advised that shortness of breath may develop or worsen during treatment either due to disease progression or in rare cases, due to a direct effect of the drug. Patients should be instructed to immediately report a developing or worsening of shortness of breath to the treating physician. Gemcitabine should not be used in pregnancy unless the physician feels the potential benefit justifies the risk of potential harm to the fetus.

Adverse Reactions: The overall safety database for gemcitabine consists of a total of 979 patients to whom gemcitabine was administered as a single agent, using starting doses in the range of 800 to 1 250 mg/madministered weekly as a 30-minute infusion for the treatment of a wide variety of malignancies. Of the 979 patients only 10.4% (102) were discontinued due to an adverse event regardless of causality. WHO grade 3 or 4 toxicity of nonlaboratory events, was less than 1% for all parameters except nausea and vomiting, pulmonary toxicity, infection and pain.

Data are also shown for the subset of patients (N=360) with nonsmall cell lung cancer treated in 4 clinical studies (2 studies WHO laboratory toxicities; 2 studies nonlaboratory WHO-toxicities) and the subset of patients (N=159) with pancreatic cancer treated in 5 clinical studies (WHO laboratory and nonlaboratory toxicities). The frequency of all grades were generally similar for the overall safety database and the subsets of patients with nonsmall cell lung cancer and pancreatic cancer.

*TESS: An event was considered treatment-emergent, if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that although the events were reported during therapy, they were not necessarily caused by the therapy.

Hematologic: Myelosuppression is the major dose-limiting toxicity with gemcitabine; it was usually of short duration, reversible and not cumulative over time. Less than 1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients and less than 1% of patients required platelet transfusion. The incidence of major infection (WHO grade toxicity of 3) was only 1.1% and only one grade 4 toxicity for infection occurred.

Gastrointestinal: Mild or moderate nausea and vomiting (WHO toxicity grade 1 and 2) was reported in 64% of all patients. WHO grade 3 toxicity, defined as vomiting requiring therapy, was reported in 17.1% of patients. Any patient who received prophylactic antiemetics, was automatically graded WHO grade 3, even if they only developed mild nausea. Diarrhea and stomatitis were usually mild and occurred in less than 13% of patients. WHO toxicity for constipation was mild (WHO grade 1) in the majority of cases and was reported for 7.8% of patients.

Hepatic: Gemcitabine was associated with transient elevations of serum transaminases (predominantly WHO grades 1 and 2) in approximately 2/3 of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of treatment with gemcitabine or with greater total cumulative dose.

Renal: Mild Proteinuria and hematuria were commonly reported. Clinical findings consistent with the hemolytic uremic syndrome (HUS) were reported in 6 out of 2 429 patients (0.25%) receiving gemcitabine in clinical trials (see Warnings). Renal failure associated with HUS, may not be reversible even with discontinuation of therapy and dialysis may be required.

Fever and Infection: Fever of any severity was reported in 37.3% of patients. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable. Less than 1% of patients were discontinued for fever. The incidence of fever contrasts with the incidence of infection (8.7%) and indicates that gemcitabine may cause fever in the absence of clinical infection (see Precautions).

Cutaneous Toxicity: A rash is seen in 24.8% of patients, it is usually mild, not dose limiting and responds to local therapy (see Precautions). The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities.

Pulmonary and Allergic: The administration of gemcitabine has been infrequently associated with shortness of breath (see Warnings, Dyspnea). Dyspnea when graded by WHO-toxicity criteria, was reported in 8%, and severe dyspnea (WHO grades 3 and 4) was reported in 1.4% of patients.

Dyspnea, regardless of causality (TESS) was reported in 23% of patients and serious dyspnea was reported in 3% of patients. It should be noted that in both of these analyses, the occurrence of dyspnea may have been due to underlying disease such as lung cancer (40% of study population) or pulmonary manifestations of other malignancies. Dyspnea was occasionally accompanied by bronchospasm.

Pulmonary effects, sometimes severe (such as pulmonary edema, interstitial pneumonitis, or adult respiratory distress syndrome [ARDS] have been reported rarely in association with gemcitabine therapy. The etiology of these effects is unknown. If such effects develop, consideration should be given to discontinuing gemcitabine. Early use of supportive care measures may help ameliorate the condition.

Edema: The occurrence of edema is reported regardless of causality, as a treatment emergent event (TESS). Edema (13%), peripheral edema (20%) and facial edema.

Flu-like Symptoms: “Flu-syndrome” was reported regardless of causality (TESS) for 18.9% of patients (N=979). Individual symptoms of headache, fever, chills, myalgia and asthenia were the most commonly reported symptoms. Cough, rhinitis, malaise, sweating and insomnia were also commonly reported. Less than 1% of patients discontinued due to flu-like symptoms.

Alopecia: Hair loss (alopecia), usually minimal, was reported for any WHO grade in only 13.7% of patients. No grade 4 toxicity (nonreversible alopecia) was reported, and only 0.4% of patients reported grade 3 toxicity (complete but reversible alopecia).

Neurotoxicity: WHO grade 1 or 2 peripheral neurotoxicity was reported for 3.3% of patients. No patient reported WHO grade 3 or 4 toxicity.

State of consciousness toxicity was usually mild to moderate (WHO grades 1 and 2), somnolence was reported for 4.6% of patients.

Extravasation: Gemcitabine is well tolerated during the infusion with only a few cases (4%) of injection site reaction reported. Gemcitabine does not appear to be a vesicant (see Dosage). There have been no reports of injection site necrosis.

Cardiac Toxicity: Less than 2% of patients discontinued therapy with gemcitabine due to cardiovascular events such as myocardial infarction, arrhythmia, chest pain, heart failure, pulmonary edema and hypertension. Many of these patients had a prior history of cardiovascular disease.

WHO grade 1 peripheral neurotoxicity is defined as paresthesia and/or decreased tendon reflexes and WHO grade 2 toxicity is defined as severe paresthesia and/or mild weakness.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no known antidote for overdoses of gemcitabine. Myelosuppression, and paresthesia were the principal toxicities seen when a single dose as high as 5 700 mg/mwas administered by i.v. infusion over 30 minutes every 2 weeks to several patients in a Phase I study. In the event of a suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.

Dosage And Administration: This preparation is for i.v. use only. It should be administered by individuals experienced in the administration of cancer chemotherapeutic drugs.

Gemcitabine should be used by i.v. infusion at a dose of 1 000 mg/mover 30 minutes.

In the treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas, gemcitabine should be administered 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.

In the palliative treatment of patients with locally advanced or metastatic nonsmall cell lung cancer, gemcitabine should be administered once weekly for 3 weeks, followed by a 1-week rest period. This 4-week cycle is repeated.

Dosage escalation or reduction is based upon the degree of toxicities experienced by the patient.

Dosage Reduction and Treatment Discontinuation: Patients receiving gemcitabine should be monitored prior to each dose for granulocyte and platelet counts and, if necessary, the dose of gemcitabine may be either reduced or withheld in the presence of hematological toxicity according to the following scale

Liver and kidney functions including transaminases and serum creatinine should also be followed in patients receiving this drug (see Precautions).

Acute shortness of breath in association with gemcitabine administration may occur. Bronchodilators, corticosteroids and/or oxygen produce symptomatic relief. Some reports of parenchymal lung toxicity were consistent with drug induced pneumonitis in association with the use of gemcitabine (see Adverse Effects, Pulmonary). The mechanism of this toxicity is not known. Patients suspected of experiencing drug-induced pneumonitis should be discontinued and not be rechallenged with the drug.

Administration Precautions: 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. The drug also does not appear to act as a vesicant in a case of extravasation. It may be administered on an outpatient basis.

As with other toxic compounds, caution should be exercised in handling and preparing solutions with gemcitabine. The use of gloves is recommended. If the solution of gemcitabine contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water or rinse the mucosa with copious amounts of water.

Parenteral drugs should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution and container permit. The reconstituted solution is stable for 24 hours at 15 to 30°C. Any unused solution should be discarded.

Reconstitution: To reconstitute, add at least 5 mL of 0.9% Sodium Chloride Injection to the 200 mg vial or at least 25 mL of 0.9% Sodium Chloride Injection to the 1 g vial. Invert to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL. 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.

Reconstitution of concentrations greater than 40 mg/mL may result in incomplete dissolution, and should not be attempted.

Solutions for Reconstitution: Sterile isotonic saline (0.9% Sodium Chloride Injection) without added preservatives.

Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.

Availability And Storage: 200 mg: Each vial of sterile lyophilized powder contains: gemcitabine HCl equivalent to gemcitabine 200 mg as free base. Nonmedicinal ingredients: mannitol and sodium acetate. Vials of 10 mL.

1 g: Each vial of sterile lyophilized powder contains: gemcitabine HCl equivalent to gemcitabine 1 g as free base. Nonmedicinal ingredients: mannitol and sodium acetate. Vials of 50 mL.

For i.v. use only. Store in glass vials, at 15 to 30°C.

GEMZAR Lilly Gemcitabine HCl Antineoplastic Agent Caution: Gemcitabine is a cytotoxic drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity. The dosage should be reduced, omitted, or the drug discontinued upon evidence of abnormal suppression of the bone marrow. Acute shortness of breath with a temporal relationship to gemcitabine administration may occur. Some reports of parenchymal lung toxicity were consistent with drug-induced pneumonitis in association with the use of gemcitabine. This preparation is for i.v. administration only.

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