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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.
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