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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.
