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Schedule-dependent Toxicity: In clinical trials evaluating the maximum tolerated dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is influenced by the length of the infusion.
Myelosuppression: Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with gemcitabine as a single agent and the risks are increased when gemcitabine is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving gemcitabine in combination with another drug.
Pulmonary Toxicity and Respiratory Failure: Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine. Permanently discontinue gemcitabine in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe pulmonary toxicity.
Hemolytic Uremic Syndrome: Hemolytic Uremic Syndrome to include fatalities from renal failure or the requirement for dialysis can occur in patients treated with gemcitabine. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS. Serious cases of thrombotic microangiopathy other than HUS have been reported with gemcitabine.
Assess renal function prior to initiation of gemcitabine and periodically during treatment. Consider the diagnosis of HUS in patients who develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN). Permanently discontinue gemcitabine in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy.
Hepatic Toxicity: Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs. Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of gemcitabine and periodically during treatment. Discontinue gemcitabine in patients that develop severe liver injury.
Exacerbation of Radiation Therapy Toxicity: Gemcitabine is not indicated for use in combination with radiation therapy.
Concurrent (given together or ≤7 days apart): Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which gemcitabine was administered at a dose of 1000 mg/m2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation.
Non-concurrent (given >7 days apart): Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who received gemcitabine after prior radiation.
Capillary Leak Syndrome: Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents. Discontinue gemcitabine if CLS develops during therapy.
Posterior Reversible Encephalopathy Syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI) and discontinue gemcitabine if PRES develops during therapy.
Carcinogenicity, Mutagenicity and Impairment of Fertility: Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay.
Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility 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 administered intravenously (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m2 basis).
Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (approximately 0.005 times 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 0.002 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays.
Renal Impairment: No clinical studies have been conducted with gemcitabine in patients with decreased renal function. Use with caution in patients with preexisting renal impairment.
Hepatic Impairment: No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function. Use with caution in patients with preexisting hepatic impairment.
Administration to patients with concurrent liver metastases or a history of alcoholism, hepatitis, or liver cirrhosis may lead to exacerbation of the underlying hepatic function impairment.
Gender: Gemcitabine clearance is affected by gender. The lower clearance in women results in higher concentrations of gemcitabine for any given dose.
Use in Pregnancy & Lactation: Embryofetal Toxicity: Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months following the final dose.
Pregnancy: Category D: Gemcitabine can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking gemcitabine, the patient should be apprised of the potential hazard to a fetus.
Nursing Mothers: 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, 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.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating gemcitabine.
Contraception: Gemcitabine can cause fetal harm when administered to a pregnant woman.
Females: Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose of gemcitabine.
Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months after the final dose.
Infertility: Males: Based on animal studies, gemcitabine may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.
Use in Children: The safety and effectiveness of gemcitabine have not been established in pediatric patients.
Use in the Elderly: Gemcitabine clearance is affected by age, however there are no recommended dose adjustments based on patients' age.
