Included as part of the "PRECAUTIONS" Section
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 [see CLINICAL PHARMACOLOGY]. Refer to the recommended INFUGEM dosing schedule [see DOSAGE AND ADMINISTRATION].
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with INFUGEM as a single agent, and the risks are increased when INFUGEM 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 gemcitabine. 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 [see ADVERSE REACTIONS].
Monitor patients receiving INFUGEM prior to each dose with a complete blood count (CBC), including differential and platelet count, and modify the dosage as recommended [see DOSAGE AND ADMINISTRATION].
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 INFUGEM.
Permanently discontinue INFUGEM in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity [see ADVERSE REACTIONS].
Hemolytic Uremic Syndrome
Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur in patients treated with INFUGEM. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS [see ADVERSE REACTIONS].
Assess renal function prior to initiation of INFUGEM and periodically during treatment. Consider the diagnosis of HUS in patients who develop 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 INFUGEM in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy.
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 [see ADVERSE REACTIONS]. Administration of INFUGEM in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency.
Assess hepatic function prior to initiation of INFUGEM and periodically during treatment. Permanently discontinue INFUGEM in patients that develop severe liver injury.
INFUGEM 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.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with INFUGEM and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the final dose of INFUGEM [see Use In Specific Populations].
Exacerbation Of Radiation Therapy Toxicity
INFUGEM is not recommended 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 receive 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. Permanently discontinue INFUGEM 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 permanently discontinue INFUGEM if PRES develops during therapy.
Carcinogenesis, Mutagenesis, 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 intraperitoneal doses of 0.5 mg/kg/day (about 1/700 the 1000 mg/m2 clinical dose based on BSA) in male mice resulted in 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 1000 mg/m2 clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the 1000 mg/m2 clinical dose based on BSA).
Use In Specific Populations
Based on animal data and its mechanism of action, INFUGEM can cause fetal harm when administered to a pregnant woman. There are no available data on the use of gemcitabine in pregnant women. In animal reproductive studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day (approximately 0.005 times the 1000 mg/m2 clinical dose on body surface area (BSA)). Gemcitabine was embryotoxic and fetotoxic in rabbits. Daily dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes, and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day (approximately 0.002 times the 1000 mg/m2 clinical dose based on BSA).
There is no information regarding the presence of gemcitabine or its metabolites in human milk, or their effects on the breastfed infant or milk production. Due to the potential for serious adverse reactions in nursing infants from INFUGEM, advise woman not to breastfeed during treatment with INFUGEM and for at least one week after the last dose.
Females And Males Of Reproductive Potential
Verify the pregnancy status of females of reproductive potential prior to initiating INFUGEM [see Pregnancy].
INFUGEM can cause fetal harm when administered to a pregnant woman [see Pregnancy].
Advise females of reproductive potential to use effective contraception during treatment with INFUGEM and for 6 months after the last dose [see Pregnancy].
Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the last dose of INFUGEM [see Nonclinical Toxicology].
Based on animal studies, INFUGEM may impair fertility in males of reproductive potential [see Nonclinical Toxicology].
The safety and effectiveness of INFUGEM have not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m2/min for 360 minutes weekly for three weeks followed by a one-week rest period. The safety and activity of gemcitabine were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m2/min administered over 360 minutes weekly for three weeks followed by a one-week rest period. Patients with M1 or M2 bone marrow on Day 28 who did not experience unacceptable toxicity were eligible to receive a maximum of one additional four-week course. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.
In clinical studies of gemcitabine enrolling 979 patients with various cancers who received gemcitabine as a single agent, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer, 175 women received gemcitabine with carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older [see DOSAGE AND ADMINISTRATION].
Gemcitabine clearance is decreased in females [see CLINICAL PHARMACOLOGY]. In single-agent studies of gemcitabine, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia [see DOSAGE AND ADMINISTRATION].