Gemcitabine

Gemcitabine is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Gemcitabine is used to treat cancers of the pancreas, lung, ovary, and breast.

Gemcitabine may also be used for purposes not listed in this medication guide.

Gemcitabine can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

Gemcitabine can affect your liver, kidneys, or lungs. Tell your doctor if you have stomach pain, dark urine, yellow skin or eyes, little or no urinating, swelling, rapid weight gain, severe shortness of breath, wheezing, or cough with foamy mucus.

If you receive gemcitabine during or after radiation treatment, tell your doctor right away if you have severe skin redness, swelling, oozing, or peeling.

You should not use gemcitabine if you are allergic to it.

To make sure gemcitabine is safe for you, tell your doctor if you have:

• kidney disease;
• liver disease (especially cirrhosis);
• a history of alcoholism; or
• if you are receiving radiation treatment.

Do not use gemcitabine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether gemcitabine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using gemcitabine.

Before receiving this medication, tell your doctor if you:

• are allergic to gemcitabine or any other medicines
• have kidney or liver disease
• are pregnant or breastfeeding
• have an infection
• have neutropenia (low white blood cell count)

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. 

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Flu-like signs. These include headache, weakness, fever, shakes, aches, pains, and sweating.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Not hungry.
• Hard stools (constipation).
• Mouth irritation or mouth sores.
• Hair loss.
• Feeling tired or weak.
• Feeling sleepy.
• Headache.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take gemcitabine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to gemcitabine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Schedule-dependent Toxicity

In clinical trials evaluating the maximum tolerated dose of Gemcitabine for Injection, USP, 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 for Injection, USP is influenced by the length of the infusion [see Clinical Pharmacology (12.3)].

Myelosuppression

Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with Gemcitabine for Injection, USP as a single agent and the risks are increased when Gemcitabine for Injection, USP 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 for Injection, USP. 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 for Injection, USP 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 for Injection, USP. Discontinue Gemcitabine for Injection, USP in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity [see Adverse Reactions (6.1 and 6.2)].

Hemolytic Uremic Syndrome

Hemolytic uremic syndrome, including fatalities from renal failure or the requirement for dialysis, can occur in patients treated with Gemcitabine for Injection, USP. 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 (6.1 and 6.2)]. Assess renal function prior to initiation of Gemcitabine for Injection, USP 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) [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. Permanently discontinue Gemcitabine for Injection, USP 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 for Injection, USP alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Administration of Gemcitabine for Injection, USP 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 [see Use in Specific Populations (8.7)]. Assess hepatic function prior to initiation of Gemcitabine for Injection, USP and periodically during treatment. Discontinue Gemcitabine for Injection, USP in patients that develop severe liver injury.

Embryofetal Toxicity

Gemcitabine for Injection, USP 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 for Injection, USP, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Exacerbation of Radiation Therapy Toxicity

Gemcitabine for Injection, USP 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 for Injection, USP 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 for Injection, USP is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemcitabine for Injection, USP after prior radiation.

Capillary Leak Syndrome

Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemcitabine for Injection, USP as a single agent or in combination with other chemotherapeutic agents. Discontinue Gemcitabine for Injection, USP if CLS develops during therapy.

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemcitabine for Injection, USP 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 for Injection, USP if PRES develops during therapy.

Mechanism of Action

Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of Gemcitabine triphosphate into DNA (self-potentiation). After the Gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death.

Pharmacokinetics

Absorption and Distribution

The pharmacokinetics of Gemcitabine were examined in 353 patients, 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 (<70 minutes) and long infusions (70 to 285 minutes). The total Gemcitabine dose varied from 500 to 3600 mg/m2.

The volume of distribution was increased with infusion length. Volume of distribution of Gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.

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. Gemcitabine plasma protein binding is negligible.

Metabolism

Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m2/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2'-deoxy-2',2'-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.

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.

Elimination

Clearance of Gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of Gemcitabine for any given dose. 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. Table 10 shows plasma clearance and half-life of Gemcitabine following short infusions for typical patients by age and gender.

Gemcitabine half-life for short infusions ranged from 42 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.

Drug Interactions

When Gemcitabine for Injection, USP (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of Gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Analysis of data from metastatic breast cancer patients shows that, on average, Gemcitabine for Injection, USP has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of Gemcitabine. Data from NSCLC patients demonstrate that Gemcitabine for Injection, USP and carboplatin given in combination does not alter the pharmacokinetics of Gemcitabine or carboplatin compared to administration of either single agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

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 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).

• Antineoplastic Agent, Antimetabolite
• Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Discontinue if severe hepatotoxicity occurs during gemcitabine treatment. The following adjustments have been reported:

Transaminases elevated (with normal bilirubin): No dosage adjustment necessary (Venook 2000).

Serum bilirubin >1.6 mg/dL: Use initial dose of 800 mg/m2; may escalate if tolerated (Ecklund 2005; Floyd 2006; Venook 2000).

Reconstitute lyophilized powder with preservative free NS; add 5 mL to the 200 mg vial, add 25 mL to the 1000 mg vial, or add 50 mL to the 2000 mg vial, resulting in a reconstituted concentration of 38 mg/mL (solutions must be reconstituted to ≤40 mg/mL to completely dissolve). Gemcitabine is also supplied as a concentrated solution for injection in different concentrations (40 mg/mL [Canada only] and 38 mg/mL); verify product concentration prior to preparation for administration.

Further dilute reconstituted lyophilized powder or concentrated solution for injection in NS for infusion; to concentrations as low as 0.1 mg/mL.

Infuse over 30 minutes; for off-label uses, infusion times may vary (refer to specific references). Note: Prolongation of the infusion time >60 minutes has been shown to increase toxicity. Gemcitabine has been administered at a fixed-dose rate (FDR) infusion rate of 10 mg/m2/minute to optimize the pharmacokinetics (off-label); prolonged infusion times increase the intracellular accumulation of the active metabolite, gemcitabine triphosphate (Ko 2006; Tempero 2003). Patients who receive gemcitabine FDR experience more grade 3/4 hematologic toxicity (Ko 2006; Poplin 2009).

For intravesicular (bladder) instillation (off-label route), gemcitabine was diluted in 50 to 100 mL normal saline; patients were instructed to retain in the bladder for 1 hour (Addeo 2010; Dalbaghi 2006)

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bleomycin: Gemcitabine may enhance the adverse/toxic effect of Bleomycin. The risk of pulmonary toxicity may be increased. Consider therapy modification

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fluorouracil (Systemic): Gemcitabine may increase the serum concentration of Fluorouracil (Systemic). Monitor therapy

Fluorouracil (Topical): Gemcitabine may increase the serum concentration of Fluorouracil (Topical). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Warfarin: Gemcitabine may enhance the anticoagulant effect of Warfarin. Monitor therapy