Gemcitabine is a deoxycytidine antimetabolite nucleoside inhibitor, closely related to cytarabine. Although cytarabine and gemcitabine are similar in structure and metabolic pathways, they differ greatly in the spectrum of antitumor activity. While cytarabine is used almost exclusively for acute leukemias, gemcitabine is active against a variety of solid tumors. It is indicated as monotherapy for locally advanced or metastatic pancreatic cancer, in combination with cisplatin for locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with paclitaxel for metastatic breast cancer, and in combination with carboplatin for advanced ovarian cancer. Increased toxicities including clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia are observed with infusion times greater than 60 minutes or dosing more frequently than once weekly.
General Administration Information
For storage information, see the specific product information within How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
-Nonvesicant
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Gemcitabine is available as a powder for injection, which requires reconstitution, and a solution for injection. Both formulations require further dilution prior to administration. It is also available as a premixed bag for IV infusion which does not require further dilution.
Intravenous Administration
Reconstitution (powder for injection)
-200 mg vial: Add 5 mL of 0.9% sodium chloride for injection to each vial, for a final concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg of gemcitabine. Shake to dissolve.
-1 g vial: Add 25 mL of 0.9% sodium chloride for injection to each vial, for a final concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 1 g of gemcitabine. Shake to dissolve.
-Storage after reconstitution: Reconstituted gemcitabine solutions are stable for 24 hours at room temperature (20 to 25 degrees Celsius or 68 to 77 degrees Fahrenheit). Do not refrigerate, as crystallization may occur. Discard unused portion.
Intravenous infusion (reconstituted powder or solution for injection):
-Dilute the appropriate amount of gemcitabine (solution for injection or reconstituted powder for injection) in 0.9% sodium chloride injection solution to a minimum final concentration of at least 0.1 mg/mL.
-Mix by gentle inversion. Do not shake.
-Storage after dilution: Store the diluted solution at controlled room temperature (20 to 25 degrees Celsius or 68 to 77 degrees Fahrenheit) for up to 24 hours (from reconstitution). Do not refrigerate, as crystallization may occur.
Administration:
Infuse intravenously over 30 minutes. In clinical trials where the infusion time was more than 60 minutes, or the frequency was more than once weekly, there was an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. However, in one clinical trial, gemcitabine was safely administered over 100 minutes (10 mg/m2/min) in combination with oxaliplatin in the treatment of advanced pancreatic cancer.
Other Injectable Administration
Premixed Infusion Bag:
NOTE: Use another formulation of gemcitabine for patients who require a dose less than 1,150 mg.
-Do not dilute prior to administration.
-Do not remove or add medication.
-Select the premixed bag based on the patient's BSA range; the administered dose may vary from the BSA-calculated dose by no more than 5%.
For doses of 1,000 mg/m2 (Indications: Non-Small Cell Lung Cancer, Ovarian Cancer, Pancreatic Cancer):
-BSA 1.16 to 1.25: 1,200 mg infusion bag
-BSA 1.26 to 1.35: 1,300 mg infusion bag
-BSA 1.36 to 1.45: 1,400 mg infusion bag
-BSA 1.46 to 1.55: 1,500 mg infusion bag
-BSA 1.56 to 1.65: 1,600 mg infusion bag
-BSA 1.66 to 1.75: 1,700 mg infusion bag
-BSA 1.76 to 1.85: 1,800 mg infusion bag
-BSA 1.86 to 1.95: 1,900 mg infusion bag
-BSA 1.96 to 2.1: 2,000 mg infusion bag
-BSA 2.11 to 2.3: 2,200 mg infusion bag
-BSA 2.31 to 2.45: 2,400 mg (e.g., 2 x 1,200 mg infusion bags)
-BSA 2.46 to 2.55: 2,500 mg (e.g., 1,200 mg infusion bag plus 1,300 mg infusion bag)
-BSA 2.56 to 2.64: 2,600 mg (e.g., 2 x 1,300 mg infusion bags)
For doses of 1,250 mg/m2 (Indications: Non-Small Cell Lung Cancer, Breast Cancer):
-BSA 1.16 to 1.24: 1,500 mg infusion bag
-BSA 1.25 to 1.32: 1,600 mg infusion bag
-BSA 1.33 to 1.4: 1,700 mg infusion bag
-BSA 1.41 to 1.47: 1,800 mg infusion bag
-BSA 1.48 to 1.56: 1,900 mg infusion bag
-BSA 1.57 to 1.68: 2,000 mg infusion bag
-BSA 1.69 to 1.84: 2,200 mg infusion bag
-BSA 1.85 to 1.96: 2,400 mg (e.g., 2 x 1,200 mg infusion bags)
-BSA 1.97 to 2.04: 2,500 mg (e.g., 1,200 mg infusion bag plus 1,300 mg infusion bag)
-BSA 2.05 to 2.12: 2,600 mg (e.g., 2 x 1,300 mg infusion bags)
-BSA 2.13 to 2.2: 2,700 mg (e.g., 1,200 mg infusion bag plus 1,500 mg infusion bag)
-BSA 2.21 to 2.28: 2,800 mg (e.g., 2 x 1,400 mg infusion bags)
-BSA 2.29 to 2.36: 2,900 mg (e.g., 1,200 mg infusion bag plus 1,700 mg infusion bag)
-BSA 2.37 to 2.44: 3,000 mg (e.g., 2 x 1,500 mg infusion bags)
-BSA 2.45 to 2.52: 3,100 mg (e.g., 1,200 mg infusion bag plus 1,900 mg infusion bag)
-BSA 2.53 to 2.6: 3,200 mg (e.g., 2 x 1,600 mg infusion bags)
-BSA 2.61 to 2.64: 3,300 mg (e.g., 1,600 mg infusion bag plus 1,700 mg infusion bag)
Administration: Infuse the total dose of gemcitabine over 30 minutes. If two premixed infusion bags are required to achieve the prescribed dose, infuse the total volume of both bags over 30 minutes.
Somnolence/drowsiness was reported in 11% (grade 3 or 4, less than 2%) of patients treated with gemcitabine monotherapy in clinical trials. Generalized adverse reactions reported with gemcitabine in combination with other chemotherapy (e.g., cisplatin, carboplatin, and paclitaxel), included somnolence (grade 1 or 2, 3% or less), fatigue (40% or less; grade 3 or 4, less than 7%), headache (14% or less), and adverse effects on mood (16% or less; grade 3, 1% or less).
Nausea and vomiting was reported in 69% of patients (grade 3 or 4, 14%) with various malignancies receiving gemcitabine monotherapy across 5 clinical trials (n = 979). Additionally, diarrhea (19%; grade 3 or 4, 1%) and stomatitis (11%; grade 3 or 4, less than 1%) were reported in monotherapy trials. Nausea (93% to 96%; grade 3 or 4, 27% to 39%) and vomiting (78% to 96%; grade 3 or 4, 23% to 39%) occurred more frequently when gemcitabine was administered with cisplatin in clinical trials, as expected; diarrhea (14% to 24%; grade 3 or 4, 2% to 4%) and stomatitis (14% to 20%; grade 3 or 4, 1% to 4%) occurred with a similar incidence to gemcitabine monotherapy. When gemcitabine was administered in combination with paclitaxel or carboplatin, the incidence of GI-related adverse reactions were similar to gemcitabine monotherapy: nausea (50% to 69%; grade 3, 1% to 6%), vomiting (29% to 46%; grade 3, 2% to 6%), constipation (less than 42%; grade 3 or 4, less than 7%), diarrhea (20% to 25%; grade 3, 3%), stomatitis/pharyngitis (13% to 22%; grade 3 or 4, less than 2%), and anorexia (grade 1 or 2, 17% or less).
Fever occurred in 41% of patients (grade 3, 2%) with various malignancies receiving gemcitabine monotherapy across 5 clinical trials (n = 979), often in the absence of clinical infection, and frequently in combination with other flu-like symptoms, such as asthenia, anorexia, headache, cough, chills, myalgia, asthenia, insomnia, rhinitis, sweating (diaphoresis), and/or malaise (19%). Fever and flu-like symptoms resulted in a discontinuation of monotherapy in less than 1% of patients. Infection occurred in 16% (grade 3 or 4, less than 2%) of monotherapy patients, with sepsis in less than 1%. After combination chemotherapy with either cisplatin or paclitaxel, infection was reported in 18% to 28% (grade 3 or 4, 4% to 5%), fever in 6% to 16% (grade 3, 1 or less), sepsis in 4% or less, and a flu-like syndrome in 3% or less. Febrile neutropenia was not described after gemcitabine monotherapy. However, in a clinical trial of patients with locally advanced or metastatic NSCLC (n = 522), febrile neutropenia occurred in 9 patients treated with gemcitabine plus cisplatin compared with 2 patients receiving cisplatin monotherapy. In a similar but smaller clinical trial (n = 135), the rate of hospitalization for febrile neutropenia in patients receiving gemcitabine plus cisplatin was lower than patients treated with cisplatin alone (7% vs. 12%). Febrile neutropenia was also more common after treatment with gemcitabine in combination with carboplatin (n = 175) or paclitaxel (n = 262) compared with either agent alone in separate clinical trials (6% or less vs. 2% or less; grade 3 or 4, less than 6% vs. less than 1%).
Skin rash was reported in 30% (grade 3 or 4, less than 1%) of patients with various malignancies receiving gemcitabine monotherapy across 5 clinical trials (n = 979). In these trials, alopecia was additionally reported in 15% (grade 3 or 4, less than 1%) of patients. When gemcitabine was administered with other chemotherapy, including cisplatin, paclitaxel, and carboplatin, rash occurred in 10% to 11% (grade 3 or 4, less than 2%) and alopecia in 49% to 90% (grade 3 or 4, 1 to 18%) of patients. Cellulitis, pseudocellulitis, and severe skin reactions including desquamation and bullous rash were also observed in postmarketing use of gemcitabine.
Hemolytic-uremic syndrome (HUS), including fatalities from renal failure (unspecified) or requiring dialysis, has been reported in 6 patients following one or more doses of gemcitabine in clinical trials (n = 2,429; 0.25%); the majority of renal failure cases leading to death were due to HUS. In patients with various cancers treated with gemcitabine monotherapy across 5 clinical trials (n = 979), additional renal adverse reactions included proteinuria (45%; grade 3, less than 1%), hematuria (35%; grade 3, less than 1%), azotemia (increased BUN) (grade 1 or 2, 16%), and increased creatinine (8%; grade 3, less than 1%). When used in combination with cisplatin (n = 311), proteinuria occurred in 12% to 23%, hematuria in 15% to 22%, elevated creatinine in 2% to 38% (grade 3 or 4, less than 5%), and azotemia in 6% or fewer patients. Monitor renal function before the first dose of gemcitabine and periodically during treatment; permanently discontinue gemcitabine therapy in patients with HUS or severe renal impairment; renal failure may not be reversible even with discontinuation of therapy. A diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or renal failure (elevation of serum creatinine or BUN).
Serious cases of thrombotic microangiopathy other than hemolytic uremic syndrome (HUS) have been reported in postmarketing experience with gemcitabine therapy.
Drug-induced hepatotoxicity, including hepatic failure and death, have been reported in patients receiving gemcitabine either as monotherapy or in combination with other hepatotoxic agents; this may be exacerbated in patients with concurrent liver metastases or pre-existing hepatitis, alcoholism, or liver cirrhosis. Elevated hepatic enzymes have been reported in patients with various malignancies receiving gemcitabine monotherapy across 5 clinical trials (n = 979), including increased ALT (68%; grade 3 or 4, 10%), increased AST (67%; grade 3 or 4, 8%), increased alkaline phosphatase (55%; grade 3 or 4, 9%), and hyperbilirubinemia (13%; grade 3 or 4, less than 3%). When given in combination with other chemotherapeutic agents including cisplatin, carboplatin, and paclitaxel, increased transaminases occurred in 3% to 22% (grade 3 or 4, 6% or less) and increased alkaline phosphatase in 16% to 19% (grade 3 or 4, 1% or less) of patients. Hepatic failure and hepatic sinusoidal obstruction syndrome (SOS), previously termed hepatic veno-occlusive disease (VOD), were reported during postmarketing use of gemcitabine. If a patient develops an elevated bilirubin with anemia, hold gemcitabine and evaluate for hemolytic uremic syndrome (HUS).
Peripheral vasculitis and gangrene have been reported during postmarketing experience with gemcitabine, including case reports of systemic vasculitis resulting in necrotizing enterocolitis and severe ischemic colitis. One case involved an 81-year old woman who, upon autopsy, was found to have experienced severe drug-induced vasculitis leading to necrotizing enterocolitis and acute renal tubular necrosis after surgery for serous carcinoma of the peritoneum and treatment with gemcitabine plus carboplatin. Another fatal case involved a 62-year old woman who developed extensive necrotizing enterocolitis secondary to vasculitis after undergoing surgery for serous ovarian cancer and chemotherapy with paclitaxel, carboplatin, and gemcitabine; she died after attempted treatment with a distal ileal resection, right hemicolectomy, ileal-transverse colon reanastamosis, and aggressive supportive management. Finally, two days after treatment with cisplatin plus gemcitabine, a 71-year-old male with bile-duct cancer and liver metastases developed abdominal pain, rapidly deteriorated, was diagnosed with severe ischemic colitis, and underwent an emergency total colectomy and ileocecal resection with ileostomy; he died 3 months later due to renal failure.
Myelosuppression, including neutropenia, thrombocytopenia, and anemia, have been reported in patients treated with gemcitabine in clinical trials; the risks are increased when gemcitabine is administered with other cytotoxic drugs. In some cases, myelosuppression has resulted in fatal infections or other complications. In patients receiving gemcitabine monotherapy across 5 clinical trials (n = 979), the following hematologic adverse reactions were reported: anemia (68%; grade 3 or 4, 8%), neutropenia (63%; grade 3 or 4, 25%), and thrombocytopenia (a24%; grade 3 or 4, 5%). When administered in combination with chemotherapy, the incidence of hematologic adverse reactions is higher, depending on the concomitant cytotoxic agent. Anemia was reported in 69% (grade 3 or 4, 7%) of patients treated with concomitant paclitaxel and in 86% to 89% (grade 3 or 4, 22% to 28%) of patients treated with concomitant cisplatin or carboplatin. Neutropenia occurred in 69% (grade 3 or 4, 48%) of patients receiving concomitant paclitaxel and in 79% to 90% (grade 3 or 4, 57% to 71%) of those who received concomitant cisplatin or carboplatin. Thrombocytopenia occurred in 26% (grade 3 or 4, less than 6%) and 78% to 85% (grade 3 or 4, 35% to 55%) of patients, respectively. Lymphopenia was additionally reported in 75% (grade 3 or 4, 43%) of patients with advanced NSCLC who were treated with gemcitabine plus cisplatin in one randomized clinical trial. Across these trials, red blood cell (monotherapy, 19%; combination therapy, 29% to 39%) and platelet (monotherapy, less than 1%; combination therapy, 3% to 28%) transfusions were more common in patients receiving gemcitabine as a part of combination therapy than in those treated with gemcitabine monotherapy. Hematologic adverse effects may be more common in patients age 65 years or older. While there were no overall differences in safety, older patients with various cancers treated with gemcitabine monotherapy experienced a higher rate of grade 3 or 4 thrombocytopenia across 5 clinical trials (n = 979), while older patients with ovarian cancer who received gemcitabine plus carboplatin experienced a significantly higher rate of grade 3 or 4 neutropenia in a separate clinical trial (n = 175). A diagnosis of hemolytic uremic syndrome should be considered if the patient develops anemia with evidence of microangiopathic hemolysis or severe thrombocytopenia.
Cardiovascular adverse reactions, including myocardial infarction, cerebrovascular accident (stroke), arrhythmia, and hypertension, have occurred in patients with various malignancies receiving gemcitabine monotherapy across 5 clinical trials (n = 979), resulting in discontinuation of therapy in 2% of patients. Congestive heart failure, myocardial infarction, arrhythmias, and supraventricular arrhythmias have all been reported in postmarketing experience with gemcitabine. Grade 3 cardiac arrhythmias occurred in 3% of NSCLC patients treated with gemcitabine plus cisplatin compared with less than 1% of those who received cisplatin alone in a randomized clinical trial. Edema (13%), peripheral edema (20%), and generalized edema (less than 1%) also occurred with gemcitabine monotherapy, resulting in discontinuation of therapy in less than 1% of patients. Edema also occurred in 12% of NSCLC patients treated with gemcitabine plus cisplatin, compared with 2% of those receiving cisplatin alone in a small randomized clinical trial (n = 135).
Hypotension was reported more often in NSCLC patients treated with gemcitabine plus cisplatin (n = 262) compared with cisplatin alone (n = 260) in a randomized clinical trial (12% vs. 7%; grade 3 or 4, 1% vs. 1%).
Pulmonary toxicity including pulmonary edema, pulmonary fibrosis, interstitial pneumonitis, and acute respiratory distress syndrome (ARDS) have been reported in postmarketing experience with gemcitabine; in some cases, these events led to fatal respiratory failure despite discontinuation of therapy. Some patients reported respiratory symptoms up to 2 weeks after the last dose of gemcitabine. Dyspnea, unrelated to the underlying disease and sometimes accompanied by bronchospasm, was reported in 23% (grade 3 or 4, less than 4%) of patients with various malignancies receiving gemcitabine monotherapy across 5 clinical trials (n = 979); bronchospasm occurred in less than 2% of monotherapy patients. When gemcitabine was administered with other chemotherapy, including cisplatin, paclitaxel, and carboplatin, severe (grade 3 or 4) dyspnea occurred in 1% to 3.4% of patients. Permanently discontinue gemcitabine for any unexplained dyspnea, with or without bronchospasm, or any evidence of pulmonary toxicity.
Gemcitabine therapy has been associated with radiation recall reactions and exacerbation of radiation toxicity. When gemcitabine was given concurrently (either together or 7 days or less apart) with thoracic radiation at a dose of 1,000 mg/m2 for up to 6 consecutive weeks to patients with NSCLC, life-threatening mucositis (especially esophagitis and pneumonitis) were reported. A radiation recall reaction has also been reported in patients treated with gemcitabine after prior radiation therapy. Excessive toxicity has not been observed when gemcitabine was administered more than 7 days before or after radiation. In a report based on 12 previously published cases, gemcitabine-related radiation recall reactions were different than what was commonly seen with other chemotherapy in that the majority of reactions (70%) affected internal tissues or organs rather than the skin; the effect on internal organs may also be correlated with a shorter time interval from the end of radiation to the initiation of chemotherapy.
Pulmonary eosinophilia (eosinophilic pneumonia) has been reported with gemcitabine treatment in postmarketing experience.
Capillary leak syndrome (CLS) with severe consequences has been reported in postmarketing experience with 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 (PRES) has been reported in postmarketing experience in patients treated with gemcitabine as a single-agent or in combination with other agents. Promptly evaluate patients who present with headache, seizures, lethargy, hypertension, confusion, blindness, and other visual impairment or neurologic disturbances for PRES with magnetic resonance imaging (MRI). Permanently discontinue gemcitabine if PRES develops during therapy.
Bleeding occurred in 17% (grade 3 or 4, less than 2%) of patients with various malignancies receiving gemcitabine monotherapy across 5 clinical trials (n = 979), resulting in discontinuation of therapy in less than 1%. When gemcitabine was administered in combination with other chemotherapy in separate clinical trials, including cisplatin, paclitaxel, and carboplatin, bleeding was reported in 9 to 14% (grade 3 or 4, 1 to 3%), compared to 3 to 4% (grade 3 or 4, 3% or less) of those receiving other chemotherapy without gemcitabine.
Electrolyte abnormalities were reported more often when gemcitabine was used in combination with cisplatin (n = 262) than with cisplatin alone (n = 260) in a randomized clinical trial of patients with locally advanced or metastatic NSCLC, including hyperglycemia (30% vs. 23%; grade 3 or 4, 4% vs. 3%), hypomagnesemia (30% vs. 17%; grade 3 or 4, 7% vs. 2%), and hypocalcemia (18% vs. 7%; grade 3 or 4, 2% vs. less than 1%).
An injection site reaction occurred in 4% of patients with various malignancies receiving gemcitabine monotherapy across 5 clinical trials (n = 979); grade 1 or 2 local reactions also occurred in 15% of patients treated with gemcitabine plus cisplatin (n = 262) compared with 6% of those who received cisplatin alone (n = 260) in a randomized trial of patients with locally advanced or metastatic NSCLC. If extravasation occurs, gemcitabine is considered a nonvesicant. Anaphylactoid reactions were additionally reported in patients who received gemcitabine monotherapy.
Paresthesias occurred in 10% (grade 3 or 4, less than 1%) of patients treated with gemcitabine monotherapy in clinical trials. Neurologic effects were more common when gemcitabine was administered with either paclitaxel or cisplatin. In a randomized clinical trial of patients with metastatic breast cancer, sensory neuropathy (peripheral neuropathy) (64% vs. 58%; grade 3 or 4, less than 6% vs. 3%) and motor neuropathy (15% vs. 10%; grade 3 or 4, less than 3% vs. less than 1%) occurred more often with gemcitabine plus paclitaxel compared with paclitaxel alone. When administered to patients with advanced NSCLC in combination with cisplatin in a randomized clinical trial, neuro-motor (35% vs. 15%; grade 3, 12% vs. 3%), neuro-sensory (23% vs. 18%; grade 3, 1% vs. 1%), and neuro-cortical adverse reactions (16% vs. 9%; grade 3 or 4, 4% vs. 1%) were reported more often compared with cisplatin alone. In a smaller trial of patients with advanced NSCLC, mild (grade 1 or 2) paresthesias occurred in 38% of patients treated with gemcitabine plus cisplatin compared with 16% (grade 3, 2%) of patients who received etoposide plus cisplatin. Grade 3 or 4 motor neuropathy was also more common in patients treated with gemcitabine plus carboplatin compared with carboplatin alone in yet another clinical trial (1.1% vs. 0.6%).
Gemcitabine is contraindicated for use in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis.
Bone marrow suppression including neutropenia, thrombocytopenia, and anemia has occurred with gemcitabine therapy; the risk is increased when used in combination with other chemotherapeutic agents. Monitor a CBC plus differential prior to each dose of gemcitabine; a dose reduction or interruption of therapy may be necessary. Patients with an active infection should be treated prior to receiving gemcitabine. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.
Gemcitabine is not recommended for use in combination with radiation therapy due to the risk of excessive toxicity. In a clinical trial of patients with non-small cell lung cancer (NSCLC) receiving concurrent (given together or 7 days or less apart) gemcitabine and thoracic radiation therapy, life-threatening mucositis, esophagitis, and pneumonitis were reported. Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation (nonconcurrent); however, radiation recall has occurred in patients who have received gemcitabine after prior radiation.
Gemcitabine should be used cautiously in patients with pre-existing hepatic disease, as treatment in patients with concurrent liver metastases or a history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency. Treatment-related hepatotoxicity has occurred with gemcitabine use, either as monotherapy or in combination with other potentially hepatotoxic drugs; some cases resulted in liver failure and death. Assess liver function tests prior to initiation of gemcitabine therapy and periodically during treatment; permanently discontinue gemcitabine in patients that develop severe hepatotoxicity.
Prolonged infusion times beyond 60 minutes, as well as more frequent than once-weekly administration, has been associated with infusion-related reactions and increased toxicity, including clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is also prolonged and volume of distribution increased with longer infusions. The manufacturer recommends administration of gemcitabine over 30 minutes; however, it has been safely administered over 100 minutes (10 mg/m2/min) in one clinical trial of patients with advanced pancreatic cancer. Use caution if administration of gemcitabine lasts beyond 60 minutes.
Pneumonitis (interstitial lung disease, ILD), pulmonary edema, acute respiratory distress syndrome (ARDS), and pulmonary fibrosis have been observed in patients treated with gemcitabine in clinical studies; some cases have been fatal, despite discontinuation of therapy. Use gemcitabine with caution in patients with pre-existing pulmonary disease or a history of interstitial pneumonitis or pulmonary fibrosis. Permanently discontinue therapy for unexplained dyspnea (with or without bronchospasm) or other evidence of severe pulmonary toxicity. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine.
Hemolytic-uremic syndrome (HUS) has been reported in patients treated with gemcitabine, including some cases requiring dialysis and fatalities due to renal failure; most gemcitabine-related cases of fatal renal failure in clinical trials were due to HUS. Permanently discontinue gemcitabine in patients with HUS or severe renal impairment. Assess renal function prior to initiation of therapy with gemcitabine and periodically during treatment. Consider HUS in patients who develop anemia with evidence of microangiopathic hemolysis, elevated bilirubin or LDH, reticulocytosis, severe thrombocytopenia, or increased serum creatinine/BUN (renal impairment). Renal failure may not be reversible, even after discontinuation of therapy.
Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), has been reported in patients treated with gemcitabine, either as monotherapy or in combination with other chemotherapeutic agents. Permanently discontinue gemcitabine in patients suspected of developing PRES. Patients with headache, lethargy, seizures, confusion, blindness, and other visual or neurologic disturbances should be evaluated for RPLS with magnetic resonance imaging (MRI). Mild to severe hypertension may also be present.
The safety and efficacy of gemcitabine have not been established in children. In a trial of pediatric patients with refractory leukemia, the maximum tolerated dose was 10 mg/m2 per minute for 360 minutes weekly for 3 weeks, followed by one week of rest. This dose of gemcitabine was administered to pediatric patients with acute lymphoblastic leukemia (ALL; n = 22) and acute myelogenous leukemia (AML; n = 10); one additional four-week course could be administered to patients with M1 or M2 bone marrow on day 28 who did not experience unacceptable toxicity. Observed toxicities included bone marrow suppression, febrile neutropenia, elevated transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.
Gemcitabine toxicity may occur earlier on therapy or with a higher frequency in geriatric patients and females, as a result of slower drug clearance leading to higher plasma and intracellular concentrations of gemcitabine and increased half-life at any dose. These patients require close monitoring during gemcitabine therapy and dose modification may be necessary. In clinical studies of patients with various cancers treated with gemcitabine monotherapy (n = 979), patients aged 65 and older had a higher rate of grade 3 or 4 thrombocytopenia compared with younger patients, although there were no overall differences in safety. In another randomized trial of women with ovarian cancer treated with gemcitabine in combination with carboplatin (n = 175), patients 65 years of age or older experienced significantly higher grade 3 or 4 neutropenia compared to younger patients; efficacy was similar between older and younger patients. Additionally, in studies of gemcitabine monotherapy, women (especially older women) were less likely to proceed to subsequent cycles of treatment, and were more likely to experience grade 3 or 4 neutropenia and thrombocytopenia.
Pregnancy should be avoided by females of reproductive potential during gemcitabine treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, gemcitabine can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving gemcitabine should be apprised of the potential hazard to the fetus. Two case reports described gemcitabine administration to pregnant women in the second trimester or later. In one case, a woman with lung cancer was administered gemcitabine and carboplatin at 25 weeks gestation. The baby was delivered at 28 weeks by elective cesarean. The baby had multiple complications from prematurity, but the authors speculated that chronic lung disease and excessive lung secretions may have been due to gemcitabine or the malignancy. At 8 months of age, the infant was successfully weaned from oxygen therapy and had age-appropriate neurodevelopment. The other case report described a pregnant woman with lung cancer who received gemcitabine in combination with cisplatin (weeks 19 to 25), in addition to cisplatin and docetaxel (weeks 9 to 18); the infant was delivered by cesarean at 33 weeks. An extensive workup of the infant failed to find any abnormalities and the infant was developing normally at 10 months of age. In animal studies, gemcitabine was embryotoxic in mice at doses approximately 0.005 times the recommended human dose on a mg/m2 basis, causing fetal malformations such as cleft palate and incomplete ossification. It was fetotoxic in rabbits at doses approximately 0.002 times the recommended human dose on a mg/m2 basis, resulting in fetal malformations such as fused pulmonary artery and absence of the gall bladder; embryotoxicity also occurred, including decreased fetal viability, reduced live litter sizes, and developmental delays.
Counsel patients about the reproductive risk and contraception requirements during gemcitabine treatment. Gemcitabine can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during treatment with gemcitabine and for 6 months after the last dose; males with female partners of reproductive potential should use effective contraception during and for at least 3 months after treatment with gemcitabine due to a risk of male-mediated teratogenicity. Females of reproductive potential should undergo pregnancy testing prior to initiation of gemcitabine. Women who become pregnant while receiving gemcitabine should be apprised of the potential hazard to the fetus. Based on animal studies, gemcitabine may cause infertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.
Due to the potential for serious adverse reactions in nursing infants from gemcitabine, advise women to discontinue breast-feeding during treatment and for at least 1 week after the final dose. It is not known whether gemcitabine is present in human milk, although many drugs are excreted in human milk.
For the treatment of non-small cell lung cancer (NSCLC):
-for the perioperative treatment of resectable non-small cell lung cancer (NSCLC) (tumors greater than or equal to 4 cm or node positive), in combination with pembrolizumab and cisplatin*:
NOTE: Pembrolizumab is FDA-approved in combination with platinum-based chemotherapy for the perioperative treatment of resectable NSCLC.
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1 and 8, in combination with cisplatin (75 mg/m2 IV on day 1), every 3 weeks for up to 4 cycles as neoadjuvant therapy in combination with pembrolizumab (200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks for 12 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity). Administer pembrolizumab prior to chemotherapy when given on the same day. Within 4 to 12 weeks after surgery, resume adjuvant pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks as monotherapy for 39 weeks or until disease recurrence or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, randomized, double-blind clinical trial (KEYNOTE-671), perioperative treatment with pembrolizumab plus neoadjuvant platinum-based chemotherapy significantly improved the median overall survival (not reached vs. 52.4 months) and median event-free survival (not reached vs. 17 months) compared with perioperative placebo plus platinum-based chemotherapy in patients with previously untreated and resectable stage II, IIIA, or IIIB (N2) NSCLC. Platinum-based chemotherapy included cisplatin plus gemcitabine for patients with squamous histology and cisplatin plus pemetrexed for patients with nonsquamous histology.
-for first-line treatment of inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) NSCLC in combination with cisplatin (EVERY 4 WEEKS):
Intravenous dosage (EVERY 4 WEEKS):
Adults: 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15, followed by cisplatin (100 mg/m2 IV) on day 1, every 28 days. Gemcitabine doses should be adjusted for hematologic toxicity based upon the granulocyte and platelet counts taken on the day of therapy. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. In a multicenter, randomized clinical trial, first-line treatment with gemcitabine cisplatin (n = 260) significantly improved overall survival compared with cisplatin alone (n = 262) in patients with inoperable stage IIIA, IIIB, or IV NSCLC (9 months vs. 7.6 months). The tumor response rate (26% vs. 10%) and time to disease progression (5.2 months vs. 3.7 months) were also significantly improved in the gemcitabine arm.
-for first-line treatment of inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) NSCLC in combination with cisplatin (EVERY 3 WEEKS):
Intravenous dosage (EVERY 3 WEEKS):
Adults: 1,250 mg/m2 IV over 30 minutes on days 1 and 8, followed by cisplatin (100 mg/m2 IV) on day 1, every 21 days. Gemcitabine doses should be adjusted for hematologic toxicity based upon the granulocyte and platelet counts taken on the day of therapy. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. In a multicenter, randomized clinical trial, overall survival was not significantly different for patients with stage IIIB or IV NSCLC treated with gemcitabine/cisplatin (n = 69) compared with etoposide/cisplatin (n = 66) (8.7 months vs. 7 months). The tumor response rate was 33% versus 14%, respectively, with a median time to disease progression of 5 months in the gemcitabine arm and 4.1 months in the etoposide arm. Alternative dosing includes gemcitabine 1,250 mg/m2 IV on days 1 and 8 followed by a lower dose of cisplatin (75 mg/m2) on day 1, every 3 weeks; also gemcitabine 1,000 mg/m2 IV on days 1 and 8, followed by cisplatin (80 mg/m2 IV) on day 1, every 3 weeks has been studied.
-for first-line treatment of inoperable, locally advanced or metastatic NSCLC in combination with carboplatin*:
Intravenous dosage:
Adults: 1,200 mg/m2 IV on days 1 and 8 in combination with carboplatin (AUC 5 IV) on day 1, every 21 days for 6 cycles. Alternatively, gemcitabine 1,000 mg/m2 IV on days 1, 8 and 15 in combination with carboplatin (AUC 5 IV) on day 1, repeated every 28 days for 4 cycles or, gemcitabine 1,000 mg/m2 IV on days 1 and 8 in combination with carboplatin (AUC 5 IV) on day 1, repeated every 21 days for 4 cycles, have also been studied.
-for the treatment of advanced or metastatic NSCLC (stage IIIB or IV) in combination with paclitaxel*:
Intravenous dosage:
Adults: Gemcitabine 1,000 mg/m2 IV on days 1 and 8 in combination with paclitaxel 200 mg/m2 IV on day 1, every 3 weeks has been given. Alternately, gemcitabine 1,250 mg/m2 IV on days 1 and 8 in combination with paclitaxel 175 mg/m2 IV on day 1, every 3 weeks has also been given.
-for first-line treatment of unresectable, locally advanced or metastatic NSCLC in combination with docetaxel*:
Intravenous dosage:
Adults: 1,000 or 1,100 mg/m2 IV days 1 and 8 in combination with docetaxel day 1 repeated every 21 days (GD regimen) has been studied. In a phase 3 trial of 311 patients with Stage IIIB or IV NSCLC, GD (gemcitabine dose, 1,000 mg/m2) was compared to cisplatin/vinorelbine (CV). Progression-free survival (4.2 months vs. 4 months) and overall survival (11.1 months vs. 9.6 months) were not significantly different between the 2 arms. Grade 3 and 4 febrile neutropenia, anemia and gastrointestinal toxicities were all significantly higher with CV, while fluid retention and grade 3 or 4 pulmonary events were greater with GD. In another phase 3 trial of 413 patients comparing GD (gemcitabine dose, 1,000 mg/m2) to CV, no difference in overall survival, the primary endpoint, was observed (9 months vs. 9.7 months). Grade 3 and 4 neutropenia and nausea/vomiting occurred more frequently with CV. In a phase 3 trial of 312 patients, GD (gemcitabine dose, 1,100 mg/m2) was compared to single-agent docetaxel. Overall survival, the primary endpoint, was significantly improved in the combination arm (9.4 months vs. 8.3 months).
-for the treatment of previously untreated advanced NSCLC in combination with topotecan*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1 and 15 in combination with topotecan (1 mg/m2 IV on days 1, 2, 3, 4, and 5). The cycle was repeated every 28 days. In a phase 2 study of 51 patients with previously untreated advanced NSCLC, 17% of patients had a partial response while 23% had stable disease. The 1-year survival rate was 39% with median survival of 7.6 months.
-for the second-line treatment of advanced NSCLC in combination with topotecan*:
Intravenous dosage:
Adults: 400 mg/m2 IV on days 1 and 5 in combination with topotecan (0.75 mg/m2 IV on days 1, 2, 3, 4, and 5). The cycle was repeated every 21 days. In a phase 2 trial, 35 patients with advanced non-small cell lung cancer received topotecan/gemcitabine in the second-line setting. Partial response was observed in 11% of patients while 23% had stable disease. Of 17 patient with refractory disease, the partial response rate was 18%, and 18% had stable disease. For all patients, the median survival was 7 months with a 1-year survival rate of 20%.
For the treatment of pancreatic cancer:
-for adjuvant treatment of pancreatic cancer as monotherapy*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15 every 28 days for 6 cycles. In a phase 3 trial, 368 patients with previously untreated pancreatic cancer were randomized to receive gemcitabine or observation after complete surgical resection. Disease-free survival (13.4 months vs. 6.9 months), the primary endpoint, and overall survival (22.8 months vs. 20.2 months) were significantly longer in the gemcitabine arm. In another phase 3 trial, 442 patients with surgically resected pancreatic cancer were randomized to receive gemcitabine before and after 5-fluorouracil (5-FU)-based chemoradiation therapy (CRT) or 5-FU before and after 5-FU-based CRT. Beginning 3 to 8 weeks after surgery, gemcitabine patients received 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15, followed in 1 to 2 weeks by 5.5 weeks of 5-FU-based CRT, which was followed in 3 to 5 weeks by gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15, every 28 days for 3 additional cycles. The prospective primary endpoints of the study were overall survival (OS) and OS in patients with tumors of the pancreatic head. No significant difference was observed in OS for the total treatment population, however patients with tumors confined to the pancreatic head (n = 330) did experience a significantly longer OS in the gemcitabine arm (20.6 months vs. 16.9 months). Grade 4 hematologic toxicities were significantly greater in patients treated with gemcitabine (14% vs. 2%).
-for the adjuvant treatment of pancreatic adenocarcinoma, in combination with capecitabine*:
NOTE: Capecitabine is FDA-approved for the adjuvant treatment of pancreatic adenocarcinoma, in combination with gemcitabine.
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1, 8, and 15, in combination with capecitabine (830 mg/m2 PO twice daily on days 1 to 21), repeated every 28 days until disease progression, unacceptable toxicity, or for a maximum of 6 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After a median follow-up of 60 months, patients with ductal adenocarcinoma of the pancreas treated with gemcitabine plus capecitabine after an R0 or R1 resection had significantly prolonged median overall survival compared with those treated with gemcitabine alone in a multicenter, randomized, open-label phase 3 clinical trial (27.7 months vs. 26 months); 5-year survival rates were 20% and 28%, respectively. In a subgroup analysis after , the magnitude of effect on median overall survival in patients with R0 resection (39.5 months vs. 27.9 months) was significantly greater than in patients with R1 resection (23.7 months vs. 23 months).
-for first-line treatment of locally advanced (nonresectable Stage II or III) or metastatic (Stage IV) pancreatic cancer, or as second-line treatment in patients who were previously treated with fluorouracil:
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 minutes once weekly for 7 consecutive weeks, followed by 1 week of rest. After week 8, administer gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15, repeated every 28 days. Gemcitabine doses should be adjusted for hematologic toxicity based upon the granulocyte and platelet counts taken on the day of therapy. In a randomized, single-blind, active-controlled clinical trial, patients with treatment-naive locally advanced or metastatic pancreatic cancer were treated with either gemcitabine (n = 63) or fluorouracil (n = 63). Clinical benefit response (defined as a reduced pain intensity or analgesic consumption of at least 50% or a 20-point or greater improvement in Karnofsky score for at least 4 weeks without worsening in other parameters, OR stable pain and performance status, with a sustained weight gain of at least 7% that was sustained for 4 weeks or longer, not due to fluid accumulation) was significantly improved in patients who received gemcitabine compared with fluorouracil (22.2% vs. 4.8%). Additionally, median overall survival (5.7 vs. 4.2 months) and time to disease progression (2.1 vs. 0.9 months) were significantly improved in patients treated with gemcitabine.
-for first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer in combination with erlotinib*:
NOTE: Erlotinib is FDA-approved for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine.
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 minutes once weekly for 7 consecutive weeks, followed by 1 week of rest, in combination with erlotinib 100 mg by mouth once daily on an empty stomach. After week 8, continue erlotinib and administer gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15, repeated every 28 days until disease progression or unacceptable toxicity. Gemcitabine doses should be adjusted for hematologic toxicity based upon the granulocyte and platelet counts taken on the day of therapy. In a randomized, double-blind, placebo-controlled clinical trial, patients with locally advanced, unresectable, or metastatic pancreatic cancer were treated with gemcitabine in combination with either erlotinib (n = 285) or placebo (n = 284). Combination with erlotinib significantly improved overall survival (6.4 vs. 6 months) and progression-free survival (PFS) (3.8 vs. 3.5 months) compared with placebo; 1-year survival was 23.8% vs. 19.4%, respectively. A tumor response (complete response plus partial response) was observed in 8.6% of patients treated with gemcitabine plus erlotinib and in 7.9% of those who received gemcitabine and placebo; the median duration of response was 23.9 weeks and 23.3 weeks, respectively.
-for the first-line treatment of metastatic pancreatic cancer in combination with nab-paclitaxel*:
NOTE: Nab-paclitaxel is FDA approved in combination with gemcitabine for the first-line treatment of metastatic pancreatic cancer.
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 to 40 minutes on days 1, 8, and 15 preceded by nab-paclitaxel (125 mg/m2 IV over 30 to 40 minutes on days 1, 8, and 15) every 28 days. In a multinational, randomized, open-label study, nab-paclitaxel plus gemcitabine (n = 431) was compared to gemcitabine 1,000 mg/m2 IV weekly for 7 weeks with a 1 week rest period in cycle 1, and then on days 1, 8, and 15 of each subsequent 28 day cycle (n = 430) until disease progression or unacceptable toxicity in patients with metastatic adenocarcinoma of the pancreas. Median overall survival (8.5 months vs. 6.7 months) and median progression free survival (5.5 months vs. 3.7 months) were improved by the combination of nab-paclitaxel and gemcitabine. Additionally, 23% of patients treated with combination therapy had a confirmed complete or partial overall response, compared to 7% of patients treated with gemcitabine alone.
-for first-line treatment of unresectable locally advanced or metastatic pancreatic cancer in combination with oxaliplatin*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 100 minutes (10 mg/m2/minute) on day 1 in combination with oxaliplatin (100 mg/m2 IV on day 2), repeated every 2 weeks until disease progression or unacceptable toxicity. In a phase 3 study of 313 patients with untreated locally advanced and metastatic unresectable pancreatic cancer, oxaliplatin and gemcitabine (GemOx) were compared to gemcitabine alone (given over 30 minutes). The primary endpoint of overall survival was not significantly different between the 2 treatments. Seventy-four percent of patients in the gemcitabine arm crossed-over to receive gemcitabine and platinum combinations at disease progression, possibly limiting this variable. Response rate and progression-free survival were each significantly better with GemOx, 26.8% and 5.8 months, as compared to gemcitabine, 17.3% and 3.7 months. In addition, clinical benefit response was significantly greater in patients who received GemOx than gemcitabine, 38.2% vs. 26.9%. In another phase 3 trial, 833 patients with previously untreated locally advanced and metastatic unresectable pancreatic cancer were randomized to receive GemOx, fixed-dose rate gemcitabine (1,500 mg/m2 IV infusion on days 1, 8, and 15 of a 28-day cycle, administered at a rate of 10 mg/m2/minute IV), or 30-minute IV infusions of gemcitabine (1,000 mg/m2 IV weekly for 7 weeks, in week 9 administration on days 1, 8, and 15 every 28 days). Neither GemOx (5.7 months) or fixed-dose-rate gemcitabine (6.2 months) produced a statistically significant difference in overall survival compared to gemcitabine as a 30-minute infusion (4.9 months). Grade 3 or 4 neutropenia and thrombocytopenia occurred more frequently in the gemcitabine fixed-dose rate arm; grade 3 or 4 sensory neuropathy occurred more frequently with GemOx.
For the treatment of breast cancer:
-for the first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated, in combination with paclitaxel:
Intravenous dosage:
Adults: 1,250 mg/m2 IV over 30 minutes, preceded by paclitaxel (175 mg/m2 IV over 3 hours), on day 1, then gemcitabine 1,250 mg/m2 IV over 30 minutes on day 8, repeated every 21 days. Gemcitabine doses should be adjusted for hematologic toxicity based upon the granulocyte and platelet counts taken on day 8 of therapy. In a randomized trial, gemcitabine plus paclitaxel was compared to paclitaxel alone in patients with metastatic breast cancer who had received prior adjuvant/neoadjuvant anthracycline chemotherapy (unless clinically contraindicated). The combination therapy resulted in statistically significant improvement in time to documented disease progression (5.2 months vs. 2.9 months) and overall response rate (40.8% vs. 22.1%) as compared with paclitaxel alone. Overall survival was not significantly improved (18.6 months vs. 15.8 months).
-for the treatment of locally recurrent unresectable or metastatic, PD-L1 positive (CPS 10 or more), triple negative breast cancer (TNBC), in combination with carboplatin and pembrolizumab*:
NOTE: Select patients for treatment based on the presence of positive PD-L1 expression. Information on FDA-approved tests for the detection of PD-L1 expression in TNBC is available at http://www.fda.gov/CompanionDiagnostics.
NOTE: Pembrolizumab is FDA-approved in combination with carboplatin and gemcitabine for this indication.
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1 and 8, every 21 days in combination with carboplatin (AUC 2 IV on days 1 and 8, every 21 days) and pembrolizumab (200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression); the number of cycles of gemcitabine plus carboplatin was not specified. In a multicenter, double-blind clinical trial (KEYNOTE-355), patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting were randomized to treatment with either pembrolizumab or placebo in combination with paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin regardless of tumor PD-L1 expression. The addition of pembrolizumab to chemotherapy significantly improved the median progression-free survival (9.7 months vs. 5.6 months) compared with placebo plus chemotherapy in the subgroup of patients with a CPS of 10 or more. The objective response rate was 53% compared with 40%, respectively (complete response, 17% vs. 13%) for a median duration of 19.3 months in the pembrolizumab arm and 7.3 months in the placebo arm.
-for the treatment of metastatic breast cancer as a single agent*:
Intravenous dosage:
Adults: 1,200 to 1,250 mg/m2 IV on days 1, 8, and 15, every 28 days; overall response rate was 16% to 29% in patients who had previously received at least 1 other chemotherapy.
For the treatment of ovarian cancer:
-for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of a platinum-based therapy, in combination with carboplatin:
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 minutes followed by carboplatin AUC 4 IV on day 1, then gemcitabine 1,000 mg/m2 IV over 30 minutes on day 8, repeated every 21 days. Gemcitabine doses should be adjusted for hematologic toxicity based upon the granulocyte and platelet counts taken on day 8 of therapy. In a phase 3 trial, treatment with gemcitabine plus carboplatin significantly improved progression-free survival compared with carboplatin alone (8.6 months vs. 5.8 months) in patients with relapsed ovarian cancer, at least 6 months after primary platinum therapy; overall survival was not significantly different between the two arms (18 months vs. 17.3 months). Other phase 2 trials have reported results of gemcitabine in combination with other agents (e.g., cisplatin, liposomal doxorubicin, or topotecan). In one trial of 42 patients with advanced ovarian cancer, gemcitabine 1,250 mg/m2 IV on day 1 and 8 of a 21-day cycle was given in combination with cisplatin (75 mg/m2 IV on day 1 prior to gemcitabine) as first-line therapy. Per an intent-to-treat analysis, the overall response rate was 57.1%. After a median follow-up of 15.8 months, the median survival was 24 months and the median PFS was 13.4 months.
-for recurrent advanced ovarian cancer as a single agent*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1, 8, and 15, every 28 days or 1,000 mg/m2 IV on days 1 and 8, every 21 days have been given. In 2 phase 3 trials, time to progression in one study and progression free survival in the other were similar to liposomal doxorubicin.
For the treatment of biliary tract cancer*:
-for the treatment of advanced or metastatic biliary tract cancer* in combination with cisplatin:
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1 and 8 in combination with cisplatin (25 mg/m2 IV on days 1 and 8) every 21 days for 8 cycles. In a phase 3 trial, 410 patients with advanced cholangiocarcinoma, gallbladder cancer, or ampullary cancer were randomized to receive gemcitabine with or without cisplatin. Overall survival, the primary endpoint, was significantly greater in the combination treatment arm (11.7 months vs. 8.1 months). Median progression-free survival was also significantly greater in the combination treatment arm (8 months vs. 5 months). Grade 3 or 4 neutropenia (25.3% vs. 16.6%) and anemia (7.6% vs. 3%) occurred significantly more often with combination therapy. Overall incidence of grade 3 or 4 toxicities were not significantly different between the two treatment arms (70.7% vs. 68.8%). Additional trials have shown a benefit for gemcitabine/cisplatin compared to cisplatin alone.
-for the treatment of locally advanced unresectable or metastatic biliary tract cancer, in combination with cisplatin and pembrolizumab*:
NOTE: Pembrolizumab is FDA-approved for the treatment of locally advanced unresectable or metastatic biliary tract cancer, in combination with gemcitabine and cisplatin.
Intravenous dosage:
Adults: 1,000 mg/m2 IV in combination with cisplatin (25 mg/m2 IV) on days 1 and 8, every 3 weeks; in KEYNOTE-966, treatment with cisplatin was limited to 8 cycles and there was no limit to the number of cycles of gemcitabine. Administer with pembrolizumab 200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks until disease progression or up to 24 months in patients without progression. Administer pembrolizumab prior to chemotherapy when given on the same day. In a multicenter, randomized, double-blind phase 3 clinical trial (KEYNOTE-966), treatment with pembrolizumab in combination with cisplatin and gemcitabine significantly improved the median overall survival compared with placebo plus cisplatin and gemcitabine (12.7 months vs. 10.9 months) in patients with locally advanced unresectable or metastatic biliary tract cancer who had not received prior systemic therapy in the advanced disease setting. The median progression-free survival was 6.5 months in the pembrolizumab arm compared with 5.6 months in the placebo arm, and the median objective response rate was 29% in each arm (complete response, 2.1% vs. 1.3%); the median duration of response was 8.3 months versus 6.8 months, respectively.
For the first-line treatment of locally advanced or metastatic transitional-cell bladder cancer*, in combination with cisplatin:
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 to 60 minutes on days 1, 8, and 15 plus cisplatin 70 mg/m2 on day 2 repeated every 28 days (GC regimen) for up to 6 cycles was compared with methotrexate 30 mg/m2 on days 1, 15, and 22, vinblastine 3 mg/m2 IV on days 2, 15, and 22, doxorubicin 30 mg/m2 on day 2, and cisplatin 70 mg/m2 on day 2 (MVAC regimen) in a multicenter, randomized, phase III trial. In a long-term analysis of this study, the improvement in overall survival (OS) (14 months vs. 15.2 months) and progression-free survival (PFS) (7.7 months vs. 8.3 months) by GC was not significantly improved compared with MVAC. The 5-year OS (13% vs. 15.3%) and PFS (9.8% vs. 11.3%) rates were also nonsignificantly lower with GC compared with MVAC; however, GC was associated with significantly less grade 3 or 4 neutropenic sepsis (1% vs. 12%) and mucositis (1% vs. 22%). Treatment-related death was also reported less often in the GC arm (1% vs. 3%).
For the treatment of malignant mesothelioma*:
-for the treatment of malignant pleural mesothelioma in combination with cisplatin or carboplatin*:
Intravenous dosage:
Adults: Gemcitabine 1,000 mg/m2 IV on days 1, 8, and 15 in combination with cisplatin 100 mg/m2 IV on day 1, every 28 days for 6 cycles. Alternately, gemcitabine 1,250 mg/m2 IV on days 1 and 8 in combination with cisplatin 80 mg/m2 IV on day 1, every 21 days for 6 cycles, has also been studied. Carboplatin AUC 5 IV on day 1 has been substituted for cisplatin, and given with gemcitabine 1,000 mg/m2 IV on days 1, 8, and 15, every 28 days for 6 cycles.
-for the treatment of relapsed malignant mesothelioma as a single-agent*:
Intravenous dosage:
Adults: 1,250 mg/m2 to 1,500 mg/m2 IV on days 1, 8, and 15, every 28 days has been given in phase II studies; overall response rates were low, ranging from 0 to 7%.
For the treatment of advanced cutaneous T-cell lymphoma (CTCL)*, including mycosis fungoides* and Sezary syndrome*:
Intravenous dosage:
Adults: 1,200 mg/m2 IV over 30 minutes on days 1, 8, and 15 repeated every 28 days for 3 to 6 cycles has been studied in nonrandomized, phase II trials; overall response rates ranged from 70% to 75%.
For the treatment of non-Hodgkin's lymphoma (NHL)*:
-for the treatment of relapsed or refractory, aggressive NHL in transplant eligible patients, in combination with dexamethasone and cisplatin (and rituximab for CD20-positive disease)*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 minutes on days 1 and 8 in combination with cisplatin 75 mg/m2 IV on day 1 and dexamethasone 40 mg orally daily on days 1, 2, 3, and 4 (GDP regimen) was evaluated in a randomized, phase III trial (NCIC-CTG LY.12 trial). Treatment was repeated every 21 days for 2 cycles. In patients with CD20-positive lymphoma, rituximab 375 mg/m2 IV was added on day 1 of each treatment cycle (R-GDP regimen). Patients in the trial could receive a third cycle of therapy if they did not achieve a complete or partial response after the second cycle. Patients with CD20-positive lymphoma who received an autologous stem-cell transplant (ASCT) were randomized to receive either rituximab 375 mg/m2 IV every 2 months for 6 cycles or observation starting 28 days post ASCT.
For the treatment of peripheral T-cell lymphoma (PTCL)*:
-for the first-line treatment of PTCL in combination with cisplatin, prednisone, and thalidomide*:
Intravenous dosage:
Adults and Adolescents 14 years and older: 800 mg/m2 IV over 30 minutes on days 1 and 8 in combination with cisplatin (25 mg/m2 IV on days 1, 2 and 3), prednisone (60 mg/m2 PO on days 1, 2, 3, 4, and 5), and thalidomide (200 mg PO daily) repeated every 21 days until disease progression or for up to 6 cycles was evaluated in patients with previously untreated PTCL in a randomized trial. Patients received aspirin 100 mg/day PO during thalidomide therapy. The use of granulocyte colony-stimulation factor was permitted as indicated.
For the treatment of urothelial carcinoma*:
-for the adjuvant treatment of locally advanced urothelial cancer of the upper urinary tract (UTUC), in combination with cisplatin*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 minutes on day 1 and 8, in combination with cisplatin (70 mg/m2 IV over 4 hours on day 1), every 21 days for 4 cycles. The cisplatin dose may be divided over 2 consecutive days for patients with baseline CrCl of 70 mL/min or higher that falls to 50 to 69 mL/min during treatment. Substitute carboplatin (AUC 4.5 or 5 IV over 1 hour) for cisplatin in patients with impaired renal function (CrCl 30 to 49 mL/min). In a randomized, phase 3 clinical trial, treatment with gemcitabine plus either cisplatin or carboplatin significantly improved disease-free survival in patients with locally advanced UTUC when initiated within 90 days after radical nephroureterectomy compared with surveillance. Based on recommendations from the independent data monitoring committee, study enrollment was ended early and patients still within the 90-day window from nephroureterectomy were offered chemotherapy.
-for the adjuvant treatment of locally advanced urothelial cancer of the upper urinary tract (UTUC), in combination with carboplatin*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 minutes on day 1 and 8, in combination with carboplatin (AUC 4.5 or 5 IV over 1 hour on day 1), every 21 days for 4 cycles. In a randomized, phase 3 clinical trial, treatment with gemcitabine plus either cisplatin or carboplatin significantly improved disease-free survival in patients with locally advanced UTUC when initiated within 90 days after radical nephroureterectomy compared with surveillance. Based on recommendations from the independent data monitoring committee, study enrollment was ended early and patients still within the 90-day window from nephroureterectomy were offered chemotherapy.
-for the first-line treatment of locally advanced or metastatic urothelial carcinoma, in combination with cisplatin and atezolizumab*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1 and 8, in combination with cisplatin (70 mg/m2 IV on day 1) and atezolizumab (1,200 mg IV over 60 minutes on day 1), every 21 days for up to 6 cycles. In a randomized phase 3 trial (the IMvigor 130 trial), the addition of atezolizumab to platinum-based chemotherapy in patients with metastatic urothelial cancer significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy alone in the intent-to-treat population; the PFS benefit in the atezolizumab arm was seen across all subgroups, although it was not statistically significant in several including patients with PD-L1 0/1 expression and in patients receiving carboplatin- versus cisplatin-based regimens. At an interim analysis after 11.8 months of follow-up, overall survival was not significantly different between groups.
-for the first-line treatment of locally advanced or metastatic urothelial carcinoma, in combination with carboplatin and atezolizumab*:
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1 and 8, in combination with carboplatin (AUC 4.5 IV on day 1) and atezolizumab (1,200 mg IV over 60 minutes on day 1), every 21 days for up to 6 cycles. In a randomized phase 3 trial (the IMvigor 130 trial), the addition of atezolizumab to platinum-based chemotherapy in patients with metastatic urothelial cancer significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy alone in the intent-to-treat population; the PFS benefit in the atezolizumab arm was seen across all subgroups, although it was not statistically significant in several including patients with PD-L1 0/1 expression and in patients receiving carboplatin- versus cisplatin-based regimens. At an interim analysis after 11.8 months of follow-up, overall survival was not significantly different between groups.
For the treatment of nasopharyngeal carcinoma*:
-for the first-line treatment of metastatic or recurrent, locally advanced nasopharyngeal carcinoma, in combination with cisplatin and toripalimab*:
NOTE: Toripalimab is FDA-approved for the first-line treatment of metastatic or recurrent, locally advanced nasopharyngeal carcinoma, in combination with cisplatin and gemcitabine.
Intravenous dosage:
Adults: 1,000 mg/m2 IV on days 1 and 8 plus cisplatin (80 mg/m2 IV on day 1) every 3 weeks for up to 6 cycles. Administer in combination with toripalimab (240 mg IV on day 1, every 3 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without progression). Administer toripalimab prior to chemotherapy when given on the same day. In the pre-specified interim analysis of a multicenter, randomized, double-blind phase 3 clinical trial (JUPITER-02), treatment with toripalimab plus cisplatin and gemcitabine significantly improved the median progression-free survival (11.7 months vs. 8 months) and the overall response rate (77% vs. 66%; complete response, 19% vs. 11%) compared with placebo plus cisplatin and gemcitabine in patients with advanced nasopharyngeal cancer who had not received previous systemic chemotherapy for recurrent or metastatic disease; the median duration of response was 10 months versus 5.7 months, comparatively. In the final overall survival analysis, median overall survival was also significantly improved in the toripalimab arm (not reached vs. 33.7 months); the 2-year and 3-year overall survival rates were 78% versus 65.1% and 64.5% versus 49.2%, respectively.
Therapeutic Drug Monitoring:
Permanently discontinue gemcitabine for any of the following:
-Unexplained dyspnea or evidence of severe pulmonary toxicity
-Hemolytic-uremic syndrome
-Capillary leak syndrome
-Posterior reversible encephalopathy syndrome (PRES)
Dosage Adjustments for Treatment-Related Toxicities:
Neutropenia, Ovarian cancer (in combination with carboplatin)
-Absolute neutrophil count (ANC) less than 1,500 cells/mm3, DAY 1: Delay treatment cycle for one week. If ANC is 1,500 cells/mm3 or higher on day 8 (and platelets are 100,000 cells/mm3 or higher), give gemcitabine at the full dose.
-ANC 1,000 to 1,499 cells/mm3, DAY 8: Administer gemcitabine at 50% of the full dose.
-ANC less than 1,000 cells/mm3, DAY 8: Hold chemotherapy. If the ANC is less than 500 cells/mm3 for more than 5 days, less than 100 cells/mm3 for more than 3 days, or if the cycle is delayed for more than one week due to neutropenia, permanently reduce the dose of gemcitabine on days 1 and 8 to 800 mg/m2. If there is a recurrence of the ANC less than 500 cells/mm3 for more than 5 days, less than 100 cells/mm3 for more than 3 days, or if the cycle is delayed for more than one week due to neutropenia, further reduce the dose of gemcitabine to 800 mg/m2 on day 1 only (no dose on day 8).
Neutropenia, Breast cancer (in combination with paclitaxel)
-ANC less than 1,500 cells/mm3, DAY 1: Delay treatment cycle for one week.
-ANC greater than or equal to 1,200 cells/mm3, DAY 8 (and platelets greater than 75,000 cells/mm3): Administer gemcitabine at the full dose.
-ANC 1,000 to 1,199 cells/mm3, DAY 8: Administer gemcitabine at 75% of the full dose.
-ANC 700 to 999 cells/mm3, DAY 8 (and platelets are greater than or equal to 50,000 cells/mm3): Administer gemcitabine at 50% of the full dose.
-ANC less than 700 cells/mm3, DAY 8: Hold chemotherapy.
Neutropenia, NSCLC (in combination with cisplatin) and pancreatic cancer (as monotherapy)
-ANC 500 to 999 cells/mm3: Administer gemcitabine at 75% of the full dose.
-ANC less than 500 cells/mm3: Hold chemotherapy.
Febrile Neutropenia
-Ovarian cancer (in combination with carboplatin): Permanently reduce the dose of gemcitabine in the next cycle to 800 mg/m2 on days 1 and 8. If febrile neutropenia recurs after the initial dose reduction, further reduce the dose of gemcitabine to 800 mg/m2 on day 1 only (no dose on day 8).
Thrombocytopenia, Ovarian cancer (in combination with carboplatin)
-Platelets less than 100,000 cells/mm3, DAY 1: Delay treatment cycle. If platelets are 100,000 cells/mm3 or higher on day 8 (and ANC is 1,500 cells/mm3 or higher), give gemcitabine at the full dose.
-Platelets 75,000 to 99,999 cells/mm3, DAY 8 (and ANC 1,000 cells/mm3 or higher): Administer gemcitabine at 50% of the full dose.
-Platelets less than 75,000 cells/mm3, DAY 8: Hold chemotherapy. If the platelet nadir is less than 25,000 cells/mm3, or if the cycle is delayed for more than one week due to thrombocytopenia, permanently reduce the dose of gemcitabine on days 1 and 8 to 800 mg/m2. If there is a recurrence of the platelet nadir to less than 25,000 cells/mm3, or if the cycle is delayed for more than one week due to thrombocytopenia, further reduce the dose of gemcitabine to 800 mg/m2 on day 1 only (no dose on day 8).
Thrombocytopenia, Breast cancer (in combination with paclitaxel)
-Platelets less than 100,000 cells/mm3, DAY 1: Delay treatment cycle for one week.
-Platelets greater than 75,000 cells/mm3, DAY 8 (and ANC greater than 1,200 cells/mm3): Administer gemcitabine at the full dose.
-Platelets 50,000 to 75,000 cells/mm3, DAY 8: Administer gemcitabine at 75% of the full dose.
-Platelets greater than or equal to 50,000 cells/mm3, DAY 8 (and ANC 700 to 999 cells/mm3): Administer gemcitabine at 50% of the full dose.
-Platelets less than 50,000 cells/mm3, DAY 8: Hold chemotherapy.
Thrombocytopenia, NSCLC (in combination with cisplatin) and pancreatic cancer (as monotherapy)
-Platelets 50,000 to 99,999 cells/mm3: Administer gemcitabine at 75% of the full dose.
-Platelets less than 50,000 cells/mm3: Hold chemotherapy.
Severe (Grade 3 or 4) non-hematologic toxicity (except for alopecia and nausea/vomiting): Hold gemcitabine, or decrease the dose by 50%, until the toxicity is resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.
Maximum Dosage Limits:
The suggested maximum tolerated dose (MTD) for gemcitabine is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state. Therefore, dosing may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.
-Adults
1,250 mg/m2 IV once weekly; number of weekly doses and length of cycle is indication-specific.
-Geriatric
1,250 mg/m2 IV once weekly; number of weekly doses and length of cycle is indication-specific.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment:
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Treatment-Related Hepatotoxicity:
Severe hepatotoxicity: Permanently discontinue gemcitabine.
Patients with Renal Impairment Dosing
Baseline Renal Impairment:
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Treatment-Related Nephrotoxicity:
Severe renal impairment: Permanently discontinue gemcitabine therapy.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Decitabine; Cedazuridine: (Major) Avoid the concomitant use of decitabine; cedazuridine with drugs that are metabolized by the enzyme cytidine deaminase (CDA), such as gemcitabine; the cytotoxicity of gemcitabine may be increased. Cedazuridine is a CDA inhibitor. CDA is one of the enzymes responsible for the metabolism of gemcitabine to form inactive metabolites.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Lithium: (Moderate) Moderate to significant dietary sodium changes, or changes in sodium and fluid intake, may affect lithium excretion. Systemic sodium chloride administration may result in increased lithium excretion and therefore, decreased serum lithium concentrations. In addition, high fluid intake may increase lithium excretion. For patients receiving sodium-containing intravenous fluids, symptom control and lithium concentrations should be carefully monitored. It is recommended that patients taking lithium maintain consistent dietary sodium consumption and adequate fluid intake during the initial stabilization period and throughout lithium treatment. Supplemental oral sodium and fluid should be only be administered under careful medical supervision.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tolvaptan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. It is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing 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 results in the initiation of apoptosis.
Gemcitabine is administered intravenously. Protein binding is negligible. The pharmacokinetics of gemcitabine are linear and are best described by a 2-compartment model. The exact sites of distribution of gemcitabine are unknown, but the distribution is affected by the duration of the infusion and gender. The volume of distribution increases with infusion length (less than 70 minutes, 50 L/m2; 70 to 285 minutes, 370 L/m2). Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Within 1 week, 92% to 98% of a dose is recovered, almost entirely in the urine; gemcitabine (less than 10%) and inactive metabolite, 2', 2'-difluorodeoxyuridine (dFdU), account for 99% of the excreted dose. The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells; the terminal half-life for this metabolite from mononuclear cells ranges from 1.7 to 19.4 hours.
Affected cytochrome P450 isoenzymes and drug transporters: None
-Special Populations
Hepatic Impairment
Clinical studies of gemcitabine have not been conducted in patients with decreased hepatic function.
Renal Impairment
Clinical studies of gemcitabine have not been conducted in patients with decreased renal function.
Geriatric
The clearance of gemcitabine decreases and the half-life of gemcitabine increases with age. Following a gemcitabine infusion of less than 70 minutes, gemcitabine clearance in men decreased according to age: 29 years, 92.2 L/hour/m2; 45 years, 75.7 L/hour/m2; 65 years, 55.1 L/hour/m2; 79 years, 40.7 L/hour/m2. The corresponding half-life in men at these age ranges was 42 minutes, 48 minutes, 61 minutes, and 79 minutes, respectively. In women, the clearance also decreases and half-life increases with age: 29 years, 69.4 L/hour/m2 and 49 minutes, respectively; 45 years, 57 L/hour/m2 and 57 minutes, respectively; 65 years, 41.5 L/hour/m2 and 73 minutes, respectively; 79 years, 30.7 L/hour/m2 and 94 minutes, respectively.
Gender Differences
The elimination of gemcitabine is 31% greater for men than for women. This difference is proposed to be due to the differences in activity of cytidine deaminase, the enzyme responsible for degrading gemcitabine to inactive metabolites.
Other
Length of infusion:
The half-life of gemcitabine for short infusions (less than 70 minutes) ranged from 42 to 94 minutes, and for long infusions (70 to 285 minutes) ranged from 245 to 638 minutes, depending on age and gender; this likely reflects a greatly increased volume of distribution with longer infusions. The volume of distribution is 50 L/m2 following infusions lasting less than 70 minutes, but increases to 370 L/m2 for long infusions.