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  • CLASSES

    Pyrimidine Analogs

    DEA CLASS

    Rx

    DESCRIPTION

    Deoxycytidine antimetabolite; closely related to cytarabine but differs in antitumor activity; active in pancreatic, lung, breast, bladder, kidney, ovarian, and head and neck cancers; being studied as a radiation sensitizer.

    COMMON BRAND NAMES

    Gemzar

    HOW SUPPLIED

    Gemcitabine/Gemcitabine Hydrochloride Intravenous Inj Sol: 1mL, 38mg
    Gemcitabine/Gemcitabine Hydrochloride/Gemzar Intravenous Inj Pwd F/Sol: 1g, 2g, 200mg

    DOSAGE & INDICATIONS

    For the treatment of non-small cell lung cancer (NSCLC).
    For first-line treatment of inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) NSCLC in combination with cisplatin.
    Intravenous dosage
    Adults

    1,000 mg/m2 IV over 30 minutes followed by cisplatin 100 mg/m2 IV on day 1, then gemcitabine 1,000 mg/m2 IV over 30 minutes on days 8 and 15, repeated every 4 weeks. Alternatively, give gemcitabine 1,250 mg/m2 IV over 30 minutes followed by cisplatin 100 mg/m2 IV on day 1, then gemcitabine 1,250 mg/m2 IV over 30 minutes on day 8, repeated every 3 weeks. Gemcitabine doses should be adjusted for hematologic toxicity based upon the granulocyte and platelet counts taken on the day of therapy. In a multinational, randomized clinical trial, patients with inoperable Stage IIIA, IIIB, or IV NSCLC treated with gemcitabine and cisplatin every 4 weeks (n = 260) had increased median overall survival (9 months vs. 7.6 months; p = 0.008) and longer median time to disease progression (5.2 months vs. 3.7 months; p = 0.009) than those patients treated with cisplatin alone (n = 262); additionally, the tumor response rate was 26% for patients who received combination therapy compared with 10% in patients treated with cisplatin alone. In another multicenter, randomized clinical trial, patients with Stage IIIB or IV NSCLC were treated with gemcitabine plus cisplatin (n = 69) or etoposide plus cisplatin (n = 66) every 21 days. In this trial, there was no difference in overall survival (8.7 months vs. 7 months; p = 0.18); however, the median time to disease progression was 5 months in patients treated with gemcitabine plus cisplatin compared with 4.1 months in those who received etoposide plus cisplatin (p = 0.015). The objective response rate was 33% compared with 14% (p = 0.01), respectively.

    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 III 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 III 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 III 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, p = 0.037).

    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 II 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 II 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 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 5-fluorouracil (5-FU).
    Intravenous dosage
    Adults

    1,000 mg/m2 IV over 30 minutes once weekly for up to 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 5-FU (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 5-FU (22.2% vs. 4.8%; p = 0.004). Additionally, median overall survival (5.7 vs. 4.2 months; p = 0.0009) and time to disease progression (2.1 vs. 0.9 months; p = 0.0013) 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 up to 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 improved overall survival (6.4 vs. 6 months; HR 0.81; p = 0.028) and progression-free survival (PFS) (3.8 vs. 3.5 months; HR 0.76; p = 0.006) 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 (p = 0.87); the median duration of response was 23.9 weeks and 23.3 weeks, respectively.

    For adjuvant treatment of pancreatic cancer†.
    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 III 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, p < 0.001), the primary endpoint, and overall survival (22.8 months vs. 20.2 months, p = 0.005) were significantly longer in the gemcitabine arm. In another phase III 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, p = 0.003). Grade 4 hematologic toxicities were significantly greater in patients treated with gemcitabine (14% vs. 2%, p < 0.0001).

    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 III 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 greater in patients who received GemOx than gemcitabine, 38.2% vs. 26.9% (p = 0.03). In another phase III trial, 833 patients with previously untreated locally advanced and metastatic unresectable pancreatic cancer were randomized to receive GemOx, fixed-dose rate gemcitabine (1500 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 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; HR 0.72; p < 0.001) and median progression free survival (5.5 months vs. 3.7 months; HR 0.69; p < 0.001) 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 (p < 0.001).

    For the treatment of metastatic breast cancer.
    In combination with paclitaxel after failure of prior anthracycline-containing adjuvant chemotherapy unless anthracyclines were clinically contraindicated.
    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 chemotherapy (unless clinically contraindicated). The combination therapy resulted in statistically significant improvement in time to documented disease progression (5.2 vs. 2.9 months; p < 0.0001) and overall response rate (40.6% vs. 22.1%; p < 0.0001) as compared to paclitaxel alone. Gemcitabine plus paclitaxel also showed a strong trend toward improved survival based on an interim survival analysis.

    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 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 III trials, time to progression in one study and progression free survival in the other were similar to liposomal doxorubicin.

    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 III trial, 356 patients with relapsed ovarian cancer at least 6 months after primary platinum therapy were randomized to gemcitabine 1,000 mg/m2 IV on days 1 and 8 plus carboplatin (AUC 4) on day 1 or carboplatin (AUC 5) single agent therapy, both given as a 21-day cycle. Progression-free survival (PFS) was 8.6 months for patients treated with gemcitabine/carboplatin therapy vs. 5.8 months for those treated with single agent carboplatin (p = 0.0038). Overall survival was not different between the 2 arms (18 months for combination therapy vs. 17.3 months for single agent carboplatin). Other phase II 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 1250 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 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 III 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 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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

    As a single agent, 1000 mg/m2 IV over 30 minutes once weekly for up to 7 consecutive weeks, followed by one week of rest.

    Elderly

    As a single agent, 1000 mg/m2 IV over 30 minutes once weekly for up to 7 consecutive weeks, followed by one week of rest.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    There have been no studies of gemcitabine in patients with severe hepatic dysfunction and no guidelines are available.
    Severe treatment-related hepatotoxicity: Permanently discontinue gemcitabine.

    Renal Impairment

    There have been no studies of gemcitabine in patients with renal dysfunction and no quantitative recommendations are available. The inactive metabolite of gemcitabine may accumulate in patients with renal dysfunction.

    ADMINISTRATION

    For storage information, see the specific product information within How Supplied section.
     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    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.

    Intravenous Administration

    Reconstitution, Powder for Injection
    200 mg vial: Add 5 mL of 0.9% sodium chloride for injection without preservatives 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 without preservatives 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.
    Reconstituted gemcitabine solutions are stable for 24 hours at room temperature (20 to 25 degrees Celsius or 68 to 77 degrees Fahrenheit). Discard unused portion.
    Do not refrigerate reconstituted gemcitabine solutions, as crystallization may occur.
    Intravenous infusion:
    Dilute the appropriate amount of gemcitabine (solution for injection or reconstituted powder for injection) in 0.9% sodium chloride injection solution; the final concentrations may be as low as 0.1 mg/mL.
    The manufacturer recommends infusing 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.
    Diluted gemcitabine solutions are stable for 24 hours at controlled room temperature (20 to 25 degrees Celsius or 68 to 77 degrees Farenheit). Discard unused portion.

    STORAGE

    Generic:
    - Discard unused portion. Do not store for later use.
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Use within 24 hours from time of preparation
    Gemzar:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not refrigerate
    - Reconstituted product is stable for 24 hours at room temperature
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Bone marrow suppression, chemotherapy, herpes infection, infection, neutropenia, thrombocytopenia, varicella, viral infection

    Myelosuppression, 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 who have had previous myelosuppressive therapy such as chemotherapy or radiation may be at risk of increased bone marrow suppression; therefore, this drug should be used only by clinicians experienced in chemotherapy. Patients with an active infection should be treated prior to receiving gemcitabine. Opportunistic infections, including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of varicella zoster, herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.

    Radiation therapy

    Gemcitabine is not indicated 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 less than or equal to 7 days 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 (non-concurrent); however, radiation recall has occurred in patients who have received gemcitabine after prior radiation.

    Alcoholism, hepatic disease, hepatitis, hepatotoxicity

    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. Gemcitabine should be used cautiously in patients with preexisting 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.

    Infusion-related reactions

    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, pulmonary disease, pulmonary edema, pulmonary fibrosis

    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.

    Capillary leak syndrome

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

    Hemolytic-uremic syndrome, renal failure, renal impairment

    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.

    Encephalopathy

    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.

    Children

    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.

    Females, geriatric

    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

    Gemcitabine is classified as FDA pregnancy category D. Although there are no adequate and well-controlled studies in pregnant women, gemcitabine is expected to cause adverse reproductive effects based on its mechanism of action. If gemcitabine is used during pregnancy or if a woman becomes pregnant during therapy, the patient should be apprised of the risk 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 of 1.5 mg/kg/day (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 of 0.1 mg/kg/day (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.

    Infertility, reproductive risk

    Counsel patients about the reproductive risk and need for contraception during gemcitabine treatment. Gemcitabine can be teratogenic if taken by the mother during pregnancy. 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. Intraperitoneal doses of gemcitabine in male mice caused moderate-to-severe hypospermatogenesis, decreased fertility (infertility), and decreased implantations at doses approximately 1/700 the human dose on a mg/m2 basis; fertility was not affected in female mice.

    Breast-feeding

    It is uncertain if gemcitabine is distributed into breast milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from this drug, a decision should be made whether to discontinue breast-feeding or to discontinue gemcitabine, taking into account the importance of gemcitabine to the mother.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 25.0-71.0
    thrombocytopenia / Delayed / 5.0-55.0
    lymphopenia / Delayed / 0-43.0
    vomiting / Early / 2.0-39.0
    nausea / Early / 1.0-39.0
    anemia / Delayed / 7.0-28.0
    alopecia / Delayed / 0-18.0
    azotemia / Delayed / 0-16.0
    elevated hepatic enzymes / Delayed / 0-10.0
    fatigue / Early / 0-7.0
    constipation / Delayed / 0-7.0
    hypomagnesemia / Delayed / 7.0-7.0
    infection / Delayed / 0-5.0
    stomatitis / Delayed / 0-4.0
    diarrhea / Early / 1.0-4.0
    dyspnea / Early / 0-4.0
    hyperglycemia / Delayed / 4.0-4.0
    hyperbilirubinemia / Delayed / 0-3.0
    bleeding / Early / 0-3.0
    pharyngitis / Delayed / 0-2.0
    fever / Early / 0-2.0
    bronchospasm / Rapid / 0-2.0
    hypocalcemia / Delayed / 2.0-2.0
    drowsiness / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    rash (unspecified) / Early / 0-1.0
    proteinuria / Delayed / 0-1.0
    hematuria / Delayed / 0-1.0
    hypotension / Rapid / 0-1.0
    capillary leak syndrome / Early / 0-1.0
    hemolytic-uremic syndrome / Delayed / 0.3-0.3
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    stroke / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    encephalopathy / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    seizures / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    peripheral edema / Delayed / 20.0-20.0
    edema / Delayed / 0-13.0
    peripheral neuropathy / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    colitis / Delayed / Incidence not known
    hemolysis / Early / Incidence not known
    hypertension / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    confusion / Early / Incidence not known

    Mild

    malaise / Early / 19.0-19.0
    anorexia / Delayed / 0-17.0
    headache / Early / 0-14.0
    injection site reaction / Rapid / 4.0-4.0
    insomnia / Early / Incidence not known
    myalgia / Early / Incidence not known
    chills / Rapid / Incidence not known
    diaphoresis / Early / Incidence not known
    rhinitis / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    lethargy / Early / Incidence not known

    DRUG INTERACTIONS

    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Azathioprine: (Minor) Additive immunosuppressant affects may be seen when azathioprine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Basiliximab: (Minor) Additive immunosuppressant affects may be seen when basiliximab is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cyclosporine: (Minor) Additive immunosuppressant affects may be seen when cyclosporine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efalizumab: (Minor) Concurrent use of efalizumab with other agents which cause bone marrow or immune suppression such as antineoplastic agents may result in additive effects. Dosage reductions may be required.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Gemcitabine is classified as FDA pregnancy category D. Although there are no adequate and well-controlled studies in pregnant women, gemcitabine is expected to cause adverse reproductive effects based on its mechanism of action. If gemcitabine is used during pregnancy or if a woman becomes pregnant during therapy, the patient should be apprised of the risk 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 of 1.5 mg/kg/day (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 of 0.1 mg/kg/day (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.

    It is uncertain if gemcitabine is distributed into breast milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from this drug, a decision should be made whether to discontinue breast-feeding or to discontinue gemcitabine, taking into account the importance of gemcitabine to the mother.

    MECHANISM OF ACTION

    Gemcitabine undergoes intracellular conversion, similar to cytarabine, to the nucleotide gemcitabine monophosphate via the enzyme deoxycytidine kinase. Gemcitabine monophosphate is subsequently phophorylated to gemcitabine triphosphate (deoxydifluorocytidine triphosphate, dFdCTP) and gemcitabine diphosphate (deoxydifluorocytidine diphosphate) via the enzymes nucloside diphosphate kinase and deoxycytidylate kinase respectively. Gemcitabine triphosphate competes with deoxycytadine triphosphate (dCTP) for incorporation into into DNA strands similar to cytarabine. However, after insertion of the gemcitabine analog into DNA, an additional base pair is added before DNA polymerase is stopped. This "masked termination" makes gemcitabine more difficult to remove from the DNA strands thus inhibiting both DNA replication and repair. Gemcitabine is also involved in several mechanisms of self-potentiation, which increase the concentration and prolong the retention of gemcitabine in tumor cells. Inhibition of ribonucleotide reductase via gemcitabine diphosphate decreases dCTP levels, facilitates the incorporation of gemcitabine triphosphate into DNA, and increases the levels of deoxycitidine kinase required for activation. Gemcitabine-induced cell death has the morphological and biological characteristics of programmed cell death or apoptosis. Compared with cytarabine, gemcitabine crosses the cell membrane better, has longer intracellular retention, and exhibits greater affinity for deoxycytidine kinase. Further, gemcitabine could have a synergistic cytotoxic action in combination with other agents that damage DNA including cisplatin, radiation, ifosfamide, and mitomycin C. Gemcitabine is cell cycle specific for S phase causing cells to accumulate at the G1—S phase boundary.

    PHARMACOKINETICS

    Gemcitabine is administered intravenously. 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 is 50 L/m2 following gemcitabine infusions of less than 70 minutes and 370 L/m2 following infusions longer than 70 minutes. This indicates the distribution of gemcitabine to the tissue compartment is only significant after long infusions. Gemcitabine is metabolized by cytidine deaminase to the inactive metabolite, 2', 2'-difluorodeoxyuridine (dFdU). Protein binding is very low (< 10%). Elimination is primarily renal, with 92—98% of the gemcitabine dose recovered as the inactive uracil metabolite and < 10% recovered as the parent compound.
     
    Infusion duration or dose does not affect overall clearance; however, the elimination of gemcitabine varies based on gender and age. The half-life of gemcitabine is affected by the duration of infusion, age, and gender due to the changes in volume of distribution and clearance.

    Intravenous Route

    The Cmax of 2', 2'-difluorodeoxyuridine (dFdU) is reached 30 minutes after the end of the infusion. The active metabolite, gemcitabine triphosphate, can be measured in peripheral mononuclear cells. The Cmax of gemcitabine triphosphate occurs in 30 minutes and reaches a plateau after doses > 350 mg/m2 suggesting a saturable accumulation process. Longer infusion rates (> 60 minutes) resulted in 2-fold higher peak mononuclear cell concentrations of gemcitabine triphosphate than the same dose given over 30 minutes.