Gemzar

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Gemzar

Classes

Pyrimidine Analogs

Administration

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

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.[28788]
 
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.[60698] [28788] [63391]
 
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.[28788] 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.[33970]

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.

Adverse Reactions
Severe

lymphopenia / Delayed / 0-43.0
vomiting / Early / 2.0-39.0
nausea / Early / 1.0-39.0
neutropenia / Delayed / 25.0-25.0
alopecia / Delayed / 0-18.0
azotemia / Delayed / 0-16.0
elevated hepatic enzymes / Delayed / 8.0-10.0
anemia / Delayed / 8.0-8.0
fatigue / Early / 0-7.0
constipation / Delayed / 0-7.0
hypomagnesemia / Delayed / 0-7.0
infection / Delayed / 0-5.0
thrombocytopenia / Delayed / 5.0-5.0
stomatitis / Delayed / 0-4.0
dyspnea / Early / 0-4.0
hyperglycemia / Delayed / 0-4.0
hyperbilirubinemia / Delayed / 0-3.0
drowsiness / Early / 0-2.0
pharyngitis / Delayed / 0-2.0
fever / Early / 0-2.0
bronchospasm / Rapid / 0-2.0
bleeding / Early / 0-2.0
hypocalcemia / Delayed / 0-2.0
diarrhea / Early / 1.0-1.0
rash / Early / 0-1.0
hematuria / Delayed / 0-1.0
proteinuria / Delayed / 0-1.0
hypotension / Rapid / 0-1.0
capillary leak syndrome / Early / 0-1.0
paresthesias / Delayed / 0-1.0
hemolytic-uremic syndrome / Delayed / 0.3-0.3
renal failure (unspecified) / Delayed / Incidence not known
thrombotic microangiopathy / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
veno-occlusive disease (VOD) / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
renal tubular necrosis / Delayed / Incidence not known
enterocolitis / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
stroke / Early / Incidence not known
pulmonary edema / Early / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
eosinophilic pneumonia / Delayed / 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
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
eosinophilia / Delayed / Incidence not known
confusion / Early / Incidence not known
peripheral neuropathy / Delayed / 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
rhinitis / Early / Incidence not known
asthenia / Delayed / Incidence not known
diaphoresis / Early / Incidence not known
insomnia / Early / Incidence not known
myalgia / Early / Incidence not known
chills / Rapid / Incidence not known
lethargy / Early / Incidence not known

Common Brand Names

Gemzar, Infugem

Dea Class

Rx

Description

Deoxycytidine antimetabolite nucleoside inhibitor
Used for breast cancer, non-small cell lung cancer (NSCLC), ovarian cancer, and pancreatic cancer
Increased toxicities occur with infusion times longer than 60 minutes or with dosing more than once weekly

Dosage And 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 (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 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 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 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 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%). 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.[28788] [63384]

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 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.[35047] [35048] 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%).[35049]

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 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 the adjuvant treatment of pancreatic ductal adenocarcinoma, in combination with capecitabine†. Intravenous dosage Adults

1,000 mg/m2 IV on days 1, 8, and 15, plus 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. 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 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 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 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 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 [49703] or 1,000 mg/m2 IV on days 1 and 8, every 21 days [49702] 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.[49702] [49703]

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).[28788]  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.[28798]

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.

For the treatment of urothelial carcinoma†. 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 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.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

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.

Renal Impairment

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.

Drug Interactions

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.
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.
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.

How Supplied

Gemcitabine/Gemcitabine Hydrochloride/Gemzar Intravenous Inj Pwd F/Sol: 1g, 2g, 200mg
Gemcitabine/Gemcitabine Hydrochloride/Infugem Intravenous Inj Sol: 1mL, 38mg, 100mg, 10-0.9%

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

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.

Mechanism Of Action

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.

Pharmacokinetics

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

Pregnancy And Lactation
Pregnancy

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.[28788] 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.[41244] 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.[28788]

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.[28788] [63384]