Gemcitabine Injection is a nucleoside metabolic inhibitor indicated:

• in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. (1.1)
• in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. (1.2)
• in combination with cisplatin for the treatment of non-small cell lung cancer. (1.3)
• as a single agent for the treatment of pancreatic cancer. (1.4)

Gemcitabine Injection in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

Gemcitabine Injection in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

Gemcitabine Injection in combination with cisplatin is indicated for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC).

Gemcitabine Injection is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine Injection is indicated for patients previously treated with fluorouracil.

Gemcitabine Injection is for intravenous use only.

• Ovarian Cancer: 1000 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.1)
• Breast Cancer: 1250 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.2)
• Non-Small Cell Lung Cancer: 1000 mg/m² over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.3)
• Pancreatic Cancer: 1000 mg/m² over 30 minutes once weekly for the first 7 weeks, then one-week rest, then once weekly for 3 weeks of each 28-day cycle. (2.4)

Recommended Dose and Schedule

The recommended dosage of Gemcitabine Injection is 1000 mg/m² intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 administered intravenously on Day 1 after Gemcitabine Injection administration. Refer to carboplatin prescribing information for additional information.

Recommended Dose and Schedule

The recommended dosage of Gemcitabine Injection is 1250 mg/m² intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m² administered as a 3-hour intravenous infusion on Day 1 before Gemcitabine Injection administration. Refer to paclitaxel prescribing information for additional information.

Recommended Dose and Schedule

Recommended Dose and Schedule

The recommended dosage of Gemcitabine Injection is 1000 mg/m² intravenously over 30 minutes. The recommended treatment schedule is as follows:

• Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one-week rest.
• After week 8: weekly dosing on Days 1, 8, and 15 of each 28-day cycle.

Permanently discontinue Gemcitabine Injection for any of the following:

• Unexplained dyspnea or evidence of severe pulmonary toxicity [see Warnings and Precautions (5.3)]
• Hemolytic uremic syndrome (HUS) or severe renal impairment [see Warnings and Precautions (5.4)]
• Severe hepatic toxicity [see Warnings and Precautions (5.5)]
• Capillary leak syndrome (CLS) [see Warnings and Precautions (5.8)]
• Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.9)]

Withhold Gemcitabine Injection or reduce dose by 50% for other Grade 3 or 4 non-hematological adverse reactions until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

Gemcitabine Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

Exercise caution and wear gloves when preparing Gemcitabine Injection solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine Injection contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.

Injection: 200 mg/5.26 mL (38 mg/mL), 1 g/26.3 mL (38 mg/mL), and 2 g/52.6 mL (38 mg/mL) as a clear and colorless to light straw-colored solution in a single-dose vial.

Gemcitabine Injection is contraindicated in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis [see Adverse Reactions (6. 1)].

• Schedule-Dependent Toxicity: Increased toxicity with infusion time greater than 60 minutes or dosing more frequently than once weekly. (5.1)
• Myelosuppression: Monitor for myelosuppression prior to each cycle and reduce or withhold dose for severe myelosuppression. (5.2)
• Pulmonary Toxicity and Respiratory Failure: Discontinue Gemcitabine Injection for unexplained dyspnea or other evidence of severe pulmonary toxicity. (5.3)
• Hemolytic Uremic Syndrome (HUS): Monitor renal function prior to initiation and during treatment. Discontinue Gemcitabine Injection for HUS or severe renal impairment. (5.4)
• Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential to use effective contraception. (5.6, 8.1)
• Exacerbation of Radiation Therapy Toxicity: May cause severe and life-threatening toxicity when administered during or within 7 days of radiation therapy. (5.7)
• Capillary Leak Syndrome: Discontinue Gemcitabine Injection. (5.8)
• Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue Gemcitabine Injection. (5.9)

In clinical trials evaluating the maximum tolerated dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is influenced by the length of the infusion [see Clinical Pharmacology (12.3)]. Refer to the recommended Gemcitabine Injection dosage [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia, occurs with gemcitabine as a single agent and the risks are increased when gemcitabine is combined with other cytotoxic drugs. In clinical trials, Grade 3–4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of the 979 patients who received single agent gemcitabine. The frequencies of Grade 3–4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8% to 28%, and 5% to 55%, respectively, in patients receiving gemcitabine in combination with another drug [see Adverse Reactions (6.1)].

Prior to each dose of Gemcitabine Injection, obtain a complete blood count (CBC) with a differential and a platelet count. Modify the dosage as recommended [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite the discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine [see Adverse Reactions (6.1, 6.2)].

Permanently discontinue Gemcitabine Injection in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe pulmonary toxicity.

Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur with gemcitabine. In clinical trials, HUS occurred in 0.25% of 2429 patients. Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1)]. Serious cases of thrombotic microangiopathy (TMA) other than HUS have been reported with gemcitabine [see Adverse Reactions (6.2)].

Assess renal function prior to initiation of Gemcitabine Injection and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis; increased bilirubin or LDH; reticulocytosis; severe thrombocytopenia; or evidence of renal failure (increased serum creatinine or BUN). Permanently discontinue Gemcitabine Injection in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the discontinuation of therapy.

Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or with other potentially hepatotoxic drugs [see Adverse Reactions (6.1, 6.2)]. Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency.

Assess hepatic function prior to initiation of Gemcitabine Injection and periodically during treatment. Permanently discontinue Gemcitabine Injection in patients who develop severe hepatic toxicity.

Based on animal data and its mechanism of action, Gemcitabine Injection can cause fetal harm when administered to a pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits.

Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with Gemcitabine Injection and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Gemcitabine Injection and for 3 months following the final dose [see Use in Specific Populations (8.1, 8.3)].

Gemcitabine is not recommended for use in combination with radiation therapy.

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 [see Adverse Reactions (6.2)]. Permanently discontinue Gemcitabine Injection if CLS develops during therapy.

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents [see Adverse Reactions (6.2)]. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI). Permanently discontinue Gemcitabine Injection if PRES develops during therapy.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hypersensitivity [see Contraindications (4)]
• Schedule-Dependent Toxicity [see Warnings and Precautions (5.1)]
• Myelosuppression [see Warnings and Precautions (5.2)]
• Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.3)]
• Hemolytic Uremic Syndrome [see Warnings and Precautions (5.4)]
• Hepatic Toxicity [see Warnings and Precautions (5.5)]
• Exacerbation of Radiation Therapy Toxicity [see Warnings and Precautions (5.7)]
• Capillary Leak Syndrome [see Warnings and Precautions (5.8)]
• Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.9)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions have been identified during post-approval use of gemcitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System: TMA

Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias

Vascular: Peripheral vasculitis, gangrene, capillary leak syndrome

Skin: Cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skin eruptions

Hepatic: Hepatic failure, hepatic veno-occlusive disease

Pulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary eosinophilia, pulmonary edema, adult respiratory distress syndrome (ARDS)

Nervous System: Posterior reversible encephalopathy syndrome (PRES)

Lactation: Advise not to breastfeed. (8.2)

Risk Summary

Based on animal data and its mechanism of action, Gemcitabine Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of gemcitabine in pregnant women. In animal reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data). Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.3)].

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Risk Summary

There is no information regarding the presence of gemcitabine or its metabolites in human milk, or their effects on the breastfed infant or on milk production. Due to the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Gemcitabine Injection and for at least one week following the last dose.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating Gemcitabine Injection [see Use in Specific Populations (8.1)].

The safety and effectiveness of gemcitabine have not been established in pediatric patients.

The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m²/min for 360 minutes weekly for three weeks followed by a one-week rest period.

The safety and activity of gemcitabine were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m²/min administered over 360 minutes weekly for three weeks followed by a one-week rest period. Patients with M1 or M2 bone marrow on Day 28 who did not experience unacceptable toxicity were eligible to receive a maximum of one additional four-week course. Toxicities observed included myelosuppression, febrile neutropenia, increased serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.

In clinical studies which enrolled 979 patients with various malignancies who received single agent gemcitabine, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3–4 thrombocytopenia in older patients as compared to younger patients.

In a randomized trial in women with ovarian cancer (Study 1), 175 women received gemcitabine with carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3–4 neutropenia in women 65 years of age or older [see Dosage and Administration (2.1)].

Gemcitabine clearance is affected by age; however, there are no recommended dose adjustments based on patients' age [see Clinical Pharmacology (12.3)].

Gemcitabine clearance is decreased in females [see Clinical Pharmacology (12.3)]. In single agent studies of gemcitabine, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3–4 neutropenia and thrombocytopenia [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

There is no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m² was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study. In the event of suspected overdose, monitor with appropriate blood counts and provide supportive therapy, as necessary.

Gemcitabine is a nucleoside metabolic inhibitor. The chemical name of gemcitabine HCl is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer). The structural formula is as follows:

Gemcitabine HCl is a white to off-white solid with a molecular formula of C₉H₁₁F₂N₃O₄ ∙ HCl and a molecular weight of 299.66 g/mol. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

Gemcitabine Injection is a sterile solution in single-dose vials for intravenous use. Each vial contains 200 mg, 1 g, or 2 g of gemcitabine equivalent to 227.7 mg, 1.139 g, or 2.227 g of gemcitabine HCl. Each mL contains 38 mg of gemcitabine free base in Water for Injection equivalent to 43.27 mg of gemcitabine HCl. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

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

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

The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total gemcitabine dose varied from 500 mg/m² to 3600 mg/m².

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine intraperitoneal doses of 0.5 mg/kg/day (about 1/700 the 1000 mg/m² clinical dose based on BSA) in male mice resulted in moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the 1000 mg/m² clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the 1000 mg/m² clinical dose based on BSA).

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine intraperitoneal doses of 0.5 mg/kg/day (about 1/700 the 1000 mg/m² clinical dose based on BSA) in male mice resulted in moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the 1000 mg/m² clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the 1000 mg/m² clinical dose based on BSA).

The efficacy of gemcitabine was evaluated in a randomized trial (Study 1) conducted in women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m² on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine administration (n = 178) or carboplatin AUC 5 on Day 1 of each 21-day cycle (n = 178). The major efficacy outcome measure was progression-free survival (PFS).

A total of 356 patients were enrolled. Demographics and baseline characteristics are shown in Table 16. Efficacy results are presented in Table 17 and Figure 1. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.

Table 16: Baseline Demographics and Clinical Characteristics for Study 1

	Gemcitabine/Carboplatin (N=178)	Carboplatin (N=178)
Median age, years	59	58
Range	36 to 78	21 to 81
Baseline ECOG performance status 0–15 patients on gemcitabine/carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.	94%	95%
Disease Status
Evaluable	8%	3%
Bidimensionally measurable	92%	96%
Platinum-free interval2 patients on gemcitabine/carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months.
6–12 months	40%	40%
>12 months	59%	60%
First-line therapy
Platinum-taxane combination	70%	71%
Platinum-non-taxane combination	29%	28%
Platinum monotherapy	1%	1%

Table 17: Efficacy Results in Study 1

Efficacy Parameter	Gemcitabine/Carboplatin (N=178)	Carboplatin (N=178)
Progression-Free Survival
Median (95% CI CI=confidence interval.) in months	8.6 (8.0, 9.7)	5.8 (5.2, 7.1)
Hazard Ratio (95% CI)	0.72 (0.57, 0.90)
p=valueLog rank, unadjusted.	p=0.0038
Overall Survival
Median (95% CI) in months	18.0 (16.2, 20.3)	17.3 (15.2, 19.3)
Hazard Ratio (95% CI)	0.98 (0.78, 1.24)
p=value	p=0.8977
Overall Response Rate by Investigator Review	47.2%	30.9%
p=valueChi square.	p=0.0016
CRCR=Complete response	14.6%	6.2%
PR with PRNMPR with PRNM=Partial response with partial response, non-measurable disease	32.6%	24.7%
Overall Response Rate by Independent Review Independently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.	46.3%	35.6%
p=value	p=0.11
CR	9.1%	4.0%
PR with PRNM	37.2%	31.7%

Figure 1: Kaplan-Meier Curves for Progression-Free Survival in Study 1

The efficacy of gemcitabine was evaluated in a randomized trial (Study 1) conducted in women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m² on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine administration (n = 178) or carboplatin AUC 5 on Day 1 of each 21-day cycle (n = 178). The major efficacy outcome measure was progression-free survival (PFS).

A total of 356 patients were enrolled. Demographics and baseline characteristics are shown in Table 16. Efficacy results are presented in Table 17 and Figure 1. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.

Table 16: Baseline Demographics and Clinical Characteristics for Study 1

	Gemcitabine/Carboplatin (N=178)	Carboplatin (N=178)
Median age, years	59	58
Range	36 to 78	21 to 81
Baseline ECOG performance status 0–15 patients on gemcitabine/carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.	94%	95%
Disease Status
Evaluable	8%	3%
Bidimensionally measurable	92%	96%
Platinum-free interval2 patients on gemcitabine/carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months.
6–12 months	40%	40%
>12 months	59%	60%
First-line therapy
Platinum-taxane combination	70%	71%
Platinum-non-taxane combination	29%	28%
Platinum monotherapy	1%	1%

Table 17: Efficacy Results in Study 1

Efficacy Parameter	Gemcitabine/Carboplatin (N=178)	Carboplatin (N=178)
Progression-Free Survival
Median (95% CI CI=confidence interval.) in months	8.6 (8.0, 9.7)	5.8 (5.2, 7.1)
Hazard Ratio (95% CI)	0.72 (0.57, 0.90)
p=valueLog rank, unadjusted.	p=0.0038
Overall Survival
Median (95% CI) in months	18.0 (16.2, 20.3)	17.3 (15.2, 19.3)
Hazard Ratio (95% CI)	0.98 (0.78, 1.24)
p=value	p=0.8977
Overall Response Rate by Investigator Review	47.2%	30.9%
p=valueChi square.	p=0.0016
CRCR=Complete response	14.6%	6.2%
PR with PRNMPR with PRNM=Partial response with partial response, non-measurable disease	32.6%	24.7%
Overall Response Rate by Independent Review Independently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.	46.3%	35.6%
p=value	p=0.11
CR	9.1%	4.0%
PR with PRNM	37.2%	31.7%

Figure 1: Kaplan-Meier Curves for Progression-Free Survival in Study 1

The efficacy of gemcitabine was evaluated in a multinational, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer and who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated.

Patients were randomized to receive gemcitabine 1250 mg/m² on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m² administered on Day 1 before gemcitabine administration (n = 267) or paclitaxel 175 mg/m² on Day 1 of each 21-day cycle (n = 262). The major efficacy outcome measure was time to documented disease progression.

A total of 529 patients were enrolled. Demographic and baseline characteristics were similar between treatment arms (Table 18).

Efficacy results are presented in Table 19 and Figure 2. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival.

Table 18: Baseline Demographics and Clinical Characteristics for Study 2

	Gemcitabine/Paclitaxel (N=267)	Paclitaxel (N=262)
Median age, years	53	52
Range	26 to 83	26 to 75
Metastatic disease	97%	97%
Baseline KPSKarnofsky Performance Status.≥90	70%	74%
Number of tumor sites
1–2	57%	59%
≥3	43%	41%
Visceral disease	73%	73%
Prior anthracycline	97%	96%

Table 19: Efficacy Results in Study 2

Efficacy Parameter	Gemcitabine/Paclitaxel (N=267)	Paclitaxel (N=262)
Time to Documented Disease Progression These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
Median (95% CI) in months	5.2 (4.2, 5.6)	2.9 (2.6, 3.7)
Hazard Ratio (95% CI)	0.650 (0.524, 0.805)
p-value	p<0.0001
Overall Survival Based on the ITT population.
Median (95% CI) in months	18.6 (16.5, 20.7)	15.8 (14.1, 17.3)
Hazard Ratio (95% CI)	0.86 (0.71, 1.04)
p-value	Not Significant
Overall Response Rate (95% CI)	40.8% (34.9, 46.7)	22.1% (17.1, 27.2)
p-value	p<0.0001

Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2

The efficacy of gemcitabine was evaluated in two randomized, multicenter trials.

The efficacy of gemcitabine was evaluated in two trials (Studies 5 and 6), a randomized, single-blind, two-arm, active-controlled trial (Study 5) conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial (Study 6) conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or a fluorouracil-containing regimen. In Study 5, patients were randomized to receive either gemcitabine 1000 mg/m² intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m² intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1000 mg/m² intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles.

The major efficacy outcome measure in both trials was "clinical benefit response". A patient was considered to have had a clinical benefit response if either of the following occurred:

• The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy.

OR

• The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation.

Study 5 enrolled 126 patients. Demographics and baseline characteristics were similar between the arms (Table 22).

The efficacy results are shown in Table 23 and Figure 4. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive fluorouracil. No confirmed objective tumor responses were observed in either treatment arm.

Table 22: Baseline Demographics and Clinical Characteristics for Study 5

	Gemcitabine (N=63)	Fluorouracil (N=63)
Male	54%	54%
Median age	62 years	61 years
Range	37 to 79	36 to 77
Stage IV disease	71%	76%
Baseline KPSKarnofsky Performance Status.≤70	70%	68%

Table 23: Efficacy Results in Study 5

Efficacy Parameter	Gemcitabine (N=63)	Fluorouracil (N=63)
Clinical Benefit Response	22.2%	4.8%
p-valuep-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other p-values are calculated using log rank test.	p=0.004
Overall Survival
Median (95% CI) in months	5.7 (4.7, 6.9)	4.2 (3.1, 5.1)
p-value	p=0.0009
Time to Disease Progression
Median (95% CI) in months	2.1 (1.9, 3.4)	0.9 (0.9, 1.1)
p-value	p=0.0013

Figure 4: Kaplan-Meier Curves for Overall Survival in Study 5

1. OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Gemcitabine Injection appears as a clear and colorless to light straw-colored solution. It is available in sterile single-dose vials individually packaged in a carton as follows:

• 200 mg/5.26 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 0409-0183-01
• 1 g/26.3 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 0409-0181-01
• 2 g/52.6 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 0409-0182-01

Myelosuppression

Advise patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider should any signs or symptoms of infection, including fever, or if bleeding, or signs of anemia, occur [see Warnings and Precautions (5.2)].

Gemcitabine Injection

1 g/26.3 mL

(38 mg/mL)

For Intravenous Use
Must Be Diluted Before Use
Store at 2 to 8°C (36 to 46°F)
26.3 mL Single-dose Vial.
Discard unused portion.

Rx only
NDC 0409-0181-01

Gemcitabine
Injection

1 g/26.3 mL

(38 mg/mL)

For Intravenous Use
Must Be Diluted Before Use
Store at 2 to 8°C (36 to 46°F)
26.3 mL Single-dose Vial
Discard Unused Portion

Caution: Cytotoxic Agent

Gemcitabine Injection

200 mg/5.26 mL

(38 mg/mL)

For Intravenous Use
Must Be Diluted Before Use
Store at 2 to 8°C (36 to 46°F)
5.26 mL Single-dose Vial.
Discard unused portion.

Rx only
NDC 0409-0183-01

Gemcitabine
Injection

200 mg/5.26 mL

(38 mg/mL)

For Intravenous Use
Must Be Diluted Before Use
Store at 2 to 8°C (36 to 46°F)
5.26 mL Single-dose Vial
Discard Unused Portion

Caution: Cytotoxic Agent

Gemcitabine Injection

2 g/52.6 mL

(38 mg/mL)

For Intravenous Use
Must Be Diluted Before Use
Store at 2 to 8°C (36 to 46°F)
52.6 mL Single-dose Vial.
Discard unused portion.

Rx only
NDC 0409-0182-01

Gemcitabine
Injection

2 g/52.6 mL

(38 mg/mL)

For Intravenous Use
Must Be Diluted Before Use
Store at 2 to 8°C (36 to 46°F)
52.6 mL Single-dose Vial
Discard Unused Portion

Caution: Cytotoxic Agent