1.1 Ovarian Cancer

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.

1.2 Breast Cancer

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.

1.3 Non-Small Cell Lung Cancer

Gemcitabine Injection is indicated in combination with cisplatin 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).

1.4 Pancreatic Cancer

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.

2.1 Ovarian Cancer

2.2 Breast Cancer

2.3 Non-Small Cell Lung Cancer

2.4 Pancreatic Cancer

2.5 Dose Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue Gemcitabine Injection for any of the following:

• Unexplained dyspnea or other 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.

2.6 Preparation and Administration

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.

Preparation

• Inspect solution and discard vial if particulate matter or discoloration is observed.
• Dilute Gemcitabine Injection with 0.9% Sodium Chloride Injection to a minimum final concentration of at least 0.1 mg/mL.
• Mix diluted solution by gentle inversion. Do not shake.

After dilution with 0.9% Sodium Chloride Injection, inspect the diluted Gemcitabine injection solution visually for particulate matter and discoloration. Discard if particulate matter or discoloration is found.

Storage

• After initial withdrawal with a needle, use the remaining portion in the vial or discard within 28 days.
• Store diluted Gemcitabine Injection at controlled room temperature 20°C to 25°C (68°F to 77°F) Discard the diluted solution after 24 hours.

Administration

• Inspect the diluted solution for particulate matter and discoloration prior to administration. Do not administer if particulate matter or discoloration is found.
• The compatibility of Gemcitabine Injection with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

5.1 Schedule-dependent Toxicity

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 dosing schedule [see Dosage and Administration ( 2.1, 2.2, 2.3, and 2.4)]. ]

5.2 Myelosuppression

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 Gemcitabine Injection dosage as recommended [see Dosage and Administration ( 2.1, 2.2, 2.3, and 2.4)] .

5.3 Pulmonary Toxicity and Respiratory Failure

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

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

5.4 Hemolytic Uremic Syndrome

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 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 discontinuation of therapy.

5.5 Hepatic Toxicity

Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions ( 6.1and 6.2)] . Administration of gemcitabine in patients with concurrent hepatic metastases or a pre-existing medical history or 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 that develop severe liver injury.

5.6 Embryofetal 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 and for 3 months following the final dose [see Use in Specific Populations ( 8.1), ( 8.3)] .

5.7 Exacerbation of Radiation Therapy Toxicity

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

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

5.9 Posterior Reversible Encephalopathy Syndrome

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.

6.1 Clinical Trials Experience

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 clinical practice.

6.2 Post-Marketing Experience

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 Disorders— peripheral vasculitis, gangrene, and 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 edema, adult respiratory distress syndrome (ARDS), pulmonary eosinophilia

Nervous System— posterior reversible encephalopathy syndrome (PRES)

8.1 Pregnancy

8.2 Lactation

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 a women not to breastfeed during treatment with Gemcitabine Injection and for one week following the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

Gemcitabine Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with Gemcitabine Injection and for 6 months after the final dose .

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the final dose of [see Nonclinical Toxicology ( 13.1)].

Infertility

Males

Based on animal studies, Gemcitabine Injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1)]. It is not known whether these effects on fertility are reversible.

8.4 Pediatric Use

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

The safety and pharmacokinetics of gemcitabine were evaluated in a trial of pediatric patients with refractory leukaemia. The maximum tolerated dose was 10 mg/m 2/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/m 2/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.

8.5 Geriatric Use

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 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)].

8.6 Gender

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) ].

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitromouse lymphoma (L5178Y) assay and was clastogenic in an in vivomouse micronucleus assay. Gemcitabine intraperitoneal doses of 0.5 mg/kg/day [about 1/700 the 1000 mg/m 2clinical dose based on body surface area (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/m 2clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the 1000 mg/m 2clinical dose based on BSA).

14.1 Ovarian Cancer

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/m 2on 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.

Figure 1: Kaplan-Meier Curve of Progression Free Survival in Study 1.

14.2 Breast Cancer

The efficacy of gemcitabine was evaluated in a multinational, randomized, open-label trial (Study 2) conducted in women receiving initial treatment for metastatic breast cancer who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive either gemcitabine 1250 mg/m 2on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m 2administered on Day 1 before gemcitabine administration (n=267) or paclitaxel 175 mg/m 2on 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.

aKarnofsky Performance Status

Figure 2: Kaplan-Meier Curve of Time to Disease Progression in Study 2

14.3 Non-Small Cell Lung Cancer (NSCLC)

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

Study 4: 21-Day Schedule

A randomized (1:1), multicenter trial (Study 4) was conducted in patients with Stage IIIB or IV NSCLC. Patients were randomized to receive either gemcitabine 1250 mg/m 2on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m 2on Day 1 after gemcitabine administration or etoposide 100 mg/m 2intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m 2on Day 1 of each 21 -day cycle. The major efficacy outcome measure was response rate. A total of 135 patients were enrolled. Demographics and baseline characteristics are summarized in Table 20. Efficacy results are presented in Table 21. There was no significant difference in survival between the two treatment arms. The median survival was 8.7 months for the gemcitabine with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 5 months compared to 4.1 months on the etoposide with cisplatin arm (Log-rank p=0.015, two-sided). The objective response rate for the gemcitabine with cisplatin arm was 33% compared to 14% on the etoposide with cisplatin arm (Fisher’s Exact p=0.01, two-sided).

Table 20: Baseline Demographics and Clinical Characteristics for Studies 3 and 4

Trial	28-day Schedule (Study 3)		21-day Schedule (Study 4)
	Gemcitabine/Cisplatin (N=260)	Cisplatin (N=262)	Gemcitabine/Cisplatin (N=69)	Etoposide/Cisplatin (N=66)
Male	70%	71%	93%	92%
Median age, years	62	63	58	60
Range	36 to 88	35 to 79	33 to 76	35 to 75
Stage IIIA	7%	7%	N/A a	N/A a
Stage IIIB	26%	23%	48%	52%
Stage IV	67%	70%	52%	49%
Baseline KPS b70 to 80	41%	44%	45%	52%
Baseline KPS b90 to 100	57%	55%	55%	49%

aN/A Not Applicable

bKarnofsky Performance Status.

Table 21: Efficacy Results for Studies 3 and 4

aCI=confidence intervals.
bp-value two-sided Fisher's Exact test for difference in binomial proportions; log rank test for time-to-event analyses.
Trial	28-day Schedule (Study 3)		21-day Schedule (Study 4)
Efficacy Parameter	Gemcitabine/ Cisplatin	Cisplatin	Gemcitabine/ Cisplatin	Etoposide/ Cisplatin
Survival
Median (95% CI a) in months	9.0 (8.2, 11.0)	7.6 (6.6, 8.8)	8.7 (7.8, 10.1)	7.0 (6.0, 9.7)
p-value b	p=0.008		p=0.18
Time to Disease Progression
Median (95% CI a) in months	5.2 (4.2, 5.7)	3.7 (3.0, 4.3)	5.0 (4.2, 6.4)	4.1 (2.4, 4.5)
p-value b	p=0.009		p=0.015
Tumor Response	26%	10%	33%	14%
p-value b	p<0.0001		p=0.01

Figure 3: Kaplan-Meier Survival Curves in Study 3

14.4 Pancreatic Cancer

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/m 2intravenously 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/m 2intravenously over 30 minutes once weekly (n=63). In the Study 6, all patients received gemcitabine 1000 mg/m 2intravenously 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

• 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. Demographics and baseline characteristics were similar between the arms (Table 22). The efficacy results are shown in Table 23and 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.

aKarnofsky Performance Status.

Figure 4: Kaplan-Meier Survival Curve.