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GEMCITABINE

Sun Pharma Global FZE

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use gemcitabine safely and effectively. See full prescribing information for gemcitabine for injection. Gemcitabine for Injection USP, Powder, Lyophilized, For Solution For Intravenous UseInitial U.S. Approval: 1996 INDICATIONS AND USAGEGemcitabine for injection is a nucleoside metabolic inhibitor indicated for: Ovarian cancer in combination with carboplatin (1.1) Breast cancer in combination with paclitaxel (1.2) Non-small cell lung cancer in combination with cisplatin (1.3) Pancreatic cancer as a single-agent (1.4) DOSAGE AND ADMINISTRATIONGemcitabine for 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: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 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 up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) Dose Reductions or discontinuation may be needed based on toxicities (2.1 to 2.4) DOSAGE FORMS AND STRENGTHS 200 mg vial for injection (3) 1 g vial for injection (3) CONTRAINDICATIONS4WARNINGS AND PRECAUTIONS Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) Pulmonary toxicity: Discontinue gemcitabine immediately for severe pulmonary toxicity. (5.3) Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue gemcitabine for HUS or severe renal toxicity (5.4) Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue gemcitabine for severe hepatic toxicity. (5.5) Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) Radiation toxicity. May cause severe and life-threatening toxicity (5.8) Side Effects6.1  To report SUSPECTED ADVERSE REACTIONS, contact CARACO Pharmaceutical Laboratories Ltd. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Ovarian Cancer


1.2 Breast Cancer


1.3 Non-Small Cell Lung Cancer


1.4 Pancreatic Cancer


2 DOSAGE AND ADMINISTRATION


2.1 Ovarian Cancer


2 66

Dose Modifications

Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Carboplatin
Absolute granulocyte count
(x 106/L)		   Platelet count
(x 106/L)		 % of full dose
≥1500
 And
 ≥100,000
 100
1000 to 1499
 and/or
 75,000 to 99,999
 50
<1000
 and/or
 <75,000
 Hold



2
  • Absolute granulocyte count <500 x 106/L for more than 5 days
  • Absolute granulocyte count <100 x 106/L for more than 3 days
  • Febrile neutropenia
  • Platelets <25,000 x 106/L
  • Cycle delay of more than one week due to toxicity
2

2.2 Breast Cancer


2 2 66

Dose Modifications
Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Paclitaxel
Absolute granulocyte count
(x 106/L)		   Platelet count
(x 106/L)		 % of full dose
≥1200
 And
 >75,000
 100
1000 to 1199
 Or
 50,000 to 75,000
 75
700 to 999
 And
 ≥50,000
 50
<700
 Or
 <50,000
 Hold

2.3 Non-Small Cell Lung Cancer


[see Clinical Studies (14.3)]2 2 2 2

Dose Modifications



2.4 Pancreatic Cancer


2

Dose Modifications

[see Warnings and Precautions (5.2)][see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]

Table 3: Dosage Reduction Guidelines
Absolute granulocyte count
(x 106/L)		   Platelet count
(x 106/L)		 % of full dose
≥1000
 And
 ≥100,000
 100
500 to 999
 Or
 50,000 to 99,999
 75
<500
 Or
 <50,000
 Hold



6666

2.5 Preparation and Administration Precautions




[see References (15)]

2.6 Preparation for Intravenous Infusion Administration










3 DOSAGE FORMS AND STRENGTHS


4 CONTRAINDICATIONS


5 WARNINGS AND PRECAUTIONS


5.1 Infusion Time


[see Clinical Studies (14.5)]

5.2 Hematology


[see Adverse Reactions (6.1)][see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

5.3 Pulmonary


[see Adverse Reactions (6.1 and 6.2)]

5.4 Renal


[see Adverse Reactions (6.1 and 6.2)]

[see Use in Specific Populations (8.6)].

5.5 Hepatic


[see Adverse Reactions (6.1 and 6.2)]

[see Use in Specific Populations (8.7)].

5.6 Pregnancy


[see Use In Specific Populations (8.1)].

5.7 Laboratory Tests


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

5.8 Radiation Therapy




Non-concurrent (given >7 days apart)

Concurrent (given together or ≤7 days apart) 2 3

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience








Single-Agent Use[see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]

2
Table 4: Selected WHO-Graded Adverse Reactions in Patients Receiving Single-Agent Gemcitabine WHO Grades (% incidence)Grade based on criteria from the World Health Organization (WHO).
All PatientsN=699 to 974; all patients with laboratory or non-laboratory data. Pancreatic Cancer PatientsN=161 to 241; all pancreatic cancer patients with laboratory or non-laboratory data. Discontinuations (%)N=979.
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 All Patients
LaboratoryRegardless of causality.
Hematologic
Anemia
68
 7
 1
 73
 8
 2
 <1
Leukopenia
62
 9
 <1
 64
 8
 1
 <1
Neutropenia
63
 19
 6
 61
 17
 7
 -
Thrombocytopenia
24
 4
 1
 36
 7
 <1
 <1
Hepatic
 <1
ALT
 68
 8
 2
 72
 10
 1
AST
 67
 6
 2
 78
 12
 5
Alkaline Phosphatase
 55
 7
 2
 77
 16
 4
Bilirubin
 13
 2
 <1
 26
 6
 2
Renal
 <1
Proteinuria
 45
 <1
 0
 32
 <1
 0
Hematuria
 35
 <1
 0
 23
 0
 0
BUN
 16
 0
 0
 15
 0
 0
Creatinine
 8
 <1
 0
 6
 0
 0
Non-laboratoryTable includes non-laboratory data with incidence for all patients ≥10%. For approximately 60% of the patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
Nausea and Vomiting
 69
 13
 1
 71
 10
 2
 <1
Fever
 41
 2
 0
 38
 2
 0
 <1
Rash
 30
 <1
 0
 28
 <1
 0
 <1
Dyspnea
 23
 3
 <1
 10
 0
 <1
 <1
Diarrhea
 19
 1
 0
 30
 3
 0
 0
Hemorrhage
 17
 <1
 <1
 4
 2
 <1
 <1
Infection
 16
 1
 <1
 10
 2
 <1
 <1
Alopecia
 15
 <1
 0
 16
 0
 0
 0
Stomatitis
 11
 <1
 0
 10
 <1
 0
 <1
Somnolence
 11
 <1
 <1
 11
 2
 <1
 <1
Paresthesias
 10
 <1
 0
 10
 <1
 0
 0

Hematologic [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)]

Gastrointestinal

Hepatic [see Adverse Reactions (6.2)]

Renal [see Adverse Reactions (6.2)]

Fever

Rash

Pulmonary [see Adverse Reactions (6.2)]

Edema

Flu-like Symptoms

Infection

Alopecia

Neurotoxicity

Extravasation

Allergic [see Contraindications (4)]

Cardiovascular [see Adverse Reactions (6.2)]

Combination Use in Non-Small Cell Lung Cancer:












Table 5: Selected CTC-Graded Adverse Reactions From Comparative Trial of Gemcitabine Plus Cisplatin Versus Single-Agent Cisplatin in NSCLC
CTC Grades (% incidence)Grade based on Common Toxicity Criteria (CTC). Table includes data for adverse reactions with incidence ≥10% in either arm.
Gemcitabine plus CisplatinN=217 to 253; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days. CisplatinN=213 to 248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days.
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
LaboratoryRegardless of causality.
Hematologic
Anemia
89
 22
 3
 67
 6
 1
RBC TransfusionPercent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
39
 13
Leukopenia
82
 35
 11
 25
 2
 1
Neutropenia
79
 22
 35
 20
 3
 1
Thrombocytopenia
85
 25
 25
 13
 3
 1
Platelet TransfusionsPercent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
21
 <1
Lymphocytes
75
 25
 18
 51
 12
 5
Hepatic
Transaminase
22
 2
 1
 10
 1
 0
Alkaline Phosphatase
19
 1
 0
 13
 0
 0
Renal
Proteinuria
23
 0
 0
 18
 0
 0
Hematuria
15
 0
 0
 13
 0
 0
Creatinine
38
 4
 <1
 31
 2
 <1
Other Laboratory
Hyperglycemia
30
 4
 0
 23
 3
 0
Hypomagnesemia
30
 4
 3
 17
 2
 0
Hypocalcemia
18
 2
 0
 7
 0
 <1
Non-laboratoryNon-laboratory events were graded only if assessed to be possibly drug-related.
Nausea
93
 25
 2
 87
 20
 <1
Vomiting
78
 11
 12
 71
 10
 9
Alopecia
53
 1
 0
 33
 0
 0
Neuro Motor
35
 12
 0
 15
 3
 0
Neuro Hearing
25
 6
 0
 21
 6
 0
Diarrhea
24
 2
 2
 13
 0
 0
Neuro Sensory
23
 1
 0
 18
 1
 0
Infection
18
 3
 2
 12
 1
 0
Fever
16
 0
 0
 5
 0
 0
Neuro Cortical
16
 3
 1
 9
 1
 0
Neuro Mood
16
 1
 0
 10
 1
 0
Local
15
 0
 0
 6
 0
 0
Neuro Headache
14
 0
 0
 7
 0
 0
Stomatitis
14
 1
 0
 5
 0
 0
Hemorrhage
14
 1
 0
 4
 0
 0
Dyspnea
12
 4
 3
 11
 3
 2
Hypotension
12
 1
 0
 7
 1
 0
Rash
11
 0
 0
 3
 0
 0

Table 6: Selected WHO-Graded Adverse Reactions From Comparative Trial of Gemcitabine Plus Cisplatin Versus Etoposide Plus Cisplatin in NSCLC
WHO Grades (% incidence)Grade based on criteria from the World Health Organization (WHO).
Gemcitabine plus CisplatinN=67 to 69; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days. Etoposide plus CisplatinN=57 to 63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days.
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
LaboratoryRegardless of causality.
Hematologic
Anemia
88
 22
 0
 77
 13
 2
RBC TransfusionsPercent of patients receiving transfusions. Percent transfusions are not WHO-graded events.
29
 21
Leukopenia
86
 26
 3
 87
 36
 7
Neutropenia
88
 36
 28
 87
 20
 56
Thrombocytopenia
81
 39
 16
 45
 8
 5
Platelet TransfusionsPercent of patients receiving transfusions. Percent transfusions are not WHO-graded events.
3
 8
Hepatic
ALT
6
 0
 0
 12
 0
 0
AST
3
 0
 0
 11
 0
 0
Alkaline Phosphatase
16
 0
 0
 11
 0
 0
Bilirubin
0
 0
 0
 0
 0
 0
Renal
Proteinuria
12
 0
 0
 5
 0
 0
Hematuria
22
 0
 0
 10
 0
 0
BUN
6
 0
 0
 4
 0
 0
Creatinine
2
 0
 0
 2
 0
 0
Non-laboratoryNon-laboratory events were graded only if assessed to be possibly drug-related. , Pain data were not collected.
Nausea and Vomiting
96
 35
 4
 86
 19
 7
Fever
6
 0
 0
 3
 0
 0
Rash
10
 0
 0
 3
 0
 0
Dyspnea
1
 0
 1
 3
 0
 0
Diarrhea
14
 1
 1
 13
 0
 2
Hemorrhage
9
 0
 3
 3
 0
 3
Infection
28
 3
 1
 21
 8
 0
Alopecia
77
 13
 0
 92
 51
 0
Stomatitis
20
 4
 0
 18
 2
 0
Somnolence
3
 0
 0
 3
 2
 0
Paresthesias
38
 0
 0
 16
 2
 0
Combination Use in Breast Cancer:




Table 7: Adverse Reactions From Comparative Trial of Gemcitabine Plus Paclitaxel Versus Single-Agent Paclitaxel in Breast CancerGrade based on Common Toxicity Criteria (CTC) Version 2 (all grades ≥10%).
CTC Grades (% incidence)
Gemcitabine plus Paclitaxel (N=262) Paclitaxel
(N=259)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
LaboratoryRegardless of causality.
Hematologic
Anemia
69
 6
 1
 51
 3
 <1
Neutropenia
69
 31
 17
 31
 4
 7
Thrombocytopenia
26
 5
 <1
 7
 <1
 <1
Leukopenia
21
 10
 1
 12
 2
 0
Hepatobiliary
ALT
18
5
<1
6
<1
0
AST
 16
 2
 0
 5
 <1
 0
Non-laboratoryNon-laboratory events were graded only if assessed to be possibly drug-related.
Alopecia
90
 14
 4
 92
 19
 3
Neuropathy-sensory
64
 5
 <1
 58
 3
 0
Nausea
50
 1
 0
 31
 2
 0
Fatigue
40
 6
 <1
 28
 1
 <1
Myalgia
33
 4
 0
 33
 3
 <1
Vomiting
29
 2
 0
 15
 2
 0
Arthralgia
24
 3
 0
 22
 2
 <1
Diarrhea
20
 3
 0
 13
 2
 0
Anorexia
17
 0
 0
 12
 <1
 0
Neuropathy-motor
15
 2
 <1
 10
 <1
 0
Stomatitis/pharyngitis
13
 1
 <1
 8
 <1
 0
Fever
13
 <1
 0
 3
 0
 0
Rash/desquamation
11
 <1
 <1
 5
 0
 0





Combination Use in Ovarian Cancer:



Table 8: Adverse Reactions From Comparative Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian CancerGrade based on Common Toxicity Criteria (CTC) Version 2 (all grades ≥10%).
CTC Grades (% incidence)
  Gemcitabine plus Carboplatin (N=175) Carboplatin
(N=174)
  All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
LaboratoryRegardless of causality.
Hematologic
Neutropenia
90
 42
 29
 58
 11
 1
Anemia
86
 22
 6
 75
 9
 2
Leukopenia
 86
 48
 5
 70
 6
 <1
Thrombocytopenia
78
 30
 5
 57
 10
 1
RBC TransfusionsPercent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.
38
 15
Platelet Transfusions
 9
 3
Non-laboratory
Nausea
69
 6
 0
 61
 3
 0
Alopecia
49
 0
 0
 17
 0
 0
Vomiting
46
 6
 0
 36
 2
 <1
Constipation
42
 6
 1
 37
 3
 0
Fatigue
40
 3
 <1
 32
 5
 0
Neuropathy-sensory
 29
 1
 0
 27
 2
 0
Diarrhea
25
 3
 0
 14
 <1
 0
Stomatitis/pharyngitis
 22
 <1
 0
 13
 0
 0
Anorexia
16
 1
 0
 13
 0
 0





6.2 Postmarketing Experience






Cardiovascular

Vascular Disorders Skin

Hepatic

Pulmonary

Renal

Injury, Poisoning, and Procedural Complications [see Warnings and Precautions (5.8)]

7 DRUG INTERACTIONS


[see Clinical Pharmacology (12.2 and 12.3)]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy






2 2 [see Warnings and Precautions (5.6)].

8.3 Nursing Mothers


8.4 Pediatric Use


22

8.5 Geriatric Use


[see Clinical Pharmacology (12.3)][see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)] [see Clinical Studies (14.1)]

8.6 Renal


[see Adverse Reactions (6.1 and 6.2)][see Warnings and Precautions (5.4)].

8.7 Hepatic


[see Adverse Reactions (6.1 and 6.2)][see Warnings and Precautions (5.5)].

8.8 Gender


[see Clinical Pharmacology (12.3)]. [see Dosage and Administration (2)]

10 OVERDOSAGE


2

11 DESCRIPTION



GEMCITABINE911234



12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


12.2 Pharmacodynamics


in vitroIn vivo

12.3 Pharmacokinetics


Absorption and Distribution

22 2



Metabolism

2



Excretion

Table 9: Gemcitabine Clearance and Half-Life for the “Typical” Patient
Age Clearance Men (L/hr/m2) Clearance Women (L/hr/m2) Half-LifeHalf-life for patients receiving a short infusion (<70 min).
Men (min)		 Half-LifeHalf-life for patients receiving a short infusion (<70 min).
Women (min)
29
 92.2
 69.4
 42
 49
45
 75.7
 57
 48
 57
65
 55.1
 41.5
 61
 73
79
 40.7
 30.7
 79
 94



Drug Interactions

2 2 2 22 [see Drug Interactions (7)]

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


in vitro in vivo in vivo in vitro in vitro2 2 2

14 CLINICAL STUDIES

14.1 Ovarian Cancer


2

Table 10: Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer - Baseline Demographics and Clinical Characteristics
Gemcitabine/Carboplatin Carboplatin
Number of randomized patients
178
 178
Median age, years
59
 58
Range
 36 to 78
 21 to 81
Baseline ECOG performance status 0 to 1Nine patients (5 on the gemcitabine plus carboplatin arm and 4 on the carboplatin arm) did not have baseline Eastern Cooperative Oncology Group (ECOG) performance status recorded.
94%
 95%
Disease Status
Evaluable
7.9%
2.8%
Bidimensionally measurable
 91.6%
 95.5%
Platinum-free intervalThree patients (2 on the gemcitabine plus carboplatin arm and 1 on the carboplatin arm) had a platinum-free interval of less than 6 months.
6 to 12 months
39.9%
39.9%
>12 months
 59%
 59.6%
First-line therapy
Platinum-taxane combination
 70.2%
71.3%
Platinum-non-taxane combination
 28.7%
27.5%
Platinum monotherapy
 1.1%
 1.1%

Table 11: Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer - Results of Efficacy Analysis
  Gemcitabine/Carboplatin (N=178) Carboplatin (N=178)
PFS
Median (95%, C.I.) months
Hazard Ratio (95%, C.I.)
8.6 (8, 9.7)
 5.8 (5.2, 7.1)
 p=0.0038Log Rank, unadjusted
0.72 (0.57, 0.9)
Overall Survival
Median (95%, C.I.) months
Hazard Ratio (95%, C.I.)
AdjustedTreatment adjusted for performance status, tumor area, and platinum-free interval. Hazard Ratio
(95%, C.I.)
18 (16.2, 20.3)
 17.3 (15.2, 19.3)
 p=0.8977Log Rank, unadjusted
0.98 (0.78, 1.24)
0.86 (0.67, 1.1)
Investigator Reviewed
Overall Response Rate
CR
PR+PRNMPartial response non-measurable disease

47.2%
14.6%
32.6%
30.9%
6.2%
24.7%
p=0.0016Chi Square
Independently Reviewed
Overall Response RateIndependent reviewers could not evaluate disease demonstrated by sonography or physical exam. , Independently reviewed cohort - Gemcitabine/Carboplatin N=121, Carboplatin N=101
CR
PR+PRNM

46.3%
9.1%
37.2%
35.6%
4%
31.7%
p=0.11Chi Square

GEMCITABINEFigure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356)

14.2 Breast Cancer


222

Table 12: Gemcitabine Plus Paclitaxel Versus Paclitaxel in Breast Cancer
  Gemcitabine/Paclitaxel Paclitaxel
Number of patients
267
 262
Median age, years
Range
53
26 to 83
 52
26 to 75
Metastatic disease
97%
 96.9%
Baseline KPSKarnofsky Performance Status. ≥90
70.4%
 74.4%
Number of tumor sites
1 to 2
≥3
56.6%
43.4%
 58.8%
41.2%
Visceral disease
73.4%
 72.9%
Prior anthracycline
96.6%
 95.8%
Overall SurvivalBased on the ITT population
Median (95%, CI)
18.6 (16.5, 20.7)
 15.8 (14.1, 17.3)
  Hazard Ratio (95%, CI) 0.86 (0.71, 1.04)
Time to Documented Disease ProgressionThese represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
Median (95%, C.I.), months
Hazard Ratio (95%, C.I.)
5.2 (4.2, 5.6)
 2.9 (2.6, 3.7)
 p<0.0001
0.65 (0.524, 0.805)
 p<0.0001
Overall Response Ratec (95%, C.I.)
40.8% (34.9, 46.7)
 22.1% (17.1, 27.2)
 p<0.0001


GEMCITABINEFigure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemcitabine Plus Paclitaxel Versus Paclitaxel Breast Cancer Study (N=529)

14.3 Non-Small Cell Lung Cancer (NSCLC)




Gemcitabine plus cisplatin versus cisplatin:

2 2 2



Gemcitabine plus cisplatin versus etoposide plus cisplatin:

2 2 2 2



GEMCITABINE
Figure 3: Kaplan-Meier Survival Curve in Gemcitabine Plus Cisplatin Versus Cisplatin NSCLC Study (N=522)
Table 13: Randomized Trials of Combination Therapy With Gemcitabine Plus Cisplatin in NSCLC
Trial 28-day Schedule28-day schedule — Gemcitabine plus cisplatin: Gemcitabine 1000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m2 on Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2 on Day 1 every 28 days. 21-day Schedule21-day schedule — Gemcitabine plus cisplatin: Gemcitabine 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 every 21 days.
Treatment Arm Gemcitabine/Cisplatin Cisplatin   Gemcitabine/Cisplatin Cisplatin/Etoposide  
Number of patients
Male
Female
 260
182
 78
 262
186
76
 
 69
64
5
 66
61
5
 
Median age, years
Range
62
36 to 88
 63
35 to 79
 
 58
33 to 76
 60
35 to 75
 
Stage IIIA
Stage IIIB
Stage IV
 7%
26%
67%
 7%
23%
70%
 		 N/AN/A Not applicable.
48%
52%
 N/AN/A Not applicable.
52%
49%
 
Baseline KPSKarnofsky Performance Status. 70 to 80
Baseline KPSKarnofsky Performance Status. 90 to 100
  41%

57%
  44%

55%
 
  45%

55%
  52%

49%
 
 
Survival
Median, months
(95%, C.I.) months
 
  9

8.2, 11
  
 7.6

6.6, 8.8
 
p=0.008

8.7

7.8, 10.1
 
7

6, 9.7
 
p=0.18
Time to Disease Progression
Median, months
(95%, C.I.) months
 
 
 
5.2
 
 4.2, 5.7
 
 
 
3.7
 
 3, 4.3
 
 
 
 p=0.009
 
 
 
5
 
 4.2, 6.4
 
 
 
4.1
 
 2.4, 4.5
 
 
 
 p=0.015
Tumor Response
26%
10%
 p<0.0001p-value for tumor response was calculated using the two-sided Fisher’s Exact test for difference in binomial proportions. All other p-values were calculated using the Log rank test for difference in overall time to an event.

 33%
 14%
 p=0.01p-value for tumor response was calculated using the two-sided Fisher’s Exact test for difference in binomial proportions. All other p-values were calculated using the Log rank test for difference in overall time to an event.

14.4 Pancreatic Cancer


2









2
Table 14: Gemcitabine Versus 5-FU in Pancreatic Cancer
  Gemcitabine 5-FU
Number of patients
Male
Female
63
34
29
 63
34
29
Median age
Range
62 years
37 to 79
 61 years
36 to 77
Stage IV disease
71.4%
 76.2%
Baseline KPSKarnofsky Performance Status. ≤70
69.8%
 68.3%
Clinical benefit response
22.2%
(NN=number of patients.=14)
 4.8%
(NN=number of patients.=3)
 p=0.004The p-value for clinical benefit response was calculated using the two-sided test for difference in binomial proportions. All other p-values were calculated using the Log rank test for difference in overall time to an event.
Survival
Median
6-month probabilityKaplan-Meier estimates.
9-month probabilityKaplan-Meier estimates.
1-year probabilityKaplan-Meier estimates.
Range
95% C.I. of the median

5.7 months
(N=30) 46%
(N=14) 24%
(N=9) 18%
0.2 to 18.6 months
4.7 to 6.9 months
4.2 months
(N=19) 29%
(N=4) 5%
(N=2) 2%
0.4 to 15.1+No progression at last visit; remains alive. months
3.1 to 5.1 months
p=0.0009
Time to Disease Progression
Median
Range
95% C.I. of the median

2.1 months
0.1+No progression at last visit; remains alive. to 9.4 months
1.9 to 3.4 months
0.9 months
0.1 to 12+No progression at last visit; remains alive. months
0.9 to 1.1 months
p=0.0013


GEMCITABINEFigure 4: Kaplan-Meier Survival Curve

14.5 Other Clinical Studies


22 2 2 [see Clinical Pharmacology (12.3)] [see Warnings and Precautions (5.1)]

15 REFERENCES

  • NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter
  • Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
  • American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs: Am J Health-Syst Pharm. 2006;63:1172-1193.
  • Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied








16.2 Storage and Handling


[see Dosage and Administration (2.5 and 2.6)]

17 PATIENT COUNSELING INFORMATION

17.1 Low Blood Cell Counts


[see Warnings and Precautions (5.2)]

17.2 Pregnancy


[see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].

17.3 Nursing Mothers


[see Use in Specific Populations (8.3)].

Distributed by:
Caraco Pharmaceutical Laboratories, Ltd.
1150 Elijah McCoy Drive, Detroit, MI 48202

Manufactured by:
Sun Pharmaceutical Ind. Ltd.
Halol-Baroda Highway,
Halol-389 350, Gujarat
India.

ISS. 05/2011
PJPI0100B

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL 200MG


NDC 47335-153-40
Gemcitabine For Injection USP
200 mg
(lyophilized)
For Intravenous Use Only
Sterile Single Use Vial
Rx only
GEMCITABINE

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON 200MG


NDC 47335-153-40
Gemcitabine For Injection USP
200 mg
(lyophilized)
For Intravenous Use Only
Sterile Single Use Vial
DO NOT REFRIGERATE
Rx only
SUN PHARMACEUTICAL INDUSTRIES LTD.
GEMCITABINE

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL 1G


NDC 47335-154-40
Gemcitabine For Injection USP
1 g
(lyophilized)
For Intravenous Use Only
Sterile Single Use Vial
Rx only
GEMCITABINE

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON 1G



NDC 47335-154-40
Gemcitabine For Injection USP
1 g
(lyophilized)
For Intravenous Use Only
Sterile Single Use Vial
DO NOT REFRIGERATE
Rx only
SUN PHARMACEUTICAL INDUSTRIES LTD.
GEMCITABINE

GEMCITABINE

GEMCITABINE HYDROCHLORIDE INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:47335-153
Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
GEMCITABINE HYDROCHLORIDE gemcitabine 200 mg

Inactive Ingredients

Ingredient Name Strength
mannitol
SODIUM ACETATE
HYDROCHLORIC ACID
SODIUM HYDROXIDE

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 5 in 1 VIAL, SINGLE-USE
2 NDC:47335-153-40 1 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078433 2011-07-25


GEMCITABINE

GEMCITABINE HYDROCHLORIDE INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:47335-154
Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
GEMCITABINE HYDROCHLORIDE gemcitabine 1 g

Inactive Ingredients

Ingredient Name Strength
mannitol
SODIUM ACETATE
HYDROCHLORIC ACID
SODIUM HYDROXIDE

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 25 in 1 VIAL, SINGLE-USE
2 NDC:47335-154-40 1 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078433 2011-07-25


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