Label: GEMCITABINE injection, solution

  • NDC Code(s): 68001-342-34, 68001-348-36, 68001-350-68, 68001-359-37
  • Packager: BluePoint Laboratories
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated September 9, 2019

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use GEMCITABINE INJECTION safely and effectively. See full prescribing information for GEMCITABINE INJECTION.



    GEMCITABINE injection, for intravenous use

    Initial U.S. Approval: 1996

    RECENT MAJOR CHANGES

    Warnings and Precautions,

    Hemolytic Uremic Syndrome (5.4)

    INDICATIONS AND USAGE

    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)

    DOSAGE AND ADMINISTRATION

    Gemcitabine Injection is for intravenous infusion use only.

    Ovarian cancer: 1000 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.1)
    Breast cancer: 1250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.2)
    Non-small cell lung cancer: 1000 mg/m 2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.3)
    Pancreatic cancer: 1000 mg/m 2 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)

    DOSAGE FORMS AND STRENGTHS

    Gemcitabine Injection in multiple dose vials containing:

    200 mg/2 mL (100 mg/mL) (3)
    1 g/10 mL (100 mg/mL) ( 3)
    1.5 g/15 mL (100 mg/mL) (3)
    2 g/20 mL (100 mg/mL) (3)

    CONTRAINDICATIONS

    Patients with a known hypersensitivity to gemcitabine. (4)

    WARNINGS AND PRECAUTIONS

    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, 5.7)
    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 therapy. Discontinue Gemcitabine Injection for HUS or severe renal impairment. (5.4)
    Hepatoxicity: Monitor hepatic function prior to initiation and during therapy. 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)

    ADVERSE REACTIONS

    The most common adverse reactions for the single agent (≥20%) are nausea/vomiting, anemia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

    USE IN SPECIFIC POPULATIONS

    Lactation: Advise not to breastfeed. (8.2)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 9/2019

  • Table of Contents
  • 1 INDICATIONS AND USAGE

    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 DOSAGE AND ADMINISTRATION

    2.1 Ovarian Cancer

    Recommended Dose and Schedule

    The recommended dosage of Gemcitabine Injection is 1000 mg/m 2 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 the carboplatin prescribing information for additional information.

    Dose Modifications

    Recommended Gemcitabine Injection dose modifications for myelosuppression are described in Table 1 and Table 2 [see Warnings and Precautions ( 5.2)]. Refer to the dose modification recommendations for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

    Table 1: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian Cancer

    Treatment Day

    Absolute neutrophil count
    (x 106/L)

    Platelet count (x 106/L)

    Dose modification

    Day 1

    Greater than or equal to 1500

    Less than 1500

    and

    or

    Greater than or equal to 100,000
    Less than 100,000

    None

    Delay Treatment Cycle

    Day 8

    Greater than or equal to 1500

    1000-1499
    Less than 1000

    and

    or
    or

    Greater than or equal to 100,000
    75,000-99,999
    Less than 75,000

    None

    50% of full dose
    Hold

    Table 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian Cancer

    Occurrence

    Myelosuppression During Treatment Cycle

    Dose Modification

    Initial Occurrence

    Absolute neutrophil count less than500 x 106/L for more than 5 days or
    Absolute neutrophil count less than 100 x 106/L for more than 3 days or
    Febrile neutropenia or
    Platelets less than 25,000x106/L
    Cycle delay of more than one week due to toxicity

    Permanently reduce Gemcitabine Injection dose to 800 mg/m2 on Days 1 and 8

    Subsequent Occurrence

    If any of the above toxicities occur after the initial dose reduction

    Permanently reduce Gemcitabine Injection to 800 mg/m2 on Day 1 only

    2.2 Breast Cancer

    Recommended Dose and Schedule

    The recommended dosage of Gemcitabine Injection is 1250 mg/m 2 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 the paclitaxel prescribing information for additional information.

    Dosage Modifications

    Recommended Gemcitabine Injection dose modifications for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

    Table 3: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Breast Cancer

    Treatment Day

    Absolute neutrophil count
    (x 106/L)

    Platelet count
    (x 10 6/L)

    Dose modification

    Day 1

    Greater than or equal to 1500

    and

    Greater than or equal to 100,000

    None

    Less than 1500

    or

    Less than 100,000

    Hold

    Day 8

    Greater than or equal to 1200

    and

    Greater than 75,000

    None

    1000-1199

    or

    50,000-75,000

    75% of full dose

    700-999

    and

    Greater than or equal to 50,000

    50% of full dose

    Less than 700

    or

    Less than 50,000

    Hold

    2.3 Non-Small Cell Lung Cancer

    Recommended Dose and Schedule

    28-day schedule

    The recommended dosage of Gemcitabine Injection is 1000 mg/m 2 intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m2 administered intravenously on Day 1 after Gemcitabine Injection administration.

    21-day schedule

    The recommended dosage of Gemcitabine Injection is 1250 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m2 therapy administered intravenously on Day 1 after Gemcitabine Injection administration.

    Refer to the cisplatin prescribing information for additional information.

    Dose Modifications

    Table 4 presents the recommended dose modifications for Gemcitabine Injection myelosuppression [see Warnings and Precautions (5.2)]. Refer to the dose modification recommendations for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

    2.4 Pancreatic Cancer

    Recommended Dose and Schedule

    The recommended dose of Gemcitabine Injection is 1000 mg/m 2 over 30 minutes intravenously. The recommended treatment schedule is as follows:

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

    Dosage Modifications

    Recommended dosage modifications for Gemcitabine Injection for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

    If myelosuppression is detected, therapy should be modified or suspended according to the guidelines in Table 4.

    Table 4: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer

    Absolute neutrophil count
    (x 106/L)

    Platelet count
    (x 106/L)

    Dose modification

    Greater than or equal to 1000

    and

    Greater than or equal to 100,000

    None

    500-999

    or

    50,000-99,999

    75% of full dose

    Less than 500

    or

    Less than 50,000

    Hold

    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.
  • 3 DOSAGE FORMS AND STRENGTHS

    Injection: 100mg/mL of gemcitabine as a clear, colorless to pale yellow solution available in sterile multiple-dose vials containing

    200 mg/2 mL (100 mg/mL)
    1 g/10 mL (100 mg/mL)
    1.5 g/15 mL (100 mg/mL)
    2 g/20 mL (100 mg/mL)
  • 4 CONTRAINDICATIONS

    Gemcitabine Injection is contraindicated in patients with a known hypersensitivity to gemcitabine.Reactions include anaphylaxis [see Adverse Reactions (6.1)].

  • 5 WARNINGS AND PRECAUTIONS

    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 (6.1 and 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.

    Concurrent (given together or ≤7 days apart)

    Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which gemcitabine was administered at a dose of 1000 mg/m 2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation.

    Non-concurrent (given >7 days apart)

    Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive gemcitabine after prior radiation.

    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 ADVERSE REACTIONS

    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)]

    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.

    Single-Agent

    The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m2 to 1250 mg/m2 intravenously over 30 minutes once weekly in 979 patients with various malignancies. The most common (≥20%) adverse reactions of single-agent gemcitabine are nausea/vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increased alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in < 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.

    Tables 5 and 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine across 5 clinical trials. Additional clinically significant adverse reactions and laboratory abnormalities are provided following Table 6.

    Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabinea
    Adverse ReactionsbGemcitabine c
    All Grades (%)Grade 3 (%)Grade 4 (%)
    a Grade based on criteria from the World Health Organization (WHO).
    b For approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
    c N=699-974; all patients with laboratory or non-laboratory data.

    Nausea and vomiting

    69

    13

    1

    Fever

    41

    2

    0

    Rash

    30

    <1

    0

    Dyspnea

    23

    3

    <1

    Diarrhea

    19

    1

    0

    Hemorrhage

    17

    <1

    <1

    Infection

    16

    1

    <1

    Alopecia

    15

    <1

    0

    Stomatitis

    11

    <1

    0

    Somnolence

    11

    <1

    <1

    Paresthesias

    10

    <1

    0

    Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single-Agent Gemcitabinea
    Laboratory AbnormalitybGemcitabinec
    All Grades (%)Grade 3 (%)Grade 4 (%)
    a Grade based on criteria from the WHO.
    b Regardless of causality.
    c N=699-974 ; all patients with laboratory or non-laboratory data.

    Hematologic

    Anemia

    68

    7

    1

    Neutropenia

    63

    19

    6

    Thrombocytopenia

    24

    4

    1

    Hepatic

    Increased ALT

    68

    8

    2

    Increased AST

    67

    6

    2

    Increased alkaline phosphatase

    55

    7

    2

    Hyperbilirubinemia

    13

    2

    <1

    Renal

    Proteinuria

    45

    <1

    0

    Hematuria

    35

    <1

    0

    Increased BUN

    16

    0

    0

    Increased creatinine

    8

    <1

    0

    Additional adverse reactions include the following:

    Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%)
    Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%);
    Flu-like Symptoms: fever, asthenia, anorexia, headache, cough, chills, myalgia, insomnia, rhinitis, sweating, and/or malaise (19%);
    Infection: Sepsis (<1%)
    Extravasation: Injection-site reactions (4%)
    Allergic: Bronchospasm (<2%); anaphylactoid reactions.

    Ovarian Cancer

    Tables 7 and 8 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine plus carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)] .

    Additional clinically significant adverse reactions, occurring in < 10% of patients, are provided following Table 8.

    The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0) and discontinuing treatment for adverse reactions (11% versus 10%), were similar between arms. Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine/ carboplatin arm.

    Table 7: Adverse Reactions Occurring >10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1a

    a Grade based on National Cancer Institute CTC Version 2.0.
    b Regardless of causality.

    Adverse Reactionsb

    Gemcitabine/ Carboplatin
    (N=175)

    Carboplatin
    (N=174)

    All Grades

    (%)

    Grade 3

    (%)

    Grade 4

    (%)

    All Grades

    (%)

    Grade 3

    (%)

    Grade 4

    (%)

         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

         Diarrhea

    25

    3

    0

    14

    <1

    0

         Stomatitis/pharyngitis

    22

    <1

    0

    13

    0

    0

    Table 8: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]

    a Grade based on National Cancer Institute CTC Version 2.0.
    b Regardless of causality.
    c Percent of patients receiving a transfusion. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

    Laboratory Abnormality b

    Gemcitabine/ Carboplatin
    (N=175)

    Carboplatin
    (N=174)

    All Grades

    (%)

    Grade 3

    (%)

    Grade 4

    (%)

    All Grades

    (%)

    Grade 3

    (%)

    Grade 4

    (%)

     Hematologic

        Neutropenia

    90

    42

    29

    58

    11

    1

        Anemia

    86

    22

    6

    75

    9

    2

        Thrombocytopenia

    78

    30

    5

    57

    10

    1

     RBC Transfusions c

    38

    -

    -

    15

    -

    -

     Platelet Transfusionsc

    9

    -

    -

    3

    -

    -

    Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis agents (7% and 3.9%). The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

    Breast Cancer

    Table 9 and 10 present the incidence of selected adverse reactions, and laboratory abnormalities, occurring in ≥10% of gemcitabine treated patients and at a higher incidence in the gemcitabine plus paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [see Clinical Studies (14.2)]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 10.

    The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.

    Table 9: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]
    a Grade based on National Cancer Institute CTC Version 2.0.
    b Non-laboratory events were graded only if assessed to be possibly drug-related.

    Adverse Reactionsb

    Gemcitabine/Paclitaxel (N=262)

    Paclitaxel (N=259)

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

         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

         Vomiting

    29

    2

    0

    15

    2

    0

         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

         Febrile neutropenia

    6

    5

    <1

    2

    1

    0

    Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2a
    a Grade based on National Cancer Institute CTC Version 2.0.
    b Regardless of causality.

    Laboratory
    Laboratory Abnormality b

    Gemcitabine/ Paclitaxel (N=262)

    Paclitaxel (N=259)

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

       Hematologic

         Anemia

    69

    6

    1

    51

    3

    <1

         Neutropenia

    69

    31

    17

    31

    4

    7

         Thrombocytopenia

    26

    5

    <1

    7

    <1

    <1

       Hepatobiliary

         Increased ALT

    18

    5

    <1

    6

    <1

    0

         Increased AST

    16

    2

    0

    5

    <1

    0

    Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).

    Non-Small Cell Lung Cancer:

    Table 11 and 12 present the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)].

    Patients randomized to gemcitabine with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving gemcitabine with cisplatin compared to those receiving cisplatin alone. The incidence of febrile neutropenia (3% versus <1%), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine with cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm.

    Table 11: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single-Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3a

    a Grade based on National Cancer Institute Common Toxicity Criteria (CTC).
    b Non-laboratory events were graded only if assessed to be possibly drug-related.
    c N=217-253; all gemcitabine/ cisplatin patients with laboratory or non-laboratory data
    d N=213-248; all cisplatin patients with laboratory or non-laboratory data.

    Adverse Reactions b

    Gemcitabine/ Cisplatinc

    Cisplatind

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

         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

         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

         Hypotension

    12

    1

    0

    7

    1

    0

         Rash

    11

    0

    0

    3

    0

    0

    Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin at Higher Incidence than in Patients Receiving Single-Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3

    a Grade based on National Cancer Institute CTC.
    b Regardless of causality.
    c N=217-253; all gemcitabine/ cisplatin patients with laboratory or non-laboratory.
    d N=213-248; all cisplatin patients with laboratory or non-laboratory data.
    e Percent of patients receiving a transfusion. Percent transfusions are not CTC-graded events.

    Laboratory Abnormality b

    Gemcitabine/ Cisplatinc

    Cisplatind

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

     Hematologic

         Anemia

    89

    22

    3

    67

    6

    1

         Thrombocytopenia

    85

    25

    25

    13

    3

    1

         Neutropenia

    79

    22

    35

    20

    3

    1

         Lymphopenia

    75

    25

    18

    51

    12

    5

         RBC transfusionse

    39

    -

    -

    13

    -

    -

         Platelet transfusionse

    21

    -

    -

    <1

    -

    -

    Renal

         Increased creatinine

    38

    4

    <1

    31

    2

    <1

         Proteinuria

    23

    0

    0

    18

    0

    0

         Hematuria

    15

    0

    0

    13

    0

    0

    Other laboratory

         Hyperglycemia

    30

    4

    0

    23

    3

    0

         Hypomagnesemia

    30

    4

    3

    17

    2

    0

         Hypocalcemia

    18

    2

    0

    7

    0

    <1

    Hepatic

    Increased transaminases

    22

    2

    1

    10

    1

    0

      Increased alkaline Phosphatase

    19

    1

    0

    13

    0

    0

    Tables 13 and 14 present the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)] . Additional clinically significant adverse reactions are provided following Table 14.

    Patients in the gemcitabine/ cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/ cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the (GC) arm and 68% in the (EC) arm. The incidence of hospitalizations for adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of patients who discontinued treatment for adverse reactions was higher in the GC arm (14% versus 8%). The proportion of patients who were hospitalized for febrile neutropenia was lower in the GC arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the GC arm.

    Table 13: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4a

    a Grade based on criteria from the World Health Organization (WHO).
    b Non-laboratory events were graded only if assessed to be possibly drug-related.
    c N=67-69; all gemcitabine/ cisplatin patients with non-laboratory data.
    d N=57-63; all cisplatin plus etoposide patients with non-laboratory data.
    e Flu-like syndrome and edema were not graded.

    Adverse Reactions d

    Gemcitabine/ Cisplatinc

    Etoposide/ Cisplatind

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

    Nausea and Vomiting

    96

    35

    4

    86

    19

    7

    Alopecia

    77

    13

    0

    92

    51

    0

    Paresthesias

    38

    0

    0

    16

    2

    0

    Infection

    28

    3

    1

    21

    8

    0

    Stomatitis

    20

    4

    0

    18

    2

    0

    Diarrhea

    14

    1

    1

    13

    0

    2

    Edemae

    12

    -

    -

    2

    -

    -

    Rash

    10

    0

    0

    3

    0

    0

    Hemorrhage

    9

    0

    3

    3

    0

    3

    Fever

    6

    0

    0

    3

    0

    0

    Flu-like syndromee

    3

    -

    -

    0

    -

    -

    Somnolence

    3

    0

    0

    3

    2

    0

    Dyspnea

    1

    0

    1

    3

    0

    0

    Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4a
    a Grade based on criteria from the WHO.
    b Regardless of causality.
    c N=67-69; all gemcitabine/ cisplatin patients with laboratory or non-laboratory data.
    d N=57-63; all cisplatin/ etoposide patients with laboratory or non-laboratory data.
    e WHO grading scale not applicable to proportion of patients with transfusions.

    Laboratory Abnormalitiesd

    Gemcitabine/ Cisplatin c

    Etoposide/ Cisplatin d

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

    All Grades
    (%)

    Grade 3
    (%)

    Grade 4
    (%)

    Hematologic

         Anemia

    88

    22

    0

    77

    13

    2

         RBC Transfusionse

    29

    -

    -

    21

    -

    -

         Neutropenia

    88

    36

    28

    87

    20

    56

         Thrombocytopenia

    81

    39

    16

    45

    8

    5

         Platelet Transfusionse

    3

    -

    -

    8

    -

    -

     Hepatic

         Increased ALT

    6

    0

    0

    12

    0

    0

         Increased AST

    3

    0

    0

    11

    0

    0

         Increased alkaline

    16

    0

    0

    11

    0

    0

    phosphatase

    Renal

         Proteinuria

    12

    0

    0

    5

    0

    0

         Hematuria

    22

    0

    0

    10

    0

    0

         Increased BUN

    6

    0

    0

    4

    0

    0

         Increased Creatinine

    2

    0

    0

    2

    0

    0

    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 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    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 reproductive 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 Special Populations (8.3)].

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

    Data

    Animal Data

    Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformation (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice [approximately 0.005 times the 1000 mg/m2 clinical dose based on body surface area (BSA)]. Gemcitabine was embryotoxic and fetotoxic in rabbits. Daily dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes, and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day (approximately 0.002 times the 1000 mg/m2 clinical dose based on BSA)

    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)].

  • 10 OVERDOSAGE

    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 should receive supportive therapy, as necessary.

  • 11 DESCRIPTION

    Gemcitabine is a nucleoside metabolic inhibitor. Gemcitabine Hydrochloride is 2’-deoxy-2’,2’-difluorocytidine monohydrochloride (β-isomer) with the following molecular structure:

    Structural Formula

    Gemcitabine Hydrochloride is a white to off white crystalline powder. The empirical formula for gemcitabine hydrochloride is C9H11F2N 3O4 • HCl and the molecular weight is 299.66.

    Gemcitabine HCl is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

    Gemcitabine Injection is a sterile, clear colorless to pale yellow solution that is provided in 100mg/mL multiple-dose vials for intravenous use only. Gemcitabine Injection is available in four presentations: 200 mg/2 mL, 1 g/10 mL, 1.5 g/15 mL or 2 g/20 mL. Each mL contains 100 mg of gemcitabine free base (equivalent to 113.85 mg of gemcitabine hydrochloride), 250 mg PEG-300, 150 mg propylene glycol, and 16 mg sodium hydroxide in dehydrated alcohol. Sodium hydroxide and/or hydrochloric acid may have been added for pH adjustment.

  • 12 CLINICAL PHARMACOLOGY

    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

    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 to 3600 mg/m2.

    Distribution

    The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.

    Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and sex. Gemcitabine plasma protein binding is negligible.

    Elimination

    Metabolism

    The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.

    Excretion

    Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m2 of radiolabeled drug as a 30 minute infusion. Within one week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2’-deoxy-2’,2’-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.

    Specific Populations

    Geriatric Patients

    Clearance of gemcitabine was affected by age. The lower clearance in the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 15 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and sex.

    Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient
    a Half-life for patients receiving <70 minute infusion.

    Age

    Clearance Men
    (L/hr/m2)

    Clearance Women
    (L/hr/m2)

    Half-Lifea Men
    (min)

    Half-Lifea Women
    (min)

    29

    92.2

    69.4

    42

    49

    45

    75.7

    57.0

    48

    57

    65

    55.1

    41.5

    61

    73

    79

    40.7

    30.7

    79

    94

    Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and for long infusions varied from 245 to 638 minutes, depending on age and sex, reflecting a greatly increased volume of distribution with longer infusions.

    Male and Female Patients

    Female patients have lower clearance and longer half-lives than male patientsas described in Table 15.

    Patients with Renal Impairment

    No clinical studies have been conducted with gemcitabine in patients with decreased renal function.

    Patients with Hepatic Impairment

    No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function.

    Drug Interaction Studies

    When gemcitabine (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m 2 on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day 1 was 128 L/hr/m 2 and on Day 8 was 107 L/hr/m2. Data from patients with NSCLC demonstrate that gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent; however, due to wide confidence intervals and small sample size, interpatient variability may be observed. Data from metastatic breast cancer patients shows that gemcitabine has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine.

  • 13 NONCLINICAL TOXICOLOGY

    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 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 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/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).

  • 14 CLINICAL STUDIES

    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/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
    a 5 patients on gemcitabine with carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.
    b 2 patients on gemcitabine with carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months
    Table 17: Efficacy Results in Study 1

    Gemcitabine /Carboplatin
    (N=178)

    Carboplatin
    (N=178)

    Median age, years

    59

    58

    Range

    36 to 79

    21 to 81

    Baseline ECOG performance status 0-1a

    94%

    95%

    Disease Status

    Evaluable

    8%

    3%

    Bidimensionally measurable

    92%

    96%

    Platinum-free intervalb

    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%

    a CI=confidence interval.
    b Log rank, unadjusted.
    c Chi square.
    d CR=Complete response.
    e PR plus PRNM=Partial response plus partial response, non-measurable disease.
    f Independently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.

    Gemcitabine /Carboplatin
    (N=178)

    Carboplatin
    (N=178)

    Progression-free Survival

         Median (95% CIa) months

    8.6 (8.0, 9.7)

    5.8 (5.2, 7.1)

         Hazard Ratio (95% CI)

    0.72 (0.57, 0.90)

         p-valueb

    p=0.0038

    Overall Survival

         Median (95% CI) months

    18.0 (16.2, 20.3)

    17.3 (15.2, 19.3)

         Hazard Ratio (95% CI)

    0.98 (0.78, 1.24)

         p-valueb

    p=0.8977

    Overall Response Rate by investigator

    47.2%

    30.9%

         p-value c

    p=0.0016

         CRd

    14.6%

    6.2%

         PR plus PRNMe

    32.6%

    24.7%

    Overall Response Ratef by independent review

    46.3%

    35.6%

         p-valuec

    p=0.11

         CRd

    9.1%

    4.0%

         PR plus PRNM e

    37.2%

    31.7%

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

    Figure 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 2 on Days 1 and 8 of a 21-day cycle and 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 KPSa ≥90

    70%

    74%

    Number Tumor Sites

    1-2

    57%

    59%

    ≥3

    43%

    41%

    Visceral Disease

    73%

    73%

    Prior anthracycline

    97%

    96%

    aKarnofsky Performance Status

    Table 19: Efficacy Results in Study 2
    a These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
    b Based on the ITT population.

    Gemcitabine/Paclitaxel, N=267

    Paclitaxel, N=262

    Efficacy Outcomes

       Time to Documented Disease Progression a

             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 b

             Median Survival (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

    40.8%

    22.1%

             (95% CI)

    (34.9, 46.7)

    (17.1, 27.2)

       p-value

    p<0.0001

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

    Figure 2

    14.3 Non-Small Cell Lung Cancer (NSCLC)

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

    Study 3: 28-Day Schedule

    A multinational, randomized trial (Study 3) compared gemcitabine with cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive either gemcitabine 1000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 on Day 1 after gemcitabine administration (n=260) or cisplatin 100 mg/m2 on Day 1 of each 28-day cycle (N=262). The major efficacy outcome measure was overall survival. A total of 522 patients were enrolled. Demographics and baseline characteristics (Table 20) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine with cisplatin arm having adenocarcinoma.

    Efficacy results are presented in Table 221 and Figure 3 for overall survival.

    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/m2 on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m2 on Day 1 after gemcitabine administration or etoposide 100 mg/m 2 intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m2 on 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/Aa

    N/Aa

    Stage IIIB

    26%

    23%

    48%

    52%

    Stage IV

    67%

    70%

    52%

    49%

    Baseline KPSb 70 to 80

    41%

    44%

    45%

    52%

    Baseline KPSb 90 to 100

    57%

    55%

    55%

    49%

    a N/A Not Applicable

    b Karnofsky Performance Status.

    Table 21: Efficacy Results for Studies 3 and 4
    a CI=confidence intervals.
    b p-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% CIa) 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-valueb

    p=0.008

    p=0.18

    Time to Disease Progression

    Median (95% CIa) 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-valueb

    p=0.009

    p=0.015

    Tumor Response

    26%

    10%

    33%

    14%

         p-valueb

    p<0.0001

    p=0.01

    Figure 3: Kaplan-Meier Survival Curves in Study 3

    Figure 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/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 the 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

    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 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, years

    62

    61

    Range

    37 to 79

    36 to 77

    Stage IV disease

    71%

    76%

    Baseline KPSa ≤70

    70%

    68%

    a Karnofsky Performance Status.

    Table 23: Efficacy Results in Study 5
    a p-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.

    Efficacy Parameter

    Gemcitabine
    (N= 63)

    Fluorouracil
    (N= 63)

    Clinical benefit response

    p-valuea

    22.2%

    4.8%

    p=0.004

    Survival

          Median (95% CI) in months

    5.7 (4.7, 6.9)

    4.2 (3.1, 5.1)

          p-value a

    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-valuea

    p=0.0013

    Figure 4: Kaplan-Meier Survival Curve.

    Figure 4
  • 15 REFERENCES

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

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Gemcitabine Injection is a clear colorless to pale yellow solution available in sterile multiple-dose vials containing:

    VialNDC number
     
    200 mg/2 mL (100 mg/mL)
    1 g/10 mL (100 mg/mL)
    1.5 g/15 mL (100 mg/mL)
    2 g/ 20 mL (100 mg/mL)
     
     
    68001-342-34
    68001-348-36
    68001-350-68
    68001-359-37
     

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15° C and 30°C (59°F and 86°F).

    After initial puncture, Gemcitabine Injection multiple-dose vials are stable for 28 days when stored at room temperature.

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

  • 17 PATIENT COUNSELING INFORMATION

    Myelosuppression

    Advise patients of the risk 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)].

    Pulmonary toxicity

    Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough [see Warnings and Precautions (5.3)].

    Hemolytic-uremic syndrome and renal failure

    Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instruct patients to immediately contact their healthcare provider for changes in the color or volume of urine output or for increased bruising or bleeding [see Warnings and Precautions (5.4)].

    Hepatotoxicity

    Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal quadrant [see Warnings and Precautions (5.5)].

    Embryo-Fetal Toxicity

    Advise females and males of reproductive potential that Gemcitabine Injection can cause fetal harm. 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 after the final dose of Gemcitabine Injection [see Warnings and Precautions (5.6)and Use in Specific Populations (8.1, 8.3) ].

    Lactation

    Advise women not to breastfeed during treatment with Gemcitabine Injection and for at least one week after the last dose [see Use in Specific Populations (8.2)].

    Infertility

    Advise males of reproductive potential of the potential for reduced fertility with Gemcitabine Injection [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

  • SPL UNCLASSIFIED SECTION

    Manufactured By:
    Intas Pharmaceuticals Limited,
    Plot No.:457, 458, Village – Matoda, Bavla Road,

    Ta.- Sanand, Dist. – Ahmedabad – 382 210. INDIA

    For BluePoint Laboratories

  • PRINCIPAL DISPLAY PANEL

    PACKAGE CARTON – 200 mg/2 mL

    NDC 68001- 342-34

    Gemcitabine Injection

    200 mg/2 mL (100 mg/mL)

    For Intravenous Infusion Only

    Must be Diluted Before Use

    Discard 28 days after initial puncture

    CAUTION: Cytotoxic Agent

    Rx only

    Sterile       Multiple-Dose Vial

    Gemcitabine RTU 200mg_2mL Carton Rev 0719
  • PRINCIPAL DISPLAY PANEL

    PACKAGE CONTAINER – 200 mg/2 mL

    NDC 68001-342-34      Rx only

    Gemcitabine Injection

    200 mg/2 mL (100 mg/mL)

    For Intravenous Infusion Only

    Must be Diluted Before Use

    Multiple-Dose Vial      Sterile

    Gemcitabine RTU 200mg_2mL Label Rev 0719
  • PRINCIPAL DISPLAY PANEL

    PACKAGE CARTON – 1 g/10 mL

    NDC 68001-348-36

    Gemcitabine Injection

    1 g/10 mL (100 mg/mL)

    For Intravenous Infusion Only

    Must be Diluted Before Use

    Discard 28 days after initial puncture

    CAUTION: Cytotoxic Agent

    Rx only

    Sterile       Multiple-Dose Vial

    Gemcitabine RTU 1g_10mL Carton Rev 0719
  • PRINCIPAL DISPLAY PANEL

    PACKAGE CONTAINER – 1 g/10 mL

    NDC 68001- 348-36      Rx only

    Gemcitabine Injection

    1 g/10 mL (100 mg/mL)

    For Intravenous Infusion Only

    Must be Diluted Before Use

    Multiple-Dose Vial      Sterile

    Gemcitabine RTU 1g_10mL Label Rev 0719
  • PRINCIPAL DISPLAY PANEL

    PACKAGE CARTON – 1.5 g/15 mL

    NDC 68001- 350-68

    Gemcitabine Injection

    1.5 g/15 mL (100 mg/mL)

    For Intravenous Infusion Only

    Must be Diluted Before Use

    Discard 28 days after initial puncture

    CAUTION: Cytotoxic Agent

    Rx only

    Sterile       Multiple-Dose Vial

    Gemcitabine RTU 1.5g_15mL Carton Rev 0719
  • PRINCIPAL DISPLAY PANEL

    PACKAGE CONTAINER – 1.5 g/15 mL

    NDC 68001-350-68      Rx only

    Gemcitabine Injection

    1.5 g/15 mL (100 mg/mL)

    For Intravenous Infusion Only

    Must be Diluted Before Use

    Multiple-Dose Vial      Sterile

    Gemcitabine RTU 1.5g_15mL Label Rev 0719
  • PRINCIPAL DISPLAY PANEL

    PACKAGE CARTON – 2 g/20 mL

    NDC 68001-359-37

    Gemcitabine Injection

    2 g/20 mL (100 mg/mL)

    For Intravenous Infusion Only

    Must be Diluted Before Use

    Discard 28 days after initial puncture

    CAUTION: Cytotoxic Agent

    Rx only

    Sterile       Multiple-Dose Vial

    Gemcitabine RTU 2g_20mL Carton Rev 0719
  • PRINCIPAL DISPLAY PANEL

    PACKAGE CONTAINER – 2 g/20 mL

    NDC 68001-359-37      Rx only

    Gemcitabine Injection

    2 g/20 mL (100 mg/mL)

    For Intravenous Infusion Only

    Must be Diluted Before Use

    Multiple-Dose Vial      Sterile

    Gemcitabine RTU 2g_20mL Label Rev 0719
  • INGREDIENTS AND APPEARANCE
    GEMCITABINE 
    gemcitabine injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:68001-342
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GEMCITABINE HYDROCHLORIDE (UNII: U347PV74IL) (GEMCITABINE - UNII:B76N6SBZ8R) GEMCITABINE100 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    ALCOHOL (UNII: 3K9958V90M)  
    POLYETHYLENE GLYCOL 300 (UNII: 5655G9Y8AQ) 250 mg  in 1 mL
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3) 150 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I) 16 mg  in 1 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:68001-342-341 in 1 CARTON05/25/2018
    12 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20960405/25/2018
    GEMCITABINE 
    gemcitabine injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:68001-348
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GEMCITABINE HYDROCHLORIDE (UNII: U347PV74IL) (GEMCITABINE - UNII:B76N6SBZ8R) GEMCITABINE100 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    ALCOHOL (UNII: 3K9958V90M)  
    POLYETHYLENE GLYCOL 300 (UNII: 5655G9Y8AQ) 250 mg  in 1 mL
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3) 150 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I) 16 mg  in 1 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:68001-348-361 in 1 CARTON05/25/2018
    110 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20960405/25/2018
    GEMCITABINE 
    gemcitabine injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:68001-350
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GEMCITABINE HYDROCHLORIDE (UNII: U347PV74IL) (GEMCITABINE - UNII:B76N6SBZ8R) GEMCITABINE100 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    ALCOHOL (UNII: 3K9958V90M)  
    POLYETHYLENE GLYCOL 300 (UNII: 5655G9Y8AQ) 250 mg  in 1 mL
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3) 150 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I) 16 mg  in 1 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:68001-350-681 in 1 CARTON05/25/2018
    115 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20960405/25/2018
    GEMCITABINE 
    gemcitabine injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:68001-359
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GEMCITABINE HYDROCHLORIDE (UNII: U347PV74IL) (GEMCITABINE - UNII:B76N6SBZ8R) GEMCITABINE100 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3) 150 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I) 16 mg  in 1 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    ALCOHOL (UNII: 3K9958V90M)  
    POLYETHYLENE GLYCOL 300 (UNII: 5655G9Y8AQ) 250 mg  in 1 mL
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:68001-359-371 in 1 CARTON05/25/2018
    120 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20960405/25/2018
    Labeler - BluePoint Laboratories (985523874)
    Registrant - Accord Healthcare Inc. (604222237)
    Establishment
    NameAddressID/FEIBusiness Operations
    Intas Pharmaceuticals Limited725927649MANUFACTURE(68001-342, 68001-348, 68001-350, 68001-359) , ANALYSIS(68001-342, 68001-348, 68001-350, 68001-359)