GEMCITABINE- gemcitabine hydrochloride injection, powder, lyophilized, for solution

Gemcitabine by

Drug Labeling and Warnings

Gemcitabine by is a Prescription medication manufactured, distributed, or labeled by Athenex Pharmaceutical Division, LLC.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    1.1 Ovarian Cancer

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

    1.4 Pancreatic Cancer

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

    Dosage Modifications

    Recommended Gemcitabine for Injection, USP dosage modifications for myelosuppression are described in Tables 1 and 2 [see Warnings and Precautions (5.2)]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

    Table 1: Recommended Dosage Modifications for Gemcitabine for Injection, USP for Myelosuppression on Day of Treatment in Ovarian Cancer
    Treatment DayAbsolute Neutrophil Count
    (x 106/L)    		Platelet Count
    (x 106/L)    		Dosage Modification
    Day 1Greater than or equal to 1500 and Greater than or equal to 100,000 None
    Less than 1500 or Less than 100,000 Delay Treatment Cycle
    Day 8Greater than or equal to 1500 and Greater than or equal to 100,000 None
    1000 to 1499 or 75,000 to 99,999 50% of full dose
    Less than 1000 or Less than 75,000 Hold
    Table 2: Recommended Dosage Modifications for Gemcitabine for Injection, USP for Myelosuppression in Previous Cycle in Ovarian Cancer
    OccurrenceMyelosuppression During Treatment CycleDosage Modification
    Initial Occurrence
    • Absolute neutrophil count less than 500 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 25,000 x 106/L or
    • Cycle delay for more than one week due to toxicity
    		Permanently reduce Gemcitabine for Injection, USP to 800 mg/m2 on Days 1 and 8
    Subsequent OccurrenceIf any of the above toxicities occur after the initial dose reduction: Permanently reduce Gemcitabine for Injection, USP to 800 mg/m2 on Day 1 only

    2.2 Breast Cancer

    Recommended Dose and Schedule

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

    Dosage Modifications

    Recommended Gemcitabine for Injection, USP dosage 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 for Injection, USP for Myelosuppression on Day of Treatment in Breast Cancer
    Treatment DayAbsolute Neutrophil Count
    (x 106/L)    		Platelet Count
    (x 106/L)    		Dosage Modification
    Day 1Greater than or equal to 1500 and Greater than or equal to 100,000 None
    Less than 1500 or Less than 100,000 Hold
    Day 8Greater than or equal to 1200 and Greater than 75,000 None
    1000 to 1199 or 50,000 to 75,000 75% of full dose
    700 to 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 for Injection, USP is 1000 mg/m2 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 for Injection, USP administration.

    21-day schedule

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

    Refer to cisplatin prescribing information for additional information.

    Dosage Modifications

    Recommended dosage modifications for Gemcitabine for Injection, USP 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)].

    2.4 Pancreatic Cancer

    Recommended Dose and Schedule

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

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

    Dosage Modifications

    Recommended dosage modifications for Gemcitabine for Injection, USP 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)].

    Table 4: Recommended Dosage Modifications for Gemcitabine for Injection, USP for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer
    Absolute Neutrophil Count
    (x 106/L)    		Platelet Count
    (x 106/L)    		Dosage Modification
    Greater than or equal to 1000 and Greater than or equal to 100,000 None
    500 to 999 or 50,000 to 99,999 75% of full dose
    Less than 500 or Less than 50,000 Hold

    2.5 Dosage Modifications for Non-Hematologic Adverse Reactions

    Permanently discontinue Gemcitabine for Injection, USP for any of the following:

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

    Withhold Gemcitabine for Injection, USP 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

    • Gemcitabine for Injection, USP vials contain no antimicrobial preservatives and are intended for single use only.
    • Gemcitabine for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
    • Exercise caution and wear gloves when preparing Gemcitabine for Injection, USP solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine for Injection, USP contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.
    • Reconstitute the 200 mg vial with 5 mL and the 1 gram vial with 25 mL of 0.9% Sodium Chloride Injection, USP to yield a Gemcitabine for Injection, USP concentration of 38 mg/mL. Reconstituted Gemcitabine for Injection, USP is a clear, colorless to light straw-colored solution.
    • Visually inspect reconstituted product for particulate matter and discoloration. Discard if particulate matter or discoloration is observed.
    • Withdraw the calculated dose from the vial and discard any unused portion.
    • Prior to administration, dilute the reconstituted solution with 0.9% Sodium Chloride Injection, USP to a minimum final concentration of at least 0.1 mg/mL.
    • Store Gemcitabine for Injection, USP solutions (reconstituted and diluted) at controlled room temperature of 20°C to 25°C (68°F to 77°F). Do not refrigerate as crystallization can occur. Discard Gemcitabine for Injection, USP solutions if not used within 24 hours after reconstitution.
    • No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
  • 3 DOSAGE FORMS AND STRENGTHS

    Gemcitabine for Injection, USP is a white to off-white lyophilized powder available in sterile single-dose vials containing 200 mg or 1 gram gemcitabine.

  • 4 CONTRAINDICATIONS

    Gemcitabine for Injection, USP 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 for Injection, USP, 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 for Injection, USP is influenced by the length of the infusion [see Clinical Pharmacology (12.3)]. Refer to the recommended Gemcitabine for Injection, USP dosage [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

    5.2 Myelosuppression

    Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with Gemcitabine for Injection, USP as a single agent and the risks are increased when Gemcitabine for Injection, USP 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 for Injection, USP. 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 for Injection, USP in combination with another drug [see Adverse Reactions (6.1)].

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

    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 the discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of Gemcitabine for Injection, USP [see Adverse Reactions (6.1, 6.2)].

    Permanently discontinue Gemcitabine for Injection, USP in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe 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 for Injection, USP. 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)].

    Assess renal function prior to initiation of Gemcitabine for Injection, USP 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 for Injection, USP in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the discontinuation of therapy.

    5.5 Hepatic Toxicity

    Drug-induced liver injury, including liver failure and death, has been reported in patients receiving Gemcitabine for Injection, USP alone or with other potentially hepatotoxic drugs [see Adverse Reactions (6.1, 6.2)]. Administration of Gemcitabine for Injection, USP in patients with concurrent liver 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 for Injection, USP and periodically during treatment. Permanently discontinue Gemcitabine for Injection, USP in patients who develop severe hepatic toxicity.

    5.6 Embryo-Fetal Toxicity

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

    Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Gemcitabine for Injection, USP 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 for Injection, USP 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 for Injection, USP 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 for Injection, USP was administered at a dose of 1000 mg/m2 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 for Injection, USP is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemcitabine for Injection, USP after prior radiation.

    5.8 Capillary Leak Syndrome

    Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemcitabine for Injection, USP as a single agent or in combination with other chemotherapeutic agents [see Adverse Reactions (6.2)]. Permanently discontinue Gemcitabine for Injection, USP if CLS develops during therapy.

    5.9 Posterior Reversible Encephalopathy Syndrome

    Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemcitabine for Injection, USP 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 for Injection, USP if PRES develops during therapy.

  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are discussed in greater detail in another section of the label

    • 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 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 practice.

    Single Agent

    The data described below reflect exposure to Gemcitabine for Injection, USP 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 for Injection, USP 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 for Injection, USP due to adverse reactions. Adverse reactions resulting in discontinuation of Gemcitabine for Injection, USP in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemcitabine for Injection, USP in <1% of 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 for Injection, USP across 5 clinical trials. Additional clinically significant adverse reactions are provided following Table 6.

    Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine for Injection, USPa

    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.

    Adverse ReactionsbGemcitabine for Injection, USPc
    All Grades
    (%)    		Grade 3
    (%)    		Grade 4
    (%)
    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 Gemcitabine for Injection, USPa

    a Grade based on criteria from the WHO.

    b Regardless of causality.

    c N=699-974; all patients with laboratory or non-laboratory data.

    Laboratory AbnormalitybGemcitabine for Injection, USPc
    All Grades
    (%)    		Grade 3
    (%)    		Grade 4
    (%)
    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, asthenia insomnia, rhinitis, sweating, and/or malaise (19%)
    • Infection: Sepsis (<1%)
    • Extravasation: Injection-site reactions (4%)
    • Allergic: Bronchospasm (<2%); anaphylactoid reactions

    Non-Small Cell Lung Cancer:

    Tables 7 and 8 presents the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of Gemcitabine for Injection, USP-treated patients and at a higher incidence in the Gemcitabine for Injection, USP with cisplatin arm, reported in a randomized trial (Study 3) of Gemcitabine for Injection, USP 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 non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)].

    Patients randomized to Gemcitabine for Injection, USP 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 for Injection, USP 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 for Injection, USP 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 7: 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 for Injection, USP/cisplatin patients with laboratory or non-laboratory data

    d N=213-248; all cisplatin patients with laboratory or non-laboratory data


    Adverse Reactionsb    		Gemcitabine for Injection, USP/CisplatincCisplatind
    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 8: Selected Laboratory Abnormalities 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 CTC.

    b Regardless of causality.

    c N=217-253; all Gemcitabine for Injection, USP plus cisplatin patients with laboratory or non-laboratory data

    d N=213-248; all cisplatin patients with laboratory or non-laboratory data

    e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.

    Laboratory AbnormalitybGemcitabine for Injection, USP/CisplatinCisplatin
    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
         RBC Transfusionse
         Platelet Transfusionse    		75
    39
    21     		25
    -
    -     		18
    -
    -     		51
    13
    <1     		12
    -
    -     		5
    -
    -
    Hepatic
         Increased Transaminases 22 2 1 10 1 0
         Increased Alkaline
         Phosphatase     		19 1 0 13 0 0
    Renal
         Elevated 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

    Tables 9 and 10 present the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of Gemcitabine for Injection, USP-treated patients and at a higher incidence in the Gemcitabine for Injection, USP with cisplatin arm, reported in a randomized trial (Study 4) of Gemcitabine for Injection, USP 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 non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)]. Additional clinically significant adverse reactions are provided following Table 10.

    Patients in the Gemcitabine for Injection, USP/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 9: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4a

    a Grade based on criteria from the WHO.

    b Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.

    c N=67-69; all Gemcitabine for Injection, USP/cisplatin patients with laboratory or non-laboratory data.

    d N=57-63; all Etoposide/cisplatin patients with laboratory or non-laboratory data.

    e Flu-like syndrome and edema were not graded.


    Adverse Reactionsb    		Gemcitabine for Injection, USP/CisplatincEtoposide/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
         Edemae12 - - 2 - -
         Rash 10 0 0 3 0 0
         Hemorrhage 9 0 3 3 0 3
         Fever 6 0 0 3 0 0
         Somnolence 3 0 0 3 2 0
         Flu-like syndromee3 - - 0 - -
         Dyspnea 1 0 1 3 0 0
    Table 10: 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 for Injection, USP/cisplatin patients with laboratory or non-laboratory data.

    d N=57-63; all Etoposide/cisplatin patients with laboratory or non-laboratory data.

    e WHO grading scale not applicable to proportion of patients with transfusions.

    Laboratory AbnormalitybGemcitabine for Injection, USP/CisplatincEtoposide/Cisplatind
    All Grades
    (%)    		Grade 3
    (%)    		Grade 4
    (%)    		All Grades
    (%)    		Grade 3
    (%)    		Grade 4
    (%)
    Hematologic
         Anemia 88 22 0 77 13 2
         Neutropenia 88 36 28 87 20 56
         Thrombocytopenia 81 39 16 45 8 5
         RBC Transfusionse29 - - 21 - -
         Platelet Transfusionse3 - - 8 - -
    Hepatic
         Increased Alkaline
         Phosphatase     		16 0 0 11 0 0
         Increased ALT 6 0 0 12 0 0
         Increased AST 3 0 0 11 0 0
         Bilirubin 0 0 0 0 0 0
    Renal
         Hematuria 22 0 0 10 0 0
         Proteinuria 12 0 0 5 0 0
         BUN 6 0 0 4 0 0
         Creatinine 2 0 0 2 0 0

    Breast Cancer

    Tables 11 and 12 presents the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of Gemcitabine for Injection, USP-treated patients and at a higher incidence in the Gemcitabine for Injection, USP with paclitaxel arm, reported in a randomized trial (Study 2) of Gemcitabine for Injection, USP 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 12.

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

    Table 11: 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)] in Study 2a

    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 for Injection, USP/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
         Febrile neutropenia     		11
    6     		<1
    5     		<1
    <1     		5
    2     		0
    1     		0
    0
    Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a 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 Abnormalityb    		Gemcitabine for Injection, USP/ 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 for Injection, USP with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).

    Ovarian Cancer

    Tables 13 and 14 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of Gemcitabine for Injection, USP-treated patients and at a higher incidence in the Gemcitabine for Injection, USP with carboplatin arm, reported in a randomized trial (Study 1) of Gemcitabine for Injection, USP with 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 14.

    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 for Injection, USP occurred in 10% of patients and Gemcitabine for Injection, USP dose was omitted in 14% of patients in the Gemcitabine for Injection, USP/carboplatin arm.

    Table 13: Adverse Reactions Occurring in >10% of Patients Receiving in 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 for Injection, USP/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 14: 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)] in Study 1a

    a Grade based on National Cancer Institute CTC Version 2.0.

    b Regardless of causality.

    c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.



    Laboratory Abnormalityb    		Gemcitabine for Injection, USP/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 Transfusionsc38 - - 15 - -
         Platelet Transfusionsc9 - - 3 - -

    Hematopoietic growth factors were administered more frequently in the Gemcitabine for Injection, USP-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%).

    The following clinically relevant Grade 3 and 4 adverse reactions occurred more frequently in the Gemcitabine for Injection, USP 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).

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during post approval use of Gemcitabine for Injection, USP. 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.

    • Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias
    • Vascular: Peripheral vasculitis, gangrene, capillary leak syndrome
    • Skin: Cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skin eruptions
    • Hepatic: Hepatic failure, hepatic veno-occlusive disease
    • Pulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, adult respiratory distress syndrome (ARDS)
    • 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 for Injection, USP 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 for Injection, USP in pregnant women. In animal reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data). Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3)].

    In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies 2 to 4% and 15 to 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 [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 for Injection, USP 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 from Gemcitabine for Injection, USP, advise women not to breastfeed during treatment with Gemcitabine for Injection, USP and for at least 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 for Injection, USP [see Use in Specific Populations (8.1)].

    Contraception

    Gemcitabine for Injection, USP 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 for Injection, USP and for 6 months after the final dose of Gemcitabine for Injection, USP.

    Males

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

    Infertility

    Males

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

    8.4 Pediatric Use

    The safety and effectiveness of Gemcitabine for Injection, USP have not been established in pediatric patients.

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

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

    8.5 Geriatric Use

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

    In a randomized trial in women with ovarian cancer (Study 1), 175 women received Gemcitabine for Injection, USP 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 for Injection, USP 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 for Injection, USP clearance is decreased in females [see Clinical Pharmacology (12.3)]. In single agent studies of Gemcitabine for Injection, USP, 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 provide 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 structural formula:

    Structural Formula

    The empirical formula for gemcitabine hydrochloride is C9H11F2N3O4 HCl. It has a molecular weight of 299.66 g/mol.

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

    Gemcitabine for Injection, USP is a sterile white to off-white lyophilized powder and available as 200 mg and 1 gram single-dose vials for intravenous use only. Each 200 mg vial contains 200 mg gemcitabine hydrochloride (expressed as free base), 200 mg mannitol and 12.5 mg sodium acetate. Each 1 gram vial contains 1 gram gemcitabine hydrochloride (expressed as free base), 1 gram mannitol, and 62.5 mg sodium acetate. Hydrochloric acid and/or sodium hydroxide 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 for Injection, USP dose varied from 500 mg/m2 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 geriatric patients 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 gender.

    Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient

    a Half-life for patients receiving a <70 minute infusion.

    AgeClearance 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 gender, reflecting a greatly increased volume of distribution with longer infusions.

    Male and Female Patients

    Females have lower clearance and longer half-lives than male patients as 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 for Injection, USP (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Data from patients with NSCLC demonstrate that Gemcitabine for Injection, USP 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 for Injection, USP 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 for Injection, USP 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 for Injection, USP 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 for Injection, USP 1000 mg/m2 on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after Gemcitabine for Injection, USP 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 for Injection, USP 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 Injection, USP 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 for Injection, USP with carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.

    b 2 patients on Gemcitabine for Injection, USP with carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months.

    Gemcitabine for Injection, USP/Carboplatin
    (N=178)    		Carboplatin
    (N=178)
    Median age, years
         Range     		59
    36 to 78     		58
    21 to 81
    Baseline ECOG performance status 0-1a94% 95%
    Disease Status
         Evaluable
         Bidimensionally measurable
    8%
    92%
    3%
    96%
    Platinum-free intervalb
         6-12 months
         >12 months
    40%
    59%
    40%
    60%
    First-line therapy
         Platinum-taxane combination
         Platinum-non-taxane combination
         Platinum monotherapy
    70%
    29%
    1%
    71%
    28%
    1%
    Table 17: Efficacy Results in Study 1

    a CI=confidence interval.

    b Log rank, unadjusted.

    c Chi square.

    d CR=Complete response.

    e PR with PRNM=Partial response with partial response, non-measurable disease.

    f Independently reviewed cohort – Gemcitabine for Injection, USP/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.


    Efficacy Parameter    		Gemcitabine for Injection, USP/Carboplatin
    (N=178)    		Carboplatin
    (N=178)
    Progression-free Survival
    Median (95% CIa) in months 8.6 (8.0, 9.7) 5.8 (5.2, 7.1)
         Hazard Ratio (95% CI) 0.72 (0.57, 0.90)
         p-valuebp=0.0038
    Overall Survival
    Median (95% CI) in months 18.0 (16.2, 20.3) 17.3 (15.2, 19.3)
         Hazard Ratio (95% CI) 0.98 (0.78, 1.24)
         p-valuebp=0.8977
    Overall Response Rate by
    Investigator Review    		47.2% 30.9%
         p-valuecp=0.0016
         CRd14.6% 6.2%
         PR with PRNMe32.6% 24.7%
    Overall Response Ratef by
    Independent Review    		46.3% 35.6%
         p-valuecp=0.11
         CRd9.1% 4.0%
         PR with PRNMe37.2% 31.7%

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

    Figure 1

    14.2 Breast Cancer

    The efficacy of Gemcitabine for Injection, USP were evaluated in a multi-national, randomized, open-label trial (Study 2) conducted in women receiving initial treatment for metastatic breast cancer and who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive either Gemcitabine for Injection, USP 1250 mg/m2 on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m2 administered on Day 1 before Gemcitabine for Injection, USP 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 for Injection, USP 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

    a Karnofsky Performance Status.

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


    Efficacy Parameter    		Gemcitabine for Injection, USP/Paclitaxel
    (N=267)    		Paclitaxel
    (N=262)
    Time to Documented Disease Progressiona
    Median (95% CI) in months 5.2 (4.2, 5.6) 2.9 (2.6, 3.7)
         Hazard Ratio (95% CI) 0.650 (0.59, 0.85)
         p-value p<0.0001
    Overall Survivalb
         Median (95% CI) in months 18.6 (16.6, 20.7) 15.8 (14.1, 17.4)
         Hazard Ratio (95% CI) 0.86 (0.71, 1.04)
         p-value Not Significant
    Overall Response Rate40.8% 22.1%
         (95% CI) (34.9, 46.7) (17.1, 27.2)
         p-value p<0.0001

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

    Figure 2

    14.3 Non-Small Cell Lung Cancer (NSCLC)

    The efficacy of Gemcitabine for Injection, USP was evaluated in two randomized, multicenter trials.

    Study 3: 28-Day Schedule

    A multinational, randomized trial (Study 3) compared Gemcitabine for Injection, USP 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 for Injection, USP 1000 mg/m2 on Days 1, 8, and 15 of each 28-day cycle with cisplatin 100 mg/m2 on Day 1 after Gemcitabine for Injection, USP 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 for Injection, USP with cisplatin arm having adenocarcinoma.

    Efficacy results are presented in Table 21 and Figure 3.

    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 for Injection, USP 1250 mg/m2 on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m2 on Day 1 after Gemcitabine for Injection, USP administration or etoposide 100 mg/m2 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 for Injection, USP with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the Gemcitabine for Injection, USP 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 for Injection, USP 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

    a N/A Not applicable.

    b Karnofsky Performance Status.

    Trial28-day Schedule (Study 3)21-day Schedule (Study 4)
    Gemcitabine for Injection, USP/Cisplatin
    (N=260)    		Cisplatin
    (N=262)    		Gemcitabine for Injection, USP/Cisplatin
    (N=69)    		Etoposide/
    Cisplatin
    (N=66)
         Male
    Median age, years
         Range     		70%
    62
    36 to 88     		71%
    63
    35 to 79     		93%
    58
    33 to 76     		92%
    60
    35 to 75
    Stage IIIA
    Stage IIIB
    Stage IV     		7%
    26%
    67%     		7%
    23%
    70%     		N/Aa
    48%
    52%     		N/Aa
    52%
    49%
    Baseline KPSb 70 to 80
    Baseline KPSb 90 to 100     		41%
    57%     		44%
    55%     		45%
    55%     		52%
    49%
    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.

    Trial28-day Schedule (Study 3)21-day Schedule (Study 4)
    Efficacy ParameterGemcitabine for Injection,
    USP/Cisplatin
    (N=260)    		Cisplatin
    (N=262)    		Gemcitabine for Injection,
    USP/Cisplatin
    (N=69)    		Etoposide/Cisplatin
    (N=66)
    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-valuefp=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-valuebp=0.009 p=0.05
    Tumor Response26% 10% 33% 14%
         p-valuebp<0.0001 p=0.01

    Figure 3: Kaplan-Meier Curves for Overall Survival in Study 3

    Figure 3

    14.4 Pancreatic Cancer

    The efficacy of Gemcitabine for Injection, USP 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 for Injection, USP 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received Gemcitabine for Injection, USP 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles.

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

    • The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy.
      OR
    • The patient was stable on all of the aforementioned parameters and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation.

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

    The efficacy results are shown in Table 23 and Figure 4. Patients treated with Gemcitabine for Injection, USP 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

    a Karnofsky Performance Status.

    Gemcitabine for Injection, USP
    (N=63)    		Fluorouracil
    (N=63)
         Male 54% 54%
    Median age 62 years 61 years
         Range 37 to 79 36 to 77
    Stage IV disease 71% 76%
    Baseline KPSa ≤70 70% 68%
    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 ParameterGemcitabine for Injection, USP
    (N=63)    		Fluorouracil
    (N=63)
    Clinical benefit response22.2% 4.8%
         p-valueap=0.004
    Overall Survival
         Median (95% CI) in months 5.7 (4.7, 6.9) 4.2 (3.1, 5.1)
         p-valueap=0.0009
    Time to Disease Progression
         Median (95% CI) in months 2.1 (1.9, 3.4) 0.9 (0.9, 1.1)
         p-valueap=0.0013

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

    Figure 4
  • 15 REFERENCES

    1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Gemcitabine for Injection, USP is supplied as follows:

    NDCGemcitabine for Injection, USPPackage Factor
    70860-204-10 200 mg Single-Dose Vial 1 vial per carton
    70860-205-50 1 gram Single-Dose Vial 1 vial per carton

    Gemcitabine for Injection, USP is a sterile white to off-white lyophilized powder.

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

    Storage Conditions

    Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]

    Sterile, Nonpyrogenic, Preservative-free, Lyophilized.
    The container closure is not made with natural rubber latex.

  • 17 PATIENT COUNSELING INFORMATION

    Myelosuppression

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

    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)].

    Hepatic Toxicity

    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 for Injection, USP can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with Gemcitabine for Injection, USP 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 for Injection, USP and for 3 months after the final dose [see Warnings and Precaution (5.6), Use in Specific Populations (8.1, 8.3)].

    Lactation

    Advise women not to breastfeed during treatment with Gemcitabine for Injection, USP 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 for Injection, USP [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

    Athenex
    Mfd. for Athenex
    Schaumburg, IL 60173 (USA)
    Made in India
    ©2019 Athenex.

    Revised: January 2019

  • PRINCIPAL DISPLAY PANEL

    PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

    NDC: 70860-204-10

    Gemcitabine for Injection, USP

    200 mg per vial

    Rx only

    For Intravenous Use Only

    Must Be Diluted

    DO NOT REFRIGERATE

    Caution: Cytotoxic Agent

    PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label
  • PRINCIPAL DISPLAY PANEL

    PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

    NDC: 70860-205-50

    Gemcitabine for Injection, USP

    1 gram per vial

    Rx only

    For Intravenous Use Only

    Must Be Diluted

    DO NOT REFRIGERATE

    Caution: Cytotoxic Agent

    PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label
  • INGREDIENTS AND APPEARANCE
    GEMCITABINE 
    gemcitabine hydrochloride injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 70860-204
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    gemcitabine hydrochloride (UNII: U347PV74IL) (gemcitabine - UNII:B76N6SBZ8R) gemcitabine200 mg  in 5 mL
    Inactive Ingredients
    Ingredient NameStrength
    mannitol (UNII: 3OWL53L36A) 200 mg  in 5 mL
    sodium acetate (UNII: 4550K0SC9B) 12.5 mg  in 5 mL
    sodium hydroxide (UNII: 55X04QC32I)  
    hydrochloric acid (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 70860-204-101 in 1 CARTON07/31/2017
    15 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20452007/31/2017
    GEMCITABINE 
    gemcitabine hydrochloride injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 70860-205
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    gemcitabine hydrochloride (UNII: U347PV74IL) (gemcitabine - UNII:B76N6SBZ8R) gemcitabine1 g  in 25 mL
    Inactive Ingredients
    Ingredient NameStrength
    mannitol (UNII: 3OWL53L36A) 1 g  in 25 mL
    sodium acetate (UNII: 4550K0SC9B) 62.5 mg  in 25 mL
    sodium hydroxide (UNII: 55X04QC32I)  
    hydrochloric acid (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 70860-205-501 in 1 CARTON07/31/2017
    125 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20452007/31/2017
    Labeler - Athenex Pharmaceutical Division, LLC. (080318964)
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