GEMCITABINE injection, solution

GEMCITABINE by

Drug Labeling and Warnings

GEMCITABINE by is a Prescription medication manufactured, distributed, or labeled by Ingenus Pharmaceuticals, LLC, Novast Laboratories , Ltd., Ingenus Pharmaceuticals GmbH. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

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

    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/m2intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 administered intravenously on Day 1 after Gemcitabine Injection administration. Refer to carboplatin prescribing information for additional information.

    Dosage Modifications

    Recommended dosage modifications for Gemcitabine Injection 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 Injection for Myelosuppression on Day of Treatment in Ovarian Cancer
    Treatment day
    		Absolute Neutrophil Count   (x 106 /L)
    		Platelet Count
    (x 106 /L)
    		Dosage 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
    		 Delay Treatment Cycle
    Day 8
    		 Greater 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 Injection for Myelosuppression in Previous Cycle in Ovarian Cancer
    Occurrence
    		Myelosuppression During Treatment Cycle
    		Dosage 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
    ● Cycle delay of more than one week due to toxicity
    		 Permanently reduce Gemcitabine
    Injection 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 dose 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/m2intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m2administered as a 3-hour intravenous infusion on Day 1 before Gemcitabine Injection administration. Refer to paclitaxel prescribing information for additional information.

    Dosage Modifications

    Recommended dosage modifications for Gemcitabine Injection 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 106/L)
    		Dosage 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 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 Injection is 1000 mg/m2intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m2administered intravenously on Day 1 after Gemcitabine Injection administration.

    21-day schedule

    The recommended dosage of Gemcitabine Injection is 1250 mg/m2intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m2administered intravenously on Day 1 after Gemcitabine Injection administration.

    Refer to cisplatin prescribing information for additional information.

    Dosage Modifications

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

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

    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)]. 

    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)
    		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 Injection for any of the following:

    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

    Gemcitabine Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1Exercise 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 for Intravenous Infusion Administration

    • Withdraw the calculated dose from the vial and discard any unused portion.
    • Prior to administration, dilute the appropriate amount of drug with 0.9% Sodium Chloride Injection to a minimum final concentration of at least 0.1 mg/mL.
    • Store diluted Gemcitabine Injection solution for no more than 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Discard if not used within 24 hours after dilution.
    • Visually inspect for particulate matter or discoloration prior to administration and discard if particulate matter or discoloration is observed.
    • No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
  • 3 DOSAGE FORMS AND STRENGTHS

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

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

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

    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 [see Adverse Reactions (6.1, 6.2)].

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

    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 evidence of renal failure (increased serum creatinine or BUN). Permanently discontinue Gemcitabine Injection in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the discontinuation of therapy.

    5.5 Hepatic Toxicity

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

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

    5.6 Embryo-Fetal Toxicity

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

    Advise pregnant women of the potential risk to a fetus.

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

    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/m2to 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 received 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:

    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 the clinical practice.

    Single Agent

    The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m2to 1250 mg/m2intravenously 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 979 patient 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 are provided following Table 6.

    Table 5: Selected Adverse Reactions Occurring in ≥ 10% of Patients Receiving Single Agent Gemcitabinea

    a  Grade based on criteria from the World Health Organization (WHO).

    b For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related.

    c N=699-974; all patients with laboratory or non-laboratory data.
    Gemcitabinec
    Adverse Reactionsb
    		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 Gemcitabinea

    a Grade based on criteria from WHO.

     b Regardless of causality.

     c  N=699-974; all patients with laboratory or non-laboratory data.
    Laboratory Abnormalityb
    		Gemcitabinec
    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, 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/carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine 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 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 in >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 Common Toxicity Criteria (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)] in Study 1a

    a  Grade based on Nutional Cancer Institute CTC Version 2.0.

    b  Regardless of causality.

    c  Percent of patients receiving transfusion. Transfusion are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.
    Laboratory Abnormalityb
    		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 Transfusionc
    		38
    		 -
    		 -
    		 15
    		 -
    		 -
    Platelet Transfusionc
    		9
    		 -
    		 -
    		 3
    		 -
    		 -

    Hematopoietic growth factors were administered more frequently in the gemcitabine-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 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

    Tables 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/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 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 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)] 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/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 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/ 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
    Increased AST
    18
    16
    5
    2
    <1
    0
    6
    5
    <1
    <1
    0
    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

    Tables 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/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 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 Reactionsb
    		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 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/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 Abnormalityb
    		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 Transfusione
    		39
    		-
    		 -
    		 13
    		-
    		 -
    Platelet Transfusionse
    		21
    		-
    		 -
    		 <1
    		-
    		 -
    Hepatic
    Increased Transaminase
    Increased Alkaline Phosphatase
    		22
     19
    		 2
     1
    		1
    0
    		10
    13
    		1
     0
    		0
     0
    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

    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 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/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/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
    Somnolence
    		3
    		0
    		0
    		3
    		2
    		0
    Flu-like Syndromee
    		3
    		-
    		 -
    		 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 WHO.

    b    Regardless of causality.

    c   N=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.

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

    e   Percent of patients receiving transfusions. WHO Grading scale not applicable to proportion patients with transfusions.

    Laboratory Abnormalityb
    		Gemcitabine/Cisplatinc
    		Etoposide/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 Transfusione
    		29
    		-
    		 -
    		 21
    		-
    		 -
    Platelet Transfusione
    		3
    		-
    		 -
    		 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
    Renal
    Hematuria
    		22
    		0
    		0
    		10
    		0
    		0
    Proteinuria
    		12
    		0
    		0
    		5
    		0
    		0
    Increased BUN
    		6
    		0
    		0
    		4
    		0
    		0
    Increased Creatinine
    		2
    		0
    		0
    		2
    		0
    		0

    6.2 Postmarketing 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 : Peripheral vasculitis, gangrene capillary leak syndrome

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

    Hepatic: Hepatic failure, hepatic veno-occlusive disease

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

    Nervous System: Posterior reversible encephalopathy syndrome (PRES)

  • 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 reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data). Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.3)].

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

    Data

    Animal Data

    Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day [about 0.005 times the 1000 mg/m2clinical dose based on body surface area (BSA)]. Gemcitabine is 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 (about 0.002 times the 1000 mg/m2clinical 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 women not to breastfeed during treatment with Gemcitabine Injection 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 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 with Gemcitabine Injection and for 3 months after the final dose [see Nonclinical Toxicology (13.1)].

    Infertility

    Males

    Based on animal studies, gemcitabine 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 in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m2/min for 360 minutes weekly for three weeks followed by a one-week rest period.

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

    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 as compared to younger patients.

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

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

    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/m2was 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. The chemical name of gemcitabine HCl, USP is 2´-

    deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer).The structural formula is as follows:

    Image

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

    Gemcitabine Injection is a sterile solution in single-dose vials for intravenous use. Each vial contains 200 mg, 1 g, or 2 g of gemcitabine equivalent to 227.7 mg, 1.139 g, or 2.227 g of gemcitabine HCl, USP. Each mL contains 38 mg of gemcitabine free base in Water for Injection equivalent to 43.27 mg of gemcitabine HCl, USP. 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 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/m2of radiolabeled drug as a 30-minute infusion. Within one (1) 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 sex.

    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

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

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

    a  Half-life for patients receiving a <70 minute infusion.
    Age
    		Clearance Men (L/hr/m 2 )
    		Clearance Women (L/hr/m 2 )
    		Half-Life a Men (min)
    		Half-Life a
    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

    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/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 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 patients with metastatic breast cancer 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 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/m2on 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 the gemcitabine/carboplatin arm and 4 patients on the carboplatin arm had no baseline Eastern

      Cooperative Oncology Group (ECOG) performance status.

     b 2 patients on the gemcitabine/carboplatin arm and 1 on the carboplatin arm had a platinum-free interval < 6 months.
    Gemcitabine/Carboplatin
    (N=178)
    		Carboplatin
    (N=178)
    Median age, years
    Range
    		 59
    36 to 78
    		 58
    21 to 81
    Baseline ECOG performance status
    0-1a
    		94%
    		 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 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.
    Efficacy parameter
    		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
    Overall Survival
    Median (95% CI) months
    		 p=0.0038
    18.0 (16.2, 20.3)
    		 17.3 (15.2, 19.3)
    Hazard Ratio (95% CI)
    p=valueb
    		0.98 (0.78, 1.24)
    p=0.8977
    Overall Response Rate by Investigator Review
    		47.2
    		 30.9
    p=valuec
    		0.0016
    CRd
    PR+PRNMe
    		14.6%
    32.6%
    		 6.2%
    24.7%
    Overall Response Rate by Independent Reviewf
    		46.3%
    		 35.6%
     p=valuec
    		p=0.11
    CRd
    PR+PRNMe

    9.1%
    37.2%
    4.0%
    31.7%

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

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

    14.2 Breast Cancer

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

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

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

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

    Table 18: Baseline Demographics and Clinical Characteristics for Study 2

    a Karnofsky Performance Status.
    Gemcitabine/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/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 (0.524, 0.805)
    p-value
    		p<0.0001
    Overall Survivalb
    Median (95% CI) in months
    		18.6
    (16.5, 20.7)
    		 15.8
    (14.1, 17.3)
    Hazard Ratio (95% CI)
    		0.86 (0.71, 1.04)
    p-value
    		Not Significant
    Overall Response Rateb
    (95% CI)
    		40.8%
    (34.9, 46.7)
    		 22.1%
    (17.1, 27.2)
    p-value
    		p<0.0001

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

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

    14.3 Non-Small Cell Lung Cancer

    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 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 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/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 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).

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

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

    a      N/A Not applicable.

    b      Karnofsky Performance Status.
    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
     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-valiue two-side Fisher's Extract 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 (N=260)
    		Cisplatin (N=262)
    		Gemcitabine/
    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-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

    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 Study 6, all patients received gemcitabine 1000 mg/m2intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles.

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

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

    OR

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

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

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

    Table 22: Baseline Demographics and Clinical Characteristics for Study 5

       a   Karnofsky Performance Status.
    Gemcitabine (N=63)
    		Fluorouracil (N=63)
    Male
    Median age
    Range
    Stage IV disease
    Baseline KPSa ≤70
    		 54%
    62 years
    37 to 79
    71%
    70%
    		 54%
    61 years
    36 to 77
    76%
    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 Parameter
    		Gemcitabine
    (N=63)
    		Fluorouracil
    (N=63)
    Clinical Benefit Response
    		22.2%
    		 4.8%
    p-valuea
    		p=0.004
    Overall Survival
    Median (95% CI) in months
    		5.7 (4.7, 6.9)
    		 4.2 (3.1, 5.1)
    p-valuea
    		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 Curves for Overall Survival in Study 5

    Image 4
  • 15 REFERENCES

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

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

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

    • 200 mg/5.26 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC: 50742-498-05
    • 1 g/26.3 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC: 50742-496-26
    • 2 g/52.6 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC: 50742-497-53

    Unopened vials of Gemcitabine Injection are stable until the expiration date indicated on the package when stored at 2° to 8°C (36° to 46°F). Do not freeze.

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

  • 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 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 [see Warnings and Precaution (5.6), 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)].

    Manufactured for:

    Ingenus Pharmaceuticals, LLC

    Orlando, FL 32839-6408

    Made in Switzerland.

    Revised: 9/2019

    image 5
  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    Vial Label - 200 mg/5.26 mL

    Vial Label - 200 mg/5.26 mL

    Vial Label - 1 g/ 26.3 mL

    Vial Label - 1 g/ 26.3 mL

    Vial Label - 2 g/ 52.6 mL

    Vial Label - 2 g/ 52.6 mL

    Carton Label - 200 mg/5.26 mL

    Carton Label - 200 mg/5.26 mL

    Carton Label - 1 g/26.3 mL

    Carton Label - 1 g/26.3 mL

    Carton Label - 2 g/52.6 mL

    Carton Label - 2 g/52.6 mL

  • INGREDIENTS AND APPEARANCE
    GEMCITABINE 
    gemcitabine injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 50742-498
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GEMCITABINE HYDROCHLORIDE (UNII: U347PV74IL) (GEMCITABINE - UNII:B76N6SBZ8R) GEMCITABINE38 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 50742-498-051 in 1 CARTON02/26/2019
    15.26 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21038302/26/2019
    GEMCITABINE 
    gemcitabine injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 50742-496
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GEMCITABINE HYDROCHLORIDE (UNII: U347PV74IL) (GEMCITABINE - UNII:B76N6SBZ8R) GEMCITABINE38 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 50742-496-261 in 1 CARTON02/26/2019
    126.3 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21038302/26/2019
    GEMCITABINE 
    gemcitabine injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 50742-497
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GEMCITABINE HYDROCHLORIDE (UNII: U347PV74IL) (GEMCITABINE - UNII:B76N6SBZ8R) GEMCITABINE38 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 50742-497-531 in 1 CARTON02/26/2019
    152.6 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21038302/26/2019
    Labeler - Ingenus Pharmaceuticals, LLC (833250017)
    Registrant - Ingenus Pharmaceuticals, LLC (833250017)
    Establishment
    NameAddressID/FEIBusiness Operations
    Ingenus Pharmaceuticals GmbH482730327MANUFACTURE(50742-498, 50742-496, 50742-497) , ANALYSIS(50742-498, 50742-496, 50742-497) , LABEL(50742-498, 50742-496, 50742-497) , PACK(50742-498, 50742-496, 50742-497) , STERILIZE(50742-498, 50742-496, 50742-497)
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