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These highlights do not include all the information needed to use GEMCITABINE INJECTION safely and effectively. See full prescribing information for GEMCITABINE INJECTION.  GEMCITABINE injection, for intravenous infusion only Initial U.S. Approval: 1996 | Gemcitabine [Actavis Pharma, Inc.] | BioPortfolio

12:52 EST 27th January 2019 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

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.

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.

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

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 5-FU.

Recommended Dose and Schedule

The recommended dose of gemcitabine injection is 1000 mg/m as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after gemcitabine injection administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.

Dose Modifications

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

Table 1: Dosage Reduction Guidelines for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian Cancer
Treatment Day Absolute granulocyte count (x 106/L) Platelet count (x 106/L) % of full dose
Day 1 ≥1500 and ≥100,000 100%
<1500 or <100,000 Delay Treatment Cycle
Day 8 ≥1500 and ≥100,000 100%
   1000 to 1499  or 75,000 to 99,999  50% 
<1000 or <75,000 Hold
Table 2: Gemcitabine Injection Dose Modification for Myelosuppression in Previous Cycle in Ovarian Cancer
Occurrence Myelosuppression During Treatment Cycle Dose Modification
Initial Occurrence Absolute granulocyte count <500 x 106/L for more than 5 days Absolute granulocyte count <100 x 106/L for more than 3 days Febrile neutropenia Platelets <25,000 x 106/L Cycle delay of more than one week due to toxicity 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

Recommended Dose and Schedule

The recommended dose of gemcitabine injection is 1250 mg/m intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m on Day 1 as a 3-hour intravenous infusion before gemcitabine injection administration.  

Dose Modifications

Recommended dose modifications for gemcitabine injection for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.

Table 3: Recommended Dose Reductions for Gemcitabine Injection for Myelosuppression on Day of Treatment in Breast Cancer
Treatment Day Absolute granulocyte count (x 106/L) Platelet count (x 106/L) % of full dose
Day 1 ≥1500 and ≥100,000 100%
<1500 or <100,000 Hold
Day 8 ≥1200 and >75,000 100%
1000 to 1199 or 50,000 to 75,000 75%
  700 to 999  and   ≥50,000  50%
<700 or <50,000 Hold

Recommended Dose and Schedule

Every 4-week schedule

The recommended dose of gemcitabine injection is 1000 mg/m intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m on Day 1 after the infusion of gemcitabine injection.

Every 3-week schedule

The recommended dose of gemcitabine injection is 1250 mg/m intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m on Day 1 after the infusion of gemcitabine injection.

Dose Modifications

Recommended dose modifications for gemcitabine injection myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for gemcitabine injection recommendations for non-hematologic adverse reactions.

Recommended Dose and Schedule

The recommended dose of gemcitabine injection is 1000 mg/m over 30 minutes intravenously. The recommended treatment schedule is as follows:

Dose Modifications

Recommended dose modifications for gemcitabine injection for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.

Patients receiving gemcitabine injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 4.

Table 4: Recommended Dose Reductions for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer 
Absolute granulocyte count (x 106/L)      Platelet count (x 106/L) % of full dose 
≥1000   And  ≥100,000  100%
500 to 999   Or  50,000 to 99,999   75%
<500  Or  <50,000  Hold

Permanently discontinue gemcitabine injection for any of the following:

Withhold gemcitabine injection or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

Exercise caution and wear gloves when preparing gemcitabine solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling gemcitabine go to “OSHA Hazardous Drugs” (refer to antineoplastic weblinks including OSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Reconstitute the vials with 0.9% sodium chloride injection without preservatives.

Each vial contains a gemcitabine concentration of 38 mg/mL. Hence, withdrawing 5.26 mL, 26.3 mL, or 52.6 mL of the vial contents will provide 200 mg, 1 g, or 2 g of gemcitabine, respectively. Prior to administration, the appropriate amount of drug must be diluted with 0.9% sodium chloride injection. Final concentrations may be as low as 0.1 mg/mL.

Reconstituted gemcitabine injection is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur.

No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

Gemcitabine injection is a clear and colorless to light straw-colored solution available in sterile single-use vials containing:

Gemcitabine injection is contraindicated in patients with a known hypersensitivity to gemcitabine.

In clinical trials evaluating the maximum tolerated dose of gemcitabine injection, 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 injection is influenced by the length of the infusion [see Clinical Pharmacology (12.3)].

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 to 4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent gemcitabine. The frequencies of Grade 3 to 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.

Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine injection. Discontinue gemcitabine injection in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity [see Adverse Reactions (6.1 and 6.2)].

Hemolytic-uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur in patients treated with gemcitabine. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1 and 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, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN) [see Dosage and Administration (2.5) and  Use in Specific Populations (8.6)]. Permanently discontinue gemcitabine injection in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy.

Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Administration of gemcitabine injection in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency [see Use in Specific Populations (8.7)]. Assess hepatic function prior to initiation of gemcitabine injection and periodically during treatment. Discontinue gemcitabine injection in patients that develop severe liver injury.

Gemcitabine can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. Advise pregnant women of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

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 and for 3 months following the final dose of gemcitabine injection [see Use in Specific Populations (8.1) and (8.3)].

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

Concurrent (given together or ≤7 days apart - Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which gemcitabine was administered at a dose of 1000 mg/m to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation.

Non-concurrent (given >7 days apart) - Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who received gemcitabine after prior radiation.

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. Discontinue gemcitabine if CLS develops during therapy.

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as a single-agent or in combination with other chemotherapeutic agents. 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) and discontinue gemcitabine if PRES develops during therapy.

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

 

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Single-Agent Use

The data described below reflect exposure to gemcitabine as a single-agent administered at doses between 800 mg/m to 1,250 mg/m over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥20%) adverse reactions of single-agent gemcitabine are nausea/vomiting, anemia, increased ALT, increased 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, increase 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 events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.

Table 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent gemcitabine across 5 clinical trials. Table 5 includes all clinical adverse reactions, reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table.

Non-Small Cell Lung Cancer

Table 6 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus cisplatin arm, reported in a randomized trial of gemcitabine plus cisplatin (n=262) administered in 28-day cycles as compared to cisplatin alone (n=260) 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 plus cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin 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 plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine plus 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 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus cisplatin arm, reported in a randomized trial of gemcitabine plus cisplatin (n=69) administered in 21-day cycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)]. A listing of clinically significant adverse reactions is provided following the table.

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 treatment-related adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients 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 gemcitabine/cisplatin arm.

Breast Cancer

Table 8 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus paclitaxel arm, reported in a randomized trial of gemcitabine plus 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)].

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 treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.

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

Ovarian Cancer

Table 9 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus carboplatin arm, reported in a randomized trial of gemcitabine plus carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 9.

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 treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for gemcitabine occurred in 10.4% of patients and gemcitabine dose was omitted in 13.7% of patients in the gemcitabine/carboplatin arm.

Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%).

The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine plus 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).

Table 5: Selected Per-Patient Incidence of Adverse Events in Patients Receiving Single-Agent Gemcitabinea
All Patients b
All Grades Grade 3 Grade 4
Grade based on criteria from the World Health Organization (WHO).
N=699 to 974; all patients with laboratory or non-laboratory data.
Regardless of causality.
For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related.
Laboratory c
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
Non-laboratory d
  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: Per-Patient Incidence of Selected Adverse Reactions from Randomized Trial of Gemcitabine plus Cisplatin versus Single-Agent Cisplatin in Patients with NSCLC Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)]a
   Gemcitabine plus Cisplatin b  Cisplatin c
    All Grades   Grade 3   Grade 4   All Grades   Grade 3   Grade 4
 a National Cancer Institute Common Toxicity Criteria (CTC) for severity grading. 
 b N=217 to 253; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days. 
 c N=213 to 248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days. 
 d Regardless of causality. 
 e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. 
 f Non-laboratory events were graded only if assessed to be possibly drug-related.
 Laboratory d            
   Hematologic            
     Anemia  89  22  3  67  6  1
     RBC Transfusione  39      13    
     Neutropenia  79  22  35  20  3  1
     Thrombocytopenia  85  25  25  13  3  1
     Platelet Transfusionse  21      <1    
     Lymphopenia  75  25  18  51  12  5
   Hepatic            
     Increased Transaminase  22  2  1  10  1  0
     Increased Alkaline Phosphatase  19  1  0  13  0  0
   Renal            
     Proteinuria  23  0  0  18  0  0
     Hematuria  15  0  0  13  0  0
     Elevated Creatinine  38  4  <1  31  2  <1
   Other Laboratory            
     Hyperglycemia  30  4  0  23  3  0
     Hypomagnesemia  30  4  3  17  2  0
     Hypocalcemia  18  2  0  7  0  <1
 Non-laboratory f            
    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 7: Per-Patient Incidence of Selected Adverse Reactions in Randomized Trial of Gemcitabine plus Cisplatin versus Etoposide plus Cisplatin in Patients with NSCLCa 
   Gemcitabine plus Cisplatin b  Etoposide plus Cisplatin c
    All Grades   Grade 3   Grade 4   All Grades   Grade 3   Grade 4
     Flu-like syndrome g 3  -  -  0  -  -
     Edema g 12  -  -  2  -  -
 a Grade based on criteria from the World Health Organization (WHO).  
 b N=67 to 69; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days. 
 c N=57 to 63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days. 
 d Regardless of causality.  
 e Percent of patients receiving transfusions. Percent transfusions are not WHO-graded events. 
 f Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.
 g Flu-like syndrome and edema were not graded. 
   Laboratory d            
   Hematologic            
      Anemia  88  22  0  77  13  2
      RBC Transfusionse  29  -  21
      Neutropenia  88  36  28  87  20  56
      Thrombocytopenia  81  39  16  45  8  5
      Platelet Transfusionse  3  -  -  8  -  -
 Hepatic            
      Increased ALT  6  0  0  12  0  0
      Increased AST  3  0  0  11  0  0
      Increased Alkaline Phosphatase  16  0  0  11  0  0
      Bilirubin  0  0  0  0  0  0
 Renal            
      Proteinuria  12  0  0  5  0  0
      Hematuria  22  0  0  10  0  0
      BUN  6  0  0  4  0  0
      Creatinine  2  0  0  2  0  0
 Non-laboratory f            
     Nausea and Vomiting  96  35  4  86  19  7
     Fever  6  0  0  3  0  0
     Rash  10  0  0  3  0  0
     Dyspnea  1  0  1  3  0  0
     Diarrhea  14  1  1  13  0  2
     Hemorrhage  9  0  3  3  0  3
     Infection  28  3  1  21  8  0
     Alopecia  77  13  0  92  51  0
     Stomatitis  20  4  0  18  2  0
     Somnolence  3  0  0  3  2  0
     Paresthesias  38  0  0  16  2  0
Table 8: Per-Patient Incidence of Selected Adverse Reactions from Comparative Trial of Gemcitabine plus Paclitaxel versus Single-Agent Paclitaxel in Breast Cancera Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)]
   Gemcitabine plus Paclitaxel  Paclitaxel
   (N=262)  (N=259)
    All Grades   Grade 3   Grade 4   All Grades   Grade 3   Grade 4
     Febrile neutropenia  6  5  <1  2  1 0
 a Severity grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0. 
 b Regardless of causality. 
 c Non-laboratory events were graded only if assessed to be possibly drug-related. 
 Laboratory b            
   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
 Non-laboratory c            
     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
Table 9: Per-Patient Incidence of Adverse Reactions in Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancera Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)]
   Gemcitabine plus Carboplatin  Carboplatin
   (N=175)  (N=174)
    All Grades   Grade 3   Grade 4   All Grades   Grade 3   Grade 4
 a Grade based on Common Toxicity Criteria (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 b            
    Hematologic            
     Neutropenia  90  42  29  58  11  1
     Anemia  86  22  6  75  9  2
     Thrombocytopenia  78  30  5  57  10  1
     RBC Transfusionsc  38      15    
     Platelet Transfusionsc  9      3    
  Non-laboratory b            
    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

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.

Cardiovascular - Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias.

Vascular Disorders - Peripheral vasculitis, gangrene and capillary leak syndrome [see Warnings and Precautions (5.8)].

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, and adult respiratory distress syndrome (ARDS) 

Nervous System - Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.9)]

No specific drug interaction studies have been conducted.

Risk Summary

Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine injection is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits [see Data]. Advise pregnant women of the potential risk to a fetus In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 0.005 times the recommended human dose on a mg/m basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 0.002 times the recommended human dose on a mg/m basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays.

There are no data on the presence of gemcitabine in human milk, or the effects of gemcitabine on the breastfed infant or milk production. Because of the potential for serious adverse reactions in nursing infants from gemcitabine injection, advise a lactating woman not to breastfeed during treatment with gemcitabine injection and for one week after the final dose.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with gemcitabine injection and for 6 months after the final dose [see Use in Specific Populations (8.1)].

Males

Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the final dose of gemcitabine injection [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on animal studies, gemcitabine injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of gemcitabine has not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine was evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m/min for 360 minutes weekly for three weeks followed by a one-week rest period. The safety and activity of gemcitabine were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m/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 bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.

In clinical studies of gemcitabine, enrolling 979 patients with various cancers who received gemcitabine as a single-agent, 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 to 4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer, 175 women received gemcitabine plus 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. Gemcitabine clearance is affected by age, however there are no recommended dose adjustments based on patients’ age [see Clinical Pharmacology (12.3)].

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

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

Gemcitabine clearance is affected by gender [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.

Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study.

Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine hydrochloride, USP is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer).

The structural formula is as follows:

The molecular formula for gemcitabine hydrochloride, USP is CHFNO4 • HCl. It has a molecular weight of 299.66.

Gemcitabine hydrochloride, USP is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

The clinical formulation is supplied as a sterile solution for intravenous single vial use only. Vials of gemcitabine injection contain either 200 mg, 1 g, or 2 g of gemcitabine hydrochloride, USP (expressed as free base). Each mL contains equivalent of 38 mg of gemcitabine in water for injection, USP. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

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 the 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.

Absorption and Distribution

The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total gemcitabine dose varied from 500 to 3600 mg/m.

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

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 gender. Gemcitabine plasma protein binding is negligible.

Metabolism

Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m/30 minute infusion of radiolabeled drug. 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.

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.

Elimination

Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 10 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.

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

Drug Interactions

When gemcitabine (1250 mg/m on Days 1 and 8) and cisplatin (75 mg/m on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m and on Day 8 was 107 L/hr/m. Analysis of data from metastatic breast cancer patients shows that, on average, 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. Data from NSCLC patients 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.

Table 10: Gemcitabine Clearance and Half-Life for the “Typical” Patient
 Age  Clearance  Clearance  Half-Life a  Half-Life a
   Men  Women  Men  Women
   (L/hr/m 2 )  (L/hr/m 2 )  (min)  (min)
 a Half-life for patients receiving <70 minute infusion. 
 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

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 IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m basis) in male mice had an effect on fertility with 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 human dose on a mg/m basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m basis).

The safety and efficacy of gemcitabine was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine infusion on Day 1 of each cycle (n = 178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n = 178) . The primary efficacy outcome measure was progression free survival (PFS).

Patient characteristics are shown in Table 11. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in Table 12 and Figure 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.

Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer (N=356)

Table 11: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer - Baseline Demographics and Clinical Characteristics
   Gemcitabine/Carboplatin  Carboplatin
 a 5 patients on the Gemcitabine plus carboplatin arm and 4 patients on the carboplatin arm with no baseline Eastern Cooperative Oncology Group (ECOG) performance status.    
 b 2 on the Gemcitabine plus carboplatin arm and 1 on the carboplatin arm had a platinum-free interval of <6 months.  
 Number of randomized patients  178  178
 Median age, years  59  58
    Range  36 to 78  21 to 81
 Baseline ECOG performance status 0 to 1a  94%  95%
 Disease Status    
    Evaluable  8%  3%
    Bidimensionally measurable  92%  96%
 Platinum-free intervalb    
    6 to 12 months  40%  40%
    >12 months  59%  60%
 First-line therapy    
    Platinum-taxane combination  70%  71%
    Platinum-non-taxane combination  29%  28%
    Platinum monotherapy  1%  1%
Table 12: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer - Efficacy Outcomes
   Gemcitabine/Carboplatin  Carboplatin
   (N=178)  (N=178)
 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. 
 Progression free Survival    
    Median (95% CIa) months  8.6 (8.0, 9.7)  5.8 (5.2, 7.1)
    Hazard Ratio (95% CI)  0.72 (0.57, 0.90)
 p=valueb  p=0.0038
 Overall Survival    
    Median (95% CI) months  18.0 (16.2, 20.3)  17.3 (15.2, 19.3)
    Hazard Ratio (95% CI)  0.98 (0.78, 1.24)
 p=valueb  p=0.8977
 Investigator Reviewed    
 Overall Response Rate  47.2%  30.9%
 p=valuec   p=0.0016
    CRd  14.6%  6.2%
    PR+PRNMe  32.6%  24.7%
 Independently Reviewed    
 Overall Response Ratef  46.3%  35.6%
 p=valuec   p=0.11
    CRd  9.1%  4.0%
    PR+PRNMe  37.2%  31.7%

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

Patients were randomized to receive gemcitabine 1250 mg/m on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m administered prior to gemcitabine on Day 1 of each cycle (n = 267). Single-agent paclitaxel 175 mg/m was administered on Day 1 of each 21-day cycle (n = 262). The primary efficacy outcome measure was time to documented disease progression.

A total of 529 patients were enrolled; 267 were randomized to gemcitabine and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see Table 13). Efficacy results are presented in Table 13 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.

Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemcitabine plus Paclitaxel versus Paclitaxel Breast Cancer Study (N=529)

Table 13: Randomized Trial of Gemcitabine plus Paclitaxel versus Paclitaxel in Breast Cancer
 a Karnofsky Performance Status. 
 b These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm. 
 c Based on the ITT population. 
   Gemcitabine/Paclitaxel  Paclitaxel
 Number of patients  267  262
 Demographic/Entry Characteristics    
   Median age, years  53  52
     Range  26 to 83  26 to 75
 Metastatic disease  97%  97%
 Baseline KPSa ≥90  70%  74%
 Number of tumor sites    
    1 to 2  57%  59%
    ≥3  43%  41%
 Visceral disease  73%  73%
 Prior anthracycline  97%  96%
 Efficacy Outcomes    
 Time to Documented Disease Progressionb    
    Median in months (95% CI)
5.2   2.9
(4.2, 5.6)   (2.6, 3.7)
    Hazard Ratio (95% CI) 0.650 (0.524, 0.805)
    p-value p<0.0001
 Overall Survivalc    
    Median Survival in months (95% CI)  18.6   15.8 
 (16.5, 20.7)  (14.1, 17.3)
    Hazard Ratio (95% CI)  0.86 (0.71, 1.04)
    p-value  Not significant
 Overall Response Rate (95% CI) 40.8% (34.9, 46.7)   22.1% (17.1, 27.2) 
     p-value  p<0.0001

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

28-Day Schedule

A multinational, randomized trial compared gemcitabine plus 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 gemcitabine 1000 mg/m on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m administered on Day 1 of each cycle or to receive cisplatin 100 mg/m on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in Table 14) 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 plus cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 14 and Figure 3 for overall survival.

21-Day Schedule

A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive gemcitabine 1250 mg/m on Days 1 and 8, and cisplatin 100 mg/m on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m on Day 1 of a 21-day cycle.

There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided, see Table 14). The median survival was 8.7 months for the gemcitabine plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the gemcitabine plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher’s Exact p=0.01, two-sided).

Figure 3: Kaplan-Meier Survival Curve in Gemcitabine plus Cisplatin versus Cisplatin NSCLC Study (N=522)

Table 14: Randomized Trials of Gemcitabine plus Cisplatin in Patients with NSCLC
  Trial  28-day Schedulea  21-day Scheduleb
  Treatment Arm   Gemcitabine plus    Cisplatin   Gemcitabine plus   Etoposide plus
    Cisplatin     Cisplatin  Cisplatin
 a 28-day schedule — Gemcitabine plus cisplatin: Gemcitabine 1000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m2 on Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2 on Day 1 every 28 days. 
 b 21-day schedule — Gemcitabine plus cisplatin: Gemcitabine 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 every 21 days. 
 c N/A Not applicable. 
 d Karnofsky Performance Status. 
 e CI=confidence intervals.
 f p-value two-sided Fisher’s Exact test for difference in binomial proportions; log rank test for time-to-event analyses. 
 Number of patients  260  262  69  66
 Demographic/Entry Characteristics        
      Male  70%  71% 93%  92%
 Median age, years  62  63  58  60
      Range  36 to 88  35 to 79  33 to 76  35 to 75
 Stage IIIA  7%  7%  N/Ac  N/Ac
 Stage IIIB  26%  23%  48%  52%
 Stage IV  67%  70%  52%  49%
 Baseline KPSd 70 to 80  41%  44%  45%  52%
 Baseline KPSd 90 to 100  57%  55%  55%  49%
 Efficacy Outcomes        
 Survival  

 
      Median, months  9.0  7.6  8.7  7.0
      (95% CIe) months  8.2, 11.0  6.6, 8.8  7.8, 10.1  6.0, 9.7
 p-valuef   p=0.008 p=0.18 
 Time to Disease Progression        
      Median in months  5.2  3.7  5.0  4.1
      (95% CIe) months  4.2, 5.7  3.0, 4.3  4.2, 6.4  2.4, 4.5
 p-valuef p=0.009 p=0.015
 Tumor Response  26% 10%   33% 14% 
 p-valuef   p<0.0001  p=0.01

The safety and efficacy of gemcitabine was evaluated in two trials, a randomized, single-blind, two-arm, active-controlled trial 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 conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive gemcitabine 1000 mg/m intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received gemcitabine 1000 mg/m intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles.

The primary 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 randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (Table 15).

The efficacy outcome results are shown in Table 15 and for overall survival in 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 5-FU. No confirmed objective tumor responses were observed in either treatment arm. 

Figure 4: Kaplan-Meier Survival Curve

Table 15: Randomized Trial of Gemcitabine versus 5-Fluorouracil in Pancreatic Cancer
   Gemcitabine  5-FU
 a Karnofsky Performance Status. 
 b 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. 
 Number of patients  63  63
 Demographic/Entry Characteristics    
      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%
 Efficacy Outcomes    
 Clinical benefit response  22.2%  4.8%
 p-valueb p=0.004
 Survival    
      Median  5.7 months  4.2 months
      (95% CI)  (4.7, 6.9)  (3.1, 5.1)
 p-valueb  p=0.0009
 Time to Disease Progression    
      Median  2.1 months  0.9 months
       (95% CI) (1.9, 3.4)  (0.9, 1.1) 
 p-valueb  p=0.0013 

Gemcitabine injection is available in sterile single-use vials individually packaged in a carton as follows:

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 [see Dosage and Administration (2.6 and 2.7)].

This vial stopper is not made with natural rubber latex.

 

Made in Italy

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Iss. 2/2018

Actavis

NDC 45963-623-57

Gemcitabine Injection

200 mg/5.26 mL

(38 mg/mL)

For Intravenous Infusion OnlyMust Be Diluted Before UseStore at 2° to 8°C (36° to 46°F).Discard Unused Portion.

CAUTION: Cytotoxic Agent

Single-Use Vial

Actavis

NDC 45963-624-58

Gemcitabine Injection

1 g/26.3 mL

(38 mg/mL)

For Intravenous Infusion OnlyMust Be Diluted Before UseStore at 2° to 8°C (36° to 46°F).Discard Unused Portion.

CAUTION: Cytotoxic Agent

Single-Use Vial

Actavis

NDC 45963-636-60

Gemcitabine Injection

2 g/52.6 mL

(38 mg/mL)

For Intravenous Infusion OnlyMust Be Diluted Before UseStore at 2° to 8°C (36° to 46°F).Discard Unused Portion.

CAUTION: Cytotoxic Agent

Single-Use Vial

Manufacturer

Actavis Pharma, Inc.

Active Ingredients

Source

Drugs and Medications [33 Associated Drugs and Medications listed on BioPortfolio]

Gemcitabine [bedford laboratories]

These highlights do not include all the information needed to use gemcitabine for injection safely and effectively. See full prescribing information for gemcitabine for injection. Gemcitabine For Inje...

Gemcitabine [dr. reddy's laboratories limited ]

These highlights do not include all the information needed to used GEMCITABINE FOR INJECTION safely and effectively. See full prescribing information for GEMCITABINE FOR INJECTION. GEMCITABINE for inj...

Gemcitabine [hospira, inc.]

These highlights do not include all the information needed to use GEMCITABINE FOR INJECTION safely and effectively. See full prescribing information for GEMCITABINE FOR INJECTION. GEMCITABINE for inje...

Gemcitabine [hospira, inc.]

These highlights do not include all the information needed to use GEMCITABINE FOR INJECTION safely and effectively. See full prescribing information for GEMCITABINE FOR INJECTION.GEMCITABINE for injec...

Gemcitabine hydrochloride [bluepoint laboratories]

These highlights do not include all the information needed to use Gemcitabine for Injection safely and effectively. See full prescribing information for Gemcitabine for Injection. Gemcitabine for inje...

Clinical Trials [1269 Associated Clinical Trials listed on BioPortfolio]

EndoTAG-1 / Gemcitabine Combination Therapy to Treat Locally Advanced and/or Metastatic Adenocarcinoma of the Pancreas

The intention of this trial is to evaluate safety and efficacy of a combination treatment of EndoTAG-1 with Gemcitabine versus Gemcitabine monotherapy.

A Phase I/II Open-Label Dose-Escalation Clinical Trial of CPI-613 in Combination With Gemcitabine in Cancer Patients

The objectives of this study are: - To determine the safety and MTD of CPI-613, when used in combination with Gemcitabine, in cancer patients. - To compare the safety an...

Nab-Paclitaxel Plus Gemcitabine Versus Gemcitabine For The First Line Treatment of Pancreas Cancer

This is a randomized, multicenter, phase II study of with nab-paclitaxel plus gemcitabine or gemcitabine alone for the treatment of chemotherapy-naïve patients with locally advanced or me...

Gemcitabine and Docetaxel With Or Without Bevacizumab in Leiomyosarcoma, Malignant Fibrous Histiocytoma and Angiosarcoma

The purpose of this study is to test whether an experimental drug called bevacizumab given together with gemcitabine and docetaxel, a standard chemotherapy regimen for sarcoma, can help sa...

Randomized Trial of Docetaxel and Gemcitabine Versus Gemcitabine in Elderly Patients With NSCLC

This trial will compare the efficacy of the docetaxel and gemcitabine combination versus monotherapy with gemcitabine as first-line treatment in elderly patients with advanced NSCLC

PubMed Articles [110 Associated PubMed Articles listed on BioPortfolio]

Comparison of Gemcitabine monotherapy with Gemcitabine and Cisplatin combination in metastatic pancreatic cancer: a retrospective analysis.

Gemcitabine is among the standard first-line agents for the treatment of metastatic pancreatic cancer. However, as the median survival with gemcitabine monotherapy is 6 months, different combinations ...

USP9X inhibition improves gemcitabine sensitivity in pancreatic cancer by inhibiting autophagy.

Gemcitabine is the cornerstone of pancreatic cancer treatment. Although effective in most patients, development of tumor resistance to gemcitabine can critically limit its efficacy. The mechanisms res...

Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway.

Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-re...

Gemcitabine exhibits a suppressive effect on pancreatic cancer cell growth by regulating processing of PVT1 to miR1207.

Gemcitabine serves as a first-line chemotherapy agent for advanced pancreatic cancer. However, the molecular basis by which gemcitabine exerts its effects is not well-established, and the targeted gen...

Poly (L-glutamic acid)-g-methoxy poly (ethylene glycol)-gemcitabine conjugate improves the anticancer efficacy of gemcitabine.

Gemcitabine is widely used for anticancer therapy. However, its short blood circulation time and poor stability greatly impair its application. To solve this problem, we prepared a poly (L-glutamic ac...

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Gilotrif (afatinib)
GILOTRIF (afatinib) is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L8...


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