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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 Injection, lyophilized powder, for intravenous useInitial U. | Gemcitabine hydrochloride [Heritage Pharmaceuticals 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 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 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 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 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 is indicated for patients previously treated with 5-FU.

Recommended Dose and Schedule

The recommended dose of Gemcitabine for Injection USP 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 for Injection USP administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.

Dose Modifications

Recommended Gemcitabine for Injection USP 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 for injection USP 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
<1500
and
or
≥100,000
<100,000
100%
Delay Treatment Cycle
Day 8
≥1500
1000-1499
<1000
and
or
or
≥100,000
75,000-99,999
<75,000
100%
50%
Hold
Table 2: Gemcitabine for Injection USP Dose Modification for Myelosuppression in Previous Cycle In Ovarian Cancer
Occurrence
Myelosuppression During Treatment Cycle
Dose Modification
Initial Occurrence
Absolute granulocyte count less than 500 x 106/L for more
than 5 days
Absolute granulocyte count less than 100 x 106/L for more 
than 3 days
Febrile neutropenia
Platelets less than 25,000x106/L
Cycle delay of more than one week due to toxicity 
Permanently reduce Gemcitabine for Injection USP 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 for Injection USP dose to 800 mg/m2 on 
Day 1 only 

Recommended Dose and Schedule

The recommended dose of Gemcitabine for Injection USP 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 for Injection USP administration.

Dose Modifications

Recommended dose modifications for Gemcitabine for Injection USP 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 for Injection USP 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%

less than 1500
or
less than 100,000
Hold
Day 8
≥1200
and
>75,000
100%

1000-1199
or
50,000-75,000
75%

700-999
and
≥50,000
50%

<700
or
<50,000
Hold

Recommended Dose and Schedule

Every 4-week schedule

The recommended dose of Gemcitabine for Injection USP 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 for Injection USP.

Every 3-week schedule

The recommended dose of Gemcitabine for Injection USP is 1250 mg/mintravenously 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 for Injection USP.

Dose Modifications

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

Recommended Dose and Schedule

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

Dose Modifications

Recommended dose modifications for Gemcitabine for Injection USP 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 for Injection USP 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 for Injection USP 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%
500-999
Or
50,000-99,999
75%
<500
Or
<50,000
Hold

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

Withhold Gemcitabine for Injection USP 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 for Injection USP 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.

Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. These dilutions each yield a gemcitabine concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine. 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 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 for Injection USP is a white to off-white lyophilized powder available in sterile single-use vials containing 200 mg or 1 g gemcitabine.

Gemcitabine for Injection USP is contraindicated in patients with a known hypersensitivity to gemcitabine.

In clinical trials evaluating the maximum tolerated dose of Gemcitabine for Injection USP, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine 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 for Injection USP 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 for Injection USP. Discontinue Gemcitabine for Injection USP 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, including fatalities from renal failure or the requirement for dialysis can occur in patients treated with Gemcitabine for Injection USP. 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 (6.1and 6.2)]. Assess renal function prior to initiation of Gemcitabine for Injection USP and periodically during treatment. Consider the diagnosis of HUS in patients who develops 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 for Injection USP 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 for Injection USP alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1and 6.2)]. Administration of Gemcitabine for Injection USP in patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency [see Use in Specific Populations (8.7)]. Assess hepatic function prior to initiation of Gemcitabine for Injection USP and periodically during treatment. Discontinue Gemcitabine for Injection USP in patients that develop severe liver injury.

Gemcitabine for Injection USP 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. If this drug is used during pregnancy, or if a woman becomes pregnant while taking Gemcitabine for Injection USP, the patient should be apprised of the potential hazard to a fetus. [see Use in Specific Populations (8.1)]

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

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

Non-concurrent (given greater than 7 days apart)— Excessive toxicity has not been observed when Gemcitabine for Injection USP is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemcitabine for Injection USP after prior radiation.

Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemcitabine for Injection USP as a single agent or in combination with other chemotherapeutic agents. Discontinue Gemcitabine for Injection USP if CLS develops during therapy.

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemcitabine for Injection USP as a single agent or in combination with other chemotherapeutic agents. 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 for Injection USP 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 for Injection USP as a single agent administered at doses between 800 mg/m to 1250 mg/m over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (greater than or equal to 20%) adverse reactions of single-agent Gemcitabine for Injection USP are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (greater than or equal to 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 for Injection USP due to adverse reactions. Adverse reactions resulting in discontinuation of Gemcitabine for Injection USP in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemcitabine for Injection USP in less than 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 for Injection USP 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 greater than or equal to 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 (greater than 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 less than 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 greater than or equal to 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 non-small cell lung cancer (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 greater than or equal to 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 (less than 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 greater than or equal to 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 less than 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 Gemcitabine for Injection USPa
aGrade based on criteria from the World Health Organization (WHO).
bN=699 to 974; all patients with laboratory or non-laboratory data.
cRegardless of causality.
dFor approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related.

All  Patientsb

All Grades
Grade 3
Grade 4
Laboratoryc



   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 - laboratoryd



   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 3-4)]a
aNational Cancer Institute Common Toxicity Criteria (CTC) for severity grading.
bN=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.
cN=213 to 248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days.
dRegardless of causality.
ePercent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
fNon-laboratory events were graded only if assessed to be possibly drug-related

Gemcitabine  plus  Cisplatinb
Cisplatinc

All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratoryd






       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 Transaminases
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 - laboratoryf






     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
aGrade based on criteria from the World Health Organization (WHO).
bN=67 to 69; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine for Injection USP at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days.
cN=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.
dRegardless of causality.
eWHO grading scale not applicable to proportion of patients with transfusions
fNon-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.
gFlu-like syndrome and edema were not graded.

Gemcitabine  plus  Cisplatinb
Etoposide  plus  Cisplatinc

All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratoryd






     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 - laboratoryf






         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
         Flu-like syndromeg
3
-
-
0
-
-
         Edemag
12
-
-
-
2
-
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 3-4)]
aSeverity grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0
bRegardless of causality.
cNon-laboratory events were graded only if assessed to be possibly drug-related.

Gemcitabine  plus  Paclitaxel
( N = 262 )
Paclitaxel
( N = 259 )

All Grades 
Grade 3 
Grade 4 
All Grades 
Grade 3 
Grade 4 
Laboratoryb






     Hematologic 






         Anemia 
69 


51 

<1 
         Neutropenia 
69 
31 
17 
31 


         Thrombocytopenia 
26 

<1 

<1 
<1 
     Hepatobiliary 






         Increased ALT 
18 

<1 

<1 

         Increased AST 
16 



<1 

Non - laboratoryc






     Alopecia 
90 
14 

92 
19 

     Neuropathy-sensory 
64 

<1 
58 


     Nausea 
50 


31 


     Fatigue 
40 

<1 
28 

<1 
     Vomiting 
29 


15 


     Diarrhea 
20 


13 


     Anorexia 
17 


12 
<1 

     Neuropathy-motor 
15 

<1 
10 
<1 

     Stomatitis/pharyngitis 
13 

<1 

<1 

     Fever 
13 
<1 




     Rash/desquamation 
11 
<1 
<1 



     Febrile neutropenia
6
5
<1
2
1
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 3-4)]
aGrade based on Common Toxicity Criteria (CTC) Version 2.0.
bRegardless of causality.
cPercent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

Gemcitabine  plus  Carboplatin ( N = 175 )
Carboplatin ( N = 174 )

All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratoryb






     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 - laboratoryb






     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 for Injection USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

Vascular 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 drug interaction studies have been conducted.

Pregnancy Category D. [see Warnings and Precautions (5.6)]

Risk Summary

Gemcitabine can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, gemcitabine is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If gemcitabine is used during pregnancy, or if the patient becomes pregnant while taking gemcitabine, the patient should be apprised of the potential hazard to a fetus.

Animal Data

Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (approximately 0.005 times the recommended human dose on a mg/mbasis). 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/mbasis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. [see Warnings and Precautions (5.6)]

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from gemcitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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/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/mwas administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study.

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

The structural formula is as follows:

The empirical formula for gemcitabine hydrochloride is CHFNO• HCl. It has a molecular weight of 299.66.

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

Gemcitabine for injection USP is supplied in a sterile form for intravenous use only. Vials of Gemcitabine for Injection USP contain either 200 mg or 1 g of gemcitabine hydrochloride USP (expressed as free base) formulated with mannitol USP (200 mg or 1 g, respectively) and sodium acetate USP (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid NF and/or sodium hydroxide NF 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 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 (less than 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 less than 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 (less than 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/mon 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
aHalf-life for patients receiving less than 70 minute infusion.

     Age

Clearance Men
(L/hr/m2)

Clearance Women
(L/hr/m2)

Half-Lifea
Men (min)

Half-Lifea
Women (min)
29
92.2
69.4
42
49
45
75.7
57.0
48
57
65
55.1
41.5
61
73
79
40.7
30.7
79
94

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/mbasis) 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/mbasis) 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
a5 patients on gemcitabine plus carboplatin arm and 4 patients on carboplatin arm with no baseline Eastern Cooperative Oncology Group (ECOG) performance status.
b2 on gemcitabine plus carboplatin arm and 1 on carboplatin arm had platinum-free interval less than 6 months.

Gemcitabine/Carboplatin
Carboplatin
Number of randomized patients
178
178
Median age, years
59
58
     Range 
36 to 78
21 to 81
 Baseline ECOG performance status 0-1a 94%
95%
Disease Status


     Evaluable 
8%
3%
     Bidimensionally measurable
92%
96%
 Platinum-free intervalb


     6-12 months
40%
40%
     >12 months
59%
60%
First-line therapy


     Platinum-taxane combination
70%
71%
     Platinum-non-taxane combination
29%
28%
     Platinum monotherapy
1%
1%
Table 12: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer - Efficacy Outcomes
aCI=confidence interval.
bLog rank, unadjusted.
cChi Square.
dCR=Complete response.
ePR plus PRNM=Partial response plus partial response, non-measurable disease.
fIndependently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.

Gemcitabine/Carboplatin
(N=178)
Carboplatin
(N=178)
Progression-free Survival


Median (95% CIa) months 
8.6 (8.0, 9.7)
5.8 (5.2, 7.1)
     Hazard Ratio (95% CI)
0.72 (0.57, 0.90)
     p-valueb p=0.0038
Overall Survival


    Median (95% CI) months
18.0 (16.2, 20.3)
17.3 (15.2, 19.3)
    Hazard Ratio (95% CI)
0.98 (0.78, 1.24)
    p-valueb p=0.8977
Investigator Reviewed


Overall Response Rate
47.2%
30.9%
     p-valuec p=0.0016
     CRd 14.6%
6.2%
     PR plus 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 plus PRNMe
37.2%
31.7%

The safety and efficacy of gemcitabine were evaluated in a multi-national, 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) or to receive 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
aKarnofsky Performance Status.
bThese represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
cBased 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 


         1-2 
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
(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 Survivalc


         Median Survival in months
(95% CI) 
18.6
(16.5, 20.7) 
15.8
(14.1, 17.3) 
         Hazard Ratio (95% CI) 
0.86 (0.71, 1.04) 
   p-value 
Not Significant 
   Overall Response Rate 
40.8% 
22.1% 
         (95% CI) 
(34.9, 46.7) 
(17.1, 27.2) 
   p-value 
p<0.0001 

    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 in Patients with NSCLC Study (N=522).

Table 14: Randomized Trials of Gemcitabine plus Cisplatin in Patients with NSCLC
a28-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.
b21-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.
cN/A Not applicable.
dKarnofsky Performance Status.
eCI=confidence intervals.
fp-value two-sided Fisher's Exact test for difference in binomial proportions; log rank test for time-to-event analyses.
Trial
28 - day  Schedulea
21 - day  Scheduleb
Treatment Arm
Gemcitabine plus Cisplatin
Cisplatin
Gemcitabine plus Cisplatin
Etoposide plus Cisplatin
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 in 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:

OR

 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
aKarnofsky Performance Status.
bp-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.

Gemcitabine
5 - FU
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 for Injection USP is available in sterile single-use vials individually packaged in a carton containing:

200 mg white to off-white, lyophilized powder in a 10-mL size sterile single-use vial - NDC 23155-213-31

1 g white to off-white, lyophilized powder in a 50-mL size sterile single-use vial - NDC 23155-214-31

Unopened vials of Gemcitabine for Injection USP are stable until the expiration date indicated on the package when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature] [see Dosage and Administration (2.6  and 2.7)].

Manufactured by:

Emcure Pharmaceuticals Ltd.,

Hinjawadi, Pune, India.

Manufactured for:

Heritage Pharmaceuticals Inc.

East Brunswick, NJ 08816

1.866.901.DRUG (3784)

 

Rev. 09/18

NDC 23155-213-31

Rx only

GEMCITABINE For Injection USP

200 mg/vial

For intravenous use only

Cytotoxic Agent

Lyophilized

Must be diluted

Sterile Single Use Vial

NDC 23155-213-31

Rx only

GEMCITABINE For Injection USP

200 mg/vial

For intravenous use only

Cytotoxic Agent

Lyophilized

Must be diluted

Sterile Single Use Vial

NDC 23155-214-31

Rx only

GEMCITABINE For Injection USP

1 g/vial

For intravenous use only

Cytotoxic Agent

Lyophilized

Must be diluted

Sterile Single Use Vial

NDC 23155-214-31

Rx only

GEMCITABINE For Injection USP

1 g/vial

For intravenous use only

Cytotoxic Agent

Lyophilized

Must be diluted

Sterile Single Use Vial

Manufacturer

Heritage Pharmaceuticals Inc.

Active Ingredients

Source

Drugs and Medications [242 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 [3153 Associated Clinical Trials listed on BioPortfolio]

Gemcitabine Hydrochloride With or Without GDC-0449 in Treating Patients With Recurrent or Metastatic Pancreatic Cancer

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Gemcitabine Hydrochloride, Dasatinib, and Erlotinib Hydrochloride in Treating Patients With Metastatic Pancreatic Cancer That Cannot Be Removed by Surgery

This phase I trial studies the side effects and best dose of gemcitabine hydrochloride and dasatinib when given together with erlotinib hydrochloride in treating patients with pancreatic c...

Cisplatin, Capecitabine, Gemcitabine Hydrochloride and Epirubicin Hydrochloride or Docetaxel in Treating Patients With Stage III or Stage IV Pancreatic Cancer

RATIONALE: Drugs used in chemotherapy, such as cisplatin, capecitabine, gemcitabine hydrochloride, epirubicin hydrochloride, and docetaxel, work in different ways to stop the growth of tum...

Gemcitabine Hydrochloride and Genistein in Treating Women With Stage IV Breast Cancer

RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride and genistein, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping...

Gemcitabine Hydrochloride, Oxaliplatin, and Erlotinib Hydrochloride in Treating Patients With Advanced Biliary Tract Cancer, Pancreatic Cancer, Duodenal Cancer, or Ampullary Cancer

RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stoppi...

PubMed Articles [318 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...

Protective effects of berberine hydrochloride on DSS-induced ulcerative colitis in rats.

Berberine hydrochloride is one the effective compound among Rhizoma Coptidis, Cortex Phellodendri, and other plants. There are several clinical functions of berberine hydrochloride including anti-infl...

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...

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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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