GEMCITABINE HYDROCHLORIDE - gemcitabine hydrochloride injection, powder, lyophilized, for solution
Heritage Pharmaceuticals Inc.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Gemcitabine for Injection USP safely and effectively. See full prescribing information for Gemcitabine for Injection USP.
Gemcitabine for Injection USP, Powder, Lyophilized, For Solution For Intravenous Use Initial U.S. Approval: 1996 INDICATIONS AND USAGEDOSAGE AND ADMINISTRATIONGemcitabine for Injection USP is for intravenous use only.
CONTRAINDICATIONSPatients with a known hypersensitivity to Gemcitabine (4) WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSThe most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Heritage Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See 17 for PATIENT COUNSELING INFORMATION See 17 for PATIENT COUNSELING INFORMATION. Revised: 10/2012 |
Absolute granulocyte count (x 106/L) |
Platelet count (x 106/L) |
% of full dose |
|
≥1500 |
and |
≥100,000 |
100 |
1000-1499 |
and/or |
75,000-99,999 |
50 |
<1000 |
and/or |
<75,000 |
Hold |
Absolute granulocyte count (x 106/L) |
Platelet count (x 106/L) |
% of full dose |
|
≥1200 |
And |
>75,000 |
100 |
1000-1199 |
Or |
50,000-75,000 |
75 |
700-999 |
And |
≥50,000 |
50 |
<700 |
Or |
<50,000 |
Hold |
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 |
Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine for Injection USP should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.
Patients treated with Gemcitabine for Injection USP who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non–hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of Gemcitabine for Injection USP at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and that non–hematologic toxicity has not been greater than WHO Grade 1.
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 those patients with a known hypersensitivity to the drug.
Patients receiving therapy with gemcitabine should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.
Caution — Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity [see Clinical Studies (14.5)].
Gemcitabine can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia [see Adverse Reactions (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy. [see Dosage and Administration (2.1, 2.2,2.3, and 2.4)].
Pulmonary toxicity has been reported with the use of gemcitabine. In cases of severe lung toxicity, gemcitabine therapy should be discontinued immediately and appropriate supportive care measures instituted [see Adverse Reactions (6.1 and 6.2)].
Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Gemcitabine should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. [see Use In Specific Populations (8.6)]
Serious hepatotoxicity, 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)]. Gemcitabine should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of gemcitabine in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency. [see Use In SpecificPopulations (8.7)]
Gemcitabine can cause fetal harm when administered to a pregnant woman. In pre-clinical studies in mice and rabbits, gemcitabine was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of gemcitabine in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. [see Use In Specific Populations (8.1)]
|
|||||||
|
All Patients* |
Pancreatic Cancer Patients† |
Discontinuation (%)‡ |
||||
|
All Grades |
Grade 3 |
Grade 4 |
All Grades |
Grade 3 |
Grade 4 |
All Patients |
Laboratory§ |
|
|
|
|
|
|
|
Hematologic |
|
|
|
|
|
|
|
Anemia |
68 |
7 |
1 |
73 |
8 |
2 |
<1 |
Leukopenia |
62 |
9 |
<1 |
64 |
8 |
1 |
<1 |
Neutropenia |
63 |
19 |
6 |
61 |
17 |
7 |
- |
Thrombocytopenia |
24 |
4 |
1 |
36 |
7 |
<1 |
<1 |
Hepatic |
|
|
|
|
|
|
<1 |
ALT |
68 |
8 |
2 |
72 |
10 |
1 |
|
AST |
67 |
6 |
2 |
78 |
12 |
5 |
|
Alkaline Phospatase |
55 |
7 |
2 |
77 |
16 |
4 |
|
Bilirubin |
13 |
2 |
<1 |
26 |
6 |
2 |
|
Renal |
|
|
|
|
|
|
<1 |
Proteinuria |
45 |
<1 |
0 |
32 |
<1 |
0 |
|
Hematuria |
35 |
<1 |
0 |
23 |
0 |
0 |
|
BUN |
16 |
0 |
0 |
15 |
0 |
0 |
|
Creatinine |
8 |
<1 |
0 |
6 |
0 |
0 |
|
Non-laboratory¶ |
|
|
|
|
|
|
|
Nausea and Vomiting |
69 |
13 |
1 |
71 |
10 |
2 |
<1 |
Fever |
41 |
2 |
0 |
38 |
2 |
0 |
<1 |
Rash |
30 |
<1 |
0 |
28 |
<1 |
0 |
<1 |
Dyspnea |
23 |
3 |
<1 |
10 |
0 |
<1 |
<1 |
Diarrhea |
19 |
1 |
0 |
30 |
3 |
0 |
0 |
Hemorrhage |
17 |
<1 |
<1 |
4 |
2 |
<1 |
<1 |
Infection |
16 |
1 |
<1 |
10 |
2 |
<1 |
<1 |
Alopecia |
15 |
<1 |
0 |
16 |
0 |
0 |
0 |
Stomatitis |
11 |
<1 |
0 |
10 |
<1 |
0 |
<1 |
Somnolence |
11 |
<1 |
<1 |
11 |
2 |
<1 |
<1 |
Paresthesias |
10 |
<1 |
0 |
10 |
<1 |
0 |
0 |
|
||||||
|
Gemcitabine plus Cisplatin* |
Cisplatin† |
||||
|
All Grades |
Grade 3 |
Grade 4 |
All Grades |
Grade 3 |
Grade 4 |
Laboratory‡ |
|
|
|
|
|
|
Hematologic |
|
|
|
|
|
|
Anemia |
89 |
22 |
3 |
67 |
6 |
1 |
RBC Transfusion§ |
39 |
|
|
13 |
|
|
Leukopenia |
82 |
35 |
11 |
25 |
2 |
1 |
Neutropenia |
79 |
22 |
35 |
20 |
3 |
1 |
Thrombocytopenia |
85 |
25 |
25 |
13 |
3 |
1 |
Platelet Transfusions§ |
21 |
|
|
<1 |
|
|
Lymphocytes |
75 |
25 |
18 |
51 |
12 |
5 |
Hepatic |
|
|
|
|
|
|
Transaminase |
22 |
2 |
1 |
10 |
1 |
0 |
Alkaline Phosphatase |
19 |
1 |
0 |
13 |
0 |
0 |
Renal |
|
|
|
|
|
|
Proteinuria |
23 |
0 |
0 |
18 |
0 |
0 |
Hematuria |
15 |
0 |
0 |
13 |
0 |
0 |
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¶ |
|
|
|
|
|
|
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 |
Neuro Hearing |
25 |
6 |
0 |
21 |
6 |
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 |
Dyspnea |
12 |
4 |
3 |
11 |
3 |
2 |
Hypotension |
12 |
1 |
0 |
7 |
1 |
0 |
Rash |
11 |
0 |
0 |
3 |
0 |
0 |
|
||||||
|
Gemcitabine plus Cisplatin* |
Etoposide plus Cisplatin† |
||||
|
All Grades |
Grade 3 |
Grade 4 |
All Grades |
Grade 3 |
Grade 4 |
Laboratory‡ |
|
|
|
|
|
|
Hematologic |
|
|
|
|
|
|
Anemia |
88 |
22 |
0 |
77 |
13 |
2 |
RBC Transfusion‡ |
29 |
|
|
21 |
|
|
Leukopenia |
86 |
26 |
3 |
87 |
36 |
7 |
Neutropenia |
88 |
36 |
28 |
87 |
20 |
56 |
Thrombocytopenia |
81 |
39 |
16 |
45 |
8 |
5 |
Platelet Transfusions‡ |
3 |
|
|
8 |
|
|
Hepatic |
|
|
|
|
|
|
ALT |
6 |
0 |
0 |
12 |
0 |
0 |
AST |
3 |
0 |
0 |
11 |
0 |
0 |
Alkaline Phospatase |
16 |
0 |
0 |
11 |
0 |
0 |
Bilirubin |
0 |
0 |
0 |
0 |
0 |
0 |
Renal |
|
|
|
|
|
|
Proteinuria |
12 |
0 |
0 |
0 |
0 |
0 |
Hematuria |
22 |
0 |
0 |
0 |
0 |
0 |
BUN |
6 |
0 |
0 |
0 |
0 |
0 |
Creatinine |
2 |
0 |
0 |
0 |
0 |
0 |
Non-laboratory¶§ |
|
|
|
|
|
|
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 |
|
Gemcitabine plus Paclitaxel (N=262) |
Paclitaxel (N=259) |
||||
|
All Grades |
Grade 3 |
Grade 4 |
All Grades |
Grade 3 |
Grade 4 |
Laboratory‡ |
|
|
|
|
|
|
Hematologic |
|
|
|
|
|
|
Anemia |
69 |
6 |
1 |
51 |
3 |
<1 |
Neutropenia |
69 |
31 |
17 |
31 |
4 |
7 |
Thrombocytopenia |
26 |
5 |
<1 |
7 |
<1 |
<1 |
Leukopenia |
21 |
10 |
1 |
12 |
2 |
0 |
Hepatobiliary |
|
|
|
|
|
|
ALT |
18 |
5 |
<1 |
6 |
<1 |
0 |
AST |
16 |
2 |
0 |
5 |
<1 |
0 |
Non-laboratory¶ |
|
|
|
|
|
|
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 |
Myalgia |
33 |
4 |
0 |
33 |
3 |
<1 |
Vomiting |
29 |
2 |
0 |
15 |
2 |
0 |
Arthralgia |
24 |
3 |
0 |
22 |
2 |
<1 |
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 |
|
||||||
|
Gemcitabine plus Carboplatin (N=175) |
Carboplatin (N=174) |
||||
|
All Grades |
Grade 3 |
Grade 4 |
All Grades |
Grade 3 |
Grade 4 |
Laboratory‡ |
|
|
|
|
|
|
Hematologic |
|
|
|
|
|
|
Neutropenia |
90 |
42 |
29 |
58 |
11 |
1 |
Anemia |
86 |
22 |
6 |
75 |
9 |
2 |
Leukopenia |
86 |
48 |
5 |
70 |
6 |
<1 |
Thrombocytopenia |
78 |
30 |
5 |
57 |
10 |
1 |
RBC Transfusion* |
38 |
|
|
15 |
|
|
Platelet Transfusions |
9 |
|
|
3 |
|
|
Non-laboratory‡ |
|
|
|
|
|
|
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 |
Neuropathy-Sensory |
29 |
1 |
0 |
27 |
2 |
0 |
Diarrhea |
25 |
3 |
0 |
14 |
<1 |
0 |
Stomatitis/pharyngitis |
22 |
<1 |
0 |
13 |
0 |
0 |
Anorexia |
16 |
1 |
0 |
13 |
0 |
0 |
No specific drug interaction studies have been conducted. Information is available on the pharmacodynamics and pharmacokinetics of gemcitabine in combination with cisplatin, paclitaxel, or carboplatin. [see Clinical Pharmacology (12.2 and 12.3)]
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 in pediatric patients has not been established. Gemcitabine was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemcitabine was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial.
Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Gemcitabine should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. [see Warnings and Precautions (5.4)]
Gemcitabine clearance is affected by gender. [see Clinical Pharmacology (12.3)] In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments [see Dosage and Administration (2)] are necessary in women. In general, in single-agent studies of gemcitabine, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. There was a greater tendency in women, especially older women, not to proceed to the next cycle.
There is no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.
Gemcitabine demonstrated dose-dependent synergistic activity with cisplatin in vitro. No effect of cisplatin on gemcitabine triphosphate accumulation or DNA double-strand breaks was observed. In vivo, gemcitabine showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Gemcitabine was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to gemcitabine 4 hours before cisplatin produced the greatest interaction.
|
||||
Age |
Clearance Men (L/hr/m2) |
Clearance Women (L/hr/m2) |
Half-Life* Men (min) |
Half-Life* Women (min) |
29 | 92.2 | 69.4 | 42 | 49 |
45 | 75.7 | 57.0 | 48 | 57 |
65 | 55.1 | 41.5 | 61 | 73 |
79 | 40.7 | 30.7 | 79 | 94 |
Gemcitabine was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS).
|
||
|
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 0-1* |
94% |
95% |
Disease Status |
||
Evaluable |
7.9% |
2.8% |
Bidimensionally measurable |
91.6% |
95.5% |
Platinum-free interval† |
||
6-12 months |
39.9% |
39.9% |
>12 months |
59.0% |
59.6% |
First-line therapy |
||
Platinum-taxane combination |
70.2% |
71.3% |
Platinum-non-taxane combination |
28.7% |
27.5% |
Platinum monotherapy |
1.1% |
1.1% |
|
|||
|
Gemcitabine/Carboplatin (N=178) |
Carboplatin (N=178) |
|
PFS |
|||
Median (95%, C.I.) months |
8.6(8.0, 9.7) |
5.8(5.2, 7.1) |
p=0.0038* |
Hazard Ratio (95%. C.I.) |
0.72(0.57, 0.90) |
||
Overall Survival |
|||
Median (95%, C.I.) months |
18.0(16.2, 20.3) |
17.3(15.2, 19.3) |
p=0.8977* |
Hazard Ratio (95%. C.I.) |
0.98(0.78, 1.24) |
||
Adjusted† Hazard Ratio (95%, C.I.) |
0.86(0.67, 1.10) |
||
Investigator Reviewed |
|||
Overall Response Rate |
47.2% |
30.9% |
p=0.0016‡ |
CR |
14.6% |
6.2% |
|
PR+PRNM§ |
32.6% |
24.7% |
|
Independently Reviewed |
|||
Overall Response Rate¶# |
46.3% |
35.6% |
p=0.11‡ |
CR |
9.1% |
4.0% |
|
PR+PRNM |
37.2% |
31.7% |
|
|
Gemcitabine/Paclitaxel |
Paclitaxel |
|
Number of patients |
267 |
262 |
|
Median age, years |
53 |
52 |
|
Range |
26 to 83 |
26 to 75 |
|
Metastatic disease |
97.0% |
96.9% |
|
Baseline KPS*≥90 |
70.4% |
74.4% |
|
Number of tumor sites |
|||
1-2 |
56.6% |
58.8% |
|
≥3 |
43.4% |
41.2% |
|
Visceral disease |
73.4% |
72.9% |
|
Prior anthracycline |
96.6% |
95.8% |
|
Overall Survival† | |||
Median (95%, CI) | 18.6 (16.5, 20.7) | 15.8 (14.1,17.3) |
|
Hazard Ratio (95%, CI) | 0.86 (0.71,1.04) |
||
Time to Documented Disease Progression‡ | p<0.0001 | ||
Median (95%, C.I.), months |
5.2(4.2, 5.6) |
2.9(2.6, 3.7) |
|
Hazard Ratio (95%, C.I.) |
0.650(0.524, 0.805) | p<0.0001 | |
Overall Response Rate‡ |
p<0.0001 |
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(95%, C.I.) |
40.8%(34.9, 46.7) |
22.1%(17.1, 27.2) |
Trial |
28-day schedulea |
21-day Scheduleb |
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Treatment Arm |
Gemcitabine/Cisplatin |
Cisplatin |
Gemcitabine/Cisplatin |
Cisplatin |
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Number of patients |
260 |
262 |
69 |
66 |
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Male |
182 |
186 |
64 |
61 |
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Female |
78 |
76 |
5 |
5 |
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Median age, years |
62 |
63 |
58 |
60 |
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Range |
36 to 88 |
35 to 79 |
33 to 76 |
35 to 75 |
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Stage IIIA |
7% |
7% |
N/Ac |
N/Ac |
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Stage IIIB |
26% |
23% |
48% |
52% |
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Stage IV |
67% |
70% |
52% |
49% |
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Baseline KPSd 70 to 80 |
41% |
44% |
45% |
52% |
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Baseline KPSd 90 to 100 |
57% |
55% |
55% |
49% |
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Survival |
p=0.008 |
p=0.18 |
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Median, months |
9.0 |
7.6 |
8.7 |
7.0 |
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(95%, C.I.) months |
8.2, 11.0 |
6.6, 8.8 |
7.8, 10.1 |
6.0, 9.7 |
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Time to Disease Progression |
p=0.009 |
p=0.015 |
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Median, months |
5.2 |
3.7 |
5.0 |
4.1 |
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(95%, C.I.) months |
4.2, 5.7 |
3.0, 4.3 |
4.2, 6.4 |
2.4, 4.5 |
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Tumor Response |
26% |
10% |
p<0.0001e |
33% |
14% |
p=0.01e |
|
Gemcitabine |
5-FU |
|
Number of patients |
63 |
63 |
|
Male |
34 |
34 |
|
Female |
29 |
29 |
|
Median age |
62 years |
61 years |
|
Range |
37 to 79 |
36 to 77 |
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Stage IV disease |
71.4% |
76.2% |
|
Baseline KPSa≤70 |
69.8% |
68.3% |
|
Clinical benefit response |
22.2% (Nc=14) |
4.8%(Nc=3) |
p=0.004e |
Survival |
p=0.0009 |
||
Median |
5.7 months |
4.2 months |
|
6-month probabilityb |
(N=30) 46% |
(N=19) 29% |
|
9-month probabilityb |
(N=14) 24% |
(N=4) 5% |
|
1-year probabilityb |
(N=9) 18% |
(N=2) 2% |
|
Range |
0.2 to 18.6 months |
0.4 to 15.1+d months |
|
95% C.I. of the median |
4.7 to 6.9 months |
3.1 to 5.1 months |
|
Time to Disease Progression |
p=0.0013 |
||
Median |
2.1 months |
0.9 months |
|
Range |
0.1+d to 9.4 months |
0.1 to 12.0+d months |
|
95% C.I. of the median |
1.9 to 3.4 |
0.9 to 1.1 months |
When gemcitabine was administered more frequently than once weekly or with infusions longer than 60 minutes, increased toxicity was observed. Results of a Phase 1 study of gemcitabine to assess the maximum tolerated dose (MTD) on a daily x 5 schedule showed that patients developed significant hypotension and severe flu-like symptoms that were intolerable at doses above 10 mg/m2. The incidence and severity of these events were dose-related. Other Phase 1 studies using a twice-weekly schedule reached MTDs of only 65 mg/m2 (30-minute infusion) and 150 mg/m2 (5-minute bolus). The dose-limiting toxicities were thrombocytopenia and flu-like symptoms, particularly asthenia. In a Phase 1 study to assess the maximum tolerated infusion time, clinically significant toxicity, defined as myelosuppression, was seen with weekly doses of 300 mg/m2 at or above a 270-minute infusion time. The half-life of gemcitabine is influenced by the length of the infusion [see Clinical Pharmacology (12.3)] and the toxicity appears to be increased if gemcitabine is administered more frequently than once weekly or with infusions longer than 60 minutes [see Warnings and Precautions (5.1)].
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 (2.5 and 2.6)]
Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur. [see Warnings and Precautions (5.2)]
There are no adequate and well-controlled studies of gemcitabine in pregnant women. Based on animal studies gemcitabine can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the risks to the fetus need to be discussed with their physician. [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]
GEMCITABINE HYDROCHLORIDE
gemcitabine hydrochloride injection, powder, lyophilized, for solution |
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GEMCITABINE HYDROCHLORIDE
gemcitabine hydrochloride injection, powder, lyophilized, for solution |
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Labeler - Heritage Pharmaceuticals Inc. (780779901) |
Registrant - Emcure Pharmaceuticals Ltd. (916921919) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
Emcure Pharmaceuticals Limited | 862602830 | MANUFACTURE(23155-213, 23155-214), ANALYSIS(23155-213, 23155-214) |