NDC 71288-117 Gemcitabine

Gemcitabine Hydrochloride

NDC Product Code 71288-117

NDC 71288-117-06

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 5.26 mL in 1 VIAL, SINGLE-DOSE

NDC 71288-117-28

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 26.3 mL in 1 VIAL, SINGLE-DOSE

NDC 71288-117-54

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 52.6 mL in 1 VIAL, SINGLE-DOSE

NDC Product Information

Gemcitabine with NDC 71288-117 is a a human prescription drug product labeled by Meitheal Pharmaceuticals Inc.. The generic name of Gemcitabine is gemcitabine hydrochloride. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Meitheal Pharmaceuticals Inc.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Gemcitabine Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • GEMCITABINE HYDROCHLORIDE 38 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Nucleic Acid Synthesis Inhibitors - [MoA] (Mechanism of Action)
  • Nucleoside Metabolic Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Meitheal Pharmaceuticals Inc.
Labeler Code: 71288
FDA Application Number: ANDA212129 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 12-11-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Gemcitabine Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Ovarian Cancer

Gemcitabine Injection in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

1.2 Breast Cancer

Gemcitabine Injection in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

1.3 Non-Small Cell Lung Cancer

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

1.4 Pancreatic Cancer

Gemcitabine Injection is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine Injection is indicated for patients previously treated with fluorouracil.

Other

Recommended Dose and ScheduleThe recommended dosage of gemcitabine injection is 1,000 mg/m


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

  • Dosage ModificationsRecommended dosage modifications for gemcitabine injection for myelosuppression are described in
  • Tables 1 and
  • 2
  • [see Warnings and Precautions (
  • 5.2)]
  • . Refer to the recommended dosage modifications for non-hematologic adverse reactions
  • [see Dosage and Administration (
  • 2.5)]
  • .
  • Table 1: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian Cancer
  • Treatment DayAbsolute Neutrophil Count(x 106/L)Platelet Count(x 106/L)Dosage ModificationDay 1
  • Greater than or equal to 1500
  • And
  • Greater than or equal to 100,000
  • None
  • Less than 1500
  • Or
  • Less than 100,000
  • Delay Treatment Cycle
  • Day 8
  • Greater than or equal to 1500
  • And
  • Greater than or equal to 100,000
  • None
  • 1000 to 1499
  • Or
  • 75,000 to 99,999
  • 50% of full dose
  • Less than 1000
  • Or
  • Less than 75,000
  • Hold
  • Table 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian Cancer
  • OccurrenceMyelosuppression During Treatment CycleDosage ModificationInitial Occurrence
  • Absolute neutrophil count less than 500 x 10
  • 6/L for more than 5 days or
  • Absolute neutrophil count less than 100 x 10
  • 6/L for more than 3 days or
  • Febrile neutropenia or
  • Platelets less than 25,000 x 10
  • 6/L
  • Cycle delay for more than one week due to toxicity
  • Permanently reduce gemcitabine injection to 800 mg/m
  • 2 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/m
  • 2 on Day 1 only

Recommended Dose and ScheduleThe recommended dosage of gemcitabine injection is 1,250 mg/m


2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m


2 administered as a 3-hour intravenous infusion on Day 1 before gemcitabine injection administration. Refer to paclitaxel prescribing information for additional information.

Dosage ModificationsRecommended dosage modifications for gemcitabine injection for myelosuppression are described in


Table 3
[see Warnings and Precautions (


5.2)].


Refer to the recommended dosage modifications for non-hematologic adverse reactions


[see Dosage and Administration (


2.5)]


.



Table 3: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Breast Cancer
Treatment DayAbsolute Neutrophil Count(x 106/L)Platelet Count(x 106/L)Dosage ModificationDay 1
Greater than or equal to 1500
And
Greater than or equal to 100,000
None
Less than 1500
Or
Less than 100,000
Hold
Day 8



Greater than or equal to 1200
And
Greater than 75,000
None
1000 to 1199
Or
50,000 to 75,000
75% of full dose
700 to 999
And
Greater than or equal to 50,000
50% of full dose
Less than 700
Or
Less than 50,000
Hold

Recommended Dose and Schedule

28-day scheduleThe recommended dosage of gemcitabine injection is 1,000 mg/m


2 intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m


2 administered intravenously on Day 1 after gemcitabine injection administration.

21-day scheduleThe recommended dosage of gemcitabine injection is 1,250 mg/m


2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m


2 administered intravenously on Day 1 after gemcitabine injection administration.



Refer to cisplatin prescribing information for additional information.

Dosage ModificationsRecommended dosage modifications for gemcitabine injection myelosuppression are described in


Table 4
[see Warnings and Precautions (


5.2)]


. Refer to the recommended dosage modifications for non-hematologic adverse reactions


[see Dosage and Administration (


2.5)]


.

  • Recommended Dose and ScheduleThe recommended dosage of gemcitabine injection is 1,000 mg/m
  • 2 intravenously over 30 minutes. The recommended treatment schedule is as follows:
  • Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one-week rest.
  • After week 8: weekly dosing on Days 1, 8, and 15 of each 28-day cycle.

Dosage ModificationsRecommended dosage modifications for gemcitabine injection for myelosuppression are described in


Table 4
[see Warnings and Precautions (


5.2)]


. Refer to the recommended dosage modifications for non-hematologic adverse reactions


[see Dosage and Administration (


2.5)]


.



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

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

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 1,000 mg/m


2 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.

  • Single AgentThe data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m
  • 2 to 1,250 mg/m
  • 2 intravenously over 30 minutes once weekly, in 979 patients with various malignancies. The most common (≥20%) adverse reactions of single agent gemcitabine are nausea/vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting, increased ALT, increased alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.
  • Tables 5 and
  • 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine across 5 clinical trials.
  • Additional clinically significant adverse reactions are provided following
  • Table 6.
  • Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine
  • Aa Grade based on criteria from the World Health Organization (WHO).
  • B For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related.
  • C N=699-974; all patients with laboratory or non-laboratory data.
  • Adverse ReactionsbGemcitabinecAll Grades (%)Grade 3 (%)Grade 4 (%)   Nausea and Vomiting
  • 69
  • 13
  • 1
  • Fever
  • 41
  • 2
  • 0
  • Rash
  • 30
  • <1
  • 0
  • Dyspnea
  • 23
  • 3
  • <1
  • Diarrhea
  • 19
  • 1
  • 0
  • Hemorrhage
  • 17
  • <1
  • <1
  • Infection
  • 16
  • 1
  • <1
  • Alopecia
  • 15
  • <1
  • 0
  • Stomatitis
  • 11
  • <1
  • 0
  • Somnolence
  • 11
  • <1
  • <1
  • Paresthesias
  • 10
  • <1
  • 0
  • Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine
  • Aa Grade based on criteria from WHO.
  • B Regardless of causality.
  • C N=699-974; all patients with laboratory or non-laboratory data.
  • Laboratory AbnormalitybGemcitabinecAll Grades (%)Grade 3 (%)Grade 4 (%)Hematologic
  • Anemia
  • 68
  • 7
  • 1
  • Neutropenia
  • 63
  • 19
  • 6
  • Thrombocytopenia
  • 24
  • 4
  • 1
  • Hepatic
  • Increased ALT
  • 68
  • 8
  • 2
  • Increased AST
  • 67
  • 6
  • 2
  • Increased Alkaline Phosphatase
  • 55
  • 7
  • 2
  • Hyperbilirubinemia
  • 13
  • 2
  • <1
  • Renal
  • Proteinuria
  • 45
  • <1
  • 0
  • Hematuria
  • 35
  • <1
  • 0
  • Increased BUN
  • 16
  • 0
  • 0
  • Increased Creatinine
  • 8
  • <1
  • 0
  • Additional adverse reactions include the following:
  • Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%)
  • Edema: Edema (13%), peripheral edema (20%), generalized edema (<1%)
  • Flu-like symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, insomnia, rhinitis, sweating, and/or malaise (19%)
  • Infection: Sepsis (<1%)
  • Extravasation: Injection-site reactions (4%)
  • Allergic: Bronchospasm (<2%); anaphylactoid reactions

Ovarian CancerTables 7 and


8 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine/carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine with carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy


[see Clinical Studies (


14.1)]


.



Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following


Table 8.



The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0) and discontinuing treatment for adverse reactions (11% versus 10%), were similar between arms. Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine/carboplatin arm.
Table 7: Adverse Reactions Occurring in >10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1


aa Grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0.



b Regardless of causality.



Adverse ReactionsbGemcitabine/Carboplatin(N=175)Carboplatin(N=174)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)   Nausea
69
6
0
61
3
0
   Alopecia
49
0
0
17
0
0
   Vomiting
46
6
0
36
2
<1
   Constipation
42
6
1
37
3
0
   Fatigue
40
3
<1
32
5
0
   Diarrhea
25
3
0
14
<1
0
   Stomatitis/Pharyngitis
22
<1
0
13
0
0
Table 8: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1


aa Grade based on National Cancer Institute CTC Version 2.0.



b Regardless of causality.



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



Laboratory AbnormalitybGemcitabine/Carboplatin(N=175)Carboplatin(N=174)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)   Hematologic
       Neutropenia
90
42
29
58
11
1
       Anemia
86
22
6
75
9
2
       Thrombocytopenia
78
30
5
57
10
1
       RBC Transfusion


c38
-
-
15
-
-
       Platelet Transfusion


c9
-
-
3
-
-
Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%).
The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

Breast CancerTables 9 and


10 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine/paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated


[see Clinical Studies (


14.2)]


. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following


Table 10.



The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for adverse reactions (7% versus 5%) and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.
Table 9: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2


aa Grade based on National Cancer Institute CTC Version 2.0.



b Non-laboratory events were graded only if assessed to be possibly drug-related.



Adverse ReactionsbGemcitabine/Paclitaxel(N=262)Paclitaxel(N=259)All Grades (%)Grade 3 (%)Grade 4 (%)All Grades (%)Grade 3 (%)Grade 4 (%)   Alopecia
90
14
4
92
19
3
   Neuropathy-Sensory
64
5
<1
58
3
0
   Nausea
50
1
0
31
2
0
   Fatigue
40
6
<1
28
1
<1
   Vomiting
29
2
0
15
2
0
   Diarrhea
20
3
0
13
2
0
   Anorexia
17
0
0
12
<1
0
   Neuropathy-Motor
15
2
<1
10
<1
0
   Stomatitis/Pharyngitis
13
1
<1
8
<1
0
   Fever
13
<1
0
3
0
0
   Rash/Desquamation
11
<1
<1
5
0
0
   Febrile Neutropenia
6
5
<1
2
1
0
Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2


aa Grade based on National Cancer Institute CTC Version 2.0.



b Regardless of causality.



Laboratory AbnormalitybGemcitabine/Paclitaxel(N=262)Paclitaxel(N=259)All Grades (%)Grade 3 (%)Grade 4 (%)All Grades (%)Grade 3 (%)Grade 4 (%)   Hematologic
       Anemia
69
6
1
51
3
<1
       Neutropenia
69
31
17
31
4
7
       Thrombocytopenia
26
5
<1
7
<1
<1
   Hepatobiliary
       Increased ALT
18
5
<1
6
<1
0
       Increased AST
16
2
0
5
<1
0
Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).

Non-Small Cell Lung CancerTables 11 and


12 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC


[see Clinical Studies (


14.3)]


.



Patients randomized to gemcitabine with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving gemcitabine with cisplatin compared to those receiving cisplatin alone. The incidence of febrile neutropenia (3% versus <1%), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine/cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm.
Table 11: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3


aa Grade based on National Cancer Institute CTC.



b Non-laboratory events were graded only if assessed to be possibly drug-related.



c N=217-253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.



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



Adverse ReactionsbGemcitabine/CisplatincCisplatindAll Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)   Nausea
93
25
2
87
20
<1
   Vomiting
78
11
12
71
10
9
   Alopecia
53
1
0
33
0
0
   Neuro Motor
35
12
0
15
3
0
   Diarrhea
24
2
2
13
0
0
   Neuro Sensory
23
1
0
18
1
0
   Infection
18
3
2
12
1
0
   Fever
16
0
0
5
0
0
   Neuro Cortical
16
3
1
9
1
0
   Neuro Mood
16
1
0
10
1
0
   Local
15
0
0
6
0
0
   Neuro Headache
14
0
0
7
0
0
   Stomatitis
14
1
0
5
0
0
   Hemorrhage
14
1
0
4
0
0
   Hypotension
12
1
0
7
1
0
   Rash
11
0
0
3
0
0
Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3


aa Grade based on National Cancer Institute CTC.



b Regardless of causality.



c N=217-253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.



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



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



Laboratory AbnormalitybGemcitabine/CisplatincCisplatindAll Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Hematologic
       Anemia
89
22
3
67
6
1
       Thrombocytopenia
85
25
25
13
3
1
       Neutropenia
79
22
35
20
3
1
       Lymphopenia
75
25
18
51
12
5
       RBC Transfusion


e39
-
-
13
-
-
       Platelet Transfusions


e21
-
-
<1
-
-
Hepatic


       Increased Transaminase Increased


       Alkaline Phosphatase



22


19



2


1



1


0



10


13



1


0



0


0



Renal
       Increased Creatinine
38
4
<1
31
2
<1
       Proteinuria
23
0
0
18
0
0
       Hematuria
15
0
0
13
0
0
Other Laboratory
       Hyperglycemia
30
4
0
23
3
0
       Hypomagnesemia
30
4
3
17
2
0
       Hypocalcemia
18
2
0
7
0
<1
Tables 13 and


14 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC


[see Clinical Studies (


14.3)]


. Additional clinically significant adverse reactions are provided following


Table 14.



Patients in the gemcitabine/cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the GC arm and 68% in the EC arm. The incidence of hospitalizations for adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of patients who discontinued treatment for adverse reactions was higher in the GC arm (14% versus 8%). The proportion of patients who were hospitalized for febrile neutropenia was lower in the GC arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the GC arm.
Table 13: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4


aa Grade based on criteria from WHO.



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



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



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



e Flu-like syndrome and edema were not graded.



Adverse ReactionsbGemcitabine/CisplatincEtoposide/CisplatindAll Grades (%)Grade 3 (%)Grade 4 (%)All Grades (%)Grade 3 (%)Grade 4 (%)   Nausea and Vomiting
96
35
4
86
19
7
   Alopecia
77
13
0
92
51
0
   Paresthesias
38
0
0
16
2
0
   Infection
28
3
1
21
8
0
   Stomatitis
20
4
0
18
2
0
   Diarrhea
14
1
1
13
0
2
   Edema


e12
-
-
2
-
-
   Rash
10
0
0
3
0
0
   Hemorrhage
9
0
3
3
0
3
   Fever
6
0
0
3
0
0
   Somnolence
3
0
0
3
2
0
   Flu-like Syndrome


e3
-
-
0
-
-
   Dyspnea
1
0
1
3
0
0
Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4


aa Grade based on criteria from WHO.



b Regardless of causality.



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



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



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



Laboratory AbnormalitybGemcitabine/CisplatincEtoposide/CisplatindAll Grades (%)Grade 3 (%)Grade 4 (%)All Grades (%)Grade 3 (%)Grade 4 (%)Hematologic
   Anemia
88
22
0
77
13
2
   Neutropenia
88
36
28
87
20
56
   Thrombocytopenia
81
39
16
45
8
5
   RBC Transfusion


e29
-
-
21
-
-
       Platelet Transfusion


e3
-
-
8
-
-
Hepatic


   Increased Alkaline



   Phosphatase
16
0
0
11
0
0
   Increased ALT
6
0
0
12
0
0
   Increased AST
3
0
0
11
0
0
Renal
   Hematuria
22
0
0
10
0
0
   Proteinuria
12
0
0
5
0
0
   Increased BUN
6
0
0
4
0
0
       Increased Creatinine
2
0
0
2
0
0

Risk SummaryBased on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman


[see Clinical Pharmacology (


12.1)]


. There are no available data on the use of gemcitabine in pregnant women. In animal reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits


(see


Data)


. Advise pregnant women of the potential risk to a fetus


[see Use in Specific Populations (


8.3)]


.



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

Data

Animal DataGemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day [about 0.005 times the 1,000 mg/m


2 clinical dose based on body surface area (BSA)]. Gemcitabine is embryotoxic and fetotoxic in rabbits. Daily dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day (about 0.002 times the 1,000 mg/m


2 clinical dose based on BSA).

Risk SummaryThere is no information regarding the presence of gemcitabine or its metabolites in human milk, or their effects on the breastfed infant or on milk production. Due to the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with gemcitabine and for at least one week following the last dose.

Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating gemcitabine


[see Use in Specific Populations (


8.1)]


.

ContraceptionGemcitabine can cause fetal harm when administered to a pregnant woman


[see Use in Specific Populations (


8.1)].

FemalesBecause of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose.

MalesBecause of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months after the final dose


[see Nonclinical Toxicology (


13.1)]


.

Infertility

MalesBased on animal studies, gemcitabine may impair fertility in males of reproductive potential


[see Nonclinical Toxicology (


13.1)].


It is not known whether these effects on fertility are reversible.

DistributionThe volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m


2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m


2.



Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and sex. Gemcitabine plasma protein binding is negligible.

Elimination

MetabolismThe 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.

ExcretionGemcitabine disposition was studied in 5 patients who received a single 1,000 mg/m


2 of radiolabeled drug as a 30-minute infusion. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2′-deoxy-2′,2′-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.

Specific Populations

Geriatric PatientsClearance of gemcitabine was affected by age. The lower clearance in geriatric patients results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations.


Table 15 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and sex.



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

Male and Female PatientsFemales have lower clearance and longer half-lives than male patients as described in


Table 15.



Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient
a Half-life for patients receiving a <70 minute infusion.



AgeClearanceMen(L/hr/m2)ClearanceWomen(L/hr/m2)Half-LifeaMen(min)Half-LifeaWomen(min)29
92.2
69.4
42
49
45
75.7
57.0
48
57
65
55.1
41.5
61
73
79
40.7
30.7
79
94

Patients with Renal ImpairmentNo clinical studies have been conducted with gemcitabine in patients with decreased renal function.

Patients with Hepatic ImpairmentNo clinical studies have been conducted with gemcitabine in patients with decreased hepatic function.

Drug Interaction StudiesWhen gemcitabine (1,250 mg/m


2 on Days 1 and 8) and cisplatin (75 mg/m


2 on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day 1 was 128 L/hr/m


2 and on Day 8 was 107 L/hr/m


2. Data from patients with NSCLC demonstrate that gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent, however, due to wide confidence intervals and small sample size, interpatient variability may be observed.



Data from patients with metastatic breast cancer shows that gemcitabine has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine.

Study 3: 28-Day ScheduleA multinational, randomized trial (Study 3) compared gemcitabine with cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive either gemcitabine 1,000 mg/m


2 on Days 1, 8, and 15 of each 28-day cycle with cisplatin 100 mg/m


2 on Day 1 after gemcitabine administration (N=260) or cisplatin 100 mg/m


2 on Day 1 of each 28-day cycle (N=262). The major efficacy outcome measure was overall survival.



A total of 522 patients were enrolled. Demographics and baseline characteristics (


Table 20) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine with cisplatin arm having adenocarcinoma.



Efficacy results are presented in


Table 21 and


Figure 3.

Study 4: 21-Day ScheduleA randomized (1:1), multicenter trial (Study 4) was conducted in patients with Stage IIIB or IV NSCLC. Patients were randomized to receive gemcitabine 1,250 mg/m


2 on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m


2 on Day 1 after gemcitabine administration or etoposide 100 mg/m


2 intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m


2 on Day 1 of each 21-day cycle. The major efficacy outcome measure was response rate.



A total of 135 patients were enrolled. Demographics and baseline characteristics are summarized in


Table 20.



Efficacy results are presented in


Table 21. There was no significant difference in survival between the two treatment arms. The median survival was 8.7 months for the gemcitabine with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 5 months compared to 4.1 months on the etoposide with cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine with cisplatin arm was 33% compared to 14% on the etoposide with cisplatin arm (Fisher's Exact p=0.01, two-sided).


Figure 3: Kaplan-Meier Curves for Overall Survival in Study 3Table 20: Baseline Demographics and Clinical Characteristics for Studies 3 and 4
a N/A Not applicable.



b Karnofsky Performance Status.



Trial28-day Schedule (Study 3)21-day Schedule (Study 4)Gemcitabine/Cisplatin(N=260)Cisplatin(N=262)Gemcitabine/Cisplatin(N=69)Etoposide/Cisplatin(N=66)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/A


aN/A


aStage IIIB
26%
23%
48%
52%
Stage IV
67%
70%
52%
49%
Baseline KPS


b70 to 80



41%



44%



45%



52%



Baseline KPS


b90 to 100



57%



55%



55%



49%



Table 21: Efficacy Results for Studies 3 and 4
a CI=confidence intervals.



b p-value two-sided Fisher's Exact test for difference in binomial proportions; log rank test for time-to-event analyses.



Trial28-day Schedule (Study 3)21-day Schedule (Study 4)Efficacy ParameterGemcitabine/Cisplatin (N=260)Cisplatin (N=262)Gemcitabine/Cisplatin (N=69)Etoposide/Cisplatin (N=66)Survival   Median (95% CI


a) in months



9.0 (8.2, 11.0)
7.6 (6.6, 8.8)
8.7 (7.8, 10.1)
7.0 (6.0, 9.7)
   p-value


bp=0.008
p=0.18
Time to Disease Progression   Median (95% CI


a) in months



5.2 (4.2, 5.7)
3.7 (3.0, 4.3)
5.0 (4.2, 6.4)
4.1 (2.4, 4.5)
   p-value


bp=0.009
p=0.015
Tumor Response26%
10%
33%
14%
   p-value


bp<0.0001
p=0.01

MyelosuppressionAdvise patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider should any signs or symptoms of infection, including fever, or if bleeding, or signs of anemia, occur


[see Warnings and Precautions (


5.2)]


.

Pulmonary ToxicityAdvise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough


[see Warnings and Precautions (


5.3)]


.

Hemolytic Uremic Syndrome and Renal FailureAdvise patients of the risks of hemolytic uremic syndrome and associated renal failure. Instruct patients to immediately contact their healthcare provider for changes in the color or volume of urine output or for increased bruising or bleeding


[see Warnings and Precautions (


5.4)]


.

Hepatic ToxicityAdvise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal quadrant


[see Warnings and Precautions (


5.5)]


.

Embryo-Fetal ToxicityAdvise females and males of reproductive potential that gemcitabine can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months after the final dose


[see Warnings and Precaution (


5.6), Use in Specific Populations (


8.1,


8.3)]


.

LactationAdvise women not to breastfeed during treatment with gemcitabine and for at least one week after the last dose


[see Use in Specific Populations (


8.2)]


.

InfertilityAdvise males of reproductive potential of the potential for reduced fertility with gemcitabine


[see Use in Specific Populations (


8.3), Nonclinical Toxicology (


13.1)]


.



meitheal


®Mfd. for Meitheal Pharmaceuticals


Chicago, IL 60631 (USA)


©2019 Meitheal Pharmaceuticals Inc.


July 2019

2.5 Dosage Modifications For Non-Hematologic Adverse Reactions

  • Permanently discontinue gemcitabine injection for any of the following:
  • Unexplained dyspnea or evidence of severe pulmonary toxicity
  • [see Warnings and Precautions (
  • 5.3)]
  • Hemolytic uremic syndrome (HUS) or severe renal impairment
  • [see Warnings and Precautions (
  • 5.4)]
  • Severe hepatic toxicity
  • [see Warnings and Precautions (
  • 5.5)]
  • Capillary leak syndrome (CLS)
  • [see Warnings and Precautions (
  • 5.8)]
  • Posterior reversible encephalopathy syndrome (PRES)
  • [see Warnings and Precautions (
  • 5.9)]
  • Withhold gemcitabine injection or reduce dose by 50% for other Grade 3 or 4 non-hematological adverse reactions until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

2.6 Preparation

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


1 Exercise caution and wear gloves when preparing gemcitabine injection solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine injection contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.

3 Dosage Forms And Strengths

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

4 Contraindications

Gemcitabine Injection is contraindicated in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis


[see Adverse Reactions (


6.1)]


.

5.1 Schedule-Dependent Toxicity

In clinical trials evaluating the maximum tolerated dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is influenced by the length of the infusion


[see Clinical Pharmacology (


12.3)]


. Refer to the recommended gemcitabine injection dosage


[see Dosage and Administration (


2.1,


2.2,


2.3,


2.4)]


.

5.2 Myelosuppression

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


[see Adverse Reactions (


6.1)]


.



Prior to each dose of gemcitabine injection, obtain a complete blood count (CBC) with a differential and a platelet count. Modify the dosage as recommended


[see Dosage and Administration (


2.1,


2.2,


2.3,


2.4)]


.

5.3 Pulmonary Toxicity And Respiratory Failure

Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite the discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine


[see Adverse Reactions (


6.1,


6.2)]


.



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

5.4 Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur with gemcitabine. In clinical trials, HUS occurred in 0.25% of 2429 patients. Most fatal cases of renal failure were due to HUS
Serious cases of thrombotic microangiopathy (TMA) other than HUS have been reported with gemcitabine
Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur with gemcitabine. In clinical trials, HUS occurred in 0.25% of 2429 patients. Most fatal cases of renal failure were due to HUS


[see Adverse Reactions (


6.1)].


Serious cases of thrombotic microangiopathy (TMA) other than HUS have been reported with gemcitabine


[see Adverse Reactions (


6.2)].


Assess renal function prior to initiation of gemcitabine and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis; increased bilirubin or LDH; reticulocytosis; severe thrombocytopenia; or evidence of renal failure (increased serum creatinine or BUN). Permanently discontinue gemcitabine in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the discontinuation of therapy.
Assess renal function prior to initiation of gemcitabine and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis; increased bilirubin or LDH; reticulocytosis; severe thrombocytopenia; or evidence of renal failure (increased serum creatinine or BUN). Permanently discontinue gemcitabine in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the discontinuation of therapy.

5.5 Hepatic Toxicity

Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or with other potentially hepatotoxic drugs


[see Adverse Reactions (


6.1,


6.2)].


Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency.



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

5.6 Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits.
Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months following the final dose


[see Use in Specific Populations (


8.1,


8.3)].

5.7 Exacerbation Of Radiation Therapy Toxicity

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

5.8 Capillary Leak Syndrome

Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents


[see Adverse Reactions (


6.2)]


. Permanently discontinue gemcitabine if CLS develops during therapy.

5.9 Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents


[see Adverse Reactions (


6.2)]


. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI). Permanently discontinue gemcitabine if PRES develops during therapy.

6 Adverse Reactions

  • The following clinically significant adverse reactions are described elsewhere in the labeling:
  • Hypersensitivity
  • [see Contraindications (
  • 4)]
  • Schedule-Dependent Toxicity
  • [see Warnings and Precautions (
  • 5.1)]
  • Myelosuppression
  • [see Warnings and Precautions (
  • 5.2)]
  • Pulmonary Toxicity and Respiratory Failure
  • [see Warnings and Precautions (
  • 5.3)]
  • Hemolytic Uremic Syndrome
  • [see Warnings and Precautions (
  • 5.4)]
  • Hepatic Toxicity
  • [see Warnings and Precautions (
  • 5.5)]
  • Exacerbation of Radiation Therapy Toxicity
  • [see Warnings and Precautions (
  • 5.7)]
  • Capillary Leak Syndrome
  • [see Warnings and Precautions (
  • 5.8)]
  • Posterior Reversible Encephalopathy Syndrome
  • [see Warnings and Precautions (
  • 5.9)]

6.1 Clinical Trials Experience

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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of gemcitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System: TMA



Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias



Vascular: Peripheral vasculitis, gangrene, capillary leak syndrome



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



Hepatic: Hepatic failure, hepatic veno-occlusive disease



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



Nervous System: Posterior reversible encephalopathy syndrome (PRES)

8.4 Pediatric Use

The safety and effectiveness of gemcitabine have not been established in pediatric patients.
The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m


2/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


2/min administered over 360 minutes weekly for three weeks followed by a one-week rest period.



Patients with M1 or M2 bone marrow on Day 28 who did not experience unacceptable toxicity were eligible to receive a maximum of one additional four-week course. Toxicities observed included myelosuppression, febrile neutropenia, increased serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.

8.5 Geriatric Use

In clinical studies which enrolled 979 patients with various malignancies who received single agent gemcitabine, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients.
In a randomized trial in women with ovarian cancer (Study 1), 175 women received gemcitabine with carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3-4 neutropenia in women 65 years of age or older


[see Dosage and Administration (


2.1)]


.



Gemcitabine clearance is affected by age; however, there are no recommended dose adjustments based on patients' age


[see Clinical Pharmacology (


12.3)]


.

8.6 Gender

Gemcitabine clearance is decreased in females


[see Clinical Pharmacology (


12.3)].


In single agent studies of gemcitabine, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3-4 neutropenia and thrombocytopenia


[see Dosage and Administration (


2.1,


2.2,


2.3,


2.4)]


.

10 Overdosage

There is no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5,700 mg/m


2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study. In the event of suspected overdose, monitor with appropriate blood counts and provide supportive therapy, as necessary.

11 Description

Gemcitabine is a nucleoside metabolic inhibitor. The chemical name of gemcitabine HCl is 2′-deoxy- 2′,2′-difluorocytidine monohydrochloride (β-isomer). The structural formula is as follows:
Gemcitabine HCl is a white to off-white solid with a molecular formula of C


9H


11F


2N


3O


4 • HCl and a molecular weight of 299.66 g/mol. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.



Gemcitabine Injection is a sterile solution in single-dose vials for intravenous use. Each vial contains 200 mg, 1 gram, or 2 grams of gemcitabine equivalent to 227.55 mg, 1.14 grams, or 2.28 grams of gemcitabine HCl. Each mL contains 38 mg of gemcitabine free base in Water for Injection equivalent to 43.26 mg of gemcitabine HCl. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

12.1 Mechanism Of Action

Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands which eventually results in the initiation of apoptotic cell death.

12.3 Pharmacokinetics

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


2 to 3,600 mg/m


2.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an


in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an


in vivo mouse micronucleus assay. Gemcitabine intraperitoneal doses of 0.5 mg/kg/day (about 1/700 the 1,000 mg/m


2 clinical dose based on BSA) in male mice resulted in moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the 1,000 mg/m


2 clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the 1,000 mg/m


2 clinical dose based on BSA).

14.1 Ovarian Cancer

The efficacy of gemcitabine was evaluated in a randomized trial (Study 1) conducted in women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1,000 mg/m


2 on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine administration (n = 178) or carboplatin AUC 5 on Day 1 of each 21-day cycle (n = 178). The major efficacy outcome measure was progression-free survival (PFS).



A total of 356 patients were enrolled. Demographics and baseline characteristics are shown in


Table 16. Efficacy results are presented in


Table 17 and


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



Table 16: Baseline Demographics and Clinical Characteristics for Study 1
a 5 patients on gemcitabine/carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.



b 2 patients on gemcitabine/carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months.



Gemcitabine/Carboplatin(N=178)Carboplatin(N=178)Median age, years


   Range



59


36 to 78



58


21 to 81



Baseline ECOG performance status 0-1


a94%
95%
Disease Status


   Evaluable


   Bidimensionally measurable



8%


92%



3%


96%



Platinum-free interval


b
   6-12 months


   >12 months



40%


59%



40%


60%



First-line therapy


   Platinum-taxane combination


   Platinum-non-taxane combination


   Platinum monotherapy



70%


29%


1%



71%


28%


1%



Table 17: Efficacy Results in Study 1
a CI=confidence interval.



b Log rank, unadjusted.



c Chi square.



d CR=Complete response



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



f Independently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.



Efficacy ParameterGemcitabine/Carboplatin


(N=178)


Carboplatin


(N=178)


Progression-Free Survival       Median (95% CI


a) in months



8.6 (8.0, 9.7)



5.8 (5.2, 7.1)



       Hazard Ratio (95% CI)
0.72 (0.57, 0.90)
p=value


bp=0.0038
Overall Survival       Median (95% CI) in months



18.0 (16.2, 20.3)



17.3 (15.2, 19.3)



       Hazard Ratio (95% CI)
0.98 (0.78, 1.24)
p=value


bp=0.8977
Overall Response Rate by Investigator Review47.2%



30.9%



p=value


cp=0.0016
CR


d       PR with PRNM


e14.6%


32.6%



6.2%


24.7%



Overall Response Rate by Independent Reviewf46.3%



35.6%



p=value


cp=0.11
       CR


d       PR with PRNM


e9.1%


37.2%



4.0%


31.7%



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

14.2 Breast Cancer

The efficacy of gemcitabine was evaluated in a multinational, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer and who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated.
Patients were randomized to receive gemcitabine 1,250 mg/m


2 on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m


2 administered on Day 1 before gemcitabine administration (n = 267) or paclitaxel 175 mg/m


2 on Day 1 of each 21-day cycle (n = 262). The major efficacy outcome measure was time to documented disease progression.



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


Table 18).



Efficacy results are presented in


Table 19 and


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



Table 18: Baseline Demographics and Clinical Characteristics for Study 2
a Karnofsky Performance Status.



Gemcitabine/Paclitaxel(N=267)Paclitaxel(N=262)Median age, years


       Range



53


26 to 83



52


26 to 75



Metastatic disease
97%
97%
Baseline KPS


a ≥90



70%
74%
Number of tumor sites


       1-2


       ≥3



57%


43%



59%


41%



Visceral disease
73%
73%
Prior anthracycline
97%
96%
Table 19: Efficacy Results in Study 2
a These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.



b Based on the ITT population.



Efficacy ParameterGemcitabine/Paclitaxel(N=267)Paclitaxel(N=262)Time to Documented Disease Progressiona       Median (95% CI) in months
5.2


(4.2, 5.6)



2.9


(2.6, 3.7)



       Hazard Ratio (95% CI)
0.650 (0.524, 0.805)
       p-value
p<0.0001
Overall Survivalb       Median (95% CI) in months
18.6


(16.5, 20.7)



15.8


(14.1, 17.3)



       Hazard Ratio (95% CI)
0.86 (0.71, 1.04)
       p-value
Not Significant
Overall Response Rateb        (95% CI)



40.8% (34.9, 46.7)



22.1% (17.1, 27.2)



       p-value
p<0.0001
Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2

14.3 Non-Small Cell Lung Cancer

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

14.4 Pancreatic Cancer

  • The efficacy of gemcitabine was evaluated in two trials (Studies 5 and 6), a randomized, single-blind, two-arm, active-controlled trial (Study 5) conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial (Study 6) conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or a fluorouracil-containing regimen. In Study 5, patients were randomized to receive either gemcitabine 1,000 mg/m
  • 2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m
  • 2 intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1,000 mg/m
  • 2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles.
  • The major efficacy outcome measure in both trials was “clinical benefit response”. A patient was considered to have had a clinical benefit response if either of the following occurred:
  • The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy.
  • OR
  • The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation.
  • Study 5 enrolled 126 patients. Demographics and baseline characteristics were similar between the arms (
  • Table 22).
  • The efficacy results are shown in
  • Table 23 and
  • Figure 4. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive fluorouracil. No confirmed objective tumor responses were observed in either treatment arm.
  • Table 22: Baseline Demographics and Clinical Characteristics for Study 5
  • A Karnofsky Performance Status.
  • GemcitabineFluorouracil(N=63)(N=63)Male
  • 54%
  • 54%
  • Median age
  • 62 years
  • 61 years
  • Range
  • 37 to 79
  • 36 to 77
  • Stage IV disease
  • 71%
  • 76%
  • Baseline KPS
  • A ≤70
  • 70%
  • 68%
  • Table 23: Efficacy Results in Study 5
  • A p-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other p-values are calculated using log rank test.
  • Efficacy ParameterGemcitabine(N=63)Fluorouracil(N=63)Clinical Benefit Response22.2%
  • 4.8%
  • P-value
  • Ap=0.004
  • Overall Survival       Median (95% CI) in months
  • 5.7 (4.7, 6.9)
  • 4.2 (3.1, 5.1)
  • P-value
  • Ap=0.0009
  • Time to Disease Progression       Median (95% CI) in months
  • 2.1 (1.9, 3.4)
  • 0.9 (0.9, 1.1)
  • P-value
  • Ap=0.0013
  • Figure 4: Kaplan-Meier Curves for Overall Survival in Study 5

15 References

  • “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 How Supplied/Storage And Handling

Gemcitabine Injection is a clear and colorless to light straw-colored solution, free of visible particulate matter, and is available in sterile single-dose vials individually packaged in a carton containing:
NDCGemcitabine Injection (38 mg per mL)Package Factor71288-


117-06



200 mg per 5.26 mL, sterile solution in a single-dose glass vial
1 vial per carton
71288-


117-28



1 gram per 26.3 mL, sterile solution in a single-dose glass vial
1 vial per carton
71288-


117-54



2 grams per 52.6 mL, sterile solution in a single-dose glass vial
1 vial per carton

Storage And Handling

Storage ConditionsStore refrigerated between 2° and 8°C (36° and 46°F).


Do not freeze.



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


1Discard unused portion.
Sterile, Nonpyrogenic, Preservative-free.


The container closure is not made with natural rubber latex.

* Please review the disclaimer below.