Gemcitabine

(Gemcitabine Hydrochloride)

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Gemcitabine Prescribing Information


Warnings and Precautions, Severe Cutaneous Adverse Reactions (SCARs) ( 5.3 Severe Cutaneous Adverse Reactions (SCARs) SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with gemcitabine treatment [see Adverse Reactions (6.2)]. Monitor patients for signs and symptoms of severe cutaneous adverse reactions. Permanently discontinue gemcitabine in patients who develop SCARs. )	7/2024

Gemcitabine for injection is a nucleoside metabolic inhibitor indicated:

in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. (
1.1 Ovarian Cancer
Gemcitabine for 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.
)
in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. (
1.2 Breast Cancer
Gemcitabine for 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.
)
in combination with cisplatin, for the treatment of non-small cell lung cancer. (
1.3 Non-Small Cell Lung Cancer
Gemcitabine for 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).
)
as a single agent for the treatment of pancreatic cancer. (
1.4 Pancreatic Cancer
Gemcitabine for 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 for injection is indicated for patients previously treated with fluorouracil.
)

Gemcitabine for injection is for intravenous use only.

Ovarian Cancer: 1000 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. (

2.1 Ovarian Cancer

Recommended Dose and Schedule

The recommended dosage of gemcitabine for injection is 1000 mg/m²intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with carboplatin AUC 4 administered intravenously on Day 1 after gemcitabine for injection administration. Refer to carboplatin prescribing information for additional information.

Dosage Modifications

Recommended gemcitabine for injection dosage modifications for myelosuppression are described in Tables 1and 2

[see Warnings and Precautions ]

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

[see Dosage and Administration ].

Table 1: Recommended Dosage Modifications for Gemcitabine For Injection for Myelosuppression on Day of Treatment in Ovarian Cancer
Treatment Day	Absolute Neutrophil Count (x 10 ⁶ /L)		Platelet Count (x 10 ⁶ /L)	Dosage Modification
Day 1	Greater than or equal to 1500	And	Greater than or equal to 100,000	None
Day 1	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 For Injection for Myelosuppression in Previous Cycle in Ovarian Cancer
Occurrence	Myelosuppression During Treatment Cycle	Dosage Modification
Initial Occurrence	Absolute neutrophil count less than 500 x 10⁶/L for more than 5 days or Absolute neutrophil count less than 100 x 10⁶/L for more than 3 days or Febrile neutropenia or Platelets less than 25,000 x 10⁶/L or Cycle delay for more than one week due to toxicity	Permanently reduce gemcitabine for injection to 800 mg/m²on Days 1 and 8
Subsequent Occurrence	If any of the above toxicities occur after the initial dose reduction:	Permanently reduce gemcitabine for injection to 800 mg/m²on Day 1 only

)

Breast Cancer: 1250 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. (

2.2 Breast Cancer

Recommended Dose and Schedule

The recommended dosage of gemcitabine for injection is 1250 mg/m²intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m²administered as a 3-hour intravenous infusion on Day 1 before gemcitabine for injection administration. Refer to paclitaxel prescribing information for additional information.

Dosage Modifications

Recommended gemcitabine for injection dosage modifications for myelosuppression are described in Table 3

[see Warnings and Precautions ].

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

[see Dosage and Administration ]

Table 3: Recommended Dosage Modifications for Gemcitabine For Injection for Myelosuppression on Day of Treatment in Breast Cancer
Treatment Day	Absolute Neutrophil Count (x 10 ⁶ /L)		Platelet Count (x 10 ⁶ /L)	Dosage Modification
Day 1	Greater than or equal to 1500	And	Greater than or equal to 100,000	None
Day 1	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

)

Non-Small Cell Lung Cancer: 1000 mg/m² over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. (
2.3 Non-Small Cell Lung Cancer
Recommended Dose and Schedule
28-day schedule
The recommended dosage of gemcitabine for injection is 1000 mg/m²intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m²administered intravenously on Day 1 after gemcitabine for injection administration.
21-day schedule
The recommended dosage of gemcitabine for injection is 1250 mg/m²intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m²administered intravenously on Day 1 after gemcitabine for injection administration.
Refer to cisplatin prescribing information for additional information.
Dosage Modifications
Recommended dosage modifications for gemcitabine for injection myelosuppression are described in Table 4
[see Warnings and Precautions ].
Refer to the recommended dosage modifications for non-hematologic adverse reactions
[see Dosage and Administration ]
.
)

Pancreatic Cancer: 1000 mg/m² over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly for 3 weeks of each 28-day cycle. (

2.4 Pancreatic Cancer

Recommended Dose and Schedule

The recommended dosage of gemcitabine for injection is 1000 mg/m²intravenously over 30 minutes. The recommended treatment schedule is as follows:

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

Dosage Modifications

Recommended dosage modifications for gemcitabine for injection for myelosuppression are described in Table 4

[see Warnings and Precautions ].

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

[see Dosage and Administration ]

Table 4: Recommended Dosage Modifications for Gemcitabine For Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer
Absolute Neutrophil Count (x 10 ⁶ /L)		Platelet Count (x 10 ⁶ /L)	Dosage Modification
Greater than or equal to 1000	And	Greater than or equal to 100,000	None
500 to 999	Or	50,000 to 99,999	75% of full dose
Less than 500	Or	Less than 50,000	Hold

)

Lactation: Advise not to breastfeed. (

8.2 Lactation

Risk Summary

There is no information regarding the presence of gemcitabine for injection 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 from gemcitabine for injection, advise women not to breastfeed during treatment with gemcitabine for injection and for at least one week following the last dose.

)

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

Reactions include anaphylaxis

[see Adverse Reactions (

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.

Single Agent

The data described below reflect exposure to gemcitabine for injection as a single agent administered at doses between 800 mg/m²to 1250 mg/m²intravenously over 30 minutes once weekly in 979 patients with various malignancies. The most common (≥20%) adverse reactions of single agent gemcitabine for injection 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 for injection due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine for injection in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine for injection 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 5and 6present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine for injection 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 For Injection^a
^aGrade based on criteria from the World Health Organization (WHO).
^bFor approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
^cN=699-974; all patients with laboratory or non-laboratory data.
Adverse Reactions ^b	Gemcitabine For Injection ^c
Adverse Reactions ^b	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Nausea and Vomiting	69	13	1
Fever	41	2	0
Rash	30	<1	0
Dyspnea	23	3	<1
Diarrhea	19	1	0
Hemorrhage	17	<1	<1
Infection	16	1	<1
Alopecia	15	<1	0
Stomatitis	11	<1	0
Somnolence	11	<1	<1
Paresthesias	10	<1	0

Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine For Injection^a
^aGrade based on criteria from the WHO.
^bRegardless of causality.
^cN=699-974; all patients with laboratory or non-laboratory data.
Laboratory Abnormality ^b	Gemcitabine For Injection ^c
Laboratory Abnormality ^b	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Hematologic
Anemia	68	7	1
Neutropenia	63	19	6
Thrombocytopenia	24	4	1
Hepatic
Increased ALT	68	8	2
Increased AST	67	6	2
Increased Alkaline Phosphatase	55	7	2
Hyperbilirubinemia	13	2	<1
Renal
Proteinuria	45	<1	0
Hematuria	35	<1	0
Increased BUN	16	0	0
Increased Creatinine	8	<1	0

Additional adverse reactions include the following:

Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%)
Edema: Edema (13%), peripheral edema (20%), generalized edema (<1%)
Flu-like symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating, and/or malaise (19%)
Infection: Sepsis (<1%)
Extravasation: Injection-site reactions (4%)
Allergic: Bronchospasm (<2%); anaphylactoid reactions

Ovarian Cancer

Tables 7and 8present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine for injection-treated patients and at a higher incidence in the gemcitabine for injection with carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine for injection 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 ]

. 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 for injection occurred in 10% of patients and gemcitabine for injection dose was omitted in 14% of patients in the gemcitabine for injection /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^a
^aGrade based on National Cancer Institute CTC Version 2.0.
^bRegardless of causality.
Adverse Reactions ^b	Gemcitabine for Injection/Carboplatin (N=175)			Carboplatin (N=174)
Adverse Reactions ^b	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^a
^aGrade based on National Cancer Institute 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.
Laboratory Abnormality ^b	Gemcitabine for Injection/Carboplatin (N=175)			Carboplatin (N=174)
Laboratory Abnormality ^b	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 Transfusions^c	38	-	-	15	-	-
Platelet Transfusions^c	9	-	-	3	-	-

Hematopoietic growth factors were administered more frequently in the gemcitabine for injection-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 for injection with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

Breast Cancer

Tables 9and 10present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine for injection-treated patients and at a higher incidence in the gemcitabine for injection with paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine for injection 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 ]

. 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 for injection/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^a
^aGrade based on National Cancer Institute CTC Version 2.0.
^bNon-laboratory events were graded only if assessed to be possibly drug-related.
Adverse Reactions ^b	Gemcitabine for Injection/Paclitaxel (N=262)			Paclitaxel (N=259)
Adverse Reactions ^b	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^a
^aGrade based on National Cancer Institute CTC Version 2.0.
^bRegardless of causality.
Laboratory Abnormality ^b	Gemcitabine for Injection/Paclitaxel (N=262)			Paclitaxel (N=259)
Laboratory Abnormality ^b	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 for injection with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).

Non-Small Cell Lung Cancer

Tables 11and 12present the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine for injection-treated patients and at a higher incidence in the gemcitabine for injection with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine for injection 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 ].

Patients randomized to gemcitabine for injection 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 for injection 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 for injection with 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^a
^aGrade based on National Cancer Institute Common Toxicity Criteria (CTC).
^bNon-laboratory events were graded only if assessed to be possibly drug-related.
^cN=217-253; all gemcitabine for injection/cisplatin patients with laboratory or non-laboratory data
^dN=213-248; all cisplatin patients with laboratory or non-laboratory data
Adverse Reactions ^b	Gemcitabine For Injection/Cisplatin ^c			Cisplatin ^d
Adverse Reactions ^b	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Nausea	93	25	2	87	20	<1
Vomiting	78	11	12	71	10	9
Alopecia	53	1	0	33	0	0
Neuro Motor	35	12	0	15	3	0
Diarrhea	24	2	2	13	0	0
Neuro Sensory	23	1	0	18	1	0
Infection	18	3	2	12	1	0
Fever	16	0	0	5	0	0
Neuro Cortical	16	3	1	9	1	0
Neuro Mood	16	1	0	10	1	0
Local	15	0	0	6	0	0
Neuro Headache	14	0	0	7	0	0
Stomatitis	14	1	0	5	0	0
Hemorrhage	14	1	0	4	0	0
Hypotension	12	1	0	7	1	0
Rash	11	0	0	3	0	0

Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3^a
^aGrade based on National Cancer Institute CTC.
^bRegardless of causality.
^cN=217-253; all gemcitabine for injection/cisplatin patients with laboratory or non-laboratory data
^dN=213-248; all cisplatin patients with laboratory or non-laboratory data
^ePercent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
Laboratory Abnormality ^b	Gemcitabine For Injection/Cisplatin ^c			Cisplatin ^d
Laboratory Abnormality ^b	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Hematologic
Anemia	89	22	3	67	6	1
Thrombocytopenia	85	25	25	13	3	1
Neutropenia	79	22	35	20	3	1
Lymphopenia	75	25	18	51	12	5
RBC Transfusions^e	39	-	-	13	-	-
Platelet Transfusions^e	21	-	-	<1	-	-
Hepatic
Increased Transaminases	22	2	1	10	1	0
Increased Alkaline Phosphatase	19	1	0	13	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 13and 14present the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine for injection-treated patients and at a higher incidence in the gemcitabine for injection with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine for injection 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 ].

Additional clinically significant adverse reactions are provided following Table 14.

Patients in the gemcitabine for injection/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^a
^aGrade based on criteria from the WHO.
^bNon-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.
^cN=67-69; all gemcitabine for injection/cisplatin patients with laboratory or non-laboratory data.
^dN=57-63; all Etoposide/cisplatin patients with laboratory or non-laboratory data.
^eFlu-like syndrome and edema were not graded.
Adverse Reactions ^b	Gemcitabine For Injection/Cisplatin ^c			Etoposide/Cisplatin ^d
Adverse Reactions ^b	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Nausea and Vomiting	96	35	4	86	19	7
Alopecia	77	13	0	92	51	0
Paresthesias	38	0	0	16	2	0
Infection	28	3	1	21	8	0
Stomatitis	20	4	0	18	2	0
Diarrhea	14	1	1	13	0	2
Edema^e	12	-	-	2	-	-
Rash	10	0	0	3	0	0
Hemorrhage	9	0	3	3	0	3
Fever	6	0	0	3	0	0
Somnolence	3	0	0	3	2	0
Flu-like Syndrome^e	3	-	-	0	-	-
Dyspnea	1	0	1	3	0	0

Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4^a
^aGrade based on criteria from the WHO.
^bRegardless of causality.
^cN=67-69; all gemcitabine for injection/cisplatin patients with laboratory or non-laboratory data.
^dN=57-63; all Etoposide/cisplatin patients with laboratory or non-laboratory data.
^eWHO grading scale not applicable to proportion of patients with transfusions.
Laboratory Abnormality ^b	Gemcitabine For Injection/Cisplatin ^c			Etoposide/Cisplatin ^d
Laboratory Abnormality ^b	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Hematologic
Anemia	88	22	0	77	13	2
Neutropenia	88	36	28	87	20	56
Thrombocytopenia	81	39	16	45	8	5
RBC Transfusions^c	29	-	-	21	-	-
Platelet Transfusions^e	3	-	-	8	-	-
Hepatic
Increased Alkaline Phosphatase	16	0	0	11	0	0
Increased ALT	6	0	0	12	0	0
Increased AST	3	0	0	11	0	0
Renal
Hematuria	22	0	0	10	0	0
Proteinuria	12	0	0	5	0	0
Increased BUN	6	0	0	4	0	0
Increased Creatinine	2	0	0	2	0	0

)]

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