Gemcitabine Dailymed

The following clinically significant adverse reactions are described elsewhere in the labelling:

• 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)]

The most common adverse reactions for the single agent (≥20%) are nausea/ vomiting, anemia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea and edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact at 1-888-557-1212 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 as a single agent administered at doses between 800 mg/m² to 1250 mg/m² 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^a

Adverse Reactionsb	Gemcitabinec
	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

^aGrade based on criteria form 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 ^cN=699-974; all patients with laboratory or non-laboratory data.

Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine ^a

Laboratory Abnormalityb	Gemcitabinec
	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

^aGrade based on criteria from WHO.

^bRegardless of causality. ^cN=699-974; all patients with laboratory or non-laboratory data.

Additional adverse reactions include the following:

• Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%)
• Edema: Edema (13%), peripheral edema (20%), and 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.

Tables 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^a

Adverse Reactionsb	Gemcitabine/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

^aGrade based on criteria from the World Health Organization (WHO). ^bRegardless of causality.

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

Laboratory Abnormalityb	Gemcitabine/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 Transfusionc	38	-	-	15	-	-
Platelet Transfusionc	9	-	-	3	-	-

^a 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.

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 Cancer.

Tables 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/neoadjuvant 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^a

Adverse Reactionsb	Gemcitabine/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	0	<1	2	1	0

^a Grade based on National Cancer Institute CTC Version 2.0. ^b Non-laboratory events were graded only if assessed to be possibly drug-related.

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

Laboratory Abnormalityb	Gemcitabine/ 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

^a Grade based on National Cancer Institute CTC Version 2.0. ^b Regardless of causality.

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 Cancer Tables 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)]^a in Study 3^a

Adverse Reactionsb	Gemcitabine plus Cisplatinc			Cisplatind
	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
aGrade 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.

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

Laboratory Abnormalityb	Gemcitabine/Cisplatinc			Cisplatind
	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 Transfusione	39	-	-	13	-	-
Platelet Transfusionse	21	-	-	<1	-	-
Hepatic
Increased Transaminase	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	0	0	7	0	<1

^a 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.

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^a

Adverse Reactionsb	Gemcitabine / Cisplatinc			Etoposide / Cisplatind
	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
Edemae	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 syndromee	3	-	-	0	-	-
Dyspnea	1	0	1	3	0	0
a 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 cisplatin / etoposide patients with laboratory or non-laboratory data. e Flu-like syndrome and edema were not graded.

Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4^a

Laboratory Abnormalityb	Gemcitabine/Cisplatinc			Etoposide/Cisplatind
	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 Transfusione	29	-	-	21	-	-
Platelet Transfusione	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

^a 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.

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)