Gemcitabine Dailymed

Recent Major Changes Section

Warnings and Precautions, Hemolytic Uremic Syndrome (5.4)

6/2019

1indications And Usage

Gemcitabine 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)
• •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)
• •in combination with cisplatin for the treatment of non-small cell lung cancer. (1.3)
• •as a single agent for the treatment of pancreatic cancer. (1.4)

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.

2dosage And Administration

Gemcitabine 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)
• •Breast Cancer: 1250 mg/m² over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.2)
• •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)
• •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)

2.1 Ovarian Cancer

Recommended Dose and Schedule

The recommended dosage of Gemcitabine Injection is 1000 mg/m² 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 Modifications

Recommended 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 Day	Absolute Neutrophil Count (× 106/L)		Platelet Count (× 106/L)	Dosage Modification
Day 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

Absolute neutrophil count less than 500 × 10⁶/L for more than 5 days or

Absolute neutrophil count less than 100 × 10⁶/L for more than 3 days or

Febrile neutropenia or

Platelets less than 25,000 × 10⁶/L

Cycle delay for more than one week due to toxicity

Table 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian Cancer

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•

•

•

•

Occurrence	Myelosuppression During Treatment Cycle	Dosage Modification
Initial Occurrence
Permanently reduce Gemcitabine Injection to 800 mg/m2 on Days 1 and 8
Subsequent Occurrence	If any of the above toxicities occur after the initial dose reduction	Permanently reduce Gemcitabine Injection dose to 800 mg/m2 on Day 1 only

2.2 Breast Cancer

Recommended Dose and Schedule

The recommended dosage of Gemcitabine Injection is 1250 mg/m² intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m² administered as a 3-hour intravenous infusion on Day 1 before Gemcitabine Injection administration. Refer to paclitaxel prescribing information for additional information.

Dosage Modifications

Recommended 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 Day	Absolute Neutrophil Count (× 106/L)		Platelet Count (× 106/L)	Dosage Modification
Day 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

2.3 Non-Small Cell Lung Cancer

Recommended Dose and Schedule

28-day schedule

The recommended dosage of Gemcitabine Injection is 1000 mg/m² intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m² administered intravenously on Day 1 after Gemcitabine Injection administration.

21-day schedule

The recommended dosage of Gemcitabine Injection is 1250 mg/m² intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m² administered intravenously on Day 1 after Gemcitabine Injection administration.

Refer to cisplatin prescribing information for additional information.

Dosage Modifications

Recommended 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)].

2.4 Pancreatic Cancer

Recommended Dose and Schedule

The recommended dosage of Gemcitabine Injection is 1000 mg/m² 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 Modifications

Recommended 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 (× 106/L)		Platelet Count (× 106/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

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.

Preparation for Intravenous Infusion Administration

• •Withdraw 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/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.

• •Schedule-Dependent Toxicity: Increased toxicity with infusion time greater than 60 minutes or dosing more frequently than once weekly. (5.1)
• •Myelosuppression: Monitor for myelosuppression prior to each cycle and reduce or withhold dose for severe myelosuppression. (5.2)
• •Pulmonary Toxicity and Respiratory Failure: Discontinue Gemcitabine Injection for unexplained dyspnea or other evidence of severe pulmonary toxicity. (5.3)
• •Hemolytic Uremic Syndrome (HUS): Monitor renal function prior to initiation and during treatment. Discontinue Gemcitabine Injection for HUS or severe renal impairment. (5.4)
• •Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5)
• •Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential to use effective contraception. (5.6, 8.1)
• •Exacerbation of Radiation Therapy Toxicity: May cause severe and life-threatening toxicity when administered during or within 7 days of radiation therapy. (5.7)
• •Capillary Leak Syndrome: Discontinue Gemcitabine Injection. (5.8)
• •Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue Gemcitabine Injection. (5.9)

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 Injection 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 [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 Injection 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 Injection 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 Injection and periodically during treatment. Permanently discontinue Gemcitabine Injection in patients who develop severe hepatic toxicity.

5.6 Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, Gemcitabine Injection 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 Injection 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 Injection 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.

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 1000 mg/m² 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.

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 Injection 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 Injection 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)]

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 Hospira, Inc. at 1-800-441-4100 or ProductComplaintsPP@hospira.com, 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 GemcitabineGrade based on criteria from the World Health Organization (WHO).

Adverse Reactions For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related.	Gemcitabine N=699–974; all patients with laboratory or non-laboratory data.
	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 GemcitabineGrade based on criteria from WHO.

Laboratory Abnormality Regardless of causality.	Gemcitabine N=699–974; all patients with laboratory or non-laboratory data.
	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, insomnia, rhinitis, sweating, and/or malaise (19%)
• •Infection: Sepsis (<1%)
• •Extravasation: Injection-site reactions (4%)
• •Allergic: Bronchospasm (<2%); anaphylactoid reactions

Ovarian Cancer

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 1Grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0.

Adverse Reactions Regardless of causality.	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

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 1Grade based on National Cancer Institute CTC Version 2.0.

Laboratory Abnormality Regardless of causality.	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 TransfusionPercent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.	38	-	-	15	-	-
    Platelet Transfusion	9	-	-	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 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/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 2Grade based on National Cancer Institute CTC Version 2.0.

Adverse Reactions Non-laboratory events were graded only if assessed to be possibly drug-related.	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	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 2Grade based on National Cancer Institute CTC Version 2.0.

Laboratory Abnormality Regardless of causality.	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

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)] in Study 3Grade based on National Cancer Institute CTC.

Adverse Reactions Non-laboratory events were graded only if assessed to be possibly drug-related.	Gemcitabine/Cisplatin N=217–253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.			Cisplatin N=213–248; all cisplatin patients with laboratory or non-laboratory data.
	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 3Grade based on National Cancer Institute CTC.

Laboratory Abnormality Regardless of causality.	Gemcitabine/Cisplatin N=217–253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.			Cisplatin N=213–248; all cisplatin patients with laboratory or non-laboratory data.
	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 TransfusionPercent of patients receiving transfusions. Percent transfusions are not CTC-graded events.	39	-	-	13	-	-
  Platelet Transfusions	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	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 4Grade based on criteria from WHO.

Adverse Reactions Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.	Gemcitabine/Cisplatin N=67–69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.			Etoposide/Cisplatin N=57–63; all etoposide/cisplatin patients with laboratory or non-laboratory data.
	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
  EdemaFlu-like syndrome and edema were not graded.	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	3	-	-	0	-	-
  Dyspnea	1	0	1	3	0	0

Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4Grade based on criteria from WHO.

Laboratory Abnormality Regardless of causality.	Gemcitabine/Cisplatin N=67–69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.			Etoposide/Cisplatin N=57–63; all etoposide/cisplatin patients with laboratory or non-laboratory data.
	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 TransfusionPercent of patients receiving transfusions. WHO Grading scale not applicable to proportion patients with transfusions.	29	-	-	21	-	-
  Platelet Transfusion	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

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)