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GEMCITABINE - SOLUTION (gemcitabine injection) Adverse Reactions

6 ADVERSE REACTIONS

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

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*
Adverse Reactions Gemcitabine
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on criteria from the World Health Organization (WHO).
For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related.
N=699–974; all patients with laboratory or non-laboratory data.
  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*
Laboratory Abnormality Gemcitabine
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on criteria from WHO.
Regardless of causality.
N=699–974; all patients with laboratory or non-laboratory data.
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 1*
Adverse Reactions Gemcitabine/Carboplatin
(N=175)
Carboplatin
(N=174)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0.
Regardless of causality.
  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*
Laboratory Abnormality Gemcitabine/Carboplatin
(N=175)
Carboplatin
(N=174)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
Regardless of causality.
Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.
  Hematologic
    Neutropenia 90 42 29 58 11 1
    Anemia 86 22 6 75 9 2
    Thrombocytopenia 78 30 5 57 10 1
    RBC Transfusion 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 2*
Adverse Reactions Gemcitabine/Paclitaxel
(N=262)
Paclitaxel
(N=259)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
Non-laboratory events were graded only if assessed to be possibly drug-related.
  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*
Laboratory Abnormality Gemcitabine/ Paclitaxel
(N=262)
Paclitaxel
(N=259)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on National Cancer Institute CTC Version 2.0.
Regardless of causality.
  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 3*
Adverse Reactions Gemcitabine/Cisplatin Cisplatin§
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on National Cancer Institute CTC.
Non-laboratory events were graded only if assessed to be possibly drug-related.
N=217–253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=213–248; all cisplatin patients with laboratory or non-laboratory data.
  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*
Laboratory Abnormality Gemcitabine/Cisplatin Cisplatin§
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on National Cancer Institute CTC.
Regardless of causality.
N=217–253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=213–248; all cisplatin patients with laboratory or non-laboratory data.
Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
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 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 4*
Adverse Reactions Gemcitabine/Cisplatin Etoposide/Cisplatin§
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on criteria from WHO.
Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.
N=67–69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=57–63; all etoposide/cisplatin patients with laboratory or non-laboratory data.
Flu-like syndrome and edema were not graded.
  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 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 4*
Laboratory Abnormality Gemcitabine/Cisplatin Etoposide/Cisplatin§
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
*
Grade based on criteria from WHO.
Regardless of causality.
N=67–69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
§
N=57–63; all etoposide/cisplatin patients with laboratory or non-laboratory data.
Percent of patients receiving transfusions. WHO Grading scale not applicable to proportion patients with transfusions.
Hematologic
  Anemia 88 22 0 77 13 2
  Neutropenia 88 36 28 87 20 56
  Thrombocytopenia 81 39 16 45 8 5
  RBC Transfusion 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)

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