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GEMCITABINE - SOLUTION Adverse Reactions (gemcitabine injection)

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 ReactionsGemcitabine
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 Vomiting69131
  Fever4120
  Rash30<10
  Dyspnea233<1
  Diarrhea1910
  Hemorrhage17<1<1
  Infection161<1
  Alopecia15<10
  Stomatitis11<10
  Somnolence11<1<1
  Paresthesias10<10
Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine*
Laboratory AbnormalityGemcitabine
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
  Anemia6871
  Neutropenia63196
  Thrombocytopenia2441
Hepatic
  Increased ALT6882
  Increased AST6762
  Increased Alkaline Phosphatase5572
  Hyperbilirubinemia132<1
Renal
  Proteinuria45<10
  Hematuria35<10
  Increased BUN1600
  Increased Creatinine8<10

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 ReactionsGemcitabine/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.
  Nausea69606130
  Alopecia49001700
  Vomiting4660362<1
  Constipation42613730
  Fatigue403<13250
  Diarrhea253014<10
  Stomatitis/Pharyngitis22<101300
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 AbnormalityGemcitabine/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
    Neutropenia90422958111
    Anemia862267592
    Thrombocytopenia7830557101
    RBC Transfusion38--15--
    Platelet Transfusion9--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 ReactionsGemcitabine/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.
  Alopecia9014492193
  Neuropathy-Sensory645<15830
  Nausea50103120
  Fatigue406<1281<1
  Vomiting29201520
  Diarrhea20301320
  Anorexia170012<10
  Neuropathy-Motor152<110<10
  Stomatitis/Pharyngitis131<18<10
  Fever13<10300
  Rash/Desquamation11<1<1500
  Febrile Neutropenia65<1210
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 AbnormalityGemcitabine/ 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
    Anemia6961513<1
    Neutropenia6931173147
    Thrombocytopenia265<17<1<1
  Hepatobiliary
    Increased ALT185<16<10
    Increased AST16205<10

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 ReactionsGemcitabine/CisplatinCisplatin§
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.
  Nausea932528720<1
  Vomiting78111271109
  Alopecia53103300
  Neuro Motor351201530
  Diarrhea24221300
  Neuro Sensory23101810
  Infection18321210
  Fever1600500
  Neuro Cortical1631910
  Neuro Mood16101010
  Local1500600
  Neuro Headache1400700
  Stomatitis1410500
  Hemorrhage1410400
  Hypotension1210710
  Rash1100300
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 AbnormalityGemcitabine/CisplatinCisplatin§
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
  Anemia892236761
  Thrombocytopenia8525251331
  Neutropenia7922352031
  Lymphopenia75251851125
  RBC Transfusion39--13--
  Platelet Transfusions21--<1--
Hepatic
  Increased Transaminase22211010
  Increased Alkaline Phosphatase19101300
Renal
  Increased Creatinine384<1312<1
  Proteinuria23001800
  Hematuria15001300
Other Laboratory
  Hyperglycemia30402330
  Hypomagnesemia30431720
  Hypocalcemia182070<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 ReactionsGemcitabine/CisplatinEtoposide/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 Vomiting9635486197
  Alopecia7713092510
  Paresthesias38001620
  Infection28312180
  Stomatitis20401820
  Diarrhea14111302
  Edema12--2--
  Rash1000300
  Hemorrhage903303
  Fever600300
  Somnolence300320
  Flu-like Syndrome3--0--
  Dyspnea101300
Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4*
Laboratory AbnormalityGemcitabine/CisplatinEtoposide/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
  Anemia8822077132
  Neutropenia883628872056
  Thrombocytopenia8139164585
  RBC Transfusion29--21--
  Platelet Transfusion3--8--
Hepatic
  Increased Alkaline Phosphatase16001100
  Increased ALT6001200
  Increased AST3001100
Renal
  Hematuria22001000
  Proteinuria1200500
  Increased BUN600400
  Increased Creatinine200200

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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