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Gemzar (Gemcitabine Hydrochloride) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in another section of the label

  • Schedule-dependent Toxicity [see Warnings and Precautions ]
  • Myelosuppression [see Warnings and Precautions]
  • Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions ]
  • Hemolytic Uremic Syndrome [see Warnings and Precautions]
  • Hepatic Toxicity [see Warnings and Precautions ]
  • Embryofetal Toxicity [see Warnings and Precautions (5.6), Use in Specific Populations (8.1), and Nonclinical Toxicology]
  • Exacerbation of Radiation Toxicity [see Warnings and Precautions ]
  • Capillary Leak Syndrome [see Warnings and Precautions]
  • Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions ]

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 clinical practice.

Single-Agent Use:

The data described below reflect exposure to Gemzar as a single agent administered at doses between 800 mg/m2 to 1250 mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥20%) adverse reactions of single-agent Gemzar are nausea/vomiting, anemia, increased ALT, increased 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, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued Gemzar due to adverse reactions. Adverse reactions resulting in discontinuation of Gemzar in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemzar in less than 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.

Table 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent Gemzar across 5 clinical trials. Table 5 includes all clinical adverse reactions, reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table.

Table 5: Selected Per-Patient Incidence of Adverse Events in Patients Receiving Single-Agent Gemzara

a Grade based on criteria from the World Health Organization (WHO).

b N=699-974; all patients with laboratory or non-laboratory data.

c Regardless of causality.

d For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related.

All Patients b
All Grades Grade 3 Grade 4
Laboratory c
     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
Non-laboratory d
     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

  • Transfusion requirements — Red blood cell transfusions (19%); platelet transfusions (<1%)
  • Fever — Fever occurred in the absence of clinical infection and frequently in combination with other flu-like symptoms.
  • Pulmonary — Dyspnea unrelated to underlying disease and sometimes accompanied by bronchospasm.
  • Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%); <1% of patients. discontinued Gemzar due to edema.
  • Flu-like Symptoms — Characterized by fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating, and/or malaise (19%); <1% of patients discontinued Gemzar due to flu-like symptoms
  • Infection — Sepsis (<1%)
  • Extravasation — Injection-site reactions (4%)
  • Allergic — Bronchospasm (<2%); anaphylactoid reactions [see Contraindications (4)].

Non-Small Cell Lung Cancer:

Table 6 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=262) administered in 28-day cycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies ].

Patients randomized to Gemzar plus cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin 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 Gemzar plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the Gemzar plus 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 6: Per-Patient Incidence of Selected Adverse Reactions from Randomized Trial of Gemzar plus Cisplatin versus Single-Agent Cisplatin in Patients with NSCLC Occurring at Higher Incidence in Gemzar-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]a

a National Cancer Institute Common Toxicity Criteria (CTC) for severity grading.

b N=217-253; all Gemzar plus cisplatin patients with laboratory or non-laboratory data Gemzar at 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days.

c N=213-248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days.

d Regardless of causality.

e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.

f Non-laboratory events were graded only if assessed to be possibly drug-related.

Gemzar plus Cisplatin b Cisplatin c
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
Laboratory d
       Hematologic
         Anemia 89 22 3 67 6 1
         RBC Transfusione 39 13
         Neutropenia 79 22 35 20 3 1
         Thrombocytopenia 85 25 25 13 3 1
         Platelet Transfusionse 21 <1
         Lymphopenia 75 25 18 51 12 5
     Hepatic
         Increased Transaminases 22 2 1 10 1 0
         Increased Alkaline Phosphatase 19 1 0 13 0 0
     Renal
         Proteinuria 23 0 0 18 0 0
         Hematuria 15 0 0 13 0 0
         Elevated creatinine 38 4 <1 31 2 <1
     Other Laboratory
         Hyperglycemia 30 4 0 23 3 0
         Hypomagnesemia 30 4 3 17 2 0
         Hypocalcemia 18 2 0 7 0 <1
Non-laboratory f
     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 7 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=69) administered in 21-day cycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies ]. A listing of clinically significant adverse reactions is provided following the table.

Patients in the Gemzar 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 treatment-related adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients 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 Gemzar/cisplatin arm.

Table 7: Per-Patient Incidence of Selected Adverse Reactions in Randomized Trial of Gemzar plus Cisplatin versus Etoposide plus Cisplatin in Patients with NSCLCa

a Grade based on criteria from the World Health Organization (WHO).

b N=67-69; all Gemzar plus cisplatin patients with laboratory or non-laboratory data. Gemzar at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days.

c N=57-63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days.

d Regardless of causality.

e WHO grading scale not applicable to proportion of patients with transfusions.

f Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.

g Flu-like syndrome and edema were not graded.

Gemzar plus Cisplatin b Etoposide plus Cisplatin c
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
Laboratory d
     Hematologic
         Anemia 88 22 0 77 13 2
         RBC Transfusionse 29 - - 21 - -
         Neutropenia 88 36 28 87 20 56
         Thrombocytopenia 81 39 16 45 8 5
         Platelet Transfusionse 3 - - 8 - -
     Hepatic
         Increased ALT 6 0 0 12 0 0
         Increased AST 3 0 0 11 0 0
         Increased Alkaline Phosphatase 16 0 0 11 0 0
         Bilirubin 0 0 0 0 0 0
     Renal
         Proteinuria 12 0 0 5 0 0
         Hematuria 22 0 0 10 0 0
         BUN 6 0 0 4 0 0
         Creatinine 2 0 0 2 0 0
Non-laboratory f
         Nausea and Vomiting 96 35 4 86 19 7
         Fever 6 0 0 3 0 0
         Rash 10 0 0 3 0 0
         Dyspnea 1 0 1 3 0 0
         Diarrhea 14 1 1 13 0 2
         Hemorrhage 9 0 3 3 0 3
         Infection 28 3 1 21 8 0
         Alopecia 77 13 0 92 51 0
         Stomatitis 20 4 0 18 2 0
         Somnolence 3 0 0 3 2 0
         Paresthesias 38 0 0 16 2 0
         Flu-like syndromeg 3 - - 0 - -
         Edemag 12 - - 2 - -

Breast Cancer

Table 8 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus paclitaxel arm, reported in a randomized trial of Gemzar plus 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].

The requirement for dose reduction of paclitaxel were higher for patients in the Gemzar/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.

Table 8: Per-Patient Incidence of Selected Adverse Reactions from Comparative Trial of Gemzar plus Paclitaxel versus Single-Agent Paclitaxel in Breast Cancera Occurring at Higher Incidence in Gemzar-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]

a Severity grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0.

b Regardless of causality.

c Non-laboratory events were graded only if assessed to be possibly drug-related.

Gemzar plus Paclitaxel
(N=262)
Paclitaxel
(N=259)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
Laboratory b
     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
Non-laboratory c
     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

Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the Gemzar plus paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).

Ovarian Cancer

Table 9 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the Gemzar plus carboplatin arm, reported in a randomized trial of Gemzar plus 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 less than 10% of patients, are provided following Table 9.

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 treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for Gemzar occurred in 10.4% of patients and Gemzar dose was omitted in 13.7% of patients in the Gemzar /carboplatin arm.

Table 9: Per-Patient Incidence of Adverse Reactions in Randomized Trial of Gemzar plus Carboplatin versus Carboplatin in Ovarian Cancera Occurring at Higher Incidence in Gemzar-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]

a Grade based on Common Toxicity Criteria (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.

Gemzar plus Carboplatin
(N=175)
Carboplatin
(N=174)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
Laboratory b
     Hematologic
         Neutropenia 90 42 29 58 11 1
         Anemia 86 22 6 75 9 2
         Thrombocytopenia 78 30 5 57 10 1
         RBC Transfusionsc 38 15
         Platelet Transfusionsc 9 3
Non-laboratory b
     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

Hematopoietic growth factors were administered more frequently in the Gemzar-containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%).

The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the Gemzar plus 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).

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Gemzar. 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.

Cardiovascular — Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias

Vascular Disorders — Peripheral vasculitis, gangrene, and capillary leak syndrome [see Warnings and Precautions ]

Skin — Cellulitis, severe skin reactions, including desquamation and bullous skin eruptions

Hepatic — Hepatic failure, hepatic veno-occlusive disease

Pulmonary — Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS)

Nervous System — Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions]



REPORTS OF SUSPECTED GEMZAR SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Gemzar. The information is not vetted and should not be considered as verified clinical evidence.

Possible Gemzar side effects / adverse reactions in 72 year old female

Reported by a physician from Colombia on 2011-10-03

Patient: 72 year old female

Reactions: Neoplasm Progression

Adverse event resulted in: death

Suspect drug(s):
Gemzar

Other drugs received by patient: Cisplatin



Possible Gemzar side effects / adverse reactions in 47 year old female

Reported by a physician from Greece on 2011-10-04

Patient: 47 year old female weighing 69.0 kg (151.8 pounds)

Reactions: Constipation

Adverse event resulted in: hospitalization

Suspect drug(s):
Gemzar
    Dosage: 800 mg, every 2 weeks
    Indication: Pancreatic Carcinoma Metastatic
    Start date: 2011-06-07

Temsirolimus
    Dosage: 25 mg, weekly
    Indication: Pancreatic Carcinoma Recurrent
    Start date: 2011-06-07

Other drugs received by patient: Dexamethasone; Zantac; Zofron; Primperan TAB; Fenistil; Cilroton; Laprazol



Possible Gemzar side effects / adverse reactions in 72 year old male

Reported by a consumer/non-health professional from United States on 2011-10-06

Patient: 72 year old male weighing 71.0 kg (156.2 pounds)

Reactions: Dyspnoea, Chest Pain, Acute Myocardial Infarction, Paraesthesia

Adverse event resulted in: hospitalization

Suspect drug(s):
Erbitux
    Dosage: drug interrupted on 12nov2010(57dy)no of infisions:7 held on:18nov10,resumed on 3dec10
    Indication: non-Small Cell Lung Cancer
    Start date: 2010-09-17

Carboplatin
    Dosage: drug interrupted on 12nov2010(57dy).no of infisions:3 held on:18nov10
    Indication: non-Small Cell Lung Cancer
    Start date: 2010-09-17

Gemzar
    Dosage: drug interrupted on 12nov2010(57dy)no of infisions:5 held on:18nov10,resumed on 3dec10
    Indication: non-Small Cell Lung Cancer
    Start date: 2010-09-17

Other drugs received by patient: Coumadin; Enalapril Maleate; Amiodarone HCL; Lipitor; Esomeprazole Sodium; Plavix; Tamsulosin HCL; Budesonide; Amlodipine; Simvastatin; Nexium; Magnesium; Fluticasone Propionate; Salmeterol Xinafoate; Formoterol Fumarate; Digoxin; Atorvastatin; Furosemide; Advair Diskus 100/50; Symbicort; Lisinopril; Atenolol



See index of all Gemzar side effect reports >>

Drug label data at the top of this Page last updated: 2014-06-10

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