A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Gemzar Side Effects, and Drug Interactions - Gemcitabine Hcl
Gemzar Side Effects, and Drug Interactions - Gemcitabine Hcl
SIDE EFFECTS
Gemzar has been used in a wide variety of malignancies, both
as a single-agent and in combination with other cytotoxic drugs.
Single-Agent Use : Myelosuppression is the principal
dose-limiting toxicity with Gemzar therapy. Dosage adjustments for hematologic
toxicity are frequently needed and are described in the DOSAGE
AND ADMINISTRATION section.
The data in Table 5 are based on 979 patients receiving Gemzar
as a single-agent administered weekly as a 30-minute infusion for treatment
of a wide variety of malignancies. The Gemzar starting doses ranged from 800
to 1250 mg/m2. Data are also shown for the subset of patients with
pancreatic cancer treated in 5 clinical studies. The frequency of all grades
and severe (WHO Grade 3 or 4) adverse events were generally similar in the single-agent
safety database of 979 patients and the subset of patients with pancreatic cancer.
Adverse reactions reported in the single-agent safety database resulted in discontinuation
of Gemzar therapy in about 10% of patients. In the comparative trial in pancreatic
cancer, the discontinuation rate for adverse reactions was 14.3% for the gemcitabine
arm and 4.8% for the 5-FU arm.
All WHO-graded laboratory events are listed in Table 5, regardless
of causality. Non-laboratory adverse events listed in Table 5 or discussed below
were those reported, regardless of causality, for at least 10% of all patients,
except the categories of Extravasation, Allergic, and Cardiovascular and certain
specific events under the Renal, Pulmonary, and Infection categories. Table
6 presents the data from the comparative trial of Gemzar and 5-FU in pancreatic
cancer for the same adverse events as those in Table 5, regardless of incidence.
|
Table 5: Selected WHO-Graded Adverse Events in Patients
Receiving Single-Agent Gemzar WHO Grades (% incidence)
|
| |
All Patientsa
|
Pancreatic Cancer Patientsb
|
Discontinuations (%)c
|
|
|
All
|
Grade
|
Grade
|
All
|
Grade
|
Grade
|
All
|
|
Grades
|
3
|
4
|
Grades
|
3
|
4
|
Patients
|
|
Laboratoryd
|
|
|
|
|
|
|
|
|
Hematologic
|
|
|
|
|
|
|
|
|
Anemia
|
68
|
7
|
1
|
73
|
8
|
2
|
<1
|
|
Leukopenia
|
62
|
9
|
<1
|
64
|
8
|
1
|
<1
|
|
Neutropenia
|
63
|
19
|
6
|
61
|
17
|
7
|
-
|
|
Thrombocytopenia
|
24
|
4
|
1
|
36
|
7
|
<1
|
<1
|
|
Hepatic
|
|
|
|
|
|
|
<1
|
|
ALT
|
68
|
8
|
2
|
72
|
10
|
1
|
|
|
AST
|
67
|
6
|
2
|
78
|
12
|
5
|
|
|
Alkaline
|
|
|
|
|
|
|
|
|
Phosphatase
|
55
|
7
|
2
|
77
|
16
|
4
|
|
|
Bilirubin
|
13
|
2
|
<1
|
26
|
6
|
2
|
|
|
Renal
|
|
|
|
|
|
|
<1
|
|
Proteinuria
|
45
|
<1
|
0
|
32
|
<1
|
0
|
|
|
Hematuria
|
35
|
<1
|
0
|
23
|
0
|
0
|
|
|
BUN
|
16
|
0
|
0
|
15
|
0
|
0
|
|
|
Creatinine
|
8
|
<1
|
0
|
6
|
0
|
0
|
|
|
Non-laboratorye
|
|
|
|
|
|
|
|
|
Nausea and Vomiting
|
69
|
13
|
1
|
71
|
10
|
2
|
<1
|
|
Pain
|
48
|
9
|
<1
|
42
|
6
|
<1
|
<1
|
|
Fever
|
41
|
2
|
0
|
38
|
2
|
0
|
<1
|
|
Rash
|
30
|
<1
|
0
|
28
|
<1
|
0
|
<1
|
|
Dyspnea
|
23
|
3
|
<1
|
10
|
0
|
<1
|
<1
|
|
Constipation
|
23
|
1
|
<1
|
31
|
3
|
<1
|
0
|
|
Diarrhea
|
19
|
1
|
0
|
30
|
3
|
0
|
0
|
|
Hemorrhage
|
17
|
<1
|
<1
|
4
|
2
|
<1
|
<1
|
|
Infection
|
16
|
1
|
<1
|
10
|
2
|
<1
|
<1
|
|
Alopecia
|
15
|
<1
|
0
|
16
|
0
|
0
|
0
|
|
Stomatitis
|
11
|
<1
|
0
|
10
|
<1
|
0
|
<1
|
|
Somnolence
|
11
|
<1
|
<1
|
11
|
2
|
<1
|
<1
|
|
Paresthesias
|
10
|
<1
|
0
|
10
|
<1
|
0
|
0
|
|
Grade based on criteria from the World Health Organization
(WHO).
|
|
a N=699-974; all patients with laboratory
or non-laboratory data.
|
|
b N=161-241; all pancreatic cancer patients
with laboratory or non-laboratory data.
|
|
c N=979.
|
|
d Regardless of causality.
|
|
e Table includes non-laboratory data with
incidence for all patients 10%. For approximately 60% of the patients,
non-laboratory events were graded only if assessed to be possibly drug-related.
|
|
Table 6: Selected WHO-Graded Adverse Events from Comparative
Trial of Gemzar and 5-FU in Pancreatic Cancer WHO Grades (% incidence)
|
| |
Gemzara
|
|
5-FUb
|
|
| |
All
|
Grade
|
Grade
|
All
|
Grade
|
Grade
|
| |
Grades
|
3
|
4
|
Grades
|
3
|
4
|
|
Laboratoryc
|
|
|
|
|
|
|
|
Hematologic
|
|
|
|
|
|
|
|
Anemia
|
65
|
7
|
3
|
45
|
0
|
0
|
|
Leukopenia
|
71
|
10
|
0
|
15
|
2
|
0
|
|
Neutropenia
|
62
|
19
|
7
|
18
|
2
|
3
|
|
Thrombocytopenia
|
47
|
10
|
0
|
15
|
2
|
0
|
|
Hepatic
|
|
|
|
|
|
|
|
ALT
|
72
|
8
|
2
|
38
|
0
|
0
|
|
AST
|
72
|
10
|
2
|
52
|
2
|
0
|
|
Alkaline
|
|
|
|
|
|
|
|
Phosphatase
|
71
|
16
|
0
|
64
|
10
|
3
|
|
Bilirubin
|
16
|
2
|
2
|
25
|
6
|
3
|
|
Renal
|
|
|
|
|
|
|
|
Proteinuria
|
10
|
0
|
0
|
2
|
0
|
0
|
|
Hematuria
|
13
|
0
|
0
|
0
|
0
|
0
|
|
BUN
|
8
|
0
|
0
|
10
|
0
|
0
|
|
Creatinine
|
2
|
0
|
0
|
0
|
0
|
0
|
|
Non-laboratoryd
|
|
|
|
|
|
|
|
Nausea and Vomiting
|
64
|
10
|
3
|
58
|
5
|
0
|
|
Pain
|
10
|
2
|
0
|
7
|
0
|
0
|
|
Fever
|
30
|
0
|
0
|
16
|
0
|
0
|
|
Rash
|
24
|
0
|
0
|
13
|
0
|
0
|
|
Dyspnea
|
6
|
0
|
0
|
3
|
0
|
0
|
|
Constipation
|
10
|
3
|
0
|
11
|
2
|
0
|
|
Diarrhea
|
24
|
2
|
0
|
31
|
5
|
0
|
|
Hemorrhage
|
0
|
0
|
0
|
2
|
0
|
0
|
|
Infection
|
8
|
0
|
0
|
3
|
2
|
0
|
|
Alopecia
|
18
|
0
|
0
|
16
|
0
|
0
|
|
Stomatitis
|
14
|
0
|
0
|
15
|
0
|
0
|
|
Somnolence
|
5
|
2
|
0
|
7
|
2
|
0
|
|
Paresthesias
|
2
|
0
|
0
|
2
|
0
|
0
|
|
Grade based on criteria from the World Health Organization
(WHO).
|
|
a N=58-63; all Gemzar patients with laboratory
or non-laboratory data.
|
|
b N=61-63; all 5-FU patients with laboratory
or non-laboratory data.
|
|
c Regardless of causality.
|
|
d Non-laboratory events were graded only if
assessed to be possibly drug-related.
|
Hematologic : In studies in pancreatic cancer myelosuppression
is the dose-limiting toxicity with Gemzar, but <1% of patients discontinued
therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions
were required by 19% of patients. The incidence of sepsis was less than 1%.
Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16%
of patients; less than 1% of patients required platelet transfusions. Patients
should be monitored for myelosuppression during Gemzar therapy and dosage modified
or suspended according to the degree of hematologic toxicity (see DOSAGE
AND ADMINISTRATION).
Gastrointestinal : Nausea and vomiting were commonly
reported (69%) but were usually of mild to moderate severity. Severe nausea
and vomiting (WHO Grade 3/4) occurred in <15% of patients. Diarrhea was reported
by 19% of patients, and stomatitis by 11% of patients.
Hepatic : In clinical trials, Gemzar was associated
with transient elevations of one or both serum transaminases in approximately
70% of patients, but there was no evidence of increasing hepatic toxicity with
either longer duration of exposure to Gemzar or with greater total cumulative
dose. Serious hepatotoxicity, including liver failure and death, has been reported
very rarely in patients receiving Gemzar alone or in combination with other
potentially hepatotoxic drugs (see Hepatic under Post-marketing experience).
Renal : In clinical trials, mild proteinuria and hematuria
were commonly reported. Clinical findings consistent with the Hemolytic Uremic
Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving Gemzar
in clinical trials. Four patients developed HUS on Gemzar therapy, 2 immediately
post-therapy. The diagnosis of HUS should be considered if the patient develops
anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or
LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure
(elevation of serum creatinine or BUN). Gemzar therapy should be discontinued
immediately. Renal failure may not be reversible even with discontinuation of
therapy and dialysis may be required (see Renal under Post-marketing
experience).
Fever : The overall incidence of fever was 41%. This
is in contrast to the incidence of infection (16%) and indicates that Gemzar
may cause fever in the absence of clinical infection. Fever was frequently associated
with other flu-like symptoms and was usually mild and clinically manageable.
Rash : Rash was reported in 30% of patients. The rash
was typically a macular or finely granular maculopapular pruritic eruption of
mild to moderate severity involving the trunk and extremities. Pruritus was
reported for 13% of patients.
Pulmonary : In clinical trials, dyspnea, unrelated to
underlying disease, has been reported in association with Gemzar therapy. Dyspnea
was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported
with the use of Gemzar (see Pulmonary under Post-marketing experience).
The etiology of these effects is unknown. If such effects develop, Gemzar should
be discontinued. Early use of supportive care measures may help ameliorate these
conditions.
Edema : Edema (13%), peripheral edema (20%), and generalized
edema (<1%) were reported. Less than 1% of patients discontinued due to edema.
Flu-like Symptoms : "Flu syndrome" was reported
for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache,
cough, chills, and myalgia were commonly reported. Fever and asthenia were also
reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and
malaise were reported infrequently. Less than 1% of patients discontinued due
to flu-like symptoms.
Infection : Infections were reported for 16% of patients.
Sepsis was rarely reported (<1%).
Alopecia : Hair loss, usually minimal, was reported
by 15% of patients.
Neurotoxicity : There was a 10% incidence of mild paresthesias
and a <1% rate of severe paresthesias.
Extravasation : Injection-site related events were reported
for 4% of patients. There were no reports of injection site necrosis. Gemzar
is not a vesicant.
Allergic : Bronchospasm was reported for less than 2%
of patients. Anaphylactoid reaction has been reported rarely. Gemzar should
not be administered to patients with a known hypersensitivity to this drug (see
CONTRAINDICATION).
Cardiovascular : During clinical trials, 2% of patients
discontinued therapy with Gemzar due to cardiovascular events such as myocardial
infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of
these patients had a prior history of cardiovascular disease (see Cardiovascular
under Post-marketing experience).
Combination Use in Non-Small Cell Lung Cancer: In the
Gemzar plus cisplatin vs. cisplatin study, dose adjustments occurred with 35%
of Gemzar injections and 17% of cisplatin injections on the combination arm,
versus 6% on the cisplatin-only arm. Dose adjustments were required in greater
than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations
for possibly drug-related adverse events occurred in 15% of patients on the
combination arm and 8% of patients on the cisplatin arm. With a median of 4
cycles of Gemzar plus cisplatin treatment, 94 of 262 patients (36%) experienced
a total of 149 hospitalizations due to possibly treatment-related adverse events.
With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced
78 hospitalizations due to possibly treatment-related adverse events.
In the Gemzar plus cisplatin vs. etoposide plus cisplatin study,
dose adjustments occurred with 20% of Gemzar injections and 16% of cisplatin
injections in the Gemzar plus cisplatin arm compared with 20% of etoposide injections
and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a
median of 5 cycles of Gemzar plus cisplatin treatment, 15 of 69 patients (22%)
experienced 15 hospitalizations due to possibly treatment-related adverse events.
With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients
(27%) experienced 22 hospitalizations due to possibly treatment-related adverse
events. In patients who completed more than one cycle, dose adjustments were
reported in 81% of the Gemzar plus cisplatin patients, compared with 68% on
the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related
adverse events occurred in 14% of patients on the Gemzar plus cisplatin arm
and in 8% of patients on the etoposide plus cisplatin arm. The incidence of
myelosuppression was increased in frequency with Gemzar plus cisplatin treatment
(~90%) compared to that with the Gemzar monotherapy
(~60%). With combination therapy Gemzar dosage adjustments
for hematologic toxicity were required more often while cisplatin dose adjustments
were less frequently required.
Table 7 presents the safety data from the Gemzar plus cisplatin
vs. cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria
(CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%)
possibly treatment-related deaths, including 3 resulting from myelosuppression
with infection and 1 case of renal failure associated with pancytopenia and
infection. No deaths due to treatment were reported on the cisplatin arm. Nine
cases of febrile neutropenia were reported on the combination therapy arm compared
to 2 on the cisplatin arm. More patients required RBC and platelet transfusions
on the Gemzar plus cisplatin arm.
Myelosuppression occurred more frequently on the combination
arm, and in 4 possibly treatment-related deaths myelosuppression was observed.
Sepsis was reported in 4% of patients on the Gemzar plus cisplatin arm compared
to 1% on the cisplatin arm. Platelet transfusions were required in 21% of patients
on the combination arm and <1% of patients on the cisplatin arm. Hemorrhagic
events occurred in 14% of patients on the combination arm and 4% on the cisplatin
arm. However, severe hemorrhagic events were rare. Red blood cell transfusions
were required in 39% of the patients on the Gemzar plus cisplatin arm, versus
13% on the cisplatin arm. The data suggest cumulative anemia with continued
Gemzar plus cisplatin use.
Nausea and vomiting despite the use of antiemetics occurred
slightly more often with Gemzar plus cisplatin therapy (78%) than with cisplatin
alone (71%). In studies with single-agent Gemzar, a lower incidence of nausea
and vomiting (58% to 69%) was reported. Renal function abnormalities, hypomagnesemia,
neuromotor, neurocortical, and neurocerebellar toxicity occurred more often
with Gemzar plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity
was similar on both arms.
Cardiac dysrrhythmias of Grade 3 or greater were reported in
7 (3%) patients treated with Gemzar plus cisplatin compared to one (<1%)
Grade 3 dysrrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia
were associated with one Grade 4 arrhythmia on the Gemzar plus cisplatin combination
arm.
Table 8 presents data from the randomized study of Gemzar plus
cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC for the
same WHO-graded adverse events as those in Table 6. One death (1.5%) was reported
on the Gemzar plus cisplatin arm due to febrile neutropenia associated with
renal failure which was possibly treatment-related. No deaths related to treatment
occurred on the etoposide plus cisplatin arm. The overall incidence of Grade
4 neutropenia on the Gemzar plus cisplatin arm was less than on the etoposide
plus cisplatin arm (28% vs. 56%). Sepsis was experienced by 2% of patients on
both treatment arms. Grade 3 anemia and Grade 3/4 thrombocytopenia were more
common on the Gemzar plus cisplatin arm. RBC transfusions were given to 29%
of the patients who received Gemzar plus cisplatin vs. 21% of patients who received
etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients
who received Gemzar plus cisplatin vs. 8% of patients who received etoposide
plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the Gemzar
plus cisplatin arm. On the Gemzar plus cisplatin arm, 7% of participants were
hospitalized due to febrile neutropenia compared to 12% on the etoposide plus
cisplatin arm. More than twice as many patients had dose reductions or omissions
of a scheduled dose of Gemzar as compared to etoposide, which may explain the
differences in the incidence of neutropenia and febrile neutropenia between
treatment arms. Flu syndrome was reported by 3% of patients on the Gemzar plus
cisplatin arm with none reported on the comparator arm. Eight patients (12%)
on the Gemzar plus cisplatin arm reported edema compared to 1 patient (2%) on
the etoposide plus cisplatin arm.
|
Table 7: Selected CTC-Graded Adverse Events from Comparative
Trial of Gemzar plus Cisplatin versus Single-Agent Cisplatin in NSCLC
CTC Grades (% incidence)
|
| |
Gemzar plus Cisplatina
|
Cisplatinb
|
| |
All
|
Grade
|
Grade
|
All
|
Grade
|
Grade
|
| |
Grades
|
3
|
4
|
Grades
|
3
|
4
|
|
Laboratoryc
|
|
|
|
|
|
|
|
Hematologic
|
|
|
|
|
|
|
|
Anemia
|
89
|
22
|
3
|
67
|
6
|
1
|
|
RBC Transfusiond
|
39
|
|
|
13
|
|
|
|
Leukopenia
|
82
|
35
|
11
|
25
|
2
|
1
|
|
Neutropenia
|
79
|
22
|
35
|
20
|
3
|
1
|
|
Thrombocytopenia
|
85
|
25
|
25
|
13
|
3
|
1
|
|
Platelet Transfusionsd
|
21
|
|
|
<1
|
|
|
|
Lymphocytes
|
75
|
25
|
18
|
51
|
12
|
5
|
|
Hepatic
|
|
|
|
|
|
|
|
Transaminase
|
22
|
2
|
1
|
10
|
1
|
0
|
|
Alkaline Phosphatase
|
19
|
1
|
0
|
13
|
0
|
0
|
|
Renal
|
|
|
|
|
|
|
|
Proteinuria
|
23
|
0
|
0
|
18
|
0
|
0
|
|
Hematuria
|
15
|
0
|
0
|
13
|
0
|
0
|
|
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-laboratorye
|
|
|
|
|
|
|
|
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
|
|
Constipation
|
28
|
3
|
0
|
21
|
0
|
0
|
|
Neuro Hearing
|
25
|
6
|
0
|
21
|
6
|
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
|
|
Dyspnea
|
12
|
4
|
3
|
11
|
3
|
2
|
|
Hypotension
|
12
|
1
|
0
|
7
|
1
|
0
|
|
Rash
|
11
|
0
|
0
|
3
|
0
|
0
|
|
Grade based on Common Toxicity Criteria (CTC). Table
includes data for adverse events with incidence ³10%
in either arm.
|
|
a 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.
|
|
b N=213-248; all cisplatin patients with laboratory
or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every
28 days.
|
|
c Regardless of causality.
|
|
d Percent of patients receiving transfusions.
Percent transfusions are not CTC-graded events.
|
|
e Non-laboratory events were graded only if
assessed to be possibly drug-related.
|
|
Table 8: Selected WHO-Graded Adverse Events from Comparative
Trial of Gemzar plus Cisplatin versus Etoposide plus Cisplatin in NSCLC
WHO Grades (% incidence)
|
|
|
Gemzar plus Cisplatina
|
Etoposide plus Cisplatinb
|
| |
All Grades
|
Grade 3
|
Grade 4
|
All Grades
|
Grade 3
|
Grade 4
|
|
Laboratoryc
|
|
|
|
|
|
|
|
Hematologic
|
|
|
|
|
|
|
|
Anemia
|
88
|
22
|
0
|
77
|
13
|
2
|
|
RBC Transfusionsd
|
29
|
|
|
21
|
|
|
|
Leukopenia
|
86
|
26
|
3
|
87
|
36
|
7
|
|
Neutropenia
|
88
|
36
|
28
|
87
|
20
|
56
|
|
Thrombocytopenia
|
81
|
39
|
16
|
45
|
8
|
5
|
|
Platelet Transfusionsd
|
3
|
|
|
8
|
|
|
|
Hepatic
|
|
|
|
|
|
|
|
ALT
|
6
|
0
|
0
|
12
|
0
|
0
|
|
AST
|
3
|
0
|
0
|
11
|
0
|
0
|
|
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-laboratorye,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
|
|
Constipation
|
17
|
0
|
0
|
15
|
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
|
|
Grade based on criteria from the World Health Organization
(WHO).
|
|
a 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.
|
|
b N=57-63; all cisplatin plus etoposide patients
with laboratory or non-laboratory data. Cisplatin at 100 mg/m2
on Day 1 and I.V. etoposide at 100 mg/m2 on Days 1, 2, and
3 every 21 days.
|
|
c Regardless of causality.
|
|
d Percent of patients receiving transfusions.
Percent transfusions are not WHO-graded events.
|
|
e Non-laboratory events were graded only if
assessed to be possibly drug-related.
|
|
f Pain data were not collected.
|
Combination Use in Breast Cancer: In the Gemzar plus
paclitaxel versus paclitaxel study, dose reductions occurred with 8% of Gemzar
injections and 5% of paclitaxel injections on the combination arm, versus 2%
on the paclitaxel arm. On the combination arm, 7% of Gemzar doses were omitted
and <1% of paclitaxel doses were omitted, compared to <1% of paclitaxel
doses on the paclitaxel arm. A total of 18 patients (7%) on the Gemzar plus
paclitaxel arm and 12 (5%) on the paclitaxel arm discontinued the study because
of adverse events. There were two deaths on study or within 30 days after study
drug discontinuation that were possibly drug-related, one on each arm.
Table 9 presents the safety data occurrences of ³10%
(all grades) from the Gemzar plus paclitaxel versus paclitaxel study in breast
cancer.
|
Table 9: Adverse Events from Comparative Trial of Gemzar
plus Paclitaxel versus Single-Agent Paclitaxel in Breast Cancera
CTC Grades (% incidence)
|
| |
Gemzar plus Paclitaxel (N=262)
|
Paclitaxel (N=259)
|
| |
| |
All
|
Grade
|
Grade
|
All
|
Grade
|
Grade
|
| |
Grades
|
3
|
4
|
Grades
|
3
|
4
|
|
Laboratoryb
|
|
|
|
|
|
|
|
Hematologic
|
|
|
|
|
|
|
|
Anemia
|
69
|
6
|
1
|
51
|
3
|
<1
|
|
Neutropenia
|
69
|
31
|
17
|
31
|
4
|
7
|
|
Thrombocytopenia
|
26
|
5
|
<1
|
7
|
<1
|
<1
|
|
Leukopenia
|
21
|
10
|
1
|
12
|
2
|
0
|
|
Hepatobiliary
|
|
|
|
|
|
|
|
ALT
|
18
|
5
|
<1
|
6
|
<1
|
0
|
|
AST
|
16
|
2
|
0
|
5
|
<1
|
0
|
|
Non-laboratoryc
|
|
|
|
|
|
|
|
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
|
|
Myalgia
|
33
|
4
|
0
|
33
|
3
|
<1
|
|
Vomiting
|
29
|
2
|
0
|
15
|
2
|
0
|
|
Arthralgia
|
24
|
3
|
0
|
22
|
2
|
<1
|
|
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
|
|
Constipation
|
11
|
<1
|
0
|
12
|
0
|
0
|
|
Bone pain
|
11
|
2
|
0
|
10
|
<1
|
0
|
|
Pain-other
|
11
|
<1
|
0
|
8
|
<1
|
0
|
|
Rash/desquamation
|
11
|
<1
|
<1
|
5
|
0
|
0
|
|
a Grade based on Common Toxicity Criteria (CTC) Version 2.0
(all grades ³10%).
|
|
b Regardless of causality. c Non-laboratory events
were graded only if assessed to be possibly drug-related.
|
The following are the clinically relevant adverse events that
occurred in >1% and <10% (all grades) of patients on either arm. In parentheses
are the incidences of Grade 3 and 4 adverse events (Gemzar plus paclitaxel versus
paclitaxel): febrile neutropenia (5.0% versus 1.2%), infection (0.8% versus
0.8%), dyspnea (1.9% versus 0), and allergic reaction/hypersensitivity (0 versus
0.8%).
No differences in the incidence of laboratory and non-laboratory
events were observed in patients 65 years or older, as compared to patients
younger than 65.
Post-marketing experience: The following adverse events
have been identified during post-approval use of Gemzar. These events have occurred
after Gemzar single-agent use and Gemzar in combination with other cytotoxic
agents. Decisions to include these events are based on the seriousness of the
event, frequency of reporting, or potential causal connection to Gemzar.
Cardiovascular : Congestive heart failure and myocardial
infarction have been reported very rarely with the use of Gemzar. Arrhythmias,
predominantly supraventricular in nature, have been reported very rarely.
Vascular Disorders : Vascular toxicity reported with
Gemzar includes clinical signs of vasculitis, which has been reported very rarely.
Gangrene has also been reported very rarely.
Skin : Cellulitis and non-serious injection site reactions
in the absence of extravasation have been rarely reported.
Hepatic : Serious hepatotoxicity including liver failure
and death has been reported very rarely in patients receiving Gemzar alone or
in combination with other potentially hepatotoxic drugs.
Pulmonary : Parenchymal toxicity, including interstitial
pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress
syndrome (ARDS), has been reported rarely following one or more doses of Gemzar
administered to patients with various malignancies. Some patients experienced
the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory
failure and death occurred very rarely in some patients despite discontinuation
of therapy.
Renal : Hemolytic-Uremic Syndrome (HUS) and/or renal
failure have been reported following one or more doses of Gemzar. Renal failure
leading to death or requiring dialysis, despite discontinuation of therapy,
has been rarely reported. The majority of the cases of renal failure leading
to death were due to HUS.
DRUG INTERACTIONS
When Gemzar (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on
Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was
128 L/hr/m2 and on Day 8 was 107 L/hr/m2. The clearance of cisplatin in the same study was
reported to be 3.94 mL/min/m2 with a corresponding half-life of 134 hours.
top
