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
Eloxatin Side Effects, and Drug Interactions - Oxaliplatin
Eloxatin Side Effects, and Drug Interactions - Oxaliplatin
SIDE EFFECTS
More than 1500 patients with advanced colorectal cancer have been treated
in clinical studies with ELOXATIN either as a single agent or in combination
with other medications. The most common adverse reactions were peripheral
sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea
(see PRECAUTIONS). Four-hundred
and fifty patients (about 150 receiving the combination of ELOXATIN and
5-FU/LV) were studied in a randomized trial in patients with refractory
and relapsed colorectal cancer (see CLINICAL
STUDIES). The adverse event profile in this study was similar
to that seen in other studies and the adverse reactions in this trial
are shown in the tables below.
Thirteen percent of patients in the ELOXATIN and infusional 5-FU/LV-combination
arm and 18% in the infusional 5-FU/LV arm had to discontinue treatment
because of adverse effects related to gastrointestinal or hematologic
adverse events, or neuropathies. Both 5-FU and ELOXATIN are associated
with gastrointestinal and hematologic adverse events. When ELOXATIN is
administered in combination with infusional 5-FU, the incidence of these
events is increased.
The incidence of death within 30 days of treatment, regardless of causality,
was 5% with the ELOXATIN and infusional 5-FU/LV combination, 8% with ELOXATIN
alone, and 7% with infusional 5-FU/LV. Of the 7 deaths that occurred on
the ELOXATIN and infusional 5-FU/LV combination arm within 30 days of
stopping treatment, 3 may have been treatment related, associated with
gastrointestinal bleeding or dehydration.
The following table provides adverse events reported in the study (see
CLINICAL STUDIES) in decreasing
order of frequency in the ELOXATIN and infusional 5-FU/LV combination
arm for events with overall incidences >5% and for Grade 3/4
events with incidences >1%. This table does not include hematologic
and blood chemistry abnormalities; these are shown separately below.
Table 5 – Adverse Experience Reported
in Colorectal Cancer Clinical Trial
(>5% of all patients and with >1% NCI Grade 3/4 events)
|
|
5-FU/LV
(N=142) |
ELOXATIN
(N=153) |
ELOXATIN
+ 5-FU/LV
(N=150) |
| Adverse Event (WHO/Pref) |
All Grades
(%) |
Grade 3/4
(%) |
All Grades
(%) |
Grade 3/4
(%) |
All Grades
(%) |
Grade 3/4
(%) |
| Any Event |
98 |
41 |
100 |
46 |
99 |
73 |
| Neuropathy |
17 |
0 |
76 |
7 |
74 |
7 |
| Acute |
10 |
0 |
65 |
5 |
56 |
2 |
| Persistent |
9 |
0 |
43 |
3 |
48 |
6 |
| Fatigue |
52 |
6 |
61 |
9 |
68 |
7 |
| Diarrhea |
44 |
3 |
46 |
4 |
67 |
11 |
| Nausea |
59 |
4 |
64 |
4 |
65 |
11 |
| Vomiting |
27 |
4 |
37 |
4 |
40 |
9 |
| Stomatitis |
32 |
3 |
14 |
0 |
37 |
3 |
| Abdominal Pain |
31 |
5 |
31 |
7 |
33 |
4 |
| Fever |
23 |
1 |
25 |
1 |
29 |
1 |
| Anorexia |
20 |
1 |
20 |
2 |
29 |
3 |
| Dyspnea |
11 |
2 |
13 |
7 |
20 |
4 |
| Back Pain |
16 |
4 |
11 |
0 |
19 |
3 |
| Coughing |
9 |
0 |
11 |
0 |
19 |
1 |
| Edema |
13 |
1 |
10 |
1 |
15 |
1 |
| Pain |
9 |
3 |
14 |
3 |
15 |
2 |
| Injection Site Reaction |
5 |
1 |
9 |
0 |
10 |
3 |
| Thrombo-embolism |
4 |
2 |
2 |
1 |
9 |
8 |
| Hypokalemia |
3 |
1 |
3 |
2 |
9 |
4 |
| Dehydration |
6 |
4 |
5 |
3 |
8 |
3 |
| Chest Pain |
4 |
1 |
5 |
1 |
8 |
1 |
| Febrile Neutropenia |
1 |
1 |
0 |
0 |
6 |
6 |
| Gastro-esophageal Reflux |
3 |
0 |
1 |
0 |
5 |
2 |
The following table provides adverse events reported in the study (see
CLINICAL STUDIES) in decreasing
order of frequency in the ELOXATIN and infusional 5-FU/LV combination
arm for events with overall incidences >5% but with incidences
<1% NCI Grade 3/4 events.
Table 6 – Adverse Experience Reported in Colorectal Cancer
Clinical Trial
(>5% of all patients but with <1% NCI Grade 3/4 events)
Adverse Event
(WHO/Pref) |
5-FU/LV
(N=142)
All Grades (%) |
ELOXATIN
(N=153)
All Grades (%) |
ELOXATIN
+ 5-FU/LV
(N=150)
All Grades (%)
|
| Constipation |
23 |
31 |
32 |
| Headache |
8 |
13 |
17 |
| Rhinitis |
4 |
6 |
15 |
| Dyspepsia |
10 |
7 |
14 |
| Taste Perversion |
1 |
5 |
13 |
| Dizziness |
8 |
7 |
13 |
| Hand-Foot Syndrome |
13 |
1 |
11 |
| Flushing |
2 |
3 |
10 |
| Peripheral Edema |
11 |
5 |
10 |
| Allergic Reaction |
1 |
3 |
10 |
| Arthralgia |
10 |
7 |
10 |
| Upper Resp Tract Infection |
4 |
7 |
10 |
| Pharyngitis |
10 |
2 |
9 |
| Rash |
5 |
5 |
9 |
| Insomnia |
4 |
11 |
9 |
| Epistaxis |
1 |
2 |
9 |
| Mucositis |
10 |
2 |
7 |
| Alopecia |
3 |
3 |
7 |
| Abnormal Lacrimation |
6 |
1 |
7 |
| Rigors |
6 |
9 |
7 |
| Hematuria |
4 |
0 |
6 |
| Dysuria |
1 |
1 |
6 |
| Hiccup |
0 |
2 |
5 |
| Flatulence |
6 |
3 |
5 |
Adverse events were similar in men and women and in patients
<65 and >65 years, but older patients may have been more
susceptible to dehydration, diarrhea, hypokalemia and fatigue. The following
additional adverse events, at least possibly related to treatment and
potentially important, were reported in >2% and <5% of the
patients in the ELOXATIN and infusional 5-FU/LV combination arm (listed
in decreasing order of frequency): anxiety, myalgia, erythematous rash,
increased sweating, conjunctivitis, weight decrease, dry mouth, rectal
hemorrhage, depression, ataxia, ascites, hemorrhoids, muscle weakness,
nervousness, tachycardia, abnormal micturition frequency, dry skin, pruritus,
hemoptysis, purpura, vaginal hemorrhage, melena, somnolence, pneumonia,
proctitis, involuntary muscle contractions, intestinal obstruction, gingivitis,
tenesmus, hot flashes, enlarged abdomen, urinary incontinence.
Hematologic
The following table lists the hematologic changes occurring in >5%
of patients, based on laboratory values and NCI grade.
Table 7 – Adverse Hematologic Experiences (>5%
of patients)
|
Hematology
Parameter
|
5-FU/LV
(N=142) |
ELOXATIN
(N=153) |
ELOXATIN
+ 5-FU/LV
(N=150) |
All Grades
(%) |
Grade 3/4
(%) |
All Grades
(%) |
Grade 3/4
(%) |
All Grades
(%) |
Grade 3/4
(%) |
| Anemia |
68 |
2 |
64 |
1 |
81 |
2 |
| Leukopenia |
34 |
1 |
13 |
0 |
76 |
19 |
| Neutropenia |
25 |
5 |
7 |
0 |
73 |
44 |
| Thrombo-cytopenia |
20 |
0 |
30 |
3 |
64 |
4 |
Thrombocytopenia
Thrombocytopenia was frequently reported with the combination of ELOXATIN
and infusional 5-FU/LV. The incidence of Grade 3/4 thrombocytopenia was
4%. Grade 3/4 hemorrhagic events were reported at low frequency and the
incidence of these events was similar for the combination of ELOXATIN
and infusional 5-FU/LV and the infusional 5-FU/LV control group. The incidence
of all hemorrhagic events, however, was higher on the ELOXATIN combination
arm compared to the 5-FU/LV arm. These events included gastrointestinal
bleeding, hematuria, and epistaxis.
Neutropenia
Neutropenia was frequently observed with the combination of ELOXATIN
and infusional 5-FU/LV, with Grade 3 and 4 events reported in 27% and
17% of previously treated patients, respectively. The incidence of febrile
neutropenia was 1% in the infusional 5-FU/LV arm and 6% (less than 1%
of cycles) in the ELOXATIN and infusional 5-FU/LV combination arm.
Gastrointestinal
In patients receiving the combination of ELOXATIN and infusional 5-FU/LV,
the incidence of Grade 3/4 nausea, vomiting, diarrhea, and mucositis/stomatitis
increased compared to infusional 5-FU/LV controls (see Table
5).
The incidence of gastrointestinal adverse events appears to be similar
across cycles. Premedication with antiemetics, including 5-HT3
blockers, is recommended. Diarrhea and mucositis may be exacerbated by
the addition of ELOXATIN to infusional 5-FU/LV, and should be managed
with appropriate supportive care. Since cold temperature can exacerbate
acute neurological symptoms, ice (mucositis prophylaxis) should be avoided
during the infusion of ELOXATIN.
Dermatologic
ELOXATIN did not increase the incidence of alopecia compared to infusional
5-FU/LV alone. No complete alopecia was reported. The incidence of hand-foot
syndrome was 13% in the infusional 5-FU/LV arm and 11% in the ELOXATIN
and infusional 5-FU/LV combination arm.
Care of Intravenous Site:
Extravasation may result in local pain and inflammation that may be severe
and lead to complications, including necrosis. Injection site reaction,
including redness, swelling, and pain, have been reported.
Neurologic
ELOXATIN is consistently associated with two types of peripheral neuropathy
(see PRECAUTIONS, Neuropathy).
Seventy-four percent of patients experienced neuropathy. The incidence
of overall and Grade 3/4 persistent peripheral neuropathy was 48% and
6%, respectively. These events can occur without any prior acute event.
The majority of the patients (80%) that developed Grade 3 persistent neuropathy
progressed from prior Grade 1 or 2 events. The median number of cycles
administered on the ELOXATIN with infusional 5-FU/LV combination arm was
6 cycles. In clinical trials that have studied similar administration
schedules of this combination regimen, but for a longer time (median cycles
ranged 10-12), a higher incidence (17%) of Grade 3/4 persistent neurotoxicity
was observed.
Allergic reactions
Hypersensitivity to ELOXATIN has been observed (<1% Grade 3/4) in
clinical studies. These allergic reactions, which can be fatal, were similar
in nature and severity to those reported with other platinum-containing
compounds, i.e., rash, urticaria, erythema, pruritus, and, rarely, bronchospasm
and hypotension. These reactions are usually managed with standard epinephrine,
corticosteroid, and antihistamine therapy. (See WARNINGS
for anaphylactic/anaphylactoid reactions.)
Renal
About 10% of patients in all groups had some degree of elevation of serum
creatinine. The incidence of Grade 3/4 elevations in serum creatinine
in the ELOXATIN and infusional 5-FU/LV combination arm was 1%.
Hepatic
The following table lists the clinical chemistry changes associated with
hepatic toxicity occurring in >5% of patients, based on laboratory
values and NCI CTC grade.
Table 8 – Adverse Hepatic – Clinical Chemistry Experience
(>5% of patients)
| |
5-FU/LV
(N=142) |
ELOXATIN
(N=153) |
ELOXATIN
+ 5-FU/LV
(N=150) |
|
Clinical
Chemistry
|
All Grades
(%) |
Grade 3/4
(%) |
All Grades
(%) |
Grade 3/4
(%) |
All Grades
(%) |
Grade 3/4
(%) |
| ALT (SGPT-ALAT) |
28 |
3 |
36 |
1 |
31 |
0 |
| AST (SGOT-ASAT) |
39 |
2 |
54 |
4 |
47 |
0 |
| Total Bilirubin |
22 |
6 |
13 |
5 |
13 |
1 |
Thromboembolism
The incidence of thromboembolic events was 4% in the infusional 5-FU/LV
arm, and 9% in the ELOXATIN and infusional 5-FU/LV combination arm.
Postmarketing Experience
The following events have been reported from worldwide postmarketing
experience:
Body as a whole:
-angioedema, anaphylactic shock
Central and peripheral nervous system disorders:
-loss of deep tendon reflexes, dysarthria, Lhermitte’s sign, cranial
nerve palsies, fasciculations
Gastrointestinal system disorders:
-severe diarrhea/vomiting resulting in hypokalemia, metabolic acidosis;
ileus; intestinal obstruction, pancreatitis
Hearing and vestibular system disorders:
-deafness
Platelet, bleeding, and clotting disorders:
-immuno-allergic thrombocytopenia
Red blood cell disorders:
-hemolytic uremic syndrome
Respiratory system disorders:
-pulmonary fibrosis, and other interstitial lung diseases
Vision disorders:
-decrease of visual acuity, visual field disturbance, optic neuritis
DRUG INTERACTIONS
No specific cytochrome P450-based drug interaction studies have been
conducted. No pharmacokinetic interaction between 85 mg/m2
ELOXATIN and infusional 5-FU has been observed in patients treated every
2 weeks. Increases of 5-FU plasma concentrations by approximately 20%
have been observed with doses of 130 mg/m2 ELOXATIN dosed every
3 weeks. Since platinum containing species are eliminated primarily through
the kidney, clearance of these products may be decreased by coadministration
of potentially nephrotoxic compounds; although, this has not been specifically
studied. (See CLINICAL PHARMACOLOGY.)
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