Important Safety
Information Including
Boxed Warning
Anaphylactic-like reactions to ELOXATIN have been reported and may occur within minutes
of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines have
been employed to alleviate symptoms.
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Adverse Events
In clinical studies of Eloxatin alone or in combination with other medications, the most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue, and stomatitis. The most common adverse reactions in patients previously untreated and treated for advanced colorectal cancer were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.
Hematologic
Thrombocytopenia
Thrombocytopenia was frequently reported with the combination of Eloxatin and
infusional 5-FU/LV. The incidence of all hemorrhagic events in the adjuvant
and previously treated patients was higher on the Eloxatin combination arm compared
to the infusional 5-FU/LV arm. These events included gastrointestinal bleeding,
hematuria, and epistaxis. In the adjuvant trial, two patients died from intracerebral
hemorrhages.
The incidence of grade 3/4 thrombocytopenia was 2% in adjuvant patients with
colon cancer. In patients treated for advanced colorectal cancer the incidence
of grade 3/4 thrombocytopenia was 3-5%, and the incidence of these events was
greater for the combination of Eloxatin and 5-FU/LV over the irinotecan plus
5-FU/LV or 5-FU/LV control groups. Grade 3/4 gastrointestinal bleeding was reported
in 0.2% of adjuvant patients receiving Eloxatin and 5-FU/LV. In the previously
untreated patients, the incidence of epistaxis was 10% in the Eloxatin and 5-FU/LV
arm, and 2% and 1%, respectively, in the irinotecan plus 5-FU/LV or irinotecan
plus Eloxatin arms.
Neutropenia
Neutropenia was frequently observed with the combination of Eloxatin and 5-FU/LV,
with grade 3 and 4 events reported in 29% and 12% of adjuvant patients with
colon cancer, respectively. In the adjuvant trial, 3 patients died from sepsis/neutropenic
sepsis. Grade 3 and 4 events were reported in 35% and 18% of the patients previously
untreated for advanced colorectal cancer, respectively. Grade 3 and 4 events
were reported in 27% and 17% of previously treated patients, respectively. In
adjuvant patients the incidence of either febrile neutropenia (0.7%) or documented
infection with concomitant grade 3/4 neutropenia (1.1%) was 1.8% in the Eloxatin
and 5-FU/LV arm. The incidence of febrile neutropenia in the patients previously
untreated for advanced colorectal cancer was 15% (3% of cycles) in the irinotecan
plus 5-FU/LV arm and 4% (less than 1% of cycles) in the Eloxatin and 5-FU/LV
combination arm. Additionally, in this same population, infection with grade
3 or 4 neutropenia was 12% in the irinotecan plus 5-FU/LV and 8% in the Eloxatin
and 5-FU/LV combination. The incidence of febrile neutropenia in the previously
treated patients was 1% in the 5-FU/LV arm and 6% (less than 1% of cycles) in
the Eloxatin and 5-FU/LV combination arm.
Gastrointestinal
In patients receiving the combination of Eloxatin plus infusional
5-FU/LV for adjuvant treatment for colon cancer the incidence of grade 3/4 nausea
and vomiting was greater than in those receiving infusional 5-FU/LV alone (see table).
In patients previously untreated for advanced colorectal cancer receiving the
combination of Eloxatin and 5-FU/LV, the incidence of grade 3 and 4 vomiting
and diarrhea was less compared to irinotecan plus 5-FU/LV controls (see table).
In previously treated patients receiving the combination of Eloxatin and 5-FU/LV,
the incidence of grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis
increased compared to 5-FU/LV controls (see table).
The incidence of gastrointestinal adverse events in the previously untreated
and previously treated patients 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 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 5-FU/LV alone. No complete alopecia was reported. The incidence of grade
3/4 skin disorders was 2% in both the Eloxatin plus infusional
5-FU/LV and the infusional 5-FU/LV alone arms in the adjuvant colon cancer patients.
The incidence of hand-foot syndrome in patients previously untreated for advanced
colorectal cancer was 2% in the irinotecan plus 5-FU/LV arm and 7% in the Eloxatin
and 5-FU/LV combination arm. The incidence of hand-foot syndrome in previously
treated patients was 13% in the 5-FU/LV arm and 11% in the Eloxatin and 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 reactions, including
redness, swelling, and pain, have been reported.
Neurologic
Peripheral sensory neuropathy was reported in adjuvant patients
treated with the Eloxatin combination with a frequency of 92% (all grades) and
13% (grade 3), and by 18 months of follow-up, 21% patients had persistent peripheral
sensory neuropathy (all grades). In these patients the median cycle of onset
for grade 3 peripheral sensory neuropathy was 9. In patients previously untreated
for advanced colorectal cancer neuropathy was reported in 82% (all grades) and
19% (grade 3/4), and in the previously treated patients in 74% (all grades)
and 7% (grade 3/4) events. Eloxatin is consistently associated with two types
of peripheral neuropathy. In the previously treated patients, the incidence
of overall and grade 3/4 persistent peripheral neuropathy was 48% and 6%, respectively.
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 5-FU/LV combination arm in the previously treated patients
was 6.
Pulmonary
Eloxatin has been associated with pulmonary fibrosis. One patient
treated with the Eloxatin combination regimen in the adjuvant trial died from
eosinophilic pneumonia.
Allergic Reactions
Grade 3/4 hypersensitivity to Eloxatin has been observed in
2-3% of colon cancer patients. These allergic reactions, which can be fatal,
can occur at any cycle, and were similar in nature and severity to those reported
with other platinum-containing compounds, such as rash, urticaria, erythema,
pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated
with hypersensitivity reactions reported in the previously untreated patients
were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin
infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension,
disorientation, and syncope. These reactions are usually managed with standard
epinephrine, corticosteroid, antihistamine therapy, and may require discontinuation
of therapy.
Anticoagulation and Hemorrhage
There have been reports while on study and from postmarketing
surveillance of prolonged prothrombin time and INR occasionally associated with
hemorrhage in patients who received Eloxatin plus 5-FU/LV while on anticoagulants.
Patients receiving Eloxatin plus 5- FU/LV and requiring oral anticoagulants
may require closer monitoring.
Renal
About 5-10% 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 5-FU/LV combination arm was 1% in the previously treated
patients. Serum creatinine measurements were not reported in the adjuvant trial.
Hepatic
Hepatotoxicity (defined as elevation of liver enzymes) appears
to be related to Eloxatin combination therapy. The following tables list the
clinical chemistry changes associated with hepatic toxicity occurring in >5%
of patients, based on adverse events reported and NCI CTC grade for adjuvant
patients and patients previously untreated for advanced colorectal cancer, laboratory
values, and NCI CTC grade for previously treated patients.
Adverse Hepatic Experiences in Patients With Stage II or III
Colon Cancer Receiving Adjuvant Therapy
(>5% of patients)
| Increase in Transaminases |
57 |
2 |
34 |
1 |
| ALP Increased |
42 |
<1 |
20 |
<1 |
| Bilirubinemia |
20 |
4 |
20 |
5 |
Adverse Hepatic – Clinical Chemistry Experience in Patients Previously
Untreated for Advanced Colorectal Cancer
(>5% of patients)
| ALT (SGPT-ALAT) |
6 |
1 |
2 |
0 |
5 |
2 |
| AST (SGOT-ASAT) |
17 |
1 |
2 |
1 |
11 |
1 |
| Alkaline Phosphatase |
16 |
0 |
8 |
0 |
14 |
2 |
| Total Bilirubin |
6 |
1 |
3 |
1 |
3 |
2 |
Adverse Hepatic – Clinical Chemistry Experience in Previously Treated Patients
(>5% of patients)
| 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 in adjuvant patients
with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-FU/LV arm and 6%
(1.2% grade 3/4) in the Eloxatin and infusional 5-FU/LV combined arm, respectively.
The incidence was 6 and 9% of the patients previously untreated for advanced colorectal
cancer and previously treated patients in the Eloxatin and 5-FU/LV combination
arm, respectively.
INDICATIONS
Eloxatin® (oxaliplatin injection), used in combination with infusional
5-FU/LV, is
indicated for
- Adjuvant treatment of stage III colon cancer patients who have undergone complete
resection of the primary tumor.
- Treatment of advanced carcinoma of the colon or rectum.
Clinical Safety Considerations
Anaphylactic-like reactions to ELOXATIN have been reported and may occur within
minutes of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines
have been employed to alleviate symptoms.
- ELOXATIN should not be administered to patients with a history of known allergy
to ELOXATIN or other platinum compounds. Hypersensitivity and anaphylactic/anaphylactoid
reactions to ELOXATIN have been reported and were similar in nature and severity
to those reported with other platinum compounds (ie, rash, urticaria, erythema,
pruritus, and, rarely, bronchospasm and hypotension). These reactions occur within
minutes of administration and should be managed with appropriate supportive therapy.
Drug-related deaths from this reaction have been reported.
- ELOXATIN may cause fetal harm when administered to a pregnant woman. Women of childbearing
potential should be advised not to become pregnant while receiving ELOXATIN. It
is not known whether ELOXATIN or its derivatives are excreted in human milk.
- ELOXATIN has been associated with pulmonary fibrosis (<1% of study patients),
which may be fatal. The combined incidence of cough and dyspnea was 7.4% (<1%
grade 3, no grade 4) in the ELOXATIN plus 5-FU/LV arm compared to 4.5% (no grade
3, 0.1% grade 4) in the 5-FU/LV alone arm in the adjuvant colon cancer study. In
this study, one patient died from eosinophilic pneumonia in the ELOXATIN combination
arm. The combined incidence of cough, dyspnea, and hypoxia was 43% (7% grade 3 and
4) in the ELOXATIN plus 5-FU/LV arm compared to 32% (5% grade 3 and 4) in the irinotecan
plus 5-FU/LV arm in patients with previously untreated colorectal cancer. In case
of unexplained respiratory symptoms, ELOXATIN should be discontinued until pulmonary
investigation excludes interstitial lung disease or pulmonary fibrosis.
- ELOXATIN is associated with two types of primarily peripheral sensory neuropathy:
an acute, reversible type of early onset and a persistent type (>14 days). In
patients with advanced colorectal cancer paresthesias occurred in 77% (all grades)
and 18% (grade 3/4) of previously untreated patients. In previously treated patients,
acute neuropathy occurred in 56% (all grades) and 2% (grade 3/4) of patients; persistent
neuropathy occurred in 48% (all grades) and 6% (grade 3/4) of patients. In patients
with stage II and III colon cancer, paresthesia was seen in 92% (all grades) and
13% (grade 3/4) of patients; 21% (all grades), 0.5% (grade 3/4) had residual paresthesia
at 18-month follow-up.
- Hepatotoxicity, as evidenced in the adjuvant study by increase in transaminases
and alkaline phosphatase was observed more commonly in the ELOXATIN combination
arm. The incidence of increased bilirubin was similar on both arms. Changes noted
on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal
alterations, perisinusoidal fibrosis and veno-occlusive lesions. Hepatic vascular
disorders should be considered and, if appropriate, investigated in case of abnormal
liver function test results or portal hypertension not explained by liver metastases.
- Monitoring of white blood cell count with differential, hemoglobin, platelet count
and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended
before each ELOXATIN cycle.
- The safety and effectiveness of ELOXATIN plus 5-FU/LV in patients with renal impairment
have not been evaluated. Since the primary route of platinum elimination is renal,
this combination should be used with caution in patients with preexisting renal
impairment. Clearance of these products may be decreased by coadministration of
potentially nephrotoxic compounds, although this has not been specifically studied.
- The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope
were higher in patients ≥65 years old.
- 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, has been reported.
- There have been reports of prolonged prothrombin time and INR occasionally associated
with hemorrhage in patients receiving ELOXATIN plus 5-FU/LV while on anticoagulants.
Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require
closer monitoring.
- The most common adverse reactions in patients with stage II or III colon cancer
receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia,
anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis,
fatigue, and stomatitis. The most common adverse reactions in patients with advanced
colorectal cancer were peripheral sensory neuropathy, fatigue, neutropenia, nausea,
emesis, and diarrhea.
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