Black Box Warning And Important Safety Information

Efficacy of Eloxatin With 5-fluorouracil/leucovorin (5-FU/LV) in
Elderly Patients

A pooled analysis of 3,742 patients from 4 phase III trials was conducted to compare the safety and efficacy of Eloxatin + 5-FU/LV (FOLFOX4) in patients <70 years and ≥70 years of age.¹

Study Design¹

This analysis included patients from 4 phase III trials (Table 1).

Table 1. Pooled analysis of 4 phase III trials

Study Name	Study Design
Study A: MOSAIC*	FOLFOX4 vs. LV5FU2 as adjuvant treatment for colon cancer (FOLFOX4: n = 1,123)
Study B: de Gramont et al	FOLFOX4 vs. LV5FU2 as 1^st-line treatment for MCRC (FOLFOX4: n = 210)
Study C: Goldberg et al	FOLFOX4 vs. IFL vs. IROX as 1^st-line treatment for MCRC (FOLFOX4: n = 267)
Study D: Rothenberg et al	FOLFOX4 vs. IFL vs. Eloxatin alone as 2^nd-line treatment for MCRC (FOLFOX4: n = 281)

*MOSAIC: Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer.
LV5FU2 = infusion leucovorin + bolus and infusion fluorouracil; IFL = irinotecan plus bolus 5-FU/LV; IROX = irinotecan + Eloxatin.

Table 2. Patient Age by Trial

Efficacy Outcomes¹

Dose intensity did not differ between patients <70 years and patients ≥70 years at any cycle for either Eloxatin or infusional FU.
After adjustment for metastatic treatment, age was not significantly associated with survival. (P=0.22).
In 3 trials, both separately and pooled, overall survival was similar among patients above and below the age of 70 years (Figure 1).

Figure 1. Overall survival in elderly vs. non-elderly patients
Overall Survival (mCRC Trials)—FOLFOX4 In Elderly vs Non-Elderly Patients.¹

Overall survival in elderly vs. non-elderly patients

Safety Outcomes¹

Overall, similar toxicity patterns were observed across the 2 age groups:
- Only grade ≥3 hematologic toxicity and thromboscity was significantly higher in older patients; however, the incidence of severe infection did not differ by age. In study C (Goldberg et al), infection was more common in younger patients (14% age<Rothemberg et al), infection was more common in older patients(1% age<70, 7% age>70;Pi-.02)
- Older age was not associated with increased rates of severe (grade ≥3) neurologic adverse events, diarrhea or nausea/vomiting.

Pooled Analysis: Percentage of Patients With Adverse Events (NCI-CTC Grade ≥ 3)

Enlarge Table

^†P-value from a logistic regression for age as a dichotomous variable (age <70 vs ≥ 70) in a model adjusted for study, gender, and performance status
^±P <.001 in model with age as a continuous variable
^§P=.003 in model with age as a continuous variable

^*In study C (Goldberg et al), infection was more common in younger patients (14% age <70, 6% age ≥ 70; P =.10); in study D (Rothenberg et al), infection was more common in older patients (1% age <70, 7% age ≥ 70; P =.02).

This pooled analysis study concluded that age alone should not impact treatment decisions for patients with colorectal cancer who are considering treatment with FOLFOX4. The presence or absence of comorbid medical conditions is a more relevant factor.¹

INDICATIONS

ELOXATIN, used in combination with infusional 5-FU/LV, is indicated for:

Adjuvant treatment of stage Ill colon cancer patients who have undergone complete resection of the primary tumor
Treatment of advanced carcinoma of the colon or rectum

Important Safety Information

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, and discontinuation of ELOXATIN therapy may be required.

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-FULV 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 Ill colon cancer, paresthesia was seen in 92% (all grades) and 13% (grade 3/4) of patients; 21% (all grades) and 0.5% (grade 3/4) of patients 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 was 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 Ill 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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References:

Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006;24:4085-4091.

Eloxatin.com Registration | Colorectal Cancer Symptoms | Colorectal Cancer Treatment | Colorectal Cancer Side Effects

ELOXATIN, 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. The indication is based on an improvement in disease-free survival, with no demonstrated benefit in overall survival after a median follow-up of 4 years
Treatment of advanced carcinoma of the colon or rectum

Clinical Safety Considerations

ELOXATIN should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

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) and 0.5% (grade 3/4) of patients 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 was 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

Efficacy of Eloxatin With 5-fluorouracil/leucovorin (5-FU/LV) in Elderly Patients

Study Design1