Included as part of the PRECAUTIONS section.

Allergic Reactions

See BOXED WARNING

Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to ELOXATIN has been observed in 2-3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and 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, bronchospasmand 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. Drug-related deaths associated with platinumcompounds fromanaphylaxis have been reported.

Neuropathy

ELOXATIN is associated with two types of neuropathy:

An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received ELOXATIN with 5-FU/LV). In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the ELOXATIN with 5 FU/LV combination armwas 6.

An acute syndrome of pharyngolaryngeal dysesthesia seen in 1-2% (grade 3/4) of patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasmor bronchospasm(no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of ELOXATIN because cold temperature can exacerbate acute neurological symptoms .

A persistent ( > 14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking fromimpaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving ELOXATIN with 5-FU/LV. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed fromprior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of ELOXATIN.

In the adjuvant colon cancer trial, neuropathy was graded using a prelisted module derived fromthe Neuro-Sensory section of the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1, as follows:

Table 1 - NCI CTC Grading for Neuropathy in Adjuvant Patients

Peripheral sensory neuropathy was reported in adjuvant patients treated with the ELOXATIN combination with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).

In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different fromthe NCI CTC scale, Version 2.0 (see below).

Table 2 - Grading Scale for Paresthesias/Dysesthesias in Advanced Colorectal Cancer Patients

Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer 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. Information regarding reversibility of neuropathy was not available fromthe trial for patients who had not been previously treated for colorectal cancer.

Pulmonary Toxicity

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% (any grade) and < 1% (grade 3) with no grade 4 events in the ELOXATIN plus infusional 5-FU/LV armcompared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-FU/LV alone armin adjuvant colon cancer patients. In this study, one patient died fromeosinophilic pneumonia in the ELOXATIN combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the ELOXATIN plus 5-FU/LV armcompared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-FU/LV armof unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, ELOXATIN should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

Hepatotoxicity

Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the ELOXATIN combination armthan in the control 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, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases [see Clinical Trials Experience).

Pregnancy

Pregnancy Category D

ELOXATIN may cause fetal harmwhen administered to a pregnant woman. There are no adequate and well-controlled studies of ELOXATIN in pregnant women. Pregnant rats were administered 1 mg/kg/day oxaliplatin (less than one-tenth the recommended human dose based on body surface area) during gestation days 1-5 (pre-implantation), 6-10, or 11-16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6-10 and 11-16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6-10. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ELOXATIN.[See Use in Specific Patient Populations]

Recommended Laboratory Tests

Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each ELOXATIN cycle [see DOSAGE AND ADMINISTRATION].

There have been reports while on study and frompost-marketing 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.

Patient Counseling Information

Information for Patients

Patients and patients' caregivers should be informed of the expected side effects of ELOXATIN, particularly its neurologic effects, both the acute, reversible effects and the persistent neurosensory toxicity. Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects. Patients should be instructed to avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.

Patients must be adequately informed of the risk of low blood cell counts and instructed to contact their physician immediately should fever, particularly if associated with persistent diarrhea, or evidence of infection develop.

Patients should be instructed to contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-termanimal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).

In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).

Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day x 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.

Use In Specific Populations

Pregnancy

Pregnancy Category D[see WARNINGS and PRECAUTIONS]

Nursing Mothers

It is not known whether ELOXATIN or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants fromELOXATIN, a decision should be made whether to discontinue nursing or delay the use of the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase I and 2 Phase II trials in 159 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed.

In a Phase I/II study, oxaliplatin was administered as a 2-hour IV infusion on days 1, 8 and 15 every 4 weeks (1 cycle), for a maximumof 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase I study received oxaliplatin at 6 dose levels starting at 40 mg/m² with escalation to 110 mg/m². The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m² dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m² IV in the Phase II portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse events. No responses were observed.

In a second Phase I study, oxaliplatin was administered to 26 pediatric patients as a 2-hour IV infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m² with escalation to 160 mg/m², for a maximumof 6 cycles. In a separate cohort, oxaliplatin 85 mg/m² was administered on day 1 every 2 weeks, for a maximumof 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m² dose. Based on these studies, oxaliplatin 130 mg/m² as a 2-hour IV infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase II studies. A dose of 85 mg/m² on day 1 every 2 weeks was also found to be tolerable.

In one Phase II study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m² every 3 weeks for a maximumof 12 months in absence of progressive disease or unacceptable toxicity. In patients < 10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse events reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed.

In a second Phase II study, 47 pediatric patients with recurrent solid tumors, including Ewing sarcoma or peripheral PNET, osteosarcoma, rhabdomyosarcoma and neuroblastoma, received oxaliplatin 130 mg/m² every 3 weeks for a maximumof 12 months or 17 cycles. In patients ≤ 12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse events reported were sensory neuropathy (53%, G3/4: 15%), thrombocytopenia (40%, G3/4: 26%), anemia (40%, G3/4: 15%), vomiting (32%, G3/4: 0%), nausea (30%, G3/4: 2%) and AST increased (26%, G3/4: 4%). No responses were observed.

The pharmacokinetic parameters of ultrafiltrable platinumhave been evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h/m². The inter-patient variability of platinumclearance in pediatric cancer patients was 41%. Mean platinumpharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC_0-48 of 7.52 ± 5.07 mcg•h/mL and AUC_inf of 8.83 ± 1.57 mcg•h/mL at 85 mg/m² of oxaliplatin and Cmax of 1.10 + 0.43 mcg/mL, AUC_0-48 of 9.74 ± 2.52 mcg•h/mL and AUCinf of 17.3 ± 5.34 mcg•h/mL at 130 mg/m² of oxaliplatin.

Geriatric Use

No significant effect of age on the clearance of ultrafilterable platinumhas been observed. In the adjuvant therapy colon cancer randomized clinical trial, [see Clinical Studies ]723 patients treated with ELOXATIN and infusional 5-FU/LV were < 65 years and 400 patients were ≥ 65 years. The effect of ELOXATIN on disease free survival benefit in patients > 65 years of age was not conclusive.

In the previously untreated for advanced colorectal cancer randomized clinical trial [see Clinical Studies] of ELOXATIN, 160 patients treated with ELOXATIN and 5-FU/LV were < 65 years and 99 patients were 65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the ≥ 65 year old patients as in the overall study population. In the previously treated randomized clinical trial [see Clinical Studies] of ELOXATIN, 95 patients treated with ELOXATIN and 5-FU/LV were < 65 years and 55 patients were ≥ 65 years. The rates of overall adverse events, including grade 3 and 4 events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients ≥ 65 years old. No adjustment to starting dose was required in patients ≥ 65 years old.

Patients with Renal Impairment

The safety and effectiveness of the combination of ELOXATIN and 5-FU/LV in patients with renal impairment have not been evaluated. The combination of ELOXATIN and 5-FU/LV should be used with caution in patients with preexisting renal impairment since the primary route of platinumelimination is renal. Clearance of ultrafilterable platinumis decreased in patients with mild, moderate, and severe renal impairment. A pharmacodynamic relationship between platinumultrafiltrate levels and clinical safety and effectiveness has not been established [see ADVERSE REACTIONS and CLINICAL PHARMACOLOGY].

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