Eloxatin Warnings, Precautions, Pregnancy, Nursing, Abuse - Oxaliplatin

Eloxatin Warnings, Precautions, Pregnancy, Nursing, Abuse - Oxaliplatin

WARNINGS

As in the case for other platinum compounds, hypersensitivity and anaphylactic/anaphylactoid reactions to ELOXATIN have been reported (see ADVERSE REACTIONS). These allergic reactions 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 occur within minutes of administration and should be managed with appropriate supportive therapy. Drug-related deaths associated with platinum compounds from this reaction have been reported.

Pregnancy Category D

ELOXATIN may cause fetal harm when administered to a pregnant woman. 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.

PRECAUTIONS

General

ELOXATIN should be administered under the supervision of a qualified 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.

Neuropathy

Neuropathy was graded using a study-specific neurotoxicity scale, which was different than the National Cancer Institute Common Toxicity Criteria, Version 2.0 (NCI CTC) (see below). 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 infusional
  5-FU/LV. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. Ice (mucositis prophylaxis) should be avoided during the infusion of ELOXATIN because cold temperature can exacerbate acute neurological symptoms. (See DOSAGE AND ADMINISTRATION, Dose Modifications.)
  
  An acute syndrome of pharyngolaryngeal dysesthesia seen in 1-2% of patients is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing).
  
   
• A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysethesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g. writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving ELOXATIN with infusional 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 from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of ELOXATIN.

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 from the trial for patients who had not been previously treated for colorectal cancer.

Neurotoxicity scale:

The grading scale for paresthesias/dysesthesias was: Grade 1, resolved and did not interfere with functioning; Grade 2, interfered with function but not daily activities; Grade 3, pain or functional impairment that interfered with daily activities; Grade 4, persistent impairment that is disabling or life-threatening.

Pulmonary Toxicity

ELOXATIN has been associated with pulmonary fibrosis (0.7% of study patients), which may be fatal. 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.

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).

Laboratory Test Interactions

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal 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.

Pregnancy Category D - See WARNINGS

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 from ELOXATIN, 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 safety and effectiveness of ELOXATIN in pediatric patients have not been established.

Patients with Renal Impairment - The safety and effectiveness of the combination of ELOXATIN and infusional 5-FU/LV in patients with renal impairment have not been evaluated. The combination of ELOXATIN and infusional 5-FU/LV should be used with caution in patients with preexisting renal impairment since the primary route of platinum elimination is renal. Clearance of ultrafilterable platinum is decreased in patients with mild, moderate, and severe renal impairment. A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established. (See CLINICAL PHARMACOLOGY and ADVERSE REACTIONS.)

Geriatric Use - No significant effect of age on the clearance of ultrafilterable platinum has been observed. In the randomized clinical trial (see CLINICAL STUDIES) of ELOXATIN, 95 patients treated with ELOXATIN and infusional 5-FU/LV were <65 years and 55 patients were >65 years. The rates of overall adverse events, including Grade 3/4 events, were similar across and within arms in the different age groups. The incidence of diarrhea, dehydration,