Neuropathy

Oxaliplatin 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 oxaliplatin with fluorouracil/leucovorin. 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 oxaliplatin with fluorouracil/leucovorin combination arm was 6. 

An acute syndrome of pharyngolaryngeal dysesthesia seen in 1% to 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 laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of oxaliplatin 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 from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving oxaliplatin with fluorouracil/leucovorin. 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 oxaliplatin. 

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

Peripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin 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 from the NCI CTC scale, Version 2.0 (see below). 

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.

Reversible Posterior Leukoencephalopathy Syndrome 

Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension [see Adverse Reactions (6.2)]. Diagnosis of RPLS is based upon confirmation by brain imaging.