Pharmaceutical-Approval Update: Oncology – Oxaliplatin for Injection (Eloxatin™)
Manufacturer: Sanofi-Synthelabo, Inc. Drug Class: Platinum antineoplastic agent Description: Oxaliplatin for injection is an organoplatinum complex in which the platinum atom is joined with 1,2-diamino-cyclohexane (DACH) and with an oxalate ligand as a “leaving group,” an atom (or group of atoms) that is displaced as stable species and takes the bonding electrons with it. Oxali-platin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which co-valently bind with macromolecules. Both interstrand and intra-strand platinum-DNA cross-links are formed. These crosslinks inhibit DNA replication and transcription. Cytotoxicity is nonspecific for the cell cycle.
Indication: Used in combination with infusional 5-fluo-rouracil/leucovorin (5-FU/LV), oxaliplatin is indicated for treating metastatic carcinoma of the colon or rectum that has recurred or progressed during or within six months after completion of first-line combination therapy with bolus 5-FU/LV and irinotecan (Camptosar®).
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Pharmacology: A multicenter, randomized, three-arm controlled study was conducted in the U.S. and Canada to compare the efficacy and safety of oxaliplatin in combination with infusional 5-FU/LV at the same dose and 5-FU/LV alone and with single-agent oxaliplatin in patients with advanced colorectal cancer with relapsing or progressive disease during or within six months of first-line therapy with bolus 5-FU/LV and irino-tecan. Tumor response rates were analyzed after 450 patients were enrolled. Survival rates for all patients enrolled in the completed study have yet to be assessed.
Patient accrual is complete, and 821 patients have enrolled. The median number of cycles administered per patient was six for the oxaliplatin/infusional 5-FU/LV combinations and three each for 5-FU/LV alone and for oxaliplatin alone.
Tumor response rates for patients receiving the oxali-platin/infusional 5-FU/LV combination were greater than those for patients receiving infusional 5-FU/LV or oxaliplatin alone. Patients enrolled for evaluation of tumor response must have had at least one unidimensional lesion measuring 20 mm or larger, as detected by conventional computed tomography (CT) or magnetic resonance imaging, or measuring 10 mm or larger, as detected by spiral CT. Tumor response rates and disease progression were assessed every three cycles.
Events were limited to disease progression, as noted by an independent radiographic review. At the time of the interim analysis, 49% of the progression events had occurred, as confirmed by radiography. In the interim analysis, an estimated two-month increase in median time to radiographic disease progression was observed, compared with infusional 5-FU/LV alone. Warnings (Boxed): Oxaliplatin should be administered under the supervision of a qualified physician experienced in the use of chemotherapeutic agents for cancer. Adequate diagnostic and treatment facilities must be available for the appropriate management of therapy and complications.
Anaphylactic-like reactions have occurred within minutes after its administration. Epinephrine, corticosteroids, and anti-histamines have been used to alleviate symptoms. Warnings: Oxaliplatin may cause hypersensitivity and ana-phylactic or anaphylactoid reactions. These allergic reactions (e.g., rash, urticaria, erythema, pruritus, and, rarely, bron-chospasm and hypotension) were similar in nature and severity to those reported with other platinum-containing compounds. They 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. Oxaliplatin may cause fetal harm in pregnant women, and women of childbearing age should be advised to avoid becoming pregnant during treatment.
Neuropathy. There have been reports of an early-onset, acute, reversible, primarily peripheral sensory neuropathy that occurs within hours or one to two days of dosing and resolves within 14 days and that may recur with further dosing. A persistent, primarily peripheral sensory neuropathy, lasting more than 14 days, has been characterized by pares-thesias, dysesthesias, and hypoesthesias along with deficits in proprioception that interfere with daily activities (e.g., writing, buttoning clothes, swallowing, and difficulty in walking).
Pulmonary Toxicity. The product has been associated with pulmonary fibrosis (in 0.7% of study patients), which is sometimes fatal.
Adverse Drug Effects. The most frequently reported ADEs with oxaliplatin/infusional 5-FU/LV are acute neuropathy (56%), persistent neuropathy (48%), fatigue (68%), diarrhea (67%), nausea (65%), and vomiting (40%). Hematological changes include anemia (81%), leukopenia (76%), neutropenia (73%), and thrombocytopenia (64%).
Conclusion: Oxaliplatin is used in combination with infu-sional 5-FU and leucovorin to treat advanced colorectal cancer in patients with recurrent or worsening disease after initial therapy with irinotecan plus bolus 5-FU/LV. Compared with the standard treatment (irinotecan plus 5-FU/LCV), the oxali-platin/5-FU/LV regimen was superior in terms of prolonging survival, in shrinking tumors in some patients, and in delaying tumor regrowth.