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Serious and fatal hypersensitivity adverse reactions, including anaphylaxis, can occur with ELOXATIN within minutes of administration and during any cycle. ELOXATIN is contraindicated in patients with hypersensitivity reactions to oxaliplatin and other platinum-based drugs. Immediately and permanently discontinue ELOXATIN for hypersensitivity reactions and administer appropriate treatment. (4, 5.1)
ELOXATIN is contraindicated in patients with hypersensitivity reactions to platinum-based drugs [see Contraindications (4)]. Immediately and permanently discontinue ELOXATIN for hypersensitivity reactions and administer appropriate treatment for management of hypersensitivity reactions.
At the end of a 2-hour infusion of ELOXATIN, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. The decline of ultrafiltrable platinum levels following ELOXATIN administration is triphasic, including two distribution phases (t1/2α; 0.43 hours and t1/2β; 16.8 hours).
Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks.
Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.
Advise patients of the potential risk of hypersensitivity and that ELOXATIN is contraindicated in patients with a history of hypersensitivity reactions to oxaliplatin and other platinum-based drugs. Instruct patients to seek immediate medical attention for signs of severe hypersensitivity reaction such as chest tightness; shortness of breath; wheezing; dizziness or faintness; or swelling of the face, eyelids, or lips [see Warnings and Precautions (5.1)].
A subset of PDAC tumors (approximately 15% of all cases) is characterized by mutations in genes that are related to the DNA damage response [54]. Amongst those, PDAC tumors carrying mutations in BRCA1/2 genes are of highest interest as they are supposed to be defective in homologous recombination DNA damage repair [189]. Accordingly, patients with BRCA1/2-mutated tumors were reported to benefit significantly more from platinum-based chemotherapy than patients with BRCA1/2 wildtype tumors [190, 191]. For BRCA1/2-deficient tumors, the inhibition of Poly-(ADP-ribose)-polymerase (PARP) may be promising, since this enzyme shares an axis of synthetic lethality with BRCA1/2 [192]. Initial trials examining the therapeutic potential of PARP inhibitors in patients with BRCA1/2-deficient PDAC reported promising results [193,194,195,196]. Currently, the randomized phase III POLO trial is evaluating PARP inhibition in patients who received first-line platinum-based chemotherapy, and results are awaited in 2019 (NCT02184195). Beyond BRCA1/2, mutations in other genes of the DNA damage response, including ATM, may select for PARP inhibitor sensitivity [197]. 2b1af7f3a8