Pemetrexed (Alimta®) is a multitargeted antifolate drug approved as a single agent or in combination with cisplatin for the treatment of a small number of malignancies including advanced and metastatic non-squamous non-small cell lung cancer (NSCLC), and malignant pleural mesothelioma. This review reports the recent peer-reviewed publications and original findings regarding cutaneous adverse reactions (CARs) to pemetrexed. Pemetrexed-related CARs are frequently reported under the unspecific term ‘skin rash’. However, more specific diseases were tentatively identified as alopecias, urticarial vasculitis, acute generalized exanthematous pustulosis, toxic epidermal necrolysis, radiation recall dermatitis and pityriasis lichenoides. Most of the skin reactions occur shortly after pemetrexed administration. As with methotrexate-related CARs, the cell cycle arrest in the S phase may be regarded as a direct and major cause of the cytotoxic pathobiology. An adverse immune reaction is unlikely. In conclusion, pemetrexed is responsible for CARs exhibiting a variety of clinical presentations. Their origin is likely attributed to direct cytotoxicity following the cell cycle arrest in the S phase and cell necrosis.

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