Pharmaceutical-Approval Update: Oncology – Pemetrexed for Injection (Alimta®)
Manufacturer: Eli Lilly Drug Class: Antifolate antineoplastic agent Description: Pemetrexed for injection exerts its action by disrupting folate-dependent metabolic processes that are essential for cell replication. By inhibiting dihydrofolate reduc-tase, thymidylate synthase, and glycinamide ribonucleotide formyl transferase, it interrupts the de novo synthesis of both purines and pyrimidines. As a single agent, it is active against a variety of solid tumors.
Indication: In combination with cisplatin, pemetrexed is indicated for patients with unresectable malignant pleural mesothelioma or who are otherwise not candidates for curative surgery. Malignant mesotheliomas are aggressive neoplasms that arise from the surface serosal cells of the pleural, peritoneal, and pericardial cavities.
Pemetrexed 500 mg/m2 is administered as an intravenous (IV) infusion over 10 minutes on the first day of each 21-day cycle. Cisplatin 75 mg/m2 is infused over two hours, beginning approximately 30 minutes after the pemetrexed injection. Pharmacology: The effectiveness of pemetrexed was established in a clinical trial that compared it in combination with cisplatin and with cisplatin alone. The multicenter, randomized, single-blind study included 448 chemotherapy-naive patients with malignant pleural mesothelioma. Patients receiving peme-trexed and cisplatin lived three months longer after randomization than did patients who were given cisplatin alone (12 vs. 9 months). Lung function (i.e., forced vital capacity) also improved in the pemetrexed/cisplatin arm compared with the control arm. Pemetrexed must be administered with vitamin B12 and folic acid supplementation to decrease the incidence and severity of adverse drug events (ADEs).
Decreased Renal Function. This product is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance of 45 ml/minute or greater. Because insufficient numbers of patients have been studied with creatinine clearance below 45 ml/minute to recommend the appropriate dose, pemetrexed should not be administered when the creatinine clearance is below 45 ml/minute.
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Bone Marrow Suppression. Pemetrexed can suppress bone marrow function, resulting in manifestations of neutro-penia, thrombocytopenia, and anemia. Myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on the nadir absolute neutrophil count, the platelet count, and the maximum nonhematologic toxicity seen in the previous cycle.
Folate and Vitamin B12 Supplementation. Patients receiving pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematological and gastrointestinal toxicities (e.g., neutropenia, febrile neutropenia, and infections).
Pregnancy Category D. This agent may cause fetal harm during pregnancy, although no studies have been conducted in pregnant women. When given to mice on gestation days six through 15, the agent was fetotoxic and teratogenic, causing fetal malformations and cleft palate. Embryotoxicity was characterized by increased embryo fetal deaths and reduced litter sizes.
Precautions: The product should be administered under the supervision of a qualified physician with experience in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are available.
Skin rashes have been reported more frequently in patients who are not taking corticosteroids in clinical trials. In patients with clinically significant third-space fluid, practitioners should consider draining the effusion before prescribing pemetrexed. Complete blood counts, including platelet counts and periodic chemistry profiles should be assessed for all patients receiving this product. Patients should be monitored for nadir and recovery values before each dose on days eight and 15 of each cycle, and they should not begin a new cycle of treatment unless the absolute neutrophil count is 1,500 cells/mm3 or higher, the platelet count is 100,000 cells/mm3 or higher, and the creatinine clearance is 45 ml/minute or greater. erectalis
Practitioners should use caution when administering ibupro-fen with pemetrexed for injection in patients with mild to moderate renal insufficiency. If concomitant administration of a nonsteroidal anti-inflammatory drug (NSAID) is necessary, patients should be monitored closely for renal and gastrointestinal toxicity and especially for myelosuppression. Conclusion: Although asbestos exposure has been established as the primary cause of malignant pleural mesothelioma, there is a long latency period of 30 to 45 years between exposure and development of the disease. Shipyard, insulation, and construction workers and and asbestos miners and manufacturers seem to be at highest risk. The male-to-female ratio is approximately 4:1. The disease affects between 10,000 and 15,000 people worldwide each year, and this figure is increasing. Most people learn that they have it only after the disease has progressed to an advanced stage, when treatment with surgery or radiation is not possible.
When given with cisplatin, pemetrexed is the first and only chemotherapy FDA-approved drug approved for the treatment of this malignancy when surgery is not an option.