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Drug Information Summaries
NCI's drug information summaries provide consumer-friendly information about certain drugs that are approved by the U.S. Food and Drug Administration (FDA) to treat cancer or conditions related to cancer.
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FDA Approval for Pemetrexed DisodiumBrand name(s): Alimta®
Malignant Pleural Mesothelioma On February 4, 2004, the U.S. Food and Drug Administration approved pemetrexed disodium for injection (Alimta®, made by Eli Lilly and Company) in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are not otherwise candidates for curative surgery.
Safety and efficacy were demonstrated in one multicenter, randomized trial in 456 patients comparing the combination of pemetrexed disodium and cisplatin with cisplatin alone. Supplementation with vitamin B12 and folic acid was instituted during the trial to decrease adverse effects. Subsequently, all patients, including previously enrolled patients, were given vitamin supplementation.
In an analysis of all patients who were randomized and treated, the combination of pemetrexed disodium and cisplatin was associated with a statistically significant improvement in survival compared to cisplatin alone. The median survivals were 12.1 versus 9.3 months, respectively (p = 0.020). This superiority in the combination arm was also demonstrated in the fully vitamin supplemented subgroup. The median survivals were 13.3 and 10.0 months in the combination and cisplatin alone groups, respectively (p = 0.051).
The principal adverse effects of the pemetrexed disodium plus cisplatin regimen were myelosuppression (in which the bone marrow produces fewer blood cells), fatigue, nausea, vomiting, and dyspnea (difficulty breathing). Most Grade 3/4 adverse effects were significantly reduced by vitamin supplementation without any efficacy decrement.
Pemetrexed disodium, 500 mg/m2, was diluted in 100 mL normal saline and administered as a 10-minute intravenous infusion. Approximately 30 minutes after pemetrexed disodium administration, cisplatin, 75 mg/m2 over 2 hours, was administered. Both drugs were given every 21 days.
Folic acid, 350 to 1000 micrograms orally, was given daily, beginning 1 to 3 weeks prior to the first chemotherapy dose and continued daily for one to three weeks after treatment discontinuation. A vitamin B12 injection, 1000 micrograms intramuscularly, was administered one to three weeks before the first chemotherapy dose and repeated approximately every nine weeks until treatment discontinuation.
Dexamethasone 4 mg (or an equivalent corticosteroid) twice daily was administered orally for skin rash prophylaxis to all patients one day prior to, on the day of, and one day after each dose of pemetrexed disodium.
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
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Non-Small Cell Lung Cancer
On August 19, 2004, the U.S. Food and Drug Association granted accelerated approval to pemetrexed disodium for injection (Alimta®, made by Eli Lilly and Company) as a single agent for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy.
Safety and efficacy were demonstrated in one multicenter, randomized trial in 571 patients comparing single-agent pemetrexed disodium versus docetaxel. Pemetrexed disodium, 500 mg/m2 intravenously, was administered over 10 minutes on day 1 of each 21-day cycle. Patients receiving pemetrexed disodium also received dexamethasone for skin rash prophylaxis and vitamin B12 and folic acid supplementation.
The primary efficacy endpoint was survival. Pemetrexed disodium failed to demonstrate superior survival compared to docetaxel. Non-inferiority for overall survival could not be demonstrated because there was only one small historical study (total 104 patients) from which to estimate docetaxel's survival effect. A meta-analysis of multiple historical studies is usually required for this survival effect estimation.
In addition, comparison of the survival effect in the current randomized trial was confounded by a 32 percent crossover rate of pemetrexed disodium patients to docetaxel after tumor progression. The median survival time was 8.3 months for pemetrexed disodium-treated patients and 7.9 months for docetaxel-treated patients. Secondary efficacy endpoints included response rate (pemetrexed disodium 9.1 percent, docetaxel 8.8 percent), progression-free survival (pemetrexed disodium and docetaxel, medians 2.9 months) and time-to-progressive disease (pemetrexed disodium, median 3.4 months; docetaxel, median 3.5 months).
Pemetrexed disodium has a more favorable safety profile than docetaxel. Pemetrexed disodium caused less neutropenia, febrile neutropenia, neutropenic infections and need for granulocyte/macrophage colony stimulating factors. Pemetrexed disodium causes less severe alopecia. Elevation of hepatic transaminases was more frequent with pemetrexed disodium than docetaxel. Accelerated approval was based on the improved safety profile and effects on surrogate endpoints.
As a condition of accelerated approval, Eli Lilly and Company is required to conduct additional studies to demonstrate a clinical benefit, such as increased survival or improved disease-related symptoms.
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
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This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other
products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.
For further information related to oncology drug approvals, regulatory information and other oncology resources, please refer to the FDA's Oncology Tools Web site.
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