Alimta® (Pemetrexed)

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Title Pemetrexed: Recommended Dosing Sequence in Combination With Cisplatin

Pemetrexed should be administrated 30 minutes before cisplatin.

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Detailed Information

This medical response may not completely match the information in the current local labeling for PEMETREXED. Please see local labeling for approved label information.

Pemetrexed in combination with cisplatin is indicated

  • for the initial treatment of patients with locally advanced or metastatic nonsquamous NSCLC, and
  • for the treatment of patients with MPM.1

The recommended dose of pemetrexed is 500 mg/m2 administered as an IV infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.1

Pemetrexed was administered prior to cisplatin in both the pivotal trial for MPM and the first-line treatment of NSCLC.2,3 The same dosing sequence was maintained in recent trials for advanced NSCLC.4-6

Dosing Sequence Rationale

Adequate Hydration

Patients should receive appropriate hydration prior to and/or after receiving cisplatin.1 The administration of cisplatin 30 minutes after pemetrexed is to allow for a saline flush, as well as any needed prehydration for cisplatin administration.1

Synergistic Effects

Pemetrexed is a pyrimidine and purine inhibitor and therefore it may influence cisplatin in the formation or the repair of formed adducts. Given that both chemotherapeutic agents are cell-cycle specific, their effect on the cell cycle can alter their individual cytotoxic effects.7,8

The interaction of pemetrexed and cisplatin may be dependent on the sequence of drug exposure, as well as on the tumor type. An in vitro study demonstrated that the simultaneous exposure to pemetrexed and cisplatin produced antagonistic effects in A549 lung, MCF7 breast and PA1 ovarian carcinoma cells, but additive effects in WiDr colon carcinoma cells.9 In contrast, the same study demonstrated that pemetrexed followed by cisplatin produced synergistic effects in MCF7 cells, greater than additive effects in A549 and PA1 cells, and additive effects in WiDr cells. Cisplatin followed by pemetrexed produced antagonistic effects in A549, MCF7, and PA1 cells and additive effects in WiDr cells. The investigators concluded that the administration of pemetrexed prior to cisplatin would be the preferred sequence.9

References

1Data on file, Eli Lilly and Company and/or one of its subsidiaries.

2Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636-2644. https://doi.org/10.1200/JCO.2003.11.136

3Scagliotti GV, Kortsik C, Dark GG, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non–small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer Res. 2005;11(2):690-696. http://clincancerres.aacrjournals.org/cgi/content/abstract/11/2/690

4Tachihara M, Dokuni R, Okuno K, et al. Phase II study of adjuvant chemotherapy with pemetrexed and cisplatin with a short hydration method for completely resected nonsquamous non–small cell lung cancer. Thorac Cancer. 2020;11(9):2536-2541. https://doi.org/10.1111/1759-7714.13567

5Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non–small-cell lung cancer. J Clin Oncol. 2013;31(23):2895-2902. http://dx.doi.org/10.1200/JCO.2012.47.1102

6Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. http://dx.doi.org/10.1056/NEJMoa1801005

7Jäckel M, Köpf-Maier P. Influence of cisplatin on cell-cycle progression in xenografted human head and neck carcinomas. Cancer Chemother Pharmacol. 1991;27(6):464-471. http://dx.doi.org/10.1007/BF00685161

8Tonkinson JL, Marder P, Andis SL, et al. Cell cycle effects of antifolate antimetabolites: implications for cytotoxicity and cytostasis. Cancer Chemother Pharmacol. 1997;39(6):521-531. http://dx.doi.org/10.1007/s002800050608

9Kano Y, Akutsu M, Tsunoda S, et al. Schedule-dependent interactions between pemetrexed and cisplatin in human carcinoma cell lines in vitro. Oncol Res. 2006;16(2):85-95. https://doi.org/10.3727/000000006783981215

Glossary

IV = intravenous

MPM = malignant pleural mesothelioma

NSCLC = non-small cell lung cancer

Fecha de la última revisión: 2021 M04 28


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