Prior Authorization Guideline

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1 Prior Authorization Guideline Guideline: PS Inj - Alimta Therapeutic Class: Antineoplastic Agents Therapeutic Sub-Class: Antifolates Client: PS Inj Approval Date: 8/2/2004 Revision Date: 12/5/2006 I. BENEFIT COVERAGE Table 1. Formulary status Non-Preferred Products Alimta (permetrexed) Preferred Products II. INDICATIONS A. FDA Approved Indications 1. Mesothelioma Alimta in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 2. Non-Small Cell Lung Cancer Alimta as a single-agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy. The effectiveness of Alimta in second-line NSCLC was based on the surrogate endpoint, response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable survival effect or improvement of disease-related symptoms. III. GUIDELINE A. Malignant Pleural Mesothelioma 1. Alimta will be approved based on all of the following criteria: a. Confirmed diagnosis of malignant pleural mesothelioma b. Disease is unresectable or patient is not a candidate for curative surgery c. Used in combination with cisplatin

2 Authorization for therapy will be issued for length of therapy B. Non-Small Cell Lung Cancer (NSCLC) 1. Alimta will be approved based on all of the following criteria: a. Confirmed diagnosis of locally advanced or metastatic (Stage III or IV) non-small cell lung cancer b. Prior history of first-line chemotherapy treatment for non-small cell lung cancer (e.g. bevacizumab, or cisplatin-based or paclitaxel chemotherapy regimens) 2 Authorization for therapy will be issued for length of therapy IV. CONTRAINDICATIONS AND WARNINGS A. Contraindications Alimta is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. B. Warnings 1. Decreased Renal Function Alimta is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance Ý45 ml/min. Insufficient numbers of patients have been studied with creatinine clearance <45 ml/min to give a dose recommendation. Therefore, Alimta should not be administered to patients whose creatinine clearance is <45 ml/min. 2. Bone Marrow Suppression Alimta can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia), myelosuppression is usually the doselimiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle. 3. Need for Folate and Vitamin B 12 Supplementation Patients treated with Alimta must be instructed to take folic acid and vitamin B 12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered. 4. Pregnancy Category D Alimta may cause fetal harm when administered to a pregnant woman. Pemetrexed was fetotoxic and teratogenic in mice at i.p. doses of 0.2 mg/kg (0.6 mg/m2) or 5 mg/kg (15 mg/m2) when given on gestation days 6 through 15. Pemetrexed caused fetal malformations (incomplete ossification of talus and skull bone) at 0.2 mg/kg (about 1/833

3 the recommended i.v. human dose on a mg/m2 basis), and cleft palate at 5 mg/kg (about 1/33 the recommended i.v. human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. There are no studies of Alimta in pregnant women. Patients should be advised to avoid becoming pregnant. If Alimta is used during pregnancy, or if the patient becomes pregnant while taking Alimta, the patient should be apprised of the potential hazard to the fetus. V. DOSING Alimta Mesothelioma: 500 mg/m 2 IV infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of Alimta administration. Non-Small Cell Lung Cancer: Premedication Regimen 500 mg/m 2 IV infusion over 10 minutes on Day 1 of each 21-day cycle. Dexamethasone 4 mg po twice daily the day before, the day of, and the day after Alimta administration. Folic acid 350 to 1000 mcq daily, at least 5 daily doses during the 7-days period preceding the first dose of Alimta, continued during the full course and for 21 days after the last dose of Alimta. Vitamin B mcg IM during the week preceding the first dose of Alimta and every 3 cycles thereafter. Subsqeuent Vitamin B 12 injections may be given the same day as Alimta. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hemotologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment should be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Table 2-4. Table 2: Dose Reduction for Alimta and Cisplatin Hemotologic Toxicities Nadir ANC < 500/mm 3 and nadir 75% of previous dose (both drugs) platelets 50,000/mm 3 Nadir platelets < 50,000/mm 3 50% of previous dose (both drugs) regardless of nadir ANC. Table 3: Dose Reduction Nonhematologic Toxicities a,b Dose of Alimta Dose of Cisplatin Any Grade 3 c or 4 toxicities 75% of previous dose 75% of previous dose except mucositis Any diarrhea requiring 75% of previous dose 75% of previous dose

4 hospitalization Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC) b Excluding neurotoxicity Except Grade 3 transaminase elevation Table 4: Dose Reduction for Alimta and Cisplatin Neurotoxicity CTC Grade Dose of Alimta Dose of Cisplatin % of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose VI. AVAILABILITY Alimta injection is available in sterile single-use vials containing 500 mg of permetrexed. VII. BACKGROUND A. Description Alimta, permetrexed for injection, is an antifolate antineoplastic agent that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. B. Clinical Studies 1. Malignant Pleural Mesothelioma In a multicenter, Phase III, single-blind, randomized trial (n=456), the efficacy and toxicity of permetrexed with cisplatin was compared to cisplatin alone in patients with malignant pleural mesothelioma (MPM). The primary outcome was survival. On an intent-to-treat basis, the median survival time was significantly longer for patients treated with permetrexed and cisplatin versus cisplatin alone: 12.1 months vs. 9.3 months (logrank p=0.020). The 2.8-month survival benefit represents a hazard ratio of 0.77 or relative risk reduction for death of 23%. 2. Non-Small Cell Lung Cancer In a Phase III, randomized trial (n=571), the efficacy and toxicity of pemetrexed was compared to docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with one prior chemotherapy. 3 The primary endpoint was overall survival. On an intent-to-treat basis, the median survival time for permetrexed was 8.3 months versus 7.9 for docetaxel (HR, 0.99; 95% CI: ; noninferiority p=0.226). In incidence of Grade 3 and 4 hematologic toxicities such as neutropenia, febrile neutropenia, and neutropenia with infection was significantly less (p<0.001, <0.001, =0.004, respectively) in patients taking permetrexed compared to docetaxel. The authors concluded that treatment with permetrexed demonstrated clinically equivalent efficacy with significant improved safety profile compared with those receiving docetaxel. The authors suggest that treatment with pemetrexed should be considered standard treatment option for second-line NSCLC. C. National Guidelines 1. National Comprehensive Cancer Network 2

5 Non-Small Cell Lung Cancer For recurrent and metastatic disease, first-line therapy with bevacizumab in combination with chemotherapy is the preferred treatment option for patients with performance status (PS) of 0-2 who meet the eligibility criteria (nonsquamous cell histology, no history of hemoptysis, no CNS metastases and no ongoing therapeutic anticoagulation). In patients with who are non-candidates for bevacizumab treatment, platinum-based chemotherapy regimen is recommended as first-line chemotherapy for the treatment of advanced disease. As yet, there is no evidence that one platinum-based regimen is better than others. Docetaxel, permetrexed, and erlotinib are recommended single agent second-line chemotherapy regimens for patients with PS of 0-2 and who have experienced disease progression during or after first-line therapy. VIII. REFERENCES 1. Alimta Prescribing Information. Eli Lilly and Company, January National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology v Non-Small Cell Lung Cancer. Available at: Accessed November 16, Vogelzang NJ 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: Hanna N et al. Randomized phase III trial of permetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22: This Prior Authorization Guideline represents the recommendation of Prescription Solutions Pharmacy and Therapeutics (P&T) Committee. It is based upon the P&T Committee s review of the available evidence as of the date of drafting or revision of this Prior Authorization Guideline. It is subject to updating from time to time, based upon changes in scientific knowledge and information. This Prior Authorization Guideline is intended as a resource for making coverage decisions for Health Plan members, but it does not replace an individualized case-by-case review and medical necessity determination for each Health Plan member. Copyright 2006 by Prescription Solutions. All rights reserved. This Prior Authorization Guideline is intended for use by Prescription Solutions and Health Plan employees and applicable contracted providers and practitioners only. The information contained in this Prior Authorization Guideline is confidential and proprietary to Prescription Solutions and shall not be used, reproduced, or transferred in whole or in part without Prescription Solutions prior written consent.