Prior Authorization Guideline

Prior Authorization Guideline Guideline: PDP PSERS - Novantrone Therapeutic Class: Antineoplastic Agents Therapeutic Sub-Class: Anthrecenedione Client: 2007 PDP PSERS Inj Approval Date: 5/18/2001 Revision Date: 2/20/2007 I. BENEFIT COVERAGE Table 1. Formulary status Non-Formulary Products * Brand product subject to Prior Authorization Formulary Products Tier 4 Novantrone (mitoxantrone)* II. INDICATIONS A. FDA Approved Indications 1. Multiple Sclerosis Novantrone is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). Novantrone is not indicated in the treatment of patients with primary progressive multiple sclerosis. 1 2. Prostate Cancer Novantrone in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer. 1 3. Acute Non-Lymphocytic Leukemia (ANLL) Novantrone in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias. 1 III. GUIDELINE A. Multiple Sclerosis

1. Initial Therapy a. Novantrone will be approved based on all of the following criteria: (1) Failure, intolerance, or contraindication to generic mitoxantrone (2) Confirmed diagnosis of one of the following: 1 (a) Secondary progressive multiple sclerosis: gradually worsening disability with or without superimposed relapses; 2 OR (b) Progressive relapsing multiple sclerosis: progression of disability from the onset with superimposed relapses; 2 OR (c) Worsening relapsing-remitting multiple sclerosis: neurological status remains significantly abnormal in between MS relapses 3 (3) Disease progression despite one of the following therapies: 4,a (a) Avonex (interferon beta-1a) (b) Betaseron (interferon beta-1b) (c) Copaxone (glatiramer acetate) (d) Rebif (interferon beta-1a) (4) Left ventricular ejection fraction (LVEF) 50% by echocardiogram or multigated radionuclide angiography (MUGA) 1,2,5-6 (5) Neutrophil count of 1,500 cell/mm 3 or greater 1 (6) A lifetime cumulative dose greater than 140 mg/m 2 has not been received 1 1, 5-6,b Initial authorization will be issued for 12 weeks of therapy. 2. Re-authorization a. Novantrone will be re-authorized based on all of the following criteria: (1) Left ventricular ejection fraction (LVEF) 50% 1,2,5-6 (2) A lifetime cumulative dose greater than 140mg/m 2 has not been received 1 1, 5-6,b Re-authorization will be issued for 12 weeks of therapy.

B. Prostate Cancer 1. Novantrone will be approved based on all of the following criteria: a. Failure, intolerance, or contraindication to generic mitoxantrone b. Confirmed diagnosis of hormone-refractory metastatic prostate cancer 12 c. Left ventricular ejection fraction (LVEF) 50% by echocardiogram or multi-gated radionuclide angiography (MUGA) 1,2,5-6 d. Neutrophil count of 1,500 cell/mm 3 or greater 1 C. Acute Non-Lymphocytic Leukemia (ANLL) 1. Novantrone will be approved based on all of the following criteria: a. Failure, intolerance, or contraindication to generic mitoxantrone b. Confirmed diagnosis of acute non-lymphocytic leukemia (also known as acute myeloid leukemia) c. Left ventricular ejection fraction (LVEF) 50% by echocardiogram or multi-gated radionuclide angiography (MUGA) 1,2,5-6 IV. CONTRAINDICATIONS AND WARNINGS 1 A. Contraindications B. Warnings Novantrone is contraindicated in patients who have demonstrated prior hypersensitivity to it. 1. Black Box Warning Novantrone (mitoxantrone for injection concentrate) should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. Novantrone should be given slowly into a freely flowing intravenous infusion. It must never be given subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration.

NOT FOR INTRATHECAL USE. Severe injury with permanent sequelae can result from intrathecal administration. Except for the treatment of acute nonlymphocytic leukemia, Novantrone therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm 3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Novantrone. Use of Novantrone has been associated with cardiotoxicity. Cardiotoxicity can occur at any time during Novantrone therapy, and the risk increases with cumulative dose. Congestive heart failure (CHF), potentially fatal, may occur either during therapy with Novantrone or months to years after termination of therapy. All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of Novantrone therapy. Baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated radionuclide angiography (MUGA) should be performed. Multiple sclerosis patients with a baseline LVEF <50% should not be treated with Novantrone. LVEF should be reevaluated by echocardiogram or MUGA prior to each dose administered to patients with multiple sclerosis. Additional doses of Novantrone should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below 50% or a clinically significant reduction in LVEF during Novantrone therapy. Patients with multiple sclerosis should not receive a cumulative dose greater than 140 mg/m2. In cancer patients, the risk of symptomatic congestive heart failure (CHF) was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m 2. Presence or history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with Novantrone may occur whether or not cardiac risk factors are present. Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone. In a cohort of mitoxantrone treated MS patients followed for varying periods of time, an elevated leukemia risk of 0.25% (2/802) has been observed. Postmarketing cases of secondary AML have also been reported. In 1,774 patients with breast cancer who received Novantrone concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related AML, was estimated as 1.1% and 1.6% at 5 and 10 years, respectively Secondary acute myelogenous leukemia (AML) has been reported in cancer patients treated with anthracyclines. Novantrone is an anthracenedione, a related drug. The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. 2. Preganancy Novantrone may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. There are no adequate and wellcontrolled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each

dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus. 3. Secondary leukemia Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone. In a cohort of mitoxantrone treated MS patients followed for varying periods of time, an elevated leukemia risk of 0.25% (2/802) has been observed. Postmarketing cases of secondary AML have also been reported.in breast cancer patients who received Novantrone concomitantly with other cytotoxic agents and radiotherapy. Secondary AML has also been reported in cancer patients treated with anthracyclines. Novantrone is an anthracenedione, a related drug. The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. V. DOSING Novantrone Injection Multiple Sclerosis: 12 mg/m 2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Novantrone should not be administered to patients with a left ventricular ejection fraction (LVEF) <50%, or to those who have received a cumulative lifetime dose of 140 mg/m 2. Hormone-Refractory Prostate Cancer Combination Initial Therapy for ANLL in Adults 12 to 14 mg/m 2 given as a short intravenous infusion every 21 days. 12 mg/m 2 daily on Days 1-3 given as an intravenous infusion, and 100 mg/m 2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1-7. In the event of an incomplete antileukemic response, a second induction course may be given. Novantrone should be given for 2 days and cytarabine for 5 days using the same daily dosage levels. Consolidation therapy which was used in two large randomized multi-center trials consisted of Novantrone, 12 mg/m 2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m 2 for 5 days given as a continuous 24-hour infusion on Days 1-5. The first course was given approximately 6 weeks after the final induction course, the second was generally administered 4 weeks after the first. Severe myelosuppression occurred.

VI. AVAILABILITY Novantrone: 20 mg (10 ml), 25 mg (12.5 ml), and 30 mg (15 ml) multidose vials VII. BACKGROUND A. Description 1 Novantrone (mitoxantrone hydrochloride) is a synthetic antineoplastic anthracenedione. Mitoxantrone, a DNA-reactive agent intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. Novantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL- 2. B. Clinical Studies 1. Multiple Sclerosis A 24 month, multi-center, double-blind, phase III controlled trial was conducted in 194 patients. 2 All patients had either worsening relapsing-remitting or secondary progressive MS, and were placed in three different groups: placebo (n=65), mitoxantrone 5 mg/m 2 (p=66), and mitoxantrone 12 mg/m 2 (p=63). The primary outcomes measured was a compilation of the expanded disability status scale (EDSS), ambulatory index (AI), number of treated relapse, time to first treated relapse, and the standardized neurological status (SNS). At the end of the two years, the 12 mg/m 2 group had a significant improvement (p<0.0001) over the placebo group in terms of the primary outcomes using a multivariate comparison. The mitoxantrone 5 mg/m 2 group was included primarily for exploratory purposes, and showed a significant difference compared to placebo only in the mean change of EDSS scores. A one year, randomized, double-blind, placebo-controlled trial of mitoxantrone was conducted in 25 patients. 7 All patients had relapsing-remitting MS with a minimum of two attacks two years preceding study entry, and serial enhanced MRI. The patients were divided into two groups, mitoxantrone 8 mg/m 2 monthly (n=13) and placebo (n=12), balanced for age, gender, duration of illness, and neurological disability. The results were not significant in terms of new, enlarging, or Gadolinium-DTPA enhancing lesions between the two groups via serial Gd-DTPA enhanced MRI; however, there was a trend towards a decreasing number of enlarging and Gd-DTPA enhancing lesions. Due to the small sample size and short duration of the study, conclusive evidence for mitoxantrone s role in MS could not be made. 2. Prostate Cancer A comparison of docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer in 674 men was studied. 8 The patients were randomly assigned to one of two treatment groups, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg/m 2 of docetaxel on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel (n=338); or 12 mg/m 2 of mitoxantrone on day 1 plus 5 mg of prednisone twice daily

(n=336). The primary end point was overall survival. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). A total of 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg/m 2 of mitoxantrone every three weeks, 75 mg/m 2 of docetaxel every three weeks, or 30 mg/m 2 of docetaxel weekly for five of every six weeks. 9 The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone. 3. Acute Non-Lymphocytic Leukemia A randomized, multi-center, phase 3 study in which 328 patients over 55 years of age with previously untreated AML were randomized to receive mitoxantrone (10 mg/m 2 per day x 5) and etoposide (100 mg/m 2 per day x 5) [ME]; or cytarabine (200 mg/m 2 per day x 7) and daunorubicin (45 mg/m 2 ) per day x 3) [AD] as induction therapy. 10 The complete remission rate was 34% (95% confidence interval [CI] 26%-41%) for patients in the ME, and 43% (CI 35%-51%) for patients in the AD treatment arm (one-tailed P-value=.96). The rates of resistant disease were 43 and 34%, respectively, for the 2 treatment arms (one-tailed P-value=.95). The estimated overall survival at 2 years was 11% and 19% for patients randomized to ME and to AD induction therapy, respectively (one-tailed P- value=.99). After accounting for the independent prognostic factors associated with survival (karyotype, performance status, age, white blood cell count), exploratory analysis suggested there was a worse survival for patients who received ME compared with AD induction therapy (2-tailed P-value=.0066). C. National Guidelines 1. Acute Non-Lymphocytic Leukemia a. The National Comprehensive Cancer Network (NCCN) (2006) 11 The NCCN recommendation for patients with acute myeloid leukemia (also known as acute non-lymphocytic leukemia) with unknown cytogenics at induction be on mitoxantrone (1 cycle) or high-dose cytarabine with either idarubicin or daunorubicin if < 60 years of age (Category 2B); or on mitoxantrone (7+3) or standard-dose cytarabine (Category 1) if 60 years of age. 2. Prostate Cancer a. The National Comprehensive Cancer Network (NCCN) (2005) 12

The NCCN recommends that systemic chemotherapy should be reserved for patients with hormone-refractory metastatic prostate cancer, except when the patients are in clinical trials. The standard of care for these patients should be docetaxel-based regimens. Mitoxantrone in combination with prednisone does provide some palliative benefits for hormone-refractory prostate cancer patients suffering from painful bony metastases; however, use of this regimen as second-line therapy has yet to be determined. 3. Multiple Sclerosis a. The American Academy of Neurology (2002) 4 Based on one Class I study and limited Class II and II studies, the Academy states that although Novantrone appears to have a beneficial effect on disease progression in patients with multiple sclerosis whose clinical condition is deteriorating, this agent is of limited use and of potentially great toxicity (Type B recommendation). Therefore, it should be reserved for patients with rapidly advancing disease who have failed other therapies. VIII. DEFINITIONS Multiple sclerosis 2 1. Relapsing- remitting: clearly defined acute attacks followed by complete or incomplete recovery 2. Secondary progressive: gradually worsening disability with or without superimposed relapses 3. Primary progressive: progression of disability from the onset 4. Progressive relapsing: progression of disability from the onset with superimposed relapses 5. Worsening: neurological status remains significantly abnormal in between MS relapses 3 IX. REFERENCES 1. Novantrone Prescribing Information. Serono, Inc., March 2005. 2 Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomized, mulitcentre trial. Lancet 2002;360:2018-25. 3. Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61:1332-38. 4. The American Academy of Neurology. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Available at: http://www.guideline.gov/summary/summary.aspx?doc_id=5330&nbr=003643&string=multi ple+and+sclerosis#s23. Accessed December 13, 2006. 5. Avasarala JR, Cross AH, Clifford DB, Singer BA, Siegal BA, Abbey EE. Rapid onset mitoxantron-induced cardiotoxicity in secondary progressive multiple sclerosis. Mult Scler. 2003;9:59-62. 6. Ghalie RG, Edan G, Laurent M, et al. Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS. Neurology. 2002;59:909-13.

7. Bastianello S, Pozzilli C, D Andrea F, et al. A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year. Can J Neurol Sci. 1994;21:266-70. 8. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-20. 9. Tannock IF, de Wit R, Berry WR, et al. Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12. 10. Anderson JE, Kopecky KJ, Willman CL, et al. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood. 2002;100:3869-76. Epub 2002 Aug 1. 11. NCCN Practice Guidelines in Oncology. Acute Myeloid Leukemia v.1.2006. Available at: http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed December 19, 2006. 12 NCCN Practice Guidelines in Oncology. Prostate Cancer v.2.2005. Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed December 19, 2006. 13. Avonex Prescribing Information. Biogen Idec Inc., May 2006. 14. Betaseron Prescribing Information. Chiron, Corp., July1993. 15. Rebif Prescribing Information. Serono, Inc., Septemeber 2005 16. Copaxone Prescribing Information. Baxter Pharmaceutical Solutions, May 2006. X. ENDNOTES a. Avonex, Betaseron, Rebif, and Copaxone are all FDA approved for the treatment of patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. 13-16 b. All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of Novantrone therapy. Baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated radionuclide angiography (MUGA) should be performed. Multiple sclerosis patients with a baseline LVEF <50% should not be treated with Novantrone. LVEF should be reevaluated by echocardiogram or MUGA prior to each dose administered to patients with multiple sclerosis. Additional doses of Novantrone should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below 50% or a clinically significant reduction in LVEF during Novantrone therapy. 1 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.