Clinical Policy: Nabilone (Cesamet), Dronabinol (Marinol, Syndros) Reference Number: CP.CPA.242 Effective Date: 11.16.16 Last Review Date: 11.17 Revision Log Line of Business: Medicaid

See Important Reminder at the end of this policy for important regulatory and legal information.

Description The following are synthetic cannabinoids requiring prior authorization: dronabinol (Marinol®, Syndros®), nabilone (Cesamet™)

FDA approved indication Marinol Cesamet Syndros Controlled Substance Schedule Category CIII CII CII Treatment of and vomiting associated with X X X cancer in patients who have failed to respond adequately to conventional antiemetic treatments Treatment of Anorexia associated with weight loss X X in patients with acquired immune deficiency syndrome (AIDS)

Policy/Criteria Provider must submit documentation (which may include office chart notes and lab results) supporting that member has met all approval criteria

It is the policy of health plans affiliated with Centene Corporation® that Cesamet, Marinol, and Syndros are medically necessary when the following criteria are met:

I. Initial Approval Criteria A. Nausea and Vomiting Associated with Cancer Chemotherapy (must meet all): 1. Diagnosis of nausea and vomiting associated with cancer chemotherapy; 2. Patient has received highly or moderately emetogenic chemotherapy; 3. Failure of a trial of a 5-HT3 serotonin antagonist (e.g. ondansetron), in combination with Emend® and dexamethasone unless contraindicated or clinically significant adverse effects are experienced; 4. Failure of TWO of the following unless contraindicated or clinically significant adverse effects are experienced: metoclopramide, prochlorperazine, lorazepam; 5. Dose does not exceed 15 mg/m2 per dose (6 doses per day) (Marinol), 6 mg/day (Cesamet), 12.6 mg/m2 per dose (6 doses per day) (Syndros). Approval duration: Length of benefit

B. Anorexia (Marinol and Syndros requests only) (must meet all): 1. Diagnosis of anorexia with weight loss in patients with AIDS or cancer;

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2. Prescribed for appetite stimulation; 3. Request is for Marinol or Syndros; 4. Failure of a trial of megestrol at maximally indicated doses unless contraindicated or clinically significant adverse effects are experienced; 5. Dose does not exceed 20 mg/day (Marinol), 16.8 mg/day (Syndros). Approval duration: Length of benefit

C. Other diagnoses/indications 1. Refer to CP.PMN.53 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized)

II. Continued Therapy A. All indications in Section I (must meet all): 1. Currently receiving medication via a health plan affiliated with Centene Corporation or member has previously met initial approval criteria; 2. Member is responding positively to therapy; 3. If request is for a dose increase, new dose does not exceed the FDA approved maximum recommended dose for the relevant indication. Approval duration: Length of benefit

B. Other diagnoses/indications (must meet 1 or 2): 1. Currently receiving medication via a health plan affiliated with Centene Corporation and documentation supports positive response to therapy. Approval duration: Duration of request or 12 months (whichever is less); or 2. Refer to CP. PMN.53 if diagnosis is NOT specifically listed under section (Diagnoses/Indications for which coverage is NOT authorized)

III. Diagnoses/Indications for which coverage is NOT authorized: A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policy – CP. PMN.53 or evidence of coverage documents

IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AIDS: acquired immune deficiency syndrome

Appendix B: General Information  Cesamet may be administered for 48 hours after the last dose of each cycle of chemotherapy.  Cesamet is not intended for use on an as-needed basis.  Because of its potential to alter the mental state, Cesamet is intended for use under circumstances that permit close supervision of the patient by a responsible individual particularly during initial use of Cesamet and during dose adjustments.  Marinol capsules contain cannabinoid and sesame oil and should never be used by patients allergic to these substances.

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 The following table is the National Comprehensive Cancer Network’s classification for emetogenic potential of significant chemotherapy and other agents.

Agents Frequency of Emesis AC combination defined as either or High Emetic Risk with , > 250 mg/m2, , >90% cyclophosphamide > 1,500 mg/m2, , doxorubicin ≥ 60 mg/m² epirubicin >90 mg/m², ifosamide > 2 g/m² per dose, mechlorethamine, streptozocin aldesleukin > 12-15 million IU/m2, amifostine > 300 mg/m2, Moderate Emetic Risk 30- , , , , 90% , carmustine ≤ 250 mg/m2, , cyclophosphamide ≤ 1500 mg/m2, > 200 mg/m2, , , doxorubicin <60 mg/ m², epirubicin ≤ 90 mg/m², idarubicin, <2 g/m² per dose, interferon alfa ≥10 million IU/m2, , , (MTX) ≥250 mg/m2, , ado-trastuzumab emtansine, amifostine ≤ 300 mg/m2, Low Emetic Risk aldesleukin ≤ 12 million IU/m2, belinostatm, blinatumomab, 10-30% brentuximab vedotin, cabazitaxol, , cytarabine (low dose) 100 - 200 mg/m2, , doxorubicin (liposomal), , , 5-, , , interferon alfa > 5 <10 million IU/m2, ixabepilone, MTX > 50 mg/m2 < 250 mg/m2, mitomcyin, mitoxantrone, omacetaxine, , paclitaxel-albumin, , , , ,, , ziv-aflibercept alemtuzumab, , bevacizumab, , Minimal Emetic Risk , cetuximab, 2-chlorodeoxyadenosine (), <10% cytarabine < 100 mg/m2, decitabine, denileukin diftitox, dexrazoxane, , interferon alfa ≤ 5 million IU/m2, ipilimumab, MTX ≤ 50 mg/m2, , nivolumab, obinutuzumab, ofatumumab, panitumumab, ,peginterferon, pembrolizumab, pertuzumab, rituximab, temsirolimus, trastuzumab, , , , vincristine (liposomal), altretamine, busulfan (≥ 4 mg/d), crizotinib, cyclophosphamide Emetogenic potential of oral (≥100 mg/m2/d), estramustine, etoposide, lomustin (single antineoplastic agents: day), , , temozolomide (> 75 mg/m2/d), Moderate to High vismodegib Afatinib, axitinib, ,bosutinib, busulfan (< 4 mg/d), Emetogenic potential or oral cabozantinib, , , cyclophosphamide antineoplastic agents: (< 100 mg/m2/d), dasatinib,dabrafenib, erlotinib, everolimus, Minimal to low fludarabine, gefitinib, hydroxyurea, imatinib, lapatinib, lenalidomide, melphalan, , methotrexate, nilotinib, pazopanib, pomalidomide, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, temozolomide (≤ 75 mg/m2/d),

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thalidomide, thioguanine, topotecan, trametinib, , vandetanib, vemurafenib,

Appendix C: Therapeutic Alternatives Drug Dosing Regimen Dose Limit/Maximum Dose 5-HT3 Antagonists Moderately emetogenic chemotherapy As specified by length Ondansetron (MEC): of chemotherapy (Zofran®)* 12 years or older: 8 mg PO beginning 30 minutes before chemotherapy; repeat dose 8 hours after initial dose, then 8 mg PO BID for 1 to 2 days after chemotherapy completed

Adults: 0.15 mg/kg IV for 3 doses up to a maximum of 16 mg per dose. The first dose is infused over 15 minutes beginning 30 minutes before the start of chemotherapy. Subsequent doses may be repeated twice, administered 4 and 8 hours after the first dose.

Highly emetogenic chemotherapy (HEC): Adults: 24 mg PO (given as three 8 mg tablets) 30 minutes prior to start of single day chemotherapy

Adults: 0.15 mg/kg IV for 3 doses up to a maximum of 16 mg per dose. The first dose is infused over 15 minutes beginning 30 minutes before the start of chemotherapy. Subsequent doses may be repeated twice, administered 4 and 8 hours after the first dose. 5-HT3 Antagonists Moderately emetogenic chemotherapy: As specified by length Anzemet® of chemotherapy (dolasetron)* Adults: 100 mg PO within 1 hour prior to chemotherapy 5-HT3 Antagonists Moderately and highly emetogenic As specified by length Granisetron* chemotherapy: of chemotherapy

2 mg PO QD 1 hour prior to chemotherapy OR 1 mg BID 1 hour prior to chemotherapy and then 12 hours later 5-HT3 Antagonists MEC and HEC: As specified by length of chemotherapy

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Drug Dosing Regimen Dose Limit/Maximum Dose Sancuso® Adults: Apply a single patch to the upper (granisetron)* outer arm from 24 to 48 hours before chemotherapy. Remove the patch a minimum of 24 hours after completion of chemotherapy.

The patch can be worn for up to 7 days depending on the duration of . 5-HT3 Antagonists Highly or Moderately emetogenic As specified by length Aloxi® chemotherapy: of chemotherapy (palonosetron)* 0.25 mg IV infused over 30 seconds beginning 30 minutes prior to chemotherapy NK1 Receptor Moderately and highly emetogenic 1 x 125 mg and 2 x 80 Antagonist chemotherapy: mg capsules per cycle Emend® (aprepitant)* 125 mg PO 1 hour prior to chemotherapy and 80 mg on days 2, 3 Oral corticosteroids 20 mg (12 mg with Emend) PO 40 mg/day Dexamethasone (prechemotherapy) and 8 mg PO daily on Days 2, 3 Various chemotherapy dosage regimens Phenothiazines Oral: 5-10 mg PO q 6-8 hours. PO/IM 40 mg/day Promethazine Rectal: 25 mg PR q 12 hours PR: 50 mg/day (Phenergan) Intramuscular/Intravenous: 5-10 mg IM or IV q3-4 hours PRN Dopamine Receptor 1-2mg/kg dose IV 30 minutes before Antagonist chemotherapy. May repeat every 2 hours Metoclopramide for 2 doses then repeat every 3 hours for 3 (Reglan, Metozolv) doses. Benzodiazepines Oral: 2.5 mg PO the evening prior to and 10 mg/day Lorazepam (Ativan) after initiation of chemotherapy

Intramuscular/Intravenous: 0.025-0.05 mg/kg (maximum 4 mg) IM or IV given slowly (2 mg/min) 30 to 35 minutes prior to chemotherapy. May supplement with 1-2 mg PO every hour PRN

Various chemotherapy dosage regimens Miscellaneous Weight loss due to AIDS wasting 20 mg/day Oxandrolone 2.5 – 20 mg PO QD in 2 to 4 divided doses (Oxandrin®) for 2 to 4 weeks

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Drug Dosing Regimen Dose Limit/Maximum Dose Miscellaneous Weight loss due to anorexia 800 mg/day Megestrol suspension 400-800 mg PO QD (Megace®) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic *Requires Prior Authorization

V. Dosage and Administration Drug Indication Dosing Regimen Maximum Dose Nabilone Nausea & 1 or 2 mg PO BID. 1st dose is given 1-3 6 mg/day (Cesamet) Vomiting hours before chemotherapy. A dose the night before chemotherapy may be useful. Start with the lower dose and increase as necessary. Max dose 6 mg/day in divided doses TID. Dosing may continue during entire course of each cycle of chemotherapy and, if needed, for 48 hours after the last dose of each cycle of chemotherapy. Safety and effectiveness have not been established in patients younger than 18

Dronabinol Nausea & Initially given as 5 mg/m2 PO per dose. 15 mg/m2 per dose (Marinol) Vomiting 1st dose is given 1-3 hours before (6 doses per day) chemotherapy, then every 2-4 hours after chemotherapy for total of 4-6 doses/day. This dose may be increased by 2.5 mg/m² increments to a maximum 15 mg/m2 per dose.

Appetite Initially, 2.5 mg PO BID before lunch 20 mg/day Stimulant and dinner. The dose may be increased to a maximum dose 20 mg/day administered in divided oral doses Dronabinol Nausea & Initially given as 4.2 mg/m2 PO per 12.6 mg/m2 per (Syndros) Vomiting dose. 1st dose is given 1-3 hours before dose (6 doses per chemotherapy, then every 2-4 hours day) after chemotherapy for total of 4-6 doses/day. This dose may be increased by 2.1 mg/m² increments to a maximum 12.6 mg/m2 per dose.

Appetite Initially, 2.1 mg PO BID before lunch 16.8 mg/day Stimulant and dinner. The dose may be increased

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to a maximum dose 16.8 mg/day administered in divided oral doses

VI. Product Availability Drug Availability Dronabinol 2.5 mg, 5 mg, 10 mg capsules (Marinol) Nabilone 1 mg capsules (Cesamet) Dronabinol 5 mg/ml oral solution (Syndros)

VII. References 1. Marinol [Prescribing Information] North Chicago, IL: AbbVie, Inc; February 2013. 2. Cesamet [Prescribing Information] Somerset, NJ: MEDA Pharmaceuticals Inc.; September 2013. 3. Syndros [Prescribing Information] Lakewood, NJ: Insys Therapeutics, Inc.; May 2017. 4. Basch E, Prestrud AA, Hesketh, PJ, et al. Antiemetics: American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Update 2011 J Clin Oncol 29:4189-4198. 5. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology - Antiemesis V.1.2012. NCCN Web site. Available at http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed June 10, 2017 6. Clinical Pharmacology Web site, Available at http://clinicalpharmacologyip.com/default.aspx. Accessed June 10, 2017. 7. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed June 10, 2017. 8. Cesamet. American Hospital Formulary Service Drug Information. Available at: http://www.medicinescomplete.com/mc/ahfs/current/ . Accessed June 10, 2017. 9. Marinol. American Hospital Formulary Service Drug Information. Available at: http://www.medicinescomplete.com/mc/ahfs/current/. Accessed June 10, 2017 .

Reviews, Revisions, and Approvals Date P&T Approval Date Converted to new template. Minor changes to verbiage and 06.10.17 11.17 grammar. References updated. Added Syndros to criteria. 09.21.17

Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and

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accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.

The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures.

This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time.

This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions.

Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan.

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services.

Note: For Medicaid members, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.

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©2016 Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene® and Centene Corporation® are registered trademarks exclusively owned by Centene Corporation.

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