STEP THERAPY CRITERIA BRAND NAME* (Generic) GRALISE (Gabapentin Extended Release Tablet)

Home , Gabapentin enacarbil, Neuropathic pain, Pregabalin

STEP THERAPY CRITERIA BRAND NAME* (generic) GRALISE (gabapentin extended release tablet)

HORIZANT (gabapentin enacarbil extended release tablet)

LYRICA CR (pregabalin extended-release)

Status: CVS Caremark Criteria Type: Initial Step Therapy; Post Step Therapy Prior Authorization Ref # 656-D * Drugs that are listed in the target drug box include both brand and generic and all dosage forms and strengths unless otherwise stated

FDA-APPROVED INDICATIONS Gralise Gralise is indicated for the management of postherpetic neuralgia.

Gralise is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

Horizant Treatment of Restless Legs Syndrome Horizant (gabapentin enacarbil) Extended-Release Tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. Horizant is not recommended for patients who are required to sleep during the daytime and remain awake at night. Management of Postherpetic Neuralgia Horizant (gabapentin enacarbil) Extended-Release Tablets are indicated for the management of postherpetic neuralgia (PHN) in adults.

Lyrica Lyrica is indicated for:  Management of neuropathic pain associated with diabetic peripheral neuropathy  Management of postherpetic neuralgia  Adjunctive therapy for the treatment of partial onset seizures in patients 4 years of age and older  Management of fibromyalgia  Management of neuropathic pain associated with spinal cord injury

Compendial Uses  Cancer-Related Neuropathic Pain6  Cancer Treatment Related Neuropathic Pain6,12

Lyrica CR Lyrica CR is indicated for the management of:  Neuropathic pain associated with diabetic peripheral neuropathy

This document contains confidential and proprietary information of CVS Caremark and cannot be reproduced, distributed or printed without written permission from CVS Caremark. This document contains references to brand-name prescription drugs that are trademarks or registered trademarks of pharmaceutical manufacturers not affiliated with CVS Caremark. 1

 Postherpetic neuralgia

Efficacy of Lyrica CR has not been established for the management of fibromyalgia or as adjunctive therapy for adult patients with partial onset seizures.

INITIAL STEP THERAPY If the patient has filled a prescription for at least a 30 day supply of regular-release generic gabapentin within the past 120 days under a prescription benefit administered by CVS/caremark, then the requested Gralise, Horizant, Lyrica, or Lyrica CR will be paid under that prescription benefit. If the patient does not meet the initial step therapy criteria, then the system will reject with a message indicating that a prior authorization (PA) is required. The prior authorization criteria would then be applied to requests submitted for evaluation to the PA unit.

COVERAGE CRITERIA The requested drug will be covered with prior authorization when the following criteria are met:  The patient has experienced an inadequate treatment response, intolerance, or contraindication to regular- release generic gabapentin OR  Lyrica (pregabalin) or Lyrica CR (pregabalin extended-release) is being prescribed for the management of neuropathic pain associated with diabetic peripheral neuropathy OR  Lyrica (pregabalin) is being prescribed for the management of fibromyalgia, the management of neuropathic pain associated with diabetic peripheral neuropathy, or the management of neuropathic pain associated with spinal cord injury OR  Horizant (gabapentin enacarbil) is being prescribed for the treatment of Restless Legs Syndrome

RATIONALE If the patient has filled a prescription for at least a 30 day supply of regular-release generic gabapentin within the past 120 days under a prescription benefit administered by CVS/caremark, then the requested drug will be paid under that prescription benefit.

If the patient does not meet the initial step therapy criteria, then prior authorization is required.

The intent of the criteria is to provide coverage consistent with product labeling, FDA guidance, standards of medical practice, evidence-based drug information, and/or published guidelines. Gralise (gabapentin extended-release) is indicated for the management of postherpetic neuralgia (PHN).1 Horizant extended-release (gabapentin enacarbil extended-release) tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. Horizant extended-release (gabapentin enacarbil extended-release) tablets are also indicated for the management of postherpetic neuralgia in adults.2 Lyrica (pregabalin) is indicated for management of neuropathic pain associated with diabetic peripheral neuropathy, management of postherpetic neuralgia (DPN), adjunctive therapy for the treatment of partial onset seizures in patients 4 years of age and older, management of fibromyalgia (FM), and management of neuropathic pain associated with spinal cord injury.3 Lyrica CR (pregabalin extended-release) is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and management of postherpetic neuralgia (PHN).4

Gabapentin (regular-release) is indicated for management of postherpetic neuralgia in adults. Gabapentin (regular- release) is also indicated as adjunctive therapy in the treatment of partial seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy.7

According to the Report of the Quality Standards Subcommittee of the American Academy of Neurology, gabapentin is effective in the reduction of pain from postherpetic neuralgia.11 Likewise, the American Academy of Neurology and American Epilepsy Society, state that gabapentin is appropriate for adjunctive treatment of refractory partial seizures in adults and children.15 Gabapentin has also shown to have analgesic effects in many cases of neuropathic pain

syndromes.5-13 The National Comprehensive Cancer Network (NCCN) guidelines state that antidepressants and anticonvulsants are first-line analgesics for the treatment of cancer-related neuropathic pain. NCCN Guidelines for Adult Cancer Pain also state that neuropathic pain may be an adverse effect of chemotherapy (e.g., vincristine) or radiation therapy. The most commonly employed anticonvulsant drugs for the treatment of cancer pain are gabapentin and pregabalin.12 Therefore, a trial of regular-release generic gabapentin will be required for the diagnosis of postherpetic neuralgia prior to approval of Gralise, Horizant, Lyrica, or Lyrica CR, for cancer related neuropathic pain or cancer treatment related neuropathic pain prior to approval of Lyrica or Lyrica CR, or for the diagnosis of partial onset seizures prior to the approval of Lyrica.

The American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation guideline for painful diabetic neuropathy states that Lyrica (pregabalin) is established as effective and should be offered, if clinically appropriate, for the relief of diabetic peripheral neurophathy.9 The American Diabetes Association recommends that pregabalin should be considered as the initial approach in the symptomatic treatment for neuropathic pain in diabetes.13 Therefore, Lyrica (pregabalin) or Lyrica CR (pregabalin extended-release) will be approved for the management of neuropathic pain associated with diabetic peripheral neuropathy without requiring a trial of regular-release generic gabapentin.

There are varying levels of evidence for the use of gabapentin for the treatment of fibromyalgia, Restless Legs Syndrome, and neuropathic pain with spinal cord injury.8-14 Therefore, Lyrica will be approved for the diagnosis of fibromyalgia and neuropathic pain with spinal cord injury and Horizant will be approved for the diagnosis of Restless Legs Syndrome without requiring a trial of regular-release generic gabapentin. The efficacy of Lyrica CR has not been established for the management of fibromyalgia.

REFERENCES 1. Gralise [package insert]. North Chicago, IL: Abbott Laboratories; September 2015. 2. Horizant [package insert]. Research Triangle Park, NC: GlaxoSmithKline; October 2016. 3. Lyrica [package insert]. New York, NY: Parke-Davis; May 2018. 4. Lyrica CR [package insert]. New York, NY: Parke-Davis; October 2017. 5. AHFS DI (Adult and Pediatric) [database online]. Hudson, OH: Lexi-Comp, Inc.; http://online.lexi.com/lco/action/index/dataset/complete_ashp [available with subscription]. Accessed May 2018. 6. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomson Reuters (Healthcare) Inc. Updated periodically. http://www.thomsonhc.com [available with subscription]. Accessed May 2018. 7. Neurontin [package insert]. New York, NY: Parke-Davis Division of Pfizer Inc; February 2018. 8. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update. Mayo Clin Proc. 2010;85(3)(suppl):S3-S14. 9. Bril V, England J, Franklin G, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758-1765. 10. Wiffen PJ, Derry S, Moore RA, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia – an overview of Cochrane reviews (Review). Cochrane Database of Systematic Reviews. 2013; 1: Art. No.: CD010567. 11. Dubinsky R, Kabbani H, El-Chami Z, et al. Practice parameter: treatment of postherpetic neuralgia: an evidence- based report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004 63(6):959-965. 12. NCCN Guidelines. Version 1.2018 Adult Cancer Pain. http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Accessed May 2018 13. Pop-Busui R, Boulton, A, Feldman E, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. January 2017; 40(1): 136-154.. 14. Winkelman, J, Armstrong M, et al. Practice guideline summary: Treatment of restless leg syndrome in adults. Neurology 2016;87:2585–2593 15. French J, Kanner A, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1252- 1260.

Written by: UM Development (NB) Date Written: 06/2006 Revised: (NB) 06/2007; (CT) 05/2008, 05/2009, 05/2010, 04/2011 (added Gralise/Horizant and questions 2 and 3), 02/2012, (TM) 06/2012 (update PIs added question 4), 10/2012 (extended duration), (TM) 03/2013, (PL) 09/2013, 05/2014, (JH) 05/2015; (KM) 05/2016 (no clinical changes), 05/2017, 09/2017 (added cancer treatment pain), 10/2017 (added Lyrica CR); (DS) 05/2018 (no clinical changes) Reviewed: Medical Affairs 06/2006, 06/2007; (WF) 05/2008, 05/2009; (KP) 05/2010, 04/2011, 02/2012, 06/2012, 10/2012, (DC) 03/2013, (LCB) 05/2014, (DNC) 05/2015; (AN) 09/2017; (DNC) 10/2017 External Review: 09/2006, 10/2007, 08/2008, 10/2009, 12/2010, 04/2011, 06/2012, 06/2013, 10/2013, 02/2014, 10/2014, 10/2015, 02/2016, 10/2016, 10/2017, 12/2017, 10/2018

CRITERIA FOR APPROVAL

1 Has the patient experienced an inadequate treatment response, intolerance, or Yes No contraindication to regular-release generic gabapentin? [If yes, then no further questions.]

2 Is this request for Horizant (gabapentin enacarbil)? Yes No [If no, then skip to question 4.]

3 Is Horizant (gabapentin enacarbil) being prescribed for the treatment of Restless Legs Yes No Syndrome? [No further questions.]

4 Is this request for Lyrica CR (pregabalin extended-release)? Yes No [If no, then skip to question 6.]

5 Is Lyrica CR (pregabalin extended-release) being prescribed for management of Yes No neuropathic pain associated with diabetic peripheral neuropathy? [No further questions.]

6 Is this request for Lyrica (pregabalin)? Yes No

7 Is Lyrica (pregabalin) being prescribed for one of the following: A) Management of Yes No fibromyalgia, B) Management of neuropathic pain associated with diabetic peripheral neuropathy, C) Management of neuropathic pain associated with spinal cord injury?

Guidelines for Approval Duration of Approval 36 Months Set 1 – Trial of Regular-Release Generic Gabapentin Set 2 – Lyrica CR Diabetic Peripheral Neuropathy (DPN) Yes to question(s) No to question(s) Yes to question(s) No to question(s) 1 None 4 1 5 2 Set 3 – Lyrica Fibromyalgia (FM), Diabetic Peripheral Set 4 – Horizant Restless Leg Syndrome (RLS) Neuropathy (DPN), Spinal Cord Injury (SCI) Yes to question(s) No to question(s) Yes to question(s) No to question(s) 6 1 2 1 7 2 3 4

Mapping Instructions Yes No DENIAL REASONS – DO NOT USE FOR MEDICARE PART D 1. Approve, 36 Months Go to 2 2. Go to 3 Go to 4 3. Approve, 36 Months Deny You do not meet the requirements of your plan. Your plan covers this drug when you have one of these conditions: - You have Restless Legs Syndrome - When you have tried generic gabapentin and it either did not work for you or you cannot use it. Your request has been denied based on the information we have.

[Short Description: No approvable diagnosis; no inadequate response, intolerance or contraindication to generic gabapentin] 4. Go to 5 Go to 6 5. Approve, 36 Months Deny You do not meet the requirements of your plan. Your plan covers this drug when you have one of these conditions: - You have nerve pain associated with diabetes - When you have tried generic gabapentin and it either did not work for you or you cannot use it. Your request has been denied based on the information we have.

[Short Description: No approvable diagnosis; no inadequate response, intolerance or contraindication to generic gabapentin] 6. Go to 7 Deny You do not meet the requirements of your plan. Your plan covers this drug when you have tried generic gabapentin and it either did not work for you or you cannot use it. Your request has been denied based on the information we have

[Short Description: No inadequate response, intolerance or contraindication to generic gabapentin] 7. Approve, 36 Months Deny You do not meet the requirements of your plan. Your plan covers this drug when you have one of these conditions: - You have fibromyalgia - You have nerve pain associated with diabetes - You have nerve pain associated with spinal cord injury - When you have tried generic gabapentin and it either did not work for you or you cannot use it. Your request has been denied based on the information we have.

[Short Description: No approvable diagnosis; no inadequate response, intolerance or contraindication to generic gabapentin]