Drug Therapy Guidelines Triptans: almotriptan, Amerge®, Axert®, Frova®, Imitrex® and sumatriptan tablets/nasal spray/injection, Maxalt/MLT®, naratriptan, Onzetra™

Xsail™, Relpax® and eletriptan tablets,

rizatriptan/ODT, Sumavel®, Tosymra™, Treximet®,

Zembrace™ SymTouch™, zolmitriptan/ODT tablets, Applicable Zomig/ZMT® tablets/nasal spray Medical Benefit Effective: 5/28/2021 Pharmacy- Formulary 1 x Next Review: 3/22 Pharmacy- Formulary 2 x Date of Origin: 8/29/06 Pharmacy- Formulary 3/Exclusive x Review Dates: 8/06, 11/07, 12/08, 12/09, 6/10, 3/11, 3/12, 3/13, Pharmacy- Formulary 4/AON x 3/14, 3/15, 3/16, 3/17, 3/18, 3/19, 3/20, 2/21, 3/21

I. Medication Description

Serotonin receptor agonists are used to treat (not prevent) acute attacks of migraine headaches. These medications work by binding to specific serotonin receptors in the brain which in turn decreases the release of chemicals responsible for the vasodilation of cerebral blood vessels, decreases the activity of pain signaling neurons, and reduces inflammation.

II. Position Statement

 For all lines of business, coverage is provided immediately, without requiring prior authorization, for preferred/formulary medications with associated quantity limit restrictions.  Quantity limitations criteria do not apply when the medication is requested by a neurologist.  Coverage is determined through a prior authorization process with supporting clinical evidence for all other requests for members aged 18 and older.

III. Policy

Formulary 1: See Sections B and C Formulary 2: See Sections A and C Formulary 3/Exclusive: See Sections A and C Formulary 4/AON: See Sections A and C

A. Non-preferred medications: Amerge, Axert, Frova, Imitrex, Maxalt, Onzetra, Relpax, Tosymra, Treximet, Zembrace, Zomig, Zolmitriptan nasal spray Plan-preferred medications: eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan tablets, zolmitriptan oral disintegrating tablets B. Non-preferred medications: Amerge, Axert, Frova, Imitrex, Maxalt, Onzetra, Relpax, Tosymra, Zembrace, Zomig, Zolmitriptan nasal spray Plan-preferred medications: eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan tablets, zolmitriptan oral disintegrating tablets C. Coverage will be provided as follows:

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Drug Therapy Guidelines Triptans Last Review Date: 3/2021

 When requesting coverage of a brand medication for which a plan-preferred A/B rated generic is available, coverage will be provided when there is sufficient evidence that the use of the A/B rated generic equivalent has resulted in inadequate results AND  Coverage of any non-preferred medication will be provided when the patient has experienced intolerance or therapeutic failure with at least one plan-preferred medication first OR when at least ONE of the following criteria is met: o The plan-preferred medications are contraindicated or will likely cause an adverse reaction by or physical or mental harm to the member. o The plan-preferred medications are expected to be ineffective based on the known clinical history and conditions of the member and the member’s prescription drug regimen. o The member has tried the plan-preferred medications or another prescription drug in the same pharmacologic class or with the same mechanism of action and such prescription drug was discontinued due to lack of efficacy or effectiveness, diminished effect, or an adverse event. o The member is stable on the medication selected by their healthcare professional for the medical condition under consideration (where “stable” is defined as receiving the medication for an adequate period of time, have achieved optimal response, and continued favorable outcomes are expected UNLESS the medication was initially selected due to the availability of a drug sample or a coupon card). o The plan-preferred medication is not in the best interest of the member because it will likely cause a significant barrier to the member’s adherence or to compliance with the member’s plan of care, will likely worsen a comorbid condition of the member, or will likely decrease the member’s ability to achieve or maintain reasonable functional ability in performing daily activities.

IV. Quantity Limitations

Medication Covered per 30 days Covered per 90 days Imitrex/sumatriptan  25mg, 50mg tablets 18 36  100mg tablets 9 27  4mg injection doses 12 36  6mg injection doses 8 24  Nasal spray 5mg or 20mg 12 24  Sumavel 4mg injection 12 36  Sumavel 6mg injection 8 24 Tosymra 10mg Nasal spray 12 36 Treximet 9 27 Axert/almotriptan  6.25mg tablets 12 36  12.5mg tablets 8 24 Relpax/eletriptan  20mg tablets 12 36  40mg tablets 8 24

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Drug Therapy Guidelines Triptans Last Review Date: 3/2021

Frova 2.5mg tablets 12 36 Amerge/naratriptan  1mg tablets 12 36  2.5mg tablets 9 27 Maxalt/Maxalt MLT/rizatriptan 5mg, 10mg tablets 12 36 Zomig/Zomig ZMT/zolmitriptan  2.5mg tablets 12 36  5mg tablets 8 24  Nasal spray 12 24 Zembrace Symtouch (per dose) 8 24 Onzetra Xsail (per dose) 8 24

 Coverage for a greater quantity of triptans is determined through a prior authorization process with the following criteria: o Medication must be prescribed by (or in consultation with) a neurologist OR o When prescribed by other providers: . Member must be experiencing a greater number of headaches per month than what the general covered quantity can treat AND . Member must be receiving preventative therapy for migraine headaches.

VI. Coverage Duration

 Coverage is approved indefinitely for the life of this policy once coverage criteria are met for non-preferred medications.  Duration of coverage for increased quantities will be limited to 12 months.

VII. Coverage Renewal Criteria

n/a

X. Billing/Coding Information

Please see individual prescribing information for products.

XII. Summary of Policy Changes

 6/1/11: Addition of naratriptan (generic Amerge) to the preferred medications in this class; Removal of Maxalt/Maxalt MLT from preferred products; Clarification of coverage of Axert in treatment of migraine in adolescent members (12 to 17 years); Change in quantity limit for naratriptan to 9 tablets/30 days, 27 tablets/90 days to reflect packaging in units of 9 tablets.  11/2011: Sumavel no longer targeted medication, quantity limits remain in place  6/15/12: addition of Alsuma to policy, extended authorization duration  6/15/13: rizatriptan/rizatriptan ODT and Zecuity added to policy; Typo re: quantity of Sumavel covered per month fixed; Brands with available generics are now non-preferred Page 3 of 5

Drug Therapy Guidelines Triptans Last Review Date: 3/2021

 6/2013: added zolmitriptan/ODT to policy  5/14/14: zolmitriptan and rizatriptan considered preferred for both Exchange and Commercial  6/15/14: simplified increased quantity coverage criteria; clarified quantity limits via mail order  6/15/15: no policy changes  7/1/15: formulary distinctions made  5/16/16: Zembrace quantity limits added  5/26/16: Onzetra quantity limits added  6/10/16: Onzetra considered non-preferred  6/15/16: no policy changes  6/16/16: Zembrace considered non-preferred  4/5/17: removed Zecuity due to no availability  5/1/17: step therapy criteria added  8/21/17: addition of eletriptan to preferred medications; removal of Relpax from preferred medications  9/20/17: updated duration of coverage for increased quantities  1/31/18: updated criteria concerning requests from neurologists  5/1/18: removed Alsuma as product is off-market  5/15/19: added Tosymra to policy; updated quantity limitations  5/1/20: no policy changes  2/5/21: moved zolmitriptan nasal spray to non-preferred  2/10/21: formulary distinctions made  5/28/21: no policy changes

XIII. References

1. Clinical Pharmacology (search for various serotonin receptor agonists). Accessed 1/2021. 2. Comparison of available triptans. Pharmacist’s Letter/Prescriber’s Letter 2009; May 2009. 3. Product Information: Sumatriptan/naproxen (Treximet® – GlaxoSmithKline). Revised 5/2016. 4. Product Information: Naratriptan (Amerge® - GlaxoSmithKline). Revised 12/2016. 5. Product Information: Rizatriptan (Maxalt®, Maxalt-MLT® - Merck). Revised 3/2015. 6. Product Information: Sumatriptan nasal spray (Imitrex® NS –GlaxoSmithKline). Revised 12/2017. 7. Product Information: Sumatriptan tablets (Imitrex® - GlaxoSmithKline). Revised 12/2017. 8. Product Information: Sumatriptan injection (Imitrex® Injection -GlaxoSmithKline). Revised 12/2017. 9. Product Information: Zolmitriptan tablets (Zomig®, Zomig-ZMT®- IMPAX). Revised September 2012. 10. Product Information: Zolmitriptan nasal spray (Zomig® Nasal Spray – IMPAX). Revised 11/2016. 11. Product Information: Almotriptan (Axert®– Janssen). Revised 5/2017. 12. Product Information: Frovatriptan (Frova®– Endo). Revised 8/2018. 13. Product Information: Eletriptan (Relpax®- Pfizer). Revised 11/2013. 14. Product Information: sumatriptan iontophoretic transdermal system (Zecuity® - NuPath Inc). Revised 2/2016. 15. Product Information: sumatriptan injection (Sumavel® DosePro® - Endo). Revised 6/2016. 16. Product information: sumatriptan injection (Alsuma® - Pfizer). Revised 4/2014. 17. Product Information: OnzetraTM XsailTM. Revised 1/2016. 18. Product Information: ZembraceTM SymTouchTM. Revised 1/2016. 19. Dowson A. Eur Neurol 1996;36(suppl 2):28-31 20. Eur Neurol 1996;32(suppl 2):24-7 Page 4 of 5

Drug Therapy Guidelines Triptans Last Review Date: 3/2021

21. Fletcher PE, et al. Headache Treatment: Trial Methodology and New Drugs. Lippincott-Raven Publishers, 1997 22. Lipton RB et al. Prevalence and Burden of Migraine in the United States: Data from the American Migraine Study II. Headache 2001;41:646-657. 23. Solomon GD, et al. Neurology 1997;49:1219-25 24. Visser WH, et al. Neurology 1996;46:522-6 25. Beckett B. Headache disorder, in Dipiro J (ed): Pharmacotherapy: a pathophysiologic approach. Stamford, Simon & Schuster, 1997; pp1279-91. 26. Consultation with Dr. Richard Lipton, Migraine Specialist, Department of Neurology, Montefiore Medical Center, Bronx, New York, Nov. 1996. 27. Gaist D et al. Misuse of sumatriptan. Lancet 1994;344:1090. 28. Gaist D, Tsiropoulos I, Sindrup SH. Inappropriate use of sumatriptan: population based register and interview study. BMJ 1998;316:1352-3. 29. Greiner DL et al. Sumatriptan use in a large group-model health maintenance organization. Am J Health Syst Pharm 1996;53:633-8. 30. Honkasalo ML et al. A population-based survey of headache and migraine in 22,809 adults. Headache. 1993;33:403-12. 31. Klassen A, Elkind A, Asgharnedjad M, et al. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind placebo-controlled, parallel-group study. Headache 1997;37:640-5. 32. Lipton RB, Stewart WF. Clinical applications of zolmitriptan. Cephalalgia 1997;18:53-9. 33. Mathew N. Dosing and administration of ergotamine and dihydroergotamine. Headache 1997;37:s26-32. 34. Mathew N, Asgharnejad M, Peykamian M, et al. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled crossover study. Neurology 1997;49:1485-90. 35. Peroutka S. Drugs effective in the therapy of migraine, Hardman J, Goodman A, Gilman, Limbird L (eds): Goodman & Gilman’s The pharmacological basis of therapeutics, New York, 1996, pp487-502. 36. Rapport AM, Ramadan NM. Adelman JU. Optimizing the dose of zolmitriptan for the acute treatment of migraine. Neurology 1997;49:1210-8. 37. Salonen R, Ashford E, Dathlof C, et al. Intranasal sumatriptan for the acute treatment of migraine. Neurology 1994;241:463-9. 38. Silberstein SD. Practice parameter: evidenced based guidelines for migraine headache (an evidenced- based review): Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2000;55(6):754-63. 39. Solomon GD, Cady RK, Klapper JA. Clinical efficacy and tolerability of 2.5mg zolmitriptan for the acute treatment of migraine. Neurology 1997;49:1219-25. 40. Teall J, Tuchman M,. Cutler N, et al. Rizatriptan (Maxalt) for the acute treatment of migraine and migraine recurrence- a placebo controlled, outpatient study. Headache 1998;38:281-7. 41. Tosymra™ [package insert]. Princeton, NJ: Dr. Reddy’s Labs LTD; Revised 1/2019.

The Plan fully expects that only appropriate and medically necessary services will be rendered. The Plan reserves the right to conduct pre-payment and post-payment reviews to assess the medical appropriateness of the above-referenced therapies.

The preceding policy applies only to members for whom the above named pharmacy benefit medications are included on their covered formulary. Members with closed formulary benefits are subject to trying all appropriate formulary alternatives before a coverage exception for a non-formulary medication will be considered.

The preceding policy is a guideline to allow for coverage of the pertinent medication/product, and is not meant to serve as a clinical practice guideline.

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