Subject: Anti-Migraine Agents

Status	Drug	PR	PR-QL	PR-AL	ST	M EX‡
Triptans-(Selective Serotonin Agonists 5-HT)
P	sumatriptan		X
P	Amerge®  (naratriptan)		X
P	Maxalt®, Maxalt MLT®  (rizatriptan)		X
FE	Axert®  (almotriptan)		X		X	X
FE	Frova®  (frovatriptan)		X		X	X
FE	Imitrex®  (sumatriptan)		X		X	X
FE	Relpax®  (eletriptan)		X		X	X
FE	Sumavel®  (sumatriptan)		X		X	X
FE	Treximet™  (sumatriptan-naproxen )		X		X	X
FE	Zomig®, Zomig ZMT®  (zolmitriptan)		X		X	X
Other Agents used for Migraine
P	apap isometheptene dichloral
P	butorphanol ns		X
P	ergotamine/caffeine
NP	Cafergot®  (ergotamine/caffeine)
NP	Ergomar®  (ergotamine)
NP	Midrin®  (apap isometheptene dichloral )
FE	Migranal®  (dihydroergotamine nasal spray)		X		X	X

Policy:

1. Precertification Criteria

Under some plans, including plans that use an open or closed formulary, Amerge, Axert, butorphanol ns, Frova, Imitrex, Maxalt/Maxalt MLT, Migranal, Relpax, sumatriptan, Sumavel, Treximet and Zomig/Zomig ZMT are subject to precertification.  If precertification requirements apply Aetna considers Amerge, Axert, butorphanol ns, Frova, Imitrex, Maxalt/Maxalt MLT, Migranal, Relpax, sumatriptan, Sumavel, Treximet and Zomig/Zomig ZMT to be medically necessary for those members who meet the following precertification criteria:

According to the manufacturer, the safety of treating an average of more than the number of headaches listed below in a 30-day period has not been established. Clinical guidelines recommend two treatment days per week for abortive therapy. A quantity of each drug will be considered medically necessary as indicated in the table below.

Drug	Maximum Daily Dose/ Dosing Interval	Dosage Strength	Quantity Limits
butorphanol ns	2-3 times daily	Nasal solution 10 mg/ml	Up to 2 bottles in 30 days
Amerge	Up to 4 headaches	1 mg, 2.5 mg	Up to 9 tablets in 30 days
Axert	Up to 4 headaches	6.25 mg, 12.5 mg	Up to 6 tablets in 30 days
Frova	Up to 4 headaches	2.5 mg	Up to 9 tablets in 30 days
sumatriptan, Imitrex	Up to 4 headaches	25 mg, 50 mg, 100 mg	Up to 9 tablets in 30 days
sumatriptan, Imitrex	Up to 4 headaches	Nasal spray	Up to 6 sprays in 30 days
sumatriptan, Imitrex	Up to 4 headaches	Injection kits	Up to 4 kits (8 syringes) in 30 days
sumatriptan, Imitrex	Up to 4 headaches	Injection, 4mg/0.5ml vials, 6mg/0.5ml vials	Up to 10 vials (5ml) in 30 days
sumatriptan, Imitrex	Up to 4 headaches	Injection, 4mg/0.5ml syringes	Up to 8 syringes in 30 days
Maxalt, Maxalt MLT	Up to 4 headaches	5 mg, 10 mg	Up to 12 tablets in 30 days
Migranal	Up to 4 headaches	4 mg/ml nasal spray	Up to 1 box per 30 days
Relpax	Up to 3 headaches	20 mg	Up to 6 tablets in 30 days
Relpax	Up to 3 headaches	40 mg	Up to 6 tablets in 30 days
Sumavel	Up to 4 headaches	Injection 6mg/0.5 ml syringes	Up to 6 syringes in 30 days
Treximet	Up to 5 headaches	85 / 500 mg	Up to 9 tablets in 30 days
Zomig, Zomig ZMT	Up to 3 headaches	2.5 mg	Up to 6 tablets in 30 day
Zomig, Zomig ZMT	up to 3 headaches	5 mg	Up to 6 tablets in 30 day
Zomig	Up to 3 headaches	Nasal spray	Up to 6 sprays in 30 days





For coverage of additional quantities, a member's treating physician must request prior authorization through the Pharmacy Management Precertification Unit. Additional quantities of these anti-migraine agents will be considered medically necessary for those members who meet ANY of the following criteria:

• Documented diagnosis of migraine AND member is receiving prophylactic migraine therapy OR
• Documented diagnosis of migraine AND member is being treated by a headache clinic, neurologist or specialist OR
• Documented diagnosis of cluster headaches AND member is being treated by a headache clinic, neurologist or specialist OR
• Documented diagnosis of  migraine AND member is being treated by a headache clinic, neurologist or specialist AND member has been titrated up to 2 boxes/ 30 days and requires additional/higher dosing - Migranal-only OR
• Member's physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for use of a higher dose



2. Step Therapy Criteria

Under some plans, including plans that use an open or closed formulary, Axert, Frova, Imitrex, Migranal, Relpax, Sumavel, Treximet, Zomig, and Zomig ZMT are subject to step-therapy.  Aetna considers Axert, Frova, Imitrex, Migranal, Relpax, Sumavel, Treximet, Zomig, and Zomig ZMT to be medically necessary for those members who meet the following step-therapy criteria:

For Axert, Frova, Imitrex, Migranal, Relpax, Sumavel, Zomig, and Zomig ZMT

• A documented trial of the preferred generic alternative sumatriptan for the treatment of 2 migraine episodes

For Treximet



A documented trial of concurrent use of both sumatriptan tablets (any strength) AND prescription strength naproxen >/= 500mg for the treatment of 2 migraine episodes - sumatriptan tablets and generic naproxen are alternatives on the Preferred Drug List

If it is medically necessary for a member to be treated initially with a medication subject to step-therapy, the member, a person appointed to manage the member’s care, or the member's treating physician may contact the Aetna Pharmacy Management Precertification Unit to request coverage as a medical exception at 1-800-414-2386. (See criteria under section III below).

 


3. Medical Exception Criteria

Axert, Frova, Imitrex, Migranal,  Relpax, Sumavel, Treximet, Zomig, and Zomig ZMT are  currently listed on the Aetna Formulary Exclusions and Step-Therapy lists.* Therefore, these are  excluded from coverage for members enrolled in prescription drug benefit plans that use a closed formulary or that require step-therapy criteria, unless a medical exception is granted.  Aetna considers Axert, Frova, Imitrex, Migranal, Relpax, Sumavel, Treximet, Zomig, and Zomig ZMT to be medically necessary for those members who meet the criteria specified below:

For Axert, Frova, Imitrex, Migranal, Relpax, Sumavel, Zomig and Zomig-ZMT

A documented:

• Contraindication to the preferred generic alternative sumatriptan OR 
• Intolerance to the preferred generic alternative sumatriptan OR 
• Allergy to the preferred generic alternative sumatriptan OR
• Failure of an adequate trial (2 migraine episodes) of the preferred generic alternative sumatriptan OR
• Member’s physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for non-migraine medical use (Migranal only)
  

(A AND B )-For Treximet

A. A documented:

•  Failure of concurrent use of both sumatriptan tablets (any strength) AND prescription strength
   naproxen  >/= 500mg for the treatment of 2 migraine episodes - sumatriptan tablets and generic naproxen are      alternatives on the Preferred Drug List 

AND

B. A documented:

• Contraindication to one additional preferred anti-migraine "triptan" alternative OR 
• Intolerance to one additional preferred anti-migraine "triptan" alternatives OR 
• Allergy to one additional  preferred anti-migraine "triptan" alternatives OR
• Failure of an adequate trial of one day of one additional preferred anti-migraine "triptan" alternative.
  

Special Notes:

According to the manufactures, these anti-migraine agents are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. Safety and effectiveness of these agents have not been established for cluster headache, which is present in an older, predominantly male population.

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and any of these anti-migraine agents within 24 hours is contraindicated. Because their vasospastic effects may be additive, coadministration of more than one of these anti-migraine agents (5-HT1 agonists) within 24 hours of each other is not recommended.

Place of Service:

Outpatient

The above policy is based on the following references:

1. AHFS Drug Information® with AHFSfirstReleases®. ( www.statref.com), American Society Of Health-System Pharmacists®, Bethesda, MD. Updated periodically.
2. DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically.
3. Drug Facts and Comparisons on-line. (www.drugfacts.com), Wolters Kluwer Health, St. Louis, MO. Updated periodically.
4. PDR® Electronic Library™ [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically.
5. Clinical Pharmacology [Internet database]. Gold Standard Inc. Tampa, FL. Updated periodically.
6. Goadsby PJ and Hargreaves RJ. Mechanisms of action of serotonin 5HT 1B/1D agonists: Insights into migraine pathophysiology using rizatriptan. Neurology 2000;55(Suppl 2):S8-14.
7. Silberstein SD, Goadsby PJ, and Lipton RB. Management of migraine: An algorithmic approach. Neurology 2000;55(Suppl 2):S46-52.
8. Jamieson DG. The safety of triptans in the treatment of patients with migraine. Am J Med. 2002;112:135-40.
9. Tepper SJ. Safety and rational use of the triptans. Med Clin North Am. 2001;85:959-70.
10. Salonen R. Drug comparisons: why are they so difficult? Cephalalgia. 2000;29(Suppl 2):25-32.
11. Marcus DA. Establishing a standard of speed for assessing the efficacy of the serotonin 1B/1D agonists (triptans). Arch Neurol. 2001;58:1056-8.
12. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT 1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001;358:1668-75.
13. Ryan Jr RE. Patient treatment preferences and the 5-HT 1B/1D agonists. Arch Intern Med. 2001;161:2545-53.
14. Pascual J. Clinical benefits of early triptan therapy for migraine. Headache 2002;42(Suppl 1):S10-7.
15. Goadsby PJ, Lipton RB, Ferrari MD. Migraine - Current understanding and treatment. N Engl J Med. 2002;346:257-70.
16. Pascual J, Falk RM, Piessens F, et al. Consistent efficacy and tolerability of almotriptan in the acute treatment of multiple migraine attacks: results of a large, randomized, double-blind, placebo-controlled study. Cephalalgia 2000;20:588-96.
17. Gras J, Cardelus I, Llenas J, Palacios JM. Cardiovascular safety profile of almotriptan, a new indolic derivative for the treatment of migraine. Eur J Pharmacol. 2000;410:53-9.
18. Dodick DW. Oral almotriptan in the treatment of migraine: Safety and tolerability. Headache 2001;41:449-55.
19. Saper JR. The use of rizatriptan in the treatment of acute, multiple migraine attacks. Neurology 2000;55(Suppl 2):S15-8.
20. Silberstein SD. Rizatriptan versus usual care in long-term treatment of migraine. Neurology 2000;55(Suppl 2):S25-8.
21. Hargreaves RJ. Pharmacology and potential mechanisms of action of rizatriptan. Cephalalgia 2000;20(Suppl 1): 2-9.
22. Sakai F. Safety and tolerability of rizatriptan. Cephalalgia 2000;29(Suppl 1):16-8.
23. Adelman JU, Lipton RB, Ferrari MD, et al. Comparison of rizatriptan and other triptans on stringent measures of efficacy. Neurology. 2001;57(8):1377-83.
24. Gallagher RM, Dennish G, Spierings ELH, Chitra R. A comparative trial of zolmitriptan and sumatriptan for the acute oral treatment of migraine. Headache 2000;40:119-28.
25. Ryan RE, Diamond S, Rose AM, et al. Efficacy of zolmitriptan at early time-points for the acute treatment of migraine and treatment of recurrence. CNS Drugs. 2000;13:215-26.
26. Yates R, Nairn K, Dixon R, Kemp V, Dane AL. Pharmacokinetics, dose proportionality, and tolerability of single and repeat doses of a nasal spray formulation of zolmitriptan in health volunteers. J Clin Pharmacol 2002;42:1244-1250.
27. Syrett N, Abu-Shakra S, Yates R. Zolmitriptan nasal spray: advances in migraine treatment. Neurology 2003;61(S4):S27-30.
28. Yates R, Narin K, Dixon R, Seaber E. Preliminary studies of the pharmacokinetics and tolerability of zolmitriptan nasal spray in heath volunteers. J Clin Pharmacol 2002l;42:1237-43.
29. Charlesworth BR, Dowson AJ, Purdy A, Becker WJ, Boes-Hansen S, Farkkila M. Speed of onset and efficacy of zolmitriptan nasal spray in the acute treatment of migraine. CNS Drugs 2003;17(9):653-667
30. Mathew NT, Schoenen J, Winner P, et al. Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg. Headache. 2003;43:214-22.
31. Sandrini G, Farkkila M, Burgess G, et al. Eletriptan vs sumatriptan. A double-blind, placebo-controlled, multiple migraine attack study. Neurology. 2002;59:1210-7.
32. Lipon RB, Stewart WF, Cady R, et al. Sumatriptan for the range of headaches in migraine sufferers: results of the spectrum study. Headache 2000;40:1-9
33. Cady RK, Sheftell F, Lipton RB, et al. Effect of early intervention with sumatriptan on migraine pain: Retrospective analyses of data from three clinical trials. Clin Ther. 2000;22:1035-48.
34. Hershey AD, Powers SW, LeCates S, Bentti AL. Effectiveness of nasal sumatriptan in 5- to 12-year-old children. Headache. 2001;41(7):693-7.
35. Linder SL, Winner P. Pediatric headache. Med Clin North Am. 2001;84(4):1037-53.
36. Tfelt-Hansen P. A review of evidence-based medicine and meta-analytic reviews in migraine. Cephalalgia. 2006;26(11):1265-74.
37. Rapoport A, Winner P. Nasal delivery of antimigraine drugs: clinical rationale and evidence base. Headache. 2006;46 Suppl 4:S192-201.
38. Pascual J, Mateos V, Roig C, Sanchez-Del-Rio M, Jiménez D. Marketed oral triptans in the acute treatment of migraine: a systematic review on efficacy and tolerability. Headache. 2007;47(8):1152-68.
39. Chen LC, Ashcroft DM. Meta-analysis of the efficacy and safety of zolmitriptan in the acute treatment of migraine. Headache. 2008;48(2):236-47.
40. Mathew NT, Landy S, Stark S. Fixed-dose sumatriptan and naproxen in poor responders to triptans with a short-half. Headache. 2009;49:971-82.
41. Chalaupka FD. Headache. 2009;49:762-4.
42. Ng-Mak DS, Hu Xh, Bigal M. Migraine treatment with rizatriptan and almotriptan: a cross-over study. Headache. 2009;49:655-62.

Copyright Aetna Inc. All rights reserved. Pharmacy Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

January 01, 2010