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Pharmacy Clinical Policy Bulletins
Aetna Non-Medicare Prescription Drug Plan
Subject: Anti-Migraine Agents

Status Drug PR PR-QL PR-AL ST M EX‡
Selective Serotonin Agonists 5-HT
P Amerge®  (naratriptan)   X      
P Imitrex®  (sumatriptan)   X      
P Maxalt®, Maxalt MLT®  (rizatriptan)   X      
FE Axert®  (almotriptan)   X     X
FE Frova®  (frovatriptan)   X     X
FE Relpax®  (eletriptan)   X     X
FE Zomig®, Zomig ZMT®  (zolmitriptan)   X     X
Other Agents used for Migraine
P apap isometheptene dichloral          
P butorphanol ns   X      
P dihydroergotamine          
P ergotamine/caffeine          
NP Cafergot®  (ergotamine/caffeine)          
NP Ergomar®  (ergotamine)          
NP Midrin®  (apap isometheptene dichloral )          
FE DHE-45®  (dihydroergotamine injection)         X
FE Migranal®  (dihydroergotamine nasal spray)   X     X


Policy:

  1. Precertification Criteria

    2. Under some plans, including plans that use an open or closed formulary, Amerge, Axert, butorphanol ns, Frova, Imitrex, Maxalt/Maxalt MLT, Migranal, Relpax 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 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
    Axert Up to 4 headaches 6.25 mg, 12.5 mg Up to 6 tablets in 30 days
    Amerge Up to 4 headaches 1 mg, 2.5 mg Up to 9 tablets in 30 days
    Frova Up to 4 headaches 2.5 mg Up to 9 tablets in 30 days
    Imitrex Up to 4 headaches 25 mg, 50 mg, 100 mg Up to 18 tablets in 30 days
    Imitrex Up to 4 headaches Nasal spray Up to 6 sprays in 30 days
    Imitrex Up to 4 headaches Injection kits Up to 4 kits (8 syringes) in 30 days
    Imitrex Up to 4 headaches Injection, 6mg/0.5ml vials Up to 10 vials (5ml) in 30 days
    Imitrex Up to 4 headaches Injection, 4mg/0.5mg 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 2 boxes (12 doses) per 30 days
    Relpax Up to 3 headaches 20 mg Up to 12 tablets in 30 days
    Relpax Up to 3 headaches 40 mg Up to 6 tablets in 30 days
    Zomig, Zomig ZMT Up to 3 headaches 2.5 mg Up to 12 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 (may approve up to 2 times the set qty limit)OR
    • Documented diagnosis of migraine AND member is being treated by a headache clinic or specialist(may approve up to 2 times the set qty limit)OR
    • Documented diagnosis of  cluster headaches AND member is being treated by a headache clinic or specialist (may approve up to 3 times the set qty limit for indefinite period of time)OR
    • Documented diagnosis of  migraine AND member is being treated by a headache clinic or specialist  AND member has been titrated up to 2 boxes/ 30 days and requires additional/higher dosing (one additional box  is approvable)-Migranal-only

    Migraine prophylactic meds

     verapamil  amitriptyline
     diltiazem  imipramine
     propranolol  desipramine
     atenolol  protripyline
     metoprolol  nortriptyline
     nadolol  doxepin
     divalproex sodium (DEPAKOTE  sertraline (ZOLOFT)
     trazodone  paroxetine
     valproic acid (DEPAKENE)  topiramate (TOPAMAX)
     tizanidien (ZANAFLEX)  bupropion (WELLBUTRIN)
     venlafaxine (EFFEXOR XR)  gabapentin
       


  2. Medical Exception Criteria

    3. Axert, DHE-45,Frova,Migranal, Relpax, Zomig and Zomig-ZMT are currently listed on the Aetna Formulary Exclusions List.* Therefore, they are excluded from coverage for members enrolled in prescription drug benefit plans that use a closed formulary, unless a medical exception is granted. Aetna considers Axert, Frova, Migranal, Relpax, Zomig and Zomig-ZMT to be medically necessary for those members who meet the following criteria:

    For Axert, DHE-45, Frova, Migranal, Relpax, Zomig and Zomig-ZMT

    A documented:

    • Contraindication to two preferred anti-migraine "triptan" alternatives OR 
    • Intolerance to two preferred anti-migraine "triptan" alternatives OR 
    • Allergy to two preferred anti-migraine "triptan" alternatives OR
    • Failure of an adequate trial of one day each of two preferred anti-migraine "triptan" alternatives. OR
    • Member's physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for non-migraine medical use(DHE-45, Migranal only)

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. Anon. Drugs for migraine. Med Lett 1995; 37: 17-20.
  2. Ferrari MD. Migraine. Lancet 1998; 351: 1043-1051.
  3. Dahlof C, Winter P, Whitehouse H, and Hassani H. Randomized, double-blind placebo-controlled comparison of oral naratriptan and oral sumatriptan in the acute treatment of migraine [abstract]. Neurology 199748:A85.
  4. Klassen A, Elkind A, Asghamejad M, et al Naratriptan is effective and well tolerated in the acute treatment of migraine: Results of a double-blind, placebo-controlled, crossover study. Headache 1997;37(10):640-5.
  5. Mathew NT, 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.
  6. Bomhof M, Paz J, Legg N, et al. Comparison of rizatriptan 10 mg vs. naratriptan 2.5 mg in migraine. Neurology 1999;423:173-9.
  7. Lipton RB. Methodologic issues in acute migraine clinical trials. Neurology 2000;55(Suppl 2):S1-7.
  8. 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.
  9. Silberstein SD, Goadsby PJ, and Lipton RB. Management of migraine: An algorithmic approach. Neurology 2000;55(Suppl 2):S46-52.
  10. 5-HT Agonist Comparisons: Clinical. BMMA. 1999;3(2):89.
  11. Jamieson DG. The safety of triptans in the treatment of patients with migraine. Am J Med. 2002;112:135-40.
  12. Jhee SS, Shiovitz T, Crawford AW, Cutler NR. Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents. Clin Pharmacokinet 2001;40:189-205.
  13. Tepper SJ. Safety and rational use of the triptans. Med Clin North Am. 2001;85:959-70.
  14. Salonen R. Drug comparisons: why are they so difficult? Cephalalgia. 2000;29(Suppl 2):25-32.
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  16. Marcus DA. Establishing a standard of speed for assessing the efficacy of the serotonin 1B/1D agonists (triptans). Arch Neurol. 2001;58:1056-8.
  17. 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.
  18. Ryan Jr RE. Patient treatment preferences and the 5-HT 1B/1D agonists. Arch Intern Med. 2001;161:2545-53.
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  21. 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.
  22. 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.
  23. Goldstein J, Keywood, and Hutchison J. Low 24-hour migraine recurrence during treatment with frovatriptan. Presented at Ninth Congress of the International Headache Society, Barcelona, Spain. June 22-26, 1999.
  24. Spierings ELH, Keywood C on behalf of the VML 251/96/08 investigators. Consistent migraine relief with frovatriptan, a novel 5-HT 1B/1D agonists. Present at the Ninth Congress of the International Headache Society, Barcelona, Spain. June 22-26, 1999.
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  28. Visser WH et al. Rizatriptan vs sumatriptan in the acute treatment of migraine. A placebo-controlled, dose-ranging study. Arch Neurol 1996; 53: 1132-1137.
  29. Gijsman H et al. Double-blind, placebo-controlled, dose-finding study of rizatriptan (MK-462) in the acute treatment of migraine. Cephalalgia 1997; 17: 647-651.
  30. Santanello NC et al. Improvement in migraine-specific quality of life in a clinical trial of rizatriptan. Cephalalgia 1997; 17: 867-872.
  31. Teall J et al. Rizatriptan (Maxalt) for the acute treatment of migraine and migraine recurrence. A placebo-controlled, outpatient study. Headache 1998; 38: 281-287.
  32. Dahlof CGH, Rapoport AM, Sheftell FD, and Lines CR. Rizatriptan in the treatment of migraine. Clin Ther 1999;21(11):1823-36.
  33. Pascual J, Vega P, Diener HC, et al. Comparison of rizatriptan 10 mg vs. zolmitriptan 2.5 mg in the acute treatment of migaine. Cephalalgia 2000;20:455-61.
  34. Bomhof M, Paz J, Legg N, et al. Comparison of rizatriptan 10 mg vs. naratriptan 2.5 mg in migraine. Neurology 1999;423:173-9.
  35. Goldstein J, Ryan R, Jiang K, et al. Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 mg and 50 mg in migraine. Headache 1998;38:737-47.
  36. Tfelt-Hansen P, Teall J, Rodriguez F, et al. Oral rizatriptan versus oral sumatriptan: A direct comparative study in the acute treatment of migraine. Headache 1998;38:748-55.
  37. Saper JR. The use of rizatriptan in the treatment of acute, multiple migraine attacks. Neurology 2000;55(Suppl 2):S15-8.
  38. Silberstein SD. Rizatriptan versus usual care in long-term treatment of migraine. Neurology 2000;55(Suppl 2):S25-8.
  39. Hargreaves RJ. Pharmacology and potential mechanisms of action of rizatriptan. Cephalalgia 2000;20(Suppl 1): 2-9.
  40. Sakai F. Safety and tolerability of rizatriptan. Cephalalgia 2000;29(Suppl 1):16-8.
  41. 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.
  42. Anon. Zolmitriptan for migraine. Med Lett 1998; 40: 27-28.
  43. Ferrari MD. The clinical effectiveness of 311C90 in the acute treatment of migraine. Eur Neurol 1996; 36(Suppl 2): 4-7.
  44. Thomsen LL et al. 311C90 (zolmitriptan), a novel centrally and peripheral acting oral 5-hydroxytryptamine-1D agonist: A comparison of its absorption during a migraine attack and in a migraine-free period. Cephalalgia 1996; 16: 270-275.
  45. The International 311C90 Long-term Study Group. The long-term tolerability and efficacy of oral zolmitriptan (Zomig, 311C90) in the acute treatment of migraine. An international study. Headache. 1998;38:173-83.
  46. Tepper SJ, Donnan GA, Dowson AJ, et al. A long-term study to maximize migraine relief with zolmitriptan. Curr Med Res Opin. 1999;15:254-71.
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  48. 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.
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  51. 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.
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  78. Axert Product Information. Pharmacia & Upjohn. May 2003.
  79. Frova Product Information. Elan, San Diego, CA, 2002.
  80. Imitrex Nasal Spray Product Information. GlaxoWellcome, Research Triangle Park, NC. June 2001.
  81. Imitrex Injection Product Information. GlaxoWellcome, Research Triangle Park, NC. March 2001.
  82. Imitrex tablets Product Information. GlaxoWellcome, Research Triangle Park, NC. June 2001.
  83. Maxalt Product Information. Merck, West Point, PA. October 2001.
  84. Relpax Package Information. Pfizer. New York, New York. September 2003.
  85. Zomig Product Insert. AstraZeneca, Wilmington, DE, July 2003.
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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.

February 26, 2007
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