Serotonin 5-HT1B/1D Receptor Agonists - Index

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • Jan. 20, 2023
    • Jan. 22, 2021
    • Dec. 2018
    • Dec. 2016
    • Dec. 2014
    • March 2013
    • April 2011
    • Oct. 2008
    • May 2007
    • Dec. 2006
    • Aug. 2003
    • July 2002
    • Nov. 2001
    • Sept. 2001
    • Aug. 2000
    • Oct. 1999
  • Initially developed
    • Aug. 1998

1.1. Adults

Serotonin 5-HT1B/1D receptor agonists (SRAs) are FDA-approved to manage acute migraine headache attacks with or without aura. Injectable sumatriptan is also FDA-approved to manage cluster headache episodes. The maximum recommended adult doses for available SRAs are summarized in Tables 1 and 2. Dosages exceeding these recommendations will be reviewed.

Table 1. Maximum Recommended Daily Adult Dosages for SRAs – Monotherapy1-16
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
almotriptan (generic) tablets (6.25 mg, 12.5 mg) migraine with or without aura 25 mg/day
eletriptan (Relpax®, generic) tablets (20 mg, 40 mg) migraine with or without aura 80 mg/day
frovatriptan (Frova®, generic) tablets (2.5 mg) migraine with or without aura 7.5 mg/day
naratriptan (Amerge®, generic) tablets (1 mg, 2.5 mg) migraine with or without aura 5 mg/day
rizatriptan (Maxalt®, generic) tablets (5 mg, 10 mg) migraine with or without aura 30 mg/day
rizatriptan (Maxalt -MLT®, generic) orally disintegrating tablets (5 mg, 10 mg) migraine with or without aura 30 mg/day
rizatriptan propranolol patients   migraine with or without aura 15 mg/day
sumatriptan (Imitrex®, generic) intranasal spray (5mg/spray, 20 mg/spray - 6 per package) migraine with or without aura 40 mg/day
sumatriptan (Onzetra Xsail®) intranasal powder (11 mg/actuation) migraine with or without aura 44 mg/day*
sumatriptan (Imitrex®, generic) oral tablets (25 mg, 50 mg, 100 mg) migraine with or without aura 200 mg/day
sumatriptan (Imitrex®, generic) subcutaneous injection (4 mg and 6 mg STATdose system, 6 mg/0.5 mL single dose vial) migraine with or without aura 12 mg/day
    cluster headache 12 mg/day
sumatriptan (Tosymra®) Intranasal spray (10 mg/ spray - 6 per package) migraine with or without aura 30 mg/day
sumatriptan (Zembrace® SymTouch®) 3 mg/0.5 mL auto injector migraine with or without aura 12 mg/day
zolmitriptan (Zomig®, generic) tablets (2.5 mg, 5 mg) migraine with or without aura 10 mg/day
zolmitriptan (Zomig-ZMT®, generic) orally disintegrating tablets (2.5 mg, 5 mg) migraine with or without aura 10 mg/day
zolmitriptan (Zomig®) intranasal (2.5 mg/ actuation, 5 mg/ actuation) migraine with or without aura 10 mg/day

Legend:

  • * Alternatively, patients may receive a maximum Onzetra Xsail® dose of 22 mg plus one dose of another sumatriptan product at least 2 hours later
Table 2. Maximum Recommended Daily Adult Dosages for SRAs – Combination Therapy1-2,17
Drug Name Treatment Indication Dosage Form/Strength Maximum Recommended Dosage
sumatriptan/naproxen (Treximet®, generics) migraine with or without aura tablets (85 mg/500 mg) 170 mg/1000 mg per day

1.2. Pediatrics

Rizatriptan is the only SRA FDA approved in children 6 to 17 years of age to treat acute migraine attacks in patients with a history of migraine with or without aura1,2,7. Almotriptan, zolmitriptan nasal spray, and sumatriptan/naproxen are FDA approved for patients 12 years of age and older1-3,16,17. Children/adolescents 6 to 17 years of age prescribed propranolol weighing less than 40 kg should not receive rizatriptan concurrently.7 Maximum recommended pediatric doses for SRAs are summarized in Tables 3 and 4. Dosages exceeding these recommendations will be reviewed.

Table 3. Maximum Recommended Daily Pediatric Dosages for FDA-Approved SRAs to Manage Acute Migraine With or Without Aura – Monotherapy1-3,7,16
Drug Patient Characteristics Maximum Daily Dosage
almotriptan 12 to 17 years of age 25 mg
rizatriptan 6 to 17 years of age:
Less than 40 kg
Greater than or equal to 40 kg		 5 mg
10 mg
rizatriptan propranolol patients 6 to 17 years of age: Greater than equal to 40 kg     5 mg
zolmitriptan nasal spray 12 to 17 years of age 10 mg
Table 4. Maximum Recommended Daily Pediatric Dosages for FDA-Approved SRAs to Manage Acute Migraine With or Without Aura – Combination Therapy1,2,17
Drug Patient Characteristics Maximum Daily Dosage
sumatriptan/naproxen 12 to 17 years of age 85 mg/500 mg

The remaining SRAs are not FDA-approved for use in patients less than 18 years of age as safety and efficacy have not been established in this patient population. Additionally, patients less than 18 years of age have demonstrated a significant placebo response following SRA use as well as an adverse event profile, including serious adverse events, comparable to that seen in adults4,9,10,18.

No significant data are available evaluating SRA use in pediatric patients younger than 6 years of age. In limited randomized, controlled trials, sumatriptan nasal spray has demonstrated some efficacy in mitigating migraine attacks in adolescents; children as young as 6 years of age have achieved favorable responses with intranasal sumatriptan in a few small randomized and open-label studies.19-21 However, oral sumatriptan tablets used in children 8 to 16 years of age to treat acute migraine attacks were not significantly better than placebo.22 A few small studies with oral zolmitriptan have shown mixed outcomes.23,24 Although not FDA-approved, Table 5 summarizes SRA doses that have been utilized in the pediatric population. Due to lack of definitive efficacy, prescriptions for SRAs not FDA-approved for pediatric patients will be reviewed in patients 6 to 18 years of age.

Table 5. Non FDA-Approved Pediatric Dosages for Select SRAs19-21,23-27
Drug Patient Characteristics Dose Utilized Per Headache
sumatriptan intranasal spray 6 to 17 years of age 20 mg
sumatriptan subcutaneous 6 to 18 years of age 0.06 mg/kg
sumatriptan subcutaneous sumatriptan subcutaneous
6 to 16 years of ageLess than 30 kg
Greater than or equal to 30 kg    		 3 mg
6 mg
zolmitriptan tablets 6 to 18 years of age 2.5 mg

2. Duration of Therapy

Migraine headache is a chronic, recurrent condition usually requiring long-term, intermittent therapy for pain relief. Serotonin 5-HT1B/1D receptor agonists are approved for acute treatment of migraine attacks and may be utilized indefinitely to manage migraine headaches provided that the maximum dosage recommendation is not exceeded in a 24-hour period. Additionally, the safety of treating more than 3 or 4 headaches during a 30-day period has not been established with the exception of sumatriptan/naproxen which has been FDA approved for 5 migraine headaches during a 30-day period1-17. Children/ adolescents 6 to 17 years of age are allowed only one rizatriptan dose per 24 hours, as safety and efficacy have not been determined for multiple rizatriptan doses in pediatric patients7. Maximum quantities of serotonin 5-HT1B/1D receptor agonists to be dispensed in a 30-day time period, based on number of headaches to be treated, are summarized in Tables 6 and 7 for adults and Tables 8 and 9 for adolescents. Patient profiles documenting quantities of serotonin 5-HT1B/1D receptor agonists that exceed these recommendations will be reviewed.

Table 6. Maximum Recommended SRA Adult Dosage Frequency – Monotherapy1-17
Drug Maximum Number of Headaches Treated per 30 Days Recommended Prescribed Tablet Number/Sprays or Dose per 30 Days
almotriptan tablets 4 headaches 8 x 12.5 mg tablets or 100 mg
eletriptan tablets 3 headaches 6 x 40 mg tablets or 240 mg
frovatriptan tablets 4 headaches 12 x 2.5 mg tablets or 30 mg
naratriptan tablets 4 headaches 8 x 2.5 mg tablets or 20 mg
rizatriptan tablets 4 headaches 12 x 10 mg tablets or 120 mg
rizatriptan orally disintegrating tablets (ODTs) 4 headaches 12 x 10 mg ODT or 120 mg
rizatriptan propranolol patients (regular or ODT) 4 headaches 12 x 5 mg tablets/ODT or 60 mg
sumatriptan intranasal spray (Imitrex®, generic) 4 headaches 8 x 20 mg spray or 160 mg
sumatriptan intranasal spray (Tosymra®) 4 headaches 12 x 10 mg spray or 120 mg
sumatriptan intranasal powder 4 headaches 8 x 22 mg powder or 176 mg
sumatriptan oral tablets 4 headaches 8 x 100 mg tablets or 800 mg
sumatriptan subcutaneous injection ----+ ----
zolmitriptan intranasal 4 headaches 8 x 5 mg spray or 40 mg
zolmitriptan tablets 3 headaches 6 x 5 mg tablets or 30 mg
zolmitriptan orally disintegrating tablets 3 headaches 6 x 5 mg tablets or 30 mg

Legend:

  • + Patients taking Imitrex® should not receive more than 2 subcutaneous injections in a 24-hour time period; patients taking Zembrace® should not receive more than 4 subcutaneous injections per day
Table 7. Maximum Recommended SRA Adult Dosage Frequency – Combination Therapy1,2,17
Drug Maximum Number of Headaches Treated per 30 Days Recommended Prescribed Tablet Number/Sprays or Dose per 30 Days
sumatriptan/naproxen tablets 5 headaches 10 x 85/500 mg tablets or 850 mg/5000 mg
Table 8. Maximum Recommended SRA Pediatric Dosage Frequency – Monotherapy1-3,7,16
Drug Maximum Number of Headaches Treated per 30 Days Recommended Prescribed Tablet Number/Sprays or Dose per 30 Days
almotriptan tablets 4 headaches 8 x 12.5 mg tablets or 100 mg
rizatriptan tablets Less than 40 kg: 4 headaches
Greater than or equal to 40 kg: 4 headaches		 4 x 5 mg tablets or 20 mg
4 x 10 mg tablets or 40 mg
rizatriptan orally disintegrating tablets (ODTs) Less than 40 kg: 4 headaches
Greater than or equal to 40 kg: 4 headaches		 4 x 5 mg tablets or 20 mg
4 x 10 mg tablets or 40 mg
rizatriptan propranolol patients (regular or ODT) 4 headaches 4 x 5 mg tablets or 20 mg
zolmitriptan nasal spray 4 headaches 8 x 5 mg/actuation or 40 mg
Table 9. Maximum Recommended SRA Pediatric Dosage Frequency – Combination Therapy1,2,17
Drug Maximum Number of Headaches Treated per 30 Days Recommended Prescribed Tablet Number/Sprays or Dose per 30 Days
sumatriptan/naproxen tablets 2 headaches 2 x 85 mg /500 mg tablets or 170 mg/1000 mg

 

3. Duplicative Therapy

Using two or more serotonin 5-HT1B/1D receptor agonists concurrently is not justified due to lack of additional therapeutic benefit and the potential for additive vasospastic effects. Patient profiles documenting receipt of multiple serotonin 5-HT1B/1D receptor agonists will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be reviewed to identify drug regimens that may result in clinically significant drug-drug interactions. Clinically relevant drug-drug interactions for serotonin 5-HT1B/1D receptor agonists are summarized in Tables 10 and 11. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 10. Summary of Significant SRA Drug Interactions1-16
Triptan Amphetamines CYP3A4 inhibitors Ergots Linezolid MAOIs+ Propranolol SNRIs#/SSRIs*
almotriptan √ √ √ √ √ ---- √
eletriptan √ √ √ √ √ ---- √
frovatriptan √ ---- √ √ √ ns √
naratriptan √ ---- √ √ √ ---- √
rizatriptan √ ---- √ √ √ √ √
sumatriptan √ ---- √ √ √ ---- √
zolmitriptan √ ---- √ √ √ ns √

Legend:

  • ns = not significant
  • +MAOIs = monoamine oxidase inhibitors
  • #SNRIs = serotonin-norepinephrine reuptake inhibitors
  • *SSRIs = selective serotonin reuptake inhibitors
Table 11. SRA Drug-Drug Interactions1-17
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level#
SRAs amphetamines concurrent administration may stimulate serotonin neurotransmission and increase risk of serotonin syndrome (e.g., mental status changes, diaphoresis, tremor, fever), as amphetamines increase serotonin release avoid combination, if possible; if adjunctive therapy necessary, initiate with lower doses and observe for signs/symptoms of serotonin syndrome and adjust therapy as indicated major (Micromedex), 3-moderate (CP)
almotriptan, eletriptan CYP3A4 inhibitors (e.g., azole antifungals, macrolides) adjunctive administration of CYP3A4 inhibitors with almotriptan or eletriptan (CYP3A4 substrates) may result in increased almotriptan/eletriptan serum levels and enhanced pharmacologic/toxic effects, including potential for vasospastic and/or cardiac events eletriptan contraindicated for use within 72 hours of strong CYP3A4 inhibitor; lower almotriptan dosages required when used concurrently with CYP3A4 inhibitors (maximum dose, 12.5 mg); an alternative antifungal that does not inhibit CYP3A4 (e.g., terbinafine) may be an alternative for azoles contraindicated, moderate (DrugReax), 1-contraindicated, 2-major (CP)
SRAs ergot derivatives/ergot-type medications (e.g., bromocriptine) combined administration may result in additive vasospastic effects SRAs should not be used within 24 hours of ergot derivatives/ergot-type medications contraindicated (DrugReax), 1-contraindicated (CP)
SRAs linezolid concurrent administration with SRAs metabolized by monoamine oxidase (MAO) may increase serotonin levels and the potential for serotonin syndrome, as linezolid is nonselective monoamine oxidase inhibitor (MAOI) adjunctive administration or administration within 14 days of MAOI discontinuation is contraindicated by SRA manufacturers; if combination necessary, observe patient closely for signs/symptoms of serotonin syndrome; eletriptan is not metabolized by MAO, and frovatriptan, naratriptan do not inhibit MAO - may be safe alternatives; almotriptan is metabolized by MAO but does not require dosage adjustments when used with MAOIs - may also be alternative contraindicated (DrugReax), 2-major (CP)
SRAs MAOIs+, including selegiline (high doses) adjunctive administration of SRAs with other medications having serotonergic properties like MAOIs, which decrease serotonin metabolism, may increase serotonin levels and the potential for serotonin syndrome; selegiline in doses greater than 10 mg daily may behave like an MAOI adjunctive administration or administration within 14 days of MAOI discontinuation is contraindicated by SRA manufacturers; if combination necessary, observe patient closely for signs/symptoms of serotonin syndrome; eletriptan is not metabolized by MAO, and frovatriptan, naratriptan do not inhibit MAO - may be safe alternatives; almotriptan is metabolized by MAO but does not require dosage adjustments when used with MAOIs and may also be alternative Contraindicated, major (Micromedex) 3-moderate (CP)
rizatriptan propranolol adjunctive rizatriptan-propranolol administration increases the rizatriptan AUC by as much as 70% as propranolol inhibits rizatriptan metabolism reduce rizatriptan doses (maximum daily dose, 15 mg); observe patients for enhanced rizatriptan pharmacologic/adverse effects when co-administered moderate (DrugReax), 3-moderate (CP)
SRAs SNRIs*/ SSRIs# adjunctive administration of SRAs with other medications having serotonergic properties like SNRIs/SSRIs may increase serotonin levels and the potential for serotonin syndrome avoid combination, if possible; if combined therapy necessary, monitor patient closely for signs/symptoms of serotonin syndrome and modify drug therapy as necessary major (DrugReax) 3-moderate (CP)

Legend:

  • # CP = Clinical Pharmacology
  • + MAOIs = monoamine oxidase inhibitors
  • # SNRIs = serotonin-norepinephrine reuptake inhibitors
  • * SSRIs = selective serotonin reuptake inhibitors
  • ^ SRAs = serotonin 5-HT1B/1D receptor agonists

5. References

  1.  
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 21, 2022.
  3. IMB Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed November 21, 2022.
  4. Almotriptan (Axert®) package insert. Ajanta Pharma Limited, November 2021. 
  5. Eletriptan (Relpax®) package insert. Ajanta Pharma Limited, November 2021.
  6. Frovatriptan (Frova®) package insert. Ingenus Pharmaceuticals, May 2022.
  7. Naratriptan (Amerge®) package insert. GlaxoSmithKline, October 2020.
  8. Rizatriptan (Maxalt® and Maxalt-MLT®) package insert. Breckenridge Pharmaceutical, Inc. August 2022.
  9. Sumatriptan tablets (Imitrex®) package insert. GlaxoSmithKline, December 2020.
  10. Sumatriptan injection (Imitrex®) package insert. GlaxoSmithKline, December 2021.
  11. Sumatriptan nasal spray (Imitrex®) package insert. Lannett Company, January 2022.
  12. Sumatriptan nasal powder (Onzetra® Xsail®) package insert. Currax Pharmaceuticals, February 2021.
  13. Sumatriptan nasal spray (Tosymra®) package insert. Upsher-Smith Laboratories, February 2021.
  14. Sumatriptan succinate injection (Zembrace® SymTouch®) package insert. Upsher-Smith Laboratories, February 2021.
  15. Zolmitriptan tablets (Zomig®) package insert. Ajanta Pharma, November 2021.
  16. Zolmitriptan orally disintegrating tablets (Zomig-ZMT®) package insert. Glenmark Pharmaceuticals, September 2022.
  17. Zolmitriptan nasal spray (Zomig®) package insert. Padagis Israel Pharmaceuticals, October 2021.
  18. Sumatriptan/naproxen tablets (Treximet®) Package Insert. Aurobindo Pharma, May 2021.
  19. Winner P, Linder SL, Lipton RB, et al. Eletriptan for the acute treatment of migraine in adolescents: results of a double-blind, placebo-controlled trial.  Headache. 2007;47(4):511-8.
  20. Ahonen K, Hamalainen ML, Rantala H, Hoppu K. Nasal sumatriptan is effective in treatment of migraine attacks in children: a randomized trial. Neurology. 2004;62:883-7.
  21. Winner P, Rothner AD, Saper J, et al. A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. Pediatrics. 2000;106:989-97.
  22. Ueberall MA, Wenzel D. Intranasal sumatriptan for the acute treatment of migraine in children. Neurology. 1999;52:507-10.
  23. Hamalainen ML, Hoppu K, Santavuori P. Sumatriptan for migraine attacks in children: a randomized placebo-controlled study. Do children with migraine respond to oral sumatriptan differently from adults? Neurology. 1997;48(4):1100-3.
  24. Evers S, Rahmann A, Kraemer C, et al. Treatment of childhood migraine attacks with oral zolmitriptan and ibuprofen. Neurology. 2006;67:497-9.
  25. Rothner AD, Wasiewski W, Winner P, et al. Zolmitriptan oral tablet in migraine treatment: high placebo responses in adolescents. Headache. 2006;46:101-9.
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  27. Linder SL. Subcutaneous sumatriptan in the clinical setting: the first 50 consecutive patients with acute migraine in a pediatric neurology office practice. Headache. 1996;36(7):419-422. doi:10.1046/j.1526-4610.1996.3607419.x
  28. MacDonald JT. Treatment of juvenile migraine with subcutaneous sumatriptan. Headache. 1994;34(10):581-582. doi:10.1111/j.1526-4610.1994.hed3410581.