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Criteria for Outpatient Use Guidelines

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Serotonin 5-HT1B/1D Receptor Agonists

[Developed, August 1998; Revised, October 1999, August 2000, September 2001; November 2001; July 2002; August 2003; December 2006; May 2007; May 2007 revised; October 2008; April 2011]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults
The maximum recommended adult doses for available serotonin 5-HT1B/1D receptor agonists are summarized in Table 1. Dosages exceeding these recommendations will be reviewed.

Table 1
Maximum Recommended Daily Adult Dosages for Serotonin 5-HT1B/1D Receptor Agonists
DRUG MAXIMUM DAILY DOSAGE
Monotherapy: Almotriptan (Axert®) tablets (6.25 mg, 12.5 mg) 25 mg/day
Monotherapy: Eletriptan (Relpax®) tablets (20 mg, 40 mg) 80 mg/day
Monotherapy: Frovatriptan (Frova®) tablets (2.5 mg) 7.5 mg/day
Monotherapy: Naratriptan (Amerge®) tablets (1 mg. 2.5 mg) 5 mg/day
Monotherapy: Rizatriptan tablets (Maxalt®) - 5 mg, 10 mg 30 mg/day
Monotherapy: Rizatriptan tablets orally-disintegrating tablets (Maxalt -MLT®) - 5 mg, 10 mg 30 mg/day
Monotherapy: Rizatriptan — propranolol patients 15 mg/day
Monotherapy: Sumatriptan (Imitrex®) intranasal (5 mg/spray, 20 mg/spray – 6 per package) 40 mg/day
Monotherapy: Sumatriptan (Imitrex®) oral tablets (25 mg, 50 mg, 100 mg) 200 mg/day
Monotherapy: Sumatriptan (Imitrex®) subcutaneous injection (4 mg STATdose system, 6 mg STATdose system, 6 mg/0.5 mg single dose vial) 12 mg/day
Monotherapy: Zolmitriptan intranasal (Zomig®) – 5 mg 10 mg/day
Monotherapy: Zolmitriptan intranasal (Zomig®) – 2.5 mg, 5 mg 10 mg/day
Monotherapy: Zolmitriptan intranasal (Zomig®) – orally disintegrating tablets (Zomig-ZMT®) – 2.5 mg, 5 mg 10 mg/day
Combination therapy: Sumatriptan/naproxen tablet (Treximet®) - 85 mg/500 mg 170 mg/1000 mg per day

Pediatrics

Most serotonin 5-HT1B/1D receptor agonists are not FDA-approved for use in patients under 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 serotonin 5-HT1B/1D receptor agonist use as well as an adverse event profile, including serious adverse events, comparable to that seen in adults.5, 10, 11, 15 Sumatriptan/naproxen combination therapy is not FDA- approved for use in pediatric patients due to the absence of safety/efficacy data.14

No significant data are available evaluating serotonin 5-HT1B/1D receptor agonist 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.16-19 Zolmitriptan nasal spray has demonstrated efficacy in managing acute migraine attacks in adolescents 12 to 17 years of age in one trial, while a few small studies with oral zolmitriptan have shown mixed outcomes.20-22 Studies evaluating rizatriptan use for acute migraine headache management in children/adolescents have produced mixed results.23-25 Although not FDA-approved, Table 2 summarizes serotonin 5-HT1B/1D receptor agonist doses that have been utilized in the pediatric population.

Table 2
Pediatric Dosages for Serotonin 5-HT1B/1D Receptor Agonists
DRUG PATIENT CHARACTERISTICS DOSE UTILIZED PER HEADACHE
Rizatriptan 6 to 17 years of age 20 to 39 kg 40 kg or greater 5 mg 10 mg
Sumatriptan intranasal 6 to 17 years of age 20 mg
Sumatriptan subcutaneous 6 to 18 years of age 0.06 mg/kg
Sumatriptan subcutaneous 6 to 16 years of age < 30 kg 3 mg
Sumatriptan subcutaneous 6 to 16 years of age > 30 kg 6 mg
Zolmitriptan 6 to 18 years of age 2.5 mg

Almotriptan is the only serotonin 5-HT1B/1D receptor agonist with FDA approval for use in children 12 to 17 years of age to treat acute migraine attacks in patients with a history of migraine with or without aura. Maximum recommended pediatric doses for serotonin 5-HT1B/1D receptor agonists are summarized in Table 2.  Dosages exceeding these recommendations will be reviewed.

Table 31-4
Maximum Recommended Daily Pediatric Dosages
or FDA-Approved Serotonin 5-HT1B/1D Receptor Agonists
DRUG MAXIMUM DAILY DOSAGE

Almotriptan

25 mg/day

 

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.26-28  Additionally, the safety of treating more than 3 or 4 headaches during a 30-day time period has not been established.  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 Table 4.  Patient profiles documenting quantities of serotonin 5-HT1B/1D receptor agonists that exceed these recommendations will be reviewed.

Table 4
Maximum Recommended Serotonin (5-HT1B/1D) Receptor Agonist Dosage Frequency
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 (ODT) 4 headaches 12 x 10 mg tablets or 120 mg
Rizatriptan — propanolol patients (regular or ODT) 4 headaches 12 x 5 mg tablets/ODT or 60 mg
Sumatriptan intranasal 4 headaches 8 x 20 mg spray or 160 mg
Sumatriptan subcutaneous injection ---+ ----
Sumatriptan oral tablets 4 headaches 32 sprays or 160 mg 8 tablets or 800 mg* ----
Zolmitriptan intranasal 4 headaches 8 sprays 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*
Combination Therapy: Sumatriptan/naproxen tablets 5 headaches 10 tablets or 850 mg/5000 mg

* After May 1st, 2002, the Texas Medicaid Vendor Drug Program extended dosage limits for oral sumatriptan to not exceed 900 mg/month(9 x 100 mg tablets) and oral zolmitriptan to not exceed 40 mg/month (8 x 5 mg tablets).
+Patients should not receive more than 2 sumatriptan subcutaneous injections in a 24-hour time period. 

3.* Duplicative Therapy

The use of two or more serotonin 5-HT1B/1D receptor agonists concurrently is not justified due to the potential for additive vasospastic effects. Additional therapeutic benefit is not realized when serotonin 5-HT1B/1D receptor agonists are used in combination. 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 those drug regimens which may result in clinically significant drug-drug interactions. 

Clinically relevant drug-drug interactions for serotonin 5-HT1B/1D receptor agonists are summarized in Tables 5 and 6.  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 52, 4-13, 29, 30
Summary of Significant Serotonin 5-HT1B/1D
Receptor Agonist Drug Interactions
Triptan Amphet-
amines		 CYP3A4 inhibitors Ergots Linezolid MAOIs+ Propranolol Sibutramine SNRIs#/SSRIs*
almotriptan Yes Yes Yes ---- ---- ---- Yes Yes
eletriptan Yes Yes Yes ---- ---- ---- Yes Yes
frovatriptan Yes ---- Yes ---- ---- ns Yes Yes
naratriptan Yes ---- Yes ---- ---- ---- Yes Yes
rizatriptan Yes ---- Yes Yes Yes Yes Yes Yes
sumatriptan Yes ---- Yes Yes Yes ---- Yes Yes
zolmitriptan Yes ---- Yes Yes Yes ns Yes Yes

+MAOIs = monoamine oxidase inhibitors; #SNRIs = serotonin-norepinephrine reuptake inhibitors; *SSRIs = selective serotonin reuptake inhibitors

Table 62, 4-13, 29, 30
Serotonin 5-HT1B/1D Receptor Agonists Drug-Drug Interactions
TARGET DRUG^ INTERACTING DRUG INTERACTION RECOMMENDATIONS CLINICAL SIGNIFICANCE~
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, observe for signs/symptoms of serotonin syndrome and adjust therapy as indicated 1-severe, 2-major (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 moderate (DrugReax)
2-major (CP)
2, 4 (DIF)
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-severe (CP)
1 (DIF)
select SRAs linezolid concurrent administration with SRAs metabolized by MAO may increase serotonin levels and the potential for serotonin syndrome, as linezolid is nonselective 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 an option contraindicated (DrugReax)
3-moderate (CP)
1 (DIF)
select 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 an option contraindicated (DrugReax)
1-severe, 2-major, 3-moderate (CP)
1 (DIF)

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) and observe patients for enhanced rizatriptan pharmacologic/adverse effects when administered concurrently with propranolol

moderate (DrugReax)
2-major (CP)
2 (DIF)

SRAs

sibutramine

adjunctive administration may increase serotonin levels and potential for serotonin syndrome, as sibutramine is a serotonin reuptake inhibitor

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)
2-major (CP)
1 (DIF)

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)
2-major (CP)
2 (DIF)

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

References

  1. DRUGDEX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.   Accessed April 25th, 2011.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2011. Available at: http://www.clinicalpharmacology.com. Accessed April 25th, 2011.
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  4. Almotriptan (Axert®) Package Insert. Ortho-McNeil Neurologics, Inc., April 2009.  
  5. Eletriptan (Relpax®) Package Insert.  Pfizer, Inc., May 2008.
  6. Frovatriptan (Frova®) Package Insert.  Endo Pharmaceuticals, Inc., April 2007.
  7. Naratriptan (Amerge®) Package Insert.  GlaxoSmithKline, February 2010.
  8. Rizatriptan (Maxalt® and Maxalt-MLT®) Package Insert. Merck & Co, Inc., August 2010.
  9. Sumatriptan tablets (Imitrex®) Package Insert.  GlaxoSmithKline, February 2010.
  10. Sumatriptan injection (Imitrex®) Package Insert.  GlaxoSmithKline, February 2010.
  11. Sumatriptan nasal spray (Imitrex®) Package Insert. GlaxoSmithKline, February 2010.
  12. Zolmitriptan tablets and orally disintegrating tablets (Zomig® and Zomig-ZMT®) Package Insert. AstraZeneca Pharmaceuticals, October 2008.
  13. Zolmitriptan nasal spray (Zomig®) Package Insert.  AstraZeneca Pharmaceuticals, October 2008.
  14. Sumatriptan/naproxen tablets (Treximet®) Package Insert.  GlaxoSmithKline, December 2009.
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  25. Visser WH, Winner P, Strohmaier K, et al. Rizatriptan Protocol 059 and 061 Study Groups. Rizatriptan 5 mg for the acute treatment of migraine in adolescents: results from a double-blind, single-attack study and two open-label, multiple-attack studies. Headache. 2004;44:891-9.
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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.