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