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-HT_1B/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 Interactions^1-16

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 Interactions^1-17

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	moderate
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 - contraindicated
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
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	major
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	moderate - contraindicated
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	major
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	moderate - major

Legend:

• # CP = Clinical Pharmacology
• + MAOIs = monoamine oxidase inhibitors
• # SNRIs = serotonin-norepinephrine reuptake inhibitors
• * SSRIs = selective serotonin reuptake inhibitors
• ^ SRAs = serotonin 5-HT_1B/1D receptor agonists