Moclobemide markedly inhibits metabolism of rizatriptan,and approximately doubles bioavailability of sumatriptan.The manufacturers contraindicate these triptans with moclobemide and non-selective MAOIs. Moclobemide modestly inhibited metabolism of zolmitriptan but had no clinically significant effect on almotriptan or frovatriptan. Selegiline does not interact with sumatriptan or zolmitriptan, andwould not be expected to interact with any of other triptans. Non-selective MAOIs (e.g. phenelzine) are not expected to interact with eletriptan,frovatriptan, or naratriptan. Nevertheless, themanufacturer of frovatriptan contraindicates concurrent useof MAOIs, based on a theoretical increased risk of serotonin syndrome.
Clinical evidence,mechanism, importance and management
In a study in 12 healthy subjects, moclobemide 150mg twice daily for 8 days increased AUC of a single 12.5mg dose of almotriptan given on day 8 by 37%, decreased its clearance by 27 % and increased half-life by 24%, which was not considered clinically significant (See reference number 1). These findings are consistent with fact that less than half of a dose of almotriptan is metabolised by monoamine oxidase A,(See reference number 2) and it would seem therefore that concurrent use need not be avoided. There appears to be no direct clinical information about use of non-selective MAOIs but it seems unlikely that a clinically relevant interaction will occur.
The manufacturer of eletriptan notes that it is not a substrate for monoamine oxidase,and therefore no interaction with MAOIs is expected (See reference number 3,4). Because of this,they have not undertaken a formal interaction study (See reference number 3).
The manufacturer of frovatriptan notes that it is not a substrate for,or an inhibitor of, monoamine oxidase (See reference number 5,6). Nevertheless,they say that a potential risk of serotonin syndrome or hypertension cannot be excluded when it is used with MAOIs, so concomitant use is not recommended(See reference number 5)(but see also Antimigraine drugs,). A study in 9 healthy subjects given a single 2.5mg oral dose of frovatriptan following pre-treatment with moclobemide 150mg twice daily for 7 days did not find any pharmacokinetic changes, or any changes in vital signs and ECGs of subjects. Therefore no adverse interaction would be expected with concurrent use (See reference number 7).
In a double blind,randomised, crossover study, 12 healthy subjects were given moclobemide 150mg or a placebo three times daily for 4 days, with a single 10mg dose of rizatriptan on day 4. The moclobemide increased AUCs of rizatriptan and its active (but minor) metabolite by 2.2- and 5.3-fold,respectively, and increased their maximum serum levels by 1.4- and 2.6-fold,respectively. MAO-A is principal enzyme concerned with metabolism of rizatriptan. Moclobemide inhibits this enzyme and therefore raises rizatriptan levels. Despite these rises, concurrent use of these drugs was well tolerated and any adverse effects were mild and similar to those seen when rizatriptan was given with placebo. However, because of magnitude of rises, authors recommend avoiding combination (See reference number 9). The manufacturers of rizatriptan contraindicate its use both during, and 2 weeks after stopping an MAOI, stated reasons being that similar or greater rises in serum levels may be expected with irreversible non-selective MAOIs than with moclobemide (See reference number 10,11). In addition, US manufacturers(See reference number 11) note that no interaction would be expected with selective inhibitors of MAO-A (namely selegiline and rasagiline).
Three groups of 14 subjects were given a placebo,moclobemide 150mg three times daily, or selegiline 5mg twice daily for 8 days, with subcutaneous sumatriptan 6mg on day 8. No statistically significant differences in pulse rates or in blood pressures were seen between any of groups following injection of sumatriptan. However, sumatriptan AUC of moclobemide-treated group was approximately doubled (129% increase), its clearance was reduced by 56 % and its half-life increased by 52%. The pharmacokinetic changes seen in selegiline group were not consistent. There were no differences in adverse events experienced by any of three groups (See reference number 12). An in vitro study of metabolism of sumatriptan confirms that it is MAO-A enzyme, not MAO-B, that is major enzyme involved in metabolism of sumatriptan (See reference number 13).
A comprehensive search of literature and reports from proprietary manufacturers, identified published reports of 31 patients taking sumatriptan and MAOIs concurrently, but no adverse events were reported,(See reference number 14) and a patient taking moclobemide 300mg three times daily had no adverse effects when given oral sumatriptan 100mg on six occasions (See reference number 15).
However, a patient who had taken an overdose of moclobemide, together with sumatriptan, sertraline, and citalopram developed serotonin syndrome (See reference number 16).
The interaction between moclobemide and sumatriptan appears to be established. The same interaction seems likely to occur with any RIMA or non-selective MAOI, but not with selective MAO-B inhibitors like selegiline. However, increased sumatriptan bioavailability appears not to be clinically important because, in study cited, those subjects taking moclobemide did not experience any more adverse effects than those taking selegiline or placebo. Despite this UK manufacturers of sumatriptan quite clearly say that concurrent use of sumatriptan and MAOIs is contraindicated both during and for 2 weeks after stopping an MAOI (See reference number 17).
In a series of three-period,crossover, randomised studies, 12 healthy subjects were given selegiline 10mg daily or moclobemide 150mg twice daily for 7 days, with a single 10mg oral dose of zolmitriptan on day 7 (See reference number 18). It was found that AUC of zolmitriptan was increased by 26 % by moclobemide. A threefold increase in AUC of active metabolite also occurred (See reference number 19). It is likely that moclobemide inhibited metabolism of zolmitriptan via monoamine oxidase A. Despite these increases, because of good tolerability profile of zolmitriptan, no dosage reductions are thought to be needed if given with moclobemide, but a maximum intake of 5mg in 24 hrs is recommended by UK manufacturers (See reference number 19). However, US manufacturers contraindicate use of zolmitriptan both during and for 2 weeks after use of RIMAs (See reference number 20).
Selegiline on other hand had no effect on pharmacokinetics of zolmitriptan or its metabolites, apart from a small (7%) reduction in its renal clearance (See reference number 18). This finding was expected,since selegiline is specific for monoamine oxidase B (but note that this specificity is lost at higher doses). No special precautions would therefore seem to be necessary if selegiline is given with sumatriptan.
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