Reboxetine, drug interactions

FIGURE 7—54. Heroic combo 10 SSRI plus NRI. Here, 5HT and NE are both single-boosted. The preferred NRI is selective reboxetine, as there are no drug interactions. Nonselective TCAs that are preferential NRIs such as desipramine, maprotilene, nortriptyline, or protriptyline can be combined if plasma drug levels of the TCA are monitored, especially if fluoxetine or paroxetine is the SSRI chosen. 

The norepinephrine selective uptake inhibitor reboxetine (21) is rapidly and completely absorbed, and is metabolized mainly by the cytochrome p450 3A4 because it does not interact with CYP 2D6 there is less risk of interactions with other drugs (81 -83).Mirtazepine (14)also shows little interaction with p450 cytochrome isozymes and there is only a low risk of drug interactions (84). Mirtazepine is a racemate, and the two enantiomers are eliminated at different rates, with a twofold higher rate of elimination of the (S)-enantiomer than of the (i )-enantiomer (84). 

Reboxetine seems to be an antidepressant that has negligible interference with the pharmacokinetics of other drugs thus, fewer drug-drug interactions are expected. It also may be possible to use reboxetine in combination with MAOIs, because it has no inhibitory effect on this enzyme, which would avoid tyramine-induced hypertensive reactions. 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

This antidepressant can interact with other drugs via its two mechanisms of action serotonin and NE uptake inhibition. The former action means that the same pharmacodynamic interactions will occur with venlafaxine as with SSRIs, including the serotonin syndrome. At higher doses, venlafaxine is also prone to the same pharmacodynamic interactions as NSRIs such as secondary amine TCAs like desipramine and with newer NSRIs such reboxetine. Thus, the combination of high-dose venlafaxine plus an MAOl could produce a hypertensive crisis as well as the serotonin syndrome. 

Fleishaker JC, Herman BD, Pearson LK, Ionita A, Mucci M. Evaluation of the potential pharmacokinetic/ pharmacodynamic interaction between fluoxetine and reboxetine in healthy volunteers. Clin Drug Invest 1999 18 141-50. 

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