Sertraline, drug interactions

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Extrapyramidal side effects (EPS) associated with SSRI medications used as single agents were reported as early as 1979 (Meltzer et ah, 1979). Since then, several case reports have been published on use of fluoxetine (Elamilton and Opler, 1992), paroxetine (Nicholson, 1992), and sertraline (Opler 1994). The SSRI medications in combination with neuroleptics can cause severe EPS (Tate, 1989 Ketai, 1993) above and beyond what may be associated with increased levels of antipsychotic medications (Goff et ah, 1991), and are perhaps related to pharmacokinetic drug interactions. 

The major distinguishing characteristic among the SSRIs is CYP enzyme inhibition. Fluvoxamine, fluoxetine, and paroxetine produce substantial inhibition of one or more CYP enzymes, whereas citalopram and sertraline do not (Table 7-29). In fact, fluvoxamine, fluoxetine, and paroxetine have all caused fatal drug-drug interactions via such CYP enzyme inhibition (339, 496, 497). 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Although venlafaxine can have more interactions than SSRIs pharmacodynamically, it is comparable with citalopram and sertraline in terms of not causing CYP enzyme mediated pharmacokinetic drug-drug interactions (Table 7-29). Thus, these three antidepressants have a distinct advantage over drugs such as fluoxetine, particularly in patients who are likely to be on other medications in aaaition to their antidepressant. 

Potential drug interaction between sertraline and St. John s wort cannot be ruled out in one case that experienced manic depressive disorder symptoms one to two weeks after St. John s wort was started into sertraline therapy. The patient was treated with an antipsychotic and has had no problems after discontinuing St. John s wort and decreasing the sertraline dose. 

Fluoxetine and paroxetine are potent inhibitors of the CYP2D6 isoenzyme, and this contributes to potential drug interactions (see drug interactions). In contrast, fluvoxamine is an inhibitor of CYP3A4, whereas citalopram, escitalopram, and sertraline have more modest CYP interactions. 

A meta-analysis of 20 short-term studies of five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) has been published (8). There were no overall differences in efficacy, but fluoxetine had a slower onset of action. Citalopram and sertraline were least likely to cause drug interactions, but citalopram was implicated more often in fatal overdoses. 

Drug interactions leading to the serotonin syndrome usually result from pharmacodynamic mechanisms. However, the antibiotic erythromycin may have precipitated the serotonin syndrome in a patient taking sertraline by a pharmacokinetic mechanism (22). 

Bonate PL, Kroboth PD, Smith RB, Suarez E, Oo C. Clonazepam and sertraline absence of drug interaction in a multiple-dose study. J Clin Psychopharmacol 2000 20(1) 19-27. 

MAOIs SSRIs t risk of serotonin syndrome >- For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome Additive inhibitory on serotonin reuptake Avoid co-administration. MAOIs should not be started for at least 1 week after stopping SSRIs (2 weeks after sertraline, S weeks after fluoxetine). Conversely, SSRIs should not be started for at least 2 weeks after stopping MAOIs... 

FLUOXETINE, FLUVOXAMINE, PAROXETINE BZDs - ALPRAZOLAM, DIAZEPAM, MIDAZOLAM t in plasma concentrations of these BZDs. Likely t sedation and interference with psychomotor activity Alprazolam, diazepam and midazolam are subject to metabolism by CYP3A4. Fluvoxamine, fluoxetine and possibly paroxetine are inhibitors of CYP3A4 sertraline is a weak inhibitor. SSRIs are relatively weak compared with ketoconazole, which is possibly 100 times more potent as an inhibitor Warn patients about risks associated with activities that require alertness. Consider use of alternatives such as oxazepam, lorazepam and temazepam, which are metabolized by glucuronidation >- For signs and symptoms of CNS depression, see Clinical Features of Some Adverse Drug Interactions, Central nervous system depression... 

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