Drugdrug Interactions

Many medications rely on common metabolic processes for biotransformation into an active agent or inactive metabolite. As such, the likelihood that pharmacokinetic interactions among prescription and over-the-counter medications may lead to adverse outcomes becomes greater as medications with shared metabolic pathways are administered concurrently. As noted previously, paroxetine is primarily dependent on the CYP2D6 enzyme for conversion into its inactive metabolites (Hiemke and Hartter 2000). Paroxetine is not only a substrate for this system but also an inhibitor; therefore, other drugs that use this hepatic enzyme are potentially subject to decreased clearance and subsequent increased plasma concentrations (Sindrup et al. 1992b). Concern is greatest for potential drug-drug interactions when the affected medication has a low therapeutic index.

Medications that are CYP2D6 dependent include many antipsychotics, TCAs, type IC antiarrhythmics, & -adrenergic agents, trazodone, and dextromethorphan (Nemeroff et al. 1996). Most reports of interactions between these medications and paroxetine are published as case reports from which firm conclusions regarding causality cannot be drawn (Lane 1996). In regard to the TCAs, Brosen et al. (1993) and Alderman et al. (1997) demonstrated, in prospective studies, that desipramine concentrations increased by 364% and 358%, respectively, when coadministered with paroxetine. Imipramine levels are also increased with the coadministration of paroxetine (Albers et al. 1996).

Antipsychotics are often prescribed with paroxetine in the treatment of psychotic depression and in the treatment of negative symptoms in schizophrenia or as augmentation therapy in patients with primary mood disorders. Paroxetine does not appear to potentiate the sedative effects of haloperidol (Cooper et al. 1989). Dystonia resulting from the combination of paroxetine and haloperidol has been reported (Budman et al. 1995). In one prospective study, clozapine levels increased by an average of

40% over controls when coadministered with SRIs, including paroxetine, at a mean dose of 31.2 mg (Centorrino et al. 1996). In another study using a lower dose of paroxetine (20 mg), no significant increases in clozapine concentrations were noted (Wetzel et al. 1998). These findings indicate that caution should be exercised when paroxetine and clozapine are prescribed together, particularly at higher doses of paroxetine. Case reports have demonstrated possible exaggerated extrapyramidal side effects when paroxetine was administered with perphenazine, molindone, and pimozide (Horrigan and Barnhill 1994; Malek-Ahmadi and Allen 1995; Ozdemir et al. 1997).

A number of medications that are bound to plasma proteins are capable of displacing or being displaced by highly protein-bound drugs, such as paroxetine, resulting in a potentially significant increase in the free concentration of the drug, although this mechanism rarely, if ever, is clinically meaningful (Preskorn 1993). In a prospective study with 27 patients, 5 patients developed mild bleeding when paroxetine was added to ongoing treatment with warfarin, although concentrations of warfarin and paroxetine, as well as prothrombin time, did not change significantly (Bannister et al. 1989). Although an explanation for an increased propensity for bleeding is unclear, it is recommended that anticoagulation parameters be carefully monitored when warfarin and paroxetine are coprescribed. Digoxin levels are unaffected by paroxetine treatment (Bannister et al. 1989), and lithium concentrations are also unchanged by paroxetine administration (Haenen et al. 1995).

In prospective studies involving the antiepileptic/mood stabilizers valproate and carbamazepine, as well as the anticonvulsant phenytoin, coadministration with paroxetine did not cause any significant changes in plasma levels of these drugs (Andersen et al. 1991; Kaye et al. 1989). In contrast, both phenytoin and carbamazepine have been shown to decrease plasma paroxetine concentrations by 28% (Kaye et al. 1989) and 55% (Hiemke and Hartter 2000), respectively. Valproate may increase plasma paroxetine concentrations (Andersen et al. 1991). Cimetidine, which is a potent inhibitor of the CYP2D6 isoenzyme, has been shown to result in a 50% elevation of paroxetine concentrations (Bannister et al. 1989). The clinical significance of the overall deviations in serum paroxetine concentration at steady state caused by these agents is minor because of wide interindividual pharmacokinetic variability, high therapeutic index, and lack of a concentration-efficacy relationship with paroxetine (Gunasekara et al. 1998).

Sedation is a possible side effect associated with barbiturates, benzodiazepines, and ethanol. Paroxetine does not potentiate the psychomotor effects of amobarbital, oxazepam, or alcohol (Cooper et al. 1989). No clinical or pharmacokinetic interaction was noted when paroxetine and diazepam were coadministered in a prospective study (Bannister et al. 1989).

Combination of medications that enhance serotonergic activity may result in the so-called serotonin syndrome, which may manifest as agitation, myoclonus, hyperreflexia, diarrhea, sweating, delirium, fever, elevated blood pressure, and possibly death (Weiner et al. 1997). Following case reports describing the emergence of this syndrome with the combination use of fluoxetine and MAOIs, the concomitant use of MAOIs with any of the SRIs is absolutely contraindicated, and a washout period of 14 days is recommended when switching from one agent to another (Gunasekara et al. 1998; Weiner et al. 1997). Evidence for the serotonin syndrome with paroxetine, in combination with other drugs, has been documented in case reports for moclobemide (Hawley et al. 1996), nefazodone (John et al. 1997), dextromethorphan (Skop et al. 1994), imipramine (Weiner et al. 1997), trazodone (Reeves and Bullen 1995), and others. The combination of SRIs and sumatriptan, a serotonin1D (5-HT1D) receptor agonist used in the treatment of migraine, was previously discouraged because of the theoretical risk of precipitation of the serotonin syndrome; however, a series of six cases, one involving paroxetine, of concurrent sumatriptan and SRI administration demonstrated no adverse events (Leung and Ong 1995). This lack of interaction has been confirmed in a prospective trial (Franklin et al. 1996).

Overall, paroxetine may be safely administered with other medications, as clinically indicated. Coadministration with an MAOI is absolutely contraindicated, and careful monitoring is advised when

TCAs, warfarin, and clozapine are used in conjunction with paroxetine. As with any medication, clinicians are advised to minimize polypharmacy and remain vigilant to the possibility of drug-drug interactions (see Table 15-2 for the important drug-drug interactions with paroxetine).

TABLE 15-2. Potential drug-

-drug interactions involving paroxetine

Monoamine oxidase inhibitors

Clinically significant

Tricyclic antidepressants

Clinically significant

Type IC antiarrhythmics

Probably significant

^-Adrenergic antagonists

Probably significant

Antiepileptic agents

Probably significant

Cimetidine

Probably significant

Typical antipsychotics

Possibly significant

Warfarin

Possibly significant

Clozapine

Inconclusive

Lithium

Not clinically significant

Digoxin

Not clinically significant

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