Evaluation of the potential for interactions of paroxetine with diazepam, cimetidine, warfarin, and digoxin

Bannister, Steve J.; Houser, Vincent P.; Hulse, James D.; Kisicki, James C.; Rasmussen, Jill

doi:10.1111/j.1600-0447.1989.tb07186.x

Cited by 65 publications

(23 citation statements)

References 18 publications

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“…As expected, coadministration of paroxetine and alprazolam mimics the effects observed with alprazolam alone. This coincides with reports on in vivo central nervous system effects of paroxetine in combination with benzodiazepines, 33,34 which contrasts with published results of other SSRIs with higher in vitro inhibitory CYP3A activity. [25][26][27][28] With regard to safety and tolerability outcomes, the observed side effect profiles were similar to those described previously for paroxetine and alprazolam, 6,35 and the incidence of adverse events was essentially similar during the combined sequence to the incidence reported during the single active treatments.…”

Section: Discussioncontrasting

confidence: 68%

Lack of Pharmacologic Interaction Between Paroxetine and Alprazolam at Steady State in Healthy Volunteers

Calvo¹,

García-Gea²,

Luque³

et al. 2004

Journal of Clinical Psychopharmacology

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This investigation aimed to provide evidence on the lack of pharmacokinetic interaction of paroxetine (20 mg/d) and alprazolam (1 mg/d) in combined therapy. In addition, the central effects of both drugs when administered alone and in combination were assessed to rule out any relevant synergistic depressant central effect. Twenty-five healthy young adult volunteers participated in a double-blind, double-dummy, placebo-controlled, repeated dose (15 days), 4-period crossover study. Each subject received each of 4 treatment sequences (ie, paroxetine-alprazolam placebo, alprazolam-paroxetine placebo, paroxetine-alprazolam, and paroxetine placebo-alprazolam placebo) in randomized order. The ratios for area under the curve within a dosing interval and maximum plasma concentration of the paroxetine plus alprazolam sequence to single agent paroxetine were 1.07 (90% confidence interval = 0.99 to 1.16) and 1.05 (90% confidence interval = 0.97 to 1.13), respectively, with no statistically significant differences between the 2 treatments. Similarly, for alprazolam, ratios for the combined to the single treatment sequence were 0.99 (90% confidence interval = 0.93 to 1.05) and 1.00 (90% confidence interval = 0.94 to 1.07) for area under the curve within a dosing interval and maximum plasma concentration, respectively, showing no evidence for interaction. Comparative pharmacodynamics on the combination was assessed using 6 Psychomotor Performance Tests and 5 Visual Analogue Scales focused on mood variables. Alprazolam and paroxetine plus alprazolam induced similar and significant performance impairment and sedation after both single and repeated dose administration, being less evident on day 15. After dosing, paroxetine plus alprazolam showed a lower recovery pattern than alprazolam alone, especially on day 15. No treatment sequence showed cumulative effects after repeated dose administration. Psychomotor Performance Tests and Visual Analogue Scales data suggested lack of pharmacodynamic interactions. Accordingly, study results showed no evidence for pharmacologic interactions between paroxetine and alprazolam at steady state. The most commonly reported adverse event was drowsiness, with a higher incidence under both single and combined alprazolam treatments.

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Section: Discussioncontrasting

confidence: 68%

Lack of Pharmacologic Interaction Between Paroxetine and Alprazolam at Steady State in Healthy Volunteers

Calvo¹,

García-Gea²,

Luque³

et al. 2004

Journal of Clinical Psychopharmacology

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“…Notable exceptions to this are increased circulating levels of paroxetine at steady state in the presence of the enzyme inhibitor cimetidine at steady state (19), and the ability of enzyme inducers such as phenytoin and phenobarbitone at steady state to decrease the availability of paroxetine in some individuals. Apart from reducing the mean AUC of phenytoin by 12% and increasing that of procyclidine by 39%, steady-state paroxetine (30mg daily) had little if any effect on the pharmacokinetics of a number of drugs (Table 13).…”

Section: Subjects With Hepatic Diseasementioning

confidence: 98%

“…Until more substantial data are available after repeated drug administration, it would seem advisable to commence paroxetine therapy in patients with severe hepatic impairment using doses towards the lower end of the range recommended for the genera! Table 12 summarizes the results of in viuo studies that have been undertaken to determine the effects of various drugs on the pharmacokinetics ofparoxetine (10,18,19), while Table 13 summarizes the effect of paroxetine on the pharmacokinetics of other drugs (e.g. antipyrine) (20), especially those with a narrow (19).…”

Section: Subjects With Hepatic Diseasementioning

confidence: 99%

A review of the metabolism and pharmacokinetics of paroxetine in man

Kaye

Haddock

Langley

et al. 1989

Acta Psychiatr Scand

241

159

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Acta psychiatr. scand: 80 (supp. 350): 60-75 ABSTRACT -Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeuticallyrelevant concentrations is about 95%. Paroxetine is eliminated by metabolism involving oxidation, methylation, and conjugation. All of these factors lead to wide interindividual variation in the pharmacokinetics of paroxetine. Renal clearance of the compound is negligible. The major metabolites of paroxetine are conjugates which do not compromise its selectivity nor contribute to theclinical response. Ascending single-dose studies reveal that the pharmacokinetics of paroxetine are non-linear to a limited extent in most subjects and to a marked degree in only a few. Also, steady-state pharmacokineticparameters are not predictable from single-dose data. In many subjects, daily administration of 20-50mg of paroxetine leads to little or no disproportionality in plasma levels with dose, although in a few subjects this phenomenon is evident. Steady-state plasma concentrations are generally achieved within 7 to 14 days. The terminal half-life is about one day, although there is a wide intersubject variability (e.g. with 30mg, a range of 7-65 hours was observed in a group of 28 healthy young subjects). In elderly subjects there is wide interindividual variation in steady-state pharmacokinetic parameters, with statistically significantly higher plasma concentrations and slower elimination than in younger subjects, although there is a large degree of overlap in the ranges of corresponding parameters. In severe renal impairment higher plasma levels of paroxetine are achieved than in healthy individuals after single doses. In moderate hepatic impairment the pharmacokinetics after single doses are similar to those of normal subjects. Paroxetine is not a general inducer or inhibitor of hepatic oxidation processes, and has little or no effect on the pharmacokinetics of other drugs examined. Its metabolism and pharmacokinetics are to some degree affected by the induction or inhibition of drug metabolizing enzyme(s). From a pharmacokinetic standpoint, drug interactions involving paroxetine are considered unlikely to be a frequent occurrence. Data available have failed to reveal any correlation between plasma concentrations of paroxetine and its clinical effects (either efficacy or adverse events). Paroxetine (Fig. l), a potent, selective 5-HT uptake inhibitor, currently being developed as a n antidepressant d r u g (1,2), has been review are in terms of the pure free base. extensively studied in man to examine its metabolism andpharmacokinetics. This review provides a summary of the key findings to date, extending earlier observations (3,4). Paroxetine is administered as its hydrochloride salt (BRL 29060A), but doses quoted throughout this Analytical methodology Paroxetinecan be determined in biologi...

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“…Em um deles, 5 de 27 pacientes apresentaram sangramento significativo com paroxetina (Bannister, 1989). A fluvoxamina foi relacionada à elevação da concentração do warfarin, chegando a aumentos na faixa de 65% por provável inibição da CYP 1A2 e 2C9/ 10, justificando a intensidade da elevação (Abad-Santos, 1995;Mitchell, 1997).…”

Section: N T R O D U ç ã O / J U S T I F I C a T I V A : I N T R O unclassified

Interações farmacológicas entre medicações clínicas e psiquiátricas

Marcolin

Cantarelli²,

García³

2004

Rev. psiquiatr. clín.

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Evaluation of the potential for interactions of paroxetine with diazepam, cimetidine, warfarin, and digoxin

Cited by 65 publications

References 18 publications

Lack of Pharmacologic Interaction Between Paroxetine and Alprazolam at Steady State in Healthy Volunteers

Lack of Pharmacologic Interaction Between Paroxetine and Alprazolam at Steady State in Healthy Volunteers

A review of the metabolism and pharmacokinetics of paroxetine in man

Interações farmacológicas entre medicações clínicas e psiquiátricas

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