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Sumatriptan There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e. g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised. Drugs Affecting Hepatic Metabolism Text Continues Below
The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes. Cimetidine Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine's pharmacokinetics was not studied. Phenobarbital Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30-mg dose of PAXIL was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T ˝ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect. Phenytoin When a single oral 30-mg dose of PAXIL was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T ˝ were reduced (by an average of 50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS— Postmarketing Reports). Drugs Metabolized by Cytochrome P450IID6 Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P450 isozyme P450IID6. Like other agents that are metabolized by P450IID6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (> 90%), this P450IID6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T ˝ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of PAXIL with other drugs metabolized by cytochrome P450IID6 has not been formally studied but may require lower doses than usually prescribed for either PAXIL or the other drug. Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e. g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, and Type 1C antiarrhythmics (e. g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e. g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS).
At steady state, when the P450IID6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes that, unlike P450IID6, show no evidence of saturation (see PRECAUTIONS— Tricyclic Antidepressants). Drugs Metabolized by Cytochrome P450IIIA4 An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome P450IIIA4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine's in vitro Ki and its lack of effect on terfenadine's in vivo clearance predicts its effect on other IIIA4 substrates, paroxetine's extent of inhibition of IIIA4 activity is not likely to be of clinical significance. Tricyclic Antidepressants (TCAs) Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS— Drugs Metabolized by Cytochrome P450IID6).
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of PAXIL to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events.
Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs. Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic agents that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Alcohol Although PAXIL does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL. Lithium A multiple-dose study has shown that there is no pharmacokinetic interaction between PAXIL and lithium carbonate. However, since there is little clinical experience, the concurrent administration of paroxetine and lithium should be undertaken with caution.
Digoxin The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.
Diazepam Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated. Procyclidine Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced. Beta-Blockers In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS— Postmarketing Reports). Theophylline Reports of elevated theophylline levels associated with treatment with PAXIL have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered. Electroconvulsive Therapy (ECT) There are no clinical studies of the combined use of ECT and PAXIL. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/ kg/ day (mice) and 1, 5, and 20 mg/ kg/ day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, GAD, and PTSD on a mg/ m 2 basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/ 100, 0/ 50, 0/ 50, and 4/ 50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Mutagenesis Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/ kg/ day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/ m 2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/ kg/ day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/ kg/ day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/ m 2 basis). Pregnancy Teratogenic Effects Pregnancy Category C. Reproduction studies were performed at doses up to 50 mg/ kg/ day in rats and 6 mg/ kg/ day in rabbits administered during organogenesis. These doses are equivalent to 9.7 (rat) and 2.2 (rabbit) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, GAD, and PTSD (50 mg) and 8.1 (rat) and 1.9 (rabbit) times the MRHD for OCD, on an mg/ m 2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/ kg/ day or 0.19 times (mg/ m 2 ) the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD; and at 0.16 times (mg/ m 2 ) the MRHD for OCD. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The effect of paroxetine on labor and delivery in humans is unknown. Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when PAXIL is administered to a nursing woman. Pediatric Use Safety and effectiveness in the pediatric population have not been established. Geriatric Use: In worldwide premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Page: << Prev | 1 | 2 | 3 | 4 | 5
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