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Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS.
Thioridazine: See CONTRAINDICATIONS.
Drugs Metabolized by Cytochrome P450 (CYP2D6): Like some other selective serotonin reuptake inhibitors, paroxetine inhibits the specific hepatic cytochrome P450 isozyme CYP2D6 which is responsible for the metabolism of debrisoquine and sparteine. Poor metabolizers of debrisoquine/sparteine represent approximately 5 - 10% of Caucasians. The median Cmin (ss) for paroxetine (20 mg daily) at steady state in poor metabolizers (n=8) was almost triple that reported for extensive metabolizers (n=9). Although the full clinical significance of this effect has not been established, inhibition of CYP2D6 can lead to elevated plasma levels of co-administered drugs which are metabolized by this isozyme.
In two studies, daily dosing of paroxetine (20 mg qd) under steady state conditions increased the following mean pharmacokinetic parameters for a single (100 mg) dose of desipramine in extensive metabolizers: Cmax (2 fold), AUC (6 fold), and t1/2 (3-5 fold).
Concomitant steady-state paroxetine treatment did not result in any further impairment of desipramine elimination in poor metabolizers. Insufficient information is available to provide recommendations on the necessary dosage adjustments for tricyclic antidepressants or paroxetine, if these drugs are to be used in combination. Plasma tricyclic antidepressant concentrations may need to be monitored in such instances.
Concomitant use of APO-PAROXETINE with other drugs metabolized by CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either APO-PAROXETINE or the other drug. Drugs metabolized by cytochrome P450 CYP2D6 include certain tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), selective serotonin reuptake inhibitors (e.g. fluoxetine), phenothiazine neuroleptics (e.g. perphenazine), Type IC antiarrhythmics (e.g. propafenone and flecainide), and metoprolol. 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 co-administered (see CONTRAINDICATIONS).
Drugs Metabolized by Cytochrome P450 (CYP3A4): An in vivo interaction study involving the co-administration under steady state conditions of paroxetine and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 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 cyclosporin. 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 CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity would not be expected to be of clinical significance.
Serotonergic Drugs: As with other SSRIs, co-administration with serotonergic drugs (e.g. MAO inhibitors (see CONTRAINDICATIONS), L-tryptophan) may lead to an incidence of 5-HT associated effects (see Serotonergic Syndrome under ADVERSE REACTIONS).
CNS Drugs: Experience in a limited number of healthy subjects has shown that paroxetine does not increase the sedation and drowsiness associated with haloperidol, amylbarbitone or oxazepam, when given in combination. Since the effects of concomitant administration of paroxetine with neuroleptics have not been studied, the use of APO-PAROXETINE with these drugs should be approached with caution.
Food/Antacids: The absorption and pharmacokinetics of APO-PAROXETINE are not affected by food or antacids.
Cardiovascular Drugs: Multiple dose treatment with paroxetine 30 mg/day has little or no effect on the steady-state pharmacokinetics of digoxin (0.25 mg qd) or propanolol (80 mg bid).
Microsomal Enzyme Inhibition/Induction: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug metabolizing enzymes.
Steady state levels of paroxetine (30 mg daily) were elevated by about 50% when cimetidine (300 mg tid), a known drug metabolizing enzyme inhibitor, was co-administered to steady-state. Consideration should be given to using doses of paroxetine towards the lower end of the range when co-administered with known drug metabolizing enzyme inhibitors.
Anticonvulsants: In a limited number of patients with epilepsy on long-term treatment with anticonvulsants (carbamazepine 600-900 mg/day, n=6; phenytoin 250-400 mg/day, n=6; sodium valproate 300-2500 mg/day, n=8) the co-administration of paroxetine (30 mg/day for 10 days) had no significant effect on the plasma concentrations of these anticonvulsants. In healthy volunteers, co-administration of paroxetine with phenytoin has been associated with decreased plasma levels of paroxetine and an increased incidence of adverse experiences. However, no initial dosage adjustment of paroxetine is considered necessary when the drug is to be co-administered with known drug metabolizing enzyme inducers (e.g. carbamazepine, phenytoin, sodium valproate) and any subsequent dosage adjustment should be guided by clinical effect. Co-administration of paroxetine with anticonvulsants may be associated with an increased incidence of adverse experiences.
Alcohol: The concomitant use of APO-PAROXETINE and alcohol has not been studied and is not recommended. Patients should be advised to avoid alcohol while taking APO-PAROXETINE.
Tryptophan can be metabolized to serotonin. As with other serotonin reuptake inhibitors, the use of APO-PAROXETINE together with tryptophan may result in adverse reactions consisting primarily of headache, nausea, sweating and dizziness as well as serotonin syndrome (see Postmarketing Reports under ADVERSE REACTIONS). Consequently, concomitant use of APO-PAROXETINE with tryptophan is not recommended.
Chronic daily dosing with phenobarbital (100 mg qid for 12 of paroxetine 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. No initial APO-PAROXETINE dosage adjustment is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.
Anti-cholinergic Drugs: Paroxetine has been reported to increase the systemic bioavailability of procyclidine. Steady state plasma levels of procyclidine (5 mg daily) were elevated by about 40% when 30 mg paroxetine was co-administered to steady-state. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.
Drugs Highly Bound to Plasma Protein: Paroxetine is highly bound to plasma protein, therefore administration of APO-PAROXETINE 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.
In a study of depressed patients stabilized on lithium, no pharmacokinetic interaction between paroxetine and lithium was observed. However, since there is limited experience in patients, the concurrent administration of APO-PAROXETINE and lithium should be undertaken with caution.
A multiple dose study of the interaction between paroxetine and diazepam showed no alteration in the pharmacokinetics of paroxetine that would warrant changes in the dose of paroxetine for patients receiving both drugs. The effects of paroxetine on the pharmacokinetics of diazepam were not evaluated.
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 the 5HT1 agonist, sumatriptan. If concomitant treatment with sumatriptan and an SSRI (eg., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised. The possibility of such interactions should also be considered if other 5HT1 agonists are to be used in combination with SSRIs.
Theophylline: Reports of elevated theophylline levels associated with paroxetine treatment 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.
St. John's Wort: In common with other SSRI's, pharmacodynamic interactions between paroxetine and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.
