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Seroxat: Serotonergic drugs: As with other SSRIs, co-administration with serotonergic drugs may lead to an incidence of 5-HT associated effects (see Serotonin Syndrome under Precautions). Caution should be advised and a closer clinical monitoring is required when serotonergic drugs (such as L-tryptophan, triptans, tramadol, linezolid, methylthioninium chloride (methylene blue)), SSRIs, lithium, pethidine and St. John's Wort - Hypericum perforatum - preparations) are combined with paroxetine. Caution is also advised with fentanyl used in general anaesthesia or in the treatment of chronic pain. Concomitant use of paroxetine and MAOIs is contraindicated because of the risk of serotonin syndrome (see Contraindications).
Pimozide: Increased pimozide levels of an average 2.5 times have been demonstrated in a study of a single low dose pimozide (2 mg) when co-administered with 60 mg paroxetine. This may be explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, concomitant use of pimozide and paroxetine is contraindicated (see Contraindications).
Drug metabolising enzymes: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug metabolising enzymes.
When paroxetine is to be co-administered with a known drug metabolising enzyme inhibitor, consideration should be given to using paroxetine doses at the lower end of the range.
No initial dosage adjustment is considered necessary when the drug is to be co-administered with known drug metabolising enzyme inducers (e.g. carbamazepine, rifampicin, phenobarbital, phenytoin) or with fosamprenavir/ritonavir. Any paroxetine dosage adjustment (either after initiation or following discontinuation of an enzyme inducer) should be guided by clinical effect (tolerability and efficacy).
Neuromuscular blockers: SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium and suxamethonium.
Fosamprenavir/ritonavir: Co-administration of fosamprenavir/ritonavir 700/100 mg twice daily with paroxetine 20 mg daily in healthy volunteers for 10 days significantly decreased plasma levels of paroxetine by approximately 55%. The plasma levels of fosamprenavir/ritonavir during co-administration of paroxetine were similar to reference values of other studies, indicating that paroxetine had no significant effect on metabolism of fosamprenavir/ritonavir. There are no data available about the effects of long-term co-administration of paroxetine and fosamprenavir/ritonavir exceeding 10 days.
Procyclidine: Daily administration of paroxetine increases significantly the plasma levels of procyclidine. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.
Anticonvulsants: carbamazepine, phenytoin, sodium valproate. Concomitant administration does not seem to show any effect on pharmacokinetic/dynamic profile in epileptic patients.
CYP2D6 inhibitory potency of paroxetine: As with other antidepressants, including other SSRIs, paroxetine inhibits the hepatic cytochrome P450 enzyme CYP2D6. Inhibition of CYP2D6 may lead to increased plasma concentrations of co-administered drugs metabolised by this enzyme. These include certain tricyclic antidepressants (e.g. chlomipramine, nortriptyline and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine, see Contraindications), risperidone, atomoxetine, certain Type 1c antiarrhythmics (e.g. propafenone and flecainide) and metoprolol. It is not recommended to use paroxetine in combination with metoprolol when given in cardiac insufficiency, because of the narrow therapeutic index of metoprolol in this indication.
Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75% reduction in plasma levels of one of the more active forms of tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRIs antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including paroxetine) should whenever possible be avoided (see Precautions).
Alcohol: As with other psychotropic drugs patients should be advised to avoid alcohol use while taking paroxetine.
Oral anticoagulants: A pharmacodynamic interaction between paroxetine and oral anticoagulants may occur. Concomitant use of paroxetine and oral anticoagulants can lead to an increased anticoagulant activity and haemorrhagic risk. Therefore, paroxetine should be used with caution in patients who are treated with oral anticoagulants (see Precautions).
NSAIDs and acetylsalicylic acid, and other antiplatelet agents: A pharmacodynamic interaction between paroxetine and NSAIDs/acetylsalicylic acid may occur. Concomitant use of paroxetine and NSAIDs/acetylsalicylic acid can lead to an increased haemorrhagic risk (see Precautions).
Caution is advised in patients taking SSRIs, concomitantly with oral anticoagulants, drugs known to affect platelet function or increase risk of bleeding (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCAs, acetylsalicylic acid, NSAIDs, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions that may predispose to bleeding.
Pravastatin: An interaction between paroxetine and pravastatin has been observed in studies suggesting that co-administration of paroxetine and pravastatin may lead to an increase in blood glucose levels. Patients with diabetes mellitus receiving both paroxetine and pravastatin may require dosage adjustment of oral hypoglycaemic agents and/or insulin (see Precautions).
Drugs affecting gastric pH: In vitro data have shown that dissociation of paroxetine from the oral suspension is pH-dependant. Therefore, drugs that alter gastric pH (such as antacid drugs, proton pump inhibitors or histamine H2-receptor antagonists) may affect plasma paroxetine concentrations in patients taking the oral suspension (see Precautions).
Seroxat CR: Serious Drug Interactions (see Contraindications): Monoamine Oxidase Inhibitors; Thioridazine; Pimozide.
Overview: Like some other selective serotonin re-uptake 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. Consideration should be given to decreasing the dose of the CYP2D6 metabolized drug or paroxetine and/or monitoring of drug plasma levels, especially when paroxetine is co-administered with drugs with a narrow therapeutic index. SEROXAT CR co-administration has been associated with elevated levels of the anti-cholinergic procyclidine, certain neuroleptics/antipsychotics (e.g. perphenazine, risperidone), tricyclic antidepressants (e.g. desipramine), atomoxetine, type 1C antiarrhythmics (e.g. propafenone), and theophylline.
Co-administration of phenobarbitol or phenytoin with SEROXAT CR has been associated with decreased levels of SEROXAT CR or immediate-release paroxetine. When co-administered with cimetidine, SEROXAT CR levels were elevated.
The concomitant use of SEROXAT CR and alcohol has not been studied.
Drug-Drug Interactions: Monoamine Oxidase Inhibitors: Combined use of SEROXAT CR and monoamine oxidase inhibitors [including methylthioninium chloride (methylene blue)] is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Contraindications and Precautions).
Thioridazine: Combined use of SEROXAT CR and thioridazine is contraindicated due to a potential for elevated thioridazine plasma levels. Thioridazine treatment alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death (see Contraindications).
Pimozide: In an open label study of healthy volunteers, co-administration of a single dose of 2 mg pimozide, under steady state conditions of immediate-release paroxetine (titrated to 60 mg daily) was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. This is likely explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, and produce severe cardiac arrhythmias including torsade de pointes, concomitant use of pimozide and SEROXAT CR is contraindicated (see Contraindications).
Drugs Metabolized by Cytochrome P450 (CYP2D6): In two studies, daily dosing of immediate-release 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 T½ (3-5 fold). Concomitant steady-state immediate-release 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 SEROXAT CR, if these drugs are to be used in combination. Plasma tricyclic antidepressant concentrations may need to be monitored in such instances.
Concomitant use of SEROXAT CR with other drugs metabolized by CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either SEROXAT CR or the other drug. Drugs metabolized by CYP2D6 include certain tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), selective serotonin reuptake inhibitors (e.g. fluoxetine), phenothiazine neuroleptics (e.g. perphenazine), risperidone, atomoxetine, 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, SEROXAT CR and thioridazine should not be co-administered (see Contraindications).
Fosamprenavir/ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine (by ~ 60% in one study). Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
Tamoxifen: Tamoxifen has an important active metabolite, endoxifen, which is produced by CYP2D6 and contributes significantly to the efficacy of tamoxifen. Irreversible inhibition of CYP2D6 by paroxetine leads to reduced plasma concentrations of endoxifen (see Precautions).
Neuromuscular Blockers: In vitro studies, as well as a small number of clinical reports suggest that some antidepressants including paroxetine may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of succinylcholine.
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 cytochrome 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.
Microsomal Enzyme Inhibition/Induction: The metabolism and pharmacokinetics of SEROXAT CR may be affected by the induction or inhibition of drug metabolizing enzymes.
Drugs Highly Bound to Plasma Protein: Paroxetine is highly bound to plasma protein, therefore administration of SEROXAT CR 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.
Alcohol: The concomitant use of SEROXAT CR or immediate-release paroxetine and alcohol has not been studied and is not recommended. Patients should be advised to avoid alcohol while taking SEROXAT CR.
Anti-cholinergic Drugs: Immediate-release paroxetine has been reported to increase significantly 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.
Antiretroviral: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine (by ~ 60% in one study). Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
Phenobarbital: Chronic daily dosing with phenobarbital (100 mg qid for 14 days) decreased the systemic availability of a single 30 mg dose of paroxetine in some subjects. The AUC and t1/2 of immediate-release paroxetine were reduced by an average of 25 and 38% respectively compared to immediate-release paroxetine administered alone. The effect of SEROXAT CR or immediate-release paroxetine on phenobarbital pharmacokinetics was not studied. No initial SEROXAT CR or immediate-release paroxetine dosage adjustment is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.
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 immediate-release 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 SEROXAT CR 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 SEROXAT CR with anticonvulsants may be associated with an increased incidence of adverse experiences.
Antipsychotic Drugs/Neuroleptic Malignant Syndrome: As with other SSRIs, SEROXAT CR should be used with caution in patients already receiving antipsychotics/ neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases have been reported with this combination (see Precautions).
Serotonergic Drugs: Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when SEROXAT CR is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, fentanyl and its anologues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine or St. John's Wort. (See Precautions). Concomitant use of SEROXAT CR and MAO inhibitors is contraindicated (see Contraindications).
Drugs Affecting Platelet Function (e.g. NSAIDs, ASA and other anticoagulants): 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 drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate the risk of bleeding.
Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when SEROXAT CR is initiated or discontinued (see Precautions).
Lithium: In a study of depressed patients stabilized on lithium, no pharmacokinetic interaction between paroxetine and lithium was observed. However, due to the potential for serotonin syndrome, caution is advised when SEROXAT CR is coadministered with lithium.
Triptans: 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 triptan and an SSRI (e.g. 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 (see Precautions).
Tryptophan: Tryptophan can be metabolized to serotonin. As with other serotonin reuptake inhibitors, the use of SEROXAT CR together with tryptophan may result in adverse reactions consisting primarily of headache, nausea, sweating and dizziness as well as serotonin syndrome. Consequently, concomitant use of SEROXAT CR with tryptophan is not recommended (see Precautions).
CNS Drugs: Experience in a limited number of healthy subjects has shown that immediate-release 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 SEROXAT CR or immediate-release paroxetine with neuroleptics have not been studied, the use of SEROXAT CR with these drugs should be approached with caution.
Diazepam: A multiple dose study of the interaction between immediate-release paroxetine and diazepam showed no alteration in the pharmacokinetics of immediate-release paroxetine that would warrant changes in the dose of SEROXAT CR for patients receiving both drugs. The effects of immediate-release paroxetine or SEROXAT CR on the pharmacokinetics of diazepam were not evaluated.
Cardiovascular Drugs: Multiple dose treatment with immediate-release 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).
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.
Cimetidine: 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 SEROXAT CR towards the lower end of the range when co-administered with known drug metabolizing enzyme inhibitors.
Drug-Food Interactions: At steady state, the bioavailability of 25 mg SEROXAT CR is not affected by food.
Drug-Herb Interactions: 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.
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established.
