Paroxetine Interactions
Antacids
- Aprepitant
- Aripiprazole
- Aspirin, ASA
- Astemizole
- Atomoxetine
Barbiturates
- Buspirone
- Cevimeline
- Cimetidine
- Cocaine
- Codeine
- Cyproheptadine
- Darifenacin
- Delavirdine
- Dexfenfluramine
- Dextroamphetamine
- Dextromethorphan
- Digoxin
- Donepezil
- Doxercalciferol
- Encainide
- Ethanol
- Fenfluramine
- Flecainide
- Furazolidone
- Galantamine
- Gefitinib
- Haloperidol
- Hydrocodone
- Imatinib, STI-571
- Isoniazid, INH
- Kava Kava, Piper methysticum
- Linezolid
- Lithium
- Meperidine
- Methadone
- Metoclopramide
- Metoprolol
- Mexiletine
Monoamine oxidase inhibitors (MAOIs)
Nonsteroidal antiinflammatory drugs (NSAIDs)
Phenothiazines
- Phentermine
- Phenytoin
- Pimozide
- Primidone
- Procarbazine
- Procyclidine
- Propafenone
- Propranolol
- Quinidine
- Risperidone
- Ritonavir
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin-Receptor Agonists
- Sibutramine
- St. John’s Wort, Hypericum perforatum
- Tamoxifen
- Terfenadine
- Theophylline, Aminophylline
- Tramadol
- Trazodone
Tricyclic antidepressants
- Tryptophan, 5-Hydroxytryptophan
- Valerian, Valeriana officinalis
- Warfarin
- Zolpidem
Paroxetine Interactions
NOTE: Paroxetine is a substrate and inhibitor of the hepatic CYP450 isoenzyme CYP2D6. Paroxetine potently inhibits CYP2D6 substantially in vivo, thereby inhibiting the metabolism of a number of drugs. Increased serum concentrations and possible toxicity may occur. In > 90% of patients, the CYP2D6 isoenzyme is saturated early in dosing with paroxetine. At steady state when the CYP2D6 pathway is essentially saturated (in roughly 10 - -14 days after initiation of therapy), paroxetine clearance is governed by alternative P450 isoenzymes that, unlike CYP2D6, show no evidence of saturation. Paroxetine does not appear to inhibit other CYP hepatic isoenzymes, based on in vitro studies, to any clinically significant degree. There is no in vivo evidence that paroxetine inhibits hepatic CYP3A4 to a clinically significant degree.
Due to possible additive effects on serotonin concentrations, it is advisable to avoid combinations of paroxetine with other selective serotonin reuptake inhibitors (SSRIs) (duplicative therapy). This interaction can lead to a reaction known as ‘serotonin syndrome’. The syndrome may include symptoms of confusion, nausea, sweating, agitation, or more severe symptoms, like hypertension and unresponsiveness. Additionally, the possibility of metabolic inhibition may exist if paroxetine is combined with other SSRIs, such as fluoxetine. Plasma concentrations of paroxetine may be elevated, further increasing the risk for serotonin syndrome.
The manufacturers of astemizole, pimozide, and terfenadine, respectively, consider the SSRI-type medications to be contraindicated for use concurrently. Paroxetine may not inhibit the clearance of certain medications metabolized by CYP3A4 isoenzyme, a pathway that some SSRIs are known to inhibit. Paroxetine is a known potent inhibitor of CYP2D6, and is not generally considered to inhibit CYP3A4 to any clinically significant degree in vivo. Paroxetine is 100 times less potent as a CYP3A4 inhibitor than is ketoconazole based on in vitro interaction studies. However, mean increases in pimozide AUC of 151% when co-administered with paroxetine have been noted; the manufacturer of paroxetine considers the combined use of paroxetine and pimozide contraindicated. Astemizole, pimozide and terfenadine are metabolized by CYP3A4; all of these drugs are noted to cause QT prolongation when their serum concentrations are elevated. Post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with any of these four medications.
Paroxetine potentiates serotonin by inhibiting its neuronal reuptake. Since serotonin is deaminated by monoamine oxidase type A, administration of drugs that inhibit this enzyme concurrently with SSRIs can lead to a serious reaction known as ‘serotonin syndrome.’ This reaction may include confusion, seizures, and severe hypertension as well as less severe symptoms. Most MAOIs (e.g., isocarboxazid, phenelzine, tranylcypromine) are non-specific inhibitors of MAO and, since they affect MAO type A, should not be used with SSRIs. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of paroxetine therapy, or vice versa. In addition, selegiline, although selective for MAO type B at usual doses, may inhibit MAO type A at higher doses and should also be avoided in patients receiving SSRIs. Finally, isoniazid, INH, furazolidone, linezolid (antibiotic) and procarbazine (chemotherapy agent) also possess weak non-selective MAO-inhibiting activity and should be combined with any serotonergic agent with caution.
Clinicians should be alert for pharmacokinetic interactions between tricyclic antidepressants (TCAs) and paroxetine. Cytochrome CYP2D6 is impaired by paroxetine within 1 - 2 weeks of paroxetine administration and is the isoenzyme most responsible for metabolism of tricyclic antidepressants. In one study, the Cmax, AUC, and T1/2 of desipramine were increased by two-, five- and three-fold respectively by the co-administration of paroxetine at steady-state. In several cases, symptoms of toxicity, including seizures, were reported when drugs from the SSRI and TCAs were used together. In a preliminary study of children and adolescents treated concomitantly with clomipramine and paroxetine, approximately 70% experienced QTc interval prolongation and up to 30% experienced tachycardias due to decreased metabolism of the tricyclic antidepressant via CYP2D6. Reports of sudden death or ventricular arrhythmias have occurred in children and adolescents who were given tricyclic antidepressants and SSRIs concurrently. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if a SSRI-type drug is added, and the tricyclic antidepressant dosage reduced, if warranted. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
An interaction may occur between paroxetine and either fenfluramine or dexfenfluramine. Dexfenfluramine stimulates the release of serotonin and inhibits its reuptake. Paroxetine also inhibits the reuptake of serotonin. In addition, paroxetine is a potent inhibitor of CYP2D6, an isoenzyme involved in the metabolism of dexfenfluramine. Thus, due to several mechanisms, serotonin excess and/or the serotonin syndrome may be possible if dexfenfluramine and paroxetine are used together. Due to the potential severity of the serotonin syndrome, paroxetine should not be used with dexfenfluramine. Since dexfenfluramine is the S-enantiomer of the racemic compound fenfluramine, a similar interaction may occur between paroxetine and fenfluramine.
Concomitant administration of the SSRIs and the serotonin-receptor agonists (e.g., the ‘triptans’ for migraine, like sumatriptan) has resulted in increased plasma concentrations of SSRIs and rare reports of weakness, hyperreflexia and incoordination. If concomitant treatment with 5-HT1-receptor agonists and a SSRI is clinically warranted, the patient should be advised of potential drug interaction symptoms and appropriate actions to take should they occur. All centrally-acting serotonergic agents should be used cautiously in patients receiving SSRIs.
Paroxetine impairs the metabolism of the phenothiazines. Thioridazine is specifically contraindicated for use with paroxetine. Serum concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, may increase by up to three-fold because paroxetine impairs the CYP2D6 isoenzyme metabolic pathway. Substantial increases in serum thioridazine concentrations may lead to prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias and sudden death. Substantial increases in concentrations of other phenothiazine antipsychotics may also occur, which may lead to side effects.
Paroxetine impairs metabolism of the CYP2D6 (cytochrome P-450 isoenzyme 2D6) pathway at therapeutic doses. This can result in substantial increases in concentrations of other drugs metabolized via the same pathway. Clinicians should use paroxetine cautiously with haloperidol or risperidone. Daily dosing of paroxetine 20 mg PO in patients stabilized on risperidone (4 - 8 mg/day) increased mean plasma concentrations of risperidone roughly 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. Case reports have described increased pharmacologic effects of some of these medications when they have been combined with paroxetine treatment, including suspected serotonin syndrome. Patients should be advised to report increased effects of these medications, including increased agitation, dizziness, sedation, or impairment of psychomotor performance to their health care professional.
Paroxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses, resulting in substantial increases in concentrations of other drugs metabolized via the same pathway, including some beta-blockers (e.g., metoprolol, propranolol). Clinicians should use paroxetine cautiously with metoprolol or propranolol; downward dose adjustments of the beta-blocker may be required if paroxetine is initiated; alternatively an upward dose adjustment of the beta blocker may be needed if paroxetine is discontinued. Patients should be advised to report increased effects of these medications, including hypotension or increased dizziness to their health care professional. In addition, one case report of severe hypertension has been reported when paroxetine was added to chronic metoprolol treatment.
Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving type 1C antiarrhythmics (e.g., encainide, flecainide, or propafenone) and mexiletine since these antiarrhythmics are metabolized by this isozyme. Additionally, quinidine and propafenone are inhibitors of CYP2D6 which could lead to reduced metabolism of paroxetine.
Paroxetine inhibits CYP2D6. Serum concentrations of darifenacin, a CYP2D6 substrate, may increase when used in combination with paroxetine. Patients should be monitored for increased anticholinergic effects if these drugs are coadministered.
Several studies have shown that cimetidine can increase paroxetine AUC. In one study, steady-state plasma concentrations of paroxetine were increased by 50% during co-administration of oral cimetidine (at a dose of 300 mg tid). While significant adverse effects have not been reported, patients should be monitored carefully for an increased response to paroxetine if cimetidine is coadministered. Dosage adjustments of paroxetine should be based on clinical effect for the individual.
Phenobarbital, which induces many cytochrome P-450 isoenzymes, can reduce paroxetine AUC by 25% and reduce paroxetine half-life by 38%. A similar drug interaction with other barbiturates should also be expected for paroxetine. Since primidone is metabolized to phenobarbital, primidone may also affect paroxetine pharmacokinetics in a similar manner. No initial dosage adjustment is recommended, but subsequent dosage adjustments of paroxetine should be based on clinical effect.
Paroxetine may interact with either phenytoin (or fosphenytoin), although studies have not addressed if clinically important interactions occur when the two drugs are chronically dosed. Initial studies suggested no significant effect of paroxetine on phenytoin serum concentrations, however, clinicians should keep in mind that paroxetine itself is a potent inhibitor of cytochrome 2D6, and both phenytoin and paroxetine exhibit non-linear pharmacokinetics. One post-marketing case report of elevated phenytoin serum concentrations occurring in a patient after 4 weeks of concomitant therapy with paroxetine and phenytoin has been reported to the manufacturer. In addition, phenytoin, via hepatic enzyme induction, may reduce paroxetine AUC by 50% and half-life by 35%. No initial dosage adjustment is recommended, but subsequent dosage adjustments of paroxetine or phenytoin should be based on clinical effect. Monitoring of phenytoin concentrations during concomitant therapy is recommended.
Paroxetine is a potent inhibitor of cytochrome 2D6, while carbamazepine is metabolized by CYP3A4. Studies in healthy volunteers and in epileptic patients demonstrated no effect of paroxetine on carbamazepine plasma concentrations. Nevertheless, carbamazepine plasma concentrations should be monitored after the addition of paroxetine and the dose of carbamazepine adjusted, if necessary. Close monitoring should be maintained until a new steady-state has been achieved, which theoretically can require up to 4 weeks following the final paroxetine or carbamazepine dosage adjustment.
Since tryptophan is converted to serotonin (5-hydroxytryptamine), the use of tryptophan in patients receiving SSRIs could lead to serotonin excess and, potentially, the ‘serotonin syndrome’ (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behaviors, nausea, abdominal cramps, diarrhea, palpitations, or chills). Discontinuation of tryptophan usually resolves symptoms.
Cyproheptadine is an antagonist of serotonin in the CNS, and this pharmacologic action opposes the pharmacologic actions of paroxetine. Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine. Clinically, cyproheptadine reportedly has interfered with the antidepressant and anti-bulimia actions of fluoxetine, an agent related to paroxetine, but more data are needed to confirm a direct drug-drug interaction. Granisetron, ondansetron, and methysergide also antagonize serotonin (5-HT) receptors, although no drug-drug interactions have been reported with paroxetine.
SSRI-type antidepressants such as paroxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity mimicking the serotonin syndrome. Dextromethorphan should be used in lower doses in patients receiving paroxetine since this SSRI is a potent inhibitor of CYP2D6 , the enzyme responsible for metabolism of dextromethorphan.
The effect of coadministering buspirone with paroxetine is unknown. However, use of buspirone with another SSRI (fluoxetine) in a patient with major depression, generalized anxiety disorder, and panic disorder was reported to have caused increased anxiety. In some patients with obsessive-compulsive disorder, fluoxetine and buspirone have been reported to improve efficacy. Until more data are available, careful monitoring should be undertaken when buspirone and paroxetine are used together.
A multiple-dose study has shown no pharmacokinetic interaction between paroxetine and lithium in healthy volunteers. However, there is little clinical experience with the combination and caution is advised. One case exists of a patient who experienced a symptomatic increase in paroxetine concentrations during combination therapy; the patient became symptom free after reduction of her paroxetine dosage. Fluoxetine, an agent closely related to paroxetine, has been noted to increase or decrease lithium concentrations. Monitoring of lithium concentrations may be advisable if paroxetine is added to stabilized lithium therapy. A pharmacodynamic interaction between paroxetine and lithium is also possible. Administration of paroxetine to bipolar patients with inadequate lithium concentrations (<0.6 mEq/L) can predispose the bipolar patient to symptoms of mania.
Paroxetine has been shown to increase procyclidine serum concentrations and AUC. Anticholinergic effects can be exaggerated if procyclidine is used concurrently with paroxetine, possibly due to inhibition of procyclidine metabolism. If this occurs, dosage reduction of procyclidine should be considered.
Paroxetine may slightly decrease mean digoxin area under the curve (AUC) values. Until more clinical data are known, patients should be monitored for loss of digoxin clinical effect if paroxetine is added.
Preliminary data suggest that paroxetine may potentiate the pharmacodynamic effects of warfarin. In one study of healthy volunteers, although the mean hypoprothrombinemic response to warfarin was not affected by paroxetine, several subjects had clinically significant bleeding after several days of concomitant therapy. The mechanism of this interaction is uncertain. In pharmacokinetic studies, the high protein binding of paroxetine did not result in displacement of warfarin from protein binding sites. However, the manufacturer of paroxetine notes this mechanism as a possibility for general drugs interactions. Other SSRI antidepressants are known to inhibit specific hepatic isozymes involved in warfarin metabolism. In addition, SSRI treatment may result in impaired platelet aggregation, which may result from platelet serotonin depletion and may contribute to abnormal bleeding. Even in the presence of an unaltered INR value, the co-administration of paroxetine and warfarin should be approached with caution. It would be prudent for clinicians to closely monitor the INR and the patient’s clinical status during co-use of paroxetine with warfarin.
Due to possible additive effects on serotonin concentrations, it is advisable to avoid combinations of St. John’s wort, Hypericum perforatum with SSRIs. This interaction can lead to a reaction known as ‘serotonin syndrome’. The syndrome may include symptoms of confusion, nausea, sweating, agitation, or more severe symptoms, like hypertension and unresponsiveness. Several cases of serotonin-syndrome reactions have been documented when SSRIs were used concurrently with St. John’s wort. A single case report is noted of a 50 year old woman with depression who experienced excessive sedation after ingesting paroxetine with St. John’s wort. After discontinuing her conventional paroxetine treatment for 10 days, she started St. John’s wort powder at a dose of 600 mg per day. The woman experienced no adverse events related to the change in therapy. She decided to take paroxetine 20 mg one evening due to an episode of insomnia. The next day she was found in an arousable but lethargic and incoherent state. After 2 hours, she complained of weakness, fatigue, and nausea. The patient recovered completely within 48 hours.
The German Commission E warns that any substances that act on the CNS, including psychotropic agents, may interact with kava kava. In addition, substances that act on the CNS, including psychoactive drugs and drugs used as anesthetic adjuvants, may theoretically interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Persons taking medications such as anticonvulsants, skeletal muscle relaxants, tricyclic antidepressants, MAOIs, and SSRIs should discuss the use of herbal supplements with their health care professional prior to consuming these herbs. Patients should not abruptly stop taking their prescribed psychoactive medication.
According to the manufacturer, paroxetine has been reported to cause elevations of theophylline serum concentrations in post-marketing use. The interaction has not been formally studied. It is recommended that theophylline serum concentrations be monitored when paroxetine is given concurrently with theophylline or aminophylline. Observe patients for signs or symptoms of theophylline toxicity.
Paroxetine controlled-release tablets are enteric-coated; concurrent administration with antacids may cause earlier release of paroxetine from the dosage form. Antacids do not appear to affect the bioavailability of paroxetine.
The combination of SSRIs and tramadol has been associated with serotonin syndrome and an increased risk of seizures. Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Several cases of serotonin syndrome have been reported following the administration of tramadol with paroxetine or sertraline. SSRIs inhibit the formation of the active M1 metabolite of tramadol by inhibiting cytochrome P450 2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite.
Amphetamine, cocaine, and dextroamphetamine may stimulate the release of serotonin in the CNS and thus may interact with other serotonergic agents, such as the SSRIs, venlafaxine or nefazodone. These interactions could lead to serotonin excess and, potentially, the ‘serotonin syndrome’ (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behaviors, nausea, abdominal cramps, diarrhea, palpitations, or chills). If serotonin syndrome is suspected, offending agents should be discontinued. In addition, the MAOI activity of amphetamines may be of concern with SSRI use. While fluoxetine, sertraline, or venlafaxine have occasionally been prescribed for the treatment of ADHD, the concurrent use of amphetamines with medications that inhibit serotonin reuptake should be approached with caution. Additionally, in vitro studies have demonstrated that agents such as fluoxetine, paroxetine and cocaine may inhibit the metabolism of other CNS stimulants, such as methylenedioxymethamphetamine (MDMA or ‘Ecstasy’), via inhibition of CYP2D6.
Cevimeline is metabolized by cytochrome P450 (CYP) 3A4 and CYP2D6. Paroxetine is a potent inhibitor of CYP2D6 and could lead to an increase in cevimeline plasma concentrations. Clinical interactions have not been documented at this time.
In some patients taking SSRIs, zolpidem has been associated with rare reports of disorientation, delusions, or hallucinations when administered concomitantly. In most cases the visual hallucinations were short lived (i.e., 30 minutes) but in some patients the symptoms persisted up to 7 hours in duration. The mechanism for the interaction has not been established, but is thought to be pharmacodynamic in nature. In one study, inhibition of zolpidem CYP2D6 metabolism occurred when sertraline was chronically co-administered, indicating that SSRIs that inhibit this isoenzyme may also exhibit a pharmacokinetic interaction with zolpidem.
Patients receiving concurrent pentazocine and SSRIs are at increased risk for developing serotonin syndrome; pentazocine should be used cautiously, if at all, in these patients.
Galantamine is metabolized, at least in part, through the hepatic CYP450 system. The bioavailability of galantamine is increased by about 40% when co-administered with the CYP2D6 inhibitor paroxetine. An increase in cholinergic side effects may occur, particularly nausea and vomiting.
Sibutramine is a serotonin reuptake inhibitor. Concomitant use of two serotonin-augmenting drugs has been associated with serotonin syndrome, so concurrent use of paroxetine with sibutramine is not recommended.
Trazodone inhibits serotonin reuptake, although, it is less potent than the SSRIs in this regard. However, because of this similarity in mechanism of action, patients receiving paroxetine concomitantly with trazodone should be monitored closely for adverse effects related to excessive serotonergic stimulation (’serotonin syndrome’).
Delavirdine, imatinib, STI-571, and ritonavir are potent inhibitors of cytochrome P450 2D6 , and may theoretically decrease paroxetine metabolism leading to increased adverse reactions.
Although paroxetine does not increase the impairment of mental and motor skills caused by ethanol, patients should be advised to avoid alcoholic beverages during treatment with paroxetine.
Paroxetine is a potent inhibitor of drug metabolism via the CYP2D6 pathway. This can result in increased concentrations of drugs metabolized via the same pathway, including some opiate agonists (i.e., methadone, morphine, and oxycodone). Clinicians should be alert for increased opiate effects if these drugs are used concurrently. In addition, impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates. Paroxetine should also be used cautiously in conjunction with meperidine, as meperidine blocks the neuronal reuptake of serotonin. A 42 year-old man became agitated, restless, diaphoretic, tachycardiac, and hypertensive immediately after receipt of meperidine 50 mg intravenously. Two weeks before the incident, the patient had stopped a regimen of the SSRI, fluoxetine. Serotonin syndrome was suspected, as fluoxetine and norfluoxetine have long half-lives, and previous meperidine receipt during a time when the patient had not been taking fluoxetine was uneventful.
Until more data are available, the combined use of phentermine and SSRIs should be avoided. While the combined use of phentermine with certain SSRIs (e.g., fluoxetine) has been of interest for the treatment of obesity, studies have generally not supported combined treatment due to a risk of significant weight-regain after discontinuation of use. Additionally, a few case reports suggest potential adverse effects from the combination. In vitro data suggest that fluoxetine potentiates the anorectic and neurotoxic effects of phentermine ; similar effects may occur with the use of other SSRIs. As a drug related to the amphetamines, phentermine should additionally be combined with SSRIs with caution due to the potential for excessive serotonin activity (i.e., ‘serotonin syndrome’). The slight MAOI activity of phentermine may also be of concern with SSRI use, since serotonin is deaminated by monoamine oxidase type A and increased serotonin activity may result from MAO inhibition. However, some experts have debated phentermine’s effect on MAO at therapeutic doses. Thus, while a mechanism of interaction between phentermine and SSRIs is unclear at this time, the potential for interaction exists based on current evidence.
Atomoxetine is primarily a substrate for the cytochrome P450 (CYP) isozyme CYP2D6. A dosage reduction of atomoxetine is recommended in normal populations (also known as extensive metabolizers) when atomoxetine is administered with strong inhibitors of the CYP2D6 enzyme, such as paroxetine. Paroxetine 20 mg PO daily given in combination with atomoxetine 20 mg PO every 12 hours resulted in AUC values 6- to 8-fold greater and atomoxetine Cmax values 3- to 4-fold greater than when atomoxetine was given alone. Inhibition of CYP2D6 by paroxetine markedly affects atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates. In vitro studies suggest that coadministration of CYP2D6 inhibitors to poor metabolizers will not further increase the plasma concentrations of atomoxetine.
Increased aripiprazole blood levels are expected when aripiprazole is coadministered with inhibitors of CYP2D6, such as paroxetine. A dosage adjustment of aripiprazole is necessary when these drugs are used concomitantly, and conversely, when paroxetine is discontinued in a patient taking aripiprazole.
Aprepitant is a very weak inhibitor of CYP2D6 (in vitro data). Coadministration of paroxetine 20 mg/day (a CYP2D6 substrate and inhibitor) and aprepitant (85 or 170 mg) resulted in a decrease in AUC by roughly 25% and Cmax by 20% for both paroxetine and aprepitant; an unexpected reaction. The mechanism for reduction in paroxetine concentrations is unknown, but is unlikely to be induction of CYP2D6 activity since CYP2D6 is generally known as an non-inducible enzyme. These results show that aprepitant does not inhibit the metabolism of CYP2D6 substrates in vivo.
The combined use of selective serotonin reuptake inhibitors (SSRIs) with aspirin, ASA or nonsteroidal antiinflammatory drugs (NSAIDs) may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in >26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Gefitinib may inhibit cytochrome P450 (CYP) 2D6 at clinical doses. Caution is recommended when administering gefitinib with other CYP2D6 substrates, such as paroxetine, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
There may be a potential for rare drug interactions between metoclopramide and selective serotonin reuptake inhibitors (SSRIs) and selected other drugs that inhibit serotonin reuptake (i.e., venlafaxine). The few published case reports of possible interactions have resulted in either ‘serotonin-syndrome’ type events and/or movement disorders (e.g., dystonia). The mechanism of the interactions is elusive but is thought to be a pharmacodynamic interaction; the interactions do not appear common. In most of the cases reported, a singular drug effect was not ruled out; however, the time course of the events are enough to raise suspicion that a drug interaction might be possible. Patients receiving metoclopramide concomitantly with an SSRI or venlafaxine should report any unusual movements or other unusual side effects to their health care professionals promptly.
Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). SSRIs like paroxetine are often prescribed to alleviate tamoxifen-associated hot flashes. One clinical trial tested the effects of coadministration of tamoxifen and paroxetine (a potent CYP2D6 inhibitor) on tamoxifen metabolism to its active metabolites. Coadministration of paroxetine decreased the plasma concentration of one of tamoxifen’s major active metabolites. The study was small (n=12) and measured serum drug concentrations only; clinical outcomes were not assessed. Further data are needed to assess the clinical significance of this interaction. In theory, potent inhibitors of CYP2D6 like paroxetine might reduce the efficacy of tamoxifen. However, data are not available to determine whether or not SSRIs like paroxetine should be avoided.
The manufacturer of alprazolam states that in vitro studies suggest paroxetine may inhibit the metabolism of alprazolam via inhibition of cytochrome P450 isoenzyme (CYP) 3A4. In general, paroxetine is typically considered a major inhibitor of the CYP2D6 isoenzyme, for which alprazolam is not a substrate. Nonetheless, if these 2 agents are coadministered, it may be prudent to monitor the patient for excess CNS adverse effects due to alprazolam.
Clinicians should be aware of the potential for inhibition of donepezil metabolism via CYP2D6 by selected SSRIs, which may result in the need for dosage adjustment or selection of alternative therapy should side effects occur. Fluoxetine , paroxetine , and sertraline , are potent inhibitors of the hepatic CYP2D6 isoenzyme, and concurrent use of these drugs with donepezil may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur. At least 2 case reports of an interaction with paroxetine have been published; the patients exhibited cholinergic-induced GI side effects and/or the appearance of insomnia, agitation, confusion and combativeness when paroxetine was added to donepezil therapy. The side effects subsided with the downward titration of the donepezil dosage or the discontinuation of both treatments. Both fluoxetine and fluvoxamine another SSRI, inhibit the hepatic CYP3A4 isoenzyme and may decrease the metabolism of donepezil through this pathway. Citalopram and escitalopram do not appear to inhibit other CYP hepatic isoenzymes (e.g., 3A4, 2C9, or 2E1), based on in vitro studies, to any clinically significant degree and appear least likely of the SSRIs to decrease donepezil metabolism.
Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors including paroxetine may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if paroxetine is coadministered with doxercalciferol.
[ Last revised: 10/10/2005 10:31:00 AM ]
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