pms-Fluoxetine Drug Interactions

Serious Drug Interactions: Monoamine Oxidase Inhibitors; Thioridazine. See Contraindications.
Overview: Fluoxetine, like some other agents that are metabolized by the P4502D6 system, inhibits the activity of this isoenzyme. Therefore, co-therapy with medications that are predominantly metabolized by the P4502D6 system and that have a relatively narrow therapeutic index (e.g. flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently, or has taken it in the previous 5 weeks. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by P4502D6, the need for decreased dose of the original medication should be considered. The aforementioned drugs with a narrow therapeutic index represent the greatest concern.
Other drugs that have demonstrated increased plasma values or magnified effects when co-administered with fluoxetine include: phenytoin, antipsychotics, benzodiazepines, thioridazine (see Thioridazine under Contraindications), St. John's Wort and warfarin.
As fluoxetine is highly bound to plasma proteins, co-administration with another drug which is also highly bound (e.g. warfarin, digitoxin) may result in adverse effects due to an increase in plasma levels of either unbound drug.
There are little data available on the concomitant use of fluoxetine and alcohol.
Drug-Drug Interactions: QTc-Prolonging Drugs: Pharmacokinetic and pharmacodynamic studies of fluoxetine combined with other medicinal products that prolong the QT interval have not been performed. An additive effect of fluoxetine and these medicinal products cannot be excluded. Therefore, co-administration of fluoxetine with medicinal products that have a clear QT interval prolonging effect is discouraged. Drugs that have been associated with QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list.
Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QTc prolongation and/or torsade de pointes: Class IA antiarrhythmics (e.g. quinidine, procainamide, disopyramide); Class III antiarrhythmics (e.g. amiodarone, sotalol, ibutilide, dronedarone); Class 1C antiarrhythmics (e.g. flecainide, propafenone); antipsychotics (e.g. chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone); antidepressants (e.g. citalopram, venlafaxine, tricyclic/tetracyclic antidepressants e.g. amitriptyline, imipramine, maprotiline); opioids (e.g. methadone); macrolide antibiotics and analogues (e.g. erythromycin, clarithromycin, telithromycin, tacrolimus); quinolone antibiotics (e.g. moxifloxacin, levofloxacin, ciprofloxacin); antimalarials (e.g. quinine, chloroquine); azole antifungals (e.g. ketoconazole, fluconazole, voriconazole); domperidone; 5-HT3 receptor antagonists (e.g. dolasetron, ondansetron); tyrosine kinase inhibitors (e.g. vandetanib, sunitinib, nilotinib, lapatinib); histone deacetylase inhibitors (e.g. vorinostat); beta-2 adrenoceptor agonists (e.g. salmeterol, formoterol).
Drugs that Affect Electrolytes: The concomitant use of pms-FLUOXETINE with drugs that can disrupt electrolyte levels is discouraged. Drugs that decrease electrolyte levels include, but are not limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high dose corticosteroids.
The previously mentioned lists of potentially interacting drugs are not comprehensive. (See also Pharmacology: Pharmacodynamics: Electrocardiography under Actions; Cardiovascular under Precautions; Clinical Trial Adverse Drug Reactions: Adults: ECG Findings under Adverse Reactions; Post-Market Adverse Drug Reactions under Adverse Reactions.)
Monoamine Oxidase Inhibitors: Combined use of pms-FLUOXETINE and MAO inhibitors (including the antibiotic linezolid and the thiazine dye methylthioninium chloride (methylene blue) which are less well-known examples of MAOIs) is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Monoamine Oxidase Inhibitors under Contraindications; Neurologic: Serotonin Syndrome/Neuroleptic Malignant Syndrome under Precautions).
Thioridazine: Potential Interactions with Thioridazine (see also Thioridazine under Contraindications): In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C_max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of cytochrome P4502D6 isozyme activity. Thus, this study suggests that drugs which inhibit P4502D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine.
Thioridazine administration produces a dose-related prolongation of the QTc interval which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be concomitantly administered, nor within a minimum of 5 weeks after fluoxetine has been discontinued, nor should pms-FLUOXETINE be administered within 2 weeks after thioridazine has been discontinued (see Thioridazine under 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 or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued (see Hematologic: Abnormal Bleeding under Precautions).
Drugs Tightly Bound to Plasma Protein: Because fluoxetine is highly bound to plasma protein, the administration of fluoxetine to a patient taking another drug which is tightly bound to protein (e.g. warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound fluoxetine by other tightly bound drugs.
Drugs Metabolized by P4502D6 Isoenzyme: Approximately 3 to 10% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme P4502D6. Such individuals have been referred to as "poor metabolizers" of drugs such as debrisoquine, dextromethorphan, sparteine, tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine, and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine) and Type 1C antiarrhythmics (e.g. propafenone and flecainide).
Conversely, approximately 90 to 97% of the normal population do not have this genetic defect, and are known as "extensive metabolizers". Fluoxetine, like other agents that are metabolized by the P4502D6 system, inhibits the activity of this isoenzyme, and thus may make normal "extensive" metabolizers resemble "poor metabolizers". Therapy with medications that are predominantly metabolized by the P4502D6 system and that have a relatively narrow therapeutic index (e.g. flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently, or has taken it in the previous 5 weeks.
If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by P4502D6 the need for decreased dose of the original medication should be considered. The aforementioned drugs with a narrow therapeutic index represent the greatest concern.
Tamoxifen: Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75% reduction in plasma levels of one of the more active forms of the tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including fluoxetine) should whenever possible be avoided (see General: Potential for reduced efficacy of tamoxifen with concomitant SSRI use, including fluoxetine under Precautions).
Impact of CYP2D6 Inhibition on Fluoxetine Metabolism: Both the pharmacokinetic properties and relative proportion of metabolites of fluoxetine may be affected by a patient's CYP2D6 pharmacogenetic phenotype, or by a number of different drugs known to inhibit the CYP2D6 enzyme.
Drugs Metabolized by Cytochrome P4503A4: In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a cytochrome P4503A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P4503A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of cytochrome P4503A4 activity is not likely to be of clinical significance.
Tricyclic Antidepressants: In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for three weeks or longer after fluoxetine is discontinued. Thus, the dose of tricyclic antidepressant (TCA) may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. See Pharmacology: Pharmacokinetics: Accumulation and Slow Elimination under Actions; General: Implications of the Long Elimination Half-Life of Fluoxetine under Precautions.
Lithium: There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.
Tryptophan: Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness and gastrointestinal distress.
Benzodiazepines: The half-life of concurrently administered diazepam may be prolonged in some patients.
Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Consideration should be given to monitoring of clinical status. Experience with the use of fluoxetine in combination with other CNS-active drugs is limited and caution is advised if such concomitant medication is required.
Alcohol: The concomitant use of fluoxetine and alcohol on cognitive and psychomotor effects in depressed, panic disorder or OCD patients is not known and is not recommended.
St. John's Wort: In common with other SSRI's, pharmacodynamic interactions between fluoxetine and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.
Antipsychotics: Elevation of blood levels of haloperidol and clozapine and in some cases, clinical manifestations of toxicity have been observed with coadministration of fluoxetine. Consideration should be given to monitoring of clinical status.
Serotonergic Drugs: Based on the mechanism of action of fluoxetine and the potential for serotonin syndrome, caution is advised when pms-FLUOXETINE is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, fentanyl and its analogues, dextromethorphan, tapentadol, meperidine, methadone, pentazocine or St. John's Wort (see Neurologic: Serotonin Syndrome/Neuroleptic Malignant Syndrome under Precautions).
Triptans (5HT₁ agonists): 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, or citalopram) 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 Neurologic: Serotonin Syndrome/Neuroleptic Malignant Syndrome under Precautions).
Phenytoin: In patients on stable, maintenance doses of phenytoin, plasma phenytoin concentrations increased substantially and symptoms of phenytoin toxicity appeared (nystagmus, diplopia, ataxia and CNS depression) following initiation of concomitant fluoxetine treatment.
Carbamazepine: Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Consideration should be given to monitoring of clinical status when fluoxetine treatment is initiated in these patients.
Drug-Food Interactions: Absorption of fluoxetine is not affected by food.
Drug-Herb Interactions: Interactions with fluoxetine and herbal remedy St. John's Wort may occur (see Drug-Drug Interactions: St. John's Wort as previously mentioned).
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established.
Drug-Lifestyle Interactions: Interaction with lifestyle interactions have not been established.