PMDDinteractions

Monoamine Oxidase Inhibitors (MAOI): Fluoxetine is contraindicated for use with MAOI's, or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping fluoxetine before starting treatment with an MAOI Pimozide: Fluoxetine is contraindicated for use with pimozide due to risk of drug interaction or QTc prolongation Thioridazine: Fluoxetine is contraindicated for use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine tablet.

Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine hydrochloride or when fluoxetine hydrochloride has been recently discontinued CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs Benzodiazepines: Diazepam – increased t ½, alprazolam - further psychomotor performance decrement due to increased levels Antipsychotics: Potential for elevation of haloperidol and clozapine levels Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity Serotonergic Drugs: Potential for Serotonin Syndrome Triptans: There have been rare post marketing reports of Serotonin Syndrome with use of an SSRI and a triptan Tryptophan: Concomitant use with tryptophan is not recommended Drugs that Interfere with Hemostasis (for example, NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations The potential for interaction by a variety of mechanisms (for example, pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility.

7.1 Monoamine

Oxidase Inhibitors (MAOI) Concomitant use of fluoxetine tablets in patients taking MAOIs is contraindicated. There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine, including fluoxetine tablet, should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should be allowed after stopping fluoxetine before starting an MAOI.

7.2 CNS Acting

Drugs Caution is advised if the concomitant administration of fluoxetine, including fluoxetine tablet, and other CNS acting drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status.

7.3 Serotonergic

Drugs Based on the mechanism of action of SNRIs and SSRIs, including fluoxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when fluoxetine hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, amphetamines, or St. John's Wort. The concomitant use of fluoxetine hydrochloride with SNRIs, SSRIs, or tryptophan is not recommended.

7.4 Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluoxetine hydrochloride with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

7.5 Tryptophan

Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. The concomitant use with tryptophan is not recommended.

7.6 Drugs that

Interfere with Hemostasis (for example, NSAIDS, Aspirin, Warfarin) 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 or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued.

7.7 Electroconvulsive

Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

7.8 Potential for

Other Drugs to affect Fluoxetine hydrochloride Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs.

7.9 Potential for

Fluoxetine hydrochloride to affect Other Drugs Pimozide — Concomitant use of fluoxetine hydrochloride in patients taking pimozide is contraindicated. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine. Thioridazine — Concomitant use of fluoxetine hydrochloride in patients taking thioridazine is contraindicated. Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued. 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 with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, 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. Drugs Metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (for example, tricyclic antidepressants (TCAs)), antipsychotics (for example, phenothiazines and most atypicals), and antiarrhythmics (for example, propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) 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. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (for example, flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued. Tricyclic Antidepressants (TCAs) — In 2 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 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. Benzodiazapines — 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. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (for example, warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 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 CYP3A4 activity is not likely to be of clinical significance.