Half-life: The long elimination half-lives of both fluoxetine and norfluoxetine should be borne in mind (see Pharmacology: Pharmacokinetics under Actions) when considering pharmacodynamic or pharmacokinetic drug interactions (e.g. when switching from fluoxetine to other antidepressants).
Contra-indicated combinations: Irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid): Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with an irreversible, non-selective monoamine oxidase inhibitor (MAOI).
These cases presented with features resembling serotonin syndrome (which may be confounded with [or diagnosed as] neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions. Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.
Therefore, fluoxetine is contra-indicated in combination with an irreversible, non-selective MAO I (see Contraindications). Because of the two weeks-lasting effect of the latter, treatment of fluoxetine should only be started 2 weeks after discontinuation of an irreversible, non-selective MAOI.
Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting an irreversible, nonselective MAOI.
Metroprolol used in cardiac failure: risk of metoprolol adverse events, including excessive bradycardia, may be increased because of an inhibition of its metabolism by fluoxetine (see Contraindications).
Not recommended combinations: 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 Precautions).
Alcohol: In formal testing, fluoxetine did not raise blood alcohol levels or enhance the effects of alcohol. However, the combination of SSRI treatment and alcohol is not advisable.
MAOI-A including linezolid and methylothioninium chloride (methylene blue): Risk of serotonin syndrome including diarrhea, tachycardia, sweating, tremor, confusion or coma. If the concomitant use of these active substances with fluoxetine cannot be avoided, close clinical monitoring should be undertaken and the concomitant agents should be initiated at the lower recommended doses (see Precautions).
Mequitazine: risk of mequitazine adverse events (such as QT prolongation) may be increased because of an inhibition of its metabolism by fluoxetine.
Combinations requiring caution: Phenytoin: Changes in blood levels have been observed when combined with fluoxetine. In some cases manifestations of toxicity have occurred. Consideration should be given to using conservative titration schedules of the concomitant drug and to monitoring clinical status.
Serotoninergic drugs (lithium, tramadol, triptans, tryptophan, selegiline (MAOI-B), St. John's Wort (Hypericum perforatum)): There have been reports of mild serotonin syndrome when SSRIs where given with drugs also having a serotoninergic effect. Therefore, the concomitant use of fluoxetine with these drugs should be undertaken with caution, with closer and more frequent clinical monitoring (see Precautions).
QT interval prolongation: Pharmacokinetic and pharmacodynamic studies between fluoxetine and 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 prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine), anti-malaria treatment particularly halofantrine, certain antihistamines (astemizole, mizolastine), should be used with caution (see Overdosage, Precautions and Adverse Reactions).
Drugs affecting haemostasis (oral anticoagulants, whatever their mechanism, platelets antiaggregants including aspirin and NSAIDs): risk of increased bleeding. Clinical monitoring, and more frequent monitoring of INR with oral anticoagulants, should be made. A dose adjustments during the fluoxetine treatment and after its discontinuation may be suitable (see Precautions and Adverse Reactions).
Cyproheptadine: There are individual case reports of reduced antidepressant activity of fluoxetine when used in combination with cyproheptadine.
Drugs inducing hyponatremia: Hyponatremia is an undesirable effect of fluoxetine. Use in combination with other agents associated with hyponatremia (e.g. diuretics, desmopressin, carbamazepine and oxcarbazepine) may lead to an increased risk (see Adverse Reactions).
Drugs lowering the epileptogenic threshold: Seizures are an undesirable effect of fluoxetine. Use in combination with other agents which may lower the seizure threshold (for example, TCAs, other SSRIs, phenothiazines, butyrophenones, mefloquine, chloroquine, bupropion, tramadol) may lead to an increased risk.
Other drugs metabolized by CYP2D6: Fluoxetine is a strong inhibitor of CYP2D6 enzyme, therefore concomitant therapy with drugs also metabolized by this enzyme system may lead to drug interactions, notable those having a narrow therapeutic index (such as flecainide, propafenone and nebivolol) and those that are titrated, but also with atomoxetine, carbamazepine, tricyclic antidepressants and risperidone. They should be initiated at or adjusted to the low end of their dose range. This may also apply if fluoxetine has been taken in the previous 5 weeks.