Fluoxetine Interactions
Antidiabetic Agents
- Aprepitant
- Aripiprazole
- Aspirin, ASA
- Astemizole
- Atomoxetine
- Bortezomib
- Buprenorphine
- Buspirone
Calcium-Channel Blockers
- Carbamazepine
- Celecoxib
- Cevimeline
- Chlordiazepoxide
- Cilostazol
- Cimetidine
- Cisapride
- Clonazepam
- Clorazepate
- Clozapine
- Cocaine
- Codeine
- Cyclosporine
- Cyproheptadine
- Darifenacin
- Delavirdine
- Dexfenfluramine
- Dextroamphetamine
- Dextromethorphan
- Diazepam
- Diethylpropion
- Digitoxin
- Dihydroergotamine
- Dofetilide
- Donepezil
- Doxercalciferol
- Dronabinol, THC
- Encainide
- Eplerenone
- Ergonovine
- Ergotamine
- Ethotoin
- Fenfluramine
- Fentanyl
- Flecainide
- Fluoxetine; Olanzapine
- Flurazepam
- Fosphenytoin
- Furazolidone
- Galantamine
- Gefitinib
- Haloperidol
- Hydrocodone
- Imatinib, STI-571
- Irbesartan
- Isoniazid, INH
- Kava Kava, Piper methysticum
- Levobupivacaine
- Levomethadyl
- Linezolid
- Lithium
- Loxapine
- Melatonin
- Methadone
- Methylergonovine
- Methysergide
- Metoclopramide
- Metoprolol
- Mexiletine
- Midazolam
- Modafinil
- Molindone
Monoamine oxidase inhibitors (MAOIs)
Nonsteroidal antiinflammatory drugs (NSAIDs)
Opiate agonists
- Oxycodone
- Paricalcitol
- Pentazocine
Phenothiazines
- Phentermine
- Phenytoin
- Pimozide
- Prazepam
- Procarbazine
- Propafenone
- Propranolol
- Quazepam
- Risperidone
- Ritonavir
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin-Receptor Agonists
- Sibutramine
- Sirolimus
- St. John’s Wort, Hypericum perforatum
- Sufentanil
- Terfenadine
- Thiothixene
- Tramadol
- Trazodone
- Triazolam
Tricyclic antidepressants
- Tryptophan, 5-Hydroxytryptophan
- Valerian, Valeriana officinalis
- Venlafaxine
- Vinblastine
- Voriconazole
- Warfarin
- Ziprasidone
- Zolpidem
- Zonisamide
Fluoxetine Interactions
NOTE: Fluoxetine is primarily a substrate for the isozyme CYP2D6; however, both CYP2D6 and CYP2C9 contribute to the formation of R-norfluoxetine, whereas only CYP2D6 is responsible for conversion to S-norfluoxetine. Of the SSRI-type drugs, fluoxetine is one that inhibits multiple CYP isozymes significantly. Fluoxetine and its active metabolite, norfluoxetine, inhibit the hepatic cytochrome P-450 system in vivo (particularly the CYP isoenzymes 2D6, 2C19, 3A4, 2C9 and 2C10), thereby inhibiting the metabolism of a number of drugs. Increased serum concentrations and toxicity of concomitant medications may occur. According to the manufacturer, the inhibition of the CYP3A4 isoenzyme by fluoxetine is not clinically significant; reported in vivo studies have been single dose. The pharmacokinetic properties and relative proportion of fluoxetine and metabolites may be altered in poor metabolizers. According to the manufacturer, for fluoxetine and its metabolite, the sum of the plasma concentrations of the 4 active enantiomers is comparable between poor and extensive metabolizers.
Due to possible additive effects on serotonin concentrations, it is advisable to avoid combinations of fluoxetine 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. Use extreme caution if other drug products containing fluoxetine (for example: Prozac®, Prozac® Weekly, Sarafem®) are prescribed with fluoxetine; olanzapine (SYMBYAX™) due to duplication of therapy and risk for overdosage.
Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine or duloxetine.
Fluoxetine potentiates serotonin by inhibiting its neuronal reuptake. Since serotonin is deaminated by monoamine oxidase type A, administration of drugs that can inhibit this enzyme concurrently with fluoxetine 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 monoamine oxidase inhibitors (MAOIs) (e.g., isocarboxazid, phenelzine, tranylcypromine) are non-specific inhibitors of MAO and, thus, affect MAO type A. Traditional MAOIs should not be used with SSRIs. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of fluoxetine therapy, and there should be at least 5 weeks between the discontinuation of fluoxetine therapy and commencement of MAOI therapy. This 5-week period is needed because of the long half-life of fluoxetine and its principal metabolite norfluoxetine. 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 fluoxetine. 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.
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.
Concomitant administration of the SSRIs and the serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) 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.
Fluoxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses; resulting in substantial increases in concentrations of any antipsychotic drugs metabolized via the same pathway. Fluoxetine and thioridazine should not be co-administered due to the possibility for serious cardiac events; thioridazine is contraindicated for use within 5 weeks after discontinuing fluoxetine. Because fluoxetine impairs many CYP isoenzymes, the drug may also decrease the metabolism and increase serum concentrations of clozapine, haloperidol, loxapine, molindone, other phenothiazines, pimozide, risperidone, thiothixene, or ziprasidone if co-administered. Decreased metabolism of these drugs may lead to clinically important side effects. The effects of fluoxetine on hepatic metabolism may persist after discontinuation of fluoxetine because of its long elimination half-life. Experts who authored a consensus guideline suggests that low potency conventional antipsychotics (such as the phenothiazines) should be contraindicated with the use of fluoxetine.
Some selective serotonin reuptake inhibitors are CYP3A4 inhibitors (e.g., fluoxetine, fluvoxamine, sertraline) and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity (e.g., nephrotoxicity or seizures) or require the downward dosage adjustment of cyclosporine. In 1 patient, the addition of fluoxetine to a stabilized cyclosporine regimen resulted in an increase in cyclosporine concentrations that were noted 10 days after fluoxetine initiation. A decrease in cyclosporine concentrations occurred after fluoxetine was discontinued. During both phases, the dosage of cyclosporine required adjustment. Until more data are available, cyclosporine concentrations should be monitored very carefully any time one of these SSRIs is prescribed. Although a causal relationship has not been established, the combination of cyclosporine and sertraline is also suspected of causing serotonin syndrome in a renal transplant patient. Sertraline serum concentrations may have increased due to possible CYP3A4 inhibition by cyclosporine.
An interaction may occur between fluoxetine and anorexiant agents such as dexfenfluramine, fenfluramine, or diethylpropion. Dexfenfluramine stimulates the release of serotonin and inhibits its reuptake. Diethylpropion stimulates the release of norepinephrine. Fluoxetine also inhibits the reuptake of serotonin. In addition, fluoxetine 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 fluoxetine are used together. Due to the potential severity of the serotonin syndrome, this drug combination should be avoided. Clinicians should also consider the extremely long half-life of norfluoxetine in patients who have recently been discontinued from fluoxetine therapy. Since dexfenfluramine is the S-enantiomer of the racemic compound fenfluramine, a similar interaction may occur between fluoxetine and fenfluramine.
Sibutramine is a serotonin reuptake inhibitor. Concomitant use of two serotonin-augmenting drugs has been associated with serotonin syndrome, so concurrent use of fluoxetine with sibutramine is not recommended.
Concurrent administration of drugs that can antagonize serotonin receptors (e.g., nefazodone) and inhibit serotonin reuptake (e.g., the SSRIs) can lead to serotonin excess and an infrequent reaction known as ‘serotonin syndrome.’ The syndrome may present 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. Occasionally the syndrome can include more severe symptoms, like hypertension and unresponsiveness. When a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. The possibility of such reactions can be minimized by allowing a washout period for the SSRI before initiating nefazodone therapy and by reducing the initial dose of nefazodone. Because of the long half-life of fluoxetine and its metabolites in particular, this washout period may range from one to several weeks depending on the dose and other individual patient variables. If serotonin-syndrome is suspected, offending agents should be discontinued.
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.
Clinicians should be alert for pharmacokinetic and pharmacodynamic interactions between tricyclic antidepressants and the SSRI-class of antidepressants. The SSRIs are known to inhibit isozymes of the cytochrome P-450 mixed-function oxidase system including CYP2D6 and/or CYP3A4, the isozymes responsible for metabolism of many of the tricyclic antidepressants. Cytochrome CYP2D6 is impaired most by fluoxetine and least by sertraline and is the isozyme most responsible for metabolism of tricyclic antidepressants. In several cases, symptoms of toxicity, including seizures, were reported when drugs from these 2 categories were used together. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. The CYP2D6 isozyme is a common pathway for both of these drugs and norfluoxetine also inhibits this enzyme. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if a SSRI-type drug is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7-9 days).
Diazepam is metabolized by CYP2C19 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This can result in substantial increases in the half-life of diazepam, and the psychomotor and physiological response may be altered. Fluoxetine has also been reported to lower the clearance and increase the plasma concentrations of alprazolam (also metabolized by CYP3A4) ; sedation has been enhanced when fluoxetine and alprazolam are combined. Fluoxetine could theoretically inhibit CYP3A4 metabolism of other oxidized benzodiazepines (e.g., chlordiazepoxide, clonazepam, clorazepate , flurazepam , midazolam , prazepam , quazepam , and triazolam .Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed. The pharmacokinetics of estazolam (Cmax and AUC) are not affected during multiple-dosing with fluoxetine (20 mg twice daily for 7 days).
Visual hallucinations were reported after dextromethorphan was used in a patient taking fluoxetine. Dextromethorphan is known to be metabolized by the CYP2D6 (cytochrome P-450 isozyme 2D6) pathway, a pathway which fluoxetine inhibits. Although data are limited, dextromethorphan should be used cautiously in any patient receiving fluoxetine.
Cyproheptadine is an antagonist of serotonin receptors in the CNS and this pharmacologic action opposes the pharmacologic actions of fluoxetine. 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 has reportedly lead to a worsening of depression when administered to patients taking fluoxetine; however, more data are necessary to confirm a direct drug-drug interaction. Granisetron, methysergide, and ondansetron also antagonize serotonin (5-HT) receptors, however no drug-drug interactions have been reported with fluoxetine.
The metabolism of carbamazepine may be impaired by the concomitant administration of fluoxetine. Carbamazepine is metabolized by the CYP3A4 isozyme, which is inhibited by fluoxetine. Ocular changes, vertigo, and/or tremor may occur. Carbamazepine plasma concentrations should be monitored weekly and the dose of carbamazepine adjusted to compensate for the interaction. Close monitoring should be maintained until steady state has been achieved, which theoretically can require up to 8 weeks following the final fluoxetine dosage adjustment. Not allowing enough time to reach fluoxetine steady-state in pharmacokinetic studies of fluoxetine and carbamazepine may explain why discrepancies exist in conclusions of this drug-drug interaction. Another explanation might be that carbamazepine hepatic induction canceled the inhibitory effects of fluoxetine on hepatic metabolism, however, additional data are necessary to confirm the true explanation.
Cytochrome CYP2C19 is one of two pathways by which phenytoin (or fosphenytoin) is metabolized, and fluoxetine inhibits this pathway. Phenytoin toxicity has been described in several patients after the addition of fluoxetine. Also, use caution if ethotoin is prescribed with fluoxetine.
Astemizole and terfenadine have both been removed from the US market. Astemizole and terfenadine are both metabolized via the isozyme CYP3A4. The fluoxetine metabolite norfluoxetine inhibits this pathway. Only limited data are available, however, describing the results of any potential interaction. In a single patient, symptoms suggestive of a tachyarrhythmia occurred 1 month after fluoxetine was added to a regimen containing terfenadine. Documentation of an arrhythmia, however, was poor. Because of the potential severity of this interaction, these antihistamines should be avoided in patients taking fluoxetine. Clinicians should also note the extremely long elimination half-life of norfluoxetine in patients who have recently discontinued fluoxetine therapy and also the long elimination half-life of astemizole. In an in vivo interaction study reported by the manufacturer involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine.
Although no clinical data are available, fluoxetine may inhibit the clearance of and potentiate the toxicity of cisapride. Cisapride is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit. Due to the serious nature of cisapride toxicity, fluoxetine should be avoided in these patients.
Although no clinical data are available, it is possible that inhibitors of hepatic enzymes such as cimetidine may affect fluoxetine pharmacokinetics. A significant interaction has been suggested for cimetidine-paroxetine; fluoxetine may be similarly affected by cimetidine. Until more data are available, cimetidine should be used cautiously in patients receiving fluoxetine.
In theory, fluoxetine may inhibit metabolism of beta-blockers metabolized by CYP2D6. One report is noted of an interaction between fluoxetine and metoprolol. An interaction has also been noted between fluoxetine and propranolol. Fluoxetine potentiated the negative chronotropic and dromotropic actions of the beta-blocker. Bradycardia has occurred in a patient receiving metoprolol and complete heart block occurred in a patient receiving propranolol after fluoxetine was added. The patient receiving metoprolol had been previously well on metoprolol alone and fluoxetine alone. This exaggerated pharmacodynamic response is consistent with inhibition of metabolism of these two beta-blockers by fluoxetine. Clinicians should note that fluoxetine does not inhibit the clearance of all beta-blockers.
Although clinical data are limited, fluoxetine may potentiate the hypoprothrombinemic effects of warfarin. One case is noted of positive challenge and positive dechallenge with fluoxetine on warfarin action. Fluoxetine is reported to inhibit the hepatic isozyme responsible for metabolism of warfarin (CYP2C9). In addition, fluoxetine may exert direct inhibitory effects on hemostasis, perhaps by inhibiting platelet aggregation. Bleeding has been reported in patients receiving fluoxetine without warfarin. Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein, such as warfarin, 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. Clinicians should avoid the concomitant use of these two drugs whenever possible. It would be prudent for clinicians to closely monitor the INR and the patient’s clinical status during co-use of fluoxetine with warfarin.
Although clinical data are limited, fluoxetine may interact with digitoxin. Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein, such as 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.
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.
It is unknown if melatonin would interact with psychotropic medications. One limited 4-week study in depressed patients with insomnia noted no interactions when melatonin was added to fluoxetine therapy. However, one case report of excessive melatonin ingestion in combination with fluoxetine therapy resulted in a case of acute psychosis that resolved within 24 hours of melatonin ingestion. The possibility of pharmacodynamic or pharmacokinetic interaction between fluoxetine and melatonin should be considered in this case. The possibility that similar or other psychoactive medications could interact with melatonin should also be considered.
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.
Although no clinical data are available, fluoxetine may inhibit the clearance and potentiate the actions of modafinil. Modafinil is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit.
Cilostazol is extensively metabolized by the CYP3A4 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP3A4, including some SSRIs (e.g., fluoxetine, fluvoxamine). These agents have been shown to increase both cilostazol AUC and Cmax when administered concurrently. In some studies, co-administration of these agents with cilostazol resulted in increased incidences of adverse effects, such as headache. When significant CYP3A4 inhibitors are administered concomitantly with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
Drugs that inhibit the cytochrome CYP 2C9 isoenzyme in vitro should be used cautiously in patients receiving irbesartan until further data are available regarding the clinical significance of theoretical drug interactions. Irbesartan is a substrate of the CYP 2C9 isoenzyme. Inhibitors of the CYP 2C9 isoenzyme based on in vitro studies include drugs such as fluoxetine. Clinically significant interactions between irbesartan and fluoxetine have not been reported to date.
Fluoxetine may inhibit the metabolism of alfentanil, buprenorphine, fentanyl, levomethadyl, methadone, or sufentanil via cytochrome P450 (CYP) 3A4. Increased concentrations of levomethadyl may predispose patients to the development of serious arrhythmias. In addition, fluoxetine is a relatively potent inhibitor of CYP2D6 resulting in increased concentrations of opiate agonists metabolized via this same pathway (i.e., hydrocodone, methadone, morphine, and oxycodone). Clinicians should be alert for an exaggerated opiate response if any of these drugs are given with fluoxetine. The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine. Fluoxetine 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 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.
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.
Fluoxetine may inhibit the metabolism of levobupivacaine through CYP 3A4. Concurrent administration of fluoxetine and levobupivacaine may result in increased systemic levels of levobupivacaine resulting in toxicity.
Fluoxetine should be given cautiously to patients receiving sirolimus. Fluoxetine may inhibit sirolimus metabolism in the gut and liver.
Fluoxetine may decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism.
Some serotonin reuptake inhibitors (SSRIs) are inhibitors of CYP3A4 (e.g., fluoxetine and fluvoxamine). These drugs may increase dofetilide plasma concentrations with the potential for QTc prolongation.
Cevimeline is metabolized by cytochrome P450 (CYP) 3A4 and CYP2D6. Fluoxetine is a inhibitor of CYP 2D6 and of 3A4 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.
Alosetron is metabolized by the hepatic cytochrome P450 isoenzymes CYP1A2, CYP2C9, and CYP3A4. Fluoxetine inhibits both hepatic CYP2C9 and CYP3A4 isoenzymes, and thus may decrease alosetron metabolism.
Zonisamide is metabolized by the hepatic cytochrome P450 isoenzyme CYP3A4. Fluoxetine inhibits hepatic CYP3A4 and thus may decrease the metabolism of zonisamide.
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.
Some SSRIs may interact with certain antiarrhythmics. Fluoxetine is a potent inhibitor of the hepatic CYP2D6 isoenzyme. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including encainide, flecainide, mexiletine , and propafenone . Concomitant administration of propafenone and fluoxetine in extensive metabolizers increases the S-propafenone Cmax and AUC by 39% and 50%, and the R-propafenone Cmax and AUC by 71% and 50%. Increased plasma antiarrhythmic drug concentrations may increase the risk of proarrhythmias.
Galantamine is metabolized, at least in part, through the hepatic CYP450 system. The bioavailability of galantamine may be increased by co-administration with the CYP2D6 inhibitors, including fluoxetine. An increase in cholinergic side effects may occur, particularly nausea and vomiting.
Due to ritonavir’s effect on various hepatic isoenzymes, drug interactions may occur with ritonavir and may necessitate up to a 50% dose reduction of the coadministered SSRIs. Neurologic events have been reported when ritonavir was concurrently administered with fluoxetine.
Agents that inhibit cytochrome P450 3A4, such as fluoxetine, may decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity.
Fluoxetine may increase or decrease lithium concentrations and close monitoring of lithium concentrations is advisable particularly prior to steady state. Inadequate lithium concentrations (< 0.6 mEq/L) may precipitate mania in the bipolar patient.
Some clinicians feel that buspirone should be used very cautiously, with other serotonergic drugs such as the SSRIs. However, there exist instances where these drug combinations are clinically beneficial. Until more data are available, careful monitoring should be undertaken when these combinations are used. Pharmacologically, buspirone is a serotonin agonist; the SSRIs block serotonin reuptake. Combined use of these drugs might lead to symptoms consistent with serotonin syndrome. The addition of fluoxetine to a regimen consisting of buspirone and trazodone was reported to result in an increase in anxiety-type symptoms in one patient. Another patient developed a grand mal seizure while receiving the combination of buspirone and fluoxetine.
Delavirdine is metabolized by CYP2D6 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This interaction can result in substantial increases in the trough levels of delavirdine, up to a 50% increase.
Fluoxetine is a substrate for CYP2D6 and CYP2C9; voriconazole is known to inhibit CYP2C9. If voriconazole is coadministered with fluoxetine, theoretically the metabolism of fluoxetine could be impaired and could lead to an increase in SSRI-related side effects. Additionally, fluoxetine is an inhibitor of the CYP2C9 and CYP3A4 isoenzymes, of which voriconazole is a known substrate. If fluoxetine is coadministered with voriconazole, voriconazole serum concentrations could rise. Until further information is available detailing the clinical impact of interactions between fluoxetine and voriconazole, coadminister with caution.
Fluoxetine should be used cautiously in patients taking certain ergot alkaloids. Fluoxetine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with these SSRIs when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
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. When phentermine was given with fluoxetine, adrenergic excess and dyskinesia were observed. 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.
A hypomanic episode was reported in a 21 year old female with depression and bulimia receiving fluoxetine 20 mg/day for 4 weeks after smoking marijuana. Her symptoms resolved in 4 days. Because dronabinol, THC is a synthetic analog of a naturally occurring substance found in marijuana, interactions with fluoxetine may also occur with dronabinol.
Fluoxetine inhibits the hepatic CYP3A4 isoenzyme and therefore may increase the serum concentrations of eplerenone. Increased eplerenone levels may lead to a risk of developing hyperkalemia and hypotension; monitor for signs and symptoms in patients receiving fluoxetine and eplerenone concurrently. If these medications are to be given concurrently, the initial eplerenone dose should not exceed 25 mg/day PO.
Fluoxetine is a potent inhibitor of CYP2D6, the primary isozyme involved in the metabolism of atomoxetine. A dosage adjustment of atomoxetine may be needed in normal populations (also known as extensive metabolizers) when atomoxetine is administered with inhibitors of the CYP2D6 enzyme, such as fluoxetine. 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 CYP3A4 and CYP2D6 such as fluoxetine. A dosage adjustment of aripiprazole is necessary when these drugs are used concomitantly, and conversely, when fluoxetine is discontinued in a patient taking aripiprazole.
In theory, fluoxetine may reduce the CYP3A4 metabolism of aprepitant, potentially increasing aprepitant serum concentrations and potential for toxicity. This interaction has not been studied.
The combined use of selective serotonin reuptake inhibitors (SSRIs) and 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. Since celecoxib is metabolized by cytochrome P450 2C9, concurrent administration with fluoxetine, which can inhibit this enzyme , may result in increased levels of celecoxib. The clinical significance of this interaction has not been established.
Agents that inhibit cytochrome P450 (CYP) 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with fluoxetine is not known.
Substances that are potent inhibitors of cytochrome P450 (CYP) 3A4 activity decrease the metabolism of gefitinib and increase gefitinib concentrations. This increase may be clinically relevant as adverse reactions to gefitinib are related to dose and exposure; therefore caution should be used when administering fluoxetine with gefitinib. In addition, gefitinib has been shown to inhibit CYP2D6 at clinical doses and may increase fluoxetine concentrations. Patients should be closely monitored for increased adverse reactions to either drug if given this combination.
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.
Therapy with vinblastine (predominantly metabolized by the CYP2D6 system) 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. Fluoxetine is a potent inhibitor of the CYP2D6 isoenzyme, thus impairing vinblastine metabolism which may result in elevated serum concentrations of vinblastine.
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.
Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
Fluoxetine inhibits CYP2D6 and CYP3A4. Serum concentrations of darifenacin, a CYP2D6 and CYP3A4 substrate, may increase when used in combination with fluoxetine. Patients should be monitored for increased anticholinergic effects if these drugs are coadministered.
Fluoxetine is an inhibitor of CYP3A4. Care should be taken when dosing paricalcitol, a CYP3A4 substrate, with fluoxetine; dose adjustments of paricalcitol may be required. Plasma iPTH and serum calcium and phosphorous concentrations should be closely monitored if a patient taking paricalcitol initiates or discontinues therapy with fluoxetine.
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 fluoxetine 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 fluoxetine is coadministered with doxercalciferol.
[ Last revised: 10/30/2005 5:27:00 PM ]
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