Luvox Interactions
- Alfentanil
- Alosetron
- Alprazolam
- Amiodarone
- Amphetamine
- Aprepitant
- Aripiprazole
- Aspirin, ASA
- Astemizole
- Atazanavir
- Bortezomib
- Buprenorphine
- Caffeine
Calcium-Channel Blockers
- Carbamazepine
- Cevimeline
- Chlordiazepoxide
- Cilostazol
- Cisapride
- Clonazepam
- Clorazepate
- Clozapine
- Cocaine
- Cyclosporine
- Darifenacin
- Dexfenfluramine
- Dextroamphetamine
- Diazepam
- Dihydroergotamine
- Dofetilide
- Donepezil
- Doxercalciferol
- Eplerenone
- Ergonovine
- Ergotamine
- Esomeprazole
- Estazolam
- Ethanol
- Fenfluramine
- Fentanyl
- Flurazepam
- food
- Fosphenytoin
- Furazolidone
- Galantamine
- Gefitinib
- Glimepiride
- grapefruit juice
- Green Tea
- Guarana
- Haloperidol
- Imatinib, STI-571
- Isoniazid, INH
- Kava Kava, Piper methysticum
- Lansoprazole
- Levobupivacaine
- Levomethadyl
- Lidocaine
- Linezolid
- Lithium
- Melatonin
- Meperidine
- Methadone
- Methylergonovine
- Methysergide
- Metoclopramide
- Metoprolol
- Mexiletine
- Midazolam
- Mirtazapine
- Modafinil
Monoamine oxidase inhibitors (MAOIs)
Nonsteroidal antiinflammatory drugs (NSAIDs)
- Olanzapine
- Omeprazole
- Pantoprazole
- Paricalcitol
- Pentazocine
Phenothiazines
- Phentermine
- Phenytoin
- Pimozide
- Prazepam
- Procarbazine
- Propranolol
- Quazepam
- Quinidine
- Ramelteon
- Ropinirole
- Ropivacaine
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin-Receptor Agonists
- Sibutramine
- Sirolimus
- St. John’s Wort, Hypericum perforatum
- Sufentanil
- Tacrine
- Tacrolimus
- Terfenadine
- Theophylline, Aminophylline
- Tizanidine
- tobacco
- Tolbutamide
- Tramadol
- Trazodone
- Triazolam
Tricyclic antidepressants
- Tryptophan, 5-Hydroxytryptophan
- Valerian, Valeriana officinalis
- Voriconazole
- Warfarin
- Zileuton
- Ziprasidone
- Zolpidem
- Zonisamide
Luvox (Fluvoxamine) Interactions
NOTE: Fluvoxamine is a substrate for the isozymes CYP1A2 and CYP2D6. Fluvoxamine inhibits the hepatic cytochrome P-450 system in vivo (particularly the CYP isoenzymes 1A2, 2C19, 2C9, and 3A4), thereby inhibiting the metabolism of a number of drugs. Increased serum concentrations and possible toxicity may occur. Of drugs in the SSRI class, fluvoxamine is one of the SSRI-class drugs that inhibits multiple CYP isozymes significantly.
Due to possible additive effects on serotonin concentrations, it is advisable to avoid combinations of fluvoxamine 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.
Ethanol, while not shown to impair cognitive function when combined with fluvoxamine, may adversely effect behavior and should be avoided in combination with fluvoxamine.
Alprazolam and diazepam are metabolized by the hepatic isoenzyme CYP3A4. Fluvoxamine caused a significant increase in alprazolam AUC in healthy subjects; which resulted in a greater impairment in psychomotor performance than during administration of either drug alone. Lower initial doses of alprazolam should be administered to patients receiving fluvoxamine if these drugs must be used together. The initial alprazolam dosage should be halved and titrated upward slowly as indicated. Fluvoxamine decreases the hepatic metabolism of diazepam and co-therapy is not recommended. Diazepam is metabolized by CYP2C19 and fluvoxamine inhibits this isoenzyme. It is possible that fluvoxamine may affect the metabolism of other benzodiazepines that undergo hepatic oxidation (such as chlordiazepoxide, clonazepam , clorazepate , estazolam, flurazepam, midazolam, prazepam, quazepam, and triazolam ) although clinical data are lacking for many of these. Fluvoxamine does not affect the pharmacokinetics of lorazepam, a benzodiazepine that is metabolized by conjugation.
Clinicians should be alert for pharmacokinetic interactions between tricyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs) 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. Fluvoxamine does not appear to appreciably inhibit 2D6 in vivo, but does inhibit 3A4 to some degree. Therefore, caution should be used in combining fluvoxamine with 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.
Fluvoxamine 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 fluvoxamine 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 fluvoxamine therapy, and there should be at least 2 weeks between the discontinuation of fluvoxamine therapy and commencement of MAOI therapy. 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 selected SSRIs. Finally, isoniazid, INH (antituberculosis drug), furazolidone), and linezolid (antibiotics) and procarbazine (chemotherapy agent) also possess weak non-selective MAO-inhibiting activity and should be combined with any serotonergic agent with caution.
An interaction may occur between fluvoxamine and either fenfluramine or dexfenfluramine. Dexfenfluramine stimulates the release of serotonin and inhibits its reuptake. Fluvoxamine also inhibits the reuptake of serotonin. In addition, fluvoxamine is known to inhibit several cytochrome enzymes and it is possible, though no data exist, that fluvoxamine might affect the clearance of dexfenfluramine. Thus, for a variety of reasons, serotonin excess may occur if these two drugs are used together. Due to the potential severity of the serotonin syndrome, fluvoxamine should not be used with dexfenfluramine. Since dexfenfluramine is the S-enantiomer of the racemic compound fenfluramine, a similar interaction may occur between fluvoxamine and fenfluramine.
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.
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.
Fluvoxamine should 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.
Sibutramine is a serotonin reuptake inhibitor. Concomitant use of two serotonin-augmenting drugs has been associated with serotonin syndrome, so concurrent use of fluvoxamine 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 fluvoxamine concomitantly with trazodone should be monitored closely for adverse effects related to excessive serotonergic stimulation (’serotonin syndrome’).
Astemizole, cisapride, 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. There is some evidence that fluvoxamine inhibits hepatic CYP3A4 metabolism. Because of the potential severity of these drug interactions, the manufacturer considers fluvoxamine to be contraindicated for use with astemizole, cisapride, pimozide or terfenadine.
Although data are limited fluvoxamine should be used with caution in patients receiving carbamazepine. Carbamazepine is metabolized by CYP3A4 and fluvoxamine is known to inhibit this enzyme. At least one case is noted where carbamazepine serum concentrations increased substantially when fluvoxamine was added, accompanied by signs of carbamazepine toxicity.
Fluvoxamine inhibits the activity of the hepatic isozyme CYP1A2. Examples of drugs known to be metabolized via this enzyme include the methylxanthines caffeine and theophylline. The manufacturer of fluvoxamine has noted that fluvoxamine decreases the clearance of theophylline three-fold. Therefore, if theophylline is coadministered with fluvoxamine, the theophylline daily dosage should be reduced by one-third and plasma theophylline concentrations should be monitored. Patients should report any increase in methylxanthine-induced side effects, like tremor, nausea, or vomiting promptly. During concomitant therapy with fluvoxamine, it may be prudent to minimize the consumption of caffeine from dietary supplements such as guarana and beverages including coffee, green tea, other teas, and colas in an effort to minimize caffeine-related side effects.
Fluvoxamine inhibits the activity of the CYP1A2 isoenzyme. Drugs known to be metabolized via this enzyme include clozapine. Fluvoxamine, due to inhibition of CYP1A2, can cause a 5 - 10 fold increase in clozapine serum concentrations. Clozapine serum concentrations were markedly higher in one patient after the addition of fluvoxamine. Clozapine dose-related seizures and hypotension may be more likely with the addition of fluvoxamine.
Fluvoxamine inhibits the activity of the hepatic isozyme CYP1A2 and may potentially increase plasma concentrations of tacrine. Tacrine induced cholinergic events, such as nausea, vomiting, sweating and diarrhea may occur due to elevated tacrine serum concentrations. In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five- and eight-fold increases in tacrine Cmax and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea/vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine. Other SSRI-type antidepressants that do not inhibit CYP1A2 (e.g., fluoxetine or sertraline) may be preferable for use if tacrine is administered concurrently.
Fluvoxamine inhibits the activity of hepatic isoenzymes CYP1A2. According to a manufacturer-based study, fluvoxamine co-therapy increased warfarin serum concentrations by 98%, resulting in a prolonged INR. This can increase the risk of bleeding and bruising from the anticoagulant. The INR should be monitored closely and the warfarin dose adjusted accordingly if coadministration with fluvoxamine is necessary.
Haloperidol is metabolized by CYP2D6 and CYP1A2. Fluvoxamine inhibits hepatic isozymes CYP1A2 and CYP2C19 and may decrease haloperidol metabolism. Symptoms of haloperidol excess have been observed in the patients receiving haloperidol and fluvoxamine together.
A single case report documents the development of severe somnolence within 24 hours after lithium was added to fluvoxamine. A positive rechallenge was noted and symptoms did not recur when either drug was used alone. Lithium may also enhance the serotonergic effects of fluvoxamine, which may have a positive (enhanced efficacy) or negative (serotonin syndrome) outcome. Seizures have been reported when lithium and fluvoxamine were coadministered.
In a small number of patients receiving methadone for opiate dependence, the addition of fluvoxamine has produced a substantial increase in methadone serum concentrations. Clinical symptoms of methadone excess have resulted from concurrent use. Fluvoxamine should be used cautiously in patients receiving methadone. Likewise, if fluvoxamine is discontinued, methadone serum concentrations may decrease. Similar reactions may occur in patients receiving alfentanil, buprenorphine, fentanyl, levomethadyl, or sufentanil. Increased levels of levomethadyl may predispose patients to the development of serious arrhythmias.
Limited data are available regarding a drug interaction between fluvoxamine and various beta-blockers. Fluvoxamine has been reported to cause a 5-fold increase in propranolol serum concentrations but only caused a reduction in heart rate of approximately 3 beats per minute and a reduction in diastolic blood pressure during exercise. Propranolol is metabolized by the CYP1A2 isoenzyme which fluvoxamine may inhibit. Fluvoxamine also potentiated the clinical effects (e.g. , orthostatic hypotension) of metoprolol. The pharmacokinetics of atenolol, a beta-blocker that does not undergo hepatic metabolism, were not affected. Fluvoxamine appears to affect the kinetics of some beta-blockers that undergo hepatic metabolism. If propranolol or metoprolol are administered with fluvoxamine, a reduction in the initial beta-blocker dosage and more cautious dosage titration have been recommended.
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.
The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents, may interact with the phytomedicinals kava kava, Piper methysticum or valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
Although no clinical data are available, fluvoxamine may inhibit the clearance and potentiate the actions of modafinil. Modafinil is metabolized by CYP3A4 isozyme, a pathway that fluvoxamine 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, coadministration of these agents with cilostazol resulted in increased incidences of adverse effects, such as headache. When significant CYP3A4 inhibitors are administered concomitantly with cilostazol, a cilostazol dosage reduction should be considered.
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 some SSRIs (e.g., paroxetine, sertraline) with tramadol in some cases of seizures.
Fluvoxamine may inhibit the metabolism of levobupivacaine through inhibition of CYP3A4 or 1A2. Concurrent administration of fluvoxamine (CYP1A2 and CYP3A4 inhibitor) and levobupivacaine may result in increased systemic levels of levobupivacaine resulting in toxicity.
Fluvoxamine should be given cautiously to patients receiving CYP3A4 substrates such as sirolimus or tacrolimus. Fluvoxamine may inhibit the metabolism of these medications via inhibition of CYP3A4 isoenzymes in the gut and liver.
Fluvoxamine may decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Bradycardia has been reported when fluvoxamine has been added to a stable diltiazem regimen.
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. Fluvoxamine is an inhibitor of CYP3A4 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 primarily pharmacodynamic or pharmacokinetic in nature.
The combined use of fluvoxamine and alosetron is contraindicated. Alosetron is metabolized by the hepatic cytochrome P450 isoenzymes CYP1A2, CYP2C9, and CYP3A4. Fluvoxamine inhibits both hepatic CYP1A2 and CYP3A4 isoenzymes and thus may decrease alosetron metabolism. Fluvoxamine has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolong the half-life by approximately 3-fold. Elevated serum concentrations of alosetron may result in severe constipation. Consequently, it is recommended that fluvoxamine not be used in combination with alosetron.
Zonisamide is metabolized by the hepatic cytochrome P450 isoenzyme CYP3A4. Fluvoxamine inhibits hepatic CYP3A4 and thus may decrease the metabolism of zonisamide. The potential for adverse events due to elevated serum concentrations of zonisamide may occur. Zonisamide should be avoided in combination with any potent CYP3A4 inhibitor, and used extremely cautiously, if at all with other CYP3A4 inhibitors.
Fluvoxamine induced an increase in the AUC and peak concentrations of melatonin by 23-fold and 12-fold, respectively after the coadministration of a 5 mg melatonin dose in several healthy volunteers. The mechanism is unknown. The interaction may increase the sedative effects of melatonin. The possibility that similar psychoactive medications could interact with melatonin should also be considered.
Phenytoin clearance can be decreased by drugs that inhibit hepatic microsomal enzymes, particularly the cytochrome P450 2C subset of isoenzymes. Fluvoxamine inhibits phenytoin metabolism via CYP2C19 and CYP2C9. If Selective Serotonin Reuptake Inhibitor (SSRI) therapy is required in patients taking phenytoin or fosphenytoin, SSRIs other than fluvoxamine should be considered. If fluvoxamine is added to phenytoin or fosphenytoin therapy, phenytoin serum levels should be monitored and dosage adjustments may be necessary; monitor for signs of phenytoin toxicity. Note that the hydantoin anticonvulsants may increase the metabolism of fluvoxamine, but enzyme-induction interactions are not always clinically significant.
Fluvoxamine and thioridazine should not be coadministered; their combined use is contraindicated. Thioridazine should generally not be used with the SSRIs, particularly those that inhibit CYP2D6 metabolism (e.g., fluoxetine, paroxetine, sertraline). Although fluvoxamine is not known to inhibit CYP2D6 significantly, fluvoxamine nevertheless causes increased serum concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, by roughly three-fold. Caution is advised in the use of other phenothiazines concurrently with fluvoxamine.
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.
Fluvoxamine, which appears to inhibit hepatic CYP3A4 metabolism, may theoretically increase galantamine plasma concentrations with potential for increased cholinesterase inhibitor side effects, like vomiting.
Since celecoxib is metabolized by cytochrome P450 2C9, concurrent administration with fluvoxamine, which can inhibit this enzyme, may result in increased levels of celecoxib. The clinical significance of this interactions has not been established.
Fluvoxamine should be used cautiously in patients taking certain ergot alkaloids. Fluvoxamine 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 fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution.
Agents that are known inhibitors of CYP1A2 such as fluvoxamine may result in increased ropivacaine systemic levels and toxicity when given concurrently. In vivo, the plasma clearance of ropivacaine was reduced by 70% and the half-life doubled during concurrent administration with fluvoxamine.
Although more data are needed, fluvoxamine appears to decrease the hepatic clearance of mexiletine (roughly a 55% increase in AUC and a 16% increase in peak plasma concentrations occurs). The mechanism of this interaction is most likely due to fluvoxamine inhibition of the CYP1A2 isoenzyme and a resultant 38% reduction in the clearance of mexiletine. If fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored and the patient closely observed.
Agents that inhibit cytochrome P450 3A4, such as fluvoxamine, may decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity.
Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme system. Drugs having the potential to decrease the elimination of ziprasidone via inhibition of CYP3A4 include fluvoxamine. The potential for adverse events due to elevated serum concentrations of ziprasidone may occur during concomitant therapy with CYP3A4 inhibitors; coadminister with caution.
Fluvoxamine should be used cautiously with glimepiride. The combination of fluvoxamine and glimepiride has resulted in a 43% increase in glimepiride peak plasma concentrations and an increase in glimepiride half-life in healthy volunteers; blood glucose response may be altered in diabetic patients. The mechanism of this interaction is unclear. Blood glucose concentrations should be monitored during coadministration of fluvoxamine.
Inhibitors of CYP1A2 may affect the elimination of olanzapine. Fluvoxamine is known to potently inhibit the activity of CYP1A2 and interactions with olanzapine have been reported. Fluvoxamine increases the mean olanzapine peak concentration by 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. The manufacturer of olanzapine suggests lower doses of olanzapine should be considered in patients receiving fluvoxamine. Fluvoxamine increases olanzapine plasma concentrations and may result in side effects like mydriasis, rigid movement, or tremors. Dosage adjustments of one or both medications may be needed if they are used concurrently.
Although unlikely to occur with use of mirtazapine alone, there have been rare case reports of serotonin syndrome with the drug. The coadministration of other medications that potentiate the actions of serotonin (e.g., SSRIs) could theoretically result in serotonin syndrome. A case report of serotonin syndrome from an interaction of mirtazapine with fluvoxamine has been described. In vitro studies identify mirtazapine as a substrate for several hepatic cytochrome CYP450 isoenzymes including 2D6, 1A2, and 3A4. Increased mirtazapine serum concentrations (3 - 4 fold) have been reported following the addition of fluvoxamine to stable mirtazapine regimens. It may be necessary to reduce the dosage of either mirtazapine and/or the SSRI when they are administered concurrently.
Fluvoxamine may potentially reduce the clearance of tolbutamide (CYP2C9 substrate) via inhibition of CYP2C9 isoenzymes. A small study (14 healthy subjects) has shown that fluvoxamine reduced tolbutamide clearance approximately 19% with the 75 mg/day dose of fluvoxamine; however, the increase was not statistically significant with the 150 mg/day dose fluvoxamine. Fluvoxamine also reduces the clearance of two inactive metabolites of tolbutamide (hydroxytolbutamide and carboxytolbutamide). The significance of this interaction is not established; further study is needed. Monitor blood glucose if fluvoxamine is added to tolbutamide therapy.
Fluvoxamine (moderate CYP3A4 inhibitor) may inhibit CYP3A4 metabolism of quinidine (CYP3A4 substrate). In a small open-label study (n=6), fluvoxamine (100 mg/day) has been reported to decrease the total oral clearance of quinidine by 29%. Quinidine is also a CYP2D6 inhibitor and CYP2D6 is partially responsible for fluvoxamine metabolism. In poor metabolizers, serum concentrations of fluvoxamine may rise. In an in vitro study, mean Cmax, AUC and half-life increased by 52, 200 and 62%, respectively, when combined with quinidine. Use fluvoxamine cautiously in patients that are known to poorly metabolize via CYP2D6 and in combination with drugs that inhibit CYP2D6.
Voriconazole is a substrate for the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Theoretically, drugs that are inhibitors of these enzymes, such as fluvoxamine , may result in decreased clearance and elevated voriconazole serum concentrations when coadministered. Clinicians should be alert for enhanced adverse reactions due to voriconazole if fluvoxamine is coadministered.
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.
Fluvoxamine inhibits the hepatic CYP3A4 isoenzyme and may increase 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 fluvoxamine and eplerenone concurrently. If these medications are to be given concurrently, the initial eplerenone dose should not exceed 25 mg/day PO.
Increased aripiprazole blood levels are expected when aripiprazole is coadministered with inhibitors of CYP3A4 such as fluvoxamine. A dosage adjustment of aripiprazole is necessary when these drugs are used concomitantly, and conversely, when fluvoxamine is discontinued in a patient taking aripiprazole.
Fluvoxamine may reduce the metabolism of aprepitant via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the serum concentrations of aprepitant. The clinical significance of this theoretical interaction is unknown.
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. The manufacturer of fluvoxamine also warns about combining fluvoxamine with nonsteroidal antiinflammatory drugs (NSAIDs) or ASA due to an increased risk for bleeding. 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.
In vitro studies with human liver microsomes indicate that bortezomib is a substrate for cytochrome P450 (CYP) 3A4, 2D6, 2C19, 2C9, and 1A2. Agents that inhibit these isoenzymes, such as fluvoxamine, may increase the exposure to bortezomib and increase the risk for toxicity. Fluvoxamine is an inhibitor of cytochrome P450 (CYP) 3A4, 2C19, 2C9, and 1A2.
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 fluvoxamine with gefitinib.
Fluvoxamine is a substrate for the isozymes CYP1A2 and CYP2D6. Tobacco smoke contains polycyclic aromatic hydrocarbons that induce hepatic CYP450 microsomal enzymes (e.g., CYP1A1, CYP1A2, CYP2E1) and tobacco smoking increases the metabolism of fluvoxamine. Smokers have a 25% increase in metabolism over non-smokers. Conversely, because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, the sudden cessation of tobacco smoking may result in a reduced clearance of fluvoxamine, despite the initiation of a nicotine replacement product. Monitor the patient for the desired clinical effects when changes in smoking status occur.
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.
The combination of tizanidine and fluvoxamine is contraindicated. An in vivo pharmacokinetic study revealed that fluvoxamine may drastically increase the serum concentrations of tizanidine, leading to a severe and prolonged decrease in blood pressure as well as additive CNS effects. The mean maximal effect on blood pressure was a 35 mmHg decrease in systolic blood pressure, a 20 mmHg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on a psychomotor task was significantly impaired. Systolic blood pressures dropped to 80 mmHg or less and somnolence and dizziness were prevalent for 3 - 6 hours after tizanidine intake. The mechanism appears to be due to inhibition of tizanidine hepatic metabolism (via CYP1A2) by fluvoxamine. Serum concentrations (AUC) of tizanidine (given as a single 4 mg dose) were increased a mean of 33 fold (range 14 - 103 fold) after 4 days of fluvoxamine 100 mg/day PO or placebo. Tizanidine Cmax was increased approximately 12-fold (range 5 - 32), elimination half-life was increased almost 3-fold. Serum increases of tizanidine occurred in all 10 subjects receiving active drug.
Clinicians should be aware that while fluvoxamine does not interact with most food products and may be taken without regard to meals, an interaction occurs with grapefruit juice. A single dose pharmacokinetic study shows that in patients who have ingested grapefruit juice at least 3 times per day for 5 days prior to initiation of fluvoxamine 75 mg; the mean peak and AUC increased 1.3 and 1.6 fold, respectively. The half-life of fluvoxamine was not altered. Fluvoxamine is not a known substrate for CYP3A4; therefore, the likelihood that this interaction is due to grapefruit juice inhibitory effects on CYP3A4 is remote. Altered P-glycoprotein-mediated transport, initiated by grapefruit juice, is the suspected mechanism of action. Patients receiving a new prescription for fluvoxamine should avoid chronic grapefruit juice consumption. Patients who are stable and have consumed grapefruit juice previously with fluvoxamine should either: 1) not alter their consumption of grapefruit juice while continuing to take fluvoxamine or 2) be aware that fluvoxamine may be less effective if they stop consuming grapefruit juice, and dose adjustments may be needed.
Fluvoxamine is a major inhibitor of the cytochrome P450 enzyme (CYP) 2C19. Several proton pump inhibitors (PPIs), including esomeprazole, lansoprazole, omeprazole, and pantoprazole are primary substrates of the CYP2C19 enzyme. Reduced metabolism and resulting elevated plasma concentrations of these PPIs may occur if combined with fluvoxamine. A single-dose pharmacokinetic study has shown that the mean AUC of omeprazole 40 mg was increased 2- to 6-fold when given after fluvoxamine 50 mg/day for 6 days. Monitor patients for PPI toxicity, such as headache or GI distress if these drugs are combined.
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.
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.
Fluvoxamine inhibits CYP3A4. Serum concentrations of darifenacin, a CYP3A4 substrate, may increase when used in combination with fluvoxamine. Patients should be monitored for increased anticholinergic side effects if these drugs are coadministered.
Fluvoxamine is an inhibitor of CYP3A4. Care should be taken when dosing paricalcitol, a CYP3A4 substrate, with fluvoxamine; 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 fluvoxamine.
Ramelteon should not be used in combination with fluvoxamine, a strong CYP1A2 inhibitor. When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased roughly 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone.
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 fluvoxamine 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 fluvoxamine is coadministered with doxercalciferol.
Fluvoxamine is a substrate for the isozymes CYP1A2 and CYP2D6. Amiodarone is an inhibitor of both CYP1A2 and CYP2D6 isoenzymes, and could reduce fluvoxamine metabolism. The clinical significance of this potential interaction is not known.
Fluvoxamine inhibits CYP3A4 isoenzymes, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution to reduce potential for atazanavir toxicity.
Ropinirole is primarily metabolized by cytochrome P450 1A2 (CYP1A2). In theory, ropinirole clearance may be reduced by coadministration with inhibitors of CYP1A2 such as fluvoxamine.
Zileuton is primarily metabolized by CYP1A2 isoenzymes, while fluvoxamine inhibits this isoenzyme. Although not studied, fluvoxamine may reduce CYP1A2 mediated metabolism of zileuton.
Lidocaine is metabolized by CYP3A4 and CYP1A2 isoenzymes. Although CYP3A4 has been considered to be the primary pathway for lidocaine metabolism, recent studies suggest that CYP1A2 isoenzymes contribute significantly to lidocaine metabolism. Fluvoxamine, a potent CYP1A2 inhibitor, has been shown to reduce lidocaine clearance by approximately 40 - 60% during in vivo studies. However, cytochrome activity was not measured during these trials. Since fluvoxamine has also been reported to moderately inhibit CYP3A4 isoenzymes, CYP3A4 inhibition may have also contributed to the reduction in lidocaine clearance. In one study, coadministration of lidocaine with both fluvoxamine and erythromycin has been reported to further reduce lidocaine clearance than observed with fluvoxamine alone. Examples of other CYP1A2 inhibitors which could theoretically reduce lidocaine metabolism include: ciprofloxacin, enoxacin, tacrine, and zileuton. Although not studied, these CYP1A2 inhibitors could theoretically reduce lidocaine elimination. Until further data are available, it is prudent to monitor for lidocaine toxicity and increased serum concentrations in patients receiving systemic lidocaine and significant CYP1A2 inhibitors. The magnitude of effect on lidocaine serum concentrations may be greater when a CYP3A4 inhibitor is coadministered with a CYP1A2 inhibitor.
[ Last revised: 10/30/2005 11:23:00 AM ]
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