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FluvoxaMINE

Pronunciation

Pronunciation

(floo VOKS a meen)

Index Terms

  • Fluvoxamine Maleate
  • Luvox

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 24 Hour, Oral, as maleate:

Luvox CR: 100 mg [DSC], 150 mg [DSC] [gluten free; contains fd&c blue #2 (indigotine)]

Generic: 100 mg, 150 mg

Tablet, Oral, as maleate:

Generic: 25 mg, 50 mg, 100 mg

Brand Names: U.S.

  • Luvox CR [DSC]

Pharmacologic Category

  • Antidepressant, Selective Serotonin Reuptake Inhibitor

Pharmacology

Inhibits CNS neuron serotonin uptake; minimal or no effect on reuptake of norepinephrine or dopamine; does not significantly bind to alpha-adrenergic, histamine or cholinergic receptors

Distribution

Vd: ~25 L/kg

Metabolism

Extensively hepatic via oxidative demethylation and deamination

Excretion

Urine (~85% as metabolites; ~2% as unchanged drug)

Onset of Action

Individual responses may vary; however, 8 to 12 weeks of treatment are needed for patients with obsessive-compulsive disorder and 4to 8 weeks of treatment are needed for patients with depression before determining if a patient is partially or nonresponsive (APA, 2010; APA 2007).

Time to Peak

Plasma: 3 to 8 hours

Half-Life Elimination

~14 to 16 hours; ~17 to 26 hours in the elderly

Protein Binding

~80%, primarily to albumin

Special Populations: Hepatic Function Impairment

For the immediate release tablets, a 30% decrease in clearance has been observed in patients with hepatic impairment compared with healthy subjects.

Special Populations: Elderly

For the immediate-release tablets, compared with younger subjects, clearance is reduced by 50% and mean max plasma concentrations are 40% higher in the elderly.

Special Populations: Gender

For the extended release capsules, the AUC and Cmax were increased by approximately 60% in healthy women compared with men.

Use: Labeled Indications

Obsessive-compulsive disorder: Treatment of obsessive-compulsive disorder (OCD) in pediatric patients 8 to 17 years of age and adults.

Canadian labeling: Additional use (not in US labeling): Depression: Treatment of depression in adults

Use: Unlabeled

Treatment of major depression; panic disorder; post-traumatic stress disorder (PTSD); social anxiety disorder (SAD)

Contraindications

Concurrent use with alosetron, pimozide, ramelteon, thioridazine, or tizanidine; use of MAO inhibitors intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing either fluvoxamine or the MAO inhibitor); initiation of fluvoxamine in a patient receiving linezolid or intravenous methylene blue.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to fluvoxamine or any component of the formulation; concurrent use with astemizole, cisapride, mesoridazine, or terfenadine.

Dosing: Adult

Obsessive-compulsive disorder: Oral:

Immediate release: Initial: 50 mg once daily at bedtime; may be increased in 50 mg increments at 4- to 7-day intervals, as tolerated; usual dose range: 100 to 300 mg daily; maximum dose: 300 mg daily. Note: US labeling recommends that daily doses >100 mg be given in 2 divided doses, with the larger dose administered at bedtime. Canadian labeling recommends that daily doses >150 mg be given in 2 divided doses with the larger dose administered at bedtime (maximum bedtime dose: 150 mg); if no improvement within 10 weeks consider discontinuing fluvoxamine therapy.

Extended release: Initial: 100 mg once daily at bedtime; may be increased in 50 mg increments at intervals of at least 1 week; usual dosage range: 100 to 300 mg daily; maximum dose: 300 mg daily

Depression (Canadian labeling; not an approved use in US labeling): Oral: Immediate release: Initial: 50 mg once daily at bedtime then after a few days may increase to 100 mg daily as tolerated; titrate gradually based on response and tolerability in 50 mg increments; usual dosage range: 100 to 200 mg daily; maximum dose: 300 mg daily. Doses >150 mg daily should be divided with maximum dose of 150 mg given at bedtime.

Bulimia nervosa (off-label use): Oral: Immediate release: Initial: 50 mg daily; increase dose based on response and tolerability up to 300 mg/day given in 1 or 2 divided doses (Brambilla 1995; Fichter 1996; Fichter 1997; Milano 2005). Additional data may be necessary to further define the role of fluvoxamine in this condition.

Panic disorder (off-label use): Oral: Immediate release: Initial: 25 to 50 mg daily; titrate gradually based on response and tolerability; usual dosage range: 100 to 200 mg daily (APA, 2009; Asnis, 2001).

Post-traumatic stress disorder (PTSD) (off-label use): Oral: Immediate release: 75 mg twice daily (Spivak, 2006).

Social anxiety disorder (off-label use): Oral:

Immediate release: Initial: 50 mg once daily; may increase in 50 mg increments at intervals of at least 1 week; usual dosage range: 100 to 300 mg daily (Asakura, 2007).

Extended release: Initial: 100 mg once daily at bedtime; may be increased in 50 mg increments at intervals of at least 1 week; usual dosage range: 100 to 300 mg daily; maximum dose: 300 mg daily (Davidson, 2004; Stein, 2003; Westenberg, 2004)

Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. Evidence supporting ideal taper rates is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4 to 6 months. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA, 2007; APA ,2010; Bauer, 2002; Haddad, 2001; NCCMH, 2010; Schatzberg, 2006; Shelton, 2001; Warner, 2006).

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of fluvoxamine.

Allow 14 days to elapse between discontinuing fluvoxamine and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Use with other MAO inhibitors (linezolid or IV methylene blue):

Do not initiate fluvoxamine in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.

If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving fluvoxamine and potential benefits outweigh potential risks, discontinue fluvoxamine promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume fluvoxamine 24 hours after the last dose of linezolid or IV methylene blue. Risk of administering methylene blue by non-intravenous routes or in IV doses <1 mg/kg concurrently with fluvoxamine is unclear.

Dosing: Geriatric

Refer to adult dosing. Consider a lower initial dose; titrate slowly.

Dosing: Pediatric

Obsessive-compulsive disorder: Oral: Note: Not approved for use in patients <18 years of age in Canadian labeling.

Children and Adolescents 8 to 17 years:

Immediate release: Initial: 25 mg once daily at bedtime; may be increased in 25 mg increments at 4- to 7-day intervals, as tolerated, to maximum therapeutic benefit; usual dose range: 50 to 200 mg daily. Note: When total daily dose of immediate release exceeds 50 mg, the dose should be given in 2 divided doses with larger portion administered at bedtime.

Maximum dose: Children: 8 to 11 years: 200 mg daily; Adolescents: 300 mg daily; lower doses may be effective in female versus male patients

Extended release: The extended release formulation has not been evaluated in pediatric patients; the lowest available dose of extended release capsules may not be appropriate for pediatric patients naïve to fluvoxamine.

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in manufacturer’s labeling. Limited data suggest fluvoxamine does not accumulate in patients with renal impairment. Canadian labeling recommends initiating therapy at a reduced dosage with close monitoring.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in manufacturer’s labeling. Limited data suggest fluvoxamine clearance is reduced in patients with hepatic impairment. Reduced initial dose and slow titration may be required. Monitor closely.

Administration

Oral: May be administered with or without food. Do not crush, open, or chew extended release capsules. The Canadian labeling recommends that the immediate release tablet be swallowed whole.

Storage

Protect from high humidity and store at controlled room temperature 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Agomelatine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Agomelatine. Avoid combination

Ajmaline: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Management: Patients receiving selective serotonin reuptake inhibitors should be advised to avoid alcohol. Monitor for increased psychomotor impairment in patients who consume alcohol during treatment with selective serotonin reuptake inhibitors. Consider therapy modification

Alosetron: FluvoxaMINE may decrease the metabolism of Alosetron. Avoid combination

ALPRAZolam: FluvoxaMINE may increase the serum concentration of ALPRAZolam. Monitor therapy

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Management: Consider alternatives, and use conservative initial dosing. Monitor patients receiving these combinations for signs/symptoms of serotonin toxicity. Consider therapy modification

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asenapine: FluvoxaMINE may increase the serum concentration of Asenapine. Monitor therapy

Aspirin: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Bendamustine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Bendamustine. Concentrations of the active metabolites of bendamustine may be decreased. Monitor therapy

Blood Glucose Lowering Agents: Selective Serotonin Reuptake Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Bromazepam: FluvoxaMINE may increase the serum concentration of Bromazepam. Management: With concomitant fluvoxamine, consider use of a benzodiazepine that does not undergo oxidative metabolism (e.g., lorazepam). If bromazepam is initiated in patients receiving fluvoxamine, monitor closely for increased bromazepam levels/adverse effects. Consider therapy modification

BuPROPion: May enhance the adverse/toxic effect of FluvoxaMINE. BuPROPion may increase the serum concentration of FluvoxaMINE. Monitor therapy

BusPIRone: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Selective Serotonin Reuptake Inhibitors may decrease the metabolism of BusPIRone. Management: The combination of a selective serotonin reuptake inhibitor and buspirone should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

CarBAMazepine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of CarBAMazepine. Specifically those SSRIs that inhibit CYP3A4 isoenzymes. CarBAMazepine may increase the metabolism of Selective Serotonin Reuptake Inhibitors. Specifically those agents metabolized via CYP1A2, 2C, and/or 3A4 isoenzymes. Consider therapy modification

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Cimetidine: May decrease the metabolism of Selective Serotonin Reuptake Inhibitors. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a strong CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clopidogrel: FluvoxaMINE may enhance the adverse/toxic effect of Clopidogrel. Specifically, the risk for bleeding may be increased. FluvoxaMINE may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Management: Reduce the dose of clozapine to one-third of the original dose when adding a strong CYP1A2 inhibitor, and monitor patient response closely. Return to the original clozapine dose when the strong CYP1A2 inhibitor is removed. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

CYP1A2 Substrates: CYP1A2 Inhibitors (Strong) may decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Consider therapy modification

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Cyproheptadine: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desmopressin: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Dosulepin: Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Dosulepin. Avoid combination

DULoxetine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Avoid combination

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Erlotinib: FluvoxaMINE may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Etizolam: FluvoxaMINE may increase the serum concentration of Etizolam. Management: Use lower etizolam doses when using this combination. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Flibanserin: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Monitor therapy

Fosphenytoin: FluvoxaMINE may increase the serum concentration of Fosphenytoin. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Grapefruit Juice: May increase the serum concentration of FluvoxaMINE. Monitor therapy

Haloperidol: FluvoxaMINE may increase the serum concentration of Haloperidol. Management: Monitor for increased haloperidol concentrations/effects when patients are receiving fluvoxamine, particularly when fluvoxamine dose is 150 mg/day or greater. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Iobenguane I 123: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ioflupane I 123: Selective Serotonin Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Linezolid: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

Lithium: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could increase the risk of serotonin toxicity/serotonin syndrome. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

MAO Inhibitors: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination

Melatonin: FluvoxaMINE may increase the serum concentration of Melatonin. Management: Consider the use of alternative agents in order to avoid this combination. If combined, monitor for increased melatonin effects (eg, sedation, somnolence) if combined with fluvoxamine. Consider therapy modification

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methadone: May enhance the serotonergic effect of FluvoxaMINE. This could result in serotonin syndrome. FluvoxaMINE may increase the serum concentration of Methadone. Monitor therapy

Methylene Blue: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Metoclopramide: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with selective serotonin reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

MetyroSINE: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Mexiletine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of Mexiletine. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

NSAID (COX-2 Inhibitor): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). NSAID (COX-2 Inhibitor) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

NSAID (Nonselective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (Nonselective). NSAID (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider using alternative analgesics, when appropriate, and/or addition of a gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Consider therapy modification

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

OLANZapine: FluvoxaMINE may decrease the metabolism of OLANZapine. Consider therapy modification

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pentoxifylline: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pentoxifylline. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Phenytoin: FluvoxaMINE may increase the serum concentration of Phenytoin. Monitor therapy

Pimozide: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Pimozide. Avoid combination

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Pirfenidone: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pirfenidone. Management: See full monograph for specific recommendations. Canadian product labeling specifically lists the use of pirfenidone with fluvoxamine as contraindicated. Consider therapy modification

Pomalidomide: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pomalidomide. Management: Avoid when possible. Monitor toxicity closely when combined. In patients also receiving a P-gp inhibitor and strong CYP3A4 inhibitor, reduce pomalidomide dose by 50% (Canadian labeling says to reduce dose with any use of a strong CYP1A2 inhibitor). Avoid combination

Propafenone: FluvoxaMINE may increase the serum concentration of Propafenone. Monitor therapy

Propranolol: FluvoxaMINE may increase the serum concentration of Propranolol. Management: Use a lower initial propranolol dose and be cautious with propranolol dose titration. Consider therapy modification

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

QuiNIDine: FluvoxaMINE may increase the serum concentration of QuiNIDine. QuiNIDine may increase the serum concentration of FluvoxaMINE. Monitor therapy

QuiNINE: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Ramelteon: FluvoxaMINE may increase the serum concentration of Ramelteon. Avoid combination

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Roflumilast: FluvoxaMINE may increase serum concentrations of the active metabolite(s) of Roflumilast. FluvoxaMINE may increase the serum concentration of Roflumilast. Monitor therapy

Ropivacaine: FluvoxaMINE may increase the serum concentration of Ropivacaine. Monitor therapy

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Tasimelteon: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Avoid combination

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Theophylline Derivatives: FluvoxaMINE may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: Selective Serotonin Reuptake Inhibitors may enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thioridazine: FluvoxaMINE may increase the serum concentration of Thioridazine. Avoid combination

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Thyroid Products: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Thyroid Products. Thyroid product dose requirements may be increased. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of TiZANidine. Management: Tizanidine use with ciprofloxacin or fluvoxamine is contraindicated. If use with another strong inhibitor cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on response. Monitor closely. Avoid combination

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Tricyclic Antidepressants: FluvoxaMINE may enhance the adverse/toxic effect of Tricyclic Antidepressants. FluvoxaMINE may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with fluvoxamine. Consider therapy modification

Tryptophan: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Avoid combination

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Selective Serotonin Reuptake Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Zolpidem: FluvoxaMINE may enhance the CNS depressant effect of Zolpidem. FluvoxaMINE may increase the serum concentration of Zolpidem. Monitor therapy

Adverse Reactions

Frequency varies by dosage form and indication. Adverse reactions reported as a composite of all indications.

>10%:

Central nervous system: Headache (22% to 35%), insomnia (21% to 35%), drowsiness (22% to 27%), dizziness (11% to 15%), nervousness (10% to 12%)

Gastrointestinal: Nausea (34% to 40%), diarrhea (11% to 18%), xerostomia (10% to 14%), anorexia (6% to 14%)

Genitourinary: Ejaculatory disorder (8% to 11%)

Neuromuscular & skeletal: Weakness (14% to 26%)

1% to 10%:

Cardiovascular: Chest pain (3%), palpitations (3%), vasodilation (2% to 3%), hypertension (1% to 2%), edema (≥1%), hypotension (≥1%), syncope (≥1%)

Central nervous system: Pain (10%), anxiety (5% to 8%), anorgasmia (2% to 5%), yawning (2% to 5%), abnormal dreams (3%), abnormality in thinking (3%), paresthesia (3%), agitation (2% to 3%), apathy (≥1% to 3%), central nervous system stimulation (2%), chills (2%), depression (2%), hypertonia (2%), psychoneurosis (2%), twitching (2%), amnesia (≥1%), manic reaction (≥1%), myoclonus (≥1%), psychotic reaction (≥1%), malaise (≤1%)

Dermatologic: Diaphoresis (6% to 7%), ecchymoses (4%), acne vulgaris (2%)

Endocrine & metabolic: Decreased libido (2% to 10%; incidence higher in males), hypermenorrhea (3%), weight loss (≥1% to 2%), weight gain (≥1%)

Gastrointestinal: Dyspepsia (8% to 10%), constipation (4% to 10%), vomiting (5% to 6%), abdominal pain (5%), flatulence (4%), dysgeusia (2% to 3%), dysphagia (2%), gingivitis (2%)

Genitourinary: Urinary frequency (3%), sexual disorder (2% to 3%), impotence (2%), urinary tract infection (2%), urinary retention (1%)

Hepatic: Abnormal hepatic function tests (2%)

Infection: Viral infection (2%)

Neuromuscular & skeletal: Tremor (5% to 8%), myalgia (5%), hyperkinesia (≥1%), hypokinesia (≥1%)

Ophthalmic: Amblyopia (2% to 3%)

Renal: Polyuria (2%)

Respiratory: Upper respiratory tract infection (9%), pharyngitis (6%), flu-like symptoms (3%), laryngitis (3%), bronchitis (2%), dyspnea (2%), epistaxis (2%), increased cough (≥1%), sinusitis (≥1%)

<1% (Limited to important or life-threatening): Acute renal failure, agranulocytosis, akinesia, anaphylaxis, anemia, angina, angioedema, angle-closure glaucoma, anuria, aplastic anemia, apnea, asthma, ataxia, bradycardia, bullous skin disease, cardiac conduction delay, cardiac failure, cardiomyopathy, cardiorespiratory arrest, cerebrovascular accident, cholecystitis, cholelithiasis, colitis, coronary artery disease, decreased white blood cell count, dental caries, dental extraction, diplopia, dyskinesia, dystonia, extrapyramidal reaction, first degree atrioventricular block, gastrointestinal hemorrhage, goiter, hallucination, hematemesis, hematuria, hemoptysis, hepatitis, homicidal ideation, hypercholesterolemia, hyperglycemia, hypersensitivity reaction, hypoglycemia, hypokalemia, hyponatremia, hypothyroidism, IgA vasculitis, interstitial pulmonary disease, intestinal obstruction, jaundice, leukocytosis, leukopenia, loss of consciousness, lymphadenopathy, myasthenia, myocardial infarction, myopathy, neuroleptic malignant syndrome (Stevens 2008), pancreatitis, paralysis, pericarditis, porphyria, prolonged Q-T interval on ECG, purpura, Raynaud's phenomenon (Khouri 2016; Peiró 2007), rhabdomyolysis, seizure, serotonin syndrome, ST segment changes on ECG, Stevens-Johnson syndrome, suicidal tendencies, supraventricular extrasystole, tachycardia, tardive dyskinesia, thrombocytopenia, thromboembolism, tooth abscess, toothache, toxic epidermal necrolysis, vasculitis, ventricular arrhythmia, ventricular tachycardia (including torsades de pointes)

ALERT: U.S. Boxed Warning

Suicidality and antidepressant drugs:

Antidepressants increased the risk compared with placebo of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of fluvoxamine in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults older than 24 years; there was a reduction in risk with antidepressants compared with placebo in adults 65 years and older. Depression and certain other psychiatric disorders are associated with increases in the risk of suicide. Closely observe and appropriately monitor patients of all ages who are started on therapy for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the health care provider. Fluvoxamine immediate release is not approved for use in pediatric patients, except for patients with obsessive-compulsive disorder (OCD). Fluvoxamine extended release (ER) has not been evaluated in pediatric patients.

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Fluvoxamine is FDA approved for the treatment of OCD in children ≥8 years of age.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin or other anticoagulants. Bleeding related to SSRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.

• CNS depression: Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda, 2013; Rizzoli, 2012).

• Impaired glucose control: Impaired glucose control (eg, hyperglycemia, hypoglycemia) has been reported; monitor for signs/symptoms of loss of glucose control particularly in diabetic patients.

• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John’s wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

• Sexual dysfunction: May cause or exacerbate sexual dysfunction.

• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk. Consider discontinuation if symptomatic hyponatremia occurs.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease; fluvoxamine has not been systemically evaluated in patients with a recent history of MI or unstable heart disease.

• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance is decreased and plasma concentrations are increased; a lower dosage may be needed.

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder including details regarding family history of suicide, bipolar disorder, and depression. Fluvoxamine is not FDA approved for the treatment of bipolar depression.

• Seizure disorder: Use with caution in patients with a previous seizure disorder and avoid use with unstable seizure disorder. Discontinue use if seizures occur or if seizure frequency increases.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Smokers: Fluvoxamine levels may be lower in patients who smoke.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA, 2010; Fava, 2006; Haddad, 2001; Shelton, 2001; Warner, 2006).

• Electroconvulsive therapy: risk:benefits of combined therapy with electroconvulsive therapy have not been established.

Monitoring Parameters

Evaluate mental status, suicide ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks or other unusual changes in behavior; signs/symptoms of serotonin syndrome; akathisia; weight and BMI; hepatic function (baseline and as clinically indicated).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Fluvoxamine crosses the human placenta. An increased risk of teratogenic effects, including cardiovascular defects, may be associated with maternal use of fluvoxamine or other SSRIs; however, available information is conflicting. Nonteratogenic effects in the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SSRIs/SNRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. Persistent pulmonary hypertension of the newborn (PPHN) has also been reported with SSRI exposure. The long-term effects of in utero SSRI exposure on infant development and behavior are not known.

The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy.

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, nausea, vomiting, anxiety, dry mouth, fatigue, insomnia, loss of strength and energy, lack of appetite, diarrhea, rhinorrhea, constipation, flatulence, sweating a lot, tremors, or change in taste. Have patient report immediately to prescriber vision changes, eye pain, eye irritation, signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking), signs of low sodium (headache, trouble focusing, memory problems, illogical thinking, weakness, seizures, or change in balance), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), polyuria, sexual dysfunction, loss of libido, seizures, menstrual changes, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, severe diarrhea), or priapism (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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