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Special Alerts
SSRI Use During Pregnancy and Potential Risk of Persistent Pulmonary Hypertension of the Newborn (PPHN)
December 2011
The U.S. Food and Drug Administration (FDA) has issued updated safety information regarding selective serotonin reuptake inhibitor (SSRI) use during pregnancy and the potential risk of persistent pulmonary hypertension of the newborn (PPHN). The FDA has reviewed additional studies evaluating this risk which have shown conflicting results. The FDA has concluded that based on available data, it is unclear whether SSRI use during pregnancy causes PPHN. Updates to product labeling, which will include the additional data and conflicting results, are forthcoming.
The FDA initially released communication regarding this potential risk in July 2006 following the results of a single study which found a sixfold increase of PPHN in neonates born to mothers who received an SSRI at >20 weeks gestation. As a result of the finding, product labeling was updated to include the risk of PPHN and SSRI use in late pregnancy. However, since 2006, additional studies have been published. To date, 2 studies (including the study from 2006) have suggested an increased risk for PPHN due to SSRI use during pregnancy, while 3 studies have not found an association.
The FDA is offering the following recommendations for healthcare professionals:
- At present, healthcare professionals should not alter their current clinical practice of treating depression during pregnancy.
- Healthcare professionals and patients must weigh the small potential risk of PPHN which may be associated with SSRI use during pregnancy against the substantial risks associated with either no treatment or undertreating depression during pregnancy.
- Untreated depression during pregnancy may result in poor birth outcomes (eg, low birth weight, preterm delivery, poor prenatal care).
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm283375.htm.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(floo VOKS a meen)
Generic Available (U.S.)
Yes: Excludes extended release capsule
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088625.pdf, must be dispensed with this medication.
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of obsessive-compulsive disorder (OCD)
Use: Unlabeled/Investigational
Treatment of major depression; panic disorder; anxiety disorders in children; treatment of mild dementia-associated agitation in nonpsychotic patients; post-traumatic stress disorder (PTSD); social anxiety disorder (SAD)
Pregnancy Risk Factor
C
Pregnancy Considerations
Due to adverse effects observed in animal studies, fluvoxamine is classified as pregnancy category C. Fluvoxamine crosses the human placenta. Nonteratogenic effects in the newborn following SSRI 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. An increased risk of low birth weight and low Apgar scores has also been reported. Exposure to SSRIs after the twentieth week of gestation has been associated with persistent pulmonary hypertension of the newborn (PPHN). Adverse effects may be due to toxic effects of the SSRI or drug withdrawal due to discontinuation. The long-term effects of in utero SSRI exposure on infant development and behavior are not known.Women treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued as compared to pregnant women who continue taking antidepressant medications. 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 healthcare provider, and pediatrician. If treatment during pregnancy is required, consider tapering therapy during the third trimester in order to prevent withdrawal symptoms in the infant. If this is done and the woman is considered to be at risk of relapse from her major depressive disorder, the medication can be restarted following delivery, although the dose should be readjusted to that required before pregnancy. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (Yonkers, 2009).
Lactation
Enters breast milk/consider risk:benefit (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Fluvoxamine is excreted in breast milk. Based on case reports, the dose the infant receives is relatively small and adverse events have not been observed. According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
The long-term effects on development and behavior have not been studied; therefore, fluvoxamine should be prescribed to a mother who is breast-feeding only when the benefits outweigh the potential risks.
Contraindications
Hypersensitivity to fluvoxamine or any component of the formulation; concurrent use with alosetron, pimozide, ramelteon, thioridazine, or tizanidine; use with or within 14 days of MAO inhibitors
Warnings/Precautions
Boxed warnings:
• Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• Suicidal thinking/behavior: [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 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 1-2 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; extended release capsules are not FDA approved for use in children.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. 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:
• Anticholinergic effects: Relatively devoid of these side 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.
• Neuroleptic malignant syndrome (NMS): Use with or without concomitant antipsychotic therapy has been rarely associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability (risk may be increased in patients with Parkinson's disease or Lewy body dementia).
• Serotonin syndrome (SS)/neuroleptic malignant syndrome (NMS)-like reactions: SS and NMS-like reactions have occurred with serotonin/norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) when used alone, and particularly when used in combination with serotonergic agents (eg, triptans) or antidopaminergic agents (eg, antipsychotics). The diagnosis of SS can be made using the Hunter Serotonin Toxicity Criteria (Dunkley, 2003). Identification and differentiation of SS (eg, tremor, myoclonus, agitation) and more severe NMS-like reactions (eg, hyperthermia, muscle rigidity, autonomic instability, mental status changes) can be complex; monitor patients closely for either syndrome. Discontinue treatment (and any concomitant serotonergic and/or antidopaminergic agents) 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.
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 worsen psychosis in some patients or 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. Fluvoxamine is not FDA approved for the treatment of bipolar depression.
• Seizure disorder: Use with caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism.
Concurrent drug therapy issues:
• Agents which lower seizure threshold: Use caution with concurrent use of drugs which lower the seizure threshold.
• Alosetron: Fluvoxamine may significantly increase alosetron concentrations; concurrent use contraindicated.
• Anticoagulants/Antiplatelets: Use caution with concomitant use of NSAIDs, ASA, or other drugs that affect coagulation; the risk of bleeding may be potentiated.
• CNS depressants: Use caution with concomitant therapy.
• MAO inhibitors: Potential for severe reaction when used with MAO inhibitors; autonomic instability, coma, death, delirium, diaphoresis, hyperthermia, mental status changes/agitation, muscular rigidity, myoclonus, neuroleptic malignant syndrome features, and seizures may occur. Concurrent use is contraindicated.
• Proserotonergic agents: Symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs (ie, SSRIs/SNRIs or triptans), agents which reduce fluvoxamine's metabolism, or antidopaminergic agents (including antipsychotics). Concurrent use of serotonin precursors (eg, tryptophan) is not recommended.
• Thioridazine and pimozide: Potential for QTc prolongation and arrhythmia; concurrent use of fluvoxamine with either of these agents is contraindicated.
• Tizanidine: Concomitant use may cause a significant decrease in blood pressure and increase in drowsiness; concurrent use is contraindicated.
Special populations:
• Elderly: Use caution in elderly patients; clearance may be decreased and half-life may be increased compared to younger adults. Risk of hyponatremia and other adverse events may be increased.
• Smokers: Fluvoxamine levels may be lower in patients who smoke.
Other warnings/precautions:
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
• Withdrawal syndrome: May cause dysphoric mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Upon discontinuation of fluvoxamine therapy, gradually taper dose. If intolerable symptoms occur following a decrease in dosage or upon discontinuation of therapy, then resuming the previous dose with a more gradual taper should be considered.
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%), somnolence (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: Ejaculation abnormal (8% to 11%)
Neuromuscular & skeletal: Weakness (14% to 26%)
1% to 10%:
Cardiovascular: Chest pain (3%), palpitation (3%), vasodilation (2% to 3%), hypertension (1% to 2%), edema (≤1%), hypotension (≤1%), syncope (≤1%), tachycardia (≤1%)
Central nervous system: Pain (10%), anxiety (5% to 8%), abnormal dreams (3%), abnormal thinking (3%), agitation (2% to 3%), apathy (≥1% to 3%), chills (2%), CNS stimulation (2%), depression (2%), neurosis (2%), amnesia, malaise, manic reaction, psychotic reaction
Dermatologic: Bruising (4%), acne (2%)
Endocrine & metabolic: Libido decreased (2% to 10%; incidence higher in males), anorgasmia (2% to 5%), sexual function abnormal (2% to 4%), menorrhagia (3%)
Gastrointestinal: Dyspepsia (8% to 10%), constipation (4% to 10%), vomiting (4% to 6%), abdominal pain (5%), flatulence (4%), taste perversion (2% to 3%), toothache and dental caries (2% to 3%), dysphagia (2%), gingivitis (2%), weight loss (≤1% to 2%), weight gain
Genitourinary: Polyuria (2% to 3%), impotence (2%), urinary tract infection (2%), urinary retention (1%)
Hepatic: Liver function tests abnormal (≥1% to 2%)
Neuromuscular & skeletal: Tremor (5% to 8%), myalgia (5%), paresthesia (3%), hypertonia (2%), twitching (2%), hyper-/hypokinesia, myoclonus
Ocular: Amblyopia (2% to 3%)
Respiratory: Upper respiratory infection (9%), pharyngitis (6%), yawn (2% to 5%), laryngitis (3%), bronchitis (2%), dyspnea (2%), epistaxis (2%), cough increased, sinusitis
Miscellaneous: Diaphoresis (6% to 7%), flu-like syndrome (3%), viral infection (2%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Activation syndrome, acute renal failure, aggression, agranulocytosis, akinesia, allergic reaction, amenorrhea, anaphylactic reaction, anemia, anger, angina, angioedema, anuria, aplastic anemia, apnea, asthma, ataxia, AV block, blurred vision, bradycardia, bruxism, bullous eruption, cardiomyopathy, cardiorespiratory arrest, cerebrovascular accident, cholecystitis, cholelithiasis, colitis, conduction delay, coronary artery disease, crying, deafness, delirium, diplopia, drunk feeling, dysarthria, dyskinesia, dystonia, extrapyramidal syndrome, embolus, fatigue, fever, gait disturbance, GERD, GI bleeding, glossodynia, goiter, hallucinations, heart failure, hematemesis, hematuria, hemoptysis, Henoch-Schönlein purpura, hepatitis, homicidal ideation, hypercholesterolemia, hyper-/hypoglycemia, hypokalemia, hyponatremia, hypothyroidism, ileus, impulsive behavior, inappropriate antidiuretic hormone secretion, interstitial lung disease, intestinal obstruction, irritability, jaundice, jittery, laryngismus, leukopenia, leukocytosis, lethargy, loss of consciousness, lymphadenopathy, melena, MI, muscle weakness, myasthenia, myopathy, neonatal somnolence, neuralgia, neuroleptic malignant syndrome, neuropathy, pancreatitis, paralysis, Parkinsonism, pericarditis, porphyria, priapism, purpura, QT prolongation, renal impairment, retinal detachment, rhabdomyolysis, serotonin syndrome, ST segment changes, seizure, shock, Stevens-Johnson syndrome, suicidal tendencies, supraventricular extrasystoles, tardive dyskinesia, thrombocytopenia, toxic epidermal necrolysis, vasculitis, ventricular arrhythmia, ventricular tachycardia (including torsade de pointes), white blood cells decreased
Metabolism/Transport Effects
Substrate of CYP1A2 (major), CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (strong), CYP2B6 (weak), CYP2C19 (strong), CYP2C9 (weak), CYP2D6 (weak), CYP3A4 (weak)
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. Risk D: Consider therapy modification
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: 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. Risk D: Consider therapy modification
Alosetron: FluvoxaMINE may decrease the metabolism of Alosetron. Risk X: Avoid combination
Analgesics (Opioid): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
Asenapine: FluvoxaMINE may increase the serum concentration of Asenapine. Risk C: Monitor therapy
Aspirin: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy
Bendamustine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Bendamustine. Concentrations of the active metabolites of bendamustine may be decreased. Risk C: Monitor therapy
Benzodiazepines (metabolized by oxidation): Selective Serotonin Reuptake Inhibitors may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: 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. Risk D: Consider therapy modification
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. Risk C: Monitor therapy
CarBAMazepine: May increase the metabolism of Selective Serotonin Reuptake Inhibitors. Specifically those agents metabolized via CYP1A2, 2C, and/or 3A4 isoenzymes. Selective Serotonin Reuptake Inhibitors may decrease the metabolism of CarBAMazepine. Specifically those SSRIs that inhibit CYP3A4 isoenzymes. Risk D: Consider therapy modification
Cimetidine: May decrease the metabolism of Selective Serotonin Reuptake Inhibitors. Risk D: Consider therapy modification
Clopidogrel: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
CloZAPine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of CloZAPine. Risk D: 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. Risk C: Monitor therapy
Collagenase (Systemic): Antiplatelet Agents may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
CYP1A2 Substrates: CYP1A2 Inhibitors (Strong) may decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
Cyproheptadine: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Desmopressin: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Drotrecogin Alfa (Activated): Antiplatelet Agents may enhance the adverse/toxic effect of Drotrecogin Alfa (Activated). Bleeding may occur. Management: When possible, avoid use of drotrecogin within 7 days of use of any IIb/IIIa antagonists, higher dose aspirin (more than 650 mg/day), or use of other antiplatelet agents. Risk D: Consider therapy modification
DULoxetine: FluvoxaMINE may decrease the metabolism of DULoxetine. Risk C: Monitor therapy
Erlotinib: FluvoxaMINE may increase the serum concentration of Erlotinib. Risk C: Monitor therapy
Fosphenytoin: FluvoxaMINE may increase the serum concentration of Fosphenytoin. Risk C: Monitor therapy
Glucosamine: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: 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. Risk C: Monitor therapy
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Antiplatelet Agents. Bleeding may occur. Risk D: Consider therapy modification
Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Iobenguane I 123: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
Ioflupane I 123: Selective Serotonin Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Risk C: Monitor therapy
Linezolid: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Consider alternatives. When this combination is indicated, closely monitor for signs/symptoms of serotonin toxicity/serotonin syndrome. If such symptoms occur, consider discontinuation of one or both agents. Risk D: Consider therapy modification
Lithium: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy
MAO Inhibitors: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk X: Avoid combination
Methadone: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of Methadone. Fluvoxamine appears to be the only interacting SSRI. Risk D: Consider therapy modification
Methylene Blue: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: 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. Risk D: Consider therapy modification
Mexiletine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of Mexiletine. Risk D: Consider therapy modification
NSAID (COX-2 Inhibitor): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). Risk D: Consider therapy modification
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 an gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Risk D: Consider therapy modification
OLANZapine: FluvoxaMINE may decrease the metabolism of OLANZapine. Risk D: Consider therapy modification
Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Phenytoin: FluvoxaMINE may increase the serum concentration of Phenytoin. Risk C: Monitor therapy
Pimozide: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Pimozide. Risk X: Avoid combination
Propafenone: FluvoxaMINE may increase the serum concentration of Propafenone. Risk C: 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. Risk D: Consider therapy modification
Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
QuiNIDine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of QuiNIDine. Fluvoxamine appears to be the only SSRI of concern. Risk D: Consider therapy modification
Ramelteon: FluvoxaMINE may decrease the metabolism of Ramelteon. Risk X: Avoid combination
Rivaroxaban: Antiplatelet Agents may enhance the anticoagulant effect of Rivaroxaban. Management: Avoid concurrent use of clopidogrel with rivaroxaban unless the anticipated benefits outweigh the risks of bleeding. Avoid concurrent use of rivaroxaban with other antiplatelet agents whenever possible. Risk D: Consider therapy modification
Roflumilast: FluvoxaMINE may increase serum concentrations of the active metabolite(s) of Roflumilast. FluvoxaMINE may increase the serum concentration of Roflumilast. Risk C: Monitor therapy
Ropivacaine: FluvoxaMINE may decrease the metabolism of Ropivacaine. Risk C: Monitor therapy
Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Theophylline Derivatives: FluvoxaMINE may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Risk D: Consider therapy modification
Thioridazine: FluvoxaMINE may increase the serum concentration of Thioridazine. Risk X: Avoid combination
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
TiZANidine: FluvoxaMINE may decrease the metabolism of TiZANidine. Risk X: Avoid combination
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy
TraMADol: Selective Serotonin Reuptake Inhibitors may enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. TraMADol may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk D: Consider therapy modification
Tricyclic Antidepressants: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Tryptophan: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk X: Avoid combination
Vitamin E: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Selective Serotonin Reuptake Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: The bioavailability of melatonin has been reported to be increased by fluvoxamine.
Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation). Avoid alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, celery, chamomile, coleus, cordyceps, dong quai, evening primrose, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng (American), ginseng (Panax), ginseng (Siberian), grape seed, green tea, guggul, horse chestnuts, horseradish, licorice, prickly ash, red clover, reishi, SAMe (S-adenosylmethionine), sweet clover, turmeric, white willow (all have additional antiplatelet activity).
Storage
Protect from high humidity and store at controlled room temperature 25°C (77°F).
Mechanism of Action
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
Pharmacodynamics/Kinetics
Onset of action: Depression: The onset of action is within a week; however, individual response varies greatly and full response may not be seen until 8-12 weeks after initiation of treatment.
Absorption: Steady-state plasma concentrations have been noted to be 2-3 times higher in children than those in adolescents; female children demonstrated a significantly higher AUC than males
Distribution: Vd: ~25 L/kg
Protein binding: ~80%, primarily to albumin
Metabolism: Extensively hepatic via oxidative demethylation and deamination
Bioavailability: Immediate release: 53%; not significantly affected by food
Half-life elimination: 15-16 hours; 17-26 hours in the elderly
Time to peak, plasma: 3-8 hours
Excretion: Urine (~85% as metabolites; ~2% as unchanged drug)
Dosage
Oral:
Obsessive-compulsive disorder:
Children 8-17 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: 50-200 mg/day. Note: When total daily dose exceeds 50 mg, the dose should be given in 2 divided doses with larger portion administered at bedtime.
Maximum: Children: 8-11 years: 200 mg/day, adolescents: 300 mg/day; lower doses may be effective in female versus male patients
Adults:
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: 100-300 mg/day; maximum dose: 300 mg/day. Note: When total daily dose exceeds 100 mg, the dose should be given in 2 divided doses with larger portion administered at bedtime.
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: 100-300 mg/day; maximum dose: 300 mg/day
Social anxiety disorder (unlabeled use): Adults: 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: 100-300 mg/day; maximum dose: 300 mg/day (Davidson, 2004; Stein, 2003; Westenberg, 2004)
Post-traumatic stress disorder (PTSD) (unlabeled use): Adults: Immediate release: 75 mg twice daily (Spivak, 2006)
Elderly: Reduce dose, titrate slowly
Dosage adjustment in hepatic impairment: Reduce dose, titrate slowly
Administration: Oral
May be administered with or without food. Do not crush, open, or chew extended release capsules.
Monitoring Parameters
Mental status for depression, suicide ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; akathisia, weight gain or loss, nutritional intake, sleep; liver function assessment prior to beginning drug therapy
Dietary Considerations
May be taken with or without food.
Patient Education
It may take 2-3 weeks to achieve desired results. Avoid alcohol. Maintain adequate hydration, unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, weakness, blurred vision, nausea, vomiting, dry mouth, anorexia, diarrhea, postural hypotension, or decreased sexual function or libido (reversible). Report persistent CNS effects (insomnia, anxiety, suicide ideation, sedation, seizures, mania, abnormal thinking); rash; tremors; chest pain or palpitations; or worsening of condition.
Geriatric Considerations
Given fluvoxamine's approved indication (OCD), the number of drug interactions, and the limited information available on its use in the elderly, it may be best to select a different agent when treating depression. The elderly are more prone to SSRI/SNRI-induced hyponatremia.
A systematic review and meta-analysis of antidepressant placebo-controlled trials in persons with depression and dementia found evidence "suggestive" of efficacy but not of sufficient strength to "confirm" efficacy. Antidepressant trials in this patient population are small and underpowered. Older patients with depression being treated with an antidepressant should be closely monitored for response and adverse effects. Treatment should be switched or augmented when response is inadequate with a therapeutic dose. Antidepressants that are not tolerated should be discontinued and an alternative agent should be started.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and abnormal taste. Problems with SSRI-induced bruxism have been reported and may preclude their use; clinicians attempting to evaluate any patient with bruxism or involuntary muscle movement, who is simultaneously being treated with an SSRI drug, should be aware of the potential association. See Effects on Bleeding and Dental Health Professional Considerations.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Although caution should be used in patients taking tricyclic antidepressants, no interactions have been reported with vasoconstrictors and fluvoxamine, a nontricyclic antidepressant which acts to increase serotonin; no precautions appear to be needed
Dental Comment
Problems with SSRI-induced bruxism have been reported and may preclude their use. Clinicians attempting to evaluate any patient with bruxism or involuntary muscle movement, who is simultaneously being treated with an SSRI drug, should be aware of the potential association.
Mental Health: Child/Adolescent Considerations
Children 8-17 years of age with obsessive-compulsive disorder (OCD) received 50-200 mg/day for 10 weeks (Riddle, 2001). One hundred twenty-eight children 6-17 years of age with social phobia, separation anxiety disorder, or generalized anxiety disorder, who had received psychological treatment for 3 weeks without improvement, received fluvoxamine up to 300 mg/day for 8 weeks (Research Unit, 2001).
“Fluvoxamine for the Treatment of Anxiety Disorders in Children and Adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group,” N Engl J Med, 2001, 344(17):1279-85.
Riddle MA, Reeve EA, Yaryura-Tobias JA, et al, “Fluvoxamine for Children and Adolescents With Obsessive-Compulsive Disorder: A Randomized, Controlled, Multicenter Trial,” J Am Acad Child Adolesc Psychiatry, 2001, 40(2):222-9.
Mental Health: Comment
The SSRIs as a class are generally considered to be safe and equally effective. Allow sufficient dose-response time (6-12 weeks). Differences lie in approved indications, receptor profiles, pharmacokinetics, and cytochrome P450 activity profile. Subtle differences exist in adverse effect profiles. All SSRIs have the potential to cause sexual dysfunction. Fluvoxamine is only approved in U.S. for obsessive-compulsive disorder (OCD), offers no advantage over other SSRIs, and is associated with significant CYP inhibitory properties.
Nursing: Physical Assessment/Monitoring
Taper dosage slowly when discontinuing. Assess mental status for depression, signs of clinical worsening, suicide ideation, anxiety, social functioning, mania, or panic attack.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, extended release, oral, as maleate:
Luvox® CR: 100 mg, 150 mg [gluten free]
Tablet, oral, as maleate: 25 mg, 50 mg, 100 mg
Pricing: U.S. (www.drugstore.com)
Capsule, 24-hour (Luvox CR)
100 mg (30): $254.80
150 mg (30): $272.08
Tablets (Fluvoxamine Maleate)
25 mg (30): $53.99
50 mg (30): $59.99
100 mg (50): $109.99
References
American Academy of Pediatrics Committee on Drugs, “Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.
American College of Obstetricians and Gynecologists, ACOG Practice Bulletin: Clinical Management Guidelines for Obstetricians-Gynecologists No. 92 April 2008 (Replaces Practice Bulletin Number 87, November 2007), “Use of Psychiatric Medications During Pregnancy and Lactation,” Obstet Gynecol, 2008, 111(4):1001-20.
Bandelow B, Zohar J, Hollander E, et al, “World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders -- First Revision,” World J Biol Psychiatry, 2008, 9(4): 248-312. Available at http://www.wfsbp.org/fileadmin/pdf/guides/Guidelines_Anxiety_revision.pdf
Benedek DM, Friedman MJ, Zatzick D, et al, “Guideline Watch (March 2009): Practice Guideline for the Treatment of Patients With Acute Stress Disorder and Posttraumatic Stress Disorder.” Available at http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AcuteStressDisorder-PTSD_GuidelineWatch
Boyer EW and Shannon M, “The Serotonin Syndrome,” N Engl J Med, 2005, 352:1112-20.
Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al, “Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn,” N Engl J Med, 2006, 354(6):579-87.
Davidson J, Yaryura-Tobias J, DuPont R, et al, "Fluvoxamine-Controlled Release Formulation for the Treatment of Generalized Social Anxiety Disorder," J Clin Psychopharmacol, 2004, 24(2):118-25.
De Vries MH, Raghoebar M, Mathlener IS, et al, “Single and Multiple Oral Dose Fluvoxamine Kinetics in Young and Elderly Subjects,” Ther Drug Monit, 1992, 14(6):493-8.
Dunkley EJ, Isbister GK, Sibbritt D, et al, “The Hunter Serotonin Toxicity Criteria: Simple and Accurate Diagnostic Decision Rules for Serotonin Toxicity,” QJM, 2003, 96(9):635-42.
“Fluvoxamine for the Treatment of Anxiety Disorders in Children and Adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group,” N Engl J Med, 2001, 344(17):1279-85.
Grimsley SR and Jann MW, “Paroxetine, Sertraline, and Fluvoxamine: New Selective Serotonin Reuptake Inhibitors,” Clin Pharm, 1992, 11(11):930-57.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Nelson JC and Devanand DP, "A Systematic Review and Meta-Analysis of Placebo-Controlled Antidepressant Studies in People With Depression and Dementia," J Am Geriatr Soc, 2011, 59(4):577-85.
Pass SE and Simpson RW, “Discontinuation and Reinstitution of Medications During the Perioperative Period,” Am J Health Syst Pharm, 2004, 61(9):899-912.
Rabins PV, Blacker D, Rovner BW, et al, “Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias,” October, 2007. Available at http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm
Riddle MA, Reeve EA, Yaryura-Tobias JA, et al, “Fluvoxamine for Children and Adolescents With Obsessive-Compulsive Disorder: A Randomized, Controlled, Multicenter Trial,” J Am Acad Child Adolesc Psychiatry, 2001, 40(2):222-9.
Roose SP, Glassman AH, Attia E, et al, “Comparative Efficacy of Selective Serotonin Reuptake Inhibitors and Tricyclics in the Treatment of Melancholia,” Am J Psychiatry, 1994, 151(12):1735-9.
Spivak B, Strous RD, Shaked G, et al., “Reboxetine Versus Fluvoxamine in the Treatment of Motor Vehicle Accident-Related Posttraumatic Stress Disorder: A Double-blind, Fixed-Dosage, Controlled Trial,” J Clin Psychopharmacol, 2006, 26(2):153-6.
Stein DJ, Westenberg HG, Yang H, et al, "Fluvoxamine CR in the Long-Term Treatment of Social Anxiety Disorder: The 12- to 24-Week Extension Phase of a Multicentre, Randomized, Placebo-Controlled Trial," Int J Neuropsychopharmacol, 2003, 6(4):317-23.
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Yonkers KA, Wisner KL, Stewart DE, et al, “The Management of Depression During Pregnancy: A Report From the American Psychiatric Association and the American College of Obstetricians and Gynecologists,” Obstet Gynecol, 2009, 114(3):703-13.
Westenberg HG, Stein DJ, Yang H, et al, "A Double-Blind Placebo-Controlled Study of Controlled Release Fluvoxamine for the Treatment of Generalized Social Anxiety Disorder," J Clin Psychopharmacol, 2004, 24(1):49-55.
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International Brand Names
Lexi-Comp.com
Last full review/revision December 2011
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