Fluvoxamine maleate extended-release capsules are a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of obsessive compulsive disorder (OCD) ( 1 ). Efficacy was demonstrated in: One 12-week study with fluvoxamine maleate extended-release capsules in adults ( 14.1 ). Two 10-week studies with immediate-release (IR) fluvoxamine tablets in adults and one 10-week study with IR fluvoxamine tablets in children and adolescents ( 14.1 , 14.3 ).
One maintenance study with IR fluvoxamine tablets ( 14.2 ).
1.1Obsessive Compulsive Disorder
Fluvoxamine maleate extended-release capsules are indicated for the treatment of obsessive compulsive disorder (OCD), as defined in the DSM-IV. Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.
The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of fluvoxamine maleate extended-release capsules was demonstrated in one 12-week trial in adults with fluvoxamine maleate extended-release capsules as well as in two 10-week trials in adults and in one 10-week trial in children and adolescents (ages 8 to 17 years) with immediate-release fluvoxamine tablets in outpatients with the diagnosis of OCD as defined in DSM-IV or DSM-III-R (see Clinical Studies [14.1 , 14.3] ) .
The efficacy of fluvoxamine for long-term use was established in one maintenance study in adults with immediate-release fluvoxamine tablets (see Clinical Studies [14. 2 ] ) . The health care provider who elects to prescribe fluvoxamine maleate extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Dosage and Administration [2.4] ) .
Contraindications
Coadministration of thioridazine, tizanidine, pimozide, alosetron, or ramelteon with fluvoxamine maleate extended-release capsules is contraindicated (see Warnings and Precautions [5.4 to 5.8] ) . Coadministration of thioridazine, tizanidine, pimozide, alosetron, or ramelteon ( 4 ). Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with fluvoxamine maleate extended-release capsules or within 14 days of stopping treatment with fluvoxamine maleate extended-release capsules.
Two medicines in one question?
Name two or more medicines and Osler runs an interaction check. A severe interaction is stated at the very top of the answer.
Do not use fluvoxamine maleate extended-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluvoxamine maleate extended-release capsules in a patient who is being treated with linezolid or intravenous methylene blue ( 4.1 ).
4.1Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with fluvoxamine maleate extended-release capsules or within 14 days of stopping treatment with fluvoxamine maleate extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of fluvoxamine maleate extended-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see Dosage and Administration [2.5] and Warnings and Precautions [5.2] ) .
Starting fluvoxamine maleate extended-release capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see Dosage and Administration [2.6] and Warnings and Precautions [5.2] ) .
Warnings and precautions
Clinical Worsening/Suicide Risk: Monitor for clinical worsening of suicidal thoughts/behaviors especially during the initial months of therapy and at times of dose changes ( 5.1 ). Bipolar Disorder: Screen for bipolar disorder ( 5.1 ). Serotonin Syndrome : Serotonin syndrome has been reported with SSRIs and SNRIs, including fluvoxamine maleate extended-release capsules, both when taken alone, but especially when coadministered with other serotonergic agents.
If such symptoms occur, discontinue fluvoxamine maleate extended-release capsules and serotonergic agents and initiate supportive treatment. If concomitant use of fluvoxamine maleate extended-release capsules with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 5.2 ). Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.3 ) .
Other Potentially Important Drug Interactions: Benzodiazepines: Use with caution. Coadministration with diazepam is generally not advisable ( 5.9 ). Clozapine: Clozapine levels may be increased and produce orthostatic hypotension or seizures ( 5.9 ). Methadone: Coadministration may produce opioid intoxication. Discontinuation of fluvoxamine may produce opioid withdrawal ( 5.9 ). Mexiletine: Monitor serum mexiletine levels ( 5.9 ).
Theophylline: Clearance decreased; reduce theophylline dose by one-third ( 5.9 ). Warfarin: Plasma concentrations increased and prothrombin times prolonged; monitor prothrombin time and adjust warfarin dose accordingly ( 5.9 ). Discontinuation: Symptoms associated with discontinuation have been reported ( 5.10 ). In the absence of an emergency, abrupt discontinuation not recommended ( 2.7 , 5.2 ). Abnormal Bleeding: May increase bleeding risk, especially when used with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation ( 5.11 ).
Activation of Mania/Hypomania has occurred ( 5.12 ). Seizures: Avoid administering fluvoxamine in patients with unstable epilepsy; monitor patients with controlled epilepsy; discontinue treatment if seizures occur or frequency increases ( 5.13 ). Hyponatremia: May occur with SSRIs and SNRIs, including fluvoxamine maleate extended-release capsules. The elderly may be at increased risk. Consider discontinuing in patients with symptomatic hyponatremia ( 5.14 ).
Concomitant Illness: Use caution in patients with diseases or conditions that affect hemodynamic responses or metabolism. Patients with impaired liver function may require a lower starting dose and slower titration ( 5.15 ). Sexual Dysfunction: Fluvoxamine may cause symptoms of sexual dysfunction ( 5.17 ).
5.1Clinical Worsening and Suicide Risk Patients
with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. The pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults age 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1: Drug-Placebo Differences in Number of Cases of Suicidality Per 1,000 Patients Treated Age Range Drug-Related Increases <18 14 additional cases 18 to 24 5 additional cases Age Range Drug-Related Decreases 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see Dosage and Administration–Discontinuation of Treatment with Fluvoxamine Maleate Extended-Release Capsules [2.7] , for a description of the risks of discontinuation of fluvoxamine maleate extended-release capsules).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
Drug Interactions (not described in Contraindications or Warnings and Precautions) include the following: Drugs Inhibiting or Metabolized by Cytochrome P450: Fluvoxamine inhibits several cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP3A4, and CYP2C19) ( 7.1 ). Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity with coadministration ( 7.2 ). Sumatriptan: Rare postmarketing reports of weakness, hyperreflexia, and incoordination following use of an SSRI and sumatriptan.
Monitor appropriately if concomitant treatment is clinically warranted ( 7.2 ). Tacrine: Coadministration increased tacrine C max and AUC five- and eight-fold and caused nausea, vomiting, sweating, and diarrhea ( 7.2 ). Tricyclic Antidepressants (TCAs): Coadministration significantly increased plasma TCA levels. Use caution; monitor plasma TCA levels; reduce TCA dose if indicated ( 7.2 ). Tryptophan: Severe vomiting with coadministration ( 7.2 ).
Diltiazem: Bradycardia with coadministration ( 7.3 ). Propranolol or Metoprolol: Reduce dose if coadministered with fluvoxamine and titrate more cautiously ( 7.3 ).
7.1 Potential Interactions with Drugs that Inhibit or are Metabolized by Cytochrome P450 Isoenzymes Multiple hepatic cytochrome P450 isoenzymes are involved in the oxidative biotransformation of a large number of structurally different drugs and endogenous compounds. The available knowledge concerning the relationship of fluvoxamine and the cytochrome P450 isoenzyme system has been obtained mostly from pharmacokinetic interaction studies conducted in healthy volunteers, but some preliminary in vitro data are also available.
Based on a finding of substantial interactions of fluvoxamine with certain of these drugs (see later parts of this section and also Warnings and Precautions [5] for details) and limited in vitro data for CYP3A4, it appears that fluvoxamine inhibits several cytochrome P450 isoenzymes that are known to be involved in the metabolism of other drugs such as: CYP1A2 (e.g., warfarin, theophylline, propranolol, tizanidine), CYP2C9 (e.g., warfarin), CYP3A4 (e.g., alprazolam), and CYP2C19 (e.g., omeprazole).
In vitro data suggest that fluvoxamine is a relatively weak inhibitor of CYP2D6. Approximately 7% of the normal population has a genetic code that leads to reduced levels of activity of CYP2D6 enzyme. Such individuals have been referred to as “poor metabolizers” (PM) of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants. While none of the drugs studied for drug interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study of fluvoxamine single-dose pharmacokinetics in 13 PM subjects demonstrated altered pharmacokinetic properties compared to 16 “extensive metabolizers” (EM): mean C max , AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group.
This suggests that fluvoxamine is metabolized, at least in part, by CYP2D6. Caution is indicated in patients known to have reduced levels of cytochrome P450 2D6 activity and those receiving concomitant drugs known to inhibit this cytochrome P450 isoenzyme (e.g., quinidine). The metabolism of fluvoxamine has not been fully characterized and the effects of potent cytochrome P450 isoenzyme inhibition, such as the ketoconazole inhibition of CYP3A4, on fluvoxamine metabolism have not been studied.
A clinically significant fluvoxamine interaction is possible with drugs having a narrow therapeutic ratio such as pimozide, warfarin, theophylline, certain benzodiazepines, omeprazole, and phenytoin. If fluvoxamine maleate extended-release capsules are to be administered together with a drug that is eliminated via oxidative metabolism and has a narrow therapeutic window, plasma levels and/or pharmacodynamic effects of the latter drug should be monitored closely, at least until steady-state conditions are reached (see Contraindications [4] and Warnings and Precautions [5]) .
7.2CNS Active Drugs Antipsychotics: See Warnings and Precautions
(5.2) . Benzodiazepines: See Warnings and Precautions (5.9) . Alprazolam: See Warnings and Precautions (5.9) . Diazepam: See Warnings and Precautions (5.9) . Lorazepam: A study of multiple doses of immediate-release fluvoxamine maleate tablets (50 mg given twice daily) in healthy male volunteers (N=12) and a single dose of lorazepam (4 mg single dose) indicated no significant pharmacokinetic interaction. On average, both lorazepam alone and lorazepam with fluvoxamine produced substantial decrements in cognitive functioning; however, the coadministration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone.
Alcohol: Studies involving single 40 g doses of ethanol (oral administration in one study and intravenous in the other) and multiple dosing with immediate-release fluvoxamine maleate tablets (50 mg given twice daily) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other. As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate extended-release capsules.
Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and carbamazepine. Clozapine: See Warnings and Precautions (5.9) . Lithium: As with other serotonergic drugs, lithium may enhance the serotonergic effects of fluvoxamine and, therefore, the combination should be used with caution. Seizures have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and lithium.
Methadone: See Warnings and Precautions (5.9) . Monoamine Oxidase Inhibitors: See Contraindications (4.1) and Warnings and Precautions (5.2) . Pimozide: See Contraindications (4) and Warnings and Precautions (5.6) . Ramelteon: See Contraindications (4) and Warnings and Precautions (5.8) . Serotonergic Drugs: See Warnings and Precautions (5.2) . Tacrine: In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to immediate-release fluvoxamine maleate tablets 100 mg/day administered at steady-state was associated with 5- and 8-fold increases in tacrine C max and AUC, respectively, compared to the administration of tacrine alone.
Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine. Thioridazine: See Contraindications (4) and Warnings and Precautions (5.4) . Tizanidine: See Contraindications (4) and Warnings and Precautions (5.5) . Tricyclic Antidepressants (TCAs): Significantly increased plasma TCA levels have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and amitriptyline, clomipramine or imipramine.
Caution is indicated with the coadministration of fluvoxamine maleate extended-release capsules and TCAs; plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced. Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluvoxamine maleate extended-release capsules with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Warnings and Precautions [5.2] ) .
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Adverse reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Most common reactions in controlled trials with OCD patients and patients from another studied population (incidence greater than or equal to 5% and at least twice that for placebo) were abnormal ejaculation, anorexia, anorgasmia, asthenia, diarrhea, nausea, somnolence, sweating and tremor ( 6.2 ).
The following additional reactions occurred: anxiety, decreased libido, myalgia, pharyngitis, and vomiting in the OCD population; and dyspepsia, dizziness, insomnia, and yawning in another studied population. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trial Data Sources
Fluvoxamine maleate extended-release capsules were studied in one 12-week controlled trial in patients with OCD (N = 124; mean exposure 66.6 days) and in two 12-week controlled trials for another condition (N = 279; mean exposure 59.2 days). Patients in these trials were initiated on 100 mg/day and were titrated in 50 mg increments over the first 6 weeks to within a range of 100 mg to 300 mg/day. The reactions listed in Table 2 show reactions from the two populations separately.
Table 3 shows reactions from the three controlled studies combined.
6.2 Adverse Reactions Observed in Controlled Trials Adverse Reactions Associated with Discontinuation of Treatment: Of the 124 patients with OCD and 279 patients in other studies treated with fluvoxamine maleate extended-release capsules in controlled clinical trials, 19% and 26% discontinued treatment due to an adverse reaction. The most common reactions (greater than or equal to 1%) associated with discontinuation and considered to be drug related (i.e., those reactions associated with dropout at a rate at least twice that of placebo) were anorexia (including, but not limited to, loss of appetite and decreased appetite) ( 1%), anxiety (3%), asthenia (3%), diarrhea (2%), dizziness (4%), headache (2%), insomnia (5%), nausea (7%), nervousness (1%), somnolence (5%), and thinking abnormal (1%).
Commonly Observed Adverse Reactions: Fluvoxamine maleate extended-release capsules have been studied in one controlled trial in patients with OCD (N = 124) and two controlled trials for another condition (N = 279). In general, adverse reaction rates were similar in the two data sets as well as in a study of pediatric patients with OCD treated with immediate-release fluvoxamine maleate tablets. The most commonly observed treatment-emergent adverse reactions associated with the use of fluvoxamine maleate extended-release capsules and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) and derived from Table 2 were: abnormal ejaculation, anorexia, anorgasmia, asthenia, diarrhea, nausea, somnolence, sweating, and tremor .
In the one controlled trial in patients with OCD, the following additional reactions occurred at an incidence of 5% or greater and at least twice that for placebo: anxiety, decreased libido, myalgia, pharyngitis, and vomiting . The following additional reactions occurred in another studied population: dyspepsia, dizziness, insomnia, and yawning . In a study evaluating immediate-release fluvoxamine maleate tablets in pediatric patients with OCD, the following additional reactions were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash .
Adverse Reactions Occurring at an Incidence of Greater Than or Equal To 2%: Table 2 enumerates adverse reactions that occurred in adults at a frequency of 2% or more, and were more frequent than in the placebo group, among patients treated with fluvoxamine maleate extended-release capsules in two short-term, placebo-controlled trials (12 weeks) in another population and one short-term placebo-controlled OCD trial (12 weeks) and in which patients were dosed once-a-day in a range of 100 to 300 mg/day.
This table shows the percentage of patients in each group who had at least one occurrence of a reaction at some time during their treatment. Reported adverse reactions were classified using a COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors may differ from those that prevailed in the clinical trials.
Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing health care provider with some basis for estimating the relative contribution of drug and non-drug factors to the side-effect incidence rate in the population studied. Table 2: Treatment-Emergent Adverse Reaction Incidence Rates by Body System in Adult OCD Patients and Another Studied Population 1 PERCENTAGE OF PATIENTS REPORTING REACTION OBSESSIVE COMPULSIVE DISORDER OTHER STUDIED POPULATION BODY SYSTEM/ FLUVOXAMINE MALEATE FLUVOXAMINE MALEATE EXTENDED-RELEASE PLACEBO EXTENDED-RELEASE PLACEBO ADVERSE REACTION N = 124 N = 124 N = 279 N = 276 1 Events for which fluvoxamine maleate incidence was equal to or less than placebo include the following for OCD patients: abdominal pain, flu syndrome, infection, palpitation, flatulence, increased appetite, weight gain, abnormal dreams, amnesia, hypertonia, nervousness, paresthesia, increased cough, dyspnea, rhinitis, and ear pain.
In the other studied population the following events were seen: abdominal pain, accidental injury, back pain, flu syndrome, infection, pain, flatulence, pharyngitis, rhinitis, rash, and dysmenorrhea. 2 Term includes body aches/pains, dental pain, pain from surgery, unspecified pain, and general pain secondary to injuries (sprains, fractures). 3 Includes, but is not limited to, loss of appetite and decreased appetite.
6.3Other Adverse Reactions in OCD Pediatric Population
In pediatric patients (N=57) treated with immediate-release fluvoxamine maleate tablets, the overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions, not appearing in Table 2, were reported in two or more of the pediatric patients and were mo
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
FLUVOXAMINE MALEATE 150MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
Sumatriptan -There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised. Tryptophan: Tryptophan may enhance the serotonergic effects of fluvoxamine, and the combination should, therefore, be used with caution.
