Dosage Form: tablet
FULL PRESCRIBING INFORMATION
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Fluvoxamine Maleate Tablets or any other antidepressant 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 to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Fluvoxamine Maleate Tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See WARNINGS AND PRECAUTIONS-Clinical Worsening and Suicide Risk [5.1].)
Indications and Usage for Fluvoxamine
Obsessive-Compulsive Disorder
Fluvoxamine Maleate Tablets, USP are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in DSM-III-R or DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.
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 efficacy of Fluvoxamine Maleate Tablets, USP was established in three trials in outpatients with OCD: two 10-week trials in adults, one 10-week trial in pediatric patients (ages 8-17). (See CLINICAL STUDIES [14].)
Fluvoxamine Dosage and Administration
Adults
The recommended starting dose for Fluvoxamine Maleate Tablets in adult patients is 50 mg, administered as a single daily dose at bedtime. In the controlled clinical trials establishing the effectiveness of Fluvoxamine Maleate Tablets in OCD, patients were titrated within a dose range of 100 to 300 mg/day. Consequently, the dose should be increased in 50 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day. It is advisable that a total daily dose of more than 100 mg should be given in two divided doses. If the doses are not equal, the larger dose should be given at bedtime.
Pediatric Population (children and adolescents)
The recommended starting dose for Fluvoxamine Maleate Tablets in pediatric populations (ages 8-17 years) is 25 mg, administered as a single daily dose at bedtime. In a controlled clinical trial establishing the effectiveness of Fluvoxamine Maleate Tablets in OCD, pediatric patients (ages 8-17) were titrated within a dose range of 50 to 200 mg/day. Physicians should consider age and gender differences when dosing pediatric patients. The maximum dose in children up to age 11 should not exceed 200 mg/day. Therapeutic effect in female children may be achieved with lower doses. Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. The dose should be increased in 25 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved. It is advisable that a total daily dose of more then 50 mg should be given in two divided doses. If the two divided doses are not equal, the larger dose should be given at bedtime.
Elderly or Hepatically Impaired Patients
Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of Fluvoxamine maleate. Consequently, it may be appropriate to modify the initial dose and the subsequent dose titration for these patient groups.
Pregnant Women During the Third Trimester
Neonates exposed to Fluvoxamine Maleate Tablets and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding and may be at risk for persistent pulmonary hypertension of the newborn (PPHN). (See USE IN SPECIFIC POPULATIONS [8.1].) When treating pregnant women with Fluvoxamine Maleate Tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Fluvoxamine Maleate Tablets in the third trimester.
Switching Patients To or From a Monoamine Oxidase Inhibitor
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Fluvoxamine Maleate Tablets. Similarly, at least 14 days should be allowed after stopping Fluvoxamine Maleate Tablets before starting an MAOI.
Discontinuation of Treatment with Fluvoxamine Maleate Tablets
Symptoms associated with discontinuation of other SSRIs or SNRIs have been reported. (See WARNINGS AND PRECAUTIONS [5.9].) Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
Dosage Forms and Strengths
Fluvoxamine Maleate Tablets, USP are available as:
Tablets 25 mg: oval, beige, biconvex film-coated tablets with “357” debossed on one side and plain on the other side
Tablets 50 mg: oval, yellow, biconvex film-coated tablets with “361” debossed on one side and scored on the other side
Tablets 100 mg: oval, red, biconvex film-coated tablets with “362” debossed on one side and scored on the other side
Contraindications
Coadministration of tizanidine, thioridazine, alosetron, or pimozide with Fluvoxamine Maleate Tablets is contraindicated. (See WARNINGS AND PRECAUTIONS [5.4-5.7].)
The use of MAOIs concomitantly with or within 14 days of treatment with Fluvoxamine Maleate Tablets is contraindicated. (See WARNINGS AND PRECAUTIONS [5.2].)
Warnings and Precautions
Clinical 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. 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 18-24) 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 aged 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 1000 patients treated) are provided in Table 1.
| Age Range | Increases Compared to Placebo |
|---|---|
| <18 | 14 ADDITIONAL CASES |
| 18-24 | 5 ADDITIONAL CASES |
| Age Range | Decreases Compared to Placebo |
| 25-64 | 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 Tablets [5.9], for a description of the risks of discontinuation of Fluvoxamine Maleate Tablets).
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 immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Fluvoxamine Maleate Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Fluvoxamine Maleate Tablets are not approved for use in treating bipolar depression.
Potential for Monoamine Oxidase Inhibitors Interaction
In patients receiving another serotonin reuptake inhibitor drug in combination with monoamine oxidase inhibitors (MAOIs), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have discontinued that drug and have been started on an MAOI. Some cases presented with features resembling a serotonin syndrome or neuroleptic malignant syndrome.
Therefore, Fluvoxamine Maleate Tablets should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping Fluvoxamine Maleate Tablets before starting an MAOI. (See DOSAGE AND ADMINISTRATION [2.5] and CONTRAINDICATIONS [4].)
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Fluvoxamine Maleate Tablets treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of Fluvoxamine Maleate Tablets with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Fluvoxamine Maleate Tablets with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of Fluvoxamine Maleate Tablets with serotonin precursors (such as tryptophan) is not recommended.
Treatment with Fluvoxamine Maleate Tablets and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Potential Thioridazine Interaction
The effect of Fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased threefold following coadministration of Fluvoxamine.
Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of Fluvoxamine may be even more pronounced when it is administered at higher doses.
Therefore, Fluvoxamine and thioridazine should not be coadministered. (See CONTRAINDICATIONS [4].)
Potential Tizanidine Interaction
Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of Fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in 10 healthy male subjects. Tizanidine Cmax was increased approximately 12-fold (range 5-fold to 32-fold), elimination half-life was increased by almost 3-fold, and AUC increased 33-fold (range 14-fold to 103-fold). The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on the psychomotor task was significantly impaired. Fluvoxamine and tizanidine should not be used together. (See CONTRAINDICATIONS [4].)
Potential Pimozide Interaction
Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug. An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, a substantial pharmacokinetic interaction has been observed for Fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by CYP3A4. Although it has not been definitively demonstrated that Fluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of Fluvoxamine with alprazolam. Consequently, it is recommended that Fluvoxamine not be used in combination with pimozide. (See CONTRAINDICATIONS [4].)
Potential Alosetron Interaction
Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received Fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. (See CONTRAINDICATIONS [4] and LotronexTM (alosetron) package insert.)
Other Potentially Important Drug Interactions
Benzodiazepines: Benzodiazepines metabolized by hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used with caution because the clearance of these drugs is likely to be reduced by Fluvoxamine. The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by Fluvoxamine.
Alprazolam -When Fluvoxamine maleate (100 mg q.d.) and alprazolam (1 mg q.i.d.) were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, Cmax, T1/2) of alprazolam were approximately twice those observed when alprazolam was administered alone; oral clearance was reduced by about 50%. The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory. This interaction, which has not been investigated using higher doses of Fluvoxamine, may be more pronounced if a 300 mg daily dose is coadministered, particularly since Fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100-300 mg. If alprazolam is coadministered with Fluvoxamine Maleate Tablets, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for Fluvoxamine Maleate Tablets.
Diazepam - The coadministration of Fluvoxamine Maleate Tablets and diazepam is generally not advisable. Because Fluvoxamine reduces the clearance of both diazepam and its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration.
Evidence supporting the conclusion that it is inadvisable to coadminister Fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of Fluvoxamine were administered a single oral dose of 10 mg of diazepam. In these subjects (N=8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the 2 week long study.
It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration. Moreover, as noted with alprazolam, the effect of Fluvoxamine may even be more pronounced when it is administered at higher doses.
Accordingly, diazepam and Fluvoxamine should not ordinarily be coadministered.
Clozapine: Elevated serum levels of clozapine have been reported in patients taking Fluvoxamine maleate and clozapine. Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse events may be higher when Fluvoxamine and clozapine are coadministered. Patients should be closely monitored when Fluvoxamine maleate and clozapine are used concurrently.
Methadone: Significantly increased methadone (plasma level:dose) ratios have been reported when Fluvoxamine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Opioid withdrawal symptoms were reported following Fluvoxamine maleate discontinuation in another patient.
Mexiletine: The effect of steady-state Fluvoxamine (50 mg b.i.d. for 7 days) on the single dose pharmacokinetics of mexiletine (200 mg) was evaluated in 6 healthy Japanese males. The clearance of mexiletine was reduced by 38% following coadministration with Fluvoxamine compared to mexiletine alone. If Fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored.
Ramelteon: When Fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and Fluvoxamine, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with Fluvoxamine.
Theophylline: The effect of steady-state Fluvoxamine (50 mg bid) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with Fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for Fluvoxamine Maleate Tablets.
Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with Fluvoxamine (see WARNINGS AND PRECAUTIONS, Abnormal Bleeding [5.10]).
Warfarin - When Fluvoxamine maleate (50 mg t.i.d.) was administered concomitantly with warfarin for two weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and Fluvoxamine Maleate Tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for Fluvoxamine Maleate Tablets.
Discontinuation of Treatment with Fluvoxamine Maleate Tablets
During marketing of Fluvoxamine Maleate Tablets and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Fluvoxamine Maleate Tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. (See DOSAGE AND ADMINISTRATION [2.7].)
Abnormal Bleeding
SSRIs and SNRIs, including Fluvoxamine Maleate Tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Fluvoxamine Maleate Tablets and NSAIDs, aspirin, or other drugs that affect coagulation [see section 5.8].
Activation of Mania/Hypomania
During premarketing studies involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with Fluvoxamine. In a ten week pediatric OCD study, 2 out of 57 patients (4%) treated with Fluvoxamine experienced manic reactions, compared to none of 63 placebo patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Fluvoxamine Maleate Tablets should be used cautiously in patients with a history of mania.
Seizures
During premarketing studies, seizures were reported in 0.2% of Fluvoxamine-treated patients. Caution is recommended when the drug is administered to patients with a history of convulsive disorders. Fluvoxamine should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Treatment with Fluvoxamine should be discontinued if seizures occur or if seizure frequency increases.
Hyponatremia
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Fluvoxamine Maleate Tablets. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs (see USE IN SPECIFIC POPULATION, Geriatric Use [8.5]). Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Fluvoxamine Maleate Tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Use in Patients with Concomitant Illness
Closely monitored clinical experience with Fluvoxamine Maleate Tablets in patients with concomitant systemic illness is limited. Caution is advised in administering Fluvoxamine Maleate Tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism.
Fluvoxamine Maleate Tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing. Evaluation of the electrocardiograms for patients with depression or OCD who participated in premarketing studies revealed no differences between Fluvoxamine and placebo in the emergence of clinically important ECG changes.
Patients with Hepatic Impairment - In patients with liver dysfunction, Fluvoxamine clearance was decreased by approximately 30%. Patients with liver dysfunction should begin with a low dose of Fluvoxamine Maleate Tablets and increase it slowly with careful monitoring.
Laboratory Tests
There are no specific laboratory tests recommended.
Adverse Reactions
Adverse Reactions Leading to Treatment Discontinuation
Of the 1087 OCD and depressed patients treated with Fluvoxamine maleate in controlled clinical trials in North America, 22% discontinued due to an adverse reaction. Adverse reactions that led to discontinuation in at least 2% of Fluvoxamine maleate-treated patients in these trials were: nausea (9%), insomnia (4%), somnolence (4%), headache (3%), and asthenia, vomiting, nervousness, agitation, and dizziness (2% each).
Incidence in Controlled Trials
Commonly Observed Adverse Reactions in Controlled Clinical Trials: Fluvoxamine Maleate Tablets have been studied in 10-week short-term controlled trials of OCD (N=320) and depression (N=1350). In general, adverse reaction rates were similar in the two data sets as well as in the pediatric OCD study. The most commonly observed adverse reactions associated with the use of Fluvoxamine Maleate Tablets and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) derived from Table 2 were: nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, and vomiting. In a pool of two studies involving only patients with OCD, the following additional reactions were identified using the above rule: anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion, and urinary frequency. In a study of 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 1%: Table 2 enumerates adverse reactions that occurred in adults at a frequency of 1% or more, and were more frequent than in the placebo group, among patients treated with Fluvoxamine Maleate Tablets in two short-term placebo controlled OCD trials (10 week) and depression trials (6 week) in which patients were dosed in a range of generally 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 standard 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 physician with some basis for estimating the relative contribution of drug and non-drug factors to the side-effect incidence rate in the population studied.
| BODY SYSTEM/ ADVERSE REACTION | Percentage of Patients Reporting Reaction | |
|---|---|---|
| Fluvoxamine N = 892 | PLACEBO N = 778 | |
1Reactions for which Fluvoxamine maleate incidence was equal to or less than placebo are not listed in the table above. 2 Includes “toothache,” “tooth extraction and abscess,” and “caries.” 3 Mostly feeling warm, hot, or flushed. 4 Mostly “blurred vision.” 5 Mostly “delayed ejaculation.” 6 Incidence based on number of male patients. | ||
| BODY AS WHOLE | ||
| Headache | 22 | 20 |
| Asthenia | 14 | 6 |
| Flu Syndrome | 3 | 2 |
| Chills | 2 | 1 |
| CARDIOVASCULAR | ||
| Palpitations | 3 | 2 |
| DIGESTIVE SYSTEM | ||
| Nausea | 40 | 14 |
| Diarrhea | 11 | 7 |
| Constipation | 10 | 8 |
| Dyspepsia | 10 | 5 |
| Anorexia | 6 | 2 |
| Vomiting | 5 | 2 |
| Flatulence | 4 | 3 |
| Tooth Disorder2 | 3 | 1 |
| Dysphagia | 2 | 1 |
| NERVOUS SYSTEM | ||
| Somnolence | 22 | 8 |
| Insomnia | 21 | 10 |
| Dry Mouth | 14 | 10 |
| Nervousness | 12 | 5 |
| Dizziness | 11 | 6 |
| Tremor | 5 | 1 |
| Anxiety | 5 | 3 |
| Vasodilatation3 | 3 | 1 |
| Hypertonia | 2 | 1 |
| Agitation | 2 | 1 |
| Decreased Libido | 2 | 1 |
| Depression | 2 | 1 |
| CNS Stimulation | 2 | 1 |
| RESPIRATORY SYSTEM | ||
| Upper Respiratory Infection | 9 | 5 |
| Dyspnea | 2 | 1 |
| Yawn | 2 | 0 |
| SKIN | ||
| Sweating | 7 | 3 |
| SPECIAL SENSES | ||
| Taste Perversion | 3 | 1 |
| Amblyopia4 | 3 | 2 |
| UROGENITAL | ||
| Abnormal Ejaculation5,6 | 8 | 1 |
| Urinary Frequency | 3 | 2 |
| Impotence6 | 2 | 1 |
| Anorgasmia | 2 | 0 |
| Urinary Retention | 1 | 0 |
Adverse Reactions in OCD Placebo Controlled Studies Which are Markedly Different (defined as at least a two-fold difference) in Rate from the Pooled Reaction Rates in OCD and Depression Placebo Controlled Studies: The reactions in OCD studies with a two-fold decrease in rate compared to reaction rates in OCD and depression studies were dysphagia and amblyopia (mostly blurred vision). Additionally, there was an approximate 25% decrease in nausea.
The reactions in OCD studies with a two-fold increase in rate compared to reaction rates in OCD and depression studies were: asthenia, abnormal ejaculation (mostly delayed ejaculation), anxiety, rhinitis, anorgasmia (in males), depression, libido decreased, pharyngitis, agitation, impotence, myoclonus/twitch, thirst, weight loss, leg cramps, myalgia, and urinary retention. These reactions are listed in order of decreasing rates in the OCD trials.
Other Adverse Reactions in OCD Pediatric Population
In pediatric patients (N=57) treated with 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 more frequent with Fluvoxamine Maleate Tablets than with placebo: cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, manic reaction, rash, sinusitis, and weight decrease.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder and with aging, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs), can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.
Table 3 displays the incidence of sexual side effects reported by at least 2% of patients taking Fluvoxamine Maleate Tablets in placebo-controlled trials in depression and OCD.
| Fluvoxamine Maleate Tablets N = 892 | Placebo N = 778 | |
|---|---|---|
| * Based on the number of male patients. | ||
| Abnormal Ejaculation* | 8% | 1% |
| Impotence* | 2% | 1% |
| Decreased Libido | 2% | 1% |
| Anorgasmia | 2% | 0% |
There are no adequate and well-controlled studies examining sexual dysfunction with Fluvoxamine treatment.
Fluvoxamine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae and upon discontinuation of Fluvoxamine.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Vital Sign Changes
Comparisons of Fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various vital signs variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various vital signs variables revealed no important differences between Fluvoxamine maleate and placebo.
Laboratory Changes
Comparisons of Fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various serum chemistry, hematology, and urinalysis variables and on (2) incidence of patients meeting crit
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