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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.
TABLE 1: DRUG-PLACEBO DIFFERENCES IN NUMBER OF CASES OF SUICIDALITY
PER 1000 PATIENTS TREATED
|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 (fluvoxamine maleate) Tablets, for a description of the risks of discontinuation of Fluvoxamine Maleate (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 (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 (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 and CONTRAINDICATIONS)
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 (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 (fluvoxamine maleate) Tablets with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Fluvoxamine Maleate (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 (fluvoxamine maleate) Tablets with serotonin precursors (such as tryptophan) is not recommended.
Treatment with Fluvoxamine Maleate (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)
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 C^ 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)
Potential Pimozide Interaction
Pimozide is metabolized by the cytochrome P4503 A4 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 CYP3 A4. 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)
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 and Lotronex™ (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 (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 (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 (fluvoxamine maleate) Tablets.
Diazepam - The coadministration of Fluvoxamine Maleate (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 (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 (fluvoxamine maleate) and clozapine are used concurrently.
Methadone - Significantly increased methadone (plasma levehdose) ratios have been reported when fluvoxamine maleate (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 nonsmoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with fluvoxamine maleate (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 (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).
Warfarin - When fluvoxamine maleate (fluvoxamine maleate) (50 mg ti.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 (fluvoxamine maleate) Tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for Fluvoxamine Maleate (fluvoxamine maleate) Tablets.
Discontinuation of Treatment with Fluvoxamine Maleate Tablets
During marketing of Fluvoxamine Maleate (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 (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)
SSRIs and SNRIs, including Fluvoxamine Maleate (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 andcohort 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 (fluvoxamine maleate) Tablets and NSAIDs, aspirin, or other drugs that affect coagulation [see Other Potentially Important Drug Interactions].
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 (fluvoxamine maleate) Tablets should be used cautiously in patients with a history of mania.
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 may occur as a result of treatment with SSRIs and SNRIs, including Fluvoxamine Maleate (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 Populations, Geriatric Use). Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Fluvoxamine Maleate (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 (fluvoxamine maleate) Tablets in patients with concomitant systemic illness is limited. Caution is advised in administering Fluvoxamine Maleate (fluvoxamine maleate) Tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism.
Fluvoxamine Maleate (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 (fluvoxamine maleate) Tablets and increase it slowly with careful monitoring.
There are no specific laboratory tests recommended.
Patient Counseling Information
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Fluvoxamine Maleate (fluvoxamine maleate) Tablets and should counsel them in the appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions" is available for Fluvoxamine Maleate (fluvoxamine maleate) Tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Fluvoxamine Maleate (fluvoxamine maleate) Tablets.
Clinical Worsening and Suicide Risk
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate the need for very close monitoring and possibly changes in the medication (see Boxed Warning and WARNINGS AND PRECAUTIONS).
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluvoxamine and triptans, tramadol, or other serotonergic agents (see WARNINGS AND PRECAUTIONS-Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions).
Interference with Cognitive or Motor Performance
Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that Fluvoxamine Maleate (fluvoxamine maleate) Tablets therapy does not adversely affect their ability to engage in such activities.
Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy with Fluvoxamine Maleate (fluvoxamine maleate) Tablets (see Use In Specific Populations).
Patients receiving Fluvoxamine Maleate (fluvoxamine maleate) Tablets should be advised to notify their physicians if they are breast-feeding an infant. (See Use In Specific Populations - Nursing Mothers.)
Patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for clinically important interactions with Fluvoxamine Maleate (fluvoxamine maleate) Tablets.
Patients should be cautioned about the concomitant use of fluvoxamine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see WARNINGS AND PRECAUTIONS - Warfarin and Other Drugs That Interfere With Hemostasis).
Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when fluvoxamine and tizanidine are used together, fluvoxamine should not be used with tizanidine (see WARNINGS AND PRECAUTIONS).
Because of the potential for the increased risk of serious adverse reactions when fluvoxamine and alosetron are used together, fluvoxamine should not be used with Lotronex™ (alosetron) (see WARNINGS AND PRECAUTIONS).
As with other psychotropic medications, patients should be advised to avoid alcohol while taking Fluvoxamine Maleate (fluvoxamine maleate) Tablets.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis: There was no evidence of carcinogenicity in rats treated orally with fluvoxamine maleate for 30 months or hamsters treated orally with fluvoxamine maleate (fluvoxamine maleate) for 20 (females) or 26 (males) months. The daily doses in the high dose groups in these studies were increased over the course of the study from a minimum of 160 mg/kg to a maximum of 240 mg/kg in rats, and from a minimum of 135 mg/kg to a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 6 times the maximum human daily dose on a mg/m2 basis.
Mutagenesis: No evidence of genotoxic potential was observed in a mouse micronucleus test, an in vitro chromosome aberration test, or the Ames microbial mutagen test with or without metabolic activation.
Impairment of Fertility: In a study in which male and female rats were administered fluvoxamine (60,120, or 240 mg/kg) prior to and during mating and gestation, fertility was impaired at oral doses of 120 mg/kg or greater, as evidenced by increased latency to mating, decreased sperm count, decreased epididymal weight, and decreased pregnancy rate. In addition, the numbers of implantations and embryos were decreased at the highest dose. The no effect dose for fertility impairment was 60 mg/kg (approximately 2 times the maximum recommended human dose [MRHD] on a mg/m2 basis).
Use In Specific Populations
Teratogenic Effects - Pregnancy Category C: When pregnant rats were given oral doses of fluvoxamine (60,120, or 240 mg/kg) throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater. Decreased fetal body weight was seen at the high dose. The no effect dose for developmental toxicity in this study was 60 mg/kg (approximately 2 times the MRHD on a mg/m2 basis).
In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2 times the MRHD on a mg/m2 basis) during organogenesis, no adverse effects on embryofetal development were observed.
In other reproduction studies in which female rats were dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.1 times the MRHD on a mg/m2 basis).
Nonteratogenic Effects: Neonates exposed to fluvoxamine maleate (fluvoxamine maleate) and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on postmarketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs or SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS AND PRECAUTIONS).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN is associated with substantial neonatal morbidity and mortality. In a case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. PPHN occurs in 1-2 per 1000 live births in the general population.
When treating a pregnant woman with fluvoxamine maleate (fluvoxamine maleate) during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
Labor And Delivery
The effect of fluvoxamine on labor and delivery in humans is unknown.
As for many other drugs, fluvoxamine is secreted in human breast milk. The decision of whether to discontinue nursing or to discontinue the drug should take into account the potential for serious adverse effects from exposure to fluvoxamine in the nursing infant as well as the potential benefits of Fluvoxamine Maleate (fluvoxamine maleate) Tablets therapy to the mother.
The efficacy of fluvoxamine maleate (fluvoxamine maleate) for the treatment of obsessive compulsive disorder was demonstrated in a 10-week multicenter placebo controlled study with 120 outpatients ages 8-17. In addition, 99 of these outpatients continued open-label fluvoxamine maleate (fluvoxamine maleate) treatment for up to another one to three years, equivalent to 94 patient years. The adverse event profile observed in that study was generally similar to that observed in adult studies with fluvoxamine. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)
Decreased appetite and weight loss have been observed in association with the use of fluvoxamine as well as other SSRIs. Consequently, regular monitoring of weight and growth is recommended if treatment of a child with an SSRI is to be continued long term.
The risks, if any, that may be associated with fluvoxamine's extended use in children and adolescents with OCD have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that fluvoxamine is safe for use in children and adolescents derives from relatively short term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that fluvoxamine possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of fluvoxamine to have adverse effects in chronic use (see WARNINGS AND PRECAUTIONS - Clinical Worsening and Suicide Risk).
Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established. (See Boxed Warning and WARNINGS AND PRECAUTIONS - Clinical Worsening and Suicide Risk) Anyone considering the use of Fluvoxamine Maleate (fluvoxamine maleate) Tablets in a child or adolescent must balance the potential risks with the clinical need.
Approximately 230 patients participating in controlled premarketing studies with Fluvoxamine Maleate (fluvoxamine maleate) Tablets were 65 years of age or over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. However, SSRIs and SNRIs, including Fluvoxamine Maleate (fluvoxamine maleate) Tablets, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see WARNINGS AND PRECAUTIONS). Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients (see CLINICAL PHARMACOLOGY - Elderly), and greater sensitivity of some older individuals also cannot be ruled out. Consequently, a lower starting dose should be considered in elderly patients and Fluvoxamine Maleate (fluvoxamine maleate) Tablets should be slowly titrated during initiation of therapy.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/9/2011
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