FLUVOXAMINE MALEATE TABLETS, USP

(One Medication Guide Attached)

Rx only

Revised AUGUST 2007 

11001256

Fluvoxamine Maleate is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to a new chemical series, the 2-aminoethyl oxime ethers of aralkylketones. It is chemically unrelated to other SSRIs and clomipramine. It is chemically designated as 5-methoxy-4'-(trifluoromethyl) valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1). The structural formula is as follows:

Fluvoxamine Maleate is a white or off white, odorless, crystalline powder which is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether. Each tablet, for oral administration contains, 25 mg, 50 mg or 100 mg of fluvoxamine maleate. In addition, each tablet contains the following inactive ingredients: mannitol, methylcellulose, pregelatinized starch, silicon dioxide, starch and sodium stearyl fumarate. The 25 mg also contains FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide. The 50 mg also contains D&C yellow no. 10 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide. The 100 mg also contains hypromellose, polyethylene glycol, polysorbate 80, synthetic black iron oxide, synthetic red iron oxide, synthetic yellow iron oxide and titanium dioxide.

Fluvoxamine Maleate meets USP Related Compound Test 2.

The mechanism of action of fluvoxamine maleate in Obsessive Compulsive Disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. In preclinical studies, it was found that fluvoxamine inhibited neuronal uptake of serotonin.

In in vitro studies fluvoxamine maleate had no significant affinity for histaminergic, alpha or beta adrenergic, muscarinic, or dopaminergic receptors. Antagonism of some of these receptors is thought to be associated with various sedative, cardiovascular, anticholinergic, and extrapyramidal effects of some psychotropic drugs.

The multiple-dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6-11) and adolescents (ages 12-17). Steady-state plasma fluvoxamine concentrations were 2-3 fold higher in children than in adolescents. AUC and C_max in children were 1.5 to 2.7-fold higher than that in adolescents (see table below). As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0-12) and C_max compared to male children and, therefore, lower doses of fluvoxamine maleate tablets may produce therapeutic benefit (see table below). No gender differences were observed in adolescents. Steady-state plasma fluvoxamine concentrations were similar in adults and adolescents at a dose of 300 mg/day, indicating that fluvoxamine exposure was similar in these two populations (see table below). Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.

Comparison of Mean (SD) fluvoxamine pharmacokinetic parameters between children, adolescents and adults.

Comparison of Mean (SD) fluvoxamine pharmacokinetic parameters between male and female children (6-11 years).

Fluvoxamine maleate tablets are indicated for the treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD), as defined in the DSM-III-R. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

The efficacy of fluvoxamine maleate tablets was established in three 10-week trials with obsessive compulsive outpatients with the diagnosis of Obsessive Compulsive Disorder as defined in DSM-III-R. (See Clinical Trials under CLINICAL PHARMACOLOGY.)

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 effectiveness of fluvoxamine maleate tablets for long-term use, i.e., for more than 10 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use fluvoxamine maleate tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. (See DOSAGE AND ADMINISTRATION.)

Co-administration of thioridazine, terfenadine, astemizole, cisapride, pimozide, alosetron or tizanidine with fluvoxamine maleate is contraindicated (see WARNINGS, PRECAUTIONS and Lotronex™ (alosetron) package insert).

Fluvoxamine maleate tablets are contraindicated in patients with a history of hypersensitivity to fluvoxamine maleate.

In patients receiving another serotonin reuptake inhibitor drug in combination with monoamine oxidase inhibitors (MAOI), 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 a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, it is recommended that fluvoxamine maleate tablets not be used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI. After stopping fluvoxamine maleate tablets, at least 2 weeks should be allowed before starting a MAOI.

The effect of fluvoxamine (25 mg bid 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 co-administration of fluvoxamine.

Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade 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 co-administered (see CONTRAINDICATIONS and PRECAUTIONS).

Terfenadine, astemizole, cisapride, and pimozide are all metabolized by the cytochrome P450IIIA4 isozyme, and it has been demonstrated that ketoconazole, a potent inhibitor of IIIA4, blocks the metabolism of these drugs, resulting in increased plasma concentrations of parent drug. Increased plasma concentrations of terfenadine, astemizole, cisapride, and pimozide cause QT prolongation and have 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 the IIIA4 isozyme. Although it has not been definitively demonstrated that fluvoxamine is a potent IIIA4 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 either terfenadine, astemizole, cisapride, or pimozide (see CONTRAINDICATIONS and PRECAUTIONS).

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 subjects. Tizanidine C_max 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 a psychomotor task was significantly impaired. Fluvoxamine and tizanidine should not be used together (See CONTRAINDICATIONS and PRECAUTIONS).

Fluvoxamine, an inhibitor of several CYP isozymes, has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. Consequently, it is recommended that fluvoxamine not be used in combination with alosetron (See CONTRAINDICATIONS, PRECAUTIONS, and Lotronex™ (alosetron) package insert).

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.

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 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION-Discontinuation of Treatment with Fluvoxamine Maleate Tablets, 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 health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for fluvoxamine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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 is not approved for use in treating bipolar depression.

(Also see PRECAUTIONS – Drug Interactions)

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluvoxamine and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for fluvoxamine. 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 spans. Patients should be given the opportunity to discuss the spans of the Medication Guide and to obtain answers to any questions they may have. The complete div 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.

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 a need for very close monitoring and possibly changes in the medication.

Since any psychoactive drug may impair judgement, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that fluvoxamine 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 tablets.

Patients receiving fluvoxamine maleate tablets should be advised to notify their physicians if they are breast feeding an infant. (See PRECAUTIONS, 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 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.

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.

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).

As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets.

Patients should be advised to notify their physicians if they develop a rash, hives, or a related allergic phenomenon during therapy with fluvoxamine maleate tablets.

There are no specific laboratory tests recommended.

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 therapy to the mother.

The efficacy of 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 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, 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: Clinical Worsening and Suicide Risk).

Safety and effectiveness in the pediatric population other than pediatric patients with obsessive compulsive disorder have not been established (see BOX WARNING and WARNINGS – Clinical Worsening and Suicide Risk). Anyone considering the use of fluvoxamine maleate in a child or adolescent must balance the potential risks with he clinical need.

Approximately 230 patients participating in controlled premarketing studies with fluvoxamine maleate 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, fluvoxamine has been associated with several cases of clinically significant hyponatremia in elderly patients (see PRECAUTIONS, General). Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients (see Pharmacokinetics under CLINICAL PHARMACOLOGY), and greater sensitivity of some older individuals also cannot be ruled out. Consequently, fluvoxamine maleate tablets should be slowly titrated during initiation of therapy.

Of the 1087 OCD and depressed patients treated with fluvoxamine maleate in controlled clinical trials conducted in North America, 22% discontinued treatment due to an adverse event. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) included:

In pediatric patients (N=57) treated with fluvoxamine maleate tablets, the overall profile of adverse events was generally similar to that seen in adult studies, as shown in Table 3. However, the following adverse events, not appearing in Table 3, were reported in two or more of the pediatric patients and were more frequent with fluvoxamine maleate tablets than with placebo: abnormal thinking, cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, infection, manic reaction, rash, sinusitis, and weight decrease.

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 (SSRI’s) 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.

The table below displays the incidence of sexual side effects reported by at least 2% of patients taking fluvoxamine in placebo controlled trials in depression and OCD.

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 SSRI’s, physicians should routinely inquire about such possible side effects.

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.

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 criteria for potentially important changes from baseline on various serum chemistry, hematology, and urinalysis variables revealed no important differences between fluvoxamine maleate and placebo.

Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) mean change from baseline on various ECG variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various ECG variables revealed no important differences between fluvoxamine maleate and placebo.

During premarketing clinical trials conducted in North America and Europe, multiple doses of fluvoxamine maleate were administered for a combined total of 2737 patient exposures in patients suffering OCD or Major Depressive Disorder. Untoward events associated with this exposure were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a limited (i.e., reduced) number of standard event categories.

In the tabulations which follow, a standard COSTART-based Dictionary terminology has been used to classify reported adverse events. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. The frequencies presented, therefore, represent the proportion of the 2737 patient exposures to multiple doses of fluvoxamine maleate who experienced an event of the type cited on at least one occasion while receiving fluvoxamine maleate. All reported events are included in the ul below, with the following exceptions: 1) those events already uled in Table 3, which tabulates incidence rates of common adverse experiences in placebo-controlled OCD and depression clinical trials, are excluded; 2) those events for which a drug cause was considered remote (i.e., neoplasia, gastrointestinal carcinoma, herpes simplex, herpes zoster, application site reaction, and unintended pregnancy) are omitted; and 3) events which were reported in only one patient and judged to not be potentially serious are not included. It is important to emphasize that, although the events reported did occur during treatment with fluvoxamine maleate, a causal relationship to fluvoxamine maleate has not been established.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring between 1/100 and 1/1000 patients; and rare adverse events are those occurring in less than 1/1000 patients.

Voluntary reports of adverse events in patients taking fluvoxamine maleate that have been received since market introduction and are of unknown causal relationship to fluvoxamine maleate tablets use include: ventricular tachycardia (including torsades de pointes), porphyria, toxic epidermal necrolysis, Stevens-Johnson syndrome, Henoch-Schoenlein purpura, bullous eruption, priapism, agranulocytosis, aplastic anemia, anaphylactic reaction, angioedema, vasculitis, hyponatremia, acute renal failure, hepatitis, pancreatitis, ileus, serotonin syndrome, neuropathy, laryngismus, and severe akinesia with fever when fluvoxamine was co-administered with antipsychotic medication.

Fluvoxamine maleate tablets are not controlled substances.

The potential for abuse, tolerance and physical dependence with fluvoxamine maleate has been studied in a nonhuman primate model. No evidence of dependency phenomena was found. The discontinuation effects of fluvoxamine maleate were not systematically evaluated in controlled clinical trials. Fluvoxamine maleate tablets were not systematically studied in clinical trials for potential for abuse, but there was no indication of drug-seeking behavior in clinical trials. It should be noted, however, that patients at risk for drug dependency were systematically excluded from investigational studies of fluvoxamine maleate. Generally, it is not possible to predict on the basis of preclinical or premarketing clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of fluvoxamine maleate misuse or abuse (i.e., development of tolerance, incrementation of dose, drug-seeking behavior).

Worldwide exposure to fluvoxamine maleate includes over 45,000 patients treated in clinical trials and an estimated exposure of 23,000,000 patients treated during worldwide marketing experience (circa 1999). Of the 462 cases of deliberate or accidental overdose involving fluvoxamine maleate reported from this population, there were 44 deaths. Of these, six were in patients taking fluvoxamine maleate alone and the remaining 38 were in patients taking fluvoxamine maleate along with other drugs. Among non-fatal overdose cases, 373 patients had complete recovery; four patients experienced adverse sequelae of overdosage, to include persistent mydriasis, unsteady gait, kidney complications (from trauma associated with overdose), and bowel infarction requiring a hemicolectomy. In the remaining 41 patients, the outcome was unknown. The largest known ingestion of fluvoxamine maleate involved 12,000 mg (equivalent to 2 to 3 months' dosage). The patient fully recovered. However, ingestions as low as 1,400 mg have been associated with lethal outcome, indicating considerable prognostic variability.

Commonly (>5%) observed adverse events associated with fluvoxamine maleate overdose include coma, hypokalemia, hypotension, nausea, respiratory difficulties, somnolence, tachycardia and vomiting. Other notable signs and symptoms seen with fluvoxamine maleate overdose (single or multiple drugs) include bradycardia, ECG abnormalities, (such as heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm), convulsions, tremor, diarrhea, and increased reflexes.

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluvoxamine are known.

A specific caution involves patients taking, or recently having taken, fluvoxamine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Tricyclic Antidepressants (TCAs) under PRECAUTIONS).

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are uled in the Physicians’ Desk Reference (PDR).

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 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.

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 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 than 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 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.

Although the efficacy of fluvoxamine maleate beyond 10 weeks of dosing for OCD has not been documented in controlled trials, OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

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 (see PRECAUTIONS). 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.

Symptoms associated with discontinuation of other SSRIs and SNRIs have been reported (see PRECAUTIONS). 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.

Fluvoxamine Maleate Tablets, USP are available as:

25 mg: Off-white, oval, film-coated, biconvex, unscored tablet. Debossed with stylized b on one side and 967 on the other side. Available in bottles of:

50 mg: Yellow, oval, film-coated, biconvex, scored tablet. Debossed with stylized b on one side and 968/50 on the scored side. Available in bottles of:

100 mg: Brown, oval, film-coated, biconvex, scored tablet. Debossed with stylized b on one side and 969/100 on the scored side. Available in bottles of:

Dispense with a child-resistant closure in a tight container.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Protect from high humidity.

Lotronex™ is a registered trademark of GlaxoSmithkline.

BARR LABORATORIES, INC.

POMONA, NY 10970

Revised AUGUST 2007

BR-0967, 0968, 0969

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Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions

Rx only

Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:

• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.

2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.

3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?

• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a ul of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

Revised: AUGUST 2007