LUVOX CR - fluvoxamine maleate capsule, extended release 
Jazz Pharmaceuticals, Inc.
LUVOX® CR (fluvoxamine maleate) Extended-Release Capsules
100 mg and 150 mg
Rx only
Rev 0209
Suicidality and Antidepressant Drugs
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 LUVOX® CR (fluvoxamine maleate) Extended-Release Capsules 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. LUVOX CR Capsules are not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)

DESCRIPTION

LUVOX® CR is an extended-release capsule for oral administration that contains fluvoxamine maleate, a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the distinct chemical series, the 2-aminoethyl oxime ethers of aralkylketones.

Fluvoxamine maleate 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) and has the empirical formula C15H21O2N2F3•C4H4O4. Its molecular weight is 434.41.

The structural formula is:

Fluvoxamine maleate is a white to off-white, odorless, crystalline powder that is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether.

LUVOX CR Capsules are available in 100 mg and 150 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate, each capsule contains the following inactive ingredients: talc, sugar spheres, ammonio methacrylate copolymer type B, dibutyl sebacate, red iron oxide, FD&C Blue No. 2, titanium dioxide, gelatin (porcine- or bovine-derived), and Opacode Grey. LUVOX CR Capsules are gluten-free.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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. Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitro and in vivo.

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.

Pharmacokinetics

Bioavailability:

A single-dose crossover study in 28 healthy subjects was conducted to compare the pharmacokinetics of fluvoxamine after administration of LUVOX CR Capsules and immediate-release fluvoxamine maleate tablets.

In the single-dose crossover study, mean Cmax was 38% lower and relative bioavailability was 84% for LUVOX CR Capsules versus immediate-release fluvoxamine maleate tablets.

In a multiple-dose proportionality study, LUVOX CR Capsules were administered over a dose range of 100 mg/day to 300 mg/day to 20 healthy volunteers. Steady-state plasma concentrations were achieved within a week of dosing. Mean maximum plasma concentrations were 47 ng/mL, 161 ng/mL, and 319 ng/mL, respectively, at the 100 mg, 200 mg, and 300 mg administered dose levels. Fluvoxamine exhibited nonlinear pharmacokinetics producing disproportionately higher concentrations over the dose range. The AUC and Cmax values increased 5.7-fold following the 3-fold increase in dose from 100 mg to 300 mg.

Food caused the mean AUC and Cmax of fluvoxamine to increase only slightly; therefore, administration of LUVOX CR Capsules with food does not significantly affect the absorption of fluvoxamine.

Distribution/Protein Binding:

The mean apparent volume of distribution for fluvoxamine is approximately 25 L/kg, suggesting extensive tissue distribution.

Approximately 80% of fluvoxamine is bound to plasma protein, mostly albumin, over a concentration range of 20 ng/mL to 2000 ng/mL.

Metabolism:

Fluvoxamine maleate is extensively metabolized by the liver; the main metabolic routes are oxidative demethylation and deamination. Nine metabolites were identified following a 5 mg radiolabelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. A third metabolite, fluvoxethanol, formed by oxidative deamination, accounted for about 10%. Fluvoxamine acid and fluvoxethanol were tested in an in vitro assay of serotonin and norepinephrine reuptake inhibition in rats; they were inactive except for a weak effect of the former metabolite on inhibition of serotonin uptake (1-2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged. (see PRECAUTIONS – Drug Interactions.)

Elimination:

Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours.

After administration of a 100 mg, single oral dose of LUVOX CR Capsules, the mean plasma half-life of fluvoxamine in healthy male and female volunteers was 16.3 hours.

Gender:

In a study with 15 male and 13 female healthy volunteers who were administered LUVOX CR Capsules 100 mg, AUC and Cmax of fluvoxamine were increased by approximately 60% in females compared to males. There were no differences in the elimination half-life between males and females.

Elderly Subjects:

In a study using immediate-release fluvoxamine maleate tablets at 50 mg and 100 mg and comparing elderly (ages 66-73 years) and young subjects (ages 19-35 years), mean maximum plasma concentrations in the elderly were 40% higher. The multiple-dose elimination half-life of fluvoxamine was 17.4 hours and 25.9 hours in the elderly compared to 13.6 hours and 15.6 hours in the young subjects at steady state for 50 mg and 100 mg doses, respectively.

In elderly patients administered immediate-release fluvoxamine maleate tablets, the clearance of fluvoxamine was reduced by about 50%; therefore, LUVOX CR Capsules should be slowly titrated during initiation of therapy.

Pediatric Subjects:

The pharmacokinetics of LUVOX CR Capsules have not been eva luated in pediatric patients. However, the multiple-dose pharmacokinetics of immediate-release fluvoxamine maleate tablets were determined in male and female children (ages 6-11 years) (Table 2) and adolescents (ages 12-17 years) (Table 1). Steady-state plasma fluvoxamine concentrations were 2-fold to 3-fold higher in children than in adolescents. AUC and Cmax in children were 1.5-fold to 2.7-fold higher than those in adolescents (See Table 1). As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0-12) and Cmax compared to male children; therefore, lower doses of immediate-release fluvoxamine maleate tablets may produce therapeutic benefit (See Table 2). 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 1). Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.

Hepatic and Renal Disease:

A cross-study comparison (healthy subjects versus patients with hepatic dysfunction) using immediate-release fluvoxamine maleate tablets suggested a 30% decrease in fluvoxamine clearance in association with hepatic dysfunction. The mean minimum plasma concentrations in renally impaired patients (creatinine clearance of 5 mL/min to 45 mL/min) after 4 weeks and 6 weeks of treatment (50 mg given twice daily, N = 13) were comparable to each other, suggesting no accumulation of fluvoxamine in these patients (see PRECAUTIONS – Use in Patients with Concomitant Illness).

Clinical Trials

Social Anxiety Disorder:

The effectiveness of LUVOX CR Capsules in the treatment of social anxiety disorder was demonstrated in two 12-week, multicenter, placebo-controlled studies of adult outpatients with social anxiety disorder (DSM-IV). Patients in these trials were titrated in 50 mg increments over the first six weeks of the study on the basis of response and tolerance from a dose of 100 mg/day to a fluvoxamine maleate dose within a range of 100 mg to 300 mg once-a-day.

In these studies, the effectiveness of LUVOX CR Capsules compared to placebo was eva luated on the basis of change from baseline in the Liebowitz Social Anxiety Scale (LSAS). LUVOX CR Capsules demonstrated statistically significant superiority over placebo at the primary endpoint (Week 12) as assessed by the LSAS total score in both studies.

The mean daily doses of LUVOX CR Capsules administered to patients in Study 1 and Study 2 were 236 mg and 204 mg, respectively, at end of study.

Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.

Obsessive Compulsive Disorder (OCD):

The effectiveness of LUVOX CR Capsules for the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled study of adult outpatients. Patients in this trial were titrated in 50 mg increments over the first six weeks of the study on the basis of response and tolerance from a dose of 100 mg/day to a fluvoxamine maleate dose within a range of 100 mg to 300 mg once-a-day. Patients in this study had moderate to severe OCD (DSM-IV), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), total scores of 26.6 and 26.3 for fluvoxamine and placebo-treatment groups, respectively.

Patients receiving LUVOX CR Capsules demonstrated statistically significant improvement over placebo patients at the primary endpoint (Week 12) compared to baseline on the Y-BOCS. The mean daily dose of LUVOX CR Capsules administered to patients was 261 mg at end of study.

Exploratory analyses for age and gender effects on outcomes did not show any significant differential responsiveness on the basis of age or sex.

The effectiveness of immediate-release fluvoxamine maleate tablets for the treatment of OCD was demonstrated in two 10-week multicenter, parallel-group studies of adult outpatients. Patients in these trials were titrated to a total daily fluvoxamine maleate dose of 150 mg/day over the first two weeks of the trial, after which the dose was adjusted within a range of 100 mg/day to 300 mg/day (given in two doses per day), on the basis of response and tolerance. Patients in these studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score of 23.

Pediatric OCD Study:

LUVOX CR Capsules have not been eva luated in pediatric patients. However, the effectiveness of immediate-release fluvoxamine maleate tablets for the treatment of OCD was demonstrated in a 10-week multicenter, parallel-group study in a pediatric outpatient population (children and adolescents, ages 8-17 years). Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 50 mg/day to 200 mg/day (given in two doses per day) on the basis of response and tolerance. All patients had moderate-to-severe OCD (DSM-III-R) with mean baseline ratings on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24.

Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender. Further exploratory analyses revealed a prominent treatment effect in the 8 year to 11 year age group and essentially no effect in the 12 year to 17 year age group. While the significance of these results is not clear, the 2-3 fold higher steady-state plasma fluvoxamine concentrations in children compared to adolescents (see Pharmacokinetics) is suggestive that decreased exposure in adolescents may have been a factor, and dose adjustment in adolescents (up to the adult maximum dose of 300 mg/day) may be indicated to achieve therapeutic benefit.

INDICATIONS AND USAGE

Social Anxiety Disorder:

LUVOX CR Capsules are indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person’s normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.

The efficacy of LUVOX CR Capsules was demonstrated in two 12-week trials in adult patients with social anxiety disorder (DSM-IV). LUVOX CR Capsules have not been studied in children or adolescents with social anxiety disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).

The effectiveness of LUVOX CR Capsules in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically eva luated in adequate and well-controlled trials. Therefore, the health care provider who elects to prescribe LUVOX CR Capsules for extended periods should periodically reeva luate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Obsessive Compulsive Disorder:

LUVOX CR Capsules are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

The efficacy of LUVOX CR Capsules was demonstrated in one 12-week trial with obsessive compulsive outpatients with the diagnosis of OCD as defined in DSM-IV (see Clinical Trials under CLINICAL PHARMACOLOGY).

The efficacy of the immediate-release fluvoxamine maleate tablets in the treatment of OCD was demonstrated in two 10-week multicenter, parallel-group studies of adult outpatients.

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 LUVOX CR Capsules for long-term use, i.e., for more than 12 weeks, has not been systematically eva luated in placebo-controlled trials. Therefore, the health care provider who elects to prescribe LUVOX CR Capsules for extended periods should periodically re-eva luate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

Co-administration of alosetron, tizanidine, thioridazine, or pimozide with LUVOX CR Capsules is contraindicated (see WARNINGS and PRECAUTIONS).

The use of MAO inhibitors used in combination with LUVOX CR Capsules, or within 14 days of discontinuing treatment with LUVOX CR Capsules, is contraindicated (see WARNINGS and PRECAUTIONS).

LUVOX CR Capsules are contraindicated in patients with a history of hypersensitivity to fluvoxamine maleate or any of the excipients.

WARNINGS

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. The pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increased 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 the Table 3.

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 PRECAUTIONS and DOSAGE AND ADMINISTRATION ― Discontinuation of Treatment with LUVOX CR Capsules, for a description of the risks of discontinuation of LUVOX CR Capsules).

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for LUVOX CR Capsules should be written for the smallest quantity of capsules 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 LUVOX CR Capsules is 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, LUVOX CR Capsules should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI (see 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 LUVOX CR Capsules 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 LUVOX CR Capsules with MAOIs intended to treat depression is contraindicated.

If concomitant treatment of LUVOX CR Capsules 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 LUVOX CR Capsules with serotonin precursors (such as tryptophan) is not recommended.

Treatment with LUVOX CR Capsules 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 immediate-release tablets given twice daily for one week) on thioridazine steady-state concentrations was eva luated in 10 male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased 3-fold 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 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, LUVOX CR Capsules and thioridazine should not be co-administered (see CONTRAINDICATIONS and PRECAUTIONS).

Potential Tizanidine Interaction

Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of immediate–release fluvoxamine maleate tablets (100 mg daily for four days) on the pharmacokinetics and pharmacodynamics of a single 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. LUVOX CR Capsules and tizanidine should not be used together (see CONTRAINDICATIONS and PRECAUTIONS).

Potential Alosetron Interaction

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 LUVOX CR Capsules not be used in combination with alosetron (see CONTRAINDICATIONS, PRECAUTIONS, and LotronexTM (alosetron) package insert).

Use with Ramelteon

Ramelteon should not be used in combination with LUVOX CR Capsules (see PRECAUTIONS: Drug Interactions).

Potential Pimozide Interaction

Pimozide is metabolized by the CYP3A4 isozyme, 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. Increased plasma concentration of pimozide causes QT prolongation and has been associated with torsade 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 CYP3A4 isozyme. 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 and PRECAUTIONS).

Other Potentially Important Drug Interactions

(Also see PRECAUTIONS – 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 immediate-release fluvoxamine maleate tablets (100 mg given once daily) and alprazolam (1 mg given 4 times per day) were co-administered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, Cmax, T½) 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 co-administered, particularly since fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100 mg to 300 mg. If alprazolam is co-administered with LUVOX CR Capsules, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for LUVOX CR Capsules.

Diazepam – The co-administration of LUVOX CR Capsules and diazepam is generally not advisable. Because fluvoxamine reduces the clearance of both diazepam and i