Luvox Cr Information
Luvox cr (Fluvoxamine) Description
Luvox cr (Fluvoxamine) 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 CHONF•CHO. 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 (Fluvoxamine) 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 (Fluvoxamine) Capsules are gluten-free.
Luvox cr (Fluvoxamine) Clinical Pharmacology
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 and .
In 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.
Luvox cr (Fluvoxamine) Indications And Usage
Luvox cr (Fluvoxamine) 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 (Fluvoxamine) Capsules was demonstrated in two 12-week trials in adult patients with social anxiety disorder (DSM-IV). Luvox cr (Fluvoxamine) Capsules have not been studied in children or adolescents with social anxiety disorder (see under ).
The effectiveness of Luvox cr (Fluvoxamine) Capsules in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the health care provider who elects to prescribe Luvox cr (Fluvoxamine) Capsules for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ).
Luvox cr (Fluvoxamine) 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 (Fluvoxamine) Capsules was demonstrated in one 12-week trial with obsessive compulsive outpatients with the diagnosis of OCD as defined in DSM-IV (see under ).
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 (Fluvoxamine) Capsules for long-term use, i.e., for more than 12 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the health care provider who elects to prescribe Luvox cr (Fluvoxamine) Capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see ).
Luvox cr (Fluvoxamine) Contraindications
Co-administration of alosetron, tizanidine, thioridazine, or pimozide with Luvox cr (Fluvoxamine) Capsules is contraindicated (see and ).
The use of MAO inhibitors used in combination with Luvox cr (Fluvoxamine) Capsules, or within 14 days of discontinuing treatment with Luvox cr (Fluvoxamine) Capsules, is contraindicated (see and ).
Luvox cr (Fluvoxamine) Capsules are contraindicated in patients with a history of hypersensitivity to fluvoxamine maleate or any of the excipients.
Luvox cr (Fluvoxamine) Warnings
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 and ― , for a description of the risks of discontinuation of Luvox cr (Fluvoxamine) 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.
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 (Fluvoxamine) Capsules should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI (see ).
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 (Fluvoxamine) 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 (Fluvoxamine) Capsules with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Luvox cr (Fluvoxamine) 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 (Fluvoxamine) Capsules with serotonin precursors (such as tryptophan) is not recommended.
Treatment with Luvox cr (Fluvoxamine) 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.
The effect of fluvoxamine (25 mg immediate-release tablets given twice daily 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 3-fold following co-administration of fluvoxamine.
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 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. Luvox cr (Fluvoxamine) Capsules and tizanidine should not be used together (see and ).
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 (Fluvoxamine) Capsules not be used in combination with alosetron (see , , and Lotronex (alosetron) package insert).
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 and ).
Luvox cr (Fluvoxamine) Precautions
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Luvox cr (Fluvoxamine) Capsules and should counsel them in the appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Luvox cr (Fluvoxamine) Capsules. 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 Luvox cr (Fluvoxamine) Capsules.
Luvox cr (Fluvoxamine) Capsules have not been evaluated in pediatric patients (see ). The efficacy of fluvoxamine maleate administered as immediate-release tablets for the treatment of OCD, 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 immediate-release fluvoxamine maleate tablets (see and).
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 .
Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see and ). Anyone considering the use of Luvox cr (Fluvoxamine) Capsules in a child or adolescent must balance the potential risks with the clinical need.
Luvox cr (Fluvoxamine) Adverse Reactions
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder and with aging, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and health care providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.
Table 6 displays the incidence of sexual side effects reported by at least 2% of patients taking Luvox cr (Fluvoxamine) Capsules in placebo-controlled trials of social anxiety disorder and OCD.
Fluvoxamine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae and upon discontinuation of fluvoxamine.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, health care providers should routinely inquire about such possible side effects.
During premarketing clinical trials conducted in North America and Europe, multiple doses of immediate-release fluvoxamine maleate tablets 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 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 list below, with the following exceptions: 1) those events already listed in Table 2, 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.
1
2
Luvox cr (Fluvoxamine) Overdosage
Exposure to immediate-release fluvoxamine maleate tablets includes over 45,000 patients treated in clinical trials and an estimated exposure of 50,000,000 patients treated during worldwide marketing experience (end of 2005). Of the 539 cases of deliberate or accidental overdose involving fluvoxamine reported from this population, there were 55 deaths. Of these, 9 were in patients thought to be taking immediate-release fluvoxamine tablets alone and the remaining 46 were in patients taking fluvoxamine along with other drugs. Among non-fatal overdose cases, 404 patients recovered completely. Five patients experienced adverse sequelae of overdosage, to include persistent mydriasis, unsteady gait, hypoxic encephalopathy, kidney complications (from trauma associated with overdose), bowel infarction requiring a hemicolectomy, and vegetative state. In 13 patients, the outcome was provided as abating at the time of reporting. In the remaining 62 patients, the outcome was unknown. The largest known ingestion of fluvoxamine immediate-release tablets 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.
In the controlled clinical trials with 403 patients treated with Luvox cr (Fluvoxamine) Capsules, there was one nonfatal intentional overdose.
Commonly (≥5%) observed adverse events associated with fluvoxamine maleate overdose include gastrointestinal complaints (nausea, vomiting, and diarrhea), coma, hypokalemia, hypotension, respiratory difficulties, somnolence, and tachycardia. Other notable signs and symptoms seen with immediate-release 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, dizziness, liver function disturbances, tremor, 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 maleate 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 under ).
In managing overdosage, consider the possibility of multiple drug involvement. The health care provider should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the (PDR).
Luvox cr (Fluvoxamine) Dosage And Administration
The recommended starting dose for Luvox cr (Fluvoxamine) Capsules in adult patients is 100 mg once per day. Luvox cr (Fluvoxamine) Capsules should be administered, with or without food, as a single daily dose at bedtime. In the controlled clinical trials establishing the effectiveness of Luvox cr (Fluvoxamine) Capsules in social anxiety disorder and OCD, patients were titrated in 50 mg increments within a dose range of 100 mg/day to 300 mg/day. Consequently, the dose should be increased in 50 mg increments every week, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day.
Capsules should not be crushed or chewed.
Dosage for Elderly or Hepatically Impaired Patients
Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of fluvoxamine maleate. Consequently, it may be appropriate to titrate slowly following the initial dose of 100 mg in these patient groups.
No neonates have been exposed to Luvox cr (Fluvoxamine) Capsules. Neonates exposed to immediate-release 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 ). When treating pregnant women with Luvox cr (Fluvoxamine) Capsules during the third trimester, the health care provider should carefully consider the potential risks and benefits of treatment. The health care provider may consider tapering Luvox cr (Fluvoxamine) Capsules in the third trimester.
Luvox cr (Fluvoxamine) How Supplied
Bottles of 30.......................NDC 68727-600-01
Bottles of 30.......................NDC 68727-601-01
Storage
Luvox cr (Fluvoxamine) Capsules should be protected from high humidity and stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Avoid exposure to temperatures above 30°C (86°F).
Dispense in tight containers.
Lotronex is a trademark of GlaxoSmithKline
LUVOX is a registered trademark of Solvay Pharmaceuticals, Inc.
Distributed by:
Palo Alto, CA 94304
LCR-PI-05 Rev 0209
© 2009 Jazz Pharmaceuticals, Inc.
Luvox cr (Fluvoxamine) Medication Guideantidepressant Medicines, Depression And Other Serious Mental Illnesses, And Suicidal Thoughts Or Actions
Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
Palo Alto, CA 94304
LCR-MG-04 Rev 0208
© 2008 Jazz Pharmaceuticals, Inc.
