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Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Trial Data Sources
LUVOX CR Capsules were studied in one 12-week controlled trial in patients with OCD (N = 124; mean exposure 66.6 days) and in two 12-week controlled trials for another condition (N = 279; mean exposure 59.2 days). Patients in these trials were initiated on 100 mg/day and were titrated in 50 mg increments over the first 6 weeks to within a range of 100 mg to 300 mg/day. The reactions listed in Table 2 show reactions from the two populations separately. Table 3 shows reactions from the three controlled studies combined.
Adverse Reactions Observed In Controlled Trials
Adverse Reactions Associated with Discontinuation of Treatment
Of the 124 patients with OCD and 279 patients in other studies treated with LUVOX CR Capsules in controlled clinical trials, 19% and 26% discontinued treatment due to an adverse reaction. The most common reactions ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those reactions associated with dropout at a rate at least twice that of placebo) were anorexia (including, but not limited to, loss of appetite and decreased appetite) (1%), anxiety (3%), asthenia (3%), diarrhea (2%), dizziness (4%), headache (2%), insomnia (5%), nausea (7%), nervousness (1%), somnolence (5%), and thinking abnormal (1%).
Commonly Observed Adverse Reactions
LUVOX CR Capsules have been studied in one controlled trial in patients with OCD (N = 124) and two controlled trials for another condition (N = 279). In general, adverse reaction rates were similar in the two data sets as well as in a study of pediatric patients with OCD treated with immediate-release fluvoxamine maleate tablets. The most commonly observed treatment-emergent adverse reactions associated with the use of LUVOX CR Capsules and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) and derived from Table 2 were: abnormal ejaculation, anorexia, anorgasmia, asthenia, diarrhea, nausea, somnolence, sweating, and tremor. In the one controlled trial in patients with OCD, the following additional reactions occurred at an incidence of 5% or greater and at least twice that for placebo: anxiety, decreased libido, myalgia, pharyngitis, and vomiting. The following additional reactions occurred in another studied population: dyspepsia, dizziness, insomnia, and yawning. In a study evaluating immediate-release fluvoxamine maleate tablets in pediatric patients with OCD, the following additional reactions were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash.
Adverse Reactions Occurring at an Incidence of ≥ 2%
Table 2 enumerates adverse reactions that occurred in adults at a frequency of 2% or more, and were more frequent than in the placebo group, among patients treated with LUVOX CR Capsules in two short-term, placebo-controlled trials (12 weeks) in another population and one short-term placebo-controlled OCD trial (12 weeks) and in which patients were dosed once-a-day in a range of 100 to 300 mg/day. This table shows the percentage of patients in each group who had at least one occurrence of a reaction at some time during their treatment. Reported adverse reactions were classified using a COSTART-based Dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing health care provider with some basis for estimating the relative contribution of drug and non-drug factors to the side-effect incidence rate in the population studied.
TABLE 2 : TREATMENT-EMERGENT ADVERSE REACTION
INCIDENCE RATES BY BODY SYSTEM IN ADULT OCD PATIENTS AND ANOTHER STUDIED
|BODY SYSTEM/ ADVERSE REACTION||PERCENTAGE OF PATIENTS REPORTING REACTION|
|OBSESSIVE COMPULSIVE DISORDER||OTHER STUDIED POPULATION|
N = 124
N = 124
N = 279
N = 276
|BODY AS A WHOLE|
|Viral Infection||2||< 1||-||-|
|Tooth Disorder||2||< 1||-||-|
|Liver Function Test Abnormal||-||-||2||< 1|
|HEMIC AND LYMPHATIC|
|METABOLIC AND NUTRITIONAL DISORDERS|
|Weight Loss||2||< 1|
|Abnormal Thinking||3||< 1||3||2|
|Agitation||2||< 1||3||< 1|
|Taste Perversion||2||< 1||2||< 1|
|Sexual Function Abnormal||2||< 1||3||< 1|
|Urinary Tract Infection||-||-||2||< 1|
|1Events for which fluvoxamine maleate
incidence was equal to or less than placebo include the following for OCD
patients: abdominal pain, flu syndrome, infection, palpitation, flatulence,
increased appetite, weight gain, abnormal dreams, amnesia, hypertonia,
nervousness, paresthesia, increased cough, dyspnea, rhinitis, and ear pain. In
the other studied population the following events were seen: abdominal pain,
accidental injury, back pain, flu syndrome, infection, pain, flatulence,
pharyngitis, rhinitis, rash, and dysmenorrhea.
2Term includes body aches/pains, dental pain, pain from surgery, unspecified pain, and general pain secondary to injuries (sprains, fractures).
3Includes, but is not limited to, loss of appetite and decreased appetite.
Other Adverse Reactions In OCD Pediatric Population
In pediatric patients (N=57) treated with immediate-release fluvoxamine maleate tablets, the overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions, not appearing in Table 2, were reported in two or more of the pediatric patients and were more frequent with immediate-release fluvoxamine maleate tablets than with placebo: cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, manic reaction, rash, sinusitis, and weight decrease.
Male And Female Sexual Dysfunction With SSRIs
Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder and with aging, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and 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 3 displays the incidence of sexual side effects reported by at least 2% of patients taking LUVOX CR Capsules in placebo-controlled trials.
TABLE 3 : PERCENTAGE OF PATIENTS REPORTING SEXUAL
ADVERSE REACTIONS IN PLACEBO-CONTROLLED TRIALS
N = 403
N = 400
|Sexual Function Abnormal|
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.
Weight And Vital Sign Changes
No statistically significant differences in weight gain or loss were found between patients treated with LUVOX CR Capsules or placebo. Comparisons of immediate-release fluvoxamine maleate tablets or LUVOX CR Capsules versus placebo groups in separate short-term 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 measures of vital signs variables revealed no important differences between fluvoxamine maleate and placebo.
Comparisons of immediate-release fluvoxamine maleate tablets or LUVOX CR Capsules versus placebo groups in separate short-term 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 immediate-release fluvoxamine maleate tablets or LUVOX CR Capsules 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.
Other Reactions Observed During The Premarketing Evaluation Of Fluvoxamine
During premarketing clinical trials conducted in North America and Europe, multiple doses of LUVOX CR Capsules or immediate-release fluvoxamine maleate tablets were administered for a combined total of 3219 patient exposures in patients suffering OCD or other studied disorders. These exposures include 482 patient exposures with LUVOX CR Capsules and 2737 patient exposures with immediate-release fluvoxamine maleate tablets. Untoward reactions 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 reactions without first grouping similar types of untoward reactions into a limited (i.e., reduced) number of standard reaction categories.
In the tabulations that follow, a COSTART-based Dictionary terminology has been used to classify reported adverse reactions. If the COSTART term for a reaction was so general as to be uninformative, it was replaced with a more informative term when possible. The frequencies presented, therefore, represent the proportion of the total patient exposures to multiple doses of fluvoxamine maleate who experienced a reaction of the type cited on at least one occasion while receiving fluvoxamine maleate. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring between 1/100 and 1/1000 patients; and Rare adverse reactions are those occurring in less than 1/1000 patients. 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.
For LUVOX CR, all reported events are included in the list below, with the following exclusions: 1) those events already listed in Table 2 or previous sections of this prescribing information; 2) those events for which there is no basis to suspect a causal relationship; and 3) events that were reported in only one patient and judged not to be potentially serious.
Cardiovascular System: Infrequent: syncope.
Digestive System: Infrequent: eructation, increased salivation.
Metabolic and Nutritional Disorders: Frequent: weight gain.
Nervous System: Infrequent: confusion, incoordination, sleep disorder, suicidal tendency.
Special Senses: Infrequent: dry eyes, photophobia, taste loss.
Urogenital System: Infrequent: vaginal hemorrhage1.
1Based on the number of females.
For immediate-release fluvoxamine tablets, all reported events are included in the list below, with the following exclusions: 1) those events already listed in Table 2, in previous sections of this prescribing information, or in the LUVOX CR list of Other Reactions Observed During Premarketing Evaluation; 2) those events for which there is no basis to suspect a causal relationship; and 3) events that were reported in only one patient and judged not to be potentially serious.
Body as a Whole: Infrequent: allergic reaction, neck pain, neck rigidity, overdose; Rare: sudden death.
Cardiovascular System: Frequent: hypotension; Infrequent: angina pectoris, bradycardia, cardiomyopathy, cardiovascular disease, cold extremities, conduction delay, myocardial infarction, pallor, pulse irregular, ST segment changes; Rare: AV block, cerebrovascular accident, embolus, pericarditis, phlebitis, pulmonary infarction, supraventricular extrasystoles.
Digestive System: Frequent: elevated liver transaminases; Infrequent: colitis, esophagitis, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal ulcer, glossitis, hemorrhoids, melena, rectal hemorrhage, stomatitis; Rare: biliary pain, cholecystitis, cholelithiasis, fecal incontinence, hematemesis, intestinal obstruction, jaundice.
Metabolic and Nutritional Systems: Frequent: edema; Infrequent: dehydration, hypercholesterolemia; Rare: diabetes mellitus, hyperglycemia, hyperlipidemia, hypoglycemia, hypokalemia, lactate dehydrogenase increased.
Nervous System: Frequent: amnesia, apathy, hyperkinesia, hypokinesia, manic reaction, myoclonus, psychotic reaction; Infrequent: agoraphobia, akathisia, ataxia, CNS depression, convulsion, delirium, delusion, depersonalization, dyskinesia, dystonia, emotional lability, euphoria, extrapyramidal syndrome, gait unsteady, hallucinations, hemiplegia, hostility, hypersomnia, hypochondriasis, hypotonia, hysteria, increased libido, paralysis, paranoid reaction, phobia, psychosis, stupor, twitching, vertigo; Rare: akinesia, coma, fibrillations, mutism, obsessions, reflexes decreased, slurred speech, tardive dyskinesia, torticollis, trismus, withdrawal syndrome.
Respiratory System: Frequent: cough increased, sinusitis; Infrequent: asthma, bronchitis, hoarseness, hyperventilation; Rare: apnea, congestion of upper airway, hemoptysis, hiccups, laryngismus, obstructive pulmonary disease, pneumonia.
Urogenital System: Infrequent: anuria, cystitis, delayed menstruation1, dysuria, female lactation1, hematuria, menopause1, metrorrhagia1, nocturia, premenstrual syndrome1, urination impaired, vaginitis1; Rare: kidney calculus, hematospermia2, oliguria.
1Based on the number of females.
2Based on the number of males.
The following adverse reactions have been identified during post-approval use of immediate-release fluvoxamine maleate tablets or LUVOX CR Capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. (Reactions that are discussed in other sections of this prescribing information are not repeated here.) These reactions include: activation syndrome, aggression, agranulocytosis, anaphylactic reaction, anger, blood glucose increased, bruxism, cardio-respiratory arrest, crying, dysarthria, dysphagia, electrocardiogram QT prolonged, fall, fatigue, feeling drunk, feeling jittery, gait disturbance, gastroesophageal reflux disease, glossodynia, hepatitis, homicidal ideation, impulsive behavior, ileus, inappropriate antidiuretic hormone secretion, interstitial lung disease, irritability, loss of consciousness, lethargy, muscular weakness, Parkinsonism, pancreatitis, pyrexia, renal impairment, rhabdomyolysis, self injurious behavior, shock, somnolence neonatal, Stevens-Johnson syndrome, tachycardia, urinary retention, ventricular arrythmia, ventricular tachycardia (including torsades de pointes known to cause cardiac arrest, sometimes fatal), vision blurred, white blood cell count decreased.
Read the Luvox CR (fluvoxamine maleate extended-release capsules) Side Effects Center for a complete guide to possible side effects
Potential Interactions With Drugs That Inhibit Or Are Metabolized By Cytochrome P450 Isoenzymes
Multiple hepatic cytochrome P450 isoenzymes are involved in the oxidative biotransformation of a large number of structurally different drugs and endogenous compounds. The available knowledge concerning the relationship of fluvoxamine and the cytochrome P450 isoenzyme system has been obtained mostly from pharmacokinetic interaction studies conducted in healthy volunteers, but some preliminary in vitro data are also available. Based on a finding of substantial interactions of fluvoxamine with certain of these drugs (see later parts of this section and also WARNINGS AND PRECAUTIONS for details) and limited in vitro data for CYP3A4, it appears that fluvoxamine inhibits several cytochrome P450 isoenzymes that are known to be involved in the metabolism of other drugs such as: CYP1A2 (e.g., warfarin, theophylline, propranolol, tizanidine), CYP2C9 (e.g., warfarin), CYP3A4 (e.g., alprazolam), and CYP2C19 (e.g., omeprazole).
In vitro data suggest that fluvoxamine is a relatively weak inhibitor of CYP2D6.
Approximately 7% of the normal population has a genetic code that leads to reduced levels of activity of CYP2D6 enzyme. Such individuals have been referred to as “poor metabolizers” (PM) of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants. While none of the drugs studied for drug interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study of fluvoxamine single-dose pharmacokinetics in 13 PM subjects demonstrated altered pharmacokinetic properties compared to 16 “extensive metabolizers” (EM): mean Cmax, AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group. This suggests that fluvoxamine is metabolized, at least in part, by CYP2D6. Caution is indicated in patients known to have reduced levels of cytochrome P450 2D6 activity and those receiving concomitant drugs known to inhibit this cytochrome P450 isoenzyme (e.g., quinidine).
The metabolism of fluvoxamine has not been fully characterized and the effects of potent cytochrome P450 isoenzyme inhibition, such as the ketoconazole inhibition of CYP3A4, on fluvoxamine metabolism have not been studied.
A clinically significant fluvoxamine interaction is possible with drugs having a narrow therapeutic ratio such as pimozide, warfarin, theophylline, certain benzodiazepines, omeprazole, and phenytoin. If LUVOX CR Capsules are to be administered together with a drug that is eliminated via oxidative metabolism and has a narrow therapeutic window, plasma levels and/or pharmacodynamic effects of the latter drug should be monitored closely, at least until steady-state conditions are reached (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).
CNS Active Drugs
Antipsychotics: See WARNINGS AND PRECAUTIONS.
Benzodiazepines: See WARNINGS AND PRECAUTIONS.
Alprazolam: See WARNINGS AND PRECAUTIONS.
Diazepam: See WARNINGS AND PRECAUTIONS.
Lorazepam: A study of multiple doses of immediate-release fluvoxamine maleate tablets (50 mg given twice daily) in healthy male volunteers (N=12) and a single dose of lorazepam (4 mg single dose) indicated no significant pharmacokinetic interaction. On average, both lorazepam alone and lorazepam with fluvoxamine produced substantial decrements in cognitive functioning; however, the coadministration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone.
Alcohol: Studies involving single 40 g doses of ethanol (oral administration in one study and intravenous in the other) and multiple dosing with immediate-release fluvoxamine maleate tablets (50 mg given twice daily) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other. As with other psychotropic medications, patients should be advised to avoid alcohol while taking LUVOX CR Capsules.
Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and carbamazepine.
Clozapine: See WARNINGS AND PRECAUTIONS.
Lithium: As with other serotonergic drugs, lithium may enhance the serotonergic effects of fluvoxamine and, therefore, the combination should be used with caution. Seizures have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and lithium.
Methadone: See WARNINGS AND PRECAUTIONS.
Serotonergic Drugs: See WARNINGS AND PRECAUTIONS.
Tacrine: In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to immediate-release fluvoxamine maleate tablets 100 mg/day administered at steady-state was associated with 5-and 8-fold increases in tacrine Cmax and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine.
Tricyclic Antidepressants (TCAs): Significantly increased plasma TCA levels have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and amitriptyline, clomipramine or imipramine. Caution is indicated with the coadministration of LUVOX CR Capsules and TCAs; plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced.
Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of LUVOX CR Capsules with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS AND PRECAUTIONS.
Sumatriptan -There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
Tryptophan: Tryptophan may enhance the serotonergic effects of fluvoxamine, and the combination should, therefore, be used with caution. Severe vomiting has been reported with the coadministration of immediate-release fluvoxamine maleate tablets and tryptophan (see WARNINGS AND PRECAUTIONS).
Administration of immediate-release fluvoxamine maleate tablets 100 mg daily for 18 days (N=8) did not significantly affect the pharmacokinetics of a 1.25 mg single intravenous dose of digoxin.
Bradycardia has been reported with the coadministration of immediate-release fluvoxamine maleate tablets and diltiazem.
See WARNINGS AND PRECAUTIONS.
Propranolol and Other Beta-Blockers
Coadministration of immediate-release fluvoxamine maleate tablets 100 mg per day and propranolol 160 mg per day in normal volunteers resulted in a mean five-fold increase (range 2 to 17) in minimum propranolol plasma concentrations. In this study, there was a slight potentiation of the propranolol-induced reduction in heart rate and reduction in the exercise diastolic pressure.
One case of bradycardia and hypotension and a second case of orthostatic hypotension have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and metoprolol.
If propranolol or metoprolol is coadministered with LUVOX CR Capsules, a reduction in the initial beta-blocker dose and more cautious dose titration are recommended. No dosage adjustment is required for LUVOX CR Capsules.
Coadministration of immediate-release fluvoxamine maleate tablets 100 mg per day with atenolol 100 mg per day (N=6) did not affect the plasma concentrations of atenolol. Unlike propranolol and metoprolol, which undergo hepatic metabolism, atenolol is eliminated primarily by renal excretion.
See WARNINGS AND PRECAUTIONS.
Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.)
See WARNINGS AND PRECAUTIONS.
Effects Of Smoking On Fluvoxamine Metabolism
Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers.
Electroconvulsive Therapy (ECT)
There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.
Monoamine Oxidase Inhibitors (MAOIs)
Drug Abuse And Dependence
Controlled Substance Class
LUVOX CR is not a controlled substance.
Physical And Psychological Dependence
The potential for abuse, tolerance, and physical dependence with immediate-release fluvoxamine maleate has been studied in a nonhuman primate model. No evidence of dependency phenomena was found. The discontinuation effects of LUVOX CR Capsules were not systematically evaluated in controlled clinical trials. LUVOX CR Capsules 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 immediate-release 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, health care providers should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of LUVOX CR misuse or abuse (i.e., development of tolerance, incrementation of dose, drug-seeking behavior).
Read the Luvox CR Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 2/3/2017
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