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.
TABLE 3 DRUG-PLACEBO DIFFERENCES IN NUMBER OF CASES OF SUICIDALITY PER 1000 PATIENTS TREATED | Age Range | Drug-Related Increases |
| <18 | 14 additional cases |
| 18-24 | 5 additional cases |
| Age Range | Drug-Related Decreases |
| 25-64 | 1 fewer case |
| ≥65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see 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).
Potential Thioridazine Interaction
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.
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 its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic co-administration.
Evidence supporting the conclusion that it is inadvisable to co-administer fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of immediate-release fluvoxamine maleate tablets were administered a single oral dose of 10 mg of diazepam. In these subjects (N = 8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the two-week long study.
It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration. Moreover, as noted with alprazolam, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses.
Accordingly, diazepam and fluvoxamine should not ordinarily be co-administered.
Mexiletine – The effect of steady-state immediate-release fluvoxamine maleate tablets (50 mg given twice daily for 7 days) on the single-dose pharmacokinetics of mexiletine (200 mg) was evaluated in 6 healthy Japanese males. The clearance of mexiletine was reduced by 38% following co-administration with fluvoxamine compared to mexiletine alone. If fluvoxamine and mexiletine are co-administered, serum mexiletine levels should be monitored.
Neuroleptic Malignant Syndrome (NMS) or NMS-Like Events:
Rare instances of neuroleptic malignant syndrome (NMS) or NMS-like events have been reported in association with fluvoxamine treatment when co-administered with anti-psychotics. Additionally, a small number of such cases have been reported with fluvoxamine treatment in the absence of anti-psychotic co-administration. These serious and sometimes fatal events can include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes. As these events may result in potentially life-threatening conditions, patients receiving this combination of therapy should be monitored for the emergence of NMS-like signs and symptoms. Treatment with fluvoxamine and any concomitant anti-psychotic agent should be discontinued immediately if such events occur and supportive symptomatic treatment should be initiated.
Theophylline:
The effect of steady-state immediate-release fluvoxamine maleate tablets (50 mg tablets given twice daily) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is co-administered with fluvoxamine maleate, its dose should be reduced to one third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for LUVOX CR Capsules.
Warfarin:
When immediate-release fluvoxamine maleate tablets (50 mg given three times per day) were administered concomitantly with warfarin for two weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and LUVOX CR Capsules should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for LUVOX CR Capsules.
Serotonin Syndrome:
The development of a potentially life-threatening serotonin syndrome may occur with LUVOX CR Capsules treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs that impair metabolism of serotonin (including MAOIs). 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).
The concomitant use of LUVOX CR Capsules with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS – Potential for Interactions with Monoamine Oxidase Inhibitors).
If concomitant treatment of LUVOX CR Capsules with a 5-hydroxtryptamine receptor agonist (triptan) is clinically warranted careful observation of the patient is advised, particularly during treatment initiation and dose increase (see PRECAUTIONS – Drug Interactions).
The concomitant use of fluvoxamine with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS – Drug Interactions).
PRECAUTIONS
General
Discontinuation of Treatment with LUVOX CR Capsules:
During marketing of immediate-release fluvoxamine maleate tablets and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with LUVOX CR Capsules. A gradual reduction in 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 health care provider may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).
Abnormal Bleeding:
SSRIs and SNRIs, including LUVOX CR Capsules, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of LUVOX CR Capsules and NSAIDs, aspirin, or other drugs that affect coagulation.
Activation of Mania/Hypomania:
During premarketing studies of immediate-release fluvoxamine maleate tablets involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with fluvoxamine. In a 10-week pediatric OCD study, 2 out of 57 patients (4%) treated with fluvoxamine experienced manic reactions, compared to none of 63 placebo patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, LUVOX CR Capsules should be used cautiously in patients with a history of mania.
Seizures:
During premarketing studies with immediate-release fluvoxamine maleate tablets, seizures were reported in 0.2% of fluvoxamine-treated patients. Caution is recommended when the drug is administered to patients with a history of convulsive disorders. Fluvoxamine should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Treatment with fluvoxamine should be discontinued if seizures occur or if seizure frequency increases.
Hyponatremia:
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including LUVOX CR Capsules. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of LUVOX CR Capsules should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Use in Patients with Concomitant Illness:
Closely monitored clinical experience with immediate-release fluvoxamine maleate tablets in patients with concomitant systemic illness is limited. Caution is advised in administering LUVOX CR Capsules to patients with diseases or conditions that could affect hemodynamic responses or metabolism.
LUVOX CR Capsules or immediate-release fluvoxamine maleate tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing. Evaluation of the electrocardiograms for patients with depression or OCD who participated in premarketing studies revealed no differences between fluvoxamine and placebo in the emergence of clinically important ECG changes.
In patients with liver dysfunction, following administration of immediate-release fluvoxamine maleate tablets, fluvoxamine clearance was decreased by approximately 30%. Patients with liver dysfunction should begin with a low dose of LUVOX CR Capsules and increase it slowly with careful monitoring.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with LUVOX CR 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 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 Capsules.
Abnormal Bleeding:
Patients should be cautioned about the concomitant use of fluvoxamine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Clinical Worsening and Suicide Risk:
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate the need for very close monitoring and possibly changes in the medication.
Interference with Cognitive or Motor Performance:
Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that LUVOX CR Capsules therapy does not adversely affect their ability to engage in such activities.
Pregnancy:
Patients should be advised to notify their health care providers if they become pregnant or intend to become pregnant during therapy with LUVOX CR Capsules.
Nursing:
Patients receiving LUVOX CR Capsules should be advised to notify their health care providers if they are breast feeding an infant (see PRECAUTIONS – Nursing Mothers).
Concomitant Medication:
Patients should be advised to notify their health care providers 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 LUVOX CR Capsules. Patients should be cautioned about the concomitant use of LUVOX CR Capsules 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.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of LUVOX CR Capsules and triptans, tramadol or other serotonergic agents.
Because of the potential for the increased risk of serious adverse reactions, including severe lowering of blood pressure and sedation, when LUVOX CR Capsules 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 LUVOX CR Capsules and alosetron are used together, fluvoxamine should not be used with LotronexTM (alosetron).
Alcohol:
Patients should be advised to avoid alcohol while taking LUVOX CR Capsules.
Allergic Reactions:
Patients should be advised to notify their health care providers if they develop a rash, hives, or a related allergic phenomenon during therapy with LUVOX CR Capsules.
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
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 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 warfarin or theophylline, certain benzodiazepines 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).
CNS Active Drugs:
Anti-psychotics: See WARNINGS – Other Potentially Important Drug Interactions – Neuroleptic Malignant Syndrome (NMS) or NMS-Like Events .
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
Alprazolam: See WARNINGS.
Diazepam: See WARNINGS.
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.
Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity have been reported with the co-administration of immediate-release fluvoxamine maleate tablets and carbamazepine.
Clozapine: Elevated serum levels of clozapine have been reported in patients taking immediate-release fluvoxamine maleate tablets and clozapine. Since clozapine related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse events may be higher when fluvoxamine and clozapine are co-administered. Patients should be closely monitored when LUVOX CR Capsules and clozapine are used concurrently.
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 co-administration of immediate-release fluvoxamine maleate tablets and lithium.
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 co-administration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone.
Methadone: Significantly increased methadone (plasma level:dose) ratios have been reported when immediate-release fluvoxamine maleate tablets were administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient.
Ramelteon: When immediate-release fluvoxamine maleate tablets 100 mg twice daily was administered for 3 days prior to single-dose co-administration of ramelteon 16 mg and immediate-release fluvoxamine maleate tablets, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with LUVOX CR Capsules (see WARNINGS).
Serotonergic Drugs: Based on the mechanism of action of LUVOX CR Capsules and the potential for serotonin syndrome, caution is advised when fluvoxamine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol or St. John’s Wort (see WARNINGS – Serotonin Syndrome). The concomitant use of LUVOX CR Capsules with other SSRIs, SNRIs, or tryptophan is not recommended (see PRECAUTIONS – Drug Interactions).
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, etc.) is clinically warranted, appropriate observation of the patient is advised.
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-fold 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 co-administration, consistent with the cholinergic effects of tacrine.
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluvoxamine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome).
Tizanidine: See CONTRAINDICATIONS and WARNINGS.
Tricyclic Antidepressants (TCAs): Significantly increased plasma TCA levels have been reported with the co-administration of immediate-release fluvoxamine maleate tablets and amitriptyline, clomipramine, or imipramine. Caution is indicated with the co-administration of LUVOX CR Capsules and TCAs; plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced.
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 co-administration of immediate-release fluvoxamine maleate tablets and tryptophan.
Other Drugs:
Theophylline: See WARNINGS.
Warfarin: See WARNINGS.
Alosetron: Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with co-administration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. (see CONTRAINDICATIONS, PRECAUTIONS, and LotronexTM (alosetron) package insert).
Digoxin: 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.
Diltiazem: Bradycardia has been reported with the co-administration of immediate-release fluvoxamine maleate tablets and diltiazem.
Propranolol and Other Beta-Blockers: Co-administration of immediate-release fluvoxamine maleate tablets 100 mg per day and propranolol 160 mg per day in normal volunteers resulted in a mean 5-fold increase (range 2-fold to 17-fold) 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 co-administration of immediate-release fluvoxamine maleate tablets and metoprolol.
If propranolol or metoprolol is co-administered 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.
Co-administration 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.
Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) –
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when LUVOX CR Capsules is initiated or discontinued.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis:
There was no evidence of carcinogenicity in rats treated orally with fluvoxamine maleate for 30 months or hamsters treated orally with fluvoxamine maleate for 20 months (females) or 26 months (males). The daily doses in the high dose groups in these studies were increased over the course of the study from a minimum of 160 mg/kg to a maximum of 240 mg/kg in rats, and from a minimum of 135 mg/kg to a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 6 times the maximum human daily dose on a mg/m2 basis.
Mutagenesis:
No evidence of genotoxic potential was observed in a mouse micronucleus test, an in vitro chromosome aberration test, or the Ames microbial mutagen test with or without metabolic activation.
Impairment of Fertility:
In a study in which male and female rats were administered fluvoxamine (60 mg/kg, 120 mg/kg, or 240 mg/kg) orally prior to and during mating and gestation, fertility was impaired at doses of 120 mg/kg or greater, as evidenced by increased latency to mating, decreased sperm count, decreased epididymal weight, and decreased pregnancy rate. In addition, the numbers of implantations and embryos were decreased at the highest dose. The no effect dose for fertility impairment was 60 mg/kg (approximately 2 times the maximum recommended human dose [MRHD] on a mg/m2 basis).
Pregnancy
Teratogenic Effects – Pregnancy Category C:
When pregnant rats were given fluvoxamine (60 mg/kg, 120 mg/kg, or 240 mg/kg) orally throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater. Decreased fetal body weight was seen at the high dose. The no effect dose for developmental toxicity in this study was 60 mg/kg (approximately 2 times the maximum recommended human dose [MRHD] on a mg/m2 basis).
In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2 times the MRHD on a mg/m2 basis) orally during organogenesis, no adverse effects on embryofetal development were observed.
In other reproductive studies in which female rats were dosed orally during pregnancy and lactation (5 mg/kg, 20 mg/kg, 80 mg/kg, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.1 times the MRHD on a mg/m2 basis).
Nonteratogenic Effects:
Neonates exposed to immediate-release fluvoxamine maleate tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on Postmarketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs or SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN is associated with substantial neonatal morbidity and mortality. In a case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately 6-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. PPHN occurs in 1-2 per 1000 live births in the general population.
When treating a pregnant woman with LUVOX CR Capsules during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
Labor and Delivery
The effect of fluvoxamine on labor and delivery in humans is unknown.
Nursing Mothers
Fluvoxamine is secreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants from LUVOX CR Capsules, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
LUVOX CR Capsules have not been evaluated in pediatric patients (see BOXED WARNING). 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 ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
Decreased appetite and weight loss have been observed in association with the use of fluvoxamine as well as other SSRIs. Consequently, regular monitoring of weight and growth is recommended if treatment of a child with an SSRI is to be continued long term.
The risks, if any, that may be associated with fluvoxamine’s extended use in children and adolescents with OCD have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that fluvoxamine is safe for use in children and adolescents derives from relatively short-term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that fluvoxamine possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of fluvoxamine to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide Risk).
Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOXED WARNING and WARNINGS – Clinical Worsening and Suicide Risk ). Anyone considering the use of LUVOX CR Capsules in a child or adolescent must balance the potential risks with the clinical need.
Geriatric Use
Approximately 230 patients and 5 patients participating in controlled premarketing studies with immediate-release fluvoxamine maleate tablets and LUVOX CR Capsules, respectively, 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, LUVOX CR Capsules should be slowly titrated during initiation of therapy. SSRIs and SNRIs, including LUVOX CR Capsules, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
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