Fluvoxamine

Fluvoxamine is used to treat obsessive-compulsive disorder (bothersome thoughts that won't go away and the need to perform certain actions over and over) and social anxiety disorder (extreme fear of interacting with others or performing in front of others that interferes with normal life). Fluvoxamine is in a class of medications called selective serotonin reuptake inhibitors (SSRIs). It works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance.

Fluvoxamine may be found in some form under the following brand names:

• Luvox

• Luvox CR

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of fluvoxamine, there are no specific foods that you must exclude from your diet when receiving this medication.

You should not take fluvoxamine if you are also using alosetron, pimozide, ramelteon, thioridazine, or tizanidine.

Do not use fluvoxamine within 14 days before or 14 days after you have taken an MAO inhibitor, such as isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, and tranylcypromine.

Some young people have thoughts about suicide when first taking an antidepressant. Stay alert to changes in your mood or symptoms. Report any new or worsening symptoms to your doctor.

Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.

Do not stop using desvenlafaxine without first talking to your doctor.

Taking fluvoxamine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking a sleeping pill, opioid medication, muscle relaxer, or medicine for anxiety, depression, or seizures.

Many drugs can interact with fluvoxamine. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• methadone, mexiletine, St. John's wort, theophylline, tramadol, tryptophan (also called L-tryptophan);

• a diuretic or "water pill";

• a blood thinner--warfarin, Coumadin, Jantoven;

• medicine to treat anxiety, mood disorders, thought disorders, or mental illness--such as clozapine, lithium, antidepressants, or antipsychotics;

• migraine headache medicine--sumatriptan, rizatriptan, zolmitriptan, and others; or

• a sedative--diazepam, alprazolam, midazolam, triazolam, Valium, Xanax.

This list is not complete and many other drugs can interact with fluvoxamine. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

 Coadministration of tizanidine, thioridazine, alosetron, or pimozide with Fluvoxamine Maleate Tablets is contraindicated.

[See WARNINGS AND PRECAUTIONS (5.4-5.7)].

Serotonin Syndrome and Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with Fluvoxamine Maleate Tablets or within 14 days of stopping treatment with Fluvoxamine Maleate Tablets is contraindicated because of an increased risk of serotonin syndrome. The use of Fluvoxamine Maleate Tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. [see DOSAGE AND ADMINISTRATION (2.5) and WARNINGS AND PRECAUTIONS (5.2)].

Starting Fluvoxamine Maleate Tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see DOSAGE AND ADMINISTRATION (2.6) and WARNINGS AND PRECAUTIONS (5.2)].

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. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

TABLE 1 DRUG-PLACEBO DIFFERENCES IN NUMBER OF CASES OF SUICIDALITY PER 1000 PATIENTS TREATED

Age Range	Increases Compared to Placebo
<18	14 Additional Cases
18-24	5 Additional Cases
Age Range	Decreases Compared to Placebo
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 DOSAGE AND ADMINISTRATION – Discontinuation of Treatment with Fluvoxamine Maleate Tablets (2.8), for a description of the risks of discontinuation of Fluvoxamine Maleate Tablets].

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Fluvoxamine Maleate Tablets should be written for the smallest quantity of tablets 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 Fluvoxamine Maleate Tablets are not approved for use in treating bipolar depression.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Fluvoxamine Maleate Tablets, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, busipirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Fluvoxamine Maleate Tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Fluvoxamine Maleate Tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Fluvoxamine Maleate Tablets. Fluvoxamine Maleate Tablets should be discontinued before initiating treatment with the MAOI. [see CONTRAINDICATIONS (4.2) and DOSAGE AND ADMINISTRATION (2.5 and 2.6)].

If concomitant use of Fluvoxamine Maleate Tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with Fluvoxamine Maleate Tablets and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Angle Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Fluvoxamine Maleate Tablets may trigger an angle closure attack in a patient with anatomically narrow angles who do not have a patent iridectomy.

Potential Thioridazine Interaction

The effect of Fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased threefold following coadministration 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, Fluvoxamine and thioridazine should not be coadministered. [See CONTRAINDICATIONS (4.1)].

Potential Tizanidine Interaction

Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of Fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in 10 healthy 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. Fluvoxamine and tizanidine should not be used together. [See CONTRAINDICATIONS (4.1)].

Potential Pimozide Interaction

Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, 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. An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, a substantial pharmacokinetic interaction has been observed for Fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by CYP3A4. 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 (4.1)].

Potential Alosetron Interaction

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 coadministration 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 (4.1) and LotronexTM (alosetron) package insert].

Other Potentially Important 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 Fluvoxamine maleate (100 mg q.d.) and alprazolam (1 mg q.i.d.) were coadministered 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 coadministered, particularly since Fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100-300 mg. If alprazolam is coadministered with Fluvoxamine Maleate Tablets, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for Fluvoxamine Maleate Tablets.

Diazepam - The coadministration of Fluvoxamine Maleate Tablets 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 coadministration.

Evidence supporting the conclusion that it is inadvisable to coadminister Fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of Fluvoxamine 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 2 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 coadministered.

Clozapine - Elevated serum levels of clozapine have been reported in patients taking Fluvoxamine maleate 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 coadministered. Patients should be closely monitored when Fluvoxamine maleate and clozapine are used concurrently.

Methadone: Significantly increased methadone (plasma level:dose) ratios have been reported when Fluvoxamine maleate was 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.

Mexiletine: The effect of steady-state Fluvoxamine (50 mg b.i.d. 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 coadministration with Fluvoxamine compared to mexiletine alone. If Fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored.

Ramelteon: When Fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and Fluvoxamine, 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 Fluvoxamine.

Theophylline: The effect of steady-state Fluvoxamine (50 mg bid) 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 coadministered 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 Fluvoxamine Maleate Tablets.

Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design 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. Thus, patients should be cautioned about the use of such drugs concurrently with Fluvoxamine [see WARNINGS AND PRECAUTIONS, Abnormal Bleeding (5.10)].

Warfarin - When Fluvoxamine maleate (50 mg t.i.d.) was administered concomitantly with warfarin for two weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and Fluvoxamine Maleate Tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for Fluvoxamine Maleate Tablets.

Discontinuation of Treatment with Fluvoxamine Maleate Tablets

During marketing of 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 Fluvoxamine Maleate Tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. [See DOSAGE AND ADMINISTRATION (2.8)].

Abnormal Bleeding

SSRIs and SNRIs, including Fluvoxamine Maleate Tablets, 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 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 Fluvoxamine Maleate Tablets and NSAIDs, aspirin, or other drugs that affect coagulation [see WARNINGS AND PRECAUTIONS (5.8)].

Activation of Mania/Hypomania

During premarketing studies involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with Fluvoxamine. In a ten 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, Fluvoxamine Maleate Tablets should be used cautiously in patients with a history of mania.

Seizures

During premarketing studies, 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 Fluvoxamine Maleate Tablets. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone (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 [see USE IN SPECIFIC POPULATION, Geriatric Use (8.5)]. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Fluvoxamine Maleate Tablets 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 Fluvoxamine Maleate Tablets in patients with concomitant systemic illness is limited. Caution is advised in administering Fluvoxamine Maleate Tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism.

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.

Patients with Hepatic Impairment - In patients with liver dysfunction, Fluvoxamine clearance was decreased by approximately 30%. Patients with liver dysfunction should begin with a low dose of Fluvoxamine Maleate Tablets and increase it slowly with careful monitoring.

Laboratory Tests

There are no specific laboratory tests recommended.

Adverse Reactions Leading to Treatment Discontinuation

Of the 1087 OCD and depressed patients treated with Fluvoxamine maleate in controlled clinical trials in North America, 22% discontinued due to an adverse reaction. Adverse reactions that led to discontinuation in at least 2% of Fluvoxamine maleate-treated patients in these trials were: nausea (9%), insomnia (4%), somnolence (4%), headache (3%), and asthenia, vomiting, nervousness, agitation, and dizziness (2% each).

Incidence in Controlled Trials

Commonly Observed Adverse Reactions in Controlled Clinical Trials: Fluvoxamine Maleate Tablets have been studied in 10-week short-term controlled trials of OCD (N=320) and depression (N=1350). In general, adverse reaction rates were similar in the two data sets as well as in the pediatric OCD study. The most commonly observed adverse reactions associated with the use of Fluvoxamine Maleate Tablets and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) derived from Table 2 were: nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, and vomiting. In a pool of two studies involving only patients with OCD, the following additional reactions were identified using the above rule: anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion, and urinary frequency. In a study of 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 1%: Table 2 enumerates adverse reactions that occurred in adults at a frequency of 1% or more, and were more frequent than in the placebo group, among patients treated with Fluvoxamine Maleate Tablets in two short-term placebo controlled OCD trials (10 week) and depression trials (6 week) in which patients were dosed in a range of generally 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 standard 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 physician 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 AND DEPRESSION POPULATIONS COMBINED1

BODY SYSTEM/ADVERSE REACTION	Percentage of Patients Reporting Reaction
	Fluvoxamine N=892	PLACEBO N=778
1Reactions for which Fluvoxamine maleate incidence was equal to or less than placebo are not listed in the table above. 2Includes “toothache,” “tooth extraction and abscess,” and “caries.” 3Mostly feeling warm, hot, or flushed. 4Mostly “blurred vision.” 5Mostly “delayed ejaculation.” 6Incidence based on number of male patients.
BODY AS WHOLE
Headache	22	20
Asthenia	14	6
Flu Syndrome	3	2
Chills	2	1
CARDIOVASCULAR
Palpitations	3	2
DIGESTIVE SYSTEM
Nausea	40	14
Diarrhea	11	7
Constipation	10	8
Dyspepsia	10	5
Anorexia	6	2
Vomiting	5	2
Flatulence	4	3
Tooth Disorder2	3	1
Dysphagia	2	1
NERVOUS SYSTEM
Somnolence	22	8
Insomnia	21	10
Dry Mouth	14	10
Nervousness	12	5
Dizziness	11	6
Tremor	5	1
Anxiety	5	3
Vasodilatation3	3	1
Hypertonia	2	1
Agitation	2	1
Decreased Libido	2	1
Depression	2	1
CNS Stimulation	2	1
RESPIRATORY SYSTEM
Upper Respiratory Infection	9	5
Dyspnea	2	1
Yawn	2	0
SKIN
Sweating	7	3
SPECIAL SENSES
Taste Perversion	3	1
Amblyopia4	3	2
UROGENITAL
Abnormal Ejaculation5,6	8	1
Urinary Frequency	3	2
Impotence6	2	1
Anorgasmia	2	0
Urinary Retention	1	0

Adverse Reactions in OCD Placebo Controlled Studies Which are Markedly Different (defined as at least a two-fold difference) in Rate from the Pooled Reaction Rates in OCD and Depression Placebo Controlled Studies: The reactions in OCD studies with a two-fold decrease in rate compared to reaction rates in OCD and depression studies were dysphagia and amblyopia (mostly blurred vision). Additionally, there was an approximate 25% decrease in nausea.

The reactions in OCD studies with a two-fold increase in rate compared to reaction rates in OCD and depression studies were: asthenia, abnormal ejaculation (mostly delayed ejaculation), anxiety, rhinitis, anorgasmia (in males), depression, libido decreased, pharyngitis, agitation, impotence, myoclonus/twitch, thirst, weight loss, leg cramps, myalgia, and urinary retention. These reactions are listed in order of decreasing rates in the OCD trials.

Other Adverse Reactions in OCD Pediatric Population

In pediatric patients (N=57) treated with 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 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 physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.

Table 3 displays the incidence of sexual side effects reported by at least 2% of patients taking Fluvoxamine Maleate Tablets in placebo-controlled trials in depression and OCD.

TABLE 3 PERCENTAGE OF PATIENTS REPORTING SEXUAL ADVERSE REACTIONS IN ADULT PLACEBO-CONTROLLED TRIALS IN OCD AND DEPRESSION

*Based on the number of male patients.
	Fluvoxamine Maleate Tablets N=892	Placebo N=778
Abnormal Ejaculation*	8%	1%
Impotence*	2%	1%
Decreased Libido	2%	1%
Anorgasmia	2%	0%

There are no adequate and well-controlled studies examining sexual dysfunction with Fluvoxamine treatment.

Fluvoxamine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae and upon discontinuation of Fluvoxamine.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Vital Sign Changes

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

Laboratory Changes

Comparisons of Fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various serum chemistry, hematology, and urinalysis variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various serum chemistry, hematology, and urinalysis variables revealed no important differences between Fluvoxamine maleate and placebo.

ECG Changes

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

Other Reactions Observed During the Premarketing Evaluation of Fluvoxamine Maleate Tablets

During premarketing clinical trials conducted in North America and Europe, multiple doses of Fluvoxamine maleate were administered for a combined total of 2737 patient exposures in patients suffering OCD or Major Depressive Disorder. Untoward 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 which follow, a standard 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. The frequencies presented, therefore, represent the proportion of the 2737 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. All reported reactions are included in the list below, with the following exceptions: 1) those reactions 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 reactions for which a drug cause was not considered likely are omitted; 3) reactions for which the COSTART term was too vague to be clinically meaningful and could not be replaced with a more informative term; and 4) reactions 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 reactions reported did occur during treatment with Fluvoxamine maleate, a causal relationship to Fluvoxamine maleate has not been established.

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.

Body as a Whole – Frequent: malaise; Infrequent: photosensitivity reaction and suicide attempt.

Cardiovascular System – Frequent: syncope.

Digestive System – Infrequent: gastrointestinal hemorrhage and melena; Rare: hematemesis.

Hemic and Lymphatic Systems – Infrequent: anemia and ecchymosis; Rare: purpura.

Metabolic and Nutritional Systems – Frequent: weight gain and weight loss.

Nervous System – Frequent: hyperkinesia, manic reaction, and myoclonus; Infrequent: abnormal dreams, akathisia, convulsion, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, and twitching; Rare: withdrawal syndrome.

Respiratory System – Infrequent: epistaxis. Rare: hemoptysis and laryngismus.

Skin – Infrequent: urticaria.

Urogenital System* – Infrequent: hematuria, menorrhagia, and vaginal hemorrhage; Rare: hematospermia.

* Based on the number of males or females, as appropriate.

Postmarketing Reports

Voluntary reports of adverse reactions in patients taking Fluvoxamine Maleate Tablets that have been received since market introduction and are of unknown causal relationship to Fluvoxamine Maleate Tablets use include: acute renal failure, agranulocytosis, amenorrhea, anaphylactic reaction, angioedema, aplastic anemia, bullous eruption, Henoch-Schoenlein purpura, hepatitis, ileus, pancreatitis, porphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsades de pointes).

Fluvoxamine maleate is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the chemical series, the 2-aminoethyl oxime ethers of aralkylketones.

It is chemically designated as 5-methoxy-4′-(trifluoromethyl)valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1) and has the empirical formula C15H21O2N2F3∙C4H4O4. Its molecular weight is 434.41.

The structural formula is:

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

Fluvoxamine Maleate Tablets are available in 25 mg, 50 mg and 100 mg strengths for oral administration. In addition to the active ingredient, Fluvoxamine maleate, each tablet contains the following inactive ingredients: carnauba wax, hypromellose, mannitol, polyethylene glycol, polysorbate 80, pregelatinized starch (potato), silicon dioxide, sodium stearyl fumarate, starch (corn), and titanium dioxide. The 50 mg and 100 mg tablets also contain synthetic iron oxides.

Fluvoxamine (Flu VOX ah meen) Tablets

Read the Medication Guide that comes with Fluvoxamine Maleate Tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

What is the most important information I should know about Fluvoxamine Maleate Tablets?

Fluvoxamine is the same kind of medicine as those used to treat depression and may cause serious side effects, including:

1.  Suicidal thoughts or actions:

• Fluvoxamine Maleate Tablets and antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. • Watch for these changes and call your healthcare provider right away if you notice: • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. • Pay particular attention to such changes when Fluvoxamine Maleate Tablets is started or when the dose is changed.
  Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:

• attempts to commit suicide • acting on dangerous impulses • acting aggressive or violent • thoughts about suicide or dying • new or worse depression • new or worse anxiety or panic attacks • feeling agitated, restless, angry or irritable • trouble sleeping • an increase in activity or talking more than what is normal for you • other unusual changes in behavior or mood

Tell your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluvoxamine Maleate Tablets may be associated with these serious side effects:

2.  Serotonin Syndrome: This condition can be life-threatening and may include:

• agitation, hallucinations, coma or other changes in mental status • coordination problems or muscle twitching (overactive reflexes) • racing heartbeat, high or low blood pressure • sweating or fever • nausea, vomiting, or diarrhea • muscle rigidity

3. Visual problems

• eye pain • changes in vision • swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

4. Severe allergic reactions:

• trouble breathing • swelling of the face, tongue, eyes, or mouth • rash, itchy welts (hives) or blisters, alone or with fever or joint pain

5. Abnormal bleeding: Fluvoxamine Maleate Tablets and antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), or a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen, naproxen, or aspirin).

6. Seizures or convulsions

7. Manic episodes:

• greatly increased energy • severe trouble sleeping • racing thoughts • reckless behavior • unusually grand ideas • excessive happiness or irritability • talking more or faster than usual

8. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.

9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:  

• headache • weakness or feeling unsteady • confusion, problems concentrating or thinking or memory problems

Do not stop Fluvoxamine Maleate Tablets without first talking to your healthcare provider.

Stopping Fluvoxamine Maleate Tablets too quickly may cause serious symptoms including:

• anxiety, irritability, high or low mood, feeling restless or changes in sleep habits • headache, sweating, nausea, dizziness • electric shock-like sensations, shaking, confusion

What is Fluvoxamine Maleate Tablets?

Fluvoxamine Maleate Tablets is a prescription medicine used to treat obsessive compulsive disorder (OCD). It is important to talk with your healthcare provider about the risks of treating OCD and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.

Talk to your healthcare provider if you do not think that your condition is getting better with Fluvoxamine Maleate Tablets treatment.

Who should not take Fluvoxamine Maleate Tablets?

Do not take Fluvoxamine Maleate Tablets if you:

• are allergic to Fluvoxamine maleate or any of the ingredients in Fluvoxamine Maleate Tablets. See the end of this Medication Guide for a complete list of ingredients in Fluvoxamine Maleate Tablets. • take a Monoamine Oxidase Inhibitor (MAOI).  Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. • Do not take an MAOI within 2 weeks of stopping Fluvoxamine Maleate Tablets unless directed to do so by your physician. • Do not start Fluvoxamine Maleate Tablets if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.   People who take Fluvoxamine Maleate Tablets close in time to an MAOI may have serious or even life-threatening side effects.  Get medical help right away if you have any of these symptoms: • high fever • uncontrolled muscle spasms • stiff muscles • rapid changes in heart rate or blood pressure • confusion • loss of consciousness (pass out) • take Mellaril® (thioridazine). Do not take Mellaril® within 2 weeks of stopping Fluvoxamine MALEATE TABLETS because this can cause serious heart rhythm problems or sudden death. • take Orap® (pimozide) because taking this drug with Fluvoxamine maleate tablets can cause serious heart rhythm problems or sudden death. • take Zanaflex® (tizanidine). Fluvoxamine maleate tablets could increase the amount of Zanaflex in your body, which could increase its actions and side effects. This could include drowsiness and a drop in blood pressure and affecting how well you do things that require alertness. • Take Lotronex® (alosetron). Fluvoxamine maleate tablets may increase the amount of Lotronex in your body, which could increase its actions and side effects.

What should I tell my healthcare provider before taking Fluvoxamine Maleate Tablets? Ask if you are not sure.
Before starting Fluvoxamine Maleate Tablets, tell your healthcare provider if you:

• Are taking certain drugs such as: • Monoamine oxidase inhibitors (MAOIs) such as Emsam® (selegiline), Nardil® (phenelzine), or  Parnate® (tranylcypromine) • Mellaril® (thioridazine): used to treat mental or mood problems • Zanaflex® (tizanidine): used to treat spasticity (a condition in which muscles keep tightening and cramping) • Orap® (pimozide): used to treat Tourette Syndrome (a brain condition causing tics) • Lotronex® (alosetron): used to treat a condition with diarrhea, continuing stomach pain, cramps, and bloating • Triptans: used to treat migraine headache • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, or antipsychotics • Tramadol: used to reduce pain • Benzodiazepines: used to reduce anxiety, stress, emotional upset, or seizures; helps you sleep; helps with alcohol withdrawal; reduces restlessness; and relaxes muscles • Methadone: used to relieve pain or to help with addiction • Clozapine: used to treat mental disorders • Mexiletine: used to treat abnormalities in heart rhythm • Theophylline: used to treat swollen air passages in your lungs, to relax the muscles in your chest to ease shortness of breath, often to treat asthma • Warfarin and other drugs that affect how your blood clots • Diuretics to treat high blood pressure, congestive heart failure, or swelling • Over-the-counter supplements such as tryptophan or St. John’s Wort • have liver problems • have kidney problems • have heart problems • have or had seizures or convulsions • have bipolar disorder or mania • have low sodium levels in your blood • have a history of a stroke • have high blood pressure • have or had bleeding problems • are pregnant or plan to become pregnant. It is not known if Fluvoxamine Maleate Tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating OCD during pregnancy. • are breast-feeding or plan to breast-feed. Some Fluvoxamine Maleate Tablets may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Fluvoxamine Maleate Tablets.

Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Fluvoxamine Maleate Tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take Fluvoxamine Maleate Tablets with your other medicines. Do not start or stop any medicine while taking Fluvoxamine Maleate Tablets without talking to your healthcare provider first.

If you take Fluvoxamine Maleate Tablets, you should not take any other medicines that contain Fluvoxamine including:  LUVOX CR®

How should I take Fluvoxamine Maleate Tablets?

• Take Fluvoxamine Maleate Tablets exactly as prescribed. Your healthcare provider may need to change the dose of Fluvoxamine Maleate Tablets until it is the right dose for you. • Fluvoxamine Maleate Tablets may be taken with or without food. • If you miss a dose of Fluvoxamine Maleate Tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Fluvoxamine Maleate Tablets at the same time. • If you take too much Fluvoxamine Maleate Tablets, call your healthcare provider or poison control center right away, or get emergency treatment.

What should I avoid while taking Fluvoxamine Maleate Tablets?

Fluvoxamine Maleate Tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how Fluvoxamine Maleate Tablets affects you. Do not drink alcohol while using Fluvoxamine Maleate Tablets.

What are the possible side effects of Fluvoxamine Maleate Tablets?

Fluvoxamine Maleate Tablets may cause serious side effects, including:

• See “What is the most important information I should know about Fluvoxamine Maleate Tablets?” • Feeling anxious or trouble sleeping

Common possible side effects in people who take Fluvoxamine Maleate Tablets include:

• nausea • sleepiness • weakness • indigestion • sweating • loss of appetite • shaking • vomiting • delayed ejaculation • inability to have an orgasm • decreased sex drive • dry mouth • stuffy nose • unusual taste • frequent urination

Other side effects in children and adolescents include:

• agitation or abnormal increase in activity • feeling depressed or sad • excessive gas • heavy menstrual periods • rash • possible slowed growth rate and weight change

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.  These are not all the possible side effects of Fluvoxamine Maleate Tablets.  For more information, ask your healthcare provider or pharmacist.

Fluvoxamine Maleate Tablets USP, 25 mg
NDC 62559-158-01
Rx only
100 Tablets

Inhibits CNS neuron serotonin uptake; minimal or no effect on reuptake of norepinephrine or dopamine; does not significantly bind to alpha-adrenergic, histamine or cholinergic receptors

Distribution

Vd: ~25 L/kg

Metabolism

Extensively hepatic via oxidative demethylation and deamination

Excretion

Urine (~85% as metabolites; ~2% as unchanged drug)

For the immediate release tablets, a 30% decrease in clearance has been observed in patients with hepatic impairment compared with healthy subjects.

There are no dosage adjustments provided in manufacturer’s labeling. Limited data suggest fluvoxamine does not accumulate in patients with renal impairment. Canadian labeling recommends initiating therapy at a reduced dosage with close monitoring.

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Agomelatine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Agomelatine. Avoid combination

Ajmaline: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Management: Patients receiving selective serotonin reuptake inhibitors should be advised to avoid alcohol. Monitor for increased psychomotor impairment in patients who consume alcohol during treatment with selective serotonin reuptake inhibitors. Consider therapy modification

Alosetron: FluvoxaMINE may decrease the metabolism of Alosetron. Avoid combination

ALPRAZolam: FluvoxaMINE may increase the serum concentration of ALPRAZolam. Monitor therapy

Amifampridine: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, both drugs have the potential to decrease the seizure threshold, possibly increasing the risk for seizures. Monitor therapy

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Management: Consider alternatives, and use conservative initial dosing. Monitor patients receiving these combinations for signs/symptoms of serotonin toxicity. Consider therapy modification

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asenapine: FluvoxaMINE may increase the serum concentration of Asenapine. Monitor therapy

Aspirin: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Bendamustine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Bendamustine. Concentrations of the active metabolites of bendamustine may be decreased. Monitor therapy

Blood Glucose Lowering Agents: Selective Serotonin Reuptake Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Bromazepam: FluvoxaMINE may increase the serum concentration of Bromazepam. Management: With concomitant fluvoxamine, consider use of a benzodiazepine that does not undergo oxidative metabolism (e.g., lorazepam). If bromazepam is initiated in patients receiving fluvoxamine, monitor closely for increased bromazepam levels/adverse effects. Consider therapy modification

BuPROPion: May enhance the adverse/toxic effect of FluvoxaMINE. BuPROPion may increase the serum concentration of FluvoxaMINE. Monitor therapy

BusPIRone: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Selective Serotonin Reuptake Inhibitors may decrease the metabolism of BusPIRone. Management: The combination of a selective serotonin reuptake inhibitor and buspirone should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

CarBAMazepine: FluvoxaMINE may increase the serum concentration of CarBAMazepine. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Cimetidine: May decrease the metabolism of Selective Serotonin Reuptake Inhibitors. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clopidogrel: FluvoxaMINE may enhance the adverse/toxic effect of Clopidogrel. Specifically, the risk for bleeding may be increased. FluvoxaMINE may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Management: Reduce the dose of clozapine to one-third of the original dose when adding a strong CYP1A2 inhibitor, and monitor patient response closely. Return to the original clozapine dose when the strong CYP1A2 inhibitor is removed. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

CYP1A2 Inducers (Moderate): May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Substrates: CYP1A2 Inhibitors (Strong) may decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Cyproheptadine: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desmopressin: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Dosulepin: Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Dosulepin. Avoid combination

DULoxetine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Avoid combination

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Erlotinib: FluvoxaMINE may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Etizolam: FluvoxaMINE may increase the serum concentration of Etizolam. Management: Use lower etizolam doses when using this combination. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Flibanserin: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Monitor therapy

Fosphenytoin: FluvoxaMINE may increase the serum concentration of Fosphenytoin. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Grapefruit Juice: May increase the serum concentration of FluvoxaMINE. Monitor therapy

Haloperidol: FluvoxaMINE may increase the serum concentration of Haloperidol. Management: Monitor for increased haloperidol concentrations/effects when patients are receiving fluvoxamine, particularly when fluvoxamine dose is 150 mg/day or greater. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: FluvoxaMINE may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, consider decreasing ibrutinib to 140 mg daily. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Consider therapy modification

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Iobenguane I 123: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ioflupane I 123: Selective Serotonin Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Linezolid: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

Lithium: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could increase the risk of serotonin toxicity/serotonin syndrome. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

MAO Inhibitors: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination

Melatonin: FluvoxaMINE may increase the serum concentration of Melatonin. Management: Consider the use of alternative agents in order to avoid this combination. If combined, monitor for increased melatonin effects (eg, sedation, somnolence) if combined with fluvoxamine. Consider therapy modification

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methadone: May enhance the serotonergic effect of FluvoxaMINE. This could result in serotonin syndrome. FluvoxaMINE may increase the serum concentration of Methadone. Monitor therapy

Methylene Blue: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with selective serotonin reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

MetyroSINE: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Mexiletine: FluvoxaMINE may increase the serum concentration of Mexiletine. Monitor therapy

Mirtazapine: May enhance the serotonergic effect of FluvoxaMINE. This could result in serotonin syndrome. FluvoxaMINE may increase the serum concentration of Mirtazapine. Management: Consider alternatives to this combination when possible. If combined, monitor for increased mirtazapine effects/toxicities and for signs and symptoms of serotonin syndrome. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Neratinib: FluvoxaMINE may increase the serum concentration of Neratinib. Management: Avoid concomitant use of neratinib and fluvoxamine if possible. If combined, monitor for increased neratinib effects/toxicities. Consider therapy modification

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

NSAID (COX-2 Inhibitor): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). NSAID (COX-2 Inhibitor) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

NSAID (Nonselective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (Nonselective). NSAID (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider using alternative analgesics, when appropriate, and/or addition of a gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Consider therapy modification

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

OLANZapine: FluvoxaMINE may increase the serum concentration of OLANZapine. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pentoxifylline: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pentoxifylline. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Phenytoin: FluvoxaMINE may increase the serum concentration of Phenytoin. Monitor therapy

Pimozide: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Pimozide. Avoid combination

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Pirfenidone: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pirfenidone. Management: See full monograph for specific recommendations. Canadian product labeling specifically lists the use of pirfenidone with fluvoxamine as contraindicated. Consider therapy modification

Pomalidomide: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pomalidomide. Management: Avoid when possible. If coadministration is necessary, reduce the pomalidomide dose 50% and monitor for increased pomalidomide effects/toxicities. Consider therapy modification

Propafenone: FluvoxaMINE may increase the serum concentration of Propafenone. Monitor therapy

Propranolol: FluvoxaMINE may increase the serum concentration of Propranolol. Management: Use a lower initial propranolol dose and be cautious with propranolol dose titration. Consider therapy modification

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

QuiNIDine: FluvoxaMINE may increase the serum concentration of QuiNIDine. QuiNIDine may increase the serum concentration of FluvoxaMINE. Monitor therapy

QuiNINE: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Ramelteon: FluvoxaMINE may increase the serum concentration of Ramelteon. Avoid combination

Ramosetron: FluvoxaMINE may increase the serum concentration of Ramosetron. Monitor therapy

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Roflumilast: FluvoxaMINE may increase serum concentrations of the active metabolite(s) of Roflumilast. FluvoxaMINE may increase the serum concentration of Roflumilast. Monitor therapy

Ropivacaine: FluvoxaMINE may increase the serum concentration of Ropivacaine. Monitor therapy

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Tasimelteon: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Avoid combination

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Theophylline Derivatives: FluvoxaMINE may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: Selective Serotonin Reuptake Inhibitors may enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thioridazine: FluvoxaMINE may increase the serum concentration of Thioridazine. Avoid combination

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Thyroid Products: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Thyroid Products. Thyroid product dose requirements may be increased. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of TiZANidine. Avoid combination

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Tricyclic Antidepressants: FluvoxaMINE may enhance the adverse/toxic effect of Tricyclic Antidepressants. FluvoxaMINE may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with fluvoxamine. Consider therapy modification

Tryptophan: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Avoid combination

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Selective Serotonin Reuptake Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Zolpidem: FluvoxaMINE may enhance the CNS depressant effect of Zolpidem. FluvoxaMINE may increase the serum concentration of Zolpidem. Monitor therapy

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, nausea, vomiting, anxiety, dry mouth, fatigue, insomnia, headache, loss of strength and energy, lack of appetite, diarrhea, constipation, flatulence, sweating a lot, tremors, common cold symptoms, or change in taste. Have patient report immediately to prescriber vision changes, eye pain, eye irritation, signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), agitation, irritability, panic attacks, behavioral changes, mood changes, excessive weight gain, excessive weight loss, polyuria, sexual dysfunction, decreased libido, seizures, menstrual changes, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), or priapism (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Applies to fluvoxamine: oral capsule extended release, oral tablet

Along with its needed effects, fluvoxamine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking fluvoxamine:

Less common

• Behavior, mood, or mental changes
• trouble with breathing
• trouble with urinating
• twitching

Rare

• Absence of or decrease in body movements
• agitation
• blurred vision
• chills
• clumsiness or unsteadiness
• confusion
• convulsions (seizures)
• diarrhea
• fever
• inability to move the eyes
• increase in body movements
• menstrual changes
• nosebleeds
• overactive reflexes
• poor coordination
• red or irritated eyes
• redness, tenderness, itching, burning, or peeling of the skin
• restlessness
• shivering
• skin rash
• sore throat
• sweating
• talking or acting with excitement you cannot control
• trembling or shaking
• unusual bruising
• unusual, incomplete, or sudden body or facial movements
• unusual secretion of milk (in females)
• weakness

Some side effects of fluvoxamine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Change in sexual performance or desire
• constipation
• headache
• trouble sleeping
• unusual tiredness

Less common

• Abdominal or stomach pain
• change in sense of taste
• decreased appetite
• feeling of constant movement of self or surroundings
• frequent urination
• heartburn
• increased sweating
• unusual weight gain or loss

Summary of Use during Lactation

Limited information indicates that maternal fluvoxamine doses of up to 300 mg daily produce low levels in breastmilk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. One infant was reported to have an elevated serum level of fluvoxamine, but most who have been tested have undetectable serum levels. No adverse effects on breastfed infants have been reported, including a limited amount of long-term follow-up on growth and development. Mothers taking an SSRI during pregnancy and postpartum may have more difficulty breastfeeding and may need additional breastfeeding support. Breastfed infants exposed to an SSRI during the third trimester of pregnancy have a lower risk of poor neonatal adaptation than formula-fed infants.

Drug Levels

Maternal Levels. In a pooled analysis of serum levels from published studies and 1 unpublished case, the authors found that 6 mothers taking an average daily dosage of 159 mg (range 50 to 300 mg) had an average milk fluvoxamine level of 174 mcg/L (range 18 to 478 mcg/L).[1] Using the average dosage and milk level data from this paper, an exclusively breastfed infant would receive an estimated 0.98% of the maternal weight-adjusted dosage of fluvoxamine.

Two mothers breastfeeding while taking stable doses of fluvoxamine were studied with timed blood and milk samples over 24 hours. The first patient, who was taking 150 mg daily and nursing a 26-month-old, had a peak milk level of 425 mcg/L at 2.1 hours after the dose. The second patient, who was taking 50 mg daily and nursing a 3-week-old, had a peak milk level of 67 mcg/L at 4.2 hours after the dose. The authors estimated the absolute infant dosages to be 38.4 and 5.4 mcg/kg daily in the two infants, respectively, or an average 1.38% and 0.8% of the maternal weight-adjusted dosage.[2]

A nursing mother was taking fluvoxamine 50 mg daily. Foremilk and hindmilk samples taken at 1 week postpartum, 12 hours after a dose contained 23 mcg/L and 27 mcg/L, respectively.[3]

Infant Levels. Four exclusively breastfed infants aged 6 to 13 weeks had undetectable (<1 mcg/L) fluvoxamine serum levels during maternal therapy with fluvoxamine in dosages of 100 to 150 mg daily.[4]

In a pooled analysis of 3 mother-infant pairs from published and unpublished cases, the authors found that breastfed infants had an average of 16% (range 0 to 45%) of their mothers' fluvoxamine plasma levels; 1 of the 3 infants had a plasma level greater than 10% of the mother's which was defined by the authors as being elevated.[1] In the infant with a serum concentration of 45% of the maternal serum concentration, the high concentration was considered anomalous by the authors and perhaps related to the infant's fluvoxamine metabolism by P450 enzymes.[5]

Serum levels of fluvoxamine were undetectable (<2 mcg/L) in a partially breastfed 26-month-old during maternal intake of 150 mg daily. Fluvoxamine was also undetectable in the serum of an exclusively breastfed 3-week-old during maternal intake of 50 mg daily.[2]

Effects in Breastfed Infants

One infant whose mother began taking fluvoxamine 100 mg daily 17 weeks postpartum was breastfed from birth to 5 months of age. The medical and nursing staff did not note any adverse effect in the infant during the 10 weeks of observation during maternal hospitalization. The infant had normal Bayley developmental scores at age 4 months and 21 months.[6]

No adverse effects were found in 2 infants, a partially breastfed 26-month-old during maternal intake of 150 mg daily, who also had a normal Denver Developmental Score, and an exclusively breastfed 3-week-old during maternal intake of 50 mg daily.[2]

Three mothers who took an average fluvoxamine dose of 117 mg once daily breastfed their infants exclusively for 4 months and at least 50% during months 5 and 6. Their infants had 6-month weight gains that were normal according to national growth standards and the mothers reported no abnormal effects in their infants.[7]

One study of the side effects of SSRI antidepressants in nursing mothers found no adverse reactions that required medical attention in one infant whose mother was taking fluvoxamine. No specific information on maternal fluvoxamine dosage, extent of breastfeeding or infant age was reported.[8]

A woman who was treated chronically with quetiapine 400 mg and fluvoxamine 200 mg daily took the drugs throughout pregnancy and postpartum. She partially breastfed her infant (extent not stated) for 3 months from birth. No adverse events were seen in the infant who developed normally.[9]

A cohort of 247 infants exposed to an antidepressant in utero during the third trimester of pregnancy were assessed for poor neonatal adaptation (PNA). Of the 247 infants, 154 developed PNA. Infants who were exclusively given formula had about 3 times the risk of developing PNA as those who were exclusively or partially breastfed. Four of the infants were exposed to low doses of fluvoxamine in utero and none had PNA.[10]

A 5-month-old infant developed severe diarrhea (15 times daily), mild vomiting (2 to 3 times daily), agitation and decreased sleep within 2 days after maternal initiation of fluvoxamine 50 mg daily. Symptoms resolved within 24 hours after the mother discontinued the drug, and recurred a week later after fluvoxamine was restarted in the mother. Other causes of the gastrointestinal symptoms could not be found. Fluvoxamine was probably the cause of the reaction. The authors speculate that the infant might have abnormal metabolism of the drug that resulted in high serum concentrations.[11]

Effects on Lactation and Breastmilk

Fluvoxamine has caused increased prolactin levels and galactorrhea in nonpregnant, nonnursing patients.[12][13][14] In one case, euprolactinemic gynecomastia and galactorrhea occurred in a 19-year-old man who was also taking risperidone.[15] In a study of cases of hyperprolactinemia and its symptoms (e.g., gynecomastia) reported to a French pharmacovigilance center, fluvoxamine was found to have a 4.5-fold increased risk of causing hyperprolactinemia compared to other drugs.[16] The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

In a small prospective study, 8 primiparous women who were taking a serotonin reuptake inhibitor (SRI; 3 taking fluoxetine and 1 each taking citalopram, duloxetine, escitalopram, paroxetine or sertraline) were compared to 423 mothers who were not taking an SRI. Mothers taking an SRI had an onset of milk secretory activation (lactogenesis II) that was delayed by an average of 16.7 hours compared to controls (85.8 hours postpartum in the SRI-treated mothers and 69.1 h in the untreated mothers), which doubled the risk of delayed feeding behavior in the untreated group. However, the delay in lactogenesis II may not be clinically important, since there was no statistically significant difference between the groups in the percentage of mothers experiencing feeding difficulties after day 4 postpartum.[17]

A case control study compared the rate of predominant breastfeeding at 2 weeks postpartum in mothers who took an SSRI antidepressant throughout pregnancy and at delivery (n = 167) or an SSRI during pregnancy only (n = 117) to a control group of mothers who took no antidepressants (n = 182). Among the two groups who had taken an SSRI, 33 took citalopram, 18 took escitalopram, 63 took fluoxetine, 2 took fluvoxamine, 78 took paroxetine, and 87 took sertraline. Among the women who took an SSRI, the breastfeeding rate at 2 weeks postpartum was 27% to 33% lower than mother who did not take antidepressants, with no statistical difference in breastfeeding rates between the SSRI-exposed groups.[18]

An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 30% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge.[19] The antidepressants used by the mothers were not specified.

Alternate Drugs to Consider

Clomipramine, Nortriptyline, Paroxetine, Sertraline

References

1. Weissman AM, Levy BT, Hartz AJ et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161:1066-78. PMID: 15169695

2. Kristensen JH, Hackett LP, Kohan R et al. The amount of fluvoxamine in milk is unlikely to be a cause of adverse effects in breastfed infants. J Hum Lact. 2002;18:139-43. PMID: 12033075

3. Weisskopf E, Panchaud A, Nguyen KA et al. Simultaneous determination of selective serotonin reuptake inhibitors and their main metabolites in human breast milk by liquid chromatography-electrospray mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2017;1057:101-9. PMID: 28511118

4. Hendrick V, Fukuchi A, Altshuler L et al. Use of sertraline, paroxetine and fluvoxamine by nursing women. Br J Psychiatry. 2001;179:163-6. PMID: 11483479

5. Arnold LM, Suckow RF, Lichtenstein PK. Fluvoxamine concentrations in breast milk and in maternal and infant sera. J Clin Psychopharmacol. 2000;20:491-2. Letter. PMID: 10917415

6. Yoshida K, Smith B, Kumar RC. Fluvoxamine in breast-milk and infant development. Br J Clin Pharmacol. 1997;44:210-1. PMID: 9278215

7. Hendrick V, Smith LM, Hwang S et al. Weight gain in breastfed infants of mothers taking antidepressant medications. J Clin Psychiatry. 2003;64:410-2. PMID: 12716242

8. Lee A, Woo J, Ito S. Frequency of infant adverse events that are associated with citalopram use during breast-feeding. Am J Obstet Gynecol. 2004;190:218-21. PMID: 14749663

9. Gentile S. Quetiapine-fluvoxamine combination during pregnancy and while breastfeeding. Arch Womens Ment Health. 2006. PMID: 16633783

10. Kieviet N, Hoppenbrouwers C, Dolman KM, Berkhof J, Wennink H, Honig A. Risk factors for poor neonatal adaptation after exposure to antidepressants in utero. Acta Paediatr. 2015;104:384-91. PMID: 25559357

11. Uguz F. Gastrointestinal side effects in the baby of a breastfeeding woman treated with low-dose fluvoxamine. J Hum Lact. 2015;31:371-3. PMID: 25896469

12. Bonin B, Vandel P, Vandel S. Fluvoxamine and galactorrhea. A case report. Therapie. 1994;49:149-51. PMID: 7817347

13. Egberts ACG, Meyboom RHB, De Koning FHP et al. Non-puerperal lactation associated with antidepressant drug use. Br J Clin Pharmacol. 1997;44:277-81. PMID: 9296322

14. Jeffries J, Bezchlibnyk-Butler K, Remington G. Amenorrhea and galactorrhea associated with fluvoxamine in a loxapine-treated patient. J Clin Psychopharmacol. 1992;12:296-7. PMID: 1527236

15. Pratheesh PJ, Praharaj SK, Srivastava A. Euprolactinemic gynecomastia and galactorrhea with risperidone-fluvoxamine combination. Psychopharmacol Bull. 2011;44:70-3. PMID: 22506441

16. Trenque T, Herlem E, Auriche P, Drame M. Serotonin reuptake inhibitors and hyperprolactinaemia: a case/non-case study in the French pharmacovigilance database. Drug Saf. 2011;34:1161-6. PMID: 22077504

17. Marshall AM, Nommsen-Rivers LA, Hernandez LL et al. Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution. J Clin Endocrinol Metab. 2010;95:837-46. PMID: 19965920

18. Gorman JR, Kao K, Chambers CD. Breastfeeding among women exposed to antidepressants during pregnancy. J Hum Lact. 2012;28:181-8. PMID: 22344850

19. Venkatesh KK, Castro VM, Perlis RH et al. Impact of antidepressant treatment during pregnancy on obstetric outcomes among women previously treated for depression. Am J Obstet Gynecol. 2017;216:S466-S467.

LactMed Record Number

324

Last Revision Date

20170601

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.