Side Effects of Luvox (fluvoxamine)

Luvox (fluvoxamine) is a selective serotonin reuptake inhibitor (SSRI) antidepressant used to treat

• obsessive-compulsive disorder (OCD),
• social anxiety disorder,
• major depression,
• management of obesity,
• bulimia,
• schizophrenia, and
• panic disorder.

Selective serotonin reuptake inhibitors affect neurotransmitters, chemicals that nerves in the brain use to communicate with each other. Neurotransmitters are released by nerves, travel across the spaces between nerves and then attach to receptors on other nerves. Many experts believe that an imbalance in neurotransmitters is the cause of depression and other psychiatric disorders.

Luvox works by inhibiting the uptake of serotonin, a neurotransmitter, from the spaces between nerve cells following its release. Therefore, there is more serotonin available in the spaces to attach to other nerves and stimulate them.

Common side effects of Luvox include

• anxiety,
• nervousness,
• sweating,
• nausea,
• decreased appetite,
• constipation,
• diarrhea,
• dry mouth,
• sleepiness,
• dizziness,
• weight loss,
• indigestion,
• vomiting,
• stomach pain,
• palpitations,
• abnormal dreams,
• insomnia, and
• sexual dysfunction.

Serious side effects of Luvox include

• abnormal bleeding,
• seizures, and
• manic episodes.

Withdrawal of Luvox may result in withdrawal symptoms such as

• dizziness,
• tiredness,
• tingling of the extremities,
• nausea,
• vivid dreams,
• irritability,
• poor mood,
• visual disturbances, and
• headaches.

Drug interactions of Luvox include monoamine oxidase inhibitors (MAOIs) and other drugs that inhibit monoamine oxidase such as linezolid and intravenous methylene blue. Such combinations may lead to confusion, high blood pressure, tremor, and increased activity.

• Luvox should not be administered within 14 days of discontinuing a MAO inhibitor, and MAO inhibitors should not be administered within 14 days of stopping Luvox.
• Similar reactions occur if Luvox is combined with tryptophan, St. John's wort, meperidine, and tramadol that increase serotonin in the brain.
• Luvox can inhibit the elimination of clozapine, necessitating dosage reductions of clozapine.
• Luvox also may inhibit the elimination and increase the blood levels of theophylline, alprazolam, and triazolam leading to side effects from these drugs.
• Luvox may increase the effect of warfarin, leading to excessive bleeding.
• Combining SSRIs with aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) or other drugs that affect bleeding may increase the likelihood of upper gastrointestinal bleeding.
• Luvox may increase blood levels of tizanidine, thioridazine, alosetron, and pimozide, leading to increased side effects of these drugs.

There are no adequate studies of Luvox in pregnant women. Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN), which can be fatal.

Luvox is excreted into breast milk. There are no adequate studies of Luvox in lactating women. Consult your doctor before breastfeeding. 

Side effects of fluvoxamine include:

• Anxiety
• Nervousness
• Sweating
• Nausea
• Decreased appetite
• Constipation
• Diarrhea
• Dry mouth
• Somnolence (sleepiness)
• Dizziness
• Weight loss
• Indigestion
• Vomiting
• Stomach pain
• Palpitations
• Abnormal dreams
• Insomnia
• Sexual dysfunction

Fluvoxamine also may cause abnormal bleeding, seizures, and manic episodes. Withdrawal of fluvoxamine may result in withdrawal symptoms. The most common symptoms of withdrawal are

• dizziness,
• tiredness,
• tingling of the extremities,
• nausea,
• vivid dreams,
• irritability, and
• poor mood.

Other symptoms include

• visual disturbances and
• headaches.

Withdrawal reactions have been reported after an average of 12 to 36 weeks of treatment, but after as few as 5 weeks. Although most authorities recommend discontinuing treatment by gradually reducing the dose, symptoms still may occur.

Symptoms generally appear within a few days of discontinuing medication and persist for an average of 12 days (up to 21 days). They are relieved within 24 hours by re-administering the medication that was discontinued.

Antidepressants may increase the risk of suicide in children and adolescents. There are concerns that antidepressants also may increase the risk of suicide in adults. Patients with major depression may experience worsening of depression or suicidal thoughts regardless of whether or not they are treated.

Therefore, patients started on antidepressants should be closely observed for signs of worsening suicidal thinking or changes in behavior.

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 COMBINEDup>1

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

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.

ViVital 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).

PoPotential Interactions With Drugs That Inhibit Or Are Metabolized By Cytochrome P450 Isoenzymes

Multiple hepatic cytochrome P450 isoenzymes are involved in the oxidative biotransformation of a large number of structurally different drugs and endogenous compounds. The available knowledge concerning the relationship of fluvoxamine and the cytochrome P450 isoenzyme system has been obtained mostly from pharmacokinetic interaction studies conducted in healthy volunteers, but some preliminary in vitro data are also available.

Based on a finding of substantial interactions of fluvoxamine with certain of these drugs and limited in vitro data for CYP3A4, it appears that fluvoxamine inhibits several cytochrome P450 isoenzymes that are known to be involved in the metabolism of other drugs such as:

• CYP1A2 (e.g., warfarin, theophylline, propranolol, tizanidine),
• CYP2C9 (e.g., warfarin),
• CYP3A4 (e.g., alprazolam), and
• CYP2C19 (e.g., omeprazole).

In vitro data suggest that fluvoxamine is a relatively weak inhibitor of CYP2D6.

Approximately 7% of the normal population has a genetic code that leads to reduced levels of activity of CYP2D6. Such individuals have been referred to as “poor metabolizers” (PM) of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants.

While none of the drugs studied for drug interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study of fluvoxamine single-dose pharmacokinetics in 13 PM subjects demonstrated altered pharmacokinetic properties compared to 16 “extensive metabolizers” (EM): mean Cmax, AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group.

This suggests that fluvoxamine is metabolized, at least in part, by CYP2D6. Caution is indicated in patients known to have reduced levels of CYP2D6 activity and those receiving concomitant drugs known to inhibit this cytochrome P450 isoenzyme (e.g., quinidine).

The metabolism of fluvoxamine has not been fully characterized and the effects of potent cytochrome P450 isoenzyme inhibition, such as the ketoconazole inhibition of CYP3A4, on fluvoxamine metabolism have not been studied.

A clinically significant fluvoxamine interaction is possible with drugs having a narrow therapeutic ratio such as pimozide, warfarin, theophylline, certain benzodiazepines, omeprazole and phenytoin. If Fluvoxamine Maleate Tablets are to be administered together with a drug that is eliminated via oxidative metabolism and has a narrow therapeutic window, plasma levels and/or pharmacodynamic effects of the latter drug should be monitored closely, at least until steady-state conditions are reached.

CNS Active Drugs

• Antipsychotics: See prescribing information.
• Benzodiazepines: See prescribing information.
• Alprazolam:  See prescribing information.
• Diazepam:  See prescribing information.
• Lorazepam: A study of multiple doses of fluvoxamine maleate (50 mg b.i.d.) in healthy male volunteers (N=12) and a single dose of lorazepam (4 mg single dose) indicated no significant pharmacokinetic interaction. On average, both lorazepam alone and lorazepam with fluvoxamine produced substantial decrements in cognitive functioning; however, the coadministration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone.
• Alcohol: Studies involving single 40 g doses of ethanol (oral administration in one study and intravenous in the other) and multiple dosing with fluvoxamine maleate (50 mg b.i.d.) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other. As with other psychotropic medications, patients should be advised to avoid alcohol while taking Fluvoxamine Maleate Tablets.
• Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity have been reported with the coadministration of fluvoxamine maleate and carbamazepine.
• Clozapine: See  See prescribing information.
• Lithium: As with other serotonergic drugs, lithium may enhance the serotonergic effects of fluvoxamine and, therefore, the combination should be used with caution. Seizures have been reported with the coadministration of fluvoxamine maleate and lithium.
• Methadone: See prescribing information.
• Monoamine Oxidase Inhibitors: See prescribing information.
• Pimozide:  See prescribing information.
• Ramelteon: See prescribing information.
• Serotonergic Drugs: See prescribing information.
• Tacrine: In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five-and eight-fold increases in tacrine Cmax and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine.
• Thioridazine:  See prescribing information.
• Tizanidine:  See prescribing information.
• Tricyclic Antidepressants (TCAs): Significantly increased plasma TCA levels have been reported with the coadministration of fluvoxamine maleate and amitriptyline, clomipramine or imipramine. Caution is indicated with the coadministration of Fluvoxamine Maleate Tablets and TCAs; plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced.
• Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluvoxamine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
• Sumatriptan: There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
• Tryptophan: Tryptophan may enhance the serotonergic effects of fluvoxamine, and the combination should, therefore, be used with caution. Severe vomiting has been reported with the coadministration of fluvoxamine maleate and tryptophan.

Other Drugs

• Alosetron:  See prescribing information and Lotronex (alosetron) package insert.
• Digoxin: Administration of fluvoxamine maleate 100 mg daily for 18 days (N=8) did not significantly affect the pharmacokinetics of a 1.25 mg single intravenous dose of digoxin.
• Diltiazem: Bradycardia has been reported with the coadministration of fluvoxamine maleate and diltiazem.
• Mexiletine:  See prescribing information.
• Propranolol and Other Beta-Blockers: Coadministration of fluvoxamine maleate 100 mg per day and propranolol 160 mg per day in normal volunteers resulted in a mean five-fold increase (range 2 to 17) in minimum propranolol plasma concentrations. In this study, there was a slight potentiation of the propranololinduced reduction in heart rate and reduction in the exercise diastolic pressure.

One case of bradycardia and hypotensiona> and a second case of orthostatic hypotension have been reported with the coadministration of fluvoxamine maleate and metoprolol.

If propranolol or metoprolol is coadministered with Fluvoxamine Maleate Tablets, a reduction in the initial beta-blocker dose and more cautious dose titration are recommended. No dosage adjustment is required for Fluvoxamine Maleate Tablets.

Coadministration of fluvoxamine maleate 100 mg per day with atenolol 100 mg per day (N=6) did not affect the plasma concentrations of atenolol. Unlike propranolol and metoprolol which undergo hepatic metabolism, atenolol is eliminated primarily by renal excretion.

• Theophylline: See prescribing information.

Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.): See prescribing information.

EfEffects Of Smoking On Fluvoxamine Metabolism

• Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers.

Electroconvulsive Therapy (ECT)

• There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.

Drug Abuse And Dependence

Controlled Substance

• Fluvoxamine Maleate Tablets are not a controlled substance.

Physical And Psychological Dependence

• The potential for abuse, tolerance and physical dependence with fluvoxamine maleate has been studied in a nonhuman primate model. No evidence of dependency phenomena was found.
• The discontinuation effects of Fluvoxamine Maleate Tablets were not systematically evaluated in controlled clinical trials.
• Fluvoxamine Maleate Tablets were not systematically studied in clinical trials for potential for abuse, but there was no indication of drug-seeking behavior in clinical trials.
• It should be noted, however, that patients at risk for drug dependency were systematically excluded from investigational studies of fluvoxamine maleate.
• Generally, it is not possible to predict on the basis of preclinical or premarketing clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed.
• Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of fluvoxamine maleate misuse or abuse (i.e., development of tolerance, incrementation of dose, drug-seeking behavior).