Luvox

In healthy volunteers, fluvoxamine maleate is well absorbed after oral administration. Following a single 100 mg oral dose, peak plasma levels of 31 to 87 ng/mL were attained 1.5 to 8 hours post-dose. Peak plasma levels and AUCs (0 to 72 hours) are directly proportionate to dose after single oral doses of 25, 50 and 100 mg. Following single doses, the mean plasma half-life is 15 hours, and slightly longer (17 to 22 hours), during repeated dosing. Steady-state plasma levels are usually achieved within 10 to 14 days. The pharmacokinetic profile in the elderly is similar to that in younger patients.

In a dose proportionality study involving fluvoxamine maleate at 100, 200 and 300 mg/day for 10 consecutive days in 30 normal volunteers, steady-state was achieved after about a week of dosing. Maximum plasma concentrations at steady-state occurred within 3 to 8 hours of dosing and reached concentrations averaging 88, 283 and 546 ng/mL, respectively. Thus, fluvoxamine maleate had nonlinear pharmacokinetics over this dose range, i.e., higher doses of fluvoxamine maleate produced disproportionately higher concentrations than predicted from the lower dose.

Metabolism and Elimination: Fluvoxamine maleate undergoes extensive hepatic transformation, mainly via oxidative demethylation, to at least 9 metabolites, which are excreted by the kidney. Ninety-four percent of an oral radioactive dose is recovered in the urine within 48 hours. The 2 major metabolites showed negligible pharmacological activity. In vitro binding of fluvoxamine maleate to human plasma proteins is about 77% at drug concentrations up to 4000 ng/mL.

Luvox (fluvoxamine maleate) is contraindicated in combined use with tizanidine, MAO inhibitors, thioridazine or mesoridazine (see Contraindications and Warnings). Isolated cases of cardiac toxicity have been reported when fluvoxamine was combined with thioridazine (see Contraindications and Warnings).

See Pregnancy.

Safety and efficacy in children under 18 years of age have not been established.

Safe use of fluvoxamine maleate during pregnancy and lactation has not been established. Like other antidepressants, fluvoxamine maleate is excreted via human milk in small quantities. Therefore, it should not be administered to women of childbearing potential or nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient outweigh the possible hazards to the child or fetus.

Post-marketing reports indicate that some neonates exposed to LUVOX, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Precautions, Serotonin Syndrome). When treating a pregnant woman with LUVOX, the physician should carefully consider the potential risks and benefits of treatment (see Dosage).

The serotonergic effects of fluvoxamine may be enhanced when used in combination with other serotonergic agents (including triptans, tramodol, SSRIs and St. John's Wort preparations).

St. John's Wort: In common with other SSRIs, pharmacodynamic interactions between fluvoxamine maleate and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.

Lithium, and possibly tryptophan, may enhance the serotonergic effects of fluvoxamine maleate; these combinations should therefore be used with caution. This may, on rare occasions, result in a serotonergic syndrome.

As with other psychotropic drugs patients should be advised to avoid alcohol use while taking fluvoxamine.

Oral Anticoagulants: In patients on oral anticoagulants and fluvoxamine, the risk for hemorrhage may increase and these patients should therefore be closely monitored.

Metabolism of Fluvoxamine: The specific CYP isoenzymes involved in the metabolism of fluvoxamine maleate remains to be identified.

Fluvoxamine maleate does not influence plasma concentrations of atenolol.

Fluvoxamine maleate is a potent inhibitor of CYP IA2, and to a lesser extent of CYP IIC and CYP IIIA4. Drugs which are largely metabolised via these isoenzymes are eliminated slower and may have higher plasma concentrations when coadministered with fluvoxamine maleate. This is particularly relevant for drugs with a narrow therapeutic index. Patients should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.

Fluvoxamine maleate does not influence plasma concentrations of digoxin. The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine maleate.

Cognitive and Motor Disturbances: Sedation may occur in some patients. Therefore, patients should be cautioned about participating in activities requiring complete mental alertness, judgment and physical coordination—such as driving an automobile or performing hazardous tasks—until they are reasonably certain that treatment with Luvox (fluvoxamine maleate) does not affect them adversely.

Concomitant Illness: Luvox (fluvoxamine maleate) has 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 premarketing clinical studies.

Hemorrhage: There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura as well as hemorrhagic manifestations e.g. gastrointestinal bleeding with SSRIs. Caution is advised in patients taking SSRIs, particularly in elderly patients and in patients who concomitantly use drugs known to affect platelet function (e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants [TCAs], ASA, NSAIDs) or drugs that increase risk of bleeding as well as in patients with a history of bleeding disorders and in those with predisposing conditions (e.g. thrombocytopenia).

Fluvoxamine maleate is also known to inhibit the CYP IIIA4 isozyme and thus may interact with CYP IIIA4 substrates like diltiazem and alprazolam. A clinically significant interaction is possible with CYP IIIA4 substrates that have a narrow therapeutic index such as carbamazepine, methadone, and cyclosporine. Such combinations should therefore be administered with caution, and consideration be given to lowering the dose of the concomitant agent. A significantly increased methadone plasma level/dose ratio was seen during concurrent administration of fluvoxamine maleate. When fluvoxamine maleate and alprazolam were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, C_max, T_1/2) of alprazolam were approximately twice those observed when alprazolam was administered alone; clearance was reduced by about 50%. Since terfenadine, astemizole, and cisapride, are metabolized by the CYP IIIA4 isozyme, theoretically there may be a potential interaction with fluvoxamine maleate. Thus, it is recommended that fluvoxamine maleate not be used in combination with either terfenadine, astemizole, or cisapride (see Contraindications).

The plasma levels of oxidatively metabolised benzodiazepines (e.g., triazolam, midazolam, alprazolam, and diazepam) are likely to be increased when coadministered with fluvoxamine. The dosage of these benzodiazepines should be reduced during coadministration with fluvoxamine.

An increase in previously stable plasma levels of those tricyclic antidepressants (e.g., clomipramine, imipramine, amitriptyline) and neuroleptics (e.g., clozapine, olanzapine) which are largely metabolized through cytochrome P450 IA2, has been reported in patients taking fluvoxamine maleate concomitantly. Thus, the combination of these drugs with fluvoxamine is not recommended.

Patients coadministered fluvoxamine maleate and CYP IA2 metabolized drugs with a narrow therapeutic index (such as tacrine, theophylline, methadone, mexiletine, clozapine, warfarin) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.

Warfarin plasma concentrations were significantly increased, and prothrombin times prolonged during concurrent administration of fluvoxamine maleate; in interaction studies, a 65% increase in warfarin plasma levels were seen.

As plasma concentrations of propranolol are increased in combination with fluvoxamine maleate, the propranolol dose may need to be lowered; a 5-fold increase in plasma levels of propranolol was seen in interaction studies.

When a single 40 mg dose of tacrine was added to fluvoxamine maleate 100 mg/day administered at steady-state, an associated five and eight fold increase in tacrine C_max and AUC, respectively, were observed.

Caffeine plasma levels are likely to be increased during coadministration with fluvoxamine maleate. Thus, patients who consume high quantities of caffeine-containing beverages should lower their intake when fluvoxamine maleate is administered and adverse caffeine effects (like tremor, palpitations, nausea, restlessness, insomnia) are observed.

As plasma concentrations of ropinirole may be increased in combination with fluvoxamine maleate thus increasing the risk of overdose, surveillance and reduction in the dosage of ropinirole during fluvoxamine maleate treatment and after its withdrawal may be required.

Fluvoxamine maleate is also believed to inhibit CYP IIC isozymes and thus may interact with CYP IIC substrates like diazepam. Clearance of both diazepam and its active metabolite N-desmethyldiazepam were reduced with concurrent administration of fluvoxamine maleate.

Patients coadministered fluvoxamine maleate and CYP IIC metabolised drugs with a narrow therapeutic index (such as phenytoin) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.

Cytochrome P450 isozyme (IID6) is responsible for the metabolism of substrates such as debrisoquine, sparteine, tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine, and desipramine), phenothiazine neuroleptics (e.g., perphenazine and thioridazine), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). In vitro data suggest that fluvoxamine maleate is a relatively weak inhibitor of the IID6 isozyme, and hence the potential for interactions with compounds metabolized by this isoenzyme is low.

Each film-coated, biconvex, round, scored, white tablet, stamped “291” twice on one side and a stylized “S” on the other, contains: fluvoxamine maleate 50 mg. Nonmedicinal ingredients: colloidal anhydrous silica, hypromellose, maize starch, mannitol, polyethylene glycol 6000, pregelatinized starch, sodium stearyl fumarate, talc and titanium dioxide. Blister packages of 30.

Each film-coated, biconvex, oval, scored, white tablet, stamped “313” twice on one side and a stylized “S” on the other contains: fluvoxamine maleate 100 mg. Nonmedicinal ingredients: colloidal anhydrous silica, hypromellose, maize starch, mannitol, polyethylene glycol 6000, pregelatinized starch, sodium stearyl fumarate, talc and titanium dioxide. Blister packages of 30.

Store in a dry place at temperatures between 15-25°C. Protect from light.

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

The effect of fluvoxamine (25 mg b.i.d. for 1 week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia. Concentrations of thioridazine and its 2 active metabolites, mesoridazine and sulforidazine, increased 3-fold following coadministration of fluvoxamine.

Thioridazine and mesoridazine 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 maleate may even be more pronounced when it is administered at higher doses. Therefore Luvox and thioridazine or mesoridazine should not be coadministered (see Contraindications and Precautions).

Terfenadine, astemizole, and cisapride are all metabolized by the cytochrome P450 IIIA4 isozyme. Since fluvoxamine maleate is known to inhibit the CYP IIIA4 isozyme, theoretically, there may be a potential interaction with terfenadine, astemizole, or cisapride. Consequently, it is recommended that fluvoxamine maleate not be used in combination with either terfenadine, astemizole, or cisapride (see Contraindications).

Patients currently taking Luvox (fluvoxamine maleate) should not be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather an abrupt cessation is recommended.

There have been reports of adverse reactions upon the discontinuation of Luvox (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see Precautions and Dosage).

Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. These events are generally self-limiting. Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors. Isolated cases of withdrawal symptoms in the newborn child have been described after the use of fluvoxamine maleate at the end of pregnancy (see Precautions and Dosage). Some newborns experience feeding and/or respiratory difficulties, seizures, temperature instability, hypoglycemia, tremor, abnormal muscle tone, jitteriness, and constant crying after third trimester exposure to SSRIs and may require prolonged hospitalization.

Anecdotal spontaneous reports, from the marketplace, but not from clinical trials, have been collected for the following adverse experiences: galactorrhoea, photosensitivity, Stevens Johnson Syndrome, alopecia, taste perversion, tinnitus, and hemorrhagic manifestations e.g. eccyhmoses, purpura, gastrointestinal bleeding (see Warnings and Precautions). Rarely, serotonin syndrome, neuroleptic malignant syndrome-like events, hyponatremia and SIADH have been reported (see Precautions, Serotonin Syndrome; and Precautions, Drug Interactions, CNS Active Drugs).

Infrequent: arthralgia, arthrosis, myalgia, myasthenia, tetany. Rare: arthritis, bone pain, leg cramps, pathological fracture, rheumatoid arthritis.

See Precautions.

Additional Adverse Events Reported in Clinical Trials: During premarketing and postmarketing studies, multiple doses of Luvox were administered to approximately 34 587 patients. All events with an incidence of >0.01% are listed, regardless of relation to drug, except those in terms so general as to be uninformative. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent (occurring on 1 or more occasions in at least 1/100 patients), infrequent (occurring in less than 1/100, but at least 1/1000 patients), or rare (occurring in less than 1/1000 but at least in 1/10 000 patients). Multiple events may have been reported by a single patient. It is important to emphasize that although the events reported did occur during treatment with Luvox, they were not necessarily caused by it.

Frequent: anorexia, constipation, diarrhea, dry mouth, dyspepsia, nausea, vomiting. Infrequent: colitis, dysphagia, eructation, flatulence, gastritis, gastroenteritis, increased appetite, thirst. Rare: biliary pain, esophagitis, fecal incontinence, gastrointestinal carcinoma, gastrointestinal hemorrhage, gingivitis, glossitis, hematemesis, hepatitis, jaundice, liver function tests abnormal, melena, mouth ulceration, rectal hemorrhage, stomatitis, tenesmus, tongue discoloration, tongue edema, tooth disorder.

Infrequent: abnormal ejaculation, dysuria, impotence, metrorrhagia, urinary frequency, urinary incontinence. Rare: amenorrhea, anorgasmia, breast pain, cystitis, dysmenorrhea, female lactation, hematuria, kidney pain, leukorrhea, menorrhagia, nocturia, polyuria, prostatic disorder, urinary retention, urinary tract infection, urinary urgency, vaginitis.

Infrequent: abnormal vision, amblyopia, hyperacusis. Rare: abnormality of accommodation, blepharitis, conjunctivitis, deafness, diplopia, dry eyes, ear pain, eye pain, lacrimation disorder, mydriasis, parosmia, photophobia, taste loss.

Frequent: sweating increased. Infrequent: cutaneous hypersensitivity reactions (including rash, pruritis, angioedema). Rare: acne, alopecia, dry skin, eczema, furunculosis, herpes simplex, herpes zoster, maculopapular rash, psoriasis, urticaria.

Rare: anemia, cyanosis, ecchymosis, lymphadenopathy, thrombocytopenia.

Frequent: weight gain. Infrequent: peripheral edema, weight loss. Rare: alcohol intolerance, dehydration, edema, obesity.

Frequent: abdominal pain, asthenia, headache, malaise. Infrequent: accidental injury, allergic reaction, back pain, chest pain, chills, fever, flu syndrome, infection, neck pain, pain, suicide attempt. Rare: abdomen enlarged, chills and fever, face edema, halitosis, hangover effect, hernia, neck rigidity, overdose, pelvic pain.

Infrequent: dyspnea, pharyngitis, rhinitis. Rare: asthma, bronchitis, cough increased, epistaxis, hiccup, hyperventilation, laryngismus, laryngitis, pneumonia, sinusitis, voice alteration, yawn.

Frequent: agitation, anxiety, dizziness, insomnia, nervousness, somnolence, thinking abnormal, tremor, vertigo. Infrequent: abnormal dreams, abnormal gait, akathisia, amnesia, apathy, ataxia, confusion, depersonalization, depression, drug dependence, emotional lability, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypoesthesia, hypokinesia, incoordination, increased salivation, libido decreased, libido increased, manic reaction, neurosis, paresthesia, psychotic depression, stupor, twitching, vasodilatation. Rare: akinesia, CNS neoplasia, CNS stimulation, coma, convulsion, delirium, delusions, dysarthria, dyskinesia, dystonia, extrapyramidal syndrome, hemiplegia, hyperesthesia, hypotonia, hysteria, myoclonus, neuralgia, neuropathy, paralysis, paranoid reaction, psychosis, reflexes decreased, schizophrenic reaction, screaming syndrome, torticollis, trismus.

Frequent: palpitation. Infrequent: angina pectoris, hypertension, hypotension, migraine, postural hypotension, syncope, tachycardia. Rare: arrhythmia, bradycardia, cerebrovascular accident, extrasystoles, hemorrhage, myocardial infarct, pallor, peripheral vascular disorder, shock.

More than 500 cases of overdosage with fluvoxamine maleate, alone or in combination with other compounds, have been reported. The most common symptoms of overdosage include gastrointestinal complaints (nausea, vomiting and diarrhea), somnolence and dizziness. Cardiac events (tachycardia, bradycardia, hypotension), liver function disturbances, convulsions and coma have also been reported. Among more than 490 patients reported to have taken deliberate overdoses of fluvoxamine maleate, there have been 44 deaths, all but 6 of which occurred in patients who were confirmed to have taken multiple medications. The highest documented dose of fluvoxamine maleate ingested by a patient is 12 g; this patient recovered completely with symptomatic treatment only.

There is no specific antidote to fluvoxamine maleate. In situations of overdosage, the stomach should be emptied as soon as possible after tablet ingestion and symptomatic treatment initiated. The repeated use of medicinal charcoal is also recommended. Due to the large distribution volume of fluvoxamine maleate, forced diuresis or dialysis is unlikely to be of benefit.

Since there is limited clinical experience in the geriatric age group, caution is recommended when administering fluvoxamine maleate to elderly patients.

The safety and effectiveness of fluvoxamine maleate in children under 18 years of age have not been established (see Warnings, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

Depression: Treatment should be initiated at the lowest possible dose (50 mg) given once daily at bedtime, and then increased to 100 mg daily at bedtime after a few days, as tolerated. The effective daily dose usually lies between 100 and 200 mg, and should be adjusted gradually according to the individual response of the patient, up to a maximum of 300 mg. Dosage increases should be made in 50 mg increments. Doses above 150 mg should be divided so that a maximum of 150 mg is given in the bedtime dose. Tablets should be swallowed with water and without chewing.

Obsessive-Compulsive Disorder: Treatment should be initiated at the lowest possible dose (50 mg) given once daily at bedtime, and then increased to 100 mg daily at bedtime after a few days, as tolerated. The effective daily dose usually lies between 100 and 300 mg, and should be adjusted gradually according to the individual response of the patient, up to a maximum of 300 mg. If no improvement is observed within 10 weeks, treatment with Luvox should be reconsidered. Dosage increases should be made in 50 mg increments. Doses above 150 mg should be divided so that a maximum of 150 mg is given in the bedtime dose. Luvox should be swallowed with water and without chewing.

Discontinuation of Treatment: Symptoms associated with the discontinuation or dosage reduction of Luvox have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (see Precautions and Adverse Effects).

A gradual reduction in the dose over several weeks rather abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Precautions and Adverse Effects).

Hepatic or Renal Insufficiency: Patients with hepatic or renal insufficiency should begin treatment with a low dose and be carefully monitored.

Post-marketing reports indicate that some neonates exposed to Luvox, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see Precautions). When treating pregnant women with Luvox, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Luvox in the third trimester.