Luvox (Fluvoxamine Maleate)

LUVOX®

Solvay Pharma

Fluvoxamine Maleate

Antidepressant – Antiobsessional Agent

Action And Clinical Pharmacology: The antidepressant and antiobsessional actions of fluvoxamine are believed to be related to its selective inhibition of presynaptic serotonin re-uptake in brain neurones.

There is minimum interference with noradrenergic processes, and, in common with several other specific inhibitors of serotonin uptake, fluvoxamine has very little in vitro affinity for a1, a2, b1, dopamine2, histamine1, serotonin1, serotonin2 or muscarinic receptors.

Pharmacokinetics: In healthy volunteers, fluvoxamine 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-postdose. 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 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 had nonlinear pharmacokinetics over this dose range, i.e., higher doses of fluvoxamine produced disproportionately higher concentrations than predicted from the lower dose.

Metabolism and Elimination: Fluvoxamine 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 to human plasma proteins is about 77% at drug concentrations up to 4 000 ng/mL.

Indications And Clinical Uses: Depression: For the symptomatic relief of depressive illness.

The effectiveness of fluvoxamine in long-term use (i.e., for more than 5 to 6 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use fluvoxamine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Obsessive-Compulsive Disorder: Fluvoxamine has been shown to significantly reduce the symptoms of obsessive-compulsive disorder. The obsessions or compulsions must be experienced as intrusive, markedly distressing, time consuming, or interfering significantly with the person’s social or occupational functioning.

The efficacy of fluvoxamine has been studied in double-blind, placebo-controlled clinical trials conducted in obsessive-compulsive outpatients. The usefulness of fluvoxamine for long-term use (i.e., for more than 10 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use fluvoxamine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contra-Indications: In patients with known hypersensitivity to the drug.

Fluvoxamine should not be administered together with MAO inhibitors. At least 2 weeks should elapse after discontinuation of MAO inhibitor therapy before fluvoxamine treatment is initiated. MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with fluvoxamine.

Precautions: Seizures: Convulsions have been reported rarely during fluvoxamine administration. Caution is recommended when the drug is administered to patients with a history of seizures. If seizures occur during fluvoxamine administration, the drug should be discontinued.

ECT: Concurrent administration with electroshock therapy should be avoided because of the absence of experience in this area.

Hepatic Enzymes: Treatment with fluvoxamine has been rarely associated with increases in hepatic enzymes, usually accompanied by symptoms. Fluvoxamine administration should be discontinued in such cases.

Combination with Alcohol: Fluvoxamine may potentiate the effects of alcohol and increase the level of psychomotor impairment.

Occupational Hazards: 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 fluvoxamine does not affect them adversely.

Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high-risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescriptions for fluvoxamine should be written for the smallest quantity of drug consistent with good patient management.

Concomitant Illness: Fluvoxamine 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.

Pregnancy and Lactation: Safe use of fluvoxamine during pregnancy and lactation has not been established. Like other antidepressants, fluvoxamine 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.

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

Drug Interactions: Combined use of fluvoxamine and MAO inhibitors is contraindicated (see Contraindications).

An increase in tricyclic antidepressant blood levels has also been reported in patients taking fluvoxamine concomitantly.

Lithium, and possibly tryptophan, may enhance the serotonergic effects of fluvoxamine; these combinations should therefore be used with caution. The serotonergic effects may also be enhanced when fluvoxamine and other agents, including sumatriptan and SSRI’s, are used in combination. This may, on rare occasions, result in a serotonergic syndrome.

Fluvoxamine may prolong the elimination of drugs which are metabolized by oxidation in the liver, and a clinically significant interaction is more likely when the second agent has a narrow therapeutic index, as is the case with warfarin, phenytoin, theophylline, clozapine and carbamazepine. Such combinations should therefore be administered with caution, and consideration be given to lowering the dose of the second agent. In interaction studies, a 5-fold increase in plasma levels of propranolol and a 65% increase in warfarin plasma levels were seen during concurrent administration of fluvoxamine. An absence of pharmacokinetic interaction has been seen with digoxin and atenolol, which are not significantly metabolized in the liver.

Cytochrome P450 Isozyme (IID6): Like other selective serotonin reuptake inhibitors, fluvoxamine inhibits the specific hepatic cytochrome P450 isozyme (IID6) which is responsible for the metabolism of debrisoquine and sparteine. Although the clinical significance of this effect has not been established, inhibition of IID6 may lead to elevated plasma levels of co-administered drugs which are metabolized by this isozyme. Drugs metabolized by cytochrome P450IID6 include the 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).

Adverse Reactions: Commonly Observed: In clinical trials, the most commonly observed adverse events associated with fluvoxamine administration, and not seen at an equivalent incidence among placebo-treated patients, were gastrointestinal complaints, including nausea (sometimes accompanied by vomiting), constipation, anorexia, diarrhea and dyspepsia; CNS complaints, including somnolence, dry mouth, nervousness, insomnia, dizziness, tremor and agitation; and asthenia. Abnormal (mostly delayed) ejaculation was frequently reported by patients with obsessive-compulsive disorder, primarily at doses over 150 mg/day.

Adverse Events Leading to Discontinuation of Treatment: Approximately 14% (14.4%) of 34 587 patients who received fluvoxamine in clinical trials discontinued treatment due to an adverse event. The more common events causing discontinuation from depression trials included nausea and vomiting, insomnia, agitation, headache, abdominal pain, somnolence, dizziness, asthenia and anorexia. The most common events causing discontinuation in patients suffering from obsessive-compulsive disorder included insomnia, asthenia and somnolence.

Incidence of Adverse Experiences: Adverse events with an incidence of ³ 5% reported in double-blind, placebo-controlled clinical trials in depression and in obsessive-compulsive disorder are presented in Table I for each indication.

During premarketing and postmarketing studies, multiple doses of fluvoxamine 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% of patients), infrequent (occurring in less than 1%, but at least 0.1% of patients), or rare (occurring in less than 0.1% but at least in 0.01% of 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 fluvoxamine, they were not necessarily caused by it.

Nervous: 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.

Digestive: 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.

Cardiovascular: 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.

Body as a Whole: 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.

Skin: Frequent: sweating increased.

Infrequent: pruritus, rash.

Rare: acne, alopecia, dry skin, eczema, furunculosis, herpes simplex, herpes zoster, maculopapular rash, psoriasis, urticaria.

Respiratory: Infrequent: dyspnea, pharyngitis, rhinitis.

Rare: asthma, bronchitis, cough increased, epistaxis, hiccup, hyperventilation, laryngismus, laryngitis, pneumonia, sinusitis, voice alternation, yawn.

Special Senses: Infrequent: abnormal vision, amblyopia, hyperacusis, taste perversion, tinnitus.

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

Musculoskeletal: Infrequent: arthralgia, arthrosis, myalgia, myasthenia, tetany.

Rare: arthritis, bone pain, leg cramps, pathological fracture, rheumatoid arthritis.

Urogenital: 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.

Metabolic and Nutritional: Frequent: weight gain.

Infrequent: peripheral edema, weight loss.

Rare: alcohol intolerance, dehydration, edema, obesity.

Hematic and Lymph Systems: Rare: anemia, cyanosis, ecchymosis, lymphadenopathy, thrombocytopenia.

Hyponatremia: Hyponatremia has been reported in association with other antidepressants, though rarely with fluvoxamine.

Adverse effects following discontinuation of treatment: Symptoms, including headache, nausea, dizziness and anxiety, have been reported after discontinuation of other antidepressants, though rarely after abrupt discontinuation of fluvoxamine.

Anecdotal spontaneous reports, from the marketplace, but not from clinical trials, have been collected for the following adverse experiences: angioedema, galactorrhea, and photosensitivity.

Symptoms And Treatment Of Overdose: Symptoms: More than 300 cases of overdosage with fluvoxamine, 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 300 patients reported to have taken deliberate overdoses of fluvoxamine, there have been 30 deaths, all but 1 of which occurred in patients who were confirmed to have taken multiple medications. The highest documented dose of fluvoxamine ingested by a patient is 12 g; this patient recovered completely with symptomatic treatment only.

Treatment: There is no specific antidote to fluvoxamine. 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, forced diuresis or dialysis is unlikely to be of benefit.

Dosage And Administration: Depression: Adults: 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 fluvoxamine 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. Fluvoxamine should be swallowed with water and without chewing.

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

Children: The safety and effectiveness of fluvoxamine in children under 18 years of age have not been established.

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

Availability And Storage: 50 mg: 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, hydroxypropyl methylcellulose, maize starch, mannitol, polyethylene glycol, pregelatinized starch, sodium stearyl fumarate, talc and titanium dioxide. Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 100.

100 mg: 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, hydroxypropyl methylcellulose, maize starch, mannitol, polyethylene glycol, pregelatinized starch, sodium stearyl fumarate, talc and titanium dioxide. Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 100.

Preserve in well-closed containers. Store in a dry place at temperatures not below 0°C and not above 30°C. (Shown in Product Recognition Section)

LUVOX® Solvay Pharma Fluvoxamine Maleate Antidepressant – Antiobsessional Agent

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