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Drug monograph
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Use:
SSRI. Depression: Adults, 50 mg once daily at bedtime; increase to 100 mg daily at bedtime after a few days, as tolerated. Usual effective daily dose: 100-200 mg; maximum is 300 mg/day. Dosage increases should be made in 50 mg increments. Doses above 150 mg should be divided with a maximum of 150 mg given at bedtime. Luvox's effectiveness in long-term use (i.e. > 5-6 weeks) has not been systematically evaluated in controlled trials. Obsessive-Compulsive Disorder (OCD): Adults, 50 mg once daily at bedtime; increase to 100 mg daily at bedtime after a few days, as tolerated. Usual effective daily dose: 100-300 mg (maximum dose). If no improvement is observed within 10 weeks, reconsider treatment with Luvox. Dosage increases should be made in 50 mg increments. Doses above j150 mg should be divided with a maximum of 150 mg given at bedtime. Luvox's effectiveness for long-term use (i.e. > 10 weeks) hasn't been systematically evaluated in controlled trials.
Hepatic or renal impairment: Initiate treatment with a low dose and monitor carefully.
Contraindications:
Do not use with, or within 2 weeks of ending MAOI therapy. At least 2 weeks should elapse before starting an MAOI follow cessation of Luvox. Concurrent administration of terfenadine, astemizole, thioridazine, mesoridazine or cisapride.
Precautions:
Use in women of child-bearing potential or nursing mothers only if clearly needed. Safety/efficacy in children < 18 years of age not established. Seizures, suicidal tendency. MI or unstable heart disease. Abnormal bleeding, hepatic enzyme increases. Avoid concurrent electroshock therapy. Consider gradual dosage reduction before stopping Luvox therapy.
Side effects:
Somnolence, dry mouth, nervousness, insomnia, dizziness, tremor, agitation, asthenia, abnormal ejaculation, g.i. disturbances including nausea, vomiting, diarrhea, constipation, anorexia and dyspepsia. Rare cases of seratonin syndrome, particularly when combined with other serotonergic drugs.
Interactions:
See Contraindications. Lithium, sumatriptan and tryptophan may enhance Luvox's serotonergic effects. Luvox co-administration may increase plasma levels of CYP450 substrates that have a narrow therapeutic index: CYP 1A2 (TCAs, neuroleptics, theophylline, warfarin, propranolol); CYP 3A4 (carbamazepine, methadone, cyclosporine); CYP2C (diazepam, phenytoin). St. John's Wort (increase in undesirable effects).
Patient tips:
Therapeutic response may be delayed until 2 or more weeks of treatment. Swallow tablets with water and without chewing. May cause dizziness (NB driving). Restrict alcohol intake.
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 alpha(1), alpha(2), beta(1), dopamine(2), histamine(1), serotonin(1), serotonin(2) 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 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.
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 4000 ng/mL.
Indications
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.
Contraindications
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:
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. 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.
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 and theophylline. 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 Effects
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:
Fifteen percent of approximately 25000 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 >= 5% reported in double-blind, placebo-controlled clinical trials in depression and in obsessive compulsive disorder are presented in table I for each indication.
Urogenital
Urinary frequency 2.2 1.6 5.0 1.3
Abnormal ejaculation 1.4 0 17.9+ 0
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*Dosage titration at study initiation varied between the depression
and OCD trials. In depression, fluvoxamine was administered: Day 1,
50 mg hs; Day 2, 100 mg; Day 3, 150 mg then titrated to response.
In OCD, fluvoxamine was administered: Days 1 to 4, 50 mg; Days 5
to 8, 100 mg, Days 9 to 14, 150 mg then titrated to response.
+Corrected for gender (males: n=78).
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During premarketing and postmarketing studies, multiple doses of fluvoxamine were administered to approximately 25000 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 System:
Frequent: Somnolence, dry mouth, insomnia, dizziness, nervousness, tremor, vertigo, thinking abnormal, agitation, anxiety, amnesia, depression.
