Each tablet contains 50 mg of fluvoxamine maleate. The tablet can be divided into equal halves.
Each tablet contains 100 mg of fluvoxamine maleate. The tablet can be divided into equal halves.
Excipients (non-medicinal ingredients)/Inactive Ingredients: Tablet core: Mannitol (E421), maize starch, pregelatinised starch, sodium stearyl fumarate, colloidal anhydrous silica.
Film-coating: Hypromellose, polyethylene glycol 6000, talc, titaniumdioxyde (E171).
Pharmacotherapeutic group: Antidepressants, Selective serotonin reuptake inhibitors. ATC code: N06AB08.
Pharmacology: Pharmacodynamics: Receptor binding studies have demonstrated that fluvoxamine is a potent serotonin reuptake inhibitor in vitro as well as in vivo and has a minimal affinity for serotonin receptors subtypes. Its capacity of binding to alpha adrenergic, beta adrenergic, histaminergic, muscarinic, cholinergic or dopaminergic receptors is negligible.
Fluvoxamine has a high affinity for sigma-1 receptors, where it acts as an agonist at therapeutic doses.
Pharmacokinetics: Absorption: Fluvoxamine is completely absorbed following oral administration. Maximum plasma concentrations occur within 3-8 hours of dosing. The mean absolute bioavailability is 53%, due to first-pass metabolism.
The pharmacokinetics of fluvoxamine is not influenced by concomitant food intake.
Distribution: In vitro plasma protein binding of fluvoxamine is 80%. Volume of distribution in humans is 25 l/kg.
Metabolism: Fluvoxamine undergoes extensive metabolism in the liver. Although CYP2D6 is in vitro the main isoenzyme involved in fluvoxamine's metabolism, plasma concentrations in poor metabolisers for CYP2D6 are not much higher than those in extensive metabolisers.
The mean plasma half-life is approximately 13-15 hours after a single dose, and slightly longer (17-22 hours) during repeated dosing, when steady-state plasma levels are usually achieved within 10-14 days.
Fluvoxamine undergoes extensive hepatic transformation, mainly via oxidative demethylation, into at least nine metabolites, which are excreted by the kidneys. The two major metabolites showed negligible pharmacological activity. The other metabolites are not expected to be pharmacologically active. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19. A moderate inhibitor was found for CYP2C9, SYP2D6 and CYP3A4.
Fluvoxamine displays linear single-dose pharmacokinetics. Steady-state concentrations are higher than calculated from single-dose data, and are disproportionally higher at higher daily doses.
Special patients groups: The pharmacokinetics of fluvoxamine is similar in healthy adults, elderly patients, and patients with renal insufficiency. The metabolism of fluvoxamine is impaired in patients with liver disease.
Steady-state plasma concentrations of fluvoxamine were twice as high in children (aged 6-11) as in adolescents (aged 12-17). Plasma concentrations in adolescents are similar to those of adults.
Toxicology: Preclinical safety data: Carcinogenesis and mutagenesis: There is no evidence of carcinogenicity or mutagenicity with fluvoxamine.
Fertility and reproductive toxicity: Reproduction studies in animals revealed impaired fertility, increased embryofoetal death and decreased foetal body weight. The effects were observed at an exposure that exceeds the exposure under therapeutic doses in humans two-fold. In addition an increased incidence of perinatal pup mortality in pre-and postnatal studies were seen.
Physical and psychological dependence: The potential for abuse, tolerance and physical dependence has been studied in a nonhuman primate model. No evidence of dependency phenomena was found.
Treatment of depressive illness and the symptoms of depressive disorder.
Treatment of symptoms of obsessive compulsive disorder (OCD).
Depression: The recommended starting dose is 50 or 100 mg, given as a single dose in the evening. It is recommended to increase the dose gradually until an effective dose is reached. The usual effective dose is 100 mg per day and should be adjusted on individual patient response. Doses of up to 300 mg per day have been given. Dosages above 150 mg should be given in divided doses.
In agreement with the consensus statement of the WHO, antidepressant medication should be continued for at least 6 months after recovery from a depressive episode.
Fluvoxamine at a fixed single daily dose of 100 mg is the recommended dose for the prevention of recurrence of depression.
Obsessive compulsive disorder: Adults: The recommended starting dose is 50 mg per day for 3 - 4 days. The effective dosage usually lies between 100 mg and 300 mg per day. The dosage should be increased gradually until the effective dosage is achieved, with a maximum of 300 mg per day for adults.
Doses up to 150 mg can be given as a single dose, preferably in the evening. It is advisable that a total daily dose of more than 150 mg is given in 2 or 3 divided doses.
If a good therapeutic response has been obtained, treatment can be continued at a dosage adjusted on an individual basis. If no improvement is observed within 10 weeks, treatment with fluvoxamine should be reconsidered. While there are no systematic studies to answer the question of how long to continue fluvoxamine treatment, OCD is a chronic condition and it is reasonable to consider continuation beyond 10 weeks in responding patients. Dosage adjustments should be made carefully on an individual patient basis, to maintain the patient at the lowest effective dose. The need for treatment should be reassessed periodically. Some clinicians advocate concomitant behavioural psychotherapy for patients who have done well on pharmacotherapy.
Children and adolescents: The starting dose for children from 8 years on and adolescents is 25mg per day, preferably at bedtime. Increase every 4-7days in 25mg increments as tolerated until an effective dose is achieved. The effective dosage usually lies between 50mg and 200mg per day, the maximum dose in children should not exceed 200mg per day. It is advisable that a total daily dose of more than 50mg should be given in two divided doses. If the two divided doses are not equal, the larger dose should be given at bedtime.
Withdrawal symptoms seen on discontinuation of fluvoxamine: Abrupt discontinuation should be avoided. When stopping treatment with fluvoxamine, the dose should be gradually reduced over a period of at least one or two weeks in order to reduce the risk of withdrawal reactions (see section Special warnings and precautions for use and section Undesirable effects). 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.
Hepatic or renal insufficiency: Patients suffering from hepatic or renal insufficiency should start on a low dose and be carefully monitored.
Method of administration: Fluvoxamine tablets should be swallowed with water and without chewing.
Symptoms: Symptoms include gastro-intestinal complaints (nausea, vomiting and diarrhoea), somnolence and dizziness. Cardiac events (tachycardia, bradycardia, hypotension), liver function disturbances, convulsions and coma have also been reported.
Fluvoxamine has a wide margin of safety in overdose. Since market introduction, reports of death attributed to overdose of fluvoxamine alone have been extremely rare. The highest documented dose of fluvoxamine ingested by a patient is 12 gram. This patient recovered completely. Occasionally, more serious complications were observed in cases of deliberate overdose of fluvoxamine in combination with other drugs.
Treatment: There is no specific antidote to fluvoxamine. In case of overdose the stomach should be emptied as soon as possible after tablet ingestion and symptomatic treatment should be given.
The repeated use of medicinal charcoal, if necessary accompanied by an osmotic laxative, is also recommended. Forced diuresis or dialysis is unlikely to be of benefit.
Fluvoxamine tablets are contraindicated in combination with tizanidine and monoamine oxidase inhibitors (MAOIs) (see section Interaction with other medicinal products and other forms of interaction).
Treatment with fluvoxamine can be initiated: two weeks after discontinuation of an irreversible MAOI, or the following day after discontinuation of a reversible MAOI (e.g. moclobemide, linezolid).
At least one week should elapse between discontinuation of fluvoxamine and initiation of therapy with any MAOI.
Fluvoxamine immediate-release tablets should not be used in combination with pimozide and ramelteon (see Interactions).
Hypersensitivity to the active substance or to any of the excipients.
Suicide/suicidal thoughts or clinical worsening: Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs.
It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which fluvoxamine are prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. Therefore when treating patients with other psychiatric disorders, they should be closely monitored.
Patients with a history of suicide-related events and those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes.Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Akathisia/psychomotor restlessness: The use of fluvoxamine has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Renal and hepatic impairment: Patients suffering from hepatic or renal insufficiency should start on a low dose and be carefully monitored. Treatment with fluvoxamine has rarely been associated with an increase in hepatic enzymes, generally accompanied by clinical symptoms. In such cases treatment should be discontinued.
Nervous system disorders: Although in animal studies fluvoxamine has no pro-convulsive properties, 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.
On rare occasions, development of a serotonin syndrome or neuroleptic malignant syndrome-like events have been reported in association with treatment of fluvoxamine, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with fluvoxamine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.
Metabolism and nutrition disorders: As with other SSRIs hyponatremia has been rarely reported and appears to be reversible when fluvoxamine is discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients.
Glycaemic control may be disturbed (i.e.,hyperglycaemia, hypoglycaemia, decreased glucose tolerance), especially in the early stages of treatment. When fluvoxamine is given to patients with a known history of diabetes mellitus, the dosage of anti-diabetic drugs may need to be adjusted.
Nausea, sometimes accompanied by vomiting, is the most frequently observed symptom associated with fluvoxamine treatment. This side effect usually diminishes within the first two weeks of treatment.
Eye Disorders: Mydriasis has been reported in association with SSRIs such as fluvoxamine. Therefore, caution should be used when prescribing fluvoxamine in patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma.
Haematological disorders: There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura as well as other haemorrhagic manifestations, such as gastrointestinal bleeding or gynaecological haemorrhage, 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 TCAs, acetylsalicylic acid, 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, or coagulation disorders).
Cardiac disorders: When combined with fluvoxamine plasma concentrations of terfenadine, astemizole or cisapride may be increased resulting in an increased risk for QT-prolongation/Torsade de Pointes. Therefore, fluvoxamine should not be co-administered with these drugs. Fluvoxamine may cause an insignificant decrease in heart beat (2-6 beats per minute).
Electroconvulsive therapy (ECT): There is limited clinical experience of concomitant administration of fluvoxamine and ECT; therefore caution is advisable.
Withdrawal reactions: It is possible that withdrawal reactions may occur on stopping therapy with fluvoxamine, although the available preclinical and clinical evidence does not suggest that this causes dependence.
The most commonly reported symptoms in association with withdrawal of the product include: dizziness, sensory disturbances (including paraesthesia, visual disturbances and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation, irritability, confusion, emotional instability, headache, nausea and/or vomiting, diarrhoea, sweating, palpitations, tremor and anxiety (see Adverse Reactions). Generally, these events are mild to moderate and are self-limiting; however in some patients they may be severe and/or prolonged. They usually occur within the first few days of discontinuing treatment. It is therefore advised that fluvoxamine should be gradually tapered when discontinuing treatment according to the patient’s needs (see Dosage & Administration).
Mania/Hypomania: Fluvoxamine should be used with caution in patients with a history of mania/hypomania. Fluvoxamine should be discontinued in any patient entering a manic phase.
Sexual dysfunction: Selective serotonin reuptake inhibitors (SSRIs) may cause symptoms of sexual dysfunction (see Adverse Reactions). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs.
Effects on ability to drive and use machines: Fluvoxamine up to 150 mg has no or negligible influence on the ability to drive and use machines. It showed no effect on psychomotor skills associated with driving and operating machinery in healthy volunteers. However, somnolence has been reported during treatment with fluvoxamine. Therefore, caution is recommended until the individual response to the drug has been determined.
Use in Children: Fluvoxamine should not be used in the treatment of children and adolescents under the age of 18 years except for patients with OCD. Due to lack of clinical experience the use of fluvoxamine in children for the treatment of depression cannot be recommended. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressant compared to those treated with placebo. If based on clinical need, a decision to treat is taken, the patient should be carefully monitored for the appearance of suicidal symptoms.
In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive behavioural development are lacking.
Young adults (ages 18 to 24 years): A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Use in the Elderly: Data in elderly subjects give no indication of clinically significant differences in normal daily dosages compared to younger subjects. However upward dose titration should be done slower in the elderly, and dosing should always be done with caution.
Pregnancy: Epidemiological data have suggested that the use of Selective Serotonin Reuptake Inhibitors (SSRIs) in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.
Fluvoxamine should not be used during pregnancy unless the clinical condition of the woman requires treatment with fluvoxamine.
Isolated cases of withdrawal symptoms in the newborn child have been described after the use of fluvoxamine at the end of pregnancy.
Some newborns experience feeding and/ or respiratory difficulties, seizures, temperature instability, hypoglycaemia, tremor, abnormal muscle tone, jitteriness, cyanosis, irritability, lethargy, somnolence, vomiting, difficulty in sleeping and constant crying after third trimester exposure to SSRIs and may require prolonged hospitalization.
Breastfeeding: Fluvoxamine is excreted via human milk in small quantities. Therefore, the drug should not be used by women who breast feed.
Fertility: Reproductive toxicity studies in animals have shown that fluvoxamine impairs male and female fertility. The relevance of these findings to humans is unknown (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Fluvoxamine should not be used in patients attempting to conceive unless the clinical condition of the patient requires treatment with fluvoxamine.
Adverse events, observed in clinical studies at frequencies listed below, are often associated with the illness and are not necessarily related to treatment. Frequency estimate: Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). (See table.)
Click on icon to see table/diagram/image
Withdrawal symptoms seen on discontinuation of fluvoxamine treatment:
Discontinuation of fluvoxamine (particularly when abrupt) commonly leads to withdrawal symptoms. It is therefore advised that when fluvoxamine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see Dosage & Administration and Precautions).
Monoamine oxidase inhibitors: Fluvoxamine should not be used in combination with MAOIs, including linezolid, due to risk of serotonin syndrome (see Contraindications).
Effect of fluvoxamine on the oxidative metabolism of other drugs: Fluvoxamine can inhibit the metabolism of drugs metabolized by certain cytochrome P450 isoenzymes (CYPs). A strong inhibition of CYP1A2 and CYP2C19 is demonstrated in in vitro and in vivo studies. CYP2C9, CYP2D6 and CYP3A4 are inhibited to a lesser extent.
Drugs which are largely metabolised via these isoenzymes may have higher/lower (e.g. in case of prodrugs like Clopidogrel) plasma concentrations of the active substance/metabolite when coadministered with Fluvoxamine. Concomitant therapy of fluvoxamine and these drugs should be initiated at or adjusted to the low vs high end of their dose range. Plasma concentrations, effects or adverse effects of co-administered drugs should be monitored and their dosage should be reduced/increased if necessary. This is particularly relevant for drugs with a narrow therapeutic index.
Ramelteon: When immediate-release fluvoxamine maleate tablets 100 mg twice daily was administered for 3 days prior to single-dose co- administration of ramelteon 16 mg and immediate-release fluvoxamine maleate tablets, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone.
Compounds with narrow therapeutic index: Co-administration of fluvoxamine and drugs with a narrow therapeutic index (such as tacrine, theophylline, methadone, mexiletine, phenytoin, carbamazepine and cyclosporine) should be carefully monitored when these drugs are metabolized exclusively or by a combination of CYPs inhibited by fluvoxamine.
If necessary, dose adjustment of these drugs is recommended.
Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, concomitant us of pimozide and fluvoxamine is contraindicated- see Contraindications.
Tricyclic antidepressants and neuroleptics: An increase in previously stable plasma levels of those tricyclic antidepressants (e.g., clomipramine, imipramine, amitriptyline) and neuroleptics (e.g., clozapine, olanzapine, quetiapine) which are largely metabolised through cytochrome P450 1A2 when given together with fluvoxamine, has been reported. A decrease in the dose of these products should be considered if treatment with fluvoxamine is initiated.
Benzodiazepines: The plasma levels of oxidatively metabolised benzodiazepines (e.g. triazolam, midazolam, alprazolam, and diazepam) are likely to be increased when co-administered with fluvoxamine. The dosage of these benzodiazepines should be reduced during co-administration with fluvoxamine.
Cases of increased plasma concentration: As plasma concentrations of ropinirol may be increased in combination with fluvoxamine thus increasing the risk of overdose, surveillance and reduction in the posology of ropinirol during fluvoxamine treatment and after its withdrawal may be required.
As plasma concentrations of propranolol are increased in combination with fluvoxamine, the propranolol dose may need to be lowered.
When given with fluvoxamine, warfarin plasma concentrations were significantly increased and prothrombin times prolonged.
Cases of increased side effects: Isolated cases of cardiac toxicity have been reported when fluvoxamine was combined with thioridazine.
Caffeine plasma levels are likely to be increased during co-administration with fluvoxamine. Thus, patients who consume high quantities of caffeine-containing beverages should lower their intake when fluvoxamine is administered and adverse caffeine effects (like tremor, palpitations, nausea, restlessness, insomnia) are observed.
Terfenadine, astemizole, cisapride, sildenafil: see section Special warnings and precautions for use.
Glucuronidation: Fluvoxamine does not influence plasma concentrations of digoxin.
Renal excretion: Fluvoxamine does not influence plasma concentrations of atenolol.
Pharmacodynamic interactions: The serotonergic effects of fluvoxamine may be enhanced when used in combination with other serotonergic agents (including triptans, tramadol, SSRIs and St. John's Wort preparations). (see Precautions).
Fluvoxamine has been used in combination with lithium in the treatment of severely ill, drug-resistant patients. However, lithium (and possibly also tryptophan) enhances the serotonergic effects of fluvoxamine. The combination should be used with caution in patients with severe, drug-resistant depression.
In patients on oral anticoagulants and fluvoxamine, the risk for haemorrhage may increase and these patients should therefore be closely monitored.
As with other psychotropic drugs patients should be advised to avoid alcohol use while taking fluvoxamine.
Incompatibilities: Not applicable.
Store below 30°C.
Store in the original package in order to protect from direct sunlight.
Shelf-Life: 2 years.
N06AB08 - fluvoxamine ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.
FC tab 50 mg (round, biconvex, scored, white to off-white) x 60's. 100 mg (oval, biconvex, scored, white to off-white) x 30's.