Fluvoxamine Maleate Synthon

Fluvoxamine maleate.

Each film-coated tablet contains 50 mg of fluvoxamine maleate.
Excipients/Inactive Ingredients: Maize starch, colloidal anhydrous silica, pregelatinised starch, sodium stearyl fumarate, mannitol, polyethylene glycol 6000, talc, titanium dioxide (E171) and methyl hydroxypropyl cellulose.

Pharmacotherapeutic Group: Antidepressants, selective serotonin reuptake inhibitors. ATC Code: N06A B08.
Pharmacology: Pharmacodynamics: The mechanism of action of fluvoxamine is thought to be related to selective serotonin reuptake inhibition in brain neurones. There is minimum interference with noradrenergic processes.
Receptor binding studies have demonstrated that fluvoxamine has negligible binding capacity to alpha adrenergic, beta adrenergic, histaminergic, muscarine cholinergic, dopaminergic or serotonergic receptors.
In placebo-controlled trial in 120 patients with OCD, aged between 8 and 17 years, a statistically significant improvement was seen in the total population in favour of fluvoxamine at 10 weeks. A further subgroup analysis showed improvement on the C-YBOCS rating scale in children whereas no effect was seen in adolescents. The mean dose was respectively 158 mg and 168 mg/day.
Pharmacokinetics: Absorption: Fluvoxamine is completely absorbed following oral administration. Maximum plasma concentration occur within 3-8 hours of dosing. The mean absolute bioavailability is 53%, due to first-pass metabolism.
The pharmacokinetics of Fluvoxamine maleate 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 a moderate inhibitor of CYP2C and CYP3A4, with only marginal inhibitory effects on CYP2D6.
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 Patient 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 concentration 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 in adults.
Toxicology: Preclinical Safety Data: There is no evidence of carcinogenicity, mutagenicity or impairment of fertility with fluvoxamine.
Reproduction studies in animals at high doses revealed no evidence of impaired fertility, reproductive performance or teratogenic effects in the offspring.
The potential for abuse tolerance and physical dependence has been studied in a non-human primate model. No evidence of dependency phenomena was found.

Depressive illness and symptoms of depressive disorder.
Obsessive-compulsive disorder (OCD).

Depression: Adult: The recommended starting dose is 50 mg or 100 mg, given as a single dose, preferably 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 responses.
Doses up to 300 mg per day have been given.
Dosages above 150 mg should be given in divided doses.
In agreement with the consensus statements of the WHO, antidepressant medication should be continued for at least 6 months after recovery from a depressive episode. A dose of 100 mg daily may be sufficient for this use.
Children/Adolescents: Fluvoxamine is not allowed as treatment of depression for children and adolescents under the age of 18 years old. The efficacy and safety of fluvoxamine are not demonstrated for this group. (See Precautions).
Obsessive-Compulsive Disorder (OCD): The recommended starting dose is 50 mg per day for 3-4 days. The effective dose usually lies between 100 mg and 300 mg per day. The dosage should be increased gradually until the effective dose 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/Adolescents: In children over 8 years and adolescents, there is limited data on a dose of up to 100 mg bid for 10 weeks. The starting dose is 25 mg per day.
Increase every 4-7 days in 25 mg increments, if tolerated, until an effective dose is achieved. The maximum dose in children should not exceed 200 mg/day (see Pharmacology: Pharmacodynamics under Actions). It is recommended to divide daily doses of more than 50 mg over 2 doses. If these doses are not of equal amount, the highest dose should be taken in the evening.
Hepatic or Renal Insufficiency: Patients suffering from hepatic or renal insufficiency should start on a low dose and be carefully monitored.
Withdrawal Symptoms seen on Discontinuation of Fluvoxamine: Abrupt discontinuation should be avoided. 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.
Administration: Fluvoxamine tablets should be swallowed with water and without chewing.

Symptoms: Gastrointestinal 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 grams. 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 are unlikely to be of benefit.

Hypersensitivity to the active substance or to any of the excipients.
Fluvoxamine maleate tablets are contraindicated in combination with monoamine oxidase inhibitors (MAOIs). 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).
At least one week should elapse between discontinuation of fluvoxamine and initiation of therapy with any MAOI.

The possibility of a suicide attempt is inherent in patients suffering from depressive period and may persist until significant remission occurs.
Patients should be carefully monitored.
Patients suffering from hepatic or renal insufficiency should start on 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.
Glycaemic control may be disturbed, especially in the early stages of treatment. The dosage of antidiabetic drugs may need to be adjusted.
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.
As with other SSRIs, hyponatremia has been rarely reported, and appears to be reversible when fluvoxamine is discontinued. Some cases were possible due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients.
There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most TCAs, aspirin, NSAIDs) as well as in patients with a history of bleeding or coagulation disorders.
Fluvoxamine should be discontinued in any patient entering a manic phase.
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.
Due to lack of clinical experience, special attention is advised in the situation of post-acute myocardial infarction.
There is limited clinical experience of concomitant administration of fluvoxamine on ECT therefore caution is advisable.
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.
Due to lack of clinical experience, fluvoxamine should not be used in children and adolescents under 18 years of age with depression. No clinical studies have been performed in this group.
Lack of inhibitors, including suicidal behaviour, have been reported with the use of SSRIs. Data regarding the safety and efficacy of fluvoxamine in adults with depression cannot be extrapolated to children.
Suicide/Suicidal Thoughts: 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 self-harm is highest shortly after presentation and the risk of suicide may increase again the early stages of recovery.
Furthermore, there is evidence that in a small group of people, antidepressants may increase the risk of suicidal thoughts and self-harm.
Other psychiatric conditions for which fluvoxamine is prescribed can also be associated with an increase risk of suicide-related events. In addition, these conditions may be co-morbid with depression. The same precautions observed when treating patients with depression should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at a greater risk of suicidal thoughts or suicidal attempts, and should receive careful monitoring during treatment.
Patients (and caregivers of patients) should be alerted about the need to monitor for the emergence of suicidal thoughts and to seek medical advice immediately if these symptoms present.
Psychomotor Restlessness: The use of fluvoxamine has been associated with the development of psychomotor restlessness, which clinically may be very similar to akathisia, characterised 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 and it may be necessary to review the use of fluvoxamine.
Withdrawal Symptoms seen on Discontinuation of Fluvoxamine Treatment: Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. In clinical trials, adverse events seen on treatment discontinuation occurred in approximately 12% of patients treated with fluvoxamine.
The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.
Dizziness, sleep disturbances (including insomnia and intense dreams), nausea, headache and asthenia are the most commonly reported reactions. Generally these symptoms are mild to moderate, however, in some patients, they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals, they may be prolonged (2-3 months or more). It is therefore advised that fluvoxamine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs.
Long-term safety data in children and adolescents, especially related to growth, sexual function, cognitive and behavioural development are lacking. Careful monitoring is therefore recommended in this patient population.
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.

Data on a limited number of exposed pregnancies indicate no adverse effects of fluvoxamine on pregnancy. To date, no other relevant epidemiological data are available.
Reproduction studies in animals at high doses revealed no evidence of impaired fertility, reproductive performance or teratogenic effects in the offspring. Caution should be exercised when prescribing to pregnant women.
Isolated cases of withdrawal symptoms in the newborn child have been described after the use of fluvoxamine at the end of pregnancy.
Fluvoxamine is excreted via human milk in small quantities. Therefore, the drug should not be used by women who breast feed.

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. Other adverse events, observed in clinical studies at frequencies listed below, are often associated with the illness and are not necessarily related to treatment.
Common (Frequency 1-10%): Body: Asthenia, headache, malaise.
Cardiovascular: Palpitations/tachycardia.
Digestive System: Abdominal pain, anorexia, constipation, diarrhoea, dry mouth, dyspepsia.
Nervous System: Agitation, anxiety, dizziness, insomnia, nervousness, somnolence, tremor.
Skin: Sweating.
Uncommon (Frequency <1%): Cardiovascular: Postural hypotension.
Musculoskeletal: Arthralgia, myalgia.
Nervous System: Ataxia, confusion, extrapyramidal symptoms, hallucinations.
Urogenital: Abnormal (delayed) ejaculation.
Skin: Cutaneous hypersensitivity reactions (including rash, pruritus, angioedema).
Rare (Frequency <0.1%): Digestive System: Liver function abnormality.
Nervous System: Convulsions, mania, psychomotor restlessness/akathisia.
Urogenital: Galactorrhoea.
Skin: Photosensitivity.
Other Adverse Events Observed during Marketing: Weight gain or weight loss have been reported.
Rarely, serotonin syndrome, neuroleptic malignant syndrome-like events, hyponatremia and SIADH have been reported. (See Precautions).
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 treatment cause dependence.
The following symptoms have been reported in association with withdrawal of the product: Dizziness, paresthesia, headache, nausea and anxiety.
The majority of the withdrawal reactions are mild and self-limiting. When stopping, a gradual dose reduction may be considered.
Haemorrhage: (See Precautions).
Very rarely, paresthesia, anorgasmy and taste perversion have been reported.
In one 10-week placebo-controlled trial in children and adolescents with OCD, frequently reported adverse events with a higher incidence than placebo, were: Insomnia, asthenia, agitation, hyperkinesia, somnolence and dyspepsia. Serious adverse events in this study included: Agitation and hypomania.
Convulsions in children and adolescents have been reported during use outside clinical trials.
Withdrawal Symptoms seen on Discontinuation of Fluvoxamine Treatment: Discontinuation of fluvoxamine (particularly when abrupt) commonly leads to withdrawal symptoms.
Dizziness, sleep disturbances (including insomnia and intense dreams), nausea, headache and asthenia are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when fluvoxamine treatment is no longer required, gradual discontinuation by dose tapering should be carried out.

Fluvoxamine should not be used in combination with MAOIs (see Contraindications).
Fluvoxamine is a potent inhibitor of CYP1A2 and to a lesser extent CYP2C and CYP3A4. Drugs which are largely metabolised via these isoenzymes are eliminated slower and may have higher plasma concentrations when co-administered with fluvoxamine. 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 has marginal inhibitory effects on CYP2D6 and seems not to affect non-oxidative metabolism or renal excretion.
CYP1A2: 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 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.
Patients co-administered fluvoxamine and CYP1A2 metabolised drugs with a narrow therapeutic index (such as tacrine, theophylline, methadone, mexiletine) should be carefully monitored and if necessary, dose adjustment of these drugs is recommended.
When given with fluvoxamine, warfarin plasma concentrations were significantly increased and prothrombin time prolonged.
Isolated cases of cardiac toxicity have been reported when fluvoxamine was combined with thioridazine.
As plasma concentrations of propranolol are increased in combination with fluvoxamine, the propranolol dose may need to be lowered.
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.
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.
CYP2C: Patients co-administered fluvoxamine and CYP2C metabolised drugs with a narrow therapeutic index (such as phenytoin) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
CYP3A4: Terfenadine, astemizole, cisapride (see Precautions).
Patients co-administered fluvoxamine and CYP3A4 metabolised drugs with a narrow therapeutic index (such as carbamazepine, cyclosporin) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
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.
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 combinations 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 of 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.

Instruction for Use, Handling and Disposal: No special requirements.
Incompatibilities: Not applicable.

Store in the original undamaged package at room temperature (at or below 25°C).

Antidepressants

N06AB08 - fluvoxamine ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.

POM

FC tab 50 mg x 30's.