SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Fluvoxamine 50 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 50 mg fluvoxamine maleate.

Excipients: 1,7 mg lactose /film-coated tablet For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

Appearance:

50 mg Film-Coated Tablets: white, biconvex, round, scored

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Major depressive episode

Obsessive-Compulsive Disorder (OCD)

4.2    Posology and method of administration Depression

Adults

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. A dose of 100 mg daily may be sufficient for this use.

Use in children and adolescents under 18 years of age

Fluvoxamine film-coated tablets should not be used for the treatment of major depressive episodes in children and adolescents under the age of 18 years (see section 4.4).

The efficacy and safety of Fluvoxamine film-coated tablets have not been established in the treatment of paediatric major depressive episodes (see 4.4).

Obsessive Compulsive Disorder

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 and adolescents under 18 years of age

In children over 8 years and adolescents there is limited data on a dose of up to 100 mg b.i.d. for 10 weeks. The starting dose is 25 mg per day. Increase every 4-7 days in 25 mg increments as tolerated until an effective dose is achieved. The maximum dose in children should not exceed 200 mg/day. (For further

details see 5.1) It is advisable that a total daily dose of more than 50 mg should be given in two divided doses. If the two divided doses are not equal, the larger dose should be given at bedtime

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. 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 4.4 and section 4.8). 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.

Method of administration

Fluvoxamine tablets should be swallowed with water and without chewing.

4.3 Contraindications

Fluvoxamine film-coated 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.

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for use

Use in children and adolescents under 18 years of age

Fluvoxamine film-coated tablets should not be used in the treatment of children and adolescents under the age of 18 years, except for patients over 8 years with Obsessive Compulsive Disorder. 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 antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless 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 and behavioural development are lacking.

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 is 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. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk o suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

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/ysychomotor restlessness

The use of fluvoxamine has been associated with the development of 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 (see section 4.8). In clinical trials adverse events seen on treatment discontinuation occurred in approximately 12% of patients treated with fluvoxamine, a comparative incidence for placebo treated patients is not currently available. 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, sensory disturbance (including paraesthesia, visual disturbances and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation and anxiety, irritability, confusion, emotional instability, nausea and/or vomiting and diarrhoea, sweating and palpitations, headache and tremor 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 selflimiting 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 (see "Withdrawal Symptoms Seen on Discontinuation of Fluvoxamine", Section

4.2).

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.

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 proconvulsive 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 possibly 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 used with caution in patients with a history of mania/hypomania. 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 and 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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Fluvoxamine should not be used in combination with MAOIs (see also section

4.3).

Fluvoxamine is a potent inhibitor of CYP1A2, and to a lesser extent of 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.

In case of concomitant administration with tizanidine an increasing of the intensity and duration of its effects (3 3-fold of the AUC of tizanidine) has been reported. It was correlated with decrease in blood pressure and heart rate as well as drowsiness.

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 times 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 also section 4.4.

Patients co-administered fluvoxamine and CYP3A4 metabolised drugs with a narrow therapeutic index (such as carbamazepine, ciclosporin) 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 coadministered 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 also section 4.4)

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.

4.6 Pregnancy and lactation

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. Caution should be exercised when prescribing to pregnant women.

Animal data have shown that fluvoxamine may affect sperm quality.

Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed so far.

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.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particular 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.

4.7 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.

4.8 Undesirable effects

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 %):

General disorders: Asthenia, malaise Cardiac disorders: Palpitations/tachycardia

Gastrointestinal disorders: Abdominal pain, anorexia, constipation, diarrhoea, dry mouth, dyspepsia

Nervous system disorders: Agitation, dizziness, headache, insomnia, nervousness, somnolence, tremor

Psychiatric disorders: Anxiety

Skin and subcutaneous tissue disorders: Sweating

Uncommon (frequency < 1 %):

Vascular disorders: (Postural) hypotension

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia Nervous system disorders: Ataxia, extrapyramidal symptoms Psychiatric disorders: Confusion, hallucinations

Reproductive system and breast disorders: Abnormal (delayed) ejaculation

Skin and subcutaneous tissue disorders: Cutaneous hypersensitivity reactions (incl. rash, pruritus, angioedema)

Rare (frequency < 0.1 %):

Hepatobiliary disorders: Liver function abnormality Nervous system disorders: Convulsions Psychiatric disorders: Mania

Reproductive system and breast disorders: Galactorrhoea Skin and subcutaneous tissue disorders: Photosensitivity Psychomotor restlessness/akathisia (see section 4.4)

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 also section 4.4)

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 Haemorrhage: (see also section

4.4)

Very rarely, paresthesia, anorgasmy and taste perversion have been reported.

Cases of suicidal ideation and suicidal behaviours have been reported during fluvoxamine therapy or early after treatment discontinuation (see section 4.4)

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, sensory disturbance (including paraesthesia,

visual disturbance and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation and anxiety, irritability, confusion, emotional instability, nausea and/or vomiting and diarrhoea, sweating and palpitations, headache and tremor 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 (see section 4.2 and section 4.4).

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRs and TCAs. The mechanism leading to this risk is unknown.

4.9 Overdose

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 are unlikely to be of benefit.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressants, Selective serotonin reuptake inhibitors

ATC code: N06AB08

The mechanism of action of fluvoxamine is thought to be related to selective serotonin re-uptake 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 a 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.

5.2 Pharmacokinetic properties

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 film-coated tablets 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 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 in adults.

5.3    Preclinical safety data

Animal studies on fertility revealed reduction of mating performance, decreased sperm count, and fertility index at levels higher than human exposure.

There is no evidence of carcinogenicity or mutagenicity with fluvoxamine.

The potential for abuse, tolerance and physical dependence has been studied in a nonhuman primate model. No evidence of dependency phenomena was found.

6    PHARMACEUTICAL    PARTICULARS

6.1    List of excipients

lactose monohydrate

mannitol

maize starch

methylhydroxy propylcellulose

polyethylene glycol 4000

pregelatinized starch

sodium stearyl fumarate

silica colloidal, anhydrous

titanium dioxide (colouring agent E 171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The shelf life is 18 months.

6.4    Special precautions for storage

Do not store above 25 °C.

Store in the original package, in order to protect from light and moisture.

6.5    Nature and contents of container

Fluvoxamine 50 mg Film-Coated Tablets

Fluvoxamine 50 mg Film-Coated Tablets are packed in polyvinylchloride/aluminium or polyvinylidene chloride/aluminium blisters inserted into a carton folder.

The original packages contain:

15, 20, 30, 40, 50, 60, 90, and 100 film-coated tablets. hospital pack containing 250 (5 x 50) film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

This medicinal product does not require any special storage conditions.

7 MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Ltd 3 Howard Road,

Eaton Socon,

St. Neots,

Cambridgeshire PE19 8ET

MARKETING AUTHORISATION NUMBER(S)

PL 11311/0488

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/05/2010

DATE OF REVISION OF THE TEXT

10/09/2012