Fluvoxamine 50mg Film-Coated Tablets

Fluvoxamine 100mg Film-Coated Tablets

Fluvoxamine Maleate 50mg

Fluvoxamine Maleate 100mg

For excipients see 6.1

Oral – tablet.

Fluvoxamine 50mg Film-Coated Tablets - White to off-white, film coated circular tablets. Upper face FX/50, lower face CP.

Fluvoxamine 100mg Film-Coated Tablets - White to off-white, film coated capsule shaped tablets. Upper face FX/100, lower face CP.

Major depressive episode.

Obsessive Compulsive Disorder (OCD).

Major depressive episode:

The recommended dose is 100mg daily. Patients should start on 50 or 100mg, given as a single dose in the evening. Dosage should be reviewed and adjusted if necessary within three to four weeks of initiation of therapy and thereafter as judged clinically appropriate. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 300mg a day (see section 5.1). 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 two or three divided doses. Dosage adjustments should be made carefully on an individual patient basis, to maintain the patients at the lowest effective dose.

Patients with depression should be treated for a sufficient period of at least six months to ensure that they are free from symptoms.

Fluvoxamine should normally not be used to treat depressive illness in children and adolescents under 18 years of age (see section 4.4, Special Warnings and Precautions for Use).

Obsessive compulsive disorder:

The recommended dose is between 100-300mg daily. Patients should start at 50mg per day. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to maximum of 300mg a day (see section 5.1). 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 two or three divided doses. If a good therapeutic response has been obtained, treatment can be continued at a dosage adjusted on an individual basis.

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 patients 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. Long-term efficacy (more than 24 weeks) has not been demonstrated in OCD.

In children over eight 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 three to four days in 25 mg increments until an effective dose is achieved. The maximum dose in children should not exceed 200 mg/day. (For further details see 5.1 )

Patients suffering from hepatic or renal insufficiency should start on a low dose and be carefully monitored.

Fluvoxamine tablets should be swallowed with water and without chewing.

General information

Withdrawal:

Abrupt discontinuation should be avoided (see section 4.4 Special Warnings and Special Precautions for Use and section 4.8 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.

Fluvoxamine 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.

Fluvoxamine may, by inhibition of its metabolism, increase the plasma concentration of drugs such as pimozide and therefore increase the risk of QT prolongation and Torsade de Pointes caused by such drugs. Concomitant use is contraindicated.

Fluvoxamine may increase the plasma concentration of tizanidine increasing its adverse effects and therefore concomitant use is contraindicated.

Precautions for Use

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 Fluoxamine 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 of 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.

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.

Hepatic/renal insufficiency:

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.

Diabetes:

Fluvoxamine should be used with caution in patients with diabetes mellitus. Glycaemic control may be disturbed, especially in the early stages of treatment. The dosage of anti-diabetic drugs may need to be adjusted.

Epilepsy:

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.

Glaucoma:

Fluvoxamine should be used with caution in patients with glaucoma, which may be exacerbated by SSRIs.

Serotonin syndrome/neuroleptic malignant syndrome:

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 (see 4.8 Undesirable effects). As these syndromes may result in potentially life -threatening conditions, treatment with fluvoxamine should be discontinued if such events occur and supportive symptomatic treatment should be initiated.

Hyponatremia

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.

Coagulopathy:

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 disorders (particularly gastrointestinal bleeding) or coagulation disorders.

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.

QT prolongation:

When combined with fluvoxamine plasma concentrations of terfenadine or astemizole may be increased resulting in an increased risk for QT-prolongation/Torsade de Pointes. Therefore, fluvoxamine should not be co-administered with these drugs.

Cardiac disease:

Due to lack of clinical experience special attention is advised in patients with cardiac disease and in the situation of post-acute myocardial infarction.

Electroconvulsive therapy (ECT):

There is limited clinical experience of concomitant administration of fluvoxamine and ECT therefore caution is advisable.

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.

Children and adolescents under 18 years of age:

Fluvoxamine should not be used in the treatment of children and adolescents under the age of 18 years, except for patients with OCD.

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.

Withdrawal:

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 Undesirable effects). 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 two weeks, though in some individuals they may be prolonged (two to three 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 Posology and Method of Administration).

Fluvoxamine should not be used in combination with MAOIs (see also contraindications).

Pharmacokinetic interactions

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 more slowly 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, methadone, mexiletine) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.

Concomitant theophylline should be avoided if possible, or theophylline dosage halved.

When given with fluvoxamine, warfarin plasma concentrations were significantly increased and prothrombin times prolonged.

Increased plasma concentrations of thioridazine as well as 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.

Fluvoxamine may increase the plasma concentration of tizanidine increasing its adverse effects and therefore concomitant use is contraindicated.

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 ropinirole may be increased in combination with Fluvoxamine thus increasing the risk of overdose, surveillance and reduction in the posology of ropinirole during fluvoxamine treatment and after its withdrawal may be required.

Fluvoxamine may inhibit zolmitriptan metabolism; a reduction in zolmitriptan dosage may be necessary.

Fluvoxamine inhibits the metabolism of ropivacaine; prolonged administration of ropivacaine should be avoided.

CYP2C

Patients co-administered fluvoxamine and CYP2C metabolised drugs with a narrow therapeutic index (such as phenytoin and proguanil) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.

CYP3A4

Fluvoxamine may, by inhibition of its metabolism, increase the plasma concentration of drugs such as pimozide and therefore increase the risk of QT prolongation and Torsade de Pointes caused by such drugs. Concomitant use is contraindicated.

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.

Concomitant use of fluvoxamine and nevirapine may increase the adverse effects of nevirapine.

Oxidation

The plasma levels of oxidatively metabolised benzodiazepines (e.g. triazolam, rnidazolam, 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. Increased plasma levels of haloperidol have been reported. Reboxetine should not be given concurrently with fluvoxamine.

Glucuronidation

Fluvoxamine does not influence plasma concentrations of digoxin.

Renal excretion

Fluvoxamine does not influence plasma concentrations of atenolol.

Pharmacodynamic interactions

Alcohol: As with other psychotropic drugs patients should be advised to avoid alcohol use while taking fluvoxamine.

Anticoagulants and NSAIDs: In patients on oral anticoagulants, aspirin or other NSAIDs, and fluvoxamine, the risk for haemorrhage may increase and these patients should therefore be closely monitored.

Antiepileptics: SSRIs may antagonise the antiepileptic effect of antiepileptics.

Dopaminergics: Selegiline should not be started until one week after stopping fluvoxamine. Avoid fluvoxamine for two weeks after stopping selegiline.

Lithium: 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.

Other serotonergic agents: The serotonergic effects of fluvoxamine may be enhanced when used in combination with other serotonergic agents (including triptans, tramodol, SSRIs and St. John's Wort preparations) (see also special warnings and special precautions for use). Increased risk of CNS toxicity and serotonin syndrome with sibutramine; avoid concomitant use.

Epidemiological data have suggested that the use of 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.

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.

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.

Blood: Haemorrhage: (see also special warnings and special precautions for use)

Body: Asthenia, headache, malaise, weight gain or weight loss.

Cardiac disorders: Palpitations/tachycardia, bradycardia, postural hypotension.

Digestive system: Abdominal pain, anorexia, constipation, diarrhoea, dry mouth, dyspepsia, nausea (sometimes accompanied by vomiting), liver function abnormality, taste perversion.

Eye: visual disturbances (including abnormal or blurred vision), glaucoma.

Immune system: anaphylaxis and anaphylactoid reactions.

Metabolism and nutrition: polydipsia (rare), hypoglycaemia. 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 (see section 4.4 Special Warnings and Precautions for Use). The majority of reports were associated with older patients.

Musculoskeletal: Arthralgia, myalgia.

Nervous system: Dizziness, fatigue, insomnia, somnolence, tremor, convulsions, ataxia, extrapyramidal symptoms, hallucinations, paraesthesia. Psychomotor restlessness/akathisia (see section 4.4 Special Warnings and Special Precautions for Use).

Psychiatric: Agitation, anxiety, confusion, nervousness, mania. Panic attacks, depersonalisation, hypomania, decreased libido have also been reported.

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

Rarely, a serotonin syndrome characterised by at least three symptoms, including changes in psychiatric status and behaviour (excitement, confusion, anxiety, agitation, delirium and restlessness), motor dysfunction (tremor, rigidity, myoclonus, hyperreflexia, and ataxia), hypotension or hypertension and autonomic symptoms such as sweating, fever, shivering and diarrhoea may occur. Severe complications, including disseminated intravascular coagulation, respiratory failure, seizures and coma have also been reported (see also 4.4 Special warnings and precautions for use).

Skin: Sweating, photosensitivity, cutaneous hypersensitivity reactions (incl. rash, pruritus, angioedema, urticaria), cutaneous bleeding disorders (such as ecchymoses and purpura).

Renal and urinary: urinary retention.

Reproductive system and breast: Abnormal (delayed) ejaculation, erectile dysfunction, anorgasmy, hyperprolactinaemia, galactorrhoea.

Class effects:

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

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, asthenia, tremor and confusion 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 Posology and Method of Administration and section 4.4 Special Warnings and Special Precautions for use).

Symptoms

Symptoms include gastro-intestinal complaints (nausea, vomiting and diarrhoea), somnolence and dizziness. Cardiac events (tachycardia, bradycardia, hypotension, electrocardiographic changes), liver function disturbances, convulsions, tremor, coma, mydriasis, respiratory difficulties and hypokalemia have also been reported. Rarely features of serotonin syndrome may occur.

Fluvoxamine has a wide margin of safety in overdose. Between market introduction and 2000, when data was reviewed in the US, reports of death attributed to overdose of fluvoxamine alone had 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. The benefit of gut decontamination is uncertain, but oral activated charcoal can be considered if more than 1g has been ingested by an adult or 100mg by a child within 1 hour. Forced diuresis or dialysis are unlikely to be of benefit. It is important to maintain an adequate airway, oxygenation and ventilation and to monitor cardiac rhythm and vital signs following fluvoxamine overdose.

Single brief convulsions do not require treatment. Frequent or prolonged convulsions should be controlled with intravenous diazepam of lorazepam. Give oxygen and correct acid base balance and metabolic disturbances as required. Intravenous phenytoin may be useful if convulsions are unresponsive to these measures.

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, muscarinic 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.

Dose response:

No formal clinical trials were conducted investigating the dose response of fluvoxamine. However, it is clinical experience that up-titrating the dose might be beneficial for some patients.

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 1/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 CYP 1 A2 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.

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.

Mannitol

Pregelatinised Starch

Maize Starch

Sodium Stearyl Fumarate

Opadry White Y-1-7000 (containing hydroxypropyl methyl cellulose [HPMC], polyethylene glycol [PEG] and E171, titanium oxide).

None

36 months

Do not store above 25°C. Store in the original container.

Blister strip consisting of hard tempered aluminium foil (20 micron) and PVC film (250 micron) containing 30, 60 and 90 tablets in cartons.

None

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

U.K.

50mg tablets - PL 29831/0096

100mg tablets - PL 29831/0095

3^rd March 2008

27/10/2010