Faverin 100mg Film-coated Tablets

Addition of 'Sexual dysfunction' information to section 4.4

7.  MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited

Unit 35/36

Grange Parade

Baldoyle Industrial Estate

Dublin 13

Ireland

BGP Products Ireland Limited

4051 Kingswood Drive,

Citywest Business Campus,

Dublin 24

8. MARKETING AUTHORISATION NUMBER

PA 2136/3/2 2007/6/2

10. DATE OF REVISION OF THE TEXT

June 2017

4.4 Special warnings and precautions for use

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.

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.

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, which is similar to the incidence seen in patients taking placebo.  The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.

The most commonly reported symptoms in association with withdrawal of the product include:
Dizzinessdizziness, sensory disturbances (including paraesthesia, visual disturbances and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation and anxiety, irritability, confusion, emotional instability, headache, nausea and/or vomiting and diarrhoea, sweating and palpitations, headache and tremor and anxiety (see Section 4.8)are the most commonly reported reactions.

Generally these symptoms events 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 (see "Withdrawal Symptoms Seen on Discontinuation of Fluvoxamine", Section 4.2).

Metabolism and nutrition disorders
As with other SSRIs, hyponatraemia 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.

4.5 Interactions with other medicinal products and other forms of interaction

Pharmacodynamic interactions
The serotonergic effects of fluvoxamine may be enhanced when used in combination with other serotonergic agents (including tramadol, triptans, linezolid, 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.

Monoamine oxidase inhibitors
Fluvoxamine should not be used in combination with MAOIs, including linezolid, due to risk of serotonin syndrome (see also section 4.3 and 4.4).

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 CYP 2C19 is demonstrated in in vitro and in vivo studies. CYP2C9, CYP 2D6 and CYP3A4 are inhibited to a lesser extent.  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.

Concomitant therapy of fluvoxamine and these drugs should be initiated at or adjusted to the low end of their dose range. Plasma concentrations, effects or adverse effects of co-administered drugs should be monitored and their dosage should be reduced, if necessary.  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, 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.

Compounds with narrow therapeutic index
Patients coCo-administered administration with fluvoxamine and CYP1A2 metabolised 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.  and, iIf necessary, dose adjustment of these drugs is recommended.

An increase in previously stable plasma levels of those tricyclic antidepressants (e.g. clomipramine, imipramine, amitriptyline) and neuroleptics (e.g. clozapine and 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.

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.
As plasma concentrations of ropinirole may be increased in combination with fluvoxamine thus increasing the risk of overdose, surveillance and reduction in the dosage of ropinirole 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.

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 ropinirole may be increased in combination with fluvoxamine thus increasing the risk of overdose, surveillance and reduction in the dosage of ropinirole 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.

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

The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.

CYP3A4
Terfenadine, astemizole, cisapride , sildenafil (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 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 tramadol, triptans, linezolid, 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 Fertility, Pregnancy and lactation

4.8 Undesirable effects

In Ireland:
Reports may be made by following the links to the online reporting option accessible from the HPRA homepage, or by completing the downloadable report form also accessible from the HPRA website, which may be completed manually and submitted to the HPRA via freepost, to the following address:
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie

5.2 Pharmacokinetic properties

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.  Aa  moderate inhibition was found for  CYP2C9, CYP2D6 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 this disproportional increase is more pronounced with are disproportionately higher at.higher daily doses.

7     MARKETING AUTHORISATION HOLDER

From

Abbott Healthcare Products Limited

Section 4.2: editorial change; removal of full SmPC sub-heading references.

4.2       Posology and method of administration

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 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.

Section 4.3: inclusion of linezolid as an example of a reversible MAOI and inclusion of reference to section 4.4 for precautions to be taken in exceptional circumstances when it is necessary to prescribe linezolid.

4.3       Contraindications

Faverin tablets are contraindicated in combination with tizanidine and monoamine oxidase inhibitors (MAOIs) (see section 4.4 and 4.5).

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).

See section 4.4 for precautions in the exceptional case linezolid needs to be

given in combination with fluvoxamine.

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.

See section 4.4 for precautions in the exceptional case linezolid needs to be

given in combination with fluvoxamine.

Section 4.4: inclusion of precautions to be taken when linezolid is prescribed; editorial change, removal of full SmPC sub-heading references; the symptom of nausea is deleted and moved to section 4.8.

4.4       Special warnings and 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 Faverin 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.

Paediatric population

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

Geriatric population

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.

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.

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, which is similar to the incidence seen in patients taking placebo.  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 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 (see "Withdrawal Symptoms Seen on Discontinuation of Fluvoxamine", Section 4.2 Posology and method of administration).

Psychiatric 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.

Akathisia/psychomotor 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.

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.

In exceptional circumstances, linezolid (an antibiotic which is a reversible relatively weak non-selective MAOI) can be given in combination with fluvoxamine provided that there are facilities for close observation and management of symptoms of serotonin syndrome and monitoring of blood pressure (see section 4.3 and 4.5). If symptoms occur, physicians should consider discontinuing one or both agents.

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., hyperglycemia, hypoglycemia, 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 the following haemorrhagic disorders: gastrointestinal bleeding, gynaecological haemorrhage, and other cutaneous or mucous bleeding 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 and in those with predisposing conditions (e.g. thrombocytopenia or coagulation disorders).

Cardiac disorders

Section 4.5: under CYP1A2 inclusion of quetiapine as an example of a neuroleptic; under CYP3A4, sildenafil included; tramadol and linezolid included as examples of serotonergic agents, under the sub-heading pharmacodynamic interactions; editorial change, removal of full SmPC sub-heading references.

4.5       Interactions with other medicinal products and other forms of interaction

Fluvoxamine should not be used in combination with MAOIs (see also section 4.3 Contraindications and 4.4).

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, 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.

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.

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 ropinirole may be increased in combination with fluvoxamine thus increasing the risk of overdose, surveillance and reduction in the dosage of ropinirole 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.

Warfarin:

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

The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.

CYP3A4

Terfenadine, astemizole, cisapride , sildenafil (see also section 4.4 Special Warnings and Precautions for Use).

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 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 tramadol, triptans, linezolid, SSRIs and St. John´s Wort preparations). (See also section 4.4 Special Warnings and Precautions for Use).

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.

Section 4.8: Frequency unknown heading added to side effects table and all relevant side effects noted during clinical trials included; glaucoma included under eye disorders; editorial changes, removal of full SmPC sub-heading references.

Section 5.2: Faverin replaced by fluvoxamine.

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 Faverin fluvoxamine  is not influenced by concomitant food intake.

Section 5.3 Preclinical safety data was updated with the following content:

Carcinogenesis and mutagenesis
There is no evidence of carcinogenicity or mutagenicity with fluvoxamine.

Fertility and reproductive toxicity

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

Reproductive toxicity studies in rats have shown that fluvoxamine is embryotoxic (increased embryofetal death [resorptions], increased fetal eye abnormalities [folded retina], reduced fetal weights and delayed ossification). The effects on fetal weights and ossification are likely to be secondary to maternal toxicity (reduced maternal bodyweight and bodyweight gain). In addition an increased incidence of perinatal pup mortality in pre-and postnatal studies was seen.

The safety margin for reproductive toxicity is unknown.

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

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.

Section 4.8:
 Addition of text:

Eye Disorders: Mydriasis

Date of revision updated to Jan 2013

"Animal data have shown that fluvoxamine may affect sperm quality (see section 5.3).  Human case reports with some SSRI’s have shown that an effect on sperm quality is reversible.  Impact on human fertility has not been observed so far".

Section 5.3: following text has been added:

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

3.       Pharmaceutical Form

Film-coated tablet

Oval, biconvex, scored, white to off-white film-coated tablets imprinted '313' on both sides of the score.

           The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses
           
            The tablet can be divided into equal halves.

This SPC was updated to expand on the existing information and harmonise to CCSI.

The most significant change was to section 4.4: Warnings and precautions for use: addition of bold text

        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., hyperglycemia, hypoglycemia, 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.

Section 4.8: Addition of side effects to the frequency 'Not known: Hyperprolactinemia,  menstrual disorders (such as amenorrhea, hypomenorrhea, metrorrhagia, menorrhagia).

4.6       Fertility, Pregnancy and lactation

Pregnancy

Epidemiological data have suggested that the use of Selective Serotonin Reuptake Inhibitors (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.

Reproduction toxicity studies in animals revealed treatment related increases in embryotoxicity (embryofetal death, fetal eye abnormalities). The relevance to humans is unknown.  The safety margin for reproductive toxicity is unknown (see section 5.3).

Faverin 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 Faverin impairs male and female fertility. The safety margin for this effect was not identified.  The relevance of these findings to humans is unknown (see section 5.3).

Faverin should not be used in patients attempting to conceive unless the clinical condition of the patient requires treatment with fluvoxamine.

Section 4.8 Undesirable effects 

General disorders and administration site conditions: drug withdrawal syndrome including drug withdrawal syndrome neonatal(see section 4.6 Fertility, Pregnancy and Lactation).

5.3       Preclinical safety data

There is no evidence of carcinogenicity or mutagenicity with fluvoxamine.

Reproductive toxicity studies in rats have shown that fluvoxamine impairs male and female fertility (reduced sperm counts, increased ovary weights and reduced fertility), and is embryotoxic (increased embryofetal death [resorptions], increased fetal eye abnormalities [folded retina], reduced fetal weights and delayed ossification). The effects on fetal weights and ossification are likely to be secondary to maternal toxicity (reduced maternal bodyweight and bodyweight gain). The safety margin for reproductive toxicity is unknown.

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

The following sections have been updated;

Section 4.3

The following has been updated as highlighted;

Faverin tablets are contraindicated in combination with tizanidine and monoamine oxidase inhibitors (MAOIs) (see section 4.5).

Section 4.4

This section has been updated to include sub-headings

Section 4.5

The warfarin section has been moved and given its own sub-heading and subsequent information on cytochrome P-450 isozymes added.

Warfarin:

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

The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.

Section 4.6

This section has been updated to include the risk of PPHN.

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.

Section 4.8

This section has been updated with the SPC guidelines and the undesirable effects tabulated according to the MedDRA system organ class and ranked under headings of frequency.

Additionally, risk of bone fractures and micturition disorders have been added as below;

Renal and urinary disorders: micturition disorder (including urinary retention, urinary incontinence, pollakiura, nocturia and enuresis)

Class effects: Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving Selective Serotonin Reuptake Inhibitors (SSRIs) and Tricyclic Antidepressants (TCAs). The mechanism leading to this risk is unknown.

Section 6.4

Updated as indicated below;

Do not store above 25°C. 

Store in the original package.

In section 7, the name of the Marketing Authorisation Holder has been changed to Abbott Healthcare Products Ltd.