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FAVERIN 50MG FILM-COATED TABLETS

Active substance(s): FLUVOXAMINE MALEATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Faverin 50 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50 mg fluvoxamine maleate.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet
Round, biconvex, scored, white to off-white film coated tablets imprinted '291'
on both sides of the score.
The tablet can be divided into equal halves.

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 dose is 100 mg daily. Patients should start on 50 or 100 mg, given
as a single dose in the evening. Dosage should be reviewed and adjusted if necessary

within 3 to 4 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 300 mg 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 2 or 3 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 6 months
to ensure that they are free from symptoms.
Children/adolescents
Faverin should not be used in children and adolescents under the age of 18 years for
the treatment of major depressive episode. The efficacy and safety of Faverin have
not been established in the treatment of paediatric major depressive episode (see
section 4.4).
Obsessive Compulsive Disorder
Adults
The recommended dose is between 100-300 mg daily. Patients should start at 50 mg
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 a
maximum of 300 mg 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 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.
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.
Children/adolescents
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 section 5.1 and
5.2). 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.
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.
Hepatic or renal insufficiency
Patients suffering from hepatic or renal insufficiency should start on a low dose and
be carefully monitored.
Method of administration
Fluvoxamine tablets should be swallowed with water and without chewing.

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.

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.
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.
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. Suiciderelated 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). 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: dizziness, sensory disturbances (including paraesthesia, visual
disturbances and electric shock sensations), sleep disturbances (including insomnia
and intense dreams), agitation, irritability, confusion, emotional instability, headache,

nausea and/or vomiting and diarrhoea, sweating and palpitations, tremor and anxiety
(see section 4.8).
Generally these 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 section 4.2).
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, 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.
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
Fluvoxamine should not be co-administered with terfenadine, astemizole or cisapride
as plasma concentrations may be increased resulting in a higher risk for QTprolongation/Torsade de Pointes.
Due to lack of clinical experience, special attention is advised in the situation of postacute myocardial infarction.
Electroconvulsive therapy (ECT)
There is limited clinical experience of concomitant administration of fluvoxamine and
ECT therefore caution is advisable.
CYP2C19 inhibition
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of
fluvoxamine that inhibit the activity of this enzyme would be expected to result in
reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of
this interaction is uncertain. As a precaution concomitant use of fluvoxamine should
be discouraged (see section 4.5).

4.5

Interaction 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. Drugs which are largely metabolised via these isoenzymes
may have higher plasma concentrations of the active substance/ metabolite when coadministered with fluvoxamine.
In case of prodrugs which are activated by CYPs mentioned above, like clopidogrel,
plasma concentrations of the active substance/metabolite may be lower when coadministered with fluvoxamine. As a precaution concomitant use of clopidogrel and
fluvoxamine should be discouraged.
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.
Compounds with narrow therapeutic index
Co-administration with fluvoxamine and drugs with a narrow therapeutic index (such
as tacrine, theophylline, methadone, mexiletine, phenytoin, carbamazepine and
cyclosporine) should be carefully monitored when these drugs are metabolized
exclusively or by a combination of CYPs inhibited by fluvoxamine.
If necessary, dose adjustment of these drugs is recommended.
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 coadministered 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.
Caffeine plasma levels are likely to be increased during co-administration with
fluvoxamine. Thus, patients who consume high quantities of caffeine-containing
beverages should lower their intake when fluvoxamine is administered and adverse
caffeine effects (like tremor, palpitations, nausea, restlessness, insomnia) are
observed.
Terfenadine, astemizole, cisapride, sildenafil (see also section 4.4).
Fluvoxamine does not influence plasma concentrations of digoxin.
Fluvoxamine does not influence plasma concentrations of atenolol.

4.6

Fertility, pregnancy and lactation
Pregnancy
Epidemiological data have suggested that the use of Selective Serotonin
Reuptake Inhibitors (SSRIs) in pregnancy, particularly in late pregnancy, may
increase the risk of persistent pulmonary hypertension in the newborn (PPHN).
The observed risk was approximately 5 cases per 1000 pregnancies. In the
general population 1 to 2 cases of PPHN per 1000 pregnancies occur.
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).
Animal data have shown that fluvoxamine may affect sperm quality (see
section 5.3). 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.
Faverin should not be used in patients attempting to conceive unless the
clinical condition of the patient requires treatment with fluvoxamine.

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
Adverse events, observed in clinical studies at frequencies listed below, are
often associated with the illness and are not necessarily related to treatment.
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10),
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare
(<1/10,000), not known (cannot be estimated from the available data).

MedDra system
organ class

Common

Endocrine
disorders

Metabolism and
nutrition

Anorexia

Uncommon

Rare

Ver
y
rare

Frequency not
known
Hyperprolactine
mia,
Inappropriate
antidiuretic
hormone
secretion.
Hyponatraemia,
weight

increased,
weight
decreased

disorders

Hallucination,
confusional
stage

Psychiatric
disorders

Nervous system
disorders

Agitation,
Extrapyramidal
nervousness,
disorder, ataxia
anxiety, insomnia,
somnolence,
tremor, headache,
dizziness

Eye disorders
Renal and
urinary
disorders:

Cardiac
disorders

suicidal ideation
(see section
4.4).

Convulsion

Serotonin
syndrome,
neuroleptic
malignant
syndrome-like
events,
paresthesia,
dysgeusia, and
SIADH have
been reported
(see also section
4.4).
Psychomotor
restlessness/aka
thisia (see
section 4.4).
Glaucoma
Mydriasis.
micturition
disorder
(including
urinary
retention,
urinary
incontinence,
pollakiuria,
nocturia and
enuresis)

Palpitations/
tachycardia
(Orthostatic)
hypotension

Vascular
disorders

Gastrointestinal
disorders

Mania

Abdominal pain,
constipation,

Haemorrhage
(e.g.
gastrointestinal
haemorrhage,
gynaecological,
haemorrhage,
ecchymosis,
purpura)

diarrhoea, dry
mouth, dyspepsia,
nausea, vomiting
Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorders

Hyperhydrosis
Sweating

Musculoskeletal,
connective tissue
and bone
disorders
Reproductive
system and
breast disorders

General
disorders and
administration
site reactions

Cutaneous
hypersensitivity
reactions (incl.
angioneurotic
oedema, rash,
pruritis)
Arthralgia,
myalgia

Abnormal
(delayed)
ejaculation

Hepatic
function
abnormal
Photosensiti
v ity
reaction

**Bone
fractures

Galactorrhoea

Asthenia, malaise

Anorgasmia,
menstrual
disorders (such
as amenorrhea,
hypomenorrhea,
metrorrhagia,
menorrhagia).
drug withdrawal
syndrome
including drug
withdrawal
syndrome
neonatal.(see
section 4.6)

*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.
**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.

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

Paediatric population
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.
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard

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 deaths attributed to overdose of fluvoxamine alone
have been extremely rare. The highest documented dose of fluvoxamine
ingested by a patient is 12 grams. This patient recovered completely.
Occasionally, more serious complications were observed in cases of deliberate
overdose of fluvoxamine in combination with other drugs.
Treatment
There is no specific antidote to fluvoxamine. In case of overdose the stomach should
be emptied as soon as possible after tablet ingestion and symptomatic treatment
should be given. The repeated use of medicinal charcoal, if necessary accompanied
by an osmotic laxative, is also recommended. Forced diuresis or dialysis is 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.
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.

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 is not influenced by concomitant food intake.
Distribution
In vitro plasma protein binding of fluvoxamine is 80%. Volume of distribution in
humans is 25 l/kg.
Metabolism
Fluvoxamine undergoes extensive metabolism in the liver. Although CYP2D6 is in
vitro the main isoenzyme involved in fluvoxamine’s metabolism, plasma
concentrations in poor metabolisers for CYP2D6 are not much higher than those in
extensive metabolisers.
The mean plasma half-life is approximately 13-15 hours after a single dose and
slightly longer (17-22 hours) during repeated dosing, when steady-state plasma levels
are usually achieved within 10-14 days.
Fluvoxamine undergoes extensive hepatic transformation, mainly via oxidative
demethylation, into at least nine metabolites, which are excreted by the kidneys. The
two major metabolites showed negligible pharmacological activity. The other
metabolites are not expected to be pharmacologically active. Fluvoxamine is a potent

inhibitor of CYP1A2 and CYP2C19. A moderate inhibition was found for CYP2C9,
CYP2D6 and CYP3A4.
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 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
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. The effects were observed at
exposures
>two-fold higher than exposures at the maximum therapeutic dose. As there is
no safety margin between exposure at the NOAEL in the reproductive studies
and the exposure at the maximum therapeutic dose a risk to patients cannot be
ruled out.
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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet cores:
Mannitol
Maize starch
Pregelatinised starch
Sodium stearyl fumarate
Colloidal anhydrous silica
Film-coat:
Hypromellose
Macrogol 6000
Talc
Titanium Dioxide E171

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Do not store above 25°C.

6.5

Nature and contents of container
PVC/PVdC/Aluminium press-through blister.
Pack sizes: 5, 10, 20, 30, 50, 60, 90, 100 and 250 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special recommendation.

7

MARKETING AUTHORISATION HOLDER
Mylan Products Ltd.
20 Station Close
Potters Bar
Herts
EN6 1TL
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 46302/0034

9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21/06/2009

10

DATE OF REVISION OF THE TEXT
14/07/2017

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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