Edronax , Israel 12 August 2015

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

EDRONAX 4 mg Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 4mg of reboxetine

For full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet
White, round, convex tablet with a breakline on one side. A ‘P’ is marked on the left side of the
breakline. A ‘U’ is marked on the right side of the breakline. The side opposite the breakline is
marked ‘7671’. The tablet can be divided into equal halves.

4. CLINICAL PARTICULARS

4.1. Therapeutic Indications

Reboxetine is indicated for the acute treatment of depressive illness/major depression and for
maintaining the clinical improvement in patients initially responding to treatment.

4.2. Posology and Method of Administration

Reboxetine is for oral use.

The onset of the clinical effect is generally seen after 14 days from treatment start.

Use in adults
The recommended therapeutic dose is 4 mg twice a day (b.i.d.) i.e.8 mg/day administered orally.
The full therapeutic dose can be given upon starting treatment. After 3-4 weeks, this dose can be
increased to 10 mg/day in case of incomplete clinical response. The maximum daily dose should
not exceed 12 mg. The minimum effective dose has not yet been established.

Use in the elderly

Elderly patients have been studied in clinical trials at doses of 2 mg b.i.d. However, safety and
efficacy have not been evaluated in placebo-controlled conditions. Therefore, as for other
antidepressants that have not been studied in placebo-controlled conditions, reboxetine cannot be
recommended.

Use in children and adolescents under the age of 18 years

Reboxetine should not be used in the treatment of children and adolescents under the age of 18
years (see section 4.4).

Use in patients with renal or hepatic insufficiency

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The starting dose in patients with renal or hepatic insufficiency should be 2 mg b.i.d which can
be increased based on patient tolerance.

4.3. Contra-indications

Known hypersensitivity to reboxetine or any of the components of the product.

4.4. Special Warnings and Special Precautions for Use

Use in children and adolescents under 18 years of age

Reboxetine should not be used in the treatment of children and adolescents under the age of 18
years. 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.

As reboxetine has not been tested in patients with convulsive disorders in clinical studies and
since rare cases of seizures have been reported in clinical studies, it should be given under close
supervision to subjects with a history of convulsive disorders and it must be discontinued if the
patient develops seizures.

Concomitant use of MAO-inhibitors (including linezolid (an antibiotic which is a reversible

non-selective MAOI) and methylene blue) and reboxetine should be avoided in view of the
potential risk (tyramine-like effect) based on their mechanisms of action.

Concomitant use of reboxetine with other antidepressants (tricyclics, MAO inhibitors, SSRIs and
lithium) has not been evaluated during clinical trials.

As with all antidepressants, switches to mania/hypomania have occurred during the clinical
studies. Close supervision of bipolar patients is, therefore, recommended.

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.

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.

Clinical experience with reboxetine in patients affected by serious concomitant systemic

illnesses is limited. Close supervision should be applied in patients with current evidence of
urinary retention, prostatic hypertrophy, glaucoma and history of cardiac disease.

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At doses higher than the maximum recommended, orthostatic hypotension has been observed
with greater frequency than that observed at recommended doses. Particular attention should be
paid when administering reboxetine with other drugs known to lower blood pressure.

Clinical experience with reboxetine in the long-term treatment of elderly patients is, at present,
limited. In this population, lowering of mean potassium levels was found starting from week 14;
the magnitude of this reduction did not exceed 0.8 mmol/litre and potassium levels never
dropped below normal limits.

Mydriasis has been reported in association with reboxetine; therefore, caution should be used
when prescribing reboxetine to patients with increased intraocular pressure or those at risk of
acute narrow-angle glaucoma.

4.5. Interactions with other medicinal products and other forms of interaction

In vitro metabolism studies indicate that reboxetine is primarily metabolised by the CYP3A4
isozyme of cytochrome P450; reboxetine is not metabolized by CYP2D6. Therefore potent
inhibitors of CYP3A4 (ketoconazole, nefazodone, erythromycin and fluvoxamine), would be
expected to increase plasma concentrations of reboxetine. In a study in healthy volunteers,
ketoconazole, a potent inhibitor of CYP3A4, was found to increase plasma concentrations of the
reboxetine enantiomers by approximately 50%. Because of reboxetine’s narrow therapeutic
margin, inhibition of elimination is a major concern. Reboxetine therefore should not be given
together with drugs known to inhibit CYP3A4 such as azole antifungal agents, macrolide
antibiotics such as erythromycin, or fluvoxamine.

Low reboxetine serum levels have been reported with the concurrent administration of CYP3A4
inducers such as phenobarbital and carbamazepine. Examples of other CYP3A4 inducers that
may reduce the serum levels of reboxetine include but are not limited to phenytoin, rifampicin
and St John´s Wort.

In vitro studies have shown that reboxetine does not inhibit the activity of the following P450
isoenzymes: CYP1A2, CYP2C9, CYP2C19 and CYP2E1. Pharmacokinetic interactions would
not be expected with compounds metabolised by these enzymes. At concentrations which
exceed those in clinical use, reboxetine inhibits CYP2D6 and CYP3A4, however, the results of in
vivo studies suggest that interactions with other drugs metabolised by these enzymes are unlikely.

No significant reciprocal pharmacokinetic interaction has been found between reboxetine and
lorazepam. During their co-administration in healthy volunteers, mild to moderate drowsiness
and short lasting orthostatic acceleration of heart rate have been observed.

Reboxetine does not appear to potentiate the effect of alcohol on cognitive functions in healthy
volunteers.

Concomitant use of MAO-inhibitors (including linezolid (an antibiotic which is a reversible

non-selective MAOI) and methylene blue) and reboxetine should be avoided in view of the
potential risk (tyramine-like effect) based on their mechanisms of action.

Concomitant use of reboxetine with other antidepressants (tricyclics, MAO inhibitors, SSRIs and
lithium) has not been evaluated during clinical trials.

Concomitant use of ergot derivatives and reboxetine might result in increased blood pressure.

Food intake delayed the absorption of reboxetine, but did not significantly influence the extent of
absorption.

Although data are not available from clinical studies, the possibility of hypokalaemia with
concomitant use of potassium losing diuretics should be considered.

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In an in vivo multiple-dose study performed in healthy volunteers, no clinically significant

interaction between fluoxetine and reboxetine was observed. In patients, a different effect and
safety profile upon combination of reboxetine and fluoxetine cannot be excluded.

4.6. Pregnancy and lactation

PREGNANCY
No clinical trial data on exposure to reboxetine during pregnancy are available. However,
postmarketing safety data on a very limited number of exposed pregnancies indicate no adverse
effects of reboxetine on pregnancy or on the health of the foetus/newborn child.
Animal studies in general do not indicate direct or indirect harmful effects with respect to
pregnancy, embryonal/foetal development or parturition. Some impairment of growth and
development has been noted in rat neonates (see section 5.3).
Reboxetine should only be used in pregnancy if the potential benefits of treatment to the mother
outweigh the possible risks to the developing foetus.

LACTATION
Reboxetine is known to be excreted in breast milk. The level of active substance transferred in
breast milk is anticipated to be very low, however there is insufficient information to exclude a
risk to the nursing infant. The use of reboxetine during breastfeeding can be considered if the
potential benefits outweigh the risk for the child.

4.7. Effects on ability to drive and use machines

Although reboxetine has been shown to have negligible effect on psychomotor performance in
healthy volunteers, any psychoactive drug can impair judgement or skills. Patients should be
cautioned about driving or operating hazardous machinery until reasonably certain that their
performance has not been affected.

4.8. Undesirable effects

Over 2100 patients received reboxetine in clinical studies, approximately 250 of which received
reboxetine for at least 1 year.

The information provided in Table 1 below is a summary of adverse events observed in patients
treated with reboxetine in placebo-controlled clinical studies of 8 weeks duration or less. In
addition, the table also includes adverse events observed from postmarketing experience
(frequency not known).

Table 1: Adverse events

Very Common Uncommon Rare Frequency not

Common (≥1/100 to <1/10) (≥1/1000 to (≥1/10000 to Known
(≥1/10) <1/100) <1/1000)
Metabolism and nutrition disorders
Decreased appetite Hyponatraemia
Psychiatric disorders
Insomnia Agitation*, Aggressive
Anxiety* behaviour,
Hallucination,
Suicidal
Ideation/behaviour**
Nervous system disorders
Dizziness Headache,
Paraesthesia*,
Akathisia,

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Dysguesia
Eye disorders
Accommodation Mydriasis* Glaucoma* Intraocular pressure
disorder increased
Ear and labyrinth disorders
Vertigo
Cardiac disorders
Tachycardia,
Palpitations
Vascular disorders
Vasodilatation, Peripheral coldness,
Hypotension, Raynaud`s
Hypertension* phenomenon
Gastrointestinal disorders
Dry mouth, Vomiting*
Constipation,
Nausea*
Skin and subcutaneous tissue disorders
Hyperhidrosis Rash* Allergic dermatitis
Renal and urinary disorders
Sensation of
incomplete bladder
emptying, Urinary
tract infection,
Dysuria, Urinary
retention
Reproductive system and breast disorders
Erectile Testicular pain
dysfunction,
Ejaculatory pain,
Ejaculatory delay
General disorders and administration site conditions
Chills Irritability
* these adverse events also occurred in postmarketing experience
** Cases of suicidal ideation and suicidal behaviours have been reported during reboxetine
therapy or early after treatment discontinuation (see section 4.4).

In placebo-controlled studies of 8 weeks duration or less, adverse events were reported in

approximately 80% of reboxetine-treated patients and in approximately 70% of placebo-treated
patients. Discontinuation rates for adverse events were approximately 9% and 5% for
reboxetine-and placebo-treated patients, respectively.

As for long-term tolerability, 143 reboxetine-treated and 140 placebo-treated adult patients
participated in a long term placebo controlled study. Adverse events newly emerged on long
term treatment in 28% of the reboxetine treated patients and 23% of the placebo-treated patients
and caused discontinuation in 4% and 1% of the cases respectively. There was a similar risk of
the development of individual events with reboxetine and placebo. In the long term studies, no
individual events were seen which have not been seen on short term treatment.

In short-term controlled studies of patients with depression, no clinically significant between-

gender differences were noted in the frequency of treatment emergent symptoms, with the
exception of urologic events (such as the sensation of incomplete bladder emptying, dysuria and
urinary frequency), which were reported in a higher percentage of reboxetine-treated male
patients (31.4% [143/456]) than reboxetine-treated female patients (7.0% [59/847]). In contrast,
the frequency of urologic-related events was similar among male (5.0% [15/302]) and female
(8.4% [37/440]) placebo-treated patients.

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In the elderly population, frequency of total adverse events, as well as of individual events, was
no higher than that reported above.

In pre-marketing clinical studies, signs and symptoms newly reported following discontinuation
occurred in approximately (5%) of the reboxetine treated patients and approximately (4%) of
placebo-treated patients. In post-marketing experience, there have been a few spontaneous
reports of withdrawal symptoms including headache, dizziness, nervousness and nausea;
however, no consistent pattern of events on cessation of treatment with reboxetine was evident in
these reports.

In those short-term studies in depression where heart rate was assessed with ECG, reboxetine
was associated with mean increases in heart rate, compared to placebo, of 6 to 12 beats per
minute.

In all short-term controlled studies in depression, the mean change in pulse (in beats per minute)
for reboxetine-treated patients was 3.0, 6.4 and 2.9 in the standing, sitting and supine positions
respectively, compared with 0, 0, and –0.5 for placebo-treated patients in the corresponding
positions. In these same studies, 0.8% of reboxetine-treated patients discontinued the drug
because of tachycardia compared with 0.1% of placebo-treated patients.

Reporting of suspected adverse reactions

Any suspected adverse events should be reported to the Ministry of Health according to the
National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@
moh.health.gov.il ) or by email ([email protected] ).

4.9. Overdose

The acute toxicity studies carried out in animals indicate a very low toxicity, with a wide safety
margin with respect to the pharmacologically active doses. Clinical signs and cause of death
were related to CNS stimulation (mainly convulsive symptoms).

In a few cases doses higher than those recommended were administered to patients (12 mg to 20
mg/day) for a period ranging from a few days to some weeks during clinical studies: newly
reported complaints include postural hypotension, anxiety and hypertension. Elderly might be
particularly vulnerable to overdose.

In premarketing clinical studies, there were 5 reports of reboxetine overdose alone or in

combination with other pharmacologic agents. The amount of reboxetine ingested was 52 mg as
the sole agent by 1 patient and 20 mg in combination with other agents by another patient. The
remaining 3 patients ingested unknown quantities of reboxetine. All 5 patients recovered fully.
There were no reports of ECG abnormalities, coma, or convulsions following overdose with
reboxetine alone.

In postmarketing experience, there have been few reports of overdose in patients taking
reboxetine alone; none of these have proved fatal. Non-fatal overdoses in patients have been
reported for patients taking up to 240 mg of reboxetine. One fatal overdose was reported in a
patient who ingested reboxetine in combination with amitriptyline (doses unknown).

In case of overdose, monitoring of cardiac function and vital signs is recommended. General
symptomatic supportive and/or emetic measures might be required.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

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Pharmacotherapeutic group: Other Antidepressants

ATC code: NO6A X18

Reboxetine is a highly selective and potent inhibitor of noradrenaline reuptake. It has only a
weak effect on the 5-HT reuptake and does not affect the uptake of dopamine.

Noradrenaline reuptake inhibition and the consequent increase of noradrenaline availability in

the synaptic cleft and modification of noradrenergic transmission, reportedly is among the most
relevant mechanisms of action of known antidepressant drugs.

In vitro, studies have shown that reboxetine has no significant affinity for adrenergic (α1, α2, β)
and muscarinic receptors; antagonism of such receptors has been described to be associated with
cardiovascular, anticholinergic and sedative side effects of other antidepressant drugs.
Reboxetine is devoid of in vitro binding affinity for either α1 or α2 adrenoceptors, however, a
functional interference with α-adrenoceptors at high doses in vivo cannot be excluded.

In a post hoc stratified analysis of data from 11 placebo-controlled trials involving 2400 patients,
there was no statistical difference in response rates on the primary endpoint (HAMD 21 item
scale) for reboxetine versus placebo patients with mild to moderate severity of depression.
Efficacy was only clearly demonstrated in patients with severe or very severe depression. From
these trials there are limited efficacy data available in the use of reboxetine in patients with mild
to moderate severity of depression.

5.2. Pharmacokinetic properties

After oral administration of a single 4 mg reboxetine dose to healthy volunteers, peak levels of
about 130 ng/ml are achieved within 2 h post-dosing. Data indicate that absolute bioavailability
is at least 60%.

Reboxetine plasma levels decreased monoexponentially with a half-life of about 13 h. Steady-

state conditions are observed within 5 days. Linearity of the pharmacokinetics was shown in the
range of single oral doses in the clinically recommended dose-ranges.

The drug appears to be distributed into total body water. Reboxetine is 97 % bound to human
plasma proteins in young and 92% in elderly (with affinity markedly higher for α1 acid
glycoprotein than albumin), with no significant dependence of the concentration of drug.

Reboxetine is predominantly metabolised in vitro via cytochrome P4503A (CYP3A4). In vitro

studies have shown that reboxetine does not inhibit the activity of the following isozymes of
cytochrome P450: CYP1A2, CYP2C9, CYP2C19, and CYP2E1. Reboxetine inhibits both
CYP2D6 and CYP3A4 with low binding affinities, but has shown no effect on the in vivo
clearance of drugs metabolized by these enzymes.

The amount of radioactivity excreted in urine accounts for 78 % of the dose. Even though
unchanged drug is predominant in the systemic circulation (70% of total radioactivity, in terms
of AUC), only 10% of the dose is excreted as unchanged drug in urine. These findings suggest
that biotransformation rules the overall elimination of reboxetine and that metabolites excretion
is limited by their formation. The main metabolic pathways identified are 2-O-dealkylation,
hydroxylation of the ethoxyphenoxy ring and oxidation of the morpholine ring, followed by
partial or complete glucuro- or sulpho-conjugation.

The drug is available as a racemic mixture (with both enantiomers being active in the
experimental models): no chiral inversion, nor reciprocal pharmacokinetic interferences between
enantiomers have been observed. Plasma levels of the more potent SS enantiomer are about two
times lower and urinary excretion two times higher than those of the enantiomeric counterpart.
No significant differences were observed in the terminal half-lives of the two enantiomers.

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Increases in systemic exposure and half-life of approximately two-fold are observed in patients
with renal insufficiency and hepatic insufficiency. Similar or somewhat greater (3-fold)
increases in systemic exposure also occur in elderly patients relative to young healthy volunteers.

Data from animal studies indicate that reboxetine crosses the placenta and is distributed into
breast milk.

5.3. Pre-clinical Safety Data

Reboxetine did not induce gene mutations in bacterial or mammalian cells in vitro but induced
chromosomal aberrations in human lymphocytes in vitro. Reboxetine did not cause DNA
damage in yeast cells or rat hepatocytes in vitro. Reboxetine did not cause chromosomal damage
in an in vivo mouse micronucleus test, and did not increase tumor incidence in carcinogenecity
studies in mice and rats.

Haemosiderosis was reported in toxicity studies in rats only.

Studies in animals have not demonstrated any teratogenic effect or any effect of the compound
on global reproductive performance. Dosages that produced plasma concentrations within the
therapeutic range for humans induced an impairment of growth and development and long term
behavioural changes in offspring of rats.

In rats reboxetine is excreted in milk.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Cellulose microcrystalline
Dibasic calcium phosphate dihydrate
Crospovidone
Silicon dioxide
Magnesium stearate

6.2. Incompatibilities
Not applicable

6.3. Shelf-Life

3 years

6.4. Special Precautions for Storage

Store below 25° C.

6.5. Nature and Content of Container

The tablets are contained in aluminium PVDC / PVC-PVDC opaque blisters.

Each pack contains 20 or 60 tablets
Not all pack sizes may be marketed.

6.6. Special precautions for disposal

No special requirements.

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Manufacturer: Pfizer Italia S.r.l

License Holder: Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Hertzliya Pituach 46725

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