Edronax 4 mg Tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

20-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

29-06-2018

Aktiva substanser:
reboxetinmesilat
Tillgänglig från:
Ebb Medical AB
ATC-kod:
N06AX18
INN (International namn):
reboxetinmesilat
Dos:
4 mg
Läkemedelsform:
Tablett
Sammansättning:
reboxetinmesilat 5,224 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 60 tabletter; Blister, 100 tabletter
Bemyndigande status:
Avregistrerad
Godkännandenummer:
53433
Tillstånd datum:
2016-02-10

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

29-06-2018

Produktens egenskaper Produktens egenskaper - engelska

29-06-2018

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Package leaflet: Information for the user

Edronax 4mg tablets

reboxetine

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet

What Edronax

is and what it is used for

What you need to know before you take Edronax

How to take Edronax

Possible side effects

How to store Edronax

Contents of the pack and other information

1.

What Edronax is and what it is used for

The active substance in Edronax is reboxetine which is part of a group of medicines called antidepressants.

Edronax is used in acute treatment of depressive illness / major depression as well as for maintaining the

improvement of your symptoms when you have initially responded to treatment with reboxetine.

2.

What you need to know

before you take Edronax

Do not take Edronax

If you are allergic to Reboxetine or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor or pharmacist before taking Edronax

suffer from convulsions or epilepsy. Treatment with reboxetine should be stopped if seizures occur.

have any signs of urinary problems, enlarged prostate or a history of heart problems.

are taking medicines to lower your blood pressure.

have liver or kidney problems. Your doctor may need to adjust your dosage.

are taking any other medicine for depression such as MAO inhibitors, tricyclics, nefazodone, SSRIs

(such as fluvoxamine) or lithium.

are taking other MAO inhibitors such as linezolid (an antibiotic) or methylene blue (see section

“Other medicines and Edronax”).

ever had episodes of mania (overactive behaviour or thoughts).

have eye problems, such as certain kinds of glaucoma (increased pressure in the eye).

Thoughts of suicide and worsening of your depression:

If you are depressed you can sometimes have thoughts of harming or killing yourself

. These may be

increased when first starting antidepressants, since these medicines all take time to work, usually about two

weeks but sometimes longer.

You may be more likely to think like this:

- If you have previously had thoughts about killing or harming yourself.

- If you are a young adult. Information from clinical trials has shown an increased risk of suicidal behaviour

in adults aged less than 25 years with psychiatric conditions who were treated with an antidepressant.

If you have thoughts of harming or killing yourself at any time,

contact your doctor or go to a hospital

straight away.

You may find it helpful to tell a relative or close friend

that you are depressed, and ask them to read this

leaflet. You might ask them to tell you if they think your depression is getting worse, or if they are worried

about changes in your behaviour.

Children and adolescents

Edronax should not usually be used in children and adolescents less than 18 years old. Patients under 18

have an increased risk of undesirable effects, such as suicide attempt, suicidal thoughts and hostility (mainly

aggressiveness, oppositional behaviour and anger) when they are treated with this class of medicines.

Nevertheless, it is possible that your doctor decides to prescribe Edronax to a patient under 18 if it is in the

patient's interest. If your doctor has prescribed Edronax to a patient less than 18 years old and you want to

discuss this, please contact him/her.

Furthermore, if any of the symptoms listed above appear or worsen when a patient under 18 is taking

Edronax, you should inform your doctor.

Also, the long-term safety of Edronax in regard to growth, maturation and cognitive and behavioural

development in this age group has not yet been demonstrated.

Other medicines and Edronax

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Edronax may affect or be affected by other medicines. These include:

Certain antifungals, e.g. ketoconazole

Certain antibiotics, e.g. erythromycin, rifampicin

Medicines called ergot derivatives used to treat migraine or Parkinson’s disease

Certain antidepressants called MAO inhibitors, tricyclics, nefazodone, SSRIs (such as fluvoxamine)

or lithium

Other MAO inhibitors such as linezolid (an antibiotic) and methylene blue (used to treat high levels

of methaemoglobin in the blood)

Any potassium-losing diuretics (medicines for eliminating water), e.g thiazides

Medicines used to treat epilepsy e.g. phenobarbital, carbamazepine and phenytoin

Herbal medicines containing St. John’s Wort

(Hypericum perforatum)

Your doctor will tell you whether you can take Edronax with other medicines. Please tell your doctor or

pharmacist if you are taking or have recently taken any other medicines, including medicines obtained

without a prescription, herbal medicines, as well as vitamins and minerals.

Edronax with food and drink

Edronax can be taken with or without food.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine.

Pregnancy

There are no adequate experiences from the use of Edronax in pregnant women. Do not take Edronax if you

are pregnant, unless your doctor considers it absolutely necessary, following a careful clinical risk/benefit

consideration. Tell your doctor immediately if you are pregnant or are planning to become pregnant.

Breast-feeding

Edronax passes into the breast milk in small amounts. There is a risk of a potential effect on the baby.

Therefore, you should discuss the matter with your doctor and he/she will decide whether you should stop

breast-feeding or stop the therapy with Edronax.

Driving and using machines

Caution is recommended when driving or using machines.

You should not drive or operate machinery until you know you are not affected (i.e. feel drowsy) by

Edronax, and that it is safe to do so.

3.

How to take Edronax

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or

pharmacist if you are not sure.

The recommended dose in adults is 8 mg a day (one 4mg tablet twice a day). Based on how you respond to

the medicine, after 3 to 4 weeks your doctor may tell you to take up to 10mg per day if necessary. The

maximum daily dose should not exceed 12mg.

In patients with poor kidney or liver function, the starting dose is 4 mg per day. This may be increased

depending on the individual response.

The use of Edronax 4 mg tablets cannot be recommended for elderly patients.

Edronax should not be used in children and adolescents under 18 years.

The tablets should be taken in two divided doses, one dose in the morning and one in the evening. You

should swallow your tablet with a glass of water. The tablet can be divided into equal doses. Do not chew

the tablet.

To help you remember to take Edronax, you may find it easier to take your tablets at the same time every

day.

Like other drugs Edronax will not relieve your symptoms immediately. You should start to feel better within

a few weeks.

It is important that you continue to take your tablets, even though you feel better, until your doctor advises

you to stop. Please be patient, if you stop taking your tablets too early, your symptoms might come back.

If you take more Edronax than you should

You should never take more tablets than your doctor recommends. If you take too many tablets, contact your

doctor or local hospital immediately. If you take more Edronax than you should, you may experience

symptoms of overdose including low blood pressure, anxiety and hypertension.

If you forget to take Edronax

If you forget to take Edronax, take your next dose at the normal time. Do not take a double dose to make up

for a forgotten tablet.

If you stop taking Edronax

You should not stop your medicine without talking to your doctor, as your symptoms may come back.

There have been a few reports of withdrawal symptoms including headache, dizziness, nervousness and

nausea, (feeling sick), when patients stopped treatment with Edronax.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. With Edronax

most side effects are mild and usually go away after the first few weeks of treatment.

If any of the side effects below gets serious, or if you notice any side effects not listed in this leaflet, please

tell your doctor or pharmacist.

Very common side effects

(more than one in 10 patients)

Difficulties to sleep (insomnia)

Dizziness

Dry mouth

Constipation

Nausea (feeling sick)

Sweating

Common side effects

(less than one in 10 patients)

Headache

Lack or loss of appetite

Agitation, anxiety

Paraesthesia (pins and needles), inability to sit or stand still, altered taste sensation

Lack of visual focus

Increased heart rate, palpitation (heart pounding)

Widened blood vessels, fall in blood pressure when standing up, increased blood pressure

Vomiting

Rash

Sensation of incomplete emptying or slowed emptying of the bladder, urinary infection, painful

urination, inability to completely empty the bladder

Erectile dysfunction (impotence), ejaculatory pain or ejaculatory delay

Chills

Uncommon side effects

(between 1 and 10 out of 1000 patients)

Dilated pupils

Spinning sensation

Rare side effects

(between 1 and 10 out of 10000 patients)

Glaucoma (a condition resulting in increased pressure in the eye)

After marketing Reboxetine, the following side effects have been reported:

Hyponatremia (very low levels of sodium in the blood)

Aggressive behaviour, hallucination

Suicidal ideation, Suicidal behaviour

Cases of suicidal ideation and suicidal behaviours have been reported during

reboxetine therapy or early after treatment discontinuation (see section 2 “Warnings and

precautions”)

Cold extremities, Raynaud’s phenomenon (poor blood circulation to the extremities usually in the

toes and fingers but could also affect nose and ears, the skin turns pale and becomes cold and numb)

Allergic skin inflammation

Testicular pain

Irritability

Increased pressure in the eye

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. You can also report side effects directly via the national reporting system listed in

Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Edronax

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton or the bottle. The expiry date

refers to the last day of that month.

Do not store Edronax above 25

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Edronax contains:

The active substance is reboxetine.

Each tablet contains 4mg of reboxetine

The other ingredients are:

Cellulose microcrystalline, calcium hydrogen phosphate dihydrate, crospovidone, silica colloidal

hydrated and magnesium stearate.

What Edronax looks like and contents of the pack:

Edronax are white, round, convex tablets with a breakline. A ‘P’ is marked on the left side of the breakline

and a ‘U’ is marked on the right side. The side opposite the breakline is marked “7671”. The tablet can be

divided into equal doses.

Edronax is available in 10, 20, 50, 60, 100, 120, and 180 tablets in blisters packs, 60 tablets in glass bottles,

multipacks of 3x60, 5x60 and 10x60 tablets in blisters; and 3x60, 5x60 and 10x60 tablets in glass bottles.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

To be completed nationally

This medicinal product is authorised under the name Edronax in Austria, Belgium, Denmark, Finland,

Germany, Ireland, Italy, Luxembourg, Portugal, Sweden and United Kingdom. It is also authorised in Spain

under the name Norebox.

This leaflet was last revised in

2018-06-29.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Edronax 4 mg

Tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 4 mg 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.

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/day. 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

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.

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.

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.

Fertility, 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.

Fertility

There is no clinical trial data on fertility. However, in animal studies no effect on fertility

parameters was observed (see section 5.3).

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

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1000 to

<1/100)

Rare

(≥1/10000 to

<1/1000)

Frequency not

Known

Metabolism and nutrition disorders

Decreased appetite

Hyponatraemia

Psychiatric disorders

Insomnia

Agitation*,

Anxiety*

Aggressive

behaviour,

Hallucination,

Suicidal

Ideation/behaviour**

Nervous system disorders

Dizziness,

Headache,

Paraesthesia*,

Akathisia,

Dysguesia

Eye disorders

Accommodation

disorder

Mydriasis*

Glaucoma*

Intraocular pressure

increased

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Tachycardia,

Palpitations

Vascular disorders

Vasodilatation,

Hypotension,

Hypertension*

Peripheral coldness,

Raynaud`s

phenomenon

Gastrointestinal disorders

Dry mouth,

Constipation,

Nausea*

Vomiting*

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

dysfunction,

Ejaculatory pain,

Ejaculatory delay

Testicular pain

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.

In the elderly population, frequency of total adverse events, as well as of individual events, was

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

withdrawal

symptoms

including

headache,

dizziness,

nervousness

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

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 national reporting

system listed in Appendix V.

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

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 (

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

adrenoceptors, however,

functional interference with

-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

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. Reboxetine should be co-prescribed with

caution with potent inhibitors of CYP3A4.

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.

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.

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. In fertility studies in rats, reboxetine did not alter mating

behavior, fertility or general reproductive performance at oral doses up to 90 mg/kg/day.

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

Calcium hydrogen phosphate dihydrate

Crospovidone

Silica, colloidal hydrated

Magnesium stearate

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 Content of Container

The tablets are contained either in amber glass, type III, bottle, closed with an aluminium pilfer-

proof screw cap equipped with a polyethylene undercap or in aluminium-PVDC / PVC-PVDC

opaque blisters.

Each pack contains: 10, 20, 50, 60, 100, 120, and 180 tablets in blisters; and 60 tablets in glass

bottles.

Multipacks of 3x60, 5x60 and 10x60 tablets in blisters; and 3x60, 5x60 and 10x60 tablets in

glass bottles.

Not all pack sizes may be marketed.

6.6.

Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

To be completed nationally

8.

MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

To be completed nationally

10.

DATE OF (PARTIAL) REVISION OF THE TEXT

2018-06-29

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