Consumer medicine information

Edronax

Reboxetine

BRAND INFORMATION

Brand name

Edronax

Active ingredient

Reboxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Edronax.

What is in this leaflet

This leaflet answers some common questions about Edronax.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Edronax against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What EDRONAX is used for

What it does

Edronax is used to treat depression.

How it works

Depression is longer lasting and/or more severe than the 'low moods' everyone has from time to time due to the stress of everyday life. It is thought to be caused by a chemical imbalance in parts of the brain.

Edronax may correct this chemical imbalance and help to relieve the symptoms of depression.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

There is no evidence that Edronax is addictive.

This medicine is available only with a doctor's prescription.

Use in Children

There is not enough information to recommend the use of this medicine in children or adolescents younger than 18 years.

Before you take EDRONAX

When you must not take it

Do not take Edronax if you have an allergy to:

  • any medicine containing reboxetine
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction to Edronax may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Edronax if you are taking other medicines used to treat depression such as monoamine oxidase inhibitors (MAOIs).

Do not take Edronax if you have glaucoma (high pressure in the eye).

Do not give this medicine to children or adolescents under the age of 18 years. Safety and effectiveness in children or adolescents younger than 18 years have not been established.

Do not take this medicine after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor or pharmacist if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor or pharmacist can discuss with you the risks and benefits involved.

Tell your doctor or pharmacist if you have or have had any of the following medical conditions:

  • liver or kidney disease
  • fits or seizures
  • severe mood swings
  • difficulty in passing urine
  • glaucoma
  • prostate disease
  • heart problems, including high blood pressure, particularly if you are over 65 years old, heart failure, recent heart attack
  • overactive thyroid gland.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by Edronax or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

  • medicines used to lower blood pressure
  • medicines used to treat fungal or bacterial infections
  • carbamazepine and phenobarbital, medicines used to control fits or seizures
  • potassium-depleting diuretics, medicines used to remove fluid
  • fluvoxamine, a medicine used to treat depression
  • ergot derivatives, medicines used to treat migraine
  • lithium, a medicine used to treat certain mental conditions.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take EDRONAX

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many tablets you need to take each day. This may depend on your age, your condition and whether or not you are taking any other medicines.

The usual dose of Edronax in adults is 4 mg taken twice a day. After 3 weeks your doctor may increase the dose up to 10 mg per day, if required.

If you are over 65 years or have poor kidney or liver function, the usual starting dose is 2 mg taken twice a day. After 3 weeks your doctor may increase the dose up to 6 mg per day, if required.

How to take it

Swallow the tablets whole with a glass of water. Edronax tablets can be broken in half along the breakline if your doctor has prescribed a half tablet.

When to take it

Take your medicine at about the same time each day, once in the morning and once at night. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

Most antidepressants take some time to work, so do not be discouraged if you do not feel better straight away. Some of your symptoms may improve after two weeks but it may take four to six weeks for you to start to feel the full benefit of Edronax. You may need to take Edronax for several months or longer.

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Australian Poisons Information Centre (telephone 13 11 26) or the New Zealand National Poisons Information Centre (telephone 0800 POISON or 0800 764 766), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Edronax.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much Edronax you may feel nervous, dizzy or have a fast heart rate.

While you are taking EDRONAX

Things you must do

If you become pregnant while taking this medicine, tell your doctor or pharmacist immediately.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Edronax.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Tell your doctor if, for any reason, you have not taken your tablets exactly as prescribed. Otherwise your doctor may think that it was not effective and may change your treatment unnecessarily.

Tell your doctor immediately if you have any suicidal thoughts or other mental/mood changes. A worsening of depressive symptoms including thoughts of suicide or self-harm may occur in the first one or two months of you taking Edronax or when the doctor changes your dose. These symptoms should be controlled when the full effect of Edronax takes place.

Young adults under 24 years of age are more likely to experience these effects during the first few months of treatment.

Patients and caregivers should be alert and monitor for these effects.

Signs and symptoms of suicide include:

  • Thoughts or talk of death or suicide
  • Thoughts or talk of self-harm or harm to others
  • Any recent attempts of self-harm
  • Increase in aggressive behaviour, irritability or agitation.

Any mention of suicide or violence must be taken seriously.

If you or someone you know is demonstrating these warning signs of suicide while taking Edronax, contact your doctor or a mental health professional right away.

Discuss with your doctor any problems you may have and how you feel, especially any feelings of severe sadness or unusual bursts of energy or anger. This will help the doctor determine the best treatment for you.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not take Edronax to treat any other complaints unless your doctor or pharmacist tells you to.

Do not take any other medicines, whether they require a prescription or not, without first telling your doctor.

Do not stop taking your medicine, or change the dosage, without checking with your doctor or pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Edronax affects you. As with other medicines for depression, this medicine may cause dizziness or drowsiness in some people. Make sure you know how you react to Edronax before you drive a car, operate machinery, or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Edronax. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

It can be difficult to tell whether side effects are the result of taking Edronax, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

Do not be alarmed by the list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if...

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • dry mouth
  • headache
  • nausea, vomiting
  • constipation or diarrhoea
  • difficulty sleeping
  • increased sweating
  • fast heart beat
  • dizziness
  • eye problems
  • difficulty passing urine
  • sexual problems
  • stomach pain
  • unusual tiredness or weakness
  • tingling or numbness of the hands or feet.
  • decreased appetite
  • altered taste
  • restless leg syndrome
  • hair and skin problems

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if...

Tell your doctor as soon as possible if you notice any of the following:

  • anxiety, agitation
  • confusion
  • bleeding or bruising more easily than normal
  • frequent signs of infection such as fever, sore throat, severe chills, mouth ulcers
  • coldness or loss of blood to your extremities
  • tiredness, headache, shortness of breath when exercising, dizziness or pale skin.

Go to hospital if...

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • fits or seizures
  • chest pain
  • thoughts of suicide or attempting suicide or self harm
  • aggressive behaviour
  • change in heart beat (fast, slow, irregular), sometimes with fainting
  • itching skin rash or hives
  • shortness of breath, wheezing or trouble breathing
  • swelling of the face, lips, tongue or other part of the body.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell. Other side effects not listed above may occur in some people.

Some of these side effects (for example, high cholesterol, abnormal liver function tests) can only be found when your doctor does tests from time to time to check your progress.

After taking EDRONAX

Storage

Keep your tablets in the pack or bottle until it is time to take them. If you take the tablets out of the pack or bottle they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store Edronax or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Edronax Tablets 4 mg are white, convex, round tablets with a breakline on one side and engraved 'P' on the left of the breakline and 'U' on the right side of the breakline, and '7671' on the opposite side.

Ingredients

Active ingredient
Reboxetine mesilate.
Each 4 mg tablet contains 4 mg of reboxetine as mesilate.

Other ingredients:

  • magnesium stearate
  • microcrystalline cellulose
  • silicon dioxide
  • crospovidone
  • calcium hydrogen phosphate dihydrate.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Edronax is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW 2000
Toll Free number: 1800 675 229
Website: www.pfizer.com.au

Australian Registration Number

4 mg tablets: AUST R 79745

This leaflet was prepared in October 2019.

© Pfizer Australia Pty Ltd 2012

® Registered trademark.

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Edronax

Active ingredient

Reboxetine

Schedule

S4

 

1 Name of Medicine

Reboxetine mesilate.

6.7 Physicochemical Properties

Reboxetine mesilate is freely soluble in water (> 20% w/v).
Chemical name: (2RS, αRS)-2-[α-(2-ethoxyphenoxy)benzyl] morpholine methanesulfonate.
Reboxetine mesilate has the empirical formula C19H23NO3.CH4O3S, and a molecular weight of 409.50.

Chemical structure.


CAS number.

141425-90-3.

2 Qualitative and Quantitative Composition

Edronax tablets contain 5.2 mg reboxetine mesilate corresponding to 4 mg reboxetine free base.

3 Pharmaceutical Form

4 mg Edronax tablets (containing 5.2 mg reboxetine mesilate) are white, convex, round tablets with a breakline on one side and engraved 'P' on the left of the breakline and 'U' on the right side of the breakline, and '7671' on the opposite side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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, 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) or muscarinic receptors. Binding to such receptors has been described as being associated with cardiovascular, anticholinergic and sedative side effects of other antidepressant drugs. Reboxetine is devoid of in vitro binding to either α1 or α2 adrenoreceptors; however a functional interference with α-adrenoreceptors at high doses in vivo cannot be excluded.
In healthy volunteers the administration of reboxetine single doses of 1 and 3 mg was followed by dose dependent CNS effects with EEG modifications (decreased power of theta and fast β-waves in the frontocentral derivative) and performance improvement (peg-board test).

Clinical trials.

The initial Edronax clinical program consists of 15 phase II and III clinical trials that were conducted in adult (aged 18-65 years) and elderly (aged > 65 years) patients diagnosed with major depressive disorder (MDD).
The Hamilton Depression Rating Scale (HAMD) was used as the primary instrument for the assessment of the change in depressive symptoms in all clinical trials. The Montgomery and Asberg Rating Scale for Depression (MADRS) and the Clinical Global Impressions Scales (CGI) were used as secondary efficacy parameters. For the short-term studies in nonelderly patients (i.e. those 18 to 65 years of age), the study endpoint was defined as the absolute decrease of the mean HAMD total score or as the frequency of response (defined as ≥ 50% decrease of the HAMD total score), as measured at the last available assessment. This allowed for a global evaluation of the consistency of the results of the studies and for conclusions on the antidepressant efficacy of Edronax to be drawn.
The clinical program has demonstrated that Edronax is effective in the therapy of acute episodes of depression as well as in the prevention of relapses and recurrences of depressive illness when administered for long-term therapy. The results of the studies indicate that the primary effect of Edronax is on the primary symptom (depressed mood) of depressive illness. The remission of the acute phase of the depressive illness is associated with an improvement in the patient's quality of life in terms of social adaptation.

Short-term placebo controlled studies.

The results of the analysis of the HAMD total score for the five short-term (4 to 8 weeks), placebo controlled studies in nonelderly patients (18 to 65 years) with MDD are summarised in Table 5.
The mean HAMD total score improvement associated with Edronax treatment ranged from 9.2 to 23.1 points. The mean HAMD improvement associated with placebo was always lower than that associated with Edronax, with an average decrease of 4.5 to 11.3 points. The difference between Edronax and placebo was statistically significant in three of the five studies above. In two studies, the difference between Edronax and placebo was not statistically significant on the mean HAMD total score. In one of these studies, the active comparator imipramine also failed to show a statistically significant difference over placebo. In the other study, a number of secondary efficacy measures demonstrated statistically significant differences in favour of Edronax over placebo.
The frequency of clinically relevant improvement with Edronax was, on the average, 16% greater than with placebo, providing an unequivocal indication of the efficacy of Edronax in the acute treatment of depressive illness.

Active controlled studies.

Imipramine controlled studies.

Two 6 week studies were conducted to determine the benefits of Edronax relative to those of imipramine in the treatment of patients with MDD. A total of 237 patients were treated with Edronax compared to 233 receiving imipramine. The mean HAMD score improvement associated with Edronax treatment ranged from 13.5-15.8, compared to 13.8-14.3 for imipramine. The results of both these studies, therefore, confirmed equivalent efficacy for Edronax and imipramine.

Fluoxetine controlled studies.

Two 8 week studies were conducted to determine the benefits of Edronax relative to those of fluoxetine in the treatment of patients with MDD. A total of 200 patients were treated with Edronax compared to 213 receiving fluoxetine. The mean HAMD score improvement associated with Edronax treatment ranged from 13.4-19.2, compared to 13.3-16.8 for fluoxetine. The results of both these studies confirmed equivalent efficacy for Edronax and fluoxetine.

Long-term placebo controlled study.

The long-term efficacy of Edronax for the treatment of patients with MDD was investigated in a 1 year, double blind, randomised, parallel group, placebo controlled study. In this study, patients received open label treatment with Edronax (8 mg/day) for 6 weeks; thereafter, the patients who responded to therapy (minimum 50% decrease of the HAMD total score) were randomised to receive treatment with Edronax or placebo until relapse occurred or for up to 1 year. Two hundred and eighty-three patients participated in the double blind, long-term portion of the study: 143 were treated with Edronax and 140 were treated with placebo.
This study demonstrated the efficacy of Edronax in the maintenance therapy of depressive illness. 61% and 40%, respectively, of the responder patients on Edronax and placebo remained relapse free during the initial 6 months following randomisation, and 88% and 59%, respectively, of the patients on Edronax and placebo who entered the last 6 months of treatment remained relapse free up to the end of the study. Edronax showed a 29% advantage in relapse rate over placebo, thus confirming the efficacy of Edronax in the prevention of recurrences of new depressive episodes.

Meta-analyses of Edronax versus placebo and Edronax versus other antidepressants.

Meta-analyses of Edronax vs. placebo and Edronax vs. other antidepressants were performed for clinical studies including over 5,000 patients (see Tables 6 and 7). The response rate was defined as at least a 50% reduction in the baseline HAMD total score at the last treatment visit.
A statistically significant higher response rate was observed for Edronax compared to placebo (51.2% vs. 43.6%). These results were supported by a somewhat stronger Clinical Global Improvement measure of response.
The response rate of Edronax was not as high as that of other antidepressants (imipramine, fluoxetine, paroxetine, citalopram, dothiepin, venlafaxine), although the difference (57.5% vs. 61.1%) was not statistically significant.
The safety and efficacy of Edronax in treatment of MDD was demonstrated in these studies in which the majority of enrolled patients presented were assessed at a severe or very severe depression level at baseline.

5.2 Pharmacokinetic Properties

The pharmacokinetics of reboxetine after single and multiple oral doses have been studied in healthy young and elderly volunteers, in depressed patients, and in subjects with renal or liver insufficiency.

Absorption.

After oral administration of a single 4 mg reboxetine dose to healthy volunteers, peak levels of about 130 nanogram/mL are achieved within 2 hours postdosing. The administration of reboxetine with food delayed the rate of absorption by approximately 2 hours while not affecting the extent of absorption. Reboxetine displays linear pharmacokinetics in a dose range of up to 4 mg twice daily. Data indicate that absolute bioavailability is approximately 94%. Reboxetine plasma concentrations decay monoexponentially with a half-life of about 13 hours. 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.

Distribution.

The drug appears to be distributed into total body water. Reboxetine is 97% bound to human plasma proteins (with affinity markedly higher for α1 acid glycoprotein than albumin) with no clinically relevant dependence on the concentration of the drug. The volume of distribution of reboxetine at steady state following intravenous administration is 26 L and 63 L for the RR and SS diastereomers, respectively.
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.

Metabolism.

Reboxetine is extensively metabolised after oral administration. The drug is predominantly metabolised through hydroxylation of the ethoxyphenoxy ring, o-dealkylation and oxidation of the morpholine ring. In vitro studies indicate that CYP3A4 is the isozyme of cytochrome P450 that is primarily responsible for the metabolism of reboxetine. In vitro studies show that reboxetine has no effect on the activity of the following isozymes of cytochrome P450: CYP1A2, CYP2C9, CYP2C19 and CYP2E1. At high concentrations, reboxetine inhibits CYP2D6. In vitro studies show that reboxetine is a weak inhibitor of CYP3A4. In vitro studies have shown that the major circulating metabolite, the 3-morpholine oxidation product of reboxetine, has little or no activity on noradrenergic or serotonergic uptake, and is unlikely to contribute to the pharmacological activity of reboxetine.
The drug is available as a racemic compound: the SS enantiomer is two times more potent than the racemate, and the RR enantiomer is 10 times less potent than the racemate. No chiral inversion or reciprocal pharmacokinetic interferences between enantiomers have been observed. Plasma concentrations 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.

Excretion.

The systemic clearance of reboxetine is 43 mL/min. About 10% of the dose of reboxetine is excreted unchanged in urine. The renal clearance of SS and RR diastereomers of reboxetine is 9.3 and 2.0 mL/min, respectively.
Elimination of reboxetine is mainly via hepatic metabolism (by cytochrome P450 3A4) with a mean terminal half-life of about 12 hours. No significant difference was observed in the terminal half-lives of the RR and SS diastereomers.

Special populations.

Elderly (> 65 years).

The pharmacokinetics of reboxetine were assessed in three studies of elderly volunteers. In the first study, middle aged (50 to 63 years) and elderly (68 to 77 years) subjects showed only moderate differences in area under the plasma concentration time curve and half-life. The AUC increased by 20 to 25% and half-life was 3 to 5 hours longer in the elderly compared to healthy young volunteers given the same 4 mg dose. In the second study, elderly subjects (66 to 98 years) showed a 4-fold increase in AUC and 2-fold increase in half-life compared to young healthy males following a single 4 mg reboxetine oral dose. In the third study, the mean AUC in elderly depressed females (75 to 87 years) was approximately three times higher than in young males. A reduction in dose is warranted in elderly patients (see Section 4.2 Dose and Method of Administration).

Children.

There have been no pharmacokinetic studies in children.

Gender.

In a study in six males and six females, no differences in reboxetine pharmacokinetics were observed between genders following a 1 mg oral reboxetine dose.

Race.

The effect of race on reboxetine pharmacokinetics has not been studied.

Hepatic impairment.

Compared with young healthy volunteers receiving the same 4 mg reboxetine dose, AUC and t1/2 were approximately doubled in patients (n = 6) with alcoholic liver disease (moderate, i.e. Child-Pugh score of 7 to 9, and severe, i.e. Child-Pugh score of 10 to 13). A reduction in dose is warranted in patients with hepatic insufficiency (see Section 4.2 Dose and Method of Administration).

Renal impairment.

An increase in systemic exposure and t1/2 up to threefold was observed in patients (n = 6) with severe renal insufficiency (creatinine clearance = 10 to 20 mL/min) following a 4 mg oral dose of reboxetine. A reduction in dose is warranted in patients with compromised renal function (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Both the reboxetine S,S enantiomer and racemic reboxetine mesilate induce chromosomal aberrations in human lymphocytes in vitro. Racemic reboxetine mesilate did not induce gene mutations in bacterial or mammalian (Chinese hamster) cells in vitro, did not produce DNA damage in yeast cells or rat hepatocytes in vitro and did not cause chromosomal damage in an in vivo mouse micronucleus test.

Carcinogenicity.

Carcinogenicity studies in mice and rats showed no drug related increases in tumour incidences at oral reboxetine doses up to 45 and 90 mg/kg/day, respectively. Systemic exposure (plasma AUC) to unbound drug at the highest dose levels was approximately twofold higher than that in humans at the maximum recommended dose.

4 Clinical Particulars

4.1 Therapeutic Indications

Edronax is indicated for the treatment of major depression and is effective in preventing the relapse of depressive symptoms.

4.3 Contraindications

Hypersensitivity to reboxetine or any of the excipients.
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated.
Since reboxetine has a weak mydriatic effect, its use is not recommended in patients with narrow angle glaucoma.

4.4 Special Warnings and Precautions for Use

Seizures.

Since rare cases of seizures have been reported in clinical studies, Edronax should be given under close supervision to subjects with a history of convulsive disorder and it should be discontinued if the patient develops seizures.

Bipolar disorder and activation of mania/ hypomania.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/ manic episode in patients at risk of bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. Close supervision of patients with bipolar disorders is recommended.

Clinical worsening and suicide risk.

The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. The risk of suicide must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/ behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with comorbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analyses of 24 short-term (4 to 16 weeks), placebo controlled trials of nine antidepressant medicines (SSRIs and others) in 4,400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials) or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the initial treatment period (generally the first one to two months) in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients treated with placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine). In addition, long-term safety data in children and adolescents concerning growth, maturation, cognitive and behavioural development are lacking.
A further pooled analysis of short-term placebo controlled trials of antidepressant medicines (SSRIs and others) showed the increased risk of suicidal thinking and behaviour (suicidality) during the initial treatment period (generally the first one to two months) extends to young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. These studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Currently, data are insufficient to quantify an increased risk of suicidal thinking and behaviour associated with reboxetine treatment. Nevertheless, anyone considering the use of reboxetine in young adults must balance this potential risk with the clinical need.
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Prescriptions for Edronax should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Cardiovascular.

Patients (particularly those aged > 65 years) with a history of cardiac disease, including hypertension, should be closely supervised when being treated with reboxetine.

Orthostatic hypotension.

Orthostatic hypotension has been observed with greater frequency at doses higher than the maximum recommended. Close supervision is recommended when administering Edronax with other drugs known to lower blood pressure. Edronax should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemia, heart failure or conduction abnormalities), cerebrovascular disease and conditions that would predispose patients to hypotension (dehydration, hypovolaemia and treatment with antihypertensive medications).

Hypertension.

Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure, e.g. those with pre-existing hypertension, heart failure or recent myocardial infarction.

Tachycardia.

Reboxetine should be used with caution in patients whose underlying medical conditions might be compromised by increases in heart rate, e.g. patients with hyperthyroidism, heart failure or recent myocardial infarction.

Use in patients with concomitant illness.

Clinical experience with reboxetine in patients affected by serious concomitant illness is limited. Close supervision is recommended in patients with current evidence of urinary retention, prostatic hypertrophy and glaucoma.
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.

Use in hepatic impairment.

A reduction in dose is warranted in patients with hepatic insufficiency (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment).

Use in renal impairment.

A reduction in dose is warranted in patients with compromised renal function (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment).

Use in the elderly.

A reduction in dose is warranted in elderly patients (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations, Elderly (> 65 years)).

Paediatric use.

The efficacy and safety of reboxetine has not been satisfactorily established for the treatment of children and adolescents (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro studies show that reboxetine has no effect on the activity of the following isozymes of cytochrome P450: CYP1A2, CYP2C9, CYP2C19 and CYP2E1.
Specifically, in vitro and in vivo studies show that reboxetine is not metabolised by CYP2D6 and therefore no special precautions are necessary for individuals deficient in this enzyme.
Inhibitors of CYP2D6, such as fluoxetine and paroxetine, are unlikely to have an effect on Edronax pharmacokinetics. This was confirmed in a multiple dose study performed in healthy volunteers where no clinically significant interaction between fluoxetine and Edronax was observed.
In vitro metabolism studies indicate that reboxetine is metabolised by the 3A4 isozymes of cytochrome P450. Therefore, compounds that decrease the activity of CYP3A4 are 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%. Similar interactions are expected with other inhibitors of CYP3A4, such as azole antifungals, macrolide antibiotics and fluvoxamine.
In vitro studies show that reboxetine is a weak inhibitor of CYP3A4. However, an in vivo study has shown that Edronax did not alter the clearance of alprazolam. This is expected to apply to other CYP3A4 substrates.
Low reboxetine serum levels have been reported with the concurrent administration of CYP3A4 inducers such as phenobarbital and carbamazepine. Therefore doses of Edronax may need to be increased if given concomitantly.
Concomitant use of Edronax with lithium has not been evaluated in clinical trials, but in view of the small degree of glomerular filtration of unbound reboxetine, no effect of Edronax on lithium elimination is expected. However, monitoring of lithium levels is recommended where the two drugs are coadministered.
Concomitant use of Edronax with tricyclic antidepressants and SSRIs has not been evaluated during clinical studies.
No significant reciprocal pharmacokinetic interaction has been found between Edronax and lorazepam.
Edronax does not appear to potentiate the effect of alcohol on cognitive functions in healthy volunteers.
The small degree of glomerular filtration of unbound reboxetine means there is little likelihood that Edronax will affect the renal clearance of cardiac glycosides such as digoxin.
Coadministration of antihypertensive agents may exacerbate the orthostatic hypotensive effects of Edronax.
Concomitant use of ergot derivatives and Edronax may result in increased blood pressure.
Although data are not available from clinical studies, the possibility of hypokalaemia with concomitant use of potassium depleting diuretics should be considered.
The extent of absorption of reboxetine is not significantly influenced by concomitant food intake.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effect on fertility of male or female rats was observed at oral dose levels up to 90 mg/kg/day. Systemic exposure (plasma AUC) to unbound drug at the highest dose levels was approximately twofold higher than that in humans at the maximum recommended dose.
(Category B1)
Development studies in rats and rabbits have not shown clear evidence of teratogenic effects at oral dose levels up to 320 and 100 mg/kg/day, respectively. However, in both species, there were increases in postimplantation loss, decreases in mean foetal weight and an increased incidence of skeletal anomalies, including delayed ossification. Compared with human exposure (plasma AUC at the maximum recommended dose), estimated exposure in rats was less than human exposure, and exposure in rabbits was approximately 6-fold (reboxetine, SS enantiomer) and 16-fold (RR enantiomer) higher at the highest dose tested. At the no effect dose in rabbits (25 mg/kg/day), reboxetine exposure was similar to human exposure. Reboxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Reboxetine is excreted in milk in lactating rats. Oral doses of 25-125 mg/kg/day reduced survival of offspring and retarded postnatal growth and development. Plasma drug levels at these doses were similar to, or lower than, those in humans at the maximum recommended dose. Therefore, while no information on the excretion of reboxetine in maternal milk in humans is available, Edronax administration is not recommended in women who are breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

About 1,700 patients have received Edronax in clinical studies, 216 of which received Edronax for at least 12 months.

Short-term clinical trials.

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.
Adverse events reported during the 4-8 week studies are reported in Tables 1 and 2.
There was an increase in heart rate upon standing to values ≥ 100 beats/min mainly in adult patients (20% of the patients on short-term treatment compared with 6% on placebo, and 23% of the patients on long-term treatment compared with 17% on placebo). In all short-term controlled studies in depression, the mean change in pulse (in beats per minute) for reboxetine treated patients was 2.9, 8.3 and 3.0 in the supine, sitting and standing positions, respectively, compared with -0.5, 0 and 0 for placebo treated patients in the corresponding positions.
In the short-term controlled studies in depression, no significant mean change in blood pressure was observed. Diastolic blood pressures > 105 mmHg were observed in 5.6%, 1.0% and 3.8% of reboxetine treated patients in the supine, sitting and standing positions, respectively, compared with 1.5%, 1.0% and 2.8% for placebo treated patients in the corresponding positions. Analyses of data from the phase II and III studies in depression have demonstrated no increase in systolic blood pressure.

Long-term clinical trials.

Based on data from long-term studies which included 328 patients who were treated with Edronax for longer than 6 months, the frequency of the most common adverse events (e.g. dry mouth, constipation, tachycardia, hypotension) did not increase over time but, rather, decreased or remained constant over time. Table 3 summarises the treatment emergent symptoms (TES) that were reported in ≥ 1% of the reboxetine treated patients by duration of therapy (≤ 6 months or > 6 months). Although small, the placebo group is provided for reference purposes.
For long-term tolerability, 143 Edronax 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 Edronax 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 Edronax and placebo. Among events seen more than occasionally, no individual events not seen on short-term treatment were apparent.
No indication of a withdrawal syndrome upon Edronax discontinuation emerged from the results of the clinical trials. Adverse events following discontinuation occured in approximately 5% of patients treated with Edronax and 4% of placebo treated patients.
Apart from tachycardia, no consistent changes in ECG tracings were observed during Edronax treatment in adult patients. Similarly, no consistent changes were observed at the ophthalmological examination carried out upon long-term treatment. In the elderly population, newly observed rhythm disorders (mainly tachycardia) and conduction disorders were apparent in the ECG in approximately 15% of cases.
In a long-term study, treatment emergent rhythm disorders (including sinus tachycardia, occasional atrial and ventricular ectopics), conduction disorders, ischaemic changes (including myocardial ischaemia, repolarisation changes and nonspecific ST-T changes) and other changes (including left ventricular hypertrophy) occurred more frequently in elderly patients with a history of cardiovascular disease at baseline than in elderly patients without such a history. A similar pattern was also observed in a short-term study in elderly patients.
Abnormal laboratory test values were uncommon during Edronax therapy.

Postmarketing experience.

The following postmarketing events have been reported with reboxetine (see Table 4).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

The onset of clinical effect is usually seen after 14 days of treatment.

Use in adults.

The recommended therapeutic dose is 4 mg twice daily (8 mg/day) administered orally. After 3 weeks the dose can be increased up to 10 mg/day in case of incomplete clinical response.

Use in children and adolescents (< 18 years).

There are no data available on the use of reboxetine in children or adolescents under 18 years of age.

Dosage adjustment.

Use in the elderly (> 65 years).

The recommended therapeutic dose is 2 mg twice daily (4 mg/day) administered orally. After 3 weeks the dose can be increased up to 6 mg/day in case of incomplete clinical response.

Use in renal or hepatic impairment.

The starting dose in patients with renal or moderate to severe hepatic insufficiency should be 2 mg twice daily, increased according to patient tolerance.

4.7 Effects on Ability to Drive and Use Machines

Patients should be cautioned about driving or operating hazardous machinery until reasonably certain that their performance has not been affected.

4.9 Overdose

Clinical effects in overdose are expected to be an exaggeration of known adverse events, including seizures. In a few cases, doses higher than those recommended (12 to 20 mg/day) were administered to patients during the clinical studies for a period ranging from a few days to a few weeks. Treatment emergent adverse events included postural hypotension, anxiety and hypertension.
There are minimal reports of overdosage with reboxetine. One patient ingested 52 mg as the sole agent and developed minimal toxicity and doses up to 240 mg have been ingested with survival reported. No fatalities have been reported with reboxetine alone and there have been no reports of ECG abnormalities, coma or convulsions following overdose with reboxetine alone. One fatal overdose was reported in a patient who ingested reboxetine in combination with amitriptyline (doses unknown).
Reboxetine serum levels are not clinically useful.
In case of overdose, treatment should consist of those general measures employed in the management of overdose with any antidepressant. Treatment is symptomatic and supportive. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.
Activated charcoal may reduce absorption of the drug if given within one hour after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. Due to the large volume of distribution of this drug, forced diuresis, dialysis, haemoperfusion and exchange perfusion are unlikely to be of benefit. No specific antidotes for reboxetine are known.
Induction of emesis is not recommended.
In managing overdosage, consider the possibility of multiple drug involvement.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Magnesium stearate, microcrystalline cellulose, silicon dioxide, crospovidone, calcium hydrogen phosphate dihydrate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

The tablets are registered in blister packs of 10, 14, 20, 28, 30, 56 and 60 tablets*.
* Not all presentations available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes