Consumer medicine information

Aurorix [8847]

Moclobemide

BRAND INFORMATION

Brand name

Aurorix Tablets

Active ingredient

Moclobemide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Aurorix [8847].

What is in this leaflet

This leaflet answers some common questions about AURORIX tablets. It does not contain all 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 AURORIX tablets against the benefits they expect it will 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 AURORIX is used for

The name of your medicine is AURORIX. It contains the active ingredient called moclobemide.

AURORIX belongs to a group of medicines called antidepressants. Antidepressants are used to treat depression and work on the central nervous system. They are thought to work by their action on brain chemicals called amines, which are involved in controlling mood.

There are many different types of medicines used to treat depression. AURORIX belongs to a group of medicines called reversible inhibitors of monoamine oxidase A.

Your doctor, however, may have prescribed AURORIX for another purpose.

Ask your doctor if you have any questions why AURORIX has been prescribed for you.

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

Do not give AURORIX to children or adolescents under 18 years of age.

The safety and effectiveness of AURORIX in this age group has not been established.

Before you take AURORIX

Do not take AURORIX if:

  • you have ever had an allergic reaction to AURORIX or any of the ingredients listed in the Ingredients section of this leaflet
  • you are suffering from severe confusion
  • you are taking:
    - clomipramine (Anafranil)
    - selegiline (Eldepryl)
    - bupropion (Zyban)
    - triptans (a family of medicines commonly used to treat migraines eg. Triptazig)
    - pethidine
    - tramadol (Durotram, Zydol)
    - dextromethorphan (often found in cough and cold medicines)
    - linezolid (Zyvox).
  • you are taking other medications known as selective serotonin reuptake inhibitors or tricyclic antidepressants.

Taking AURORIX with these medicines may cause a serious reaction called serotonin syndrome. This can cause a sudden increase in body temperature, high blood pressure and convulsions.

Do not take AURORIX after the expiry date (EXP) printed on the pack.

It may have no effect at all or, worse, an entirely unexpected effect if you take it after the expiry date.

Do not take AURORIX if the packaging is torn or shows signs of tampering or if the tablets appear damaged in some way.

If it has expired or is damaged, return the product to your pharmacist for disposal.

If you are not sure if you should be taking AURORIX, talk to your doctor.

You must tell your doctor if:

  1. you are allergic to any other medicines, foods, dyes or preservatives.
  2. you have any other health problems including:
    - liver disease
    - high blood pressure
    - a personal history or family history of bipolar disorder
    - mental illness other than depression, including schizophrenia, agitation and excitation
    - thyrotoxicosis (a condition of excessive thyroid hormones)
    - phaeochromocytoma (a rare tumour of adrenal gland)
    - rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption.
  3. you are pregnant or intend to become pregnant.
  4. you are breastfeeding or wish to breastfeed.
    Your doctor will discuss the risks and benefits of using AURORIX when pregnant and while breastfeeding.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you have bought from a pharmacy, supermarket or health food shop.

Some commonly used medicines that may interfere with AURORIX are:

  • cimetidine
  • dextromethorphan (often found in cough and cold medicines)
  • pethidine
  • selegiline
  • bupropion
  • triptans
  • tramadol
  • linezolid
  • proton pump inhibitors
  • serotonin agonists (eg buspirone, sumatriptan)
  • St. John’s wort (Hypericum)-containing phytotherapeutic products.
  • opiates e.g. morphine, fentanyl and codeine
  • adrenergics
  • sibutramine.

Other antidepressant medicines may interfere with AURORIX such as fluoxetine, fluvoxamine, paroxetine, sertraline, amitryptyline and nortriptyline, trimipramine and maprotiline, venlafaxine, clomipramine, citalopram and paroxetine.

Moclobemide may cause an additional drop in blood pressure if you are taking metoprolol.

Your doctor or pharmacist has a complete list of medicines to avoid while taking AURORIX.

If you have not told your doctor about any of the above, tell them before you start taking AURORIX.

How to take AURORIX

Take AURORIX exactly as your doctor has prescribed.

How much to take

Your doctor will tell you how many AURORIX tablets to take each day.

The usual dose is between 300 mg and 600 mg per day. The tablets are taken twice daily after meals.

How to take it

Tablets should be swallowed whole with a glass of water after meals.

You should follow your doctor's instructions carefully if changing from one antidepressant to another and report any unexpected effects if they occur.

When to take it

AURORIX should be taken morning and evening at the end of your meal.

How long to take AURORIX

For depression, the length of treatment will depend on how quickly your symptoms improve. Most antidepressants take time to work so don't be discouraged if you don't feel better right away. Some of your symptoms may improve in 1 or 2 weeks but it can take up to 4 or 6 weeks to feel any real improvement. Even when you feel well, you will usually have to take AURORIX for several months or even longer to make sure the benefits will last. Continue taking it until your doctor tells you to stop.

If you forget to take AURORIX

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 then go back to taking it as soon as you would normally.

Do not double a dose to make up for one you have missed.

In case of an overdose

Immediately telephone your doctor or the Poisons Information Centre on telephone 13 11 26 for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much AURORIX. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

Some signs and symptoms of overdose include nausea, vomiting, drowsiness, slurred speech, reduced reflexes and agitation.

While you are taking AURORIX

Things you must do

Tell all doctors, dentists, and pharmacists who are treating you that you are taking AURORIX.

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

Tell your doctor if you become pregnant while taking AURORIX.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel the tablets are not helping your condition.

If you are being treated for depression, tell your doctor immediately if you feel your condition has worsened or if you are experiencing suicidal thoughts.

Be sure to discuss with your doctor any problems you may have and how you feel. This will help your doctor to determine the best treatment for you.

Be sure to keep all of your appointments with your doctor so that your progress can be checked

Things you must not do

Do not stop taking AURORIX or lower the dose without first checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Do not give this medicine to anyone else even if their symptoms seem similar to yours.

Do not use AURORIX to treat other complaints unless your doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how AURORIX affects you.

AURORIX causes dizziness in some people at first.

Although drinking alcohol is unlikely to affect your response to AURORIX, your doctor may suggest avoiding alcohol while you are being treated for depression.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking AURORIX.

AURORIX helps most people with depression, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

In the first week or two you may experience:

  • sleep disturbances, dizziness, nausea, headache, dry mouth
  • occasionally, the symptoms of depression may include thoughts of suicide or self-harm. These symptoms may continue or get worse during the first one to two months of treatment until the full antidepressant effect of the medicine becomes apparent. This is more likely to occur if you are a young adult i.e. under 24 years of age.

Contact your doctor or a mental health professional right away, or go to Accident and Emergency at your nearest hospital for treatment if you or someone you know is demonstrating any of the following warning signs of suicide while taking AURORIX:

  • 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
  • worsening of depression
  • insomnia, nervousness, jitteriness
  • mania or hypomania (or onset of early symptoms).

All thoughts or talk of suicide or violence must be taken seriously.

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

  • insomnia, disturbed sleep, restlessness, dizziness, nausea, headache, anxiety, agitation, feeling of confusion, diarrhoea, vomiting, paraesthesia, constipation, feeling of fullness, upset stomach, dry mouth, blurred vision, skin rash, flushing.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don’t understand anything in this list.

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

After taking AURORIX

Storage

Keep AURORIX where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep AURORIX in a cool dry place where the temperature stays below 30°C.

Do not store it, or any other medicine, in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the blister, they may not keep well.

Disposal

If your doctor tells you to stop taking AURORIX, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What AURORIX looks like

AURORIX comes in two strengths of tablets.

  • AURORIX 150 mg: oval, cylindrical, biconvex, pale yellow tablet marked "150" on one side with break bar on the other side.
  • AURORIX 300 mg: oval, cylindrical, biconvex, white to yellow-white marked "300" on one side with break bar on the other side.

Ingredients

Active ingredient

  • Each AURORIX 150 mg tablet contains 150 mg of the active ingredient moclobemide
  • Each AURORIX 300 mg tablet contains 300 mg of the active ingredient moclobemide

Inactive ingredients

AURORIX 150 mg and 300 mg tablets both contain:

  • Lactose, starch-maize,
  • povidone (1201),
  • sodium starch glycollate,
  • magnesium stearate (470),
  • ethyl cellulose,
  • macrogol 6000,
  • hypromellose (464),
  • purified talc (553),
  • and are coloured with titanium dioxide (171).

AURORIX 150 mg tablets also contain yellow iron oxide (172).

AURORIX tablets are gluten free.

AURORIX comes in boxes of 60 tablets.

BRAND INFORMATION

Brand name

Aurorix Tablets

Active ingredient

Moclobemide

Schedule

S4

 

1 Name of Medicine

Moclobemide.

6.7 Physicochemical Properties

The chemical name of moclobemide is p-chloro-N- (2-morpholinoethyl) benzamide. Its empirical formula is C13H17O2N2Cl with a molecular weight of 268.74.

Chemical structure.


CAS number.

71320-77-9.

2 Qualitative and Quantitative Composition

Moclobemide is a white to slightly reddish crystalline powder. It contains no crystal water and is not hygroscopic. It is soluble in water at 0.4 g/100 mL. The pKa is approximately 6.2.
Aurorix 150 mg tablets are light yellow film-coated scored tablets containing 150 mg of moclobemide.
Aurorix 300 mg tablets are white to yellow-white film-coated scored tablets containing 300 mg of moclobemide.
Aurorix 150 mg and 300 mg tablets contain lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Moclobemide is an antidepressant that affects the monoaminergic cerebral neurotransmitter system by means of a reversible inhibition of monoamine oxidase. There are two types of monoamine oxidases, A and B, which vary in their substrate specificity. Moclobemide is relatively selective for type A. At a 300 mg dose, the inhibition of monoamine oxidase A is approximately 80% while that of monoamine oxidase B is approximately 20-30%. The inhibition is short lasting (approximately 24 hours).
The metabolism of dopamine, noradrenaline and serotonin is decreased by this effect, and this leads to increased extracellular concentrations of these neuronal transmitters. As a result of its elevating effect on mood and psychomotor activity, Aurorix relieves symptoms such as dysphoria, exhaustion, lack of drive and poor ability to concentrate. First effects most often appear within the first week of therapy.
Although Aurorix has no sedative properties, it does increase total sleep time. Aurorix does not impair alertness or reaction time.
Aurorix appears to be suitable for ambulatory treatment as it is not sedating and does not impair vigilance or ability to react.
Aurorix is well tolerated. Short-term and long-term animal studies indicate low toxicity. Little hepatic or cardiac toxicity has been observed. There is a low incidence of raised liver enzymes.

Clinical trials.

Depression.

Moclobemide versus placebo.

Clinical efficacy of moclobemide in the treatment of depression has been demonstrated in four randomised, placebo controlled, double blind trials in a total of 475 patients (180 on moclobemide and 165 on placebo) using moclobemide doses of 200-600 mg/day. Three of these were multicentre trials performed predominantly in out-patients and one was a single centre study performed predominantly in inpatients. Two of the studies compared moclobemide with placebo in parallel group design and two compared with placebo on one hand and with a tricyclic antidepressant (TCA) on the other. The duration of treatment was for 4-6 weeks.
The largest of these studies included 334 patients (117 on moclobemide, 110 on placebo). The mean final improvement in depression as assessed by score on the Hamilton Depression scale (HAMD) was 48.7% for moclobemide and 31.9% for placebo treated patients. A final improvement of ≥ 50% on the HAMD occurred in 58% of moclobemide and 32% of placebo treated patients. The Clinical Global Impression (CGI) at the end of the 6 week treatment period was very good/ good in 64.3% of patients for moclobemide and 32.1% for placebo treated patients. The efficacy of moclobemide versus placebo was statistically significant (p < 0.001) on all measured efficacy parameters.
Combining the investigator's global assessment of efficacy for all 4 studies, the efficacy was rated as very good/ good in approximately 60% of patients who had received moclobemide and 30% of patients who had received placebo.

Moclobemide versus TCAs.

Moclobemide was compared to TCAs in 19 double blind studies including a total of 1070 patients (542 on moclobemide and 528 on TCA). The mean moclobemide dose in these studies was 443 mg/day and score on the HAMD was reduced by ≥ 50% in 56% of patients. Moclobemide was found to have similar efficacy to the TCAs and the CGI was very good/ good in 60.8% of moclobemide patients and 60.1% of patients treated with comparative TCA.

Moclobemide versus irreversible MAOIs.

Moclobemide was compared to the irreversible monoamine oxidase inhibitor (MAOI) tranylcypromine in 4 double blind studies with 159 patients (81 on moclobemide and 78 on tranylcypromine) using moclobemide doses of 150-350 mg/day. The mean final reduction in HAMD score was 63% in the moclobemide group and 59% in the tranylcypromine group. Tolerance was more frequently rated as better in the moclobemide group and the number of patients who prematurely terminated was three times higher in the tranylcypromine group.

Moclobemide single daily versus divided daily dosing.

This was a double blind, randomised, multicentre trial conducted in 189 patients for 6 weeks. The trial compared administration of single daily doses of moclobemide 450 mg (this could be increased up to 600 mg after 2 weeks) with this same daily dose given as three divided doses. The efficacies of the two dosing regimens were not found to be significantly different. Both the dosing regimens were found to be well tolerated although there was a significant increase in dizziness and a tendency for nausea, insomnia and headache in the once daily group.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, moclobemide is completely absorbed from the gastrointestinal tract into the portal blood. A hepatic first-pass effect reduces the systemically available dose fraction (bioavailability: F). This reduction is more pronounced after single (F: 60%) than after multiple (F: > 80%) doses.
Following the administration of a 100 mg single dose of moclobemide to healthy subjects, peak plasma concentrations ranged from 488 nanogram/mL to 1,450 nanogram/mL (mean Cmax 849 nanogram/mL) and were reached in 0.5 to 3.5 hours (mean Tmax 49 min). During the second week of a 100 mg t.i.d. dosing regimen in healthy subjects, the steady state trough concentrations of moclobemide ranged between 114 nanogram/mL and 517 nanogram/mL. An increase in the dose to 150 mg t.i.d. resulted in a greater than proportional increase in moclobemide steady state trough concentrations, namely to concentrations ranging between 346 nanogram/mL and 1,828 nanogram/mL.

Distribution.

Due to its lipophilic nature, moclobemide is extensively distributed in the body with an apparent volume of distribution (Vss) of about 1.2 L/kg. Binding of the drug to plasma proteins, mainly albumin, is relatively low (50%). Peak plasma concentrations of moclobemide increase over the first week of therapy and remain stable thereafter. When the daily dose is increased, there is a more than proportional increase in steady state concentrations.

Metabolism.

Moclobemide is almost entirely metabolised before its elimination from the body. Metabolism occurs largely via oxidative reactions on the morpholine moiety of the molecule. Moclobemide is metabolised in part by the polymorphic isoenzymes CYP2C19 and CYP2D6. Thus, in genetically or drug-induced (via metabolic inhibitors) poor metabolisers, metabolism of the drug may be affected. Approximately 2% of the Caucasian population and 15% of the Asian population can be genetically phenotyped as slow metabolisers with respect to oxidative hepatic metabolism. It was found that the area under the curve (AUC) measurement in slow metaboliser subjects was approximately 1.5 times greater than in extensive metaboliser subjects for the same dose of moclobemide. This increase is within the normal range of variation (up to twofold) typically seen in patients. Two studies conducted to investigate the magnitude of these effects suggested that, due to the presence of multiple alternative metabolic pathways, they are therapeutically unimportant and should not necessitate dosage modifications.
One metabolite, the N-oxide metabolite, has slight pharmacological activity. This and other degradation products with pharmacological activity in vitro or in animal experiments are present in the systemic circulation in man at very low concentrations only.

Excretion.

Moclobemide is rapidly eliminated from the body. Less than 1% of a dose is excreted renally unchanged. The metabolites formed are eliminated renally.
Blood clearance is approximately 20-50 L/hr, the average elimination half-life is two hours, with a slight increase at increased doses.
Multiple dose studies in the elderly and in patients with renal insufficiency suggest no dose adjustment is necessary to achieve plasma levels similar to those in young healthy subjects.

5.3 Preclinical Safety Data

Genotoxicity.

Moclobemide was not genotoxic in assays for gene mutation, chromosomal damage or DNA damage.

Carcinogenicity.

There was no evidence of carcinogenic effects following dietary administration of moclobemide to mice for 18 months at 250 mg/kg/day (750 mg/m2/day) or to rats for 24 months at 225 mg/kg/day (1350 mg/m2/day), doses which are 2 to 3 times the maximum recommended human dose calculated on a surface area basis.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depression.

4.3 Contraindications

Known hypersensitivity to the drug.
Acute confusional states.
Serotonin syndrome, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Coadministration of moclobemide with clomipramine should be avoided in clinical practice due to the risks of increased incidence of adverse reactions.
Coadministration of moclobemide with the following drugs is contraindicated: selegiline (L-deprenyl), bupropion, triptans, pethidine, tramadol, dextromethorphan, linezolid.

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. This risk must be considered in all depressed patients.
Antidepressants increased the risk compared to placebo of suicidality in children, adolescents and young adults (aged 18-24 years) during initial treatment (generally the first one to two months) in short-term studies of major depression and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults over 24 years of age, and there was a reduction in risk with antidepressants compared to placebo in adults 65 years or older.
Pooled analyses of 24 short-term (4 to 16 weeks), placebo controlled trials of nine antidepressant medicines (SSRls and others) in 4400 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 first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4%, compared with 2% of patients given 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).
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 healthcare 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.
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.
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.
Prescriptions for moclobemide should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Insomnia or nervousness or jitteriness at the beginning of treatment with moclobemide can justify a dose reduction or temporary symptomatic treatment. In case of occurrence of mania or hypomania, or the onset of early symptoms of those reactions (grandiosity, hyperactivity (including increased speech, reckless impulsivity), treatment with moclobemide will be interrupted and alternative treatment will be initiated.

Bipolar disorder/ mania.

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 at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.

Patients with excitation or agitation as main clinical feature.

Treatment of depressed patients with excitation or agitation as the main clinical feature may require addition of benzodiazepines.

Patients with schizophrenic symptoms.

As is the case with other antidepressants, an exacerbation of schizophrenic symptoms is possible when depressive patients with schizophrenic or schizoaffective psychoses are treated. Therapy with long-term neuroleptics should, if possible, be maintained in such patients.

Dietary precaution.

Treatment with moclobemide does not necessitate dietary restrictions in patients with normal dietary habits. Hypertensive patients are advised to avoid large quantities of tyramine rich food such as ripe cheese (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

St. John's wort.

St. John's wort (Hypericum) containing phytotherapeutic products should be used with care in combination with moclobemide as this may increase the serotonin concentration.

Hypertensive reactions.

There are theoretical pharmacological grounds for supposing that drugs that inhibit monoamine oxidase may provoke hypertensive reactions in patients with thyrotoxicosis or pheochromocytoma. In the absence of relevant experience with moclobemide, the drug should be prescribed with caution for patients in these groups.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Dosage in the elderly.

Paediatric use.

The safety and efficacy of Aurorix for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Aurorix should not be used in this age group for the treatment of depression or other psychiatric disorders.

Effects on laboratory tests.

Moclobemide does not affect laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Selegiline.

Coadministration of moclobemide with selegiline is contraindicated due to the relative loss of selectivity if both monoamine oxidase A and B are inhibited.

Linezolid.

Coadministration of moclobemide with linezolid is contraindicated due to the increased risk of serotonin syndrome and hypertensive crisis in vulnerable individuals.

Tramadol.

Coadministration of moclobemide with tramadol is contraindicated.

Pethidine.

High dose studies in animals have demonstrated some potentiation of analgesic effect and increased restlessness with concomitant administration of pethidine and moclobemide. Concomitant administration of pethidine and moclobemide is contraindicated because of the increased risk of serotonergic syndrome (confusion, fever, convulsions, ataxia, hyper-reflexia, myoclonus, diarrhoea).

Dextromethorphan.

Isolated cases of severe central nervous system adverse reactions have been reported after coadministration of moclobemide and dextromethorphan. Coadministration of moclobemide and dextromethorphan, which may be contained in cough cold medicines, is not recommended and if possible, alternatives not containing dextromethorphan should be given (see Section 4.4 Special Warnings and Precautions for Use).

Dextropropoxyphene.

Concomitant use of dextropropoxyphene is not advised as moclobemide may potentiate the effects of dextropropoxyphene.

Opiates.

In animals, moclobemide potentiates the effects of opiates. A dosage adjustment of the following opiate, e.g. morphine, fentanyl and codeine may therefore be necessary.

Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), irreversible MAO inhibitors, serotonin syndrome and washout periods.

Due to the possibility of development of serotonin syndrome, moclobemide should not be administered concomitantly with selective serotonin reuptake inhibitors (e.g. fluoxetine and fluvoxamine) or tricyclic antidepressants. This possibility increases with increasing dose and fatalities have occurred where one or more of these drugs have been ingested in overdose (see Section 4.9 Overdose). Generally, in patients receiving moclobemide, additional drugs that enhance serotonin, particularly in multiple drug combinations, should only be given with caution.
There are limited data (i.e. small clinical pharmacology studies and postmarketing reports) to support the safety of changing from low to moderate doses of serotonin reuptake inhibitors to moclobemide 300 mg/day by ceasing the SSRI on one day and starting moclobemide on the next. In one study, 18 healthy subjects were changed from moclobemide 300 mg on day one to fluoxetine 40 mg/day for the next 7 days then fluoxetine 20 mg/day for a further 7 days. On day 16, subjects were randomised to receive, in addition to fluoxetine 20 mg/day, moclobemide in ascending doses from 100 mg to 600 mg or placebo, for the next 8 days. On day 24, all patients received 300 mg moclobemide. There were no differences in the adverse reactions reported between the two groups, although the power of the study to detect clinically significant interactions is limited, given the number of subjects and the dose of moclobemide used. Hence, caution is recommended and the dose of moclobemide should be held at 300 mg/day for the first week. Particular attention should also be given to the patient's medical history and concomitant therapy with other psychotropic drugs known to interact with or facilitate 5-HT functions.
Similarly, there are limited data to support the safety of changing from low to moderate doses of tricyclic antidepressants, for example 150 mg or less of amitriptyline to moclobemide 300 mg per day by ceasing the tricyclic antidepressant one day and starting Aurorix the next. The patient should be seen again soon after the changeover and progress monitored appropriately. The dose of moclobemide should be maintained at 300 mg/day for the first week.
Generally, an interval of 14 days is recommended for switching from an irreversible MAO inhibitor to moclobemide (e.g. phenelzine, tranylcypromine).

Serotonin-norepinephrine reuptake inhibitors (sibutramine and venlafaxine).

In patients receiving moclobemide, additional drugs that enhance serotonin, such as venlafaxine should be given with caution. Concomitant use of sibutramine with moclobemide is not recommended.

Trimipramine and maprotiline.

Care should be taken with concomitant use of trimipramine and maprotiline as the plasma concentration of these nonselective monoamine reuptake inhibitors increases upon concomitant administration with moclobemide.

St. John's wort.

Concomitant use with St. John's wort (Hypericum) is not recommended as this may increase the serotonin concentration in the central nervous system.

Serotonin agonists.

Some serotonin agonists are metabolised predominantly by monoamine oxidase A and may need to be avoided or have their dosage reduced if administered concomitantly with moclobemide.

Triptans.

Coadministration of moclobemide with triptans is contraindicated. Triptans (e.g. sumatriptan, rizatriptan, zolmitriptan, almotriptan) are potent serotonin receptor agonists and are metabolized by monoamine oxidases (MAOs) and various cytrochrome P450 enzymes. Coadministration of moclobemide leads to an increase in the plasma concentrations of the triptans. A maximum dose of 5 mg of zolmitriptan is recommended if combined with moclobemide and concomitant treatment is not recommended if moclobemide is administered in higher dose than 150 mg twice daily.

Phenprocoumon.

Concomitant administration of moclobemide 200 mg three times per day did not influence the parameters of blood coagulation controlled by phenprocoumon. No data are available regarding warfarin and moclobemide.

Digoxin.

Concomitant administration of moclobemide to elderly patients under chronic digoxin treatment produced no significant changes in the digoxin plasma levels. There were no additional ECG disturbances, particularly no arrhythmias or conductance disturbances. Vital signs and laboratory parameters were also unaltered.

Antihypertensive treatment.

The combination of moclobemide with metoprolol, nifedipine or hydrochlorothiazide in patients stable on their antihypertensive treatment was well tolerated and in particular there were no orthostatic reactions. The therapeutic benefits of nifedipine and hydrochlorothiazide were not influenced by moclobemide. The combination of moclobemide and metoprolol led to an additional BP reduction of 10 to 15 mmHg (systolic) and 5 to 10 mmHg (diastolic). The mechanism underlying this effect is not clear. In normotensive subjects moclobemide had no effect on BP.

Sympathomimetic amines.

Possible undesired interactions between moclobemide and directly acting sympathomimetic amines were investigated in healthy subjects. Phenylephrine (PE) reactivity was investigated by infusion of increasing PE doses before and after moclobemide (100 mg single; 200 mg single; 100 mg three times per day for one week; 200 mg three times per day for three weeks) administration. After the three lowest doses, PE reactivity remained unchanged. After chronic administration of the highest dose there was a slight increase by 1.8 of the sensitivity factor in only four out of the six subjects, in the other two it was unchanged. Thus only after repeated administration of the high therapeutic doses of 200 mg three times per day moclobemide could a slight interaction be observed. PE was given intravenously, but in general it will be used as a nasal decongestant. Recommended use in these indications will be unlikely to result in concentrations of PE which cause relevant BP increases.

Cimetidine.

A pharmacokinetic interaction (reduced moclobemide clearance) occurred in healthy subjects with combined administration of moclobemide and cimetidine. Thus if moclobemide treatment is initiated in a patient pretreated with cimetidine the lowest dose should be given initially. If cimetidine has to be given after initiation of moclobemide treatment, it may be necessary to reduce the daily dose of moclobemide to half or one third and to adjust according to clinical requirement.

Proton pump inhibitors (e.g. omeprazole).

Care should be taken with concomitant use of drugs that are metabolised by CYP2C19 as moclobemide is an inhibitor of this enzyme. The plasma concentration of these drugs (such as proton pump inhibitors (e.g. omeprazole)) may be increased when concomitantly used with moclobemide. Similarly, moclobemide inhibits the metabolism of omeprazole in CYP2C19 extensive metabolisers resulting in a doubling of the omeprazole exposure.

Oral contraceptives.

The hormone levels (FSH, LH, estradiol and progesterone) were not altered when moclobemide was administered concomitantly with combined contraceptives.

Tyramine.

In animal experiments it has been shown that the pressor effects of tyramine are less with moclobemide than with other inhibitors of monoamine oxidase. Results from studies in man showed that when tyramine is administered I.V. or orally under pharmacological conditions by using a provocative model, moclobemide leads to a slight and short lasting potentiation of the tyramine pressor effect. The potentiation of the pressor effect was even lower or did not occur when tyramine was mixed with a meal. A high protein or fat content meal further reduced the potentiation. In human studies it was demonstrated that up to 100 mg tyramine, corresponding to 1,000 g to 2,000 g mild or 200 g strong cheese, or to 70 g Marmite yeast extract, can safely be ingested during chronic treatment with three times 200 mg per day moclobemide postprandially. Thus an interaction with tyramine rich foods is of no clinical importance during moclobemide treatment under normal conditions and moclobemide taken at the end of a meal. Neither age nor depression influences the interaction.

Alcohol.

Concomitant moclobemide administration did not further reduce performance in subjects with a blood content of alcohol distinctly reducing performance. Also, in elderly subjects, there was no additional influence at therapeutic doses.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no adverse effects on the fertility of rats receiving oral moclobemide 100 mg/kg/day (600 mg/m2/day), a dose slightly more than the maximum recommended human dose calculated on a surface area basis.
(Category B3)
Moclobemide and two of its metabolites were found in the amniotic fluid of pregnant rats 5 hours after dosing. Moclobemide lacked teratogenic activity in rats and rabbits at respective oral doses of 200 mg/kg/day (1200 mg/m2/day) and 100 mg/kg/day (1100 mg/m2/day), doses which are 2 to 3 times the maximum recommended human dose calculated on a surface area basis. However, there are no data on safety in human pregnancy and careful evaluation of the potential benefit and hazards to the mother and fetus should precede administration to pregnant women.
Although only a small amount of moclobemide passes into breast milk (approximately 1/30th of the maternal dose), the benefits of continuing drug therapy for the breastfeeding mother should be weighed against possible risks to the child.

4.8 Adverse Effects (Undesirable Effects)

Aurorix is usually well tolerated. No adverse event occurred with an increased frequency of more than 5% compared to placebo. The following transient effects have been observed: sleep disturbances, dizziness, nausea, dry mouth, and headache. In very rare cases, confusional states have been observed, but these rapidly disappeared on discontinuation of therapy. Insomnia, or nervousness/ jitteriness at the beginning of treatment with moclobemide can justify a dose reduction or temporary symptomatic treatment. See Tables 1 and 2.
Other adverse events with an incidence of < 1% in clinical studies, or reported in postmarketing surveillance are as follows.

Psychiatric.

Nightmares/ dreams, hallucinations, memory disturbances, disorientation, delusions, increased depression, excitation/ irritability, hypomanic symptoms, aggressive behaviour, apathy, tension.

Central and peripheral nervous system.

Migraine, extrapyramidal effects, tinnitus, dysarthria.

Gastrointestinal.

Heartburn, gastritis, meteorism, indigestion.

Cardiovascular.

Hypertension, bradycardia, extrasystoles, angina/ chest pain, phlebitic symptoms.

Dermatological/ mucocutaneous.

Exanthema, allergic skin reaction, itching, gingivitis, stomatitis, dry skin, conjunctivitis.

Genitourinary.

Disturbances of micturition (dysuria, polyuria, tenesmus), metrorrhagia, prolonged menstruation.

Miscellaneous.

General malaise, skeletal/ muscular pain, altered taste sensations, hot flushes/ cold sensation, photopsia, dyspnea, visual disturbances. There appears to be a low incidence of increased hepatic enzymes without associated clinical sequelae.
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 https://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Adults.

Aurorix therapy should be initiated in two divided daily doses. The recommended initial daily dose is 300 or 450 mg. The recommended dose range is 300-600 mg/day. The dose should not be raised until after the first week, as bioavailability increases during this period. Treatment should continue for at least 4-6 weeks in order to assess the efficacy of the drug. Aurorix should be taken after meals.

Dosage in the elderly.

No dosage adjustments are necessary in elderly patients.

Dosage in patients with impaired renal function.

Single dose pharmacokinetic data suggest that no dosage adjustment may be required in patients with reduced renal function. However, multiple dose studies with moclobemide have not been performed in patients with renal dysfunction, therefore Aurorix should be used with caution in this patient population. In normal volunteers, the absolute bioavailability almost doubles following multiple dosing as compared to a single dose.

Dosage in patients with impaired hepatic function.

In patients with severely impaired hepatic metabolism, the daily dose of Aurorix should be reduced to half or one-third of the dose to reach the usual plasma level.

4.7 Effects on Ability to Drive and Use Machines

Impairment of performance in activities requiring complete mental alertness (e.g. driving a motor vehicle) is generally not to be expected with Aurorix. The individual reaction should, however, be monitored during early treatment.

4.9 Overdose

The highest reported overdose is 20.55 g. The usual signs of overdose with moclobemide alone are nausea, vomiting, drowsiness, disorientation, slurred speech, amnesia, reduced reflexes, agitation, hypertension and convulsions.
As with other antidepressants, combination overdoses of moclobemide and other antidepressants, alcohol and other drugs can be life threatening. Fatalities have been reported in combination overdoses. Patients should be hospitalised and closely monitored so that appropriate treatment can be given. Serotonin syndrome symptoms (hypertension, spasm, altered consciousness) have been reported with mixed overdoses with clomipramine or selective serotonin reuptake inhibitors.
Management of overdose should include monitoring of vital signs and consideration of other agents ingested in multiple overdoses.
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

Lactose monohydrate, maize starch, povidone, sodium starch glycollate, magnesium stearate, ethylcellulose, macrogol 6000, hypromellose, purified talc, titanium dioxide.
Aurorix 150 mg tablets also contain yellow iron oxide.

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 30°C.

6.5 Nature and Contents of Container

Aurorix comes in two strengths of tablets.
Each Aurorix 150 mg tablet contains 150 mg of the active ingredient, moclobemide.
150 mg: Oval, cylindrical, biconvex, pale yellow tablet marked "150" on one side with a break bar on the other side, 10s* and 60s in a blister pack (PVC/Aluminium).
Each Aurorix 300 mg tablet contains 300 mg of the active ingredient, moclobemide.
300 mg: Oval, cylindrical, biconvex, white to yellow-white tablet marked "300" on one side with a break bar on the other side, 10s* and 60s in a blister pack (PVC/Aluminium).
*Not marketed.

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