Consumer medicine information

APX-Mirtazapine

Mirtazapine

BRAND INFORMATION

Brand name

APX-Mirtazapine

Active ingredient

Mirtazapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APX-Mirtazapine.

SUMMARY CMI

APX-MIRTAZAPINE

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using APX-MIRTAZAPINE?

APX-MIRTAZAPINE contains the active ingredient mirtazapine. APX-MIRTAZAPINE is used to treat depression including relapse prevention.

For more information, see Section 1. Why am I using APX-MIRTAZAPINE? in the full CMI.

2. What should I know before I use APX-MIRTAZAPINE?

Do not use if you have ever had an allergic reaction to APX-MIRTAZAPINE or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use APX-MIRTAZAPINE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APX-MIRTAZAPINE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use APX-MIRTAZAPINE?

  • The usual starting dose is 15 mg per day. Your doctor may slowly increase this dose depending on how you respond to APX-MIRTAZAPINE.
  • The effective dose for most people is usually between 30 mg and 45 mg per day.

More instructions can be found in Section 4. How do I use APX-MIRTAZAPINE? in the full CMI.

5. What should I know while using APX-MIRTAZAPINE?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APX-MIRTAZAPINE.
  • If you have any suicidal thoughts or other mental/ mood changes, tell your doctor immediately or go to the nearest hospital for treatment.
  • Tell your doctor if you feel the tablets are not helping your condition.
Things you should not do
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop using this medicine suddenly or lower the dose without first checking with your doctor.
Driving or using machines
  • Do not drive or operate machinery until you know how APX-MIRTAZAPINE affects you.
  • APX-MIRTAZAPINE may cause dizziness, drowsiness, or sleepiness in some people and affect alertness and concentration in some people.
Drinking alcohol
  • Combining APX-MIRTAZAPINE and alcohol can make you sleepier and less alert.
Looking after your medicine
  • Keep your tablets in their blister pack until it is time to take them.
  • Store below 30°C in a dark, dry place.

For more information, see Section 5. What should I know while using APX-MIRTAZAPINE? in the full CMI.

6. Are there any side effects?

Common side effects: lethargy, drowsiness or sleepiness, headache, tiredness, dry mouth, diarrhoea, constipation, increase in appetite and weight gain, nausea, vomiting. Serious side effects: skin rashes, itching or hives; swelling of the face, lips, or tongue which may cause difficulty breathing, severe skin reactions.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APX-MIRTAZAPINE

Active ingredient(s): Mirtazapine

Consumer Medicine Information (CMI)

This leaflet provides important information about using APX-MIRTAZAPINE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using APX-MIRTAZAPINE.

Where to find information in this leaflet:

1. Why am I using APX-MIRTAZAPINE?
2. What should I know before I use APX-MIRTAZAPINE?
3. What if I am taking other medicines?
4. How do I use APX-MIRTAZAPINE?
5. What should I know while using APX-MIRTAZAPINE?
6. Are there any side effects?
7. Product details

1. Why am I using APX-MIRTAZAPINE?

APX-MIRTAZAPINE medicine contains the active ingredient Mirtazapine. This medicine corrects this chemical imbalance and may help relieve the symptoms of depression.

APX-MIRTAZAPINE is used to treat depression including relapse prevention. Depression is longer lasting or more severe than "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. This affects your whole body and can cause emotional and physical symptoms such as feeling low in spirit, loss of interest in activities, unable to enjoy life, poor appetite or overeating, disturbed sleep, often waking up early, loss of sex drive, lack of energy and feeling guilty over nothing.

2. What should I know before I use APX-MIRTAZAPINE?

Warnings

Do not use APX-MIRTAZAPINE if:

  • You are allergic to mirtazapine, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
    Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips, mouth, throat or other parts of the body, shortness of breath, wheezing or trouble breathing.
  • you are taking another medicine for depression called monoamine oxidase inhibitor (MAOI) or have been taking it within the last 14 days. If you stop taking APX-MIRTAZAPINE, do not take MAOI during the next two weeks either.
    Taking APX-MIRTAZAPINE with an MAOI may cause serious reactions with a sudden increase in body temperature, extremely high blood pressure and severe convulsions.
    Examples of this type of medicine include phenelzine, tranylcypromine and selegiline.

Check with your doctor if you:

  • have any other medical conditions like:
    - thoughts of suicide or self-harm
    - epilepsy (fits or convulsions)
    - liver disease such as jaundice
    - kidney disease
    - heart disease
    - low blood pressure
    - certain kinds of heart conditions that may change your heart rhythm, a recent heart attack, heart failure, or take a certain medicine that may affect the hearts rhythm
    - any mental illness (e.g., schizophrenia, maniac depression)
    - diabetes
    - glaucoma (increased pressure in the eye)
    - problems in urinating due to an enlarged prostate
    - unexplainable high fever, sore throat and mouth ulcers
    - glucose-galactose malabsorption
    - galactose intolerance.
  • take medicines for any other condition
  • react badly to lactose or milk before you start taking APX-MIRTAZAPINE. APX-MIRTAZAPINE tablets contain lactose.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take APX-MIRTAZAPINE if you are pregnant or intend to become pregnant.

Tell your doctor if you become pregnant while taking this medicine. Do not stop taking your tablets until you have spoken to your doctor.

Like most medicines of this kind, this medicine is not recommended to be used during pregnancy. Your doctor will discuss the risks and benefits of taking this medicine when pregnant.

If you use APX-MIRTAZAPINE until, or shortly before birth, your baby should be supervised for possible adverse effects.

Do not take APX-MIRTAZAPINE if you are breastfeeding or intend to breastfeed.

It is not known whether this medicine passes into breast milk.

Use in Children

Do not give this medicine to a child or adolescent.

The safety of this medicine in patients under 18 years has not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by APX-MIRTAZAPINE or may affect how well it works. These include:

  • other medicines (e.g., SSRIs, venlafaxine, L-tryptophan, nefazodone) for depression, anxiety, obsessive compulsive disorders or pre-menstrual dysphoric disorder
  • Monoamine Oxidase Inhibitors (such as tranylcypromine, phenelzine, and selegiline)
  • medicines containing St. John's Wort (hypericum perforatum)
  • phenytoin or carbamazepine, medicines used to treat epilepsy
  • benzodiazepines, medicines used to treat anxiety and sleeping problems
  • lithium, a medicine used to treat some psychiatric conditions
  • methylene blue (used to treat high levels of methemoglobin in the blood)
  • tramadol, a pain killer
  • morphine, a medicine for severe pain
  • cetirizine, a medicine for allergies
  • warfarin, a medicine used to prevent blood clotting
  • linezolid or erythromycin, both antibiotics
  • rifampicin, a medicine used to treat tuberculosis
  • medicines used to treat fungal infections such as ketoconazole
  • HIV/AIDS medications
  • cimetidine, a medicine used to treat reflux and stomach ulcers
  • triptans such as sumatriptan, naratriptan and zolmitriptan, medicines used to treat migraine
  • medicines that may affect the heart's rhythm such as certain antibiotics and some anti-psychotics.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APX-MIRTAZAPINE.

4. How do I use APX-MIRTAZAPINE?

How much to take / use

  • The usual starting dose is 15 mg per day. Your doctor may slowly increase this dose depending on how you respond to APX-MIRTAZAPINE.
  • The effective dose for most people is usually between 30 mg and 45 mg per day.

Your doctor may have prescribed a different dose.

If you do not understand the instructions on the box, ask your doctor or pharmacist.

When to take / use APX-MIRTAZAPINE

APX-MIRTAZAPINE should be used at the same time each day.

Your doctor will tell you when to take your tablets. The tablet(s) should be taken at the same time each day, preferably as a single night-time dose before going to bed; if recommended by your doctor, APX-MIRTAZAPINE may be taken in sub-doses equally divided over the day (once in the morning and once at night-time before going to bed).

How to take it

Swallow the tablet(s), without chewing, together with some water or other fluid.

How long to take it

  • Continue taking your medicine for as long as your doctor tells you.
  • For depression, the length of treatment depends on how quickly your symptoms improve.
  • Most antidepressants take time to work, so do not be discouraged if you don't feel better right away. Some symptoms may improve in 1 to 2 weeks, but it can take up to 2 to 4 weeks to feel the full benefit of the medicine.
  • It is important to keep taking your medicine even if you feel well, usually for about 4 to 6 months or even longer, to make sure the benefits will last.

If you forget to use APX-MIRTAZAPINE

Once daily dosing

If you forget to take the tablet before you go to bed, do not take the missed dose the next morning. This medicine may cause drowsiness or sleepiness during the day. Continue treatment in the evening with your usual dose and continue to take it as you would normally.

Twice dosing daily

  • Morning dose forgotten - simply take it together with your evening dose.
  • Evening dose forgotten - do not take it with the next morning dose. Continue treatment with your normal morning and evening doses.
  • Both doses forgotten - do not try to make up for the missed tablets. Continue with your usual morning and evening dose the next day.

If you use too much APX-MIRTAZAPINE

If you think that you have used too much APX-MIRTAZAPINE, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too many APX-MIRTAZAPINE tablets, you may feel drowsy, dizzy, confused, and agitated. You may also have changes to your heart rhythm (fast, irregular heartbeat) and/or fainting which could be symptoms of a life-threatening condition known as Torsades de Pointes.

5. What should I know while using APX-MIRTAZAPINE?

Things you should do

  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking APX-MIRTAZAPINE.
  • Tell your doctor if 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.
  • Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some blood tests from time to time. This helps to prevent unwanted side effects.

Call your doctor straight away if you:

  • develop fever, chills, sore throat, or mouth ulcers or other signs of frequent infections. Stop taking APX-MIRTAZAPINE and consult with your doctor for a blood test.
    In rare cases mirtazapine can cause disturbances in the production of blood cells (bone marrow depression). Some people become less resistant to infection because APX-MIRTAZAPINE can cause a temporary shortage of white blood cells (granulocytopenia). In rare cases APX-MIRTAZAPINE can also cause a shortage of red and white blood cells, as well as blood platelets (aplastic anaemia), a shortage of blood platelets (thrombocytopenia) or an increase in the number of white blood cells (eosinophilia). While rare, these symptoms most commonly appear after 4-6 weeks of treatment.
  • have any suicidal thoughts or other mental/mood changes.
    Occasionally, the symptoms of depression or other psychiatric conditions may include thoughts of harming yourself or committing suicide. Until the full antidepressant effect of your medicine becomes apparent, it is possible these symptoms may increase in the first few weeks of treatment.
    Information from clinical trials have shown an increased risk of suicidal behaviour in young adults aged less than 25 years with psychiatric conditions who were treated with an antidepressant.
  • you or someone you know is showing warning signs of suicide-related behavior while taking APX-MIRTAZAPINE, contact your doctor or a mental health professional right away or go to the nearest hospital for treatment. These signs include:
    - thoughts or talk about 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.
    All mentions of self-harm, suicide or violence must be taken seriously.
    You may find it helpful to tell a relative or close friend that you are depressed and ask them to read this leaflet. You might ask them to tell you if they think your depression is getting worse, or if they are worried about changes in your behaviour.

Remind any doctor, dentist, or pharmacist you visit that you are using APX-MIRTAZAPINE.

Things you should not do

  • Do not stop using this medicine suddenly or lower the dose without first checking with your doctor.
    Your doctor may want to gradually reduce the amount of APX-MIRTAZAPINE you are taking before stopping completely.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.
  • Do not stop taking APX-MIRTAZAPINE even if you feel better. unless advised by your doctor.
    Suddenly stopping APX-MIRTAZAPINE may cause nausea, headache, dizziness, anxiety, agitation.
  • Do not let yourself run out of medicine over the weekend or on holidays.
  • Do not use APX-MIRTAZAPINE to treat any other condition unless your doctor tells you to do.

Driving or using machines

Do not drive or operate machinery until you know how APX-MIRTAZAPINE affects you.

APX-MIRTAZAPINE may cause dizziness, drowsiness, or sleepiness in some people and affect alertness and concentration in some people. If any of these occur, do not drive, operate machinery or anything that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Combining APX-MIRTAZAPINE and alcohol can make you sleepier and less alert. Your doctor may suggest you avoid alcohol while being treated with this medicine.

Looking after your medicine

  • Keep your tablets in their blister pack until it is time to take them.
  • The tablets may not keep as well if you take them out of the blister pack.
  • Store below 30°C in a dark, dry place.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

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

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
General disorders
  • lethargy, drowsiness or sleepiness
  • headache
  • tiredness
  • swollen ankles or feet because of fluid accommodation (oedema)
Gut or gastrointestinal related
  • diarrhoea
  • constipation
  • increase in appetite and weight gain
  • nausea, vomiting
  • dry mouth
Blood pressure related
  • dizziness or faintness when getting up quickly from a lying or sitting position (low blood pressure)
Allergy related
  • abnormal sensations in the mouth sensations of numbness in the mouth or swelling in the mouth
  • rash or skin eruptions
Joints or muscle related
  • painful joints
  • backpain
  • muscle aches and pains
  • restless legs
Skin related
  • abnormal sensation in the skin for example burning, stinging, tickling or tingling.
Hormonal related
  • increased prolactin hormone levels in blood (hyperprolactinaemia, including symptoms such as enlarged breasts and/or milky nipple discharge)
Mood or psychiatric related
  • nightmares/vivid dreams
  • sleep walking
  • memory problems
  • anxiety
  • insomnia*
  • aggression*
  • urge to move
*These maybe symptoms of depression
Others
  • speech disorders
  • difficulty in passing urine (urinary retention)
  • prolonged painful erection of the penis
  • tingling fingers or toes
Speak to your doctor if you have any of these less serious side effects and they worry you.
They are generally mild and do not cause patients to stop taking APX-MIRTAZAPINE.

Serious side effects

Serious side effectsWhat to do
Mood or psychiatric related
  • suicidal ideation or behaviour
  • epileptic attack (seizures)
  • shaking or tremors
  • attack of excessive excitability (mania)
  • agitation
  • confusions
  • hallucinations
  • fainting
Muscle related
  • sudden muscle contractions (myoclonus)
  • muscle pain, stiffness and/or weakness, darkening or discolouration of the urine (rhabdomyolysis)
Heart related
  • change to your heart rhythm
Liver related
  • yellow colouring of eyes or skin; this may suggest disturbance in liver function
Pancreas related
  • abdominal pain and nausea; this may suggest inflammation of the pancreas
Allergy related
  • skin rash, itching or hives; swelling of the face, lips or tongue which may cause difficulty breathing
  • severe skin reactions
Infection related
  • signs of infection such as sudden unexplainable high fever, sore throat and mouth ulcers
  • gastrointestinal (stomach, bowels), disturbances and other signs of infection
Serotonin syndrome
  • a combination of symptoms such as fever, sweating, increased heart rate, diarrhoea, (uncontrollable) muscle contractions, shivering, overactive reflexes, restlessness, mood changes unconsciousness and increased salivation
Others
  • generalised fluid retention with weight gain
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What APX-MIRTAZAPINE contains

Active ingredient
(main ingredient)		Mirtazapine
Other ingredients
(inactive ingredients)		Lactose monohydrate
Hyprolose
Maize starch
Colloidal anhydrous silica
Magnesium stearate
15 mg tablet: Opadry Complete Film Coating System 20A2052560 Yellow.
30 mg tablet: Opadry Complete Film Coating System 20A56788 Brown.
45 mg tablet: Opadry Complete Film Coating System 20A58806 White.
Potential allergensLactose monohydrate

What APX-MIRTAZAPINE looks like

15 mg

Yellow, biconvex capsule shaped film-coated tablets with a score line in between ‘0’ and ‘8’ on one side and ‘A’ debossed on the other side. AUST R 183398.

30 mg

Reddish brown, biconvex capsule shaped film-coated tablets with a score line in between ‘0’ and ‘9’ on one side and ‘A’ debossed on the other side. AUST R 183399.

45 mg

White, biconvex capsule shaped film-coated tablets with ‘10’ debossed on one side and ‘A’ debossed on the other side. AUST R 183400.

*Some of these presentations and pack sizes may not be marketed.

Who distributes APX-MIRTAZAPINE

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared in August 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

APX-Mirtazapine

Active ingredient

Mirtazapine

Schedule

S4

 

1 Name of Medicine

The name of the medicine is mirtazapine.

2 Qualitative and Quantitative Composition

Each tablet contains mirtazapine 15 mg, 30 mg or 45 mg.

Excipients of known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APX-Mirtazapine 15 mg.

Yellow, biconvex capsule shaped, film coated tablets with a score line in between 0 and 8 debossed on one side and 'A' on the other side.

APX-Mirtazapine 30 mg.

Reddish Brown, biconvex capsule shaped, film coated tablets with a score line in between 0 and 9 debossed on one side and 'A' on the other side.

APX-Mirtazapine 45 mg.

White, biconvex capsule shaped film coated tablets with '10' debossed on one side and 'A' on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depression including relapse prevention.

4.2 Dose and Method of Administration

The tablets should be taken orally, if necessary with fluid, and swallowed without chewing.

Adults.

Treatment should begin with 15 mg daily. The dosage generally needs to be increased to obtain an optimal clinical response. The effective daily dose is usually between 30 and 45 mg, but responses have been observed at 60 mg per day.

Elderly.

The recommended dose is the same as that for adults. In elderly patients an increase in dosing should be done under close supervision to elicit a satisfactory and safe response.
The clearance of mirtazapine may be decreased in patients with renal or hepatic insufficiency. This should be taken into account when prescribing mirtazapine to this category of patients (see Section 5.2 Pharmacokinetic Properties).
Mirtazapine has a half-life of 20-40 hours and therefore mirtazapine is suitable for once-a-day administration. It should be taken preferably as a single night-time dose before going to bed. Mirtazapine may also be given in sub-doses equally divided over the day (once in the morning and once at night-time).
Treatment should preferably be continued until the patient has been completely symptom-free for 4-6 months. After this, treatment can be gradually discontinued. Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response within 2-4 weeks. With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further 2-4 weeks, then treatment should be stopped.

Children and adolescents (< 18 years of age).

In placebo controlled trials, safety and efficacy of mirtazapine in the treatment of children and adolescents under the age of 18 years with major depressive disorder have not been established. Safety and efficacy in this population cannot be extrapolated from adult data. Therefore mirtazapine should not be used in children and adolescents under the age of 18 years.

4.3 Contraindications

Hypersensitivity to mirtazapine or to any of the excipients.
MAO Inhibitors as concomitant therapy. It is recommended that mirtazapine not be used in combination with MAO Inhibitors, or within 14 days of initiating or discontinuing therapy with a MAO Inhibitor (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

The risk of suicidality (suicidal ideation and suicidal behaviours) is inherent in depression and may persist until significant remission occurs. This risk 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/or behaviours whether or not they are taking antidepressant medication, and this risk may persist until significant remission occurs. Suicide is a known risk in depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. 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 or behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analysis of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increased the risk of suicidal ideation and/or behaviours in children, adolescents, and young adults (aged 18-24 years) with major depressive disorder (MDD) and other psychiatric disorders during the initial treatment (generally the first one to two months).
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials (4 to 16 weeks) of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in the risk of suicidality among drugs, but a tendency towards an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across different indications, with the highest incidence in MDD trials. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.
No suicides occurred in any of the paediatric trials. There were few suicides in the adult trials, but the number was not sufficient to reach any conclusion about the effect of antidepressants on suicide. It is unknown whether suicidality risk extends to longer-term use, i.e. beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
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 disorders as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidality 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 MDD or for any other condition (psychiatric or non-psychiatric) 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 mirtazapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Conditions which need supervision.

Careful dosing as well as regular and close monitoring is necessary in patients with:

Hepatic impairment.


Epilepsy and organic brain syndrome.

See Section 4.8 Adverse Effects (Undesirable Effects).
Mirtazapine should be introduced cautiously in patients who have a history of seizures. Treatment should be discontinued in any patient who develops seizures, or where there is an increase in seizure frequency.

Renal insufficiency.

Mirtazapine is substantially excreted by the kidney (75%) and the risk of decreased clearance of this drug is greater in patients with impaired renal function.

Cardiac diseases.

Such as conduction disturbances, angina pectoris and recent myocardial infarct, where normal precautions should be taken and concomitant medicines carefully administered.

Low blood pressure and conditions that would predispose patients to hypotension.

(Dehydration, hypovolemia and treatment with antihypertensive medication).

Diabetes mellitus.

In patients with diabetes, antidepressants may alter glycemic control. Insulin and/or oral hypoglycemic dosage may need to be adjusted and close monitoring is recommended.
Like with other antidepressants, the following should also be taken into account: As for antidepressants in general care should be taken in patients with:
Worsening of psychotic symptoms can occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; paranoid thoughts can be intensified.
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. When the depressive phase of the bipolar disorder is being treated, it can transform into the manic phase. Patients with a history of mania/hypomania should be closely monitored. mirtazapine should be discontinued in any patient entering a manic phase.
Care should be taken in patients with micturition disturbances like prostate hypertrophy (although problems are not to be expected because mirtazapine possesses only very weak anticholinergic activity).
Acute narrow-angle glaucoma and increased intra-ocular pressure (however mirtazapine has weak anticholinergic activity).
Akathisia/psychomotor restlessness. The use of antidepressants have been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Mirtazapine is not addictive. Post-marketing experience shows that abrupt termination of treatment after long term administration may sometimes result in withdrawal symptoms.
The majority of withdrawal reactions are mild and self limiting. Among the various reported withdrawal symptoms, dizziness, agitation, anxiety, headache and nausea are the most frequently reported. Even though they have been reported as withdrawal symptoms, it should be realised that these symptoms may be related to underlying disease. As advised in Section 4.2 Dose and Method of Administration, it is recommended to discontinue treatment with mirtazapine gradually.

Jaundice.

Treatment should be discontinued if jaundice occurs.

Hyponatremia.

Hyponatremia has been reported very rarely with the use of mirtazapine. Caution should be exercised in patients at risk, such as elderly patients or patients concomitantly treated with medications known to cause hyponatremia.

Serotonin syndrome.

Development of serotonin syndrome may occur in association with treatment with SSRIs and SNRIs, particularly when given in combination with MAOIs (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) or other serotonergic agents (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Symptoms and signs of serotonin syndrome include rapid onset of neuromuscular excitation (hyperreflexia, incoordination, myoclonus, tremor), altered mental status (confusion, agitation, hypomania) and autonomic dysfunction (diaphoresis, diarrhoea, fever, shivering and rapidly fluctuating vital signs).
Treatment with mirtazapine should be discontinued if such events occur and supportive symptomatic treatment initiated. From post marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with mirtazapine alone (see Section 4.8 Adverse Effects (Undesirable Effects)).

Lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), bullous dermatitis and erythema multiforme, which can be life-threatening or fatal, have been reported in association with mirtazapine treatment.
If signs and symptoms suggestive of these reactions appear, mirtazapine should be withdrawn immediately.
If the patient has developed one of these reactions with the use of mirtazapine, treatment with mirtazapine must not be restarted in this patient at any time.

Neutropenia, agranulocytosis.

Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with mirtazapine. The symptoms mostly appear after 2-6 weeks of treatment. The bone marrow depression is, in general, reversible after termination of treatment. However in very rare cases agranulocytosis can be fatal. Reversible agranulocytosis has been reported as a rare occurrence in clinical studies with mirtazapine. In the post-marketing period with mirtazapine very rare cases of agranulocytosis have been reported, mostly reversible, but in some cases fatal. All fatal cases concerned patients over 65 years. Post-marketing data indicate that the rate of occurrence of agranulocytosis and agranulocytosis-like disorders (whether or not causally related) amongst mirtazapine users is no greater than that in the background population. One should be alert for symptoms like fever, sore throat, stomatitis or other signs of infections. If such symptoms occur the treatment should be stopped and blood counts taken.

Use in hepatic impairment.

See conditions which need supervision, above; see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations, Renal and/or hepatic impairment.

Use in renal impairment.

See Conditions which need supervision, above; see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations, Renal and/or hepatic impairment.

Use in the elderly.

Elderly patients are often more sensitive, especially with regard to the undesirable effects of antidepressants. During clinical research with mirtazapine, undesirable effects have not been reported more often in elderly patients than in other age groups (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration).

Paediatric use (children and adolescents (< 18 years of age).

Mirtazapine should not be used to treat children or adolescents under the age of 18 years. Suicide-related behaviors (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behavior and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken; the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioral development are lacking.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

Mirtazapine is extensively metabolised by CYP2D6 (resulting in the 8-hydroxy metabolite) and CYP3A4 (N-demethyl and N-oxide metabolites) and to a lesser extent by CYP1A2. An interaction study with healthy volunteers showed no influence of paroxetine, a CYP2D6 inhibitor, on mirtazapine pharmacokinetics in steady state.
Coadministration of the potent inhibitor of CYP3A4, ketoconazole, in healthy male volunteers increased mirtazapine peak plasma concentration levels and AUC by approximately 40% and 50% respectively. Caution is needed when strong CYP3A4 inhibitors, such as the HIV protease inhibitors, azole antifungals, ketoconazole, erythromycin and nefazodone are co-administered with mirtazapine.
When cimetidine (weak inhibitor of CYP1A2, CYP2D6 and CYP3A4) is administered with mirtazapine, the mean plasma concentration of mirtazapine may increase more than 50%. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started or increased when cimetidine treatment is ended. Caution should be exercised and the dose may have to be decreased when co-administering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, ketoconazole, erythromycin, cimetidine or nefazodone.
Carbamazepine and phenytoin, inducers of CYP3A4, increased mirtazapine clearance about twofold, resulting in a decrease in mirtazapine plasma levels of 45-60%. When carbamazepine, phenytoin or another inducer of drug metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with an inducer is stopped, mirtazapine dose may have to be decreased.
In in-vivo interaction studies, mirtazapine did not influence the pharmacokinetics of paroxetine (CYP2D6 substrates), carbamazepine or phenytoin (CYP3A4 inducers), amitriptyline or cimetidine.
In a mirtazapine and lithium interaction study, the steady state pharmacokinetics of lithium were not affected by coadministration of a single oral dose of 30 mg of mirtazapine. Correspondingly, the single dose pharmacokinetics of mirtazapine were not affected by the lithium steady state.

Pharmacodynamic interactions.

Mirtazapine should not be administered concomitantly with MAO inhibitors or within two weeks after discontinuation of MAO inhibitor therapy. In the opposite way about two weeks should pass before patients treated with mirtazapine should be treated with MAO inhibitors (see Section 4.3 Contraindications). In addition, as with SSRIs, co-administration with other serotonergic active substances (L-tryptophan, triptans, tramadol, linezolid, SSRIs, venlafaxine, lithium and St. John's Wort - Hypericum perforatum - preparations) may lead to an incidence of serotonin associated effects (see Section 4.4 Special Warnings and Precautions for Use). Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine.
Mirtazapine may potentiate the sedative effects of benzodiazepines and other sedatives (especially antipsychotics, antihistamine H1 antagonists, opioids). Caution should be taken when these drugs are prescribed together with mirtazapine.
Mirtazapine may potentiate the central nervous dampening action of alcohol; patients using mirtazapine should therefore be advised to avoid alcohol during tasks which require concentration and alertness.
Mirtazapine dosed at 30 mg daily caused a small but statistically significant increase of the INR in subjects treated with warfarin. Both at continuing stable doses and higher doses of mirtazapine, a more pronounced effect cannot be excluded. It is advisable to monitor the prothrombin time more carefully in case of concomitant treatment of warfarin with mirtazapine.
From post-marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with mirtazapine in combination with SSRIs or venlafaxine. If the combination is considered therapeutically necessary, dosage changes should be made with caution and there should be adequate close monitoring for early signs of serotonergic overstimulation.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg [ca. 20 times the recommended human dose of 45 mg on a mg/m2 basis]. The drug did not affect mating and conception, but oestrus cycling was disrupted at doses that were 3 or more times the recommended human dose of 45 mg on a mg/m2 basis.
(Category B3)
There are insufficient clinical data to assess the possible effect of mirtazapine on pregnancy.
Oral dosing of pregnant rats with mirtazapine at 100 mg/kg/day was associated with a reduction in survival of the offspring, and an increased incidence of post-natal mortality. Mirtazapine was not teratogenic in rats at these dose levels, or in rabbits at oral doses up to 40 mg/kg/day.
Although studies in animals have not shown any teratogenic effects of toxicological significance the safety of mirtazapine in human pregnancy has not been established. Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to mirtazapine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).
Mirtazapine should be used during pregnancy only if it is clearly needed. Women of child-bearing potential should employ an adequate method of contraception if taking mirtazapine.
Australian categorisation definition of Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
 Although animal experiments show that mirtazapine is excreted only in very small amounts in the milk, post natal mortality was increased when lactating rats were given mirtazapine orally at 100 mg/kg/day. The use of mirtazapine in breast-feeding mothers is not recommended since no human data in breast milk are available.

4.7 Effects on Ability to Drive and Use Machines

Mirtazapine may impair concentration and alertness (more commonly in the initial phase of treatment). Patients treated with mirtazapine should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the treatment does not affect them adversely.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Depressed patients display a number of symptoms that are associated with the illness itself. It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with mirtazapine. See Table 1.

Post-marketing reports.

Skin and subcutaneous tissue disorders.

Stevens-Johnson syndrome, dermatitis bullous, erythema multiforme, toxic epidermal necrolysis, rash (including erythematous and maculopapular), rare cases of increased sweating, alopecia, pruritus and urticaria; drug reaction with eosinophilia and systemic symptoms (DRESS) (frequency not known).

Musculoskeletal connective tissue and bone disorders.

Arthralgia, myalgia, rhabdomyolysis.

Nervous system disorders.

Lethargy, dysarthria, amnesia, serotonin syndrome, somnolence (i.e. drowsiness sedation), impaired concentration, dizziness, paraesthesia, headache, hyperkinesia, rare cases of; cerebrovascular disorder, convulsions, tremor and myoclonus, movement disorders.** Very rare cases of oral paraesthesia.

Psychiatric disorders.

Suicidal ideation***, suicidal behaviour***, confusion, agitation, aggression, paroniria, less common or rare occurrences of; nightmares/vivid dreams, hallucination, mania, depression, anxiety*, insomnia* and psychomotor restlessness** and somnambulism.

Gastrointestinal disorders.

Nausea, diarrhoea, dry mouth, less common or rare cases of stomatitis, very rare cases of oral hypoaesthesia and mouth oedema.

Hepatobiliary disorders.

Hepatic function abnormal, elevated hepatic enzymes or transaminases, rare cases of jaundice, hepatitis.

Metabolism and nutrition disorders.

Hyponatraemia, increased appetite, rare cases of hypercholesterolaemia, hyperlipidaemia.

Cardiac disorders.

Tachycardia, palpitations, rare; arrhythmia, myocardial infarction, chest pain.

Vascular disorders.

Dependent oedema, hypertension, orthostatic hypotension, rare cases of thromboembolic disorder, pulmonary embolism.

Blood and lymphatic system disorders.

Leukopenia, granulocytopoenia, rare cases of agranulocytosis, (see Section 4.4 Special Warnings and Precautions for Use), rare cases of thrombocytopenia, pancytopenia, anaemia, aplastic anaemia, eosinophilia and coagulation disorder.

Endocrine disorders.

Hyperprolactinaemia (and related symptoms e.g. galactorrhea and gynaecomastia).

Renal and urinary disorders.

Rare cases of urinary retention.

Reproductive system and breast disorders.

Priapism.

General disorders and administration site conditions.

Oedema including generalised, peripheral and face oedema; fatigue/asthenia, rare cases of pyrexia, syncope, chest pain and drug withdrawal symptoms.

Investigations.

Weight gain.

Eye disorders.

Very rare cases of glaucoma.
* Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression) can develop or become aggravated. Under mirtazapine treatment, development or aggravation of anxiety and insomnia has been reported very rarely.
** Including akathisia, hyperkinesia.
*** Cases of suicidal ideation and suicidal behaviours have been reported during mirtazapine therapy or early after treatment discontinuation (see Section 4.4 Special Warnings and Precautions for Use).

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.

4.9 Overdose

Post-marketing experience concerning overdose with mirtazapine alone indicates that symptoms are usually mild. The symptoms of overdose are an exaggeration of the pharmacological action of mirtazapine and may include symptoms such as dizziness, impaired consciousness (confusion, disorientation, stupor, coma), agitation, tremor, tachycardia and hyper- and hypotension. As with all overdose attempts, the possibility of multiple drug ingestion should be borne in mind. As with antidepressants in general, serious outcomes, including fatalities, are possible at dosages much higher than the therapeutic dose, especially with mixed overdoses.

Overdose management.

Cases of overdose should receive appropriate symptomatic and supportive therapy for vital functions.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mirtazapine is an antidepressant, which can be given as treatment for episodes of major depression. Mirtazapine is an antagonist of central α2-auto and hetero-adrenoceptors which causes an increase in both noradrenaline and serotonin release. The effect of released serotonin is exerted specifically via 5-HT1 type receptors, because 5-HT2 and 5-HT3 type receptors are specifically blocked by mirtazapine. Mirtazapine is accordingly a noradrenergic and specific serotonergic antidepressant. The α2, 5-HT2 and 5-HT3 antagonistic effects all contribute to the antidepressant profile of mirtazapine. The presentation of mirtazapine is as a racemate. The two enantiomers contribute differently to its pharmacological profile. The α2 and 5-HT2 receptor blocking activity is contained in the (S)+ enantiomer, whereas the 5-HT3 receptor blocking activity is contained in the (R)-enantiomer. The presence of both enantiomers is therefore considered to be essential for the antidepressant activity of mirtazapine. In one study, there was no efficacy difference indicated between the two enantiomers, despite their different receptor affinities.
Mirtazapine is generally well tolerated. The histamine H1-antagonistic activity of mirtazapine may cause a degree of sedation in the first weeks of treatment. It has practically no anticholinergic activity.
Mirtazapine has been associated with acute postural hypotension in healthy volunteer studies but this occurred rarely in patient studies (see Section 4.8 Adverse Effects (Undesirable Effects)).

Clinical trials.

Several placebo-controlled double-blind studies have demonstrated that mirtazapine is statistically significantly more effective than placebo in the short term treatment of a major depressive episode; the efficacy is maintained during continuation treatment with mirtazapine.

Active controlled studies.

The efficacy of mirtazapine has been found to be comparable to several standard antidepressant agents (amitriptyline, doxepin, clomipramine). In addition, eleven 6 or 8 week studies and a 24 week study have been performed in moderately to severely depressed patients in which efficacy and tolerability of mirtazapine were compared to SSRIs (4 vs fluoxetine, 3 vs paroxetine, 2 vs sertraline, 2 vs fluvoxamine and 1 vs citalopram). The primary efficacy parameters in these studies were:
change from baseline on HAM-D total score (Hamilton depression rating scale, 17 items). 7 studies;
proportion or number of HAM-D 50% responders. 3 studies;
change from baseline on MADRAS total score (Montgomery-Asberg depression rating scale, 10 items). 1 study;
VAMRS 6 items (Visual Analogue Mood Rating Scale). 1 study. Change in HAM-D (12 items) total score was a secondary parameter in this study.
On an intention-to-treat basis, a total of 1402 patients were treated with mirtazapine and 1405 patients were treated with the comparator. In all 12 studies, mirtazapine proved to be at least comparable in efficacy to the SSRIs. In 11 of these studies, statistically significant greater reductions in HAM-D or MADRS total scores and more responders were observed in the mirtazapine groups at one or more timepoints in the first 4 weeks.
A meta-analysis of these 12 studies provides further comparison of the onset of efficacy of mirtazapine relative to the SSRIs studied. The primary efficacy parameter for this meta-analysis was time to first 50% reduction on recalculated HAM-D total score (17 items) or recalculated MADRS total score (10 items). There were also a number of secondary parameters which are identified in Tables 2 and 3. Table 2 provides an analysis of the relative event rates (estimated hazard ratios) for various depression parameters limited to the first 3 treatment weeks for the occurrence of the event and the entire 6-8 week study period to define whether the event was sustained or not. The increased hazard ratios demonstrate that the probability at any time t of first response (50% or more score reduction), remission, sustained response or sustained remission was consistently and significantly greater among mirtazapine-treated than SSRI-treated patients, indicating an earlier onset of efficacy. The statistically earlier onset of action observed with mirtazapine may not necessarily translate in to a meaningful clinical benefit for an individual patient. Table 3 presents the proportions of HAM-D responders and HAM-D/MADRS remitters at the various time points during treatment. At most time points there were significantly more responders and remitters among mirtazapine-treated patients than among SSRI-treated patients.
Some secondary parameter results have been excluded from Table 3. These were number of:
50% Bech responders;
50% HAM-D Factor I 'anxiety/somatisation' responders;
50% HAM-D Factor V 'retardation' responders;
50% HAM-D Factor VI 'sleep disturbance' responders HAM-D item 'depressed mood' responders (=0 or < 2);
HAM-D item 'suicide' or MADRS item 'suicidal thoughts' (=0 or < 2);
Statistically significant differences favouring mirtazapine were observed for HAM-D factors V and VI at week 1 to 6 timepoints. Statistically significant differences favouring mirtazapine were observed for HAM-D factor I at week 1 to 4 timepoints. A statistically significant difference was observed in favour of mirtazapine for Bech responders at the week 2 timepoint. There were no other statistically significant differences.
An eight-week comparative study was performed to compare the antidepressant efficacy and tolerability of mirtazapine and venlafaxine in the treatment of 157 hospitalised patients with severe depression with melancholic features (HAM-D total score > 25). In this study, mirtazapine and venlafaxine were equally effective in reducing symptoms of depression and improving quality of life during treatment.

Long-term maintenance of efficacy and relapse prevention.

The long term maintenance of antidepressant efficacy of mirtazapine was originally established in three active-controlled and active/placebo-controlled studies with treatment periods up to 24 months (amitriptyline as active). Long term maintenance of efficacy was also confirmed in extension phases of 3 SSRI comparator studies, a 24 week paroxetine comparator study and 1 venlafaxine comparator study. Additionally, a multicentre, long-term, double-blind, placebo-controlled study of relapse prevention in male and female outpatients diagnosed with moderate to severe recurrent major depression (Protocol 003041) was performed. In the initial open-label phase of the study, 421 patients were treated with mirtazapine for 8-12 weeks. Patients remitting after 8-12 weeks were randomised into the 40-week, double blind, relapse prevention phase of the study. The remitted patients were randomised to either mirtazapine at the final titrated dose they received during the open-label phase or placebo (79 to APX-Mirtazapine 81 to placebo). The results of the trial showed that mirtazapine reduced the risk of relapse by more than half (15/76=19.7% relapsed on mirtazapine versus 35/80=43.8% relapsed on placebo, p = 0.001). The treatment was well-tolerated with dropouts due to adverse events being 11.4% (9/79) from the mirtazapine group and 2.5% (2/81) from the placebo group. Further discontinuation details are summarised below in Table 4.

Elderly.

The efficacy and tolerability in elderly patients was investigated in three randomised controlled trials. In two six-week trials with a total of 270 patients aged over 55 years (mean age 70 and 62 years respectively), mirtazapine was at least as effective as amitriptyline and all treatments were well tolerated. In an eight-week study in 255 patients aged 65 and over (mean age 72 years) comparing mirtazapine with paroxetine, mean HAM-D scores were similar at end-point but lower for mirtazapine in the first 3 weeks, although only at day 14 was the difference statistically significant. Total discontinuation rates were similar (22.7% for mirtazapine versus 31.0% for paroxetine), although discontinuation due to adverse events was lower with mirtazapine than paroxetine (14.8% versus 26.2%) and discontinuation due to lack of efficacy higher (3.9% versus 0%).

5.2 Pharmacokinetic Properties

Absorption.

After oral administration of mirtazapine tablets, the active substance mirtazapine is rapidly and well absorbed (bioavailability approximately equal to 50%), reaching peak plasma levels after about 2 hours. Food intake has no clinically significant influence on the pharmacokinetics of mirtazapine.

Distribution.

Binding of mirtazapine to plasma proteins is approx. 85%. The half-life of elimination ranged from 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and shorter half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-6 days, after which there is no further accumulation.
Mirtazapine displays linear pharmacokinetics within the recommended dose range.

Metabolism.

In vitro data from human liver microsomes indicate that cytochrome P450 enzymes CYP 2D6 and CYP 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP 3A4 is considered to be responsible for the formation of the N-demethyl and N-oxide metabolites.
The presentation of mirtazapine is as a racemate. It is not known whether first pass extraction of the drug is stereoselective but it is known that the clearance of the two enantiomers is by different metabolic processes.

Excretion.

Mirtazapine is extensively metabolized and its metabolites are eliminated via the urine and faeces within four days. Major pathways of biotransformation are demethylation and oxidation, followed by conjugation. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound.

Special populations.

Renal and/or hepatic impairment.

The clearance of mirtazapine may be decreased as a result of renal or hepatic insufficiency.
Mirtazapine is substantially excreted by the kidney (75%) and the risk of decreased clearance of this drug is greater in patients with impaired renal function, see Section 4.2 Dose and Method of Administration.

Geriatric.

The recommended dosage regimen is the same as for adults. Increases should be monitored carefully, see Section 4.2 Dose and Method of Administration.

Children and adolescents.

The safety and effectiveness of mirtazapine has not been established in children and adolescents and therefore should not be prescribed in these patient groups, see Section 4.4 Special Warnings and Precautions for Use.

Sex.

The half-life of elimination of mirtazapine ranged from 20-40 hours, longer half-lives up to 65 hours have occasionally been recorded and shorter half-lives have been seen in young men.

Race.

There is no information available regarding the effect of race on the pharmacokinetics of mirtazapine.

5.3 Preclinical Safety Data

Genotoxicity.

Mirtazapine was not genotoxic in a series of tests for gene mutation and chromosomal and DNA damage.

Carcinogenicity.

An eighteen month carcinogenicity study in mice showed an increase in the development of hepatic tumours in males after mirtazapine treatment at oral doses of 20 mg/kg/day and above. In a two year carcinogenicity study in rats, oral doses of mirtazapine greater than 20 mg/kg/day were associated in males with an increased incidence of thyroid follicular cell adenomas and carcinomas.
Since the only tumours found in carcinogenicity studies with mice and rats were considered to be species-specific, non-genotoxic responses associated with long term treatment with hepatic enzyme inducers, mirtazapine is not expected to possess carcinogenic potential at therapeutic dosages in the clinic.

6 Pharmaceutical Particulars

6.1 List of Excipients

APX-Mirtazapine tablets contain the following inactive ingredients: lactose monohydrate, hyprolose, maize starch, colloidal anhydrous silica and magnesium stearate.
15 mg tablet also contains Opadry Complete Film Coating System 20A2052560 Yellow.
30 mg tablet also contains Opadry Complete Film Coating System 20A56788 Brown.
45 mg tablet also contains Opadry Complete Film Coating System 20A58806 White.

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

APX-Mirtazapine 15, 30 and 45 (15, 30 and 45 mg mirtazapine) are presented in pack sizes of 30 and 60 tablets in PVC/PVdC-Aluminium foil blister strips. Each blister strip contains 10 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Mirtazapine is a tetracyclic piperazinoazepine analogue of mianserin, a chemical structure unrelated to tricyclic antidepressants, monoamine oxidase inhibitors or selective serotonin reuptake inhibitors. Mirtazapine is a white or almost white powder, hygroscopic. It is freely soluble in anhydrous ethanol and practically insoluble in water.

Chemical structure.

The name of the medicine is mirtazapine.

Chemical name.

(14bRS)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino [2,1-a] pyrido [2,3-c][2] benzazepine.
Molecular Formula: C17H19N3. Molecular Weight: 265.4.

CAS number.

[85650-52-8].

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription only medicine).

Summary Table of Changes