Mirtazapine 30mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Mirtazapine
Available from:
Genesis Pharmaceuticals Ltd
ATC code:
N06AX11
INN (International Name):
Mirtazapine
Dosage:
30mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: ; GTIN: 5060014442536

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MIRTAZAPINE OLS 30mg

FILM-COATED TABLETS

(Package leaflet EN)

Description

Customer

2018-04-11

Date

Grasshopper Sistemas de Informação

geral@gsiportugal.com

www.gsiportugal.com

AW.CRC.164.03.V08

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In this leaflet

What Mirtazapine Tablets is and what it is used for

What you need to know before you take Mirtazapine Tablets

How to take Mirtazapine Tablets

Possible side effects

How to store Mirtazapine Tablets

Contents of the pack and other information

1. WHAT MIRTAZAPINE TABLETS IS AND WHAT IT IS USED

FOR

Mirtazapine 30mg Tablets contain the active substance, mirtazapine.

Mirtazapine is one of a group of medicines called antidepressants.

Depression is linked to a shortage of substances which carry messages in

the brain (including serotonin and noradrenaline). Mirtazapine helps to

relieve the shortage of these 'brain messages'. Common signs of depression

include feelings of worthlessness or deep sadness; difficulty with everyday

tasks; sleeping too much or not being able to sleep; feeling anxious; and

changes in appetite.

It may take 2 to 4 weeks before you start to feel better and sleep better. It is

important to take your medicine every day and not to stop taking it unless

your doctor tells you to. If you do, your symptoms may come back.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE

MIRTAZAPINE TABLETS

DO NOT TAKE Mirtazapine 30mg Tablets:

if you are allergic to mirtazapine or any of the other ingredients of

Mirtazapine 30mg Tablets

if you are taking or have recently taken (within the last two weeks)

medicines called monoamine oxidase inhibitors (MAOIs)

Warnings and precautions

Children and adolescents

Mirtazapine 30mg Tablets should normally not be used for children and

adolescents under 18 years because efficacy was not demonstrated.

Patients under 18 have an increased risk of side effects such as suicide

attempt, suicidal thoughts and hostility (predominantly aggression,

oppositional (defiant) behaviour and anger) when they take this class of

medicines. Despite this, your doctor may prescribe Mirtazapine 30mg

Tablets for patients under 18 because he/she decides that this is in their best

interests. If your doctor has prescribed Mirtazapine 30mg Tablets for a

patient under 18 and you want to discuss this, please go back to your doctor.

You should inform your doctor if any of the symptoms listed above develop

or worsen when patients under 18 are taking Mirtazapine 30mg Tablets. The

long-term safety effects concerning growth, maturation and cognitive and

behavioural development of Mirtazapine 30mg Tablets in this age group

have not yet been demonstrated. In addition, significant weight gain has

been observed in this age category more often when treated with

mirtazapine compared with adults.

Thoughts of suicide and worsening of your depression or anxiety

disorder

If you are depressed and/or have anxiety disorders you can sometimes have

thoughts of harming or killing yourself. These may be increased when first

starting antidepressants, since these medicines all take time to work, usually

about two weeks but sometimes longer.

You may be more likely to think like this:

if you have previously had thoughts about killing or harming yourself

if you are a young adult. Information from clinical trials has shown an

increased risk of suicidal behaviour in adults aged less than 25 years

with psychiatric conditions who were treated with an antidepressant.

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

doctor or go to a hospital straight away.

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

depressed or have an anxiety disorder, and ask them to read this leaflet. You

might ask them to tell you if they think your depression or anxiety is getting

worse, or if they are worried about changes in your behaviour.

Take special care with Mirtazapine 30mg Tablets and tell your doctor if

you have or have had:

epilepsy (seizures or fits)

liver disease (including jaundice)

kidney disease

heart disease

low blood pressure

difficulty in passing water (urinating), which may be caused by an

enlarged prostate

an eye disorder called glaucoma or increased pressure in the eye

diabetes

psychiatric disorders such as schizophrenia or manic depression,

delirium or senile dementia

an intolerance to some sugars, as this medicine contains lactose

Other medicines and Mirtazapine 30mg Tablets

Please tell your doctor or pharmacist if you are taking or have recently taken

any other medicines, including medicines obtained without a prescription.

DO NOT TAKE Mirtazapine 30mg Tablets if you are taking:

other antidepressants known as Monoamine Oxidase Inhibitors (MAOIs)

e.g. moclobemide, tranylcypromine and selegiline. Do not take

Mirtazapine 30mg Tablets during the two weeks after you have stopped

taking MAOIs. Do not take MAOIs until at least 2 weeks after stopping

Mirtazapine 30mg Tablets.

Take care when taking Mirtazapine 30mg Tablets with any of the

following medicines:

erythromycin, used to treat bacterial infections

certain medicines to treat fungal infections, e.g. ketoconazole

linezolid, used to treat pneumonia

rifampicin, used to treat tuberculosis

medicines for treating HIV/AIDS (e.g. HIV-protease inhibitors)

certain antidepressants, e.g. venlafaxine, L-Tryptophan, lithium and St

John's wort (can lead to the development of serotonin syndrome and

should be used with caution)

nefazodone, an antidepressant

medicines for schizophrenia (antipsychotics) e.g. olanzapine

medicines for treating anxiety or insomnia e.g. benzodiazepines

medicines for treating epilepsy (e.g. carbamazepine and phenytoin)

triptans, used to treat severe headache

tramadol, a painkiller

medicines for severe pain, e.g. morphine

medicines to treat allergies (antihistamines) e.g. cetirizine

cimetidine, a medicine used for the treatment of indigestion or stomach

ulcers

medicines to prevent blood clotting e.g. warfarin

Mirtazapine 30mg Tablets with food and drink

You may get drowsy if you drink alcohol while you are taking this medicine. It

is therefore advisable to avoid drinking any alcohol. You can take

Mirtazapine 30mg Tablets with or without food.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Limited experience with mirtazapine administration to pregnant women does

not indicate an increased risk. However, caution should be exercised when

used during pregnancy. If you use Mirtazapine 30mg Tablets until, or shortly

before birth, your baby should be supervised for possible adverse effects.

Make sure your midwife and/or doctor know you are on Mirtazapine 30mg

Tablets. When taken during pregnancy, similar drugs (SSRIs) may increase

the risk of a serious condition in babies, called persistent pulmonary

hypertension of the newborn (PPHN), making the baby breathe faster and

appear bluish. These symptoms usually begin during the first 24 hours after

the baby is born. If this happens to your baby you should contact your

midwife and/or doctor immediately.

Driving and using machines

Antidepressants can affect your concentration or judgement. When you first

start taking Mirtazapine 30mg Tablets, make sure your abilities are not

affected before you drive or operate machinery.

Mirtazapine 30mg Tablets contain lactose

If you have been told by your doctor that you have an intolerance to some

sugars, contact your doctor before taking this medicinal product.

3. HOW TO TAKE MIRTAZAPINE TABLETS

The tablets should be swallowed whole without chewing and with plenty of

fluid.

Dosage

Adults

The usual starting dose is 15mg or 30mg, taken preferably in the evening.

Your doctor may advise you to increase your dose after a few days to the

amount that may be best for you.

After 2 to 4 weeks, talk to your doctor about the effect the treatment has had.

If you still don't feel well, your doctor may prescribe a higher dose. After

another 2 to 4 weeks talk to your doctor again.

If you have the impression that the effect of Mirtazapine 30mg Tablets is too

strong or too weak, talk to your doctor or pharmacist.

Your doctor will probably advise you to take Mirtazapine 30mg Tablets as a

single dose before you go to bed, as it may help you to sleep. However, your

doctor may suggest you split your dose – for example one tablet in the

morning, and another in the evening before you go to bed.

PATIENT INFORMATION LEAFLET

MIRTAZAPINE 30mg

TABLETS

Mirtazapine

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

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

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

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

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MIRTAZAPINE OLS 30mg

FILM-COATED TABLETS

(Package leaflet EN)

Description

Customer

2018-04-11

Date

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www.gsiportugal.com

AW.CRC.164.03.V08

Code

Children

Mirtazapine 30mg Tablets are not recommended for use in children or

adolescents (under the age of 18).

Elderly people

Mirtazapine 30mg Tablets can be taken by elderly patients, any dose

changes will be done, under the close supervision by your doctor.

People with kidney or liver problems

Patients with kidney or liver problems may be given a lower dose of this

medicine.

If you take more of your medicine than you should

Call a doctor straight away or go immediately to the nearest casualty

department, taking the remaining tablets with you. The most likely signs of

overdose are drowsiness, disorientation and increased heart rate.

If you forget to take your medicine

Do not take a double dose to make up for a forgotten dose. Just skip that

dose and take your next one at the normal time.

If you stop taking your medicine

Do not suddenly stop taking Mirtazapine 30mg Tablets even if your

depression has lifted. If you stop suddenly, you may feel sick, anxious or

agitated and have headaches. It is possible that some of your symptoms

may come back.

Once you are feeling better, talk to your doctor who will tell you how to

reduce the dose gradually. This will usually be about 4 to 6 months after you

start feeling better.

4. POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not

everybody gets them.

If you experience any of the following serious side effects, stop taking

mirtazapine and tell your doctor immediately.

Uncommon (may affect up to 1 in 100 people):

feeling elated or emotionally 'high' (mania)

Rare (may affect up to 1 in 1,000 people):

yellow colouring of eyes or skin; this may suggest disturbance in liver

function (jaundice)

Not known (frequency cannot be estimated from the available data):

signs of infection such as sudden unexplainable high fever, sore throat

and mouth ulcers agranulocytosis). In rare cases mirtazapine can cause

disturbances in the production of blood cells (bone marrow depression).

Some people become less resistant to infection because mirtazapine

can cause a temporary shortage of white blood cells (granulocytopenia).

In rare cases mirtazapine can also cause a shortage of red and white

blood cells, as well as blood platelets (aplastic anemia), a shortage of

blood platelets (thrombocytopenia) or an increase in the number of white

blood cells (eosinophilia).

epileptic attack (convulsions)

a combination of symptoms such as inexplicable fever, sweating,

increased heart rate, diarrhoea, uncontrollable muscle contractions,

shivering, overactive reflexes, restlessness, mood changes,

unconsciousness and increased salivation. In very rare cases these can

be signs of serotonin syndrome

thoughts of harming or killing yourself

severe skin reactions (Stevens-Johnson Syndrome, toxic epidermal

necrolysis)

Other possible side effects with mirtazapine are:

Very common (may affect more than 1 in 10 people):

increase in appetite and weight gain

drowsiness or sleepiness

headache

dry mouth

Common (may affect up to 1 in 10 people):

lethargy

dizziness

shakiness or tremor

nausea

diarrhoea

vomiting

rash or skin eruptions (exanthema)

pain in your joints (arthralgia) or muscles (myalgia)

back pain

feeling dizzy or faint when you stand up suddenly (orthostatic

hypotension)

swelling (typically in ankles or feet) caused by fluid retention (oedema)

tiredness

vivid dreams

confusion

feeling anxious

sleeping problems

Uncommon (may affect up to 1 in 100 people):

abnormal sensation in the skin e.g. burning, stinging, tickling or tingling

(paraesthesia)

restless legs

fainting (syncope)

sensations of numbness in the mouth (oral hypoaesthesia)

low blood pressure

nightmares

feeling agitated

hallucinations

urge to move

Rare (may affect up to 1 in 1,000 people):

muscle twitching or contractions (myoclonus)

aggression

abdominal pain and nausea; this may suggest inflammation of the

pancreas (pancreatitis)

Not known (frequency cannot be estimated from the available data):

abnormal sensations in the mouth (oral paraesthesia)

swelling in the mouth (mouth oedema)

swelling throughout the body (generalized oedema)

localized swelling

hyponatraemia

inappropriate anti-diuretic hormone secretion

severe skin reactions (dermatitis bullous, erythema multiforme)

sleep walking (somnambulism)

speech disorder

Additional side effects in children and adolescents

In children under 18 years the following adverse events were observed

commonly in clinical trials: significant weight gain, hives and increased blood

triglycerides.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes

any possible side effects not listed in this leaflet. You can also report side

effects directly via Yellow Card Scheme Website:

www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety

of this medicine.

5. HOW TO STORE MIRTAZAPINE TABLETS

KEEP THIS MEDICINE OUT OF THE SIGHT AND REACH OF CHILDREN

Do not use this medicine after the expiry date which is stated on the

packaging. The expiry date refers to the last day of that month.

Store in the original package in order to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask

your pharmacist how to throw away medicines you no longer use. These

measures will help protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Mirtazapine 30mg Tablets contain

Each film-coated tablet contains 30mg of the active substance mirtazapine.

The other ingredients are lactose monohydrate, pregelatinised maize starch,

anhydrous colloidal silica, croscarmellose sodium, magnesium stearate,

hypromellose, macrogol 8000, titanium dioxide (E171), yellow iron oxide

(E172) and red iron oxide (E172).

What Mirtazapine 30mg Tablets look like and contents of the pack

Mirtazapine 30mg Tablets are brownish, oval, biconvex, film-coated tablets,

scored on both sides and marked with I on one side.

The tablets are supplied in blister packs of 28 film-coated tablets.

Marketing Authorisation Holder

Cadila Pharmaceuticals (Europe) Limited, The Pavilion, 56 Rosslyn

Crescent, Harrow, Middlesex, HA1 2SZ, UK

Manufacturer responsible for batch release

Kent Pharmaceuticals Limited, Crowbridge Road, Ashford, Kent, TN24 0GR,

U.K.

Kent Pharmaceuticals Limited, Repton Road, Measham, DE12 7DT, U.K.

Distributor

Crescent Pharma Limited, Polhampton Lane, Overton, Hampshire RG25

3ED, UK

Product Licence Number: PL 45841/0023

This leaflet was revised in April 2014.

Read the complete document

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Mirtazapine 30mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Mirtazapine 30mg film-coated tablet contains 30mg of mirtazapine.

Excipient with known effect:

Each Mirtazapine 30mg film-coated tablet contains 203.6mg lactose (as

monohydrate).

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Tablet, film coated.

Brownish, scored on both sides, oval, biconvex, film-coated tablets. Marked with “I”

on one side. The tablet can be divided into equal doses.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

Treatment of episodes of major depression.

4.2

Posology and method of administration

Posology

Adults

The effective daily dose is usually between 15mg and 45mg; the starting dose

is 15mg or 30mg. 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.

Patients with depression should be treated for a sufficient period of at least 6

months to ensure that they are free from symptoms.

It is recommended to discontinue treatment with mirtazapine gradually to

avoid withdrawal symptoms (see section 4.4).

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.

Paediatric population

Mirtazapine tablets should not be used in children and adolescents under the

age of 18 years (see section 4.4) as efficacy was not demonstrated in two

short-term clinical trials (see section 5.1) and because of safety concerns (see

sections 4.4, 4.8 and 5.1)..

Renal impairment

The clearance of mirtazapine may be decreased in patients with moderate to

severe renal impairment (creatinine clearance <40 ml/min). This should be

taken into account when prescribing Mirtazapine tablets to this category of

patients (see section 4.4).

Hepatic impairment

The clearance of mirtazapine may be decreased in patients with hepatic

impairment. This should be taken into account when prescribing Mirtazapine

tablets to this category of patients, particularly with severe hepatic impairment,

as patients with severe hepatic impairment have not been investigated (see

section 4.4).

Method of administration

Mirtazapine has an elimination half-life of 20-40 hours and therefore

Mirtazapine tablets are suitable for once daily administration. It should be

taken preferably as a single night-time dose before going to bed. Mirtazapine

tablets may also be given in two divided doses (once in the morning and once

at night-time, the higher dose should be taken at night).

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

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in

section 6.1.

Concomitant use of mirtazapine with monoamine oxidase (MAO) inhibitors

(see section 4.5).

4.4

Special warnings and precautions for use

Paediatric population

Mirtazapine should not be used in the treatment of children and adolescents

under the age of 18 years. Suicide-related behaviours (suicide attempt and

suicidal thoughts), and hostility (predominantly aggression, oppositional

behaviour and anger) were more frequently observed in clinical trials among

children and adolescents treated with antidepressants compared to those

treated with placebo. If, based on clinical need, a decision to treat is

nevertheless taken, the patient should be carefully monitored for the

appearance of suicidal symptoms. In addition, long-term safety data in

children and adolescents concerning growth, maturation and cognitive

behavioural development are lacking.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm

and suicide (suicide-related events). This risk persists until significant

remission occurs. As improvement may not occur during the first few weeks

or more of treatment, patients should be closely monitored until such

improvement occurs. It is general clinical experience that the risk of suicide

may increase in the early stages of recovery.

Patients with a history of suicide-related events, or those exhibiting a

significant degree of suicidal ideation prior to commencement of treatment are

known to be at greater risk of suicidal thoughts or suicide attempts, and should

receive careful monitoring during treatment. A meta-analysis of placebo-

controlled clinical trials of antidepressants in adult patients with psychiatric

disorders showed an increased risk of suicidal behaviour with antidepressants

compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should

accompany therapy with antidepressants especially in early treatment and

following dose changes. Patients (and caregivers of patients) should be alerted

about the need to monitor for any clinical worsening, suicidal behaviour or

thoughts and unusual changes in behaviour and to seek medical advice

immediately if these symptoms present.

With regard to the chance of suicide, in particular at the beginning of

treatment, only the smallest amount of mirtazapine should be given to the

patient consistent with good patient management, in order to reduce the risk of

overdose.

Bone marrow depression

Bone marrow depression, usually presenting as granulocytopenia or

agranulocytosis, has been reported during treatment with mirtazapine.

Reversible agranulocytosis has been reported as a rare occurrence in clinical

studies with mirtazapine. In the postmarketing period with mirtazapine very

rare cases of agranulocytosis have been reported, mostly reversible, but in

some cases fatal. Fatal cases mostly concerned patients with an age above 65.

The physician should be alert for symptoms like fever, sore throat, stomatitis

or other signs of infection; when such symptoms occur, treatment should be

stopped and blood counts taken.

Jaundice

Treatment should be discontinued if jaundice occurs.

Conditions which need supervision

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

with:

epilepsy and organic brain syndrome: Although clinical experience

indicates that epileptic seizures are rare during mirtazapine treatment, as

with other antidepressants, 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.

hepatic impairment: Following a single 15 mg oral dose of mirtazapine,

the clearance of mirtazapine was approximately 35% decreased in mild to

moderate hepatically impaired patients, compared to subjects with normal

hepatic function. The average plasma concentration of mirtazapine was

about 55% increased.

renal impairment: Following a single 15 mg oral dose of mirtazapine, in

patients with moderate (creatinine clearance <40 ml/min) and severe

(creatinine clearance

10 ml/min) renal impairment the clearance of

mirtazapine was about 30% and 50% decreased respectively, compared to

normal subjects. The average plasma concentration of mirtazapine was

about 55% and 115% increased respectively. No significant differences

were found in patients with mild renal impairment (creatinine clearance

<80 ml/min) as compared to the control group.

cardiac diseases like conduction disturbances, angina pectoris and recent

myocardial infarction, where normal precautions should be taken and

concomitant medicines carefully administered.

low blood pressure.

diabetes mellitus: In patients with diabetes, antidepressants may alter

glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to

be adjusted and close monitoring is recommended.

Like with other antidepressants, the following should be taken into account:

Worsening of psychotic symptoms can occur when antidepressants are

administered to patients with schizophrenia or other psychotic

disturbances; paranoid thoughts can be intensified

When the depressive phase of 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.

Although 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 realized that these symptoms may be

related to the underlying disease. As advised in section 4.2, it is

recommended to discontinue treatment with mirtazapine gradually.

Care should be taken in patients with micturition disturbances like prostate

hypertrophy and in patients with acute narrow-angle glaucoma and

increased intra-ocular pressure (although there is little chance of problems

with mirtazapine because of its very weak anticholinergic activity).

Akathisia/psychomotor restlessness: The use of antidepressants have been

associated with the development of akathisia, characterised 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.

Cases of QT prolongation, Torsade de Pointes, ventricular tachycardia, and

sudden death, have been reported during the post-marketing use of

mirtazapine. The majority of reports occurred in association with overdose

or in patients with other risk factors for QT prolongation, including

concomitant use of QTc prolonging medicines (see section 4.5 and section

4.9). Caution should be exercised when Mirtazapine is prescribed in

patients with known cardiovascular disease or family history of QT

prolongation, and in concomitant use with other medicinal products

thought to prolong the QTc interval.

Hyponatraemia

Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion

(SIADH), 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 hyponatraemia.

Serotonin syndrome

Interaction with serotonergic active substances: serotonin syndrome may occur

when selective serotonin reuptake inhibitors (SSRIs) are used concomitantly

with other serotonergic active substances (see section 4.5). Symptoms of

serotonin syndrome may be hyperthermia, rigidity, myoclonus, autonomic

instability with possible rapid fluctuations of vital signs, mental status changes

that include confusion, irritability and extreme agitation progressing to

delirium and coma. Caution should be advised and a closer clinical monitoring

is required when these active substances are combined with mirtazapine.

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).

Elderly patients

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.

Lactose

This medicinal product contains lactose. Patients with rare hereditary

problems of galactose intolerance, the Lapp lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

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).

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 (serotonin syndrome: see

section 4.4). Caution should be advised and a closer clinical monitoring is

required when these active substances are combined with mirtazapine.

Mirtazapine may increase the sedating properties of benzodiazepines and other

sedatives (notably most antipsychotics, antihistamine H1 antagonists, opioids).

Caution should be exercised when these medicinal products are prescribed

together with mirtazapine.

Mirtazapine may increase the CNS depressant effect of alcohol. Patients

should therefore be advised to avoid alcoholic beverages while taking

mirtazapine.

Mirtazapine dosed at 30 mg once daily caused a small but statistically

significant increase in the international normalized ratio (INR) in subjects

treated with warfarin. As at a higher dose of mirtazapine a more pronounced

effect can not be excluded, it is advisable to monitor the INR in case of

concomitant treatment of warfarin with mirtazapine.

The risk of QT prolongation and/or ventricular arrhythmias (e.g. Torsade de

Pointes) may be increased with concomitant use of medicines which prolong

the QTc interval (e.g. some antipsychotics and antibiotics).

Pharmacokinetic interactions

Carbamazepine and phenytoin, CYP3A4 inducers, increased mirtazapine

clearance about two-fold, resulting in a decrease in average plasma

mirtazapine concentration of 60% and 45%, respectively. When

carbamazepine or any other inducer of hepatic metabolism (such as

rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to

be increased. If treatment with such medicinal product is discontinued, it may

be necessary to reduce the mirtazapine dose.

Co-administration of the potent CYP3A4 inhibitor ketoconazole increased the

peak plasma levels and the AUC of mirtazapine by approximately 40 % and

50 % respectively.

When cimetidine (weak inhibitor of CYP1A2, CYP2D6 and CYP3A4) is

administered with mirtazapine, the mean plasma concentration of mirtazapine

may increase more than 50%. 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, erythromycin,

cimetidine or nefazodone.

Interaction studies did not indicate any relevant pharmacokinetic effects on

concurrent treatment of mirtazapine with paroxetine, amitriptyline, risperidone

or lithium.

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Pregnancy

Limited data of the use of mirtazapine in pregnant women do not indicate an

increased risk for congenital malformations. Studies in animals have not

shown any teratogenic effects of clinical relevance, however developmental

toxicity has been observed (see section 5.3).

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).

Caution should be exercised when prescribing to pregnant women. If

mirtazapine is used until, or shortly before birth, postnatal monitoring of the

newborn is recommended to account for possible discontinuation effects.

Breastfeeding

Animal studies and limited human data have shown excretion of mirtazapine

in breast milk only in very small amounts. A decision on whether to

continue/discontinue breast-feeding or to continue/discontinue therapy with

mirtazapine should be made taking into account the benefit of breastfeeding to

the child and the benefit of mirtazapine therapy to the woman.

Fertility

Non-clinical reproductive toxicity studies in animals did not show any effect

on fertility.

4.7.

Effects on ability to drive and use machines

Mirtazapine has minor or moderate influence on the ability to drive and use

machines. Mirtazapine may impair concentration and alertness (particularly in

the initial phase of treatment). Patients should avoid the performance of

potentially dangerous tasks, which require alertness and good concentration,

such as driving a motor vehicle or operating machinery, at any time when

affected.

4.8

Undesirable effects

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.

The most commonly reported adverse reactions, occurring in more than 5% of

patients treated with mirtazapine in randomized placebo-controlled trials (see

below) are somnolence, sedation, dry mouth, weight increased, increase in

appetite, dizziness and fatigue.

All randomized placebo-controlled trials in patients (including indications

other than major depressive disorder), have been evaluated for adverse

reactions of mirtazapine. The meta-analysis considered 20 trials, with a

planned duration of treatment up to 12 weeks, with 1501 patients (134 person

years) receiving doses of mirtazapine up to 60 mg and 850 patients (79 person

years) receiving placebo. Extension phases of these trials have been excluded

to maintain comparability to placebo treatment.

Table 1 shows the categorized incidence of the adverse reactions, which

occurred in the clinical trials statistically significantly more frequently during

treatment with mirtazapine than with placebo, added with adverse reactions

from spontaneous reporting. The frequencies of the adverse reactions from

spontaneous reporting are based on the reporting rate of these events in the

clinical trials. The frequency of adverse reactions from spontaneous reporting

for which no cases in the randomized placebo-controlled patient trials were

observed with mirtazapine has been classified as ‘not known’.

Table 1. Adverse reactions of mirtazapine

System organ

class

Very common

1/10)

Common

1/100 to

<1/10)

Uncommon

1/1,000 to

<1/100)

Rare

1/10,000 to

<1/1,000)

Frequency not

known

Blood and the

lymphatic

system disorders

Bone marrow

depression

(granulocytopenia,

agranulocytosis,

aplastic anemia

thrombocytopenia)

Eosinophilia

Endocrine

disorders

Inappropriate

antidiuretic

hormone secretion

Metabolism and

nutrition

disorders

Increase in

appetite

Weight

increased

Hyponatraemia

Psychiatric

disorders

Abnormal

dreams

Confusion

Anxiety

2, 5

Insomnia

3, 5

Nightmares2

Mania

Agitation

Hallucinations

Psychomotor

restlessness

(incl. akathisia,

hyperkinesia)

Aggression

Suicidal ideation

Suicidal behaviour

Nervous system

disorders

Somnolence

1, 4

Sedation

1, 4

Headache

Lethargy

Dizziness

Tremor

Paraesthesia

Restless legs

Syncope

Myoclonus

Convulsions

(insults)

Serotonin

syndrome

Oral paraesthesia

Dysarthria

Vascular

disorders

Orthostatic

hypotension

Hypotension

Gastrointestinal

disorders

Dry mouth

Nausea

Diarrhoea

Vomiting

Constipation

Oral

hypoaesthesia

Pancreatitis

Mouth oedema

Increased salivation

Hepatobiliary

disorders

Elevations in

serum

transaminase

activities

Skin and

subcutaneous

tissue disorders

Exanthema

Stevens-

Johnson

Syndrome

Dermatitis

bullous

Erythema

multiforme

Toxic epidermal

necrolysis

Musculoskeletal

and connective

tissue disorders

Arthralgia

Myalgia

Back pain

Rhabdomyolysis

Renal and

urinary

disorders

Urinary retention

General

disorders and

administration

site conditions

Oedema

peripheral

Fatigue

Somnambulism

Generalised

oedema

Localised oedema

Investigations

Increased creatinine

kinase

In clinical trials these events occurred statistically significantly more

frequently during treatment with mirtazapine than with placebo.

In clinical trials these events occurred more frequently during treatment with

placebo than with mirtazapine, however not statistically significantly more

frequently.

In clinical trials these events occurred statistically significantly more

frequently during treatment with placebo than with mirtazapine.

N.B. dose reduction generally does not lead to less somnolence/sedation but

can jeopardize antidepressant efficacy.

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.

Cases of suicidal ideation and suicidal behaviours have been reported during

mirtazapine therapy or early after treatment discontinuation (see section 4.4).

In laboratory evaluations in clinical trials transient increases in transaminases

and gammaglutamyltransferase have been observed (however associated

adverse events have not been reported statistically significantly more

frequently with mirtazapine than with placebo).

Paediatric population

The following adverse events were observed commonly in clinical trials in

children: weight gain, urticaria and hypertriglyceridaemia (see also section

5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal

product is important. It allows continued monitoring of the benefit/risk balance

of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via the Yellow Card Scheme; website:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the

Google Play or Apple App Store.

4.9

Overdose

Present experience concerning overdose with mirtazapine alone indicates that

symptoms are usually mild. Depression of the central nervous system with

disorientation and prolonged sedation have been reported, together with

tachycardia and mild hyper- or hypotension. However, there is a possibility of

more serious outcomes (including fatalities) at dosages much higher than the

therapeutic dose, especially with mixed overdoses.

In these cases QT prolongation and Torsade de Pointes have also been

reported.

Cases of overdose should receive appropriate symptomatic and supportive

therapy for vital functions.

ECG monitoring should be undertaken.

Activated charcoal or gastric lavage should also be considered.

Paediatric population

The appropriate actions as described for adults should be taken in case of an

overdose in paediatrics.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: other antidepressants

ATC code: N06AX11

Mechanism of action

Mirtazapine is a centrally active presynaptic

2-antagonist, which increases

central noradrenergic and serotonergic neurotransmission. The enhancement

of serotonergic neurotransmission is specifically mediated via 5-HT1

receptors, because 5-HT2- and the 5-HT3 receptors are blocked by

mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to

the antidepressant activity, the S(+) enantiomer by blocking

2 and 5-HT2

receptors and the R (-) enantiomer by blocking 5-HT3 receptors.

Clinical efficacy and safety

The histamine H1-antagonistic activity of mirtazapine is associated with its

sedative properties. It has practically no anticholinergic activity and, at

therapeutic doses, has practically no effect on the cardiovascular system.

The effect of Mirtazapine on QTc interval was assessed in a randomized,

placebo and moxifloxacin controlled clinical trial involving 54 healthy

volunteers using a regular dose of 45 mg and a supra-therapeutic dose of 75

mg. Linear e-max modelling suggested that prolongation of QTc intervals

remained below the threshold for clinically meaningful prolongation (see

section 4.4).

Paediatric population

Two randomised, double-blind, placebo-controlled trials in children aged

between 7 and 18 years with major depressive disorder (n=259) using a

flexible dose for the first 4 weeks (15-45mg mirtazapine) followed by a fixed

dose (15, 30 or 45 mg mirtazapine) for another 4 weeks failed to demonstrate

significant differences between mirtazapine and placebo on the primary and all

secondary endpoints. Significant weight gain (

7%) was observed in 48.8% of

the mirtazapine treated subjects compared to 5.7% in the placebo arm.

Urticaria (11.8% vs 6.8%) and hypertriglyceridaemia (2.9% vs 0%) were also

commonly observed.

5.2

Pharmacokinetic properties

Absorption

After oral administration of mirtazapine, the active substance mirtazapine is

rapidly and well absorbed (bioavailability

50%), reaching peak plasma levels

after approx two hours. Food intake has no influence on the pharmacokinetics

of mirtazapine.

Linearity/non-linearity

Mirtazapine displays linear pharmacokinetics within the recommended dose

range. Food intake has no influence on the pharmacokinetics of mirtazapine.

Biotransformation

Mirtazapine is extensively metabolised and eliminated via the urine and faeces

within a few days. Major pathways of biotransformation are demethylation

and oxidation followed by conjugation. In vitro data from human liver

microsomes indicate that cytochrome P450 enzymes CYP2D6 and CYP1A2

are involved in the formation of the 8-hydroxy metabolite of mirtazapine,

whereas the CYP3A4 is considered to be responsible for the formation of the

N-demethyl and N-oxide metabolites. The demethyl metabolite is

pharmacologically active and appears to have the same pharmacokinetic

profile as the parent compound.

Distribution

Binding of mirtazapine to plasma proteins is approx. 85%.

Elimination

The mean half-life of elimination is 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 3-4 days, after which there is no further

accumulation.

Special populations

The clearance of mirtazapine may be decreased as a result of renal or hepatic

impairment.

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional

studies of safety pharmacology, repeated dose toxicity, carcinogenicity,

genotoxicity

carcinogenic potential, toxicity to reproduction and development.

In reproductive toxicity studies in rats and rabbits no teratogenic effects were

observed. At two-fold systemic exposure compared to maximum human

therapeutic exposure, there was an increase in post-implantation loss, decrease

in the pup birth weights, and reduction in pup survival during the first three

days of lactation in rats.

Mirtazapine was not genotoxic in a series of tests for gene mutation and

chromosomal and DNA damage. Thyroid gland tumours found in a rat

carcinogenicity study and hepatocellular neoplasms found in a mouse

carcinogenicity study are considered to be species-specific, non-genotoxic

responses associated with long-term treatment with high doses of hepatic

enzyme inducers.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients

Core:

Lactose monohydrate

Pregelatinised maize starch

Silica colloidal anhydrous

Croscarmellose sodium

Magnesium stearate.

Film-coating:

Hypromellose

Macrogol 8000

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Talc

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years

6.4

Special precautions for storage

PVC/aluminium blister: Store in the original package. Keep the blister in the outer

carton.

Tablet container: Store in the original package. Keep the container tightly closed.

6.5

Nature and contents of container

Blister (Clear PVC/Aluminium): 6, 10, 18, 20, 28, 30, 48, 50, 60, 90, 96, 100, 200

film-coated tablets

PP Tablet container with LDPE closure (white): 10, 18, 20, 48, 50, 96, 100, 250, 500

film-coated tablets

Pack sizes above 100 tablets are intended for handling by health care professionals

and for hospital use.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7

MARKETING AUTHORISATION HOLDER

Actavis UK Limited

Whiddon Valley

Barnstaple

North Devon

EX32 8NS

United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)

PL 00142/0613

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

22/12/2008

10

DATE OF REVISION OF THE TEXT

24/09/2018

Read the complete document

Public Assessment Report

Mirtazapine 15mg Tablets

PL 20532/0018

Mirtazapine 30mg Tablets

PL 20532/0019

Mirtazapine 45mg Tablets

PL 20532/0020

MIRTAZAPINE 15MG TABLETS

PL 20532/0018

MIRTAZAPINE 30MG TABLETS

PL 20532/0019

MIRTAZAPINE 45MG TABLETS

PL 20532/0020

UKPAR

TABLE OF CONTENTS

Page

Lay Summary

Scientific discussion

Steps taken for assessment

Steps taken after authorisation – summary

Summary of Product Characteristics

Patient Information Leaflet

Labelling

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

2

MIRTAZAPINE 15MG TABLETS

PL 20532/0018

MIRTAZAPINE 30MG TABLETS

PL 20532/0019

MIRTAZAPINE 45MG TABLETS

PL 20532/0020

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) has granted Aurobindo

Pharma Limited Marketing Authorisations (licences) for the medicinal products Mirtazapine

15mg, 30mg and 45mg Tablets (PLs 20532/0018-20). These are prescription only medicines

[POMs] used for the treatment of depression.

These products contain the active substance mirtazapine.

The clinical data presented to the MHRA, before licensing, demonstrated that Mirtazapine

15mg, 30mg and 45mg Tablets are essentially similar or equivalent to the approved products,

Zispin (Mirtazapine) 15mg, 30mg and 45mg Tablets, and as such can be used

interchangeably.

No new or unexpected safety concerns arose from these applications and it was decided that

the benefits of using Mirtazapine 15mg, 30mg and 45mg Tablets outweigh the risks, hence

Marketing Authorisations have been granted.

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

3

MIRTAZAPINE 15MG TABLETS

PL 20532/0018

MIRTAZAPINE 30MG TABLETS

PL 20532/0019

MIRTAZAPINE 45MG TABLETS

PL 20532/0020

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Page

Introduction

Pharmaceutical assessment

Preclinical assessment

Clinical assessment (including statistical assessment)

Overall conclusions and risk benefit assessment

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

4

INTRODUCTION

Based on the review of the data on quality, safety and efficacy the UK granted marketing

authorisations for the medicinal products Mirtazapine 15mg, 30mg and 45mg Tablets (PLs

20532/0018-20) to Sandoz Limited on 31 July 2006. The products are prescription only

medicines.

The applications were submitted as abridged applications according to Article 10.1(a)(iii) of

Directive 2001/83/EC, claiming essential similarity to Zispin (Mirtazapine) 15mg, 30mg and

45mg Tablets.

These products contain the active ingredient mirtazapine and are indicated for the treatment

of depressive illness.

Mirtazapine is a centrally active presynaptic α

-antagonist, which increases central

noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic

neurotransmission is specifically mediated via 5-HT

receptors, because 5-HT

and 5-HT

receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to

contribute to the antidepressant activity, the S(+) enantiomer by blocking α

and 5-HT

receptors and the R(-) enantiomer by blocking 5-HT

receptors.

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

5

PHARMACEUTICAL ASSESSMENT

PL Number:

PLs 20532/0018-20

Name of Product:

Mirtazapine 15mg, 30mg and 45mg Tablets

Active (s):

Mirtazapine

Company Name:

Aurobindo Pharma Limited

E.C. Article:

10.1(a)(iii)

Legal Status:

POM

INTRODUCTION

Legal Basis

These are national applications for 3 strengths of mirtazapine tablets: 15mg, 30mg and 45mg.

These abridged applications were submitted under article 10.1(a)(iii) of Directive

2001/83/EC, citing Zispin (Mirtazapine) 30mg Tablets (Organon Laboratories Ltd – PL

00065/0145) as the UK reference product. The original products cited are Remeron

(Mirtazapine) 15mg, 30mg and 45mg tablets, licensed in the Netherlands since 1994.

Use

Mirtazapine is an anti-depressant and is indicated for the treatment of depression. The

claimed indications “Treatment of depressive illness” are consistent with those licensed in the

cross-referenced product.

Background

Details of the reference products are found below.

PL Number

Tablet strength

Granted

PL 00065/0144

Mirtazapine 15mg Tablets

4 July 1997

PL 00065/0145

Mirtazapine 30mg Tablets

4 July 1997

PL 00065/0157

Mirtazapine 45mg Tablets

13 January 2000

DRUG SUBSTANCE

General information

Nomenclature

1,2,3,4,10,14b-Hexahydro–2–methylpyrazino[2,1-a]pyrido[2,3-c][2]-benzazepine

C H N

=265.36

CAS—61337–67–5

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

6

Structure

General properties

White to creamy-white crystalline powder

Freely soluble in methanol and in dichloromethane

Melting point 114-117°C

Specific optical rotation -0.5º to +0.5º

Manufacture

Manufacturer

A suitable manufacturing site has been named.

Description of manufacturing process

A satisfactory description of the manufacturing process is provided.

Control of materials

A statement is provided that materials used are not derived from animals which are

susceptible to TSE. The starting material is satisfactorily controlled by a suitable

specification.

Satisfactory specifications are also provided for all reagents.

Characterisation

The active substance has been characterised by suitable methods.

Elucidation of structure and other characteristics

Isomerism

Mirtazapine shows optical isomerism and the compound is commercially available as the

racemic mixture (+0.5°C to – 0.5ºC).

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

7

Mitazapine is soluble in methanol and dichloromethane and practically insoluble in water, but

its solubility increases with increasing acidity.

Impurities

Details of impurities are provided.

Control of drug substance

Specification

The drug substance specification provided is acceptable.

Analytical procedures

Validation of analytical procedures

Satisfactory details are provided.

Batch analysis

Batch analysis data show compliance with the specification.

Reference standards or materials

The reference batch number, Certificates of Analysis and proof of structure data are provided.

DRUG PRODUCT

Description and composition of the drug product

Ingredients

Core ingredients

Function of ingredients

Mirtazapine

Active

Lactose monohydrate

Ph.Eur.

Diluent

Hydroxypropylcellulose

Ph.Eur.

Binder

Maize starch

Ph.Eur.

Disintegrant

Silica, colloidal anhydrous

Ph.Eur.

Glidant

Low-substituted hydroxypropyl cellulose

USNF

Disintegrant

Magnesium Stearate

Ph.Eur.

Lubricant

Coating ingredients

Opadry White 20A58806

Coating material

Opadry Yellow 20A52560

Coating material

Opadry Brown 20A56788

Coating material

Pharmaceutical development

Mirtazapine is rapidly and completely absorbed after oral administration from the gastro–

intestinal tract. Peak plasma levels are reached after about 2 hours. Steady state is reached

after 3 to 4 days. Linear pharmacokinetics are displayed within the recommended dose range.

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

8

Food intake has no influence on the pharmacokinetics. It is extensively metabolised in the

liver and eliminated in urine (75%) and faeces (15%) within a few days. Metabolism occurs

by the P450 cytochrome oxidase pathway into four metabolites via demethylation and

hydroxylation followed by glucuronide conjugation. Cytochrome 2D6 and 1A2 are involved

in the formation of 8–hydroxy metabolite and 3A in the N-desmethyl (active) and N-oxide

metabolites. Elimination of the parent compound occurs via hepatic metabolism with

demethylation and oxidation with subsequent conjugation of the metabolites. The

bioavailability of mirtazapine is 50% and half life about 20-40 hours. It is 85% plasma

bound. (Clarke’s Analysis of Drugs and Poisons 2004).

Mirtazapine’s absorption is not influenced by food (Martindale).

Essential similarity

The active is the same. The impurity profile of the proposed product is comparable to that of

the reference product. The pharmaceutical form is the same and both use the oral route.

Bioequivalence has been demonstrated.

Dose proportionality of the different strengths

Tablets are made at the same site by the same method. They have similar dissolution profiles.

They contain the same excipients in the same proportions. The pharmacokinetics are linear

over the recommended dosage range (Clarke’s Analysis of Drugs and Poisons 2004).

Container closure system

Blisters – White Opaque 250µm PVC coated with 60gm PVdC and 25µm aluminium foil

with heat seal lacquer. Both plastic and aluminium foils comply with Ph.Eur. requirements

and are food grade materials. The plastic layer complies with European Directives

EU/1991/91/EC, EU/78/142/EC and EU/94/62/EEC.

Microbial testing

Microbial testing in accordance with the Ph.Eur. is performed on the finished product.

Manufacture

The manufacturing site has been inspected by the MHRA and accepted as a suitable site to be

named on UK licences.

Description of manufacturing process and process controls

Full details provided.

Process validation and/or evaluation

Satisfactory details provided.

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

9

Control of excipients

Specifications

The following excipients comply with the Ph.Eur.:

Lactose monohydrate

Hydroxypropylcellulose

Maize starch

Silica, colloidal anhydrous

Magnesium stearate

Low substituted hydroxypropyl cellulose is controlled by USNF monograph.

Opadry coatings are controlled by satisfactory in-house specifications. Ingredients of the

coating are of pharmacopoeial quality.

Analytical procedures

Satisfactory details of analytical procedures are presented.

Justification of specifications

Certificates of Analysis demonstrating compliance with the specifications are provided.

Excipients of human or animal origin

All excipients are derived from vegetable sources except lactose monohydrate, which is

derived from healthy animals.

Control of drug product

Specification

A suitable finished product specification is provided.

Analytical procedures

Analytical procedures are adequately described.

Validation of analytical procedures

Satisfactory details are provided.

Batch analysis

The batch analysis confirms compliance with the finished product specification.

MHRA: PAR – Mirtazapine 15mg/30mg/45mg Tablets PLs 20532/0018-20

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