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MIRTAZAPINE 30MG FILM COATED TABLETS

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CONFIDENTIAL

Research & Development
Regulatory Affairs
Organon

No.: INT00029969

Prepared by:

B. Wullems

No. of pages:

14

Date:

February 2007

EU-SmPC of Remeron tablets

This report is the property of Organon. All rights strictly reserved. Use, reproduction, issue, loan or disclosure of the
contents to third parties in any form whatsoever not permitted without written authority from the proprietor except that
this document may be disclosed to appropriate institutional review committees so long as they are requested to keep
it confidential.
The information given in this document may not be used or made public without our explicit consent, and is to be
regarded as a trade secret in that it contains unpublished results of private research which are used in our business
and which gives an opportunity to obtain an advantage over competitors who do not know or use it, and/or as
commercial or financial information that is privileged or confidential in that it contains valuable data or information
which is used in our business and is of a type customarily held in strict confidence or regarded as privileged and not
disclosed to any member of the public by the person to whom it belongs. As such, it is protected from disclosure by
the law of several countries, such as the U.S. Freedom of Information Act.

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1.

2

Remeron tablets
15, 30 and 45 mg

NAME OF THE MEDICINAL PRODUCT
Remeron 15 mg film-coated tablets
Remeron 30 mg film-coated tablets
Remeron 45 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 15 mg, 30 mg or 45 mg of mirtazapine.
Excipients:
Each Remeron 15 mg film-coated tablet contains not more than 114 mg
lactose monohydrate.
Each Remeron 30 mg film-coated tablet contains not more than 228 mg
lactose monohydrate.
Each Remeron 45 mg film-coated tablet contains not more than 342 mg
lactose monohydrate.
For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM
Film-coated tablet.
Oval, biconvex and marked with 'Organon' on one side-and a code on the
other side (TZ/3 for 15 mg tablets, TZ/5 for 30 mg tablets and TZ/7 for 45 mg
tablets). The 15 mg tablets are yellow, the 30 mg tablets are red-brown, and
the 45 mg tablets are white. The 15 mg tablets and the 30 mg tablets are
scored.
The 15 and 30 mg tablets can be divided into equal halves.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications
Episode of major depression.

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4.2

3

Remeron tablets
15, 30 and 45 mg

Posology and method of administration
The tablets should be taken orally, if necessary with fluid, and swallowed
without chewing.
Adults:
The effective daily dose is usually between 15 and 45 mg; the starting dose is
15 or 30 mg (the higher dose should be taken at night).
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.
Children and adolescents under the age of 18 years:
Remeron should not be used in children and adolescents under the age of 18
years (see section 4.4).
Renal/hepatic impairment
The clearance of mirtazapine may be decreased in patients with renal or
hepatic insufficiency. This should be taken into account when prescribing
Remeron to this category of patients.
Mirtazapine has a half-life of 20-40 hours and therefore Remeron is suitable
for once-a-day administration. It should be taken preferably as a single nighttime dose before going to bed. Remeron 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.
It is recommended to discontinue treatment with mirtazapine gradually to
avoid withdrawal symptoms (see section 4.4).

4.3

Contraindications
Hypersensitivity to mirtazapine or to any of the excipients.

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4.4

4

Remeron tablets
15, 30 and 45 mg

Special warnings and precautions for use
Use in children and adolescents under 18 years of age
Remeron should not be used in the treatment of children and adolescents
under the age of 18 years. Suicide-related behaviours (suicide attempt and
suicidal thoughts), and hostility (predominantly aggression, oppositional
behaviour and anger) were more frequently observed in clinical trials among
children and adolescents treated with antidepressants compared to those
treated with placebo. If, based on clinical need, a decision to treat is
nevertheless taken, the patient should be carefully monitored for the
appearance of suicidal symptoms. In addition, long-term safety data in
children and adolescents concerning growth, maturation and cognitive and
behavioural development are lacking.
Suicide/suicidal thoughts
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, 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. In addition, there is a possibility of an
increased risk of suicidal behaviour in young adults.
Patients (and caregivers of patients) should be alerted about the need to
monitor for the emergence of such events 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 a limited number of Remeron tablets should be given to the
patient.
Bone marrow depression, usually presenting as granulocytopenia or
agranulocytosis, has been reported during treatment with Remeron. This
mostly appears after 4-6 weeks of treatment and 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 Remeron. In the postmarketing period with Remeron very

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15, 30 and 45 mg

rare cases of agranulocytosis have been reported, mostly reversible, but in
some cases fatal. All fatal cases 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.
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, Remeron 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 or renal insufficiency
– cardiac diseases like conduction disturbances, angina pectoris and recent
myocardial infarct, where normal precautions should be taken and
concomitant medicines carefully administered
– low blood pressure.
Treatment should be discontinued if jaundice occurs.
Like with other antidepressants care should be taken in patients with:
– micturition disturbances like prostate hypertrophy (although problems are
not to be expected because Remeron possesses only very weak
anticholinergic activity)
– acute narrow-angle glaucoma and increased intra-ocular pressure (also
here little chance of problems with Remeron because of its very weak
anticholinergic activity)
– 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.
Moreover, like with other antidepressants, the following should be taken into
account:
– interaction with serotonergic drugs: serotonin syndrome may occur when
selective serotonin reuptake inhibitors (SSRIs) are given in combination
with other serotonergic drugs (see section 4.5). From post marketing

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15, 30 and 45 mg

experience it appears that serotonin syndrome occurs very rarely in
patients treated with Remeron alone (see section 4.8).
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 manic-depressive psychosis 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 Remeron 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 underlying disease. As advised in section
4.2, it is recommended to discontinue treatment with mirtazapine
gradually.
elderly patients are often more sensitive, especially with regard to the
undesirable effects of antidepressants. During clinical research with
Remeron, undesirable effects have not been reported more often in
elderly patients than in other age groups.









This medicinal product contains lactose. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose 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.

-

Mirtazapine may increase the sedating properties of benzodiazepines
and other sedatives. 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.

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15, 30 and 45 mg

-

If other serotonergic drugs (e.g. SSRI and venlafaxine) are used
concomitantly with mirtazapine, there is a risk of interaction that could
lead to the development of a serotonin syndrome. 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 sufficiently close
monitoring for signs of beginning serotonergic overstimulation
maintained.

-

Mirtazapine dosed at 30 mg once daily caused a small but statistically
significant increase in the 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.

Pharmacokinetic interactions
-

Mirtazapine is extensively metabolized by CYP2D6 and CYP3A4, and to
a lesser extent by CYP1A2. An interaction study of healthy volunteers
showed that paroxetine, a CYP2D6 inhibitor, has no influence on
mirtazapine pharmacokinetics at steady state. Co-administration of the
potent CYP3A4 inhibitor ketoconazole increased the peak plasma levels
and the AUC of mirtazapine by approximately 40% and 50%
respectively. Caution should be exercised when co-administering
mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors,
azole antifungals, erythromycin or nefazodone.

-

Carbamazepine and phenytoin, CYP3A4 inducers, increased
mirtazapine clearance about twofold, resulting in a 45 to 60% decrease
in plasma mirtazapine concentrations. When carbamazepine or another
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.

-

When cimetidine is co-administered, the bioavailability of mirtazapine
may be increased by more than 50%. The mirtazapine dose may have
to be decreased when concomitant treatment with cimetidine is started
or increased when cimetidine treatment is discontinued.

-

In in vivo -interaction studies, mirtazapine did not influence the
pharmacokinetics of risperidone or paroxetine (CYP2D6 substrate),

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15, 30 and 45 mg

carbamazepine (CYP3A4 substrate), amitriptyline, cimetidine or
phenytoin.
-

4.6

No relevant clinical effects or changes in pharmacokinetics have been
observed in humans on concurrent treatment with mirtazapine and
lithium.

Pregnancy and lactation
There are no adequate data of the use of mirtazapine in pregnant women.
Studies in animals have not shown any teratogenic effects or reproductive
toxicity of clinical relevance (see section 5.3). The potential risk for humans is
unknown. Remeron should not be used during pregnancy unless clearly
indicated, following a careful clinical risk/benefit consideration.
It is unknown whether mirtazapine is excreted in human breast milk. Animal
studies 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 Remeron should be made taking into
account the benefit of breast-feeding to the child and the benefit of Remeron
therapy to the woman.

4.7

Effects on ability to drive and use machines
Remeron has minor or moderate influence on the ability to drive and use
machines. Remeron may impair concentration and alertness. Patients treated
with antidepressants should avoid the performance of potentially dangerous
tasks, which require alertness and good concentration, such as driving a
motor vehicle or operating machinery.

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 Remeron.

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Remeron tablets
15, 30 and 45 mg

9

System organ

Very

Common

Uncommon

Rare

Very rare

class

common

(≥1/100 to <1/10)

(≥1/1,000 to

(≥1/10,000 to

(<1/10,000), not

<1/100)

<1/1,000)

known (cannot be

(≥1/10)

estimated from the
available data
ƒ Bone marrow
depression
(granulocytopenia,
agranulocytosis,
aplastic anemia and
thrombocytopenia)
(see also section 4.4
'Special warnings
and special
precautions for use')
ƒ Eosinophilia

Blood and the
lymphatic
system
disorders

Metabolism and
nutrition
disorders

ƒ Increase in
appetite

Psychiatric
disorders

Nervous system
disorders

Vascular
disorders

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ƒ Somnolence
(which can lead to
impaired
concentration),
generally
occurring during
the first few weeks
of treatment.
(N.B. dose
reduction
generally does not
lead to less
sedation but can
jeopardize
antidepressant
efficacy).
ƒ Dizziness
ƒ Headache

ƒ Nightmares/vivid
dreams
ƒ Mania
ƒ Agitation
ƒ Confusion
ƒ Hallucinations
ƒ Anxiety *)
ƒ Insomnia *)
ƒ Psychomotor
restlessness **)
ƒ Convulsions
(insults), tremor,
myoclonus
ƒ Paraesthesia
ƒ Restless legs
ƒ Syncope

ƒ (Orthostatic)
hypotension

ƒ Serotonin
syndrome
ƒ Oral paraesthesia

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15, 30 and 45 mg

10

System organ

Very

Common

Uncommon

Rare

Very rare

class

common

(≥1/100 to <1/10)

(≥1/1,000 to

(≥1/10,000 to

(<1/10,000), not

<1/100)

<1/1,000)

known (cannot be

(≥1/10)

estimated from the
available data
ƒ Nausea

Gastrointestinal
disorders
Hepato-biliary
disorders

ƒ
ƒ
ƒ
ƒ

Dry mouth
Diarrhea
Vomiting
Elevations in serum
transaminase
activities

Skin and
subcutaneous
tissue disorders

ƒ Exanthema

Musculoskeletal
, connective
tissue and bone
disorders

ƒ Arthralgia/myalgia

General
disorders and
administration
site conditions

ƒ Generalised or
local oedema

Investigations

ƒ Weight gain

ƒ Oral
hypoaesthesia
ƒ Mouth oedema

ƒ Fatigue

*) Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression)
can develop or become aggravated. Under Remeron treatment, development or aggravation of anxiety and
insomnia has been reported very rarely.
**) Incl. akathisia, hyperkinesia

4.9

Overdose
Present experience concerning overdose with Remeron 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 overdosages.
Cases of overdose should receive appropriate symptomatic and supportive
therapy for vital functions. Activated charcoal or gastric lavage should also be
considered.

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5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Remeron tablets
15, 30 and 45 mg

Pharmacotherapeutic group: Antidepressant
ATC code: NO6AX11
Mirtazapine is a centrally active presynaptic α2-antagonist, which increases
central noradrenergic and serotonergic neurotransmission. The enhancement
of serotonergic neurotransmission is specifically mediated via 5-HT1
receptors, because 5-HT2 and 5-HT3 receptors are blocked by mirtazapine.
Both enantiomers of mirtazapine are presumed to contribute to the
antidepressant activity, the S(+) enantiomer by blocking α2 and 5-HT2
receptors and the R(-) enantiomer by blocking 5-HT3 receptors.
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.
5.2

Pharmacokinetic properties
After oral administration of Remeron, the active substance mirtazapine is
rapidly and well absorbed (bioavailability ≈ 50%), reaching peak plasma levels
after approx. two hours. Binding of mirtazapine to plasma proteins is approx.
85%. 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-aday dosing. Steady state is reached after 3-4 days, after which there is no
further accumulation. Mirtazapine displays linear pharmacokinetics within the
recommended dose range. Food intake has no influence on the
pharmacokinetics of mirtazapine.
Mirtazapine is extensively metabolized 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 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.

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The clearance of mirtazapine may be decreased as a result of renal or
hepatic insufficiency.
5.3

Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity, carcinogenicity,
genotoxicity, or reproductive toxicity. Mirtazapine induced no effects of clinical
relevance in chronic safety studies in rats or dogs.
In reproductive toxicity studies in rats and rabbits no teratogenic effects were
observed. At the high dose levels, 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:
maize starch
hyprolose
magnesium stearate
silica, colloidal anhydrous
lactose monohydrate
Coating layer:
hypromellose
Macrogol 8000
titanium dioxide (E171)
yellow iron oxide (E172)
red iron oxide (E172)

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(15 and 30 mg tablets only)
(30 mg tablets only)

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6.2

13

Remeron tablets
15, 30 and 45 mg

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Do not store above 30°C.
Store in the original package to protect from light and moisture.

6.5

Nature and contents of container
Child-safe, push-through strips made of opaque white polyvinyl chloride film
and aluminium foil containing a heat-seal coating on the side in contact with
the tablets.
The following packages are available for the 15 mg tablets:
-

Push-through strips with 10 tablets each. The pack contains 30 (3x10)
tablets.

-

Push-through strips with 7 tablets each. Packs containing 14 (2x7), 28
(4x7), 56 (8x7), and 70 (10x7) tablets, respectively.

The following packages are available for the 30 mg and 45 mg tablets:
-

Push-through strips with 10 tablets each. Packs containing 20 (2x10),
30 (3x10), 50 (5x10), 100 (10x10), 200 (20x10) and 500 (50x10)
tablets, respectively.

-

Push-through strips with 7 tablets each. Packs containing 14 (2x7), 28
(4x7), 56 (8x7), and 70 (10x7) tablets, respectively.

Not all pack sizes may be marketed.
6.6

Special precautions for disposal and other handling
No special requirements.

7.

MARKETING AUTHORISATION HOLDER

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8.

MARKETING AUTHORISATION NUMBER(S)

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation:
Date of last renewal:

10.

DATE OF REVISION OF THE TEXT
February 2007

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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