Mirtazapine tablets are indicated in adults for the treatment of episodes of major depression.

Posology
ADULTS
The effective daily dose is usually between 15 and 45 mg; the starting dose is 15 or 30 mg.
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).
OLDER PEOPLE
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.

PEDIATRIC POPULATION
Mirtazapine should not be used in children and adolescents under the age of 18 years 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 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 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 is suitable for
once daily administration. It should be taken preferably as a single night-time dose before going
to bed. Mirtazapine 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.

Paediatric population
Mirtazapine should not be used in the treatment of children and 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, longterm
safety data in children and adolescents concerning growth, maturation and cognitive and
behavioral 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 metaanalysis
of placebo controlled clinical trials of antidepressants in adult patients with psychiatric
disorders showed an increased risk of suicidal behavior 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 behavior or thoughts and unusual changes in behavior 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 Mirtazapine film-coated tablets 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 postmarketing use of mirtazapine. The majotity 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).
Older people
Older people 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.

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 (Ltryptophan, triptans, tramadol, linezolid, methylene blue, 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 cannot 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
twofold, 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.

Pregnancy Category C
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”
Breast-feeding
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 breast-feeding
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.

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.

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'.

¹ In clinical trials these events occurred statistically significantly more frequently during treatment with Mirtazapine than with placebo.

² In clinical trials these events occurred more frequently during treatment with placebo than with Mirtazapine, however not statistically significantly more frequently.

³ In clinical trials these events occurred statistically significantly more frequently during treatment with placebo than with Mirtazapine.

⁴ N.B. dose reduction generally does not lead to less somnolence/sedation but can jeopardize antidepressant efficacy.

⁵ 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.

⁶ 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

To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
• Other GCC States:
− Please contact the relevant competent authority.

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.

Pharmacotherapeutic group: other antidepressants, ATC code: N06AX11
Mechanism of action/pharmacodynamic effects
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.

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 only limited effects
(e.g. orthostatic hypotension) on the cardiovascular system.
Paediatric population:
Two randomized, 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.

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.
Distribution
Binding of mirtazapine to plasma proteins is approx. 85 %.
Biotransformation
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.
Elimination
Mirtazapine is extensively metabolized and eliminated via the urine and faeces within a few
days. 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.
Linearity/non-linearity
Mirtazapine displays linear pharmacokinetics within the recommended dose range.

Special populations
The clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction and development.
In reproductive toxicity studies in rats and rabbits no teratogenic effects were observed. At twofold
systemic exposure compared to maximum human therapeutic exposure, there was an
increase in postimplantation 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, nongenotoxic
responses associated with long-term treatment with high doses of hepatic enzyme
inducers.

Mirtazapine 45 mg tablets contain
Core:
• Lactose monohydrate
• Maize Starch
• Low Subs Hydroxypropyl Cellulose – LH21
• Hydroxypropyl Cellulose –Klucel EXF
• Colloidal Silicon Dioxide – Aerosil 200
• Magnesium Stearate
• Purified Water

Film Coating:
• Hypromellose (HPMC 6 Cps)
• Polyethylene Glycol 6000 P
• Titanium Dioxide
• Purified Water

Not applicable

Do not store above 30⁰C.

Tazmeron 45 mg Film coated tablet 3 x 10’s Tablets in Alu-PVC/PVDC Blister

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.