MIRTAZAPINE 15MG/ML ORAL SOLUTION
Active substance(s): MIRTAZAPINE / MIRTAZAPINE / MIRTAZAPINE
NAME OF THE MEDICINAL PRODUCT
Mirtazapine 15 mg/ml oral solution
QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of Mirtazapine oral solution contains 15 mg of mirtazapine.
Excipient(s) with known effect:
1 ml of Mirtazapine oral solution contains 700 mg maltitol liquid.
Mirtazapine oral solution contains 0.3 % v/v ethanol.
For the full list of excipients, see section 6.1.
Clear, colourless-to-straw aqueous solution.
Mirtazapine is indicated in adults for the treatment of episodes of major depression.
Posology and method of administration
The effective daily dose is usually between 15 mg (1 ml) and 45 mg (3 ml); the
starting dose is 15 mg (1 ml) or 30 mg (2 ml).
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
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).
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
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).
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).
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).
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 nighttime 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
The solution is withdrawn from the bottle with the oral syringe and can be swallowed
directly from the oral syringe. Alternatively, it can be dosed onto a spoon or into a
glass of water using the syringe.
Instructions for use:
Open the bottle: press the cap and turn it anticlockwise (Figure 1).
Insert the syringe adaptor into the bottle neck (Figure 2).
Take the syringe and put it in the adaptor opening (Figure 3).
Turn the bottle upside down (Figure 4).
Fill the syringe with a small amount of solution by pulling the piston down (Figure
4A). Then push the piston upward in order to remove any possible bubbles (Figure
4B). Finally, pull the piston down to the graduation mark corresponding to the
quantity in millilitres (ml) prescribed by your doctor. The top flat edge of the piston
should be in line with the graduation mark you are measuring to (Figure 4C).
Turn the bottle the right way up (Figure 5A).
Remove the syringe from the adaptor (Figure 5B).
Put the end of the syringe into your mouth and push the piston slowly back in to
take the medicine. Alternatively, dispense the solution onto a spoon or into a small
glass of water and take your medicine straight away.
Wash the syringe with water and let it dry before you use it again (Figure 6).
Close the bottle with the plastic screw cap - leave the syringe adaptor in the bottle.
Hypersensitivity to the active substance or to any of the excipients listed in section
Concomitant use of mirtazapine with monoamine oxidase (MAO) inhibitors (see
Special warnings and precautions for use
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 and
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
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
With regard to the chance of suicide, in particular at the beginning of treatment, only
a limited quantity of Mirtazapine oral solution should be given to the patient.
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.
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
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, characterized by a subjectively
unpleasant or distressing restlessness and need to move often accompanied by an
inability to sit or stand still. This is most likely to occur within the first few weeks
of treatment. In patients who develop these symptoms, increasing the dose may be
Cases of QT prolongation, Torsades 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, 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.
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 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.
This medicinal product contains maltitol liquid. Patients with rare hereditary
problems of fructose intolerance should not take this medicine.
This medicinal product contains small amounts of ethanol, less than 100 mg per daily
Switching from tablets to oral solution
There are slight pharmacokinetic differences between oral solution and tablets;
although these differences are likely to be of no clinical relevance, care should be
taken when switching from tablets to oral solution.
Interaction with other medicinal products and other forms of interaction
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
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. Torsades de
Pointes) may be increased with concomitant use of medicines which prolong the
QTc interval (e.g. some antipsychotics and antibiotics).
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%
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
Interaction studies have only been performed in adults.
Fertility, pregnancy and lactation
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.
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.
Non-clinical reproductive toxicity studies in animals did not show any effect on
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.
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
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.
Blood and the
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
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
gamma-glutamyltransferase have been observed (however associated adverse events
have not been reported statistically significantly more frequently with Mirtazapine
than with placebo).
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 professional are asked to report any suspected adverse reactions
via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard
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. Activated charcoal or gastric lavage should also be considered.
The appropriate actions as described for adults should be taken in case of an overdose
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
practically no effect on the cardiovascular system.
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 (15-45 mg 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.
After oral administration of Mirtazapine, the active substance mirtazapine is rapidly
and well absorbed (bioavailability ≈ 50 %), reaching peak plasma levels after approx.
one hour. Food intake has no influence on the pharmacokinetics of mirtazapine.
Binding of mirtazapine to plasma proteins is approx. 85 %.
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
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.
Mirtazapine displays linear pharmacokinetics within the recommended dose range.
The clearance of mirtazapine may be decreased as a result of renal or hepatic
Preclinical safety data
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 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.
List of excipients
Sodium benzoate (E211)
Saccharin sodium (E954)
Citric acid monohydrate (E330)
Maltitol liquid (E965)
Orange tangerine flavour No. PHL-132597 (contains ethanol)
The oral solution should not be mixed with fluids other than water.
Shelf life after first opening of the bottle: 6 weeks
Special precautions for storage
Do not store above 25ºC.
Nature and contents of container
Bottle: Amber (Type III glass)
Closure: HDPE, EPE wadded, child resistant closure
Dosing Device: Polypropylene body and purple HDPE plunger with a capacity of 3
ml and dosage graduation at every 1 ml
Bottle Adaptor: Low density polyethylene
Pack size: 66 ml
Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
MARKETING AUTHORISATION HOLDER
Rosemont Pharmaceuticals Ltd
Yorkdale Industrial Park
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT
Source: Medicines and Healthcare Products Regulatory Agency
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