This information is intended for use by health professionals

1. Name of the medicinal product

Mirtazapine 30mg Film-Coated Tablets

2. Qualitative and quantitative composition

Each tablet contains 30mg of mirtazapine

For excipients, see 6.1

3. Pharmaceutical form

Film coated oral tablet

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

4. Clinical particulars
4.1 Therapeutic indications

Treatment of depressive illness.

4.2 Posology and method of administration

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

Adults: Treatment should begin with 15 mg daily. The dosage generally needs to be increased to obtain an optimal clinical response. The effective daily dose is usually between 15 and 45 mg.

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: 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 renalimpairment (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).

Mirtazapine has a half-life of 20-40 hours and therefore mirtazapine is suitable for once-a-day administration. It should be taken preferably as a single night-time dose before going to bed. Mirtazapine may also be given in two divided doses (once in the morning and once at night-time, the higher dose should be taken at night).

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 two to four weeks. With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further two to four weeks, then treatment should be stopped.

Treatment should preferably be continued until the patient has been completely symptom-free for four to six months. After this, treatment can be gradually discontinued.

Withdrawal symptoms seen on discontinuation of Mirtazapine

Abrupt discontinuation should be avoided (see section 4.4 Special Warnings and Special Precautions for Use and section 4.8 Undesirable Effects). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

4.3 Contraindications

Hypersensitivity to mirtazapine or any of the other ingredients of mirtazapine.

Concomitant use of mirtazapine with monoamine oxidase (MAO) inhibitors (see section 4.5).

4.4 Special warnings and precautions for use

Use in children and adolescents under 18 years of age

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 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 antidepressant drugs 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 drug therapy 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 a limited number of mirtazapine 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. Antidepressants should be avoided in patients with unstable seizure disorders/epilepsy and patients with controlled epilepsy should be carefully monitored. From clinical experience it appears that insults occur rarely in patients treated with mirtazapine.

- 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 infarct, 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.

Moreover, as 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 realised 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 intraocular pressure (although there is little chance of problems with mirtazapine because of its very weak anticholinergic activity).

- akathisia/psychomotor restlessness: The use of mirtazapine has been associated with the development of psychomotor restlessness, which clinically may be very similar to 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 and it may be necessary to review the use of mirtazapine.

- 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 side-effects of antidepressants. During clinical research with mirtazapine, side-effects have not been reported more often in elderly patients than in other age groups; however experience until now is limited.

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.

Withdrawal symptoms seen on discontinuation of mirtazapine treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects). In clinical trials adverse events seen on treatment discontinuation occurred in approximately 15% of patients treated with mirtazapine. The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.

Dizziness, agitation, anxiety, headache and nausea and/or vomiting are the most commonly reported reactions. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within two weeks, though in some individuals they may be prolonged (two to three months or more). It is therefore advised that mirtazapine should be gradually tapered when discontinuing treatment over a period of several weeks, according to the patient's needs (see "Withdrawal Symptoms Seen on Discontinuation of Mirtazapine", Section 4.2 Posology and Method of Administration).

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Mirtazapine may potentiate the central nervous dampening action of alcohol; patients should therefore be advised to avoid alcohol during treatment with mirtazapine.

Mirtazapine should not be administered concomitantly with MAO inhibitors or within two weeks of cessation of therapy with these agents. 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, 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 potentiate the sedative effects of benzodiazepines and other sedatives (notably most antipsychotics, antihistamine H1 antagonists, opioids); caution should be taken when these drugs are prescribed together with 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

In vitro data suggest that mirtazapine is a very weak competitive inhibitor of the cytochrome P450 enzymes CYP1A2, CYP2D6 and CYP3A.

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.

Co-administration of the potent inhibitor of CYP3A4, ketoconazole increased the peak plasma levels and the AUC of mirtazapine by approximately 40% and 50% respectively.

Carbamazepine and phenytoin, CYP3A4 inducers, increased mirtazapine clearance about twofold, resulting in a decrease in plasma levels of 60% and 45% respectively. When carbamazepine or another inducer of drug metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with an inducer is stopped, mirtazapine dosing may have to be decreased.

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 Pregnancy and lactation

Pregnancy

Limited data of the use of mirtazapine in pregnant women do not indicate an increased risk for congenital malformations.

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).

Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg (approx. 3 and 5 times respectively the maximum recommended human dose on the basis of exposure) have revealed no evidence of teratogenic effects. There was, however, in rats an increase in post-implantation loss; there was also an increase in pup deaths during the first three days of lactation (cause of death unknown) and a decrease in pup birth weights. These findings are common with CNS-active drugs at high dose levels in animals.

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.

Lactation

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 appetite1

Hyponatraemia

Psychiatric disorders

Abnormal dreams,

Confusion,

Anxiety2,5

Insomnia3,5

Nightmares2

Mania

Agitation2

Hallucinations

Psychomotor restlessness (inc.akathisia, hyperkinesias)

Aggression

Suicidal ideation6

Suicidal behaviour6

Nervous system disorders

Somnolence1,4

Sedation1,4

Headache2

Lethargy1

Dizziness,

Tremor

Paraesthesia2

Restless legs,

Syncope

Myoclonus

Convulsions (insults),

Serotonin syndrome,

Oral paraesthesia

Dysarthria

Vascular disorders

Orthostatic hypotension

Hypotension2

Gastrointestinal disorders

Dry mouth

Nausea3

Diarrhea2

Vomiting2

Constipation1

Oral hypoaesthesia

Pancreatitis

Mouth oedema

Increased salivation

Hepato-biliary disorders

Elevations in serum transaminase activities

Jaundice

Skin and subcutaneous tissue disorders

Exanthema2

Stevens- Johnson Syndrome

Dermatitis bullous

Erythema multiforme

Toxic epidermal necrolysis

Musculoskeletal, connective tissue and bone disorders

Arthralgia

Myalgia

Back pain1

Rhabdomyolysis

Renal and urinary disorders

Urinary retention

General disorders and administration site conditions

Oedema peripheral2

Fatigue

Somnambulism

Generalised oedema

Localised oedema

Investigations

Weight increased1

Increased creatinine kinase

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 gamma-glutamyltransferase 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: www.mhra.gov.uk/yellow card.

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 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

ATC Code: NO6AX11

Pharmacotherapeutic group: Antidepressant

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 responsible for its sedative properties. Mirtazapine is generally well tolerated. It has practically no anticholinergic activity and, at therapeutic doses, has practically no effect on the cardiovascular system.

Dose response

No formal clinical trials were conducted investigating the dose response of mirtazapine. However, it is clinical experience that up-titrating the dose might be beneficial for some patients.

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

After oral administration of mirtazapine tablets, the active constituent mirtazapine is rapidly and well absorbed (bioavailability ≈ 50%), reaching peak plasma levels after about 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-a-day dosing. Steady state is reached after three to four 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 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 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. There are no differences in the pharmacokinetic parameters of racemic mirtazapine or its demethyl metabolite in extensive and poor metabolisers. Plasma metabolite profiles for the individual enantiomers are qualitatively similar in extensive and poor metabolisers.

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 or genotoxicity.

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 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, 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

Hydroxypropylcellulose

Maize starch

Colloidal anhydrous silica

Low-substituted hydroxypropyl cellulose

Magnesium stearate

Purified water

Film-coating:

Opadry Brown 20A56788

(Hydroxypropyl cellulose)

(Hypromellose)

(Titanium dioxide, E171)

(Iron oxide yellow, E172)

(Iron oxide red)

(Iron oxide black)

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months (unopened)

6.4 Special precautions for storage

Do not store above 25°C.

Keep out of the reach and sight of children.

6.5 Nature and contents of container

PVC/PVDC/aluminium foil opaque blister packs containing 28 tablets.

6.6 Special precautions for disposal and other handling

Not applicable

7. Marketing authorisation holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing authorisation number(s)

PL 29831/0142

9. Date of first authorisation/renewal of the authorisation

21 April 2007

10. Date of revision of the text

31/03/2015