Document: spc-doc_PL 06464-2055 change

• spc-doc_PL 00142-0613
• spc-doc_PL 04416-0611
• spc-doc_PL 06453-0061
• spc-doc_PL 06464-2055
• spc-doc_PL 20395-0044
• spc-doc_PL 20395-0096

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1.    NAME OF THE MEDICINAL PRODUCT

Mirtazapine 30mg Tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 30mg of mirtazapine.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Brownish, scored on both sides, 12.7 x 6.5mm oval, biconvex, film-coated tablets. Marked with I on one side.

4. CLINICAL PARTICULARS

4.1.    Therapeutic indications

Major depressive episode.

4.2.    Posology and method of administration

The tablets should be swallowed whole without chewing, with a sufficient amount of fluid. The tablets can be taken with or without food.

Adults: The initial dose is 15 or 30 mg, taken preferably in the evening. The maintenance dose is usually between 15 mg and 45 mg per day.

Elderly patients: As in adults. Changes, especially increments of dosage must be made cautiously and under close supervision.

Children and adolescents (under 18 years of age): Since the safety and efficacy of mirtazapine have not been investigated in these patients, the use is not recommended.

Renal or hepatic insufficiency: The elimination of mirtazapine may be slower in patients with renal or hepatic insufficiency. This must be considered when mirtazapine is prescribed for these patients or the clinical responses are interpreted.

Mirtazapine tablets can be taken once daily, since the elimination half-life is 20 to 40 hours. The medicine should be taken preferably as a single dose immediately before bedtime. The daily dose can also be divided into two doses taken in the morning and at the bedtime. The larger dose should be taken in the evening.

The antidepressive effect of mirtazapine usually becomes evident after 1 to 2 weeks use. Treatment with an adequate dose should result in a positive response within 2 to 4 weeks. With an insufficient response, the dose can be increased up to the maximum dose. After having obtained an optimal clinical effect and the patient is free of symptoms, the treatment should be continued for 4 to 6 months, until a gradual discontinuation can be considered. If no clinical response is observed within 2 to 4 weeks of treatment with the maximum dose, the treatment should be gradually discontinued. Gradually tapering down the dosage is necessary to avoid withdrawal symptoms.

4.3. Contraindications

Hypersensitivity to mirtazapine or any of the excipients.

4.4. Special warnings and precautions for use

Bone marrow depression, which is usually manifested by granulocytopenia or agranulocytosis, has been reported in the users of mirtazapine. This effect is usually seen after 4 to 6 weeks of treatment, but it usually disappears after discontinuation of treatment. Reversible agranulocytosis has also been reported in rare cases in clinical trials on mirtazapine. The attendant doctor should be alert for fever, throat pain, stomatitis and other signs and symptoms suggestive of infection. If these manifestations occur, the treatment should be discontinued and a complete blood count should be taken.

The medicinal product is to be used with caution, and careful monitoring to be applied in patients with:

-    epilepsy or organic brain syndrome; although clinical experience indicates that epileptic seizures are rare during mirtazapine treatment

-    hepatic or renal failure

-    heart disease, such as conduction disturbances, angina pectoris or recent cardiac infarction, which requires conventional precautions and caution during concurrent administration of other medicinal products

-    hypotension.

Like with other antidepressants, caution should be exercised when the medicinal product is administered to patients with:

-    micturition disturbances, such as prostatic hyperplasia (although mirtazapine is only slightly anticholinergic)

-    acute narrow angle glaucoma and elevated intraocular pressure (during mirtazapine treatment, the risk of these problems is very low because of the low anticholinergic effect of mirtazapine)

-    diabetes mellitus.

The treatment should be discontinued in the presence of jaundice.

Like in the case of other antidepressants, the following should be considered:

-    An exacerbation of psychotic symptoms may occur when schizophrenia or other psychoses are treated with antidepressants; paranoid thoughts can also be intensified.

-    When the depressive phase of a bipolar disorder is being treated, a switch to a manic phase may occur.

-    Because of the risk of suicide, the patient should be supplied with, especially at the onset of treatment, only a limited number of mirtazapine tablets

-    Although antidepressants do not cause dependency, abrupt cessation of long-term treatment may cause anxiety, agitation, nausea, headache and malaise.

-    Elderly patients are often more sensitive, especially to the undesirable effects of antidepressants. In clinical studies of mirtazapine, the reported incidence of undesirable effects has not been any higher in elderly patients than in other age groups. However, experience is still limited.

-    Reactions of mirtazapine in combination with other SSRIs are reported in section 4.5.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or

glucose-galactose malabsorption should not take this medicine.

4.5. Interactions 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.

If other serotonergic drugs (e.g. SSRI) are used concomitantly with mirtazapine, there is a risk of interaction that could lead to the development of a serotonin syndrome. From postmarketing experience it appears that serotonin syndrome occurs very rarely in patients treated with mirtazapine alone or in combination with SSRIs. If the combination is considered therapeutically necessary, dosage changes should be made with caution and sufficiently close monitoring for signs of beginning serotonergic over stimulation maintained.

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

Pharmacokinetic interactions

Mirtazapine is almost completely 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. Coadministration 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, a CYP3A4 inducer, 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 or phenytoin) 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), carbamazepine (CYP3A4 substrate), amitriptyline and cimetidine.

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 control the prothrombine time in case of concomitant treatment of warfarine with mirtazapine.

4.6. Pregnancy and lactation

There are no adequate data from the use of mirtazapine in pregnant women. Studies in animals have not shown any teratogenic effect or reproductive toxicity of clinical relevance (see 5.3 Preclinical safety data). The potential risk for humans is unknown. Mirtazapine should not be used during pregnancy unless clearly indicated following a careful clinical risk/benefit consideration.

Although animal experiments show that mirtazapine is excreted only in very small amounts in the milk, the use of mirtazapine in breast-feeding mothers is not recommended. No human data is available.

4.7.    Effects on ability to drive and use machines

Mirtazapine may moderately impair concentration and alertness, especially in the beginning of treatment. This should be considered before engaging in tasks requiring special alertness and concentration, such as driving and operating dangerous machines.

4.8.    Undesirable effects

Depressed patients display a number of signs and symptoms 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 mirtazapine treatment.

System organ class	Common (>1/100, <1/10)	Uncommon (>1/1 000, <1/100)	Rare (>1/10 000, <1/1000)
Blood and lymphatic system disorders			■ Acute bone marrow depression (eosinophilia, granulocytopenia, agranulocytosis, aplastic anaemia and thrombocytopenia, see also 4.4 Special warnings and special precautions for use)

Metabolism and nutrition disorders	■ Increased appetite and weight gain
Psychiatric disorders			■    Mania ■    Confusion ■    Hallucinations ■    Anxiety* ■    Insomnia* ■    Nightmares/vivid dreams
Nervous system disorders	■    Somnolence (which may impair alertness), usually occurring during the first few weeks of therapy (NB. dose reduction does not generally lead to less sedation but can jeopardize antidepressant efficacy) ■    Dizziness ■    Headache		■    Convulsions (seizures) ■    Tremor ■    Myoclonus ■    Paraesthesias ■    Restless legs
Cardiac disorders			■ (Orthostatic) hypotension/syncope
Gastrointestin al disorders		■ Nausea	■    Dry mouth ■    Diarrhoea
Hepato-biliary disorders			■ Elevations of hepatic transaminase levels
Skin and subcutaneous tissue disorders			■ Exanthema
Musculoskelet al and connective tissue disorders			■    Arthralgia ■    Myalgia
General disorders	■ Generalised or local edema and accompanying weight gain		■ Fatigue

*anxiety and insomnia, which may be symptoms of depression, can develop and become aggravated - under treatment with mirtazapine, development or aggravation of anxiety and insomnia has been reported very rarely

Although mirtazapine does not cause dependence, 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, nausea, anxiety and agitation are the most frequently reported. As advised in section 4.2 Posology and method of administration, treatment with mirtazapine should be discontinued gradually.

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 therapeutic dose, especially with mixed overdosages. Overdosage is treated with activated charcoal, support of vital functions and symptomatic treatment. Gastric lavage may be considered, if necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressants ATC code: N06AX11

Mirtazapine is a presynaptic alpha₂-antagonist, which increases noradrenergic and serotonergic neurotransmission in the central nervous system. The serotonergic effect is a result of a specific action on the 5-HTi-receptors, since mirtazapine blocks both the 5-HT₂-and the 5-HT₃-receptors. Both enantiomers of mirtazapine are active agents. The S(+) enantiomer blocks alpha₂- and 5-HT₂-receptors, whereas the R(-) enantiomer blocks 5-HT₃-receptors. The ^-antagonistic effect is considered to the cause of the sedative effect of mirtazapine. The anticholinergic effect of mirtazapine is minimal and within therapeutic doses there are seldom clinically significant cardiovascular adverse events.

Mirtazapine is an antidepressant, which can be used to treat the episodes of major depression. The presence of symptoms such as anhedonia, psychomotor inhibition, sleep disturbances (early wakening) and weight loss, increase the chance of a positive response. Other symptoms are: loss of interest, suicidal thoughts and changes in mood (better in the evening than in the morning). Mirtazapine begins to exert its effect in general after i to 2 weeks of treatment.

5.2. Pharmacokinetic properties

Absorption

After oral administration of mirtazapine tablets, the active substance mirtazapine is rapidly and well absorbed (bioavailability about 50%), reaching peak plasma levels after about 2 hours. Food intake has no influence on the pharmacokinetics of mirtazapine.

Distribution

About 85% of mirtazapine is bound to plasma proteins. Steady state concentrations are reached after 3-4 days, after which there is no further accumulation. Mirtazapine displays linear pharmacokinetics within the recommended dose range.

Metabolism and elimination

The mean half-life of elimination is 20 to 40 hours; longer half-lives, up to 65 hours, have occasionally been recorded but in young men the half-lives have been shorter. Mirtazapine is metabolized effectively and eliminated in urine and faeces over a few days. Biotransformation mainly occurs through demethylation and oxidation and subsequent conjugation. In vitro studies of human liver microsomes show that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the mirtazapine 8-hydroxy metabolite, whereas the CYP3A4 enzyme is assumed to be responsible for the formation of the N-demethyl and N-oxide metabolites. The demethyl metabolite is pharmacologically active, and its pharmacokinetic profile is similar to that of non-metabolized drug.

Special patient populations

The clearance of mirtazapine may be decreased in patients with 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 and reproductive toxicity studies in rats or rabbits. In reproductive toxicity studies in rats and rabbits at high dose levels, 20 and 17 times the maximum human dose at mg/m² basis, respectively, no teratogenic effects were observed. There were, however, increase in postimplantation loss, decrease in the pup birth weights, and reduction in pup survival during the first three days of lactation. 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 reponses associated with long-term treatment with high doses of hepatic enzyme inducers.

6. PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

Core:

Lactose monohydrate Pregelatinised maize starch Anhydrous colloidal silica Croscarmellose sodium Magnesium stearate.

Coating:

Hypromellose Macrogol 8000 Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172).

6.2.    Incompatibilities

Not applicable.