Mirtazapine 30mg Tablets

Document: spc-doc_PL 06453-0061 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Mirtazapine 30 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 30mg of mirtazapine.

Excipient(s) with known effect:

Lactose monohydrate

For the full list of excipients, see section 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 episodes

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 30mg, taken preferably in the evening. The maintenance dose is usually between 15mg and 45mg 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: 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 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 the active substance(s) or to any of the excipients listed in section 6.1.

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

4.4 Special warnings and precautions for use

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 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 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.

Bone marrow depression

Bone marrow depression, which is usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with Mirtazapine Tablets. Reversible agranulocytosis has also been reported as a rare occurrence in clinical trials with mirtazapine. In the post marketing period of Mirtazapine Tablets 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.

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 and 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, such as conduction disturbances, angina pectoris or recent myocardial infarction, where normal precautions should be taken and concomitant medicines carefully administered.

• Low blood pressure

Diabetes mellitus: antidepressants may alter glycaemic control. Insulin and/ or hypoglycaemic dosage may need to be adjusted and close monitoring is recommended.

Like with other antidepressants, the following should be considered:

• Worsening of psychotic symptoms may occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; 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. 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, such as 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 detrimental.

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 Tablets alone (see section 4.8).

Elderly patients

Elderly patients are often more sensitive, especially to the undesirable effects of antidepressants. In clinical studies of mirtazapine, undesirable effects have not been reported more often in elderly patients than in other age groups.

Lactose

Mirtazapine tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in children and adolescents under 18 years of age

Mirtazapine 30mg Tablets 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.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

- Mirtazapine should not be administered concomitantly with MAO inhibitors or within 14 days 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, antihistamines 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 30mg once daily caused a small but statistically significant increase in the international normalised 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.

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 products 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Limited data of the use of mirtazapine in pregnant women do not indicate an increased for congenital malformations. Studies in animals have not shown any teratogenic effects of clinical relevance, however developmental toxicity has been observed.

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).

Breast-feeding

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.

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 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 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 mirtazapine treatment.

The most commonly reported adverse reactions, occurring in more than 5% of patients treated with mirtazapine in randomised placebo-controlled trials (see below) are somnolence, sedation, dry mouth, weight increased, increase in appetite, dizziness and fatigue.

All randomised 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 60mg 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 for these events in the clinical trials. The frequency of adverse reactions from spontaneous reporting for which no cases in the randomised placebo-controlled patient trials were observed with mirtazapine has been classified as ‘not known’. Table 1 Adverse reactions to 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 (granulocytopaenia , agranulocytosis, aplastic anaemia, thrombocytopaenia ⁾

Eosinophilia

Endocrine

disorders

Inappropriate

antidiuretic

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
					hormone secretion
Metabolism and nutrition disorders	Weight increased ¹ Increase in appetite ¹				Hyponatraemia
Psychiatric disorders		Abnormal dreams Confusion Anxiety ² 5 Insomnia ³ 5	Nightmares ²Mania ₂ Agitation Hallucination s Psychomotor restlessness (including akathisia, hyperkinesias )	Aggression	Suicidal ideation ⁶ Suicidal behaviour 6
Nervous system disorders	Somnolence 1, 4 Sedation ¹ 4 2 Headache	Lethargy ¹ Dizziness Tremor	Paraesthesia Restless legs Syncope	Myoclonus	Convulsions (insults) Serotonin syndrome Oral paraesthesia Dysarthia
Vascular disorders		Orthostatic hypotension	Hypotension 2
Gastrointestin al disorders	Dry mouth	Nausea ³ ₂ Diarrhoea ₂ Vomiting	Oral hypoaesthesi a	Pancreatitis	Mouth oedema Increased salivation
Hepatobiliary disorders				Elevations in serum transaminas e activities
Skin and subcutaneous tissue disorders		Exanthema			Stevens-Johnson syndrome Dermatitis bullous Erythema multiforme Toxic epidermal necrolysis
Musculoskelet al & connective tissue disorders		Arthralgia Myalgia Back pain ¹
General disorders &		Oedema peripheral ¹			Somnambulism Generalised

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

administration site conditions

Fatigue

oedema

Localised oedema

Renal and

urinary

disorders

Urinary retention

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

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

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, utricaria 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 at: www.mhra.gov.uk/yellowcard.

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.

5.1 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-HTj-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 Hj-antagomstic 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 1 to 2 weeks of treatment.

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 Remeron 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

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/m basis, respectively, no teratogenic effects were observed. There were, however, increase in post-implantation 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 responses 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.

6.3. Shelf life

3 years

6.4. Special precautions for storage

Blister package: Store in the original package. Keep the blister in the outer carton.

PP container: Store in the original package. Keep the container tightly closed.

6.5. Nature and contents of container

Pack sizes

28, 30, 60, 90 and 100 tablets in clear PVC/Al blister.

28, 30, 60, 90, 100 and 250 tablets in white/opaque polypropylene tablet containers and LDPE caps.

The pack sizes of more than 100 tablets are intended for hospital use. Not all pack sizes may be marketed.

Instruction for use and handling (, and disposal)

6.6.

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Athlone Laboratories Ballymurray Roscommon Ireland

8. MARKETING AUTHORISATION NUMBER

PL 06453/0061

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13 ^th October 2004

10 DATE OF REVISION OF THE TEXT

04/04/2014