Mirtazapine 30mg Tablets
1. NAME OF THE MEDICINAL PRODUCT
Mirtazapine 30mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 30 mg of mirtazapine.
For excipients, see 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet.
Brownish, scored on both sides, 12.7 x 6.5 mm 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
Adults
The effective daily dose is usually between 15 and 45 mg; the starting dose is 15 or 30 mg.
Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response within 2-4 weeks. With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further 2-4 weeks, then treatment
should be stopped.
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 renal impairment (creatinine clearance < 40 ml/min ). This should be taken into account when prescribing mirtazapine to this category of patients (see section 4.4).
Hepatic impairment
The clearance of mirtazapine may be decreased in patients with hepatic impairment. This should be taken into account when prescribing mirtazapine to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated (see section 4.4).
Mirtazapine has an elimination half-life of 20-40 hours and therefore mirtazapine is suitable for once daily administration. It should be taken preferably as a single night-time dose before going to bed. Mirtazapine may also be given in two divided doses (once in the morning and once at night-time, the higher dose should be taken at night).
The tablets should be taken orally. The tablet will rapidly disintegrate and can be swallowed without water.
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).
4.3 Contraindications
Hypersensitivity to mirtazapine or any of the excipients.
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 film-coated tablets 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.
Jaundice
The treatment should be discontinued in the presence of jaundice.
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, 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.
• 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
• 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, caution should be exercised when the medicinal product is administered to patients with:
• 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. Patients with a history of mania/hypomania should be closely monitored. Mirtazapine should be discontinued in any patient entering a manic phase.
Although mirtazapine is not addictive, post-marketing experience shows that abrupt termination of treatment after long term administration may sometimes result in withdrawal symptoms. The majority of withdrawal reactions are mild and self-limiting. Among the various reported withdrawal symptoms, dizziness, agitation, anxiety, headache and nausea are the most frequently reported. Even though they have been reported as withdrawal symptoms, it should be realized that these symptoms may be related to the underlying disease. As advised in section 4.2, it is recommended to discontinue treatment with mirtazapine gradually.
Care should be taken in patients with micturition disturbances like prostate hypertrophy and in patients with acute narrow-angle glaucoma and increased intra-ocular pressure (although there is little chance of problems with mirtazapine because of its very weak anticholinergic activity).
• Akathisia/psychomotor restlessness: The use of antidepressants have been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
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 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.
Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 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 with mirtazapine.
Mirtazapine may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking mirtazapine.
Mirtazapine dosed at 30 mg once daily caused a small but statistically significant increase in the 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 warfarin with mirtazapine.
Pharmacokinetic interactions
Carbamazepine and phenytoin, CYP3A4 inducers, 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.
Coadministration 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.
In in vivo -interaction studies, mirtazapine did not influence the pharmacokinetics of risperidone or paroxetine (CYP2D6 substrate), carbamazepine (CYP3A4 substrate),
Lithium, amitriptyline and cimetidine.
4.6 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 effect or reproductive toxicity of clinical relevance however developmental toxicity has been observed (see section 5.3 Preclinical safety data). 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.
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).
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.
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.
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 (fc1/10) |
Common (* 1/100 to <1/10) |
Uncommon (i 1/1,000 to <1/100) |
Rare (>1/10,000 to <1/1,000) |
Frequency not known |
|
Investigations |
Weight increased1 | ||||
|
Blood and the lymphatic system disorders |
Bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia thrombocytopenia) | ||||
|
Eosinophilia | |||||
|
Nervous system disorders |
Somnolence1, 4 Sedation1, 4 |
Lethargy1 |
2 Paraesthesia |
Myoclonus |
Convulsions (insults) Serotonin syndrome |
|
2 Headache |
Oral paraesthesia | ||||
|
Dysarthria | |||||
|
Dizziness |
Restless legs | ||||
|
Tremor |
Syncope | ||||
|
Gastrointestinal disorders |
Dry mouth |
Nausea3 2 Diarrhea 2 Vomiting |
Oral hypoaesthesia |
Pancreatitis |
Mouth oedema Increased salivation |
|
Skin and subcutaneous tissue disorders |
Exanthema2 |
Stevens-Johnson Syndrome Dermatitis bullous Erythema multiforme | |||
|
Toxic epidermal necrolysis | |||||
|
Musculoskeletal and connective tissue disorders |
Arthralgia Myalgia Back pain1 | ||||
|
Metabolism and nutrition disorders |
Increase in appetite1 |
Hyponatraemia |
|
Vascular disorders |
Orthostatic hypotension |
. 2 Hypotension | |||
|
General disorders and administration site conditions |
Oedema peripheral1 Fatigue |
Somnambulism | |||
|
Hepatobiliary disorders |
Elevations in serum transaminase activities | ||||
|
Psychiatric disorders |
Abnormal dreams Confusion Anxiety2, 5 Insomnia3, 5 |
Nightmares2 Mania 2 Agitation Hallucinations Psychomotor restlessness (incl. akathisia, hyperkinesia) |
Aggression |
Suicidal ideation6 Suicidal behaviour6 | |
|
Endocrine disorders |
Inappropriate antidiuretic hormone secretion |
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 frequently.
3
In clinical trials these events occurred statistically significantly more frequently during treatment with placebo than with mirtazapine.
4N.B. dose reduction generally does not lead to less somnolence/sedation but can jeopardize antidepressant efficacy.
5 Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression) can develop or become aggravated. Under mirtazapine treatment, development or aggravation of anxiety and insomnia has been reported.
6 Cases of suicidal ideation and suicidal behaviours have been reported during mirtazapine therapy or early after treatment discontinuation (see section 4.4).
In laboratory evaluations in clinical trials transient increases in transaminases and gammaglutamyltransferase have been observed (however associated adverse events have not been reported statistically significantly more frequently with mirtazapine than with placebo).
Paediatric population
The following adverse events were observed commonly in clinical trials in children: weight gain, urticaria and hypertriglyceridaemia (see also section 5.1).
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: Other antidepressants ATC code: N06AX11
Mirtazapine is a centrally active presynaptic alpha2-antagonist, which increases central noradrenergic and serotonergic neurotransmission in the central nervous system. The serotonergic effect is a result of a specific action on the 5-HT1-receptors, since mirtazapine blocks both the 5-HT2- and the 5-HT3-receptors. Both enantiomers of mirtazapine are activeagents. The S(+) enantiomer blocks alpha2- and 5-HT2-receptors, whereas the R(-) enantiomer blocks 5-HT3- receptors. The H1-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 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 (1545 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.
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 responses associated with long-term treatment with high doses of hepatic enzyme inducers.
PHARMACEUTICAL PARTICULARS
6.
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
36 months
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.
6.6. Instruction for use and handling (, and disposal)
No special requirements.
No Data Held
7. MARKETING AUTHORISATION HOLDER
Relonchem Limited Cheshire House,
Gorsey Lane, Widnes, Cheshire,
WA8 0RP United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 20395/0044
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13 th October 2004
10 DATE OF REVISION OF THE TEXT
14/01/2014