Summary of Product Characteristics Updated 21-Jan-2014 | Kent Pharma UK Ltd
Suicide/suicidal thoughts or clinical worseningDepression 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 depressionBone 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 as a rare occurrence in clinical trials with 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 and should be introduced cautiously in patients who have a history of seizures.• 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 myocardial infarction, which requires conventional precautions and caution during concurrent administration of other medicinal products• hypotensionLike 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: antidepressants may alter glycaemic control. Insulin and/ or hypoglycaemic dosage may need to be adjusted and dose monitoring is recommended.
JaundiceThe 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. Patients with a history of mania/ hypomania should be closely monitored. Mirtazapine should be discontinued in any patient entering a manic phase.• 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. • Although antidepressants do not cause dependency, abrupt cessation of long-term treatment may cause dizziness, anxiety, agitation, nausea, headache and malaise. As advised in section 4.2, it is recommended to discontinue treatment with mirtazapine gradually.• 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.
HyponatraemiaHyponatraemia, 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 syndromeInteraction 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. From post marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with Mirtazapine Tablets alone (see section 4.8).
LactoseMirtazapine 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 ageMirtazapine 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.
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.
|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 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 2 Mania Agitation 2 Hallucinations Psychomotor restlessness (including akathisia, hyperkinesias)||Suicidal ideation 6 Suicidal behaviour 6|
|Nervous system disorders||Somnolence 1, 4 Sedation 1, 4 Headache 2||Lethargy 1 Dizziness Tremor||Paraesthesia Restless legs Syncope||Myoclonus||Convulsions (insults) Serotonin syndrome Oral paraesthesia|
|Vascular disorders||Orthostatic hypotension||Hypotension 2|
|Gastrointestinal disorders||Dry mouth||Nausea 3 Diarrhoea 2 Vomiting 2||Oral hypoaesthesia||Pancreatitis||Mouth oedema|
|Hepatobiliary disorders||Elevations in serum transaminase activities|
|Skin and subcutaneous tissue disorders||Exanthema||Stevens-Johnson syndrome Dermatitis bullous Erythema multiforme Toxic epidermal necrolysis|
|Musculoskeletal & connective tissue disorders||Arthralgia Myalgia Back pain 1|
|General disorders & administration site conditions||Oedema peripheral 1 Fatigue|
|Renal and urinary disorders||Urinary retention|
Paediatric populationThe following adverse events were observed commonly in clinical trials in children: • Weight gain • Urticaria • Hypertriglyceridaemia See also section 5.1.
Paediatric populationTwo 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.
AbsorptionAfter 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.
DistributionAbout 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 eliminationThe mean half-life of elimination is 20-40 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 populationsThe clearance of mirtazapine may be decreased in patients with renal or hepatic insufficiency.
Coating:HypromelloseMacrogol 8000Titanium dioxide (E171)Yellow iron oxide (E172).Red iron oxide (E172)
|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.|
Pack sizes28, 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.
The Bower, 4 Roundwood Avenue, Stockley Park, Heathrow, UB11 1AF
0845 437 5567
0845 437 5565
+44 (0)1233 506 574
0800 220 280