Mirtazapine

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.

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.

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 product is discontinued, it may be necessary to reduce the mirtazapine dose.

Mirtazapine may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking mirtazapine.

Co-administration 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 and the dose may have to be decreased when co-administering mirtazapine with potent CYP3A4 inhibitors.

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.

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.

Caution should be exercised and the dose may have to be decreased when co-administering mirtazapine with HIV protease inhibitors, azole antifungals, erythromycin or nefazodone.

Co-administration of mirtazapine 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). Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine.

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.

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.

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 product is discontinued, it may be necessary to reduce the mirtazapine dose.

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 cimetidine.

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

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 can not be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.

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.

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.

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.

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.

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).

Worsening of psychotic symptoms can occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; paranoid thoughts can be intensified.

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.

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 effects of clinical relevance, however developmental toxicity has been observed. 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.

Fertility

Non-clinical reproductive toxicity studies in animals did not show any effect on fertility.

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.

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.

The following list 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’.

Blood and the lymphatic system disorders

Frequency not known: Bone marrow depression (granulocytopenia, agranulocytosis, aplastic anaemia thrombocytopenia), Eosinophilia

Nervous system disorders

Very common: Somnolence^a,d, Sedation^a,d, Headache^b

Common: Lethargy^a, Dizziness, Tremor

Uncommon: Paraesthesia^b, Restless legs, Syncope

Rare: Myoclonus

Frequency not known: Convulsions (insults), Serotonin syndrome, Oral paraesthesia, Dysarthria

Gastrointestinal disorders

Very common: Dry mouth

Common: Nausea^c, Diarrhea^b, Vomiting^b, Constipationa

Uncommon: Oral hypoaesthesia

Rare: Pancreatitis

Frequency not known: Mouth oedema, Increased salivation

Skin and subcutaneous tissue disorders

Common: Exanthema^b

Frequency not known: Stevens- Johnson Syndrome, Dermatitis bullous, Erythema multiforme, Toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Common: Arthralgia, Myalgia, Back pain^a

Frequency not known: Rhabdomyolysis

Metabolism and nutrition disorders

Very common: Weight increased^a, Increase in appetite^a

Frequency not known: Hyponatraemia

Vascular disorders

Common: Orthostatic hypotension

Uncommon: Hypotension^b

General disorders and administration site conditions

Common: Oedema peripheral^a, Fatigue

Frequency not known: Somnambulism, Generalised oedema, Localised oedema

Hepatobiliary disorders

Rare: Elevations in serum transaminase activities

Renal and urinary disorders

Frequency not known: Urinary retention

Psychiatric disorders

Common: Abnormal dreams, Confusion, Anxiety^b,e, Insomnia^c,e

Uncommon: Nightmares^b, Mania, Agitation^b, Hallucinations, Psychomotor restlessness (incl. akathisia, hyperkinesia)

Rare: Aggression

Frequency not known: Suicidal ideation^f, Suicidal behaviour^f

Endocrine disorders

Frequency not known: Inappropriate antidiuretic hormone secretion

Investigations

Frequency not known: Increased creatinine kinase

^a In clinical trials these events occurred statistically significantly more frequently during treatment with mirtazapine than with placebo.
^b In clinical trials these events occurred more frequently during treatment with placebo than with mirtazapine, however not statistically significantly more frequently.
^c In clinical trials these events occurred statistically significantly more frequently during treatment with placebo than with mirtazapine.
^d N.B. dose reduction generally does not lead to less somnolence/sedation but can jeopardize antidepressant efficacy.
^e 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.
^f Cases of suicidal ideation and suicidal behaviours have been reported during mirtazapine therapy or early after treatment discontinuation.

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.