Worsening of depression and/or emergence of suicidal ideation and behavior suicidality or unusual changes in the behavior may occur in both adult and pediatric patients with major depressive disorder and other psychiatric disorder, whether or not they are taking antidepressants. This risk may persist until clinical important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, these has been a long standing concern that antidepressants may have a role in including worsening of the depression and the emergence of the suicidality in the certain patients during the early phases of treatment.
Mirtazapine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviors (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behavior 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 behavioral development are lacking.
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 post marketing 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 to symptoms such as fever, sore throat, stomatitis or other signs of infection; when such symptoms occur, treatment should be stopped and blood counts taken.
Careful dosing as well as regular and close monitoring is necessary in patients with: Epilepsy and organic brain syndrome: From clinical experience it appears that insults occur rarely in patients treated with mirtazapine.
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 like conduction disturbances, angina pectoris and recent myocardial infarction, where normal precautions should be taken and concomitant medicines carefully administered.
Low blood pressure.
As with other antidepressants, care should be taken in patients with: Micturition disturbances like prostate hypertrophy (although problems are not to be expected because mirtazapine possesses only very weak anticholinergic activity).
Acute narrow-angle glaucoma and increased intra-ocular pressure (also here little chance of problems with mirtazapine because of its very weak anticholinergic activity).
Treatment should be discontinued if jaundice occurs.
Moreover, as with other antidepressants, the following should be taken into account: Worsening of psychotic symptoms can occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; paranoid thoughts can be intensified.
When the depressive phase of manic-depressive psychosis is being treated, it can transform into the manic phase.
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.
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. It is recommended to discontinue treatment with mirtazapine gradually.
The use of antidepressants have been associated with the development of akathisia. 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.
Cases of QT prolongation, Torsade de Pointes, ventricular tachycardia, and sudden death, have been reported during the post-marketing use of 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.
Hyponatraemia 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 may occur when selective serotonin reuptake inhibitors (SSRIs) are used concomitantly with other serotonergic active substances. Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine.
Elderly patients are often more sensitive, especially with regard to the side-effects of antidepressants. During clinical research with mirtazapine, side-effects have not been reported more often in elderly patients than in other age groups; however experience until now is limited.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Weight gain: Weight gain ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open-label treatment, 8% of patients receiving mirtazapine discontinued for weight gain. In a 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients.
Cholesterol and triglycerides: In US controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine, compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting triglycerides to ≥500 mg/dL were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline.
Transaminase elevations: Clinically significant alanine aminotransferase (ALT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% of patients exposed to mirtazapine in a pool of short-term US controlled trials, compared to 0.3% of placebo patients and 2.0% of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued mirtazapine treatment. Mirtazapine should be used with caution in patients with impaired hepatic function.
Orthostatic hypotension: Mirtazapine was associated with significant orthostatic hypotension was infrequently observed in clinical trials with depressed patients.
Effects on ability to drive and use machines: Mirtazapine may impair concentration and alertness. Patients should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery.