Pharmacodynamic interactions
[...]
- The risk of QT prolongation and/or ventricular arrhythmias (e.g. torsades de pointes) may be increased with concomitant use of medicines which prolong the QTc interval (e.g. some antipsychotics and antibiotics)

Paediatric population

Interaction studies have only been performed in adults.

Section 4.6
Pregnancy
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 (see section 5.3). Caution should be exercised when prescribing to pregnant women. If Zismirt orotab 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 been investigated an the association of PPHN to mirtazapine treatment, this potential risk cannot be ruled out taking in to account the related mechanism of action (increase in serotonin concentrations).

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.

Breast-feeding
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 Zismirt orotab mirtazapine should be made taking into account the benefit of breast- feeding to the child and the benefit of Zismirt orotab mirtazapine therapy to the woman.

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

Section 4.7
Zismirt orotab Mirtazapine has minor or moderate influence on the ability to drive and use machines. Zismirt orotab 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.

Section 4.8
Gastrointestinal disorders: Constipation added under column 'common'.
Musculoskeletal and connective tissue disorders: Rhabdomyolysis added under column 'not known'.
Renal and urinary disorders: Urinary retention added under column 'not known'.
General disorders and administration site conditions: Generalised oedema and Localised oedema added under column 'not known'.
Investigations: Increased creatinine kinase added under column 'not known'.
[...]
Reporting of suspected adverse reactions: IMB contact details updated to HPRA.

Section 4.9:
Present experience concerning overdose with Mirtazapine 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 the therapeutic dose, especially with mixed overdoses. In these cases QT prolongation and torsade de pointes have also been reported.
Cases of overdose should receive appropriate symptomatic and supportive therapy for vital functions. ECG monitoring should be undertaken. Activated charcoal or gastric lavage should also be considered.

Paediatric population
The appropriate actions as described for adults should be taken in case of an overdose in paediatrics.

Section 5.1
Pharmacotherapeutic group: other antidepressants, ATC code: N06AX11

Mechanism of action/pharmacodynamic effects
Mirtazapine is a centrally active presynaptic α2-antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors, because 5-HT2 and 5-HT3 receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+)enantiomer by blocking α2 and 5-HT2 receptors and the R(-) enantiomer by blocking 5-HT3 receptors.

Clinical efficacy and safety
The histamine H1-antagonistic activity of mirtazapine is associated with its sedative properties. It has practically no anticholinergic activity and, at therapeutic doses, has only limited practically no effects (e.g. orthostatic hypotension) on the cardiovascular system.

Section 5.2
Absorption
After oral administration of Mirtazapine mirtazapine, the active substance mirtazapine is rapidly and well absorbed (bioavailability ≈ 50 %), reaching peak plasma levels after approx. two hours.
Food intake has no influence on the pharmacokinetics of mirtazapine.

Distribution
Binding of mirtazapine to plasma proteins is approx. 85 %.
The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and shorter half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-4 days, after which there is no further accumulation. Mirtazapine displays linear pharmacokinetics within the recommended dose range. Food intake has no influence on the pharmacokinetics of mirtazapine.
Biotransformation
Major pathways of biotransformation are demethylation and oxidation, followed by conjugation. In vitro data from human liver microsomes indicate that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP3A4 is considered to be responsible for the formation of the N-demethyl and N-oxide metabolites. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound.

Elimination
Mirtazapine is extensively metabolized metabolised and eliminated via the urine and faeces within a few days. Major pathways of biotransformation are demethylation and oxidation, followed by conjugation. In vitro data from human liver microsomes indicate that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP3A4 is considered to be responsible for the formation of the N-demethyl and N-oxide metabolites. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound.
The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and shorter half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-4 days, after which there is no further accumulation.

Linearity/non-linearity
Mirtazapine displays linear pharmacokinetics within the recommended dose range.

Other special populations
The clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.

Section 5.3
Preclinical Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenicity or genotoxicity, carcinogenic potential, toxicity to reproduction and development.