Summary of medicine characteristics - ZISPIN SOLTAB 30 MG ORODISPERSIBLE TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Zispin SolTab 30 mg orodispersible tablet.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Zispin SolTab 30 mg orodispersible tablet contains 30 mg of mirtazapine.
Excipient(s) with known effect
Each Zispin SolTab 30 mg orodispersible tablet contains 9.30 mg aspartame and 56 mg sucrose.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
4 CLINICAL PARTICULARS
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antidepressants, ATC code: N06AX11
Mechanism of action/pharmacodynamic effects
Mirtazapine is a centrally active presynaptic a2-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 a2 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 effects (e.g. orthostatic hypotension) on the cardiovascular system.
The effect of Zispin SolTab (mirtazapine) on QTc interval was assessed in a randomised, placebo and moxifloxacin controlled clinical trial involving 54 healthy volunteers using a regular dose of 45 mg and a supra-therapeutic dose of 75 mg. Linear e-max modelling suggested that prolongation of QTc intervals remained below the threshold for clinically meaningful prolongation (see section 4.4).
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 (15–45 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 Zispin SolTab 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 Zispin SolTab, 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 %.
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 metabolised and eliminated via the urine and faeces within a few days. 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.
Special populations
The clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
In reproductive toxicity studies in rats and rabbits no teratogenic effects were observed. At two-fold systemic exposure compared to maximum human therapeutic exposure, there was an increase in post-implantation loss, decrease in the pup birth weights, and reduction in pup survival during the first three days of lactation in rats.
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
sugar spheres
hypromellose
povidone K30
magnesium stearate
basic butylated methacrylate copolymer
aspartame (E951)
citric acid, anhydrous crospovidone (type A) mannitol (E421) microcrystalline cellulose
natural and artificial orange flavour (No. SN027512) sodium hydrogen carbonate
6.2 Incompatibilities
Not known.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light and moisture
6.5 Nature and contents of container
Child-resistant, peel-to-open, rigid perforated unit dose blister, formed from a laminate of aluminium foil and plastic films sealed to a paper-based laminate of aluminium foil coated with a heat seal lacquer.
The plastic films contain: PVC (polyvinyl chloride), polyamide and polyester.
The blisters contain 6 orodispersible tablets each. The following pack sizes are available for each strength: 6 (1×6), 18 (3×6), 30 (5×6), 48 (8×6), 90 (15×6) and 96 (16×6) and 180 (10×18 (3×6)) orodispersible tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.