3 years
Not applicable.
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
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.
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 metabolized 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.
6 January 2017
Merck Sharp & Dohme Limited
Hertford Road
Hoddesdon
Hertfordshire
EN11 9BU
United Kingdom
Store in the original package in order to protect from light and moisture.
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 (1x6), 18 (3x6), 30 (5x6), 48 (8x6), 90 (15x6) and 96 (16x6) and 180 (10x18 (3x6)) orodispersible tablets.
Not all pack sizes may be marketed.
| 15 mg | PL 00025/0546 |
| 30 mg | PL 00025/0547 |
| 45 mg | PL 00025/0548 |
No special requirements.
| Date of first authorisation: | 15 July 2003. |
| Date of latest renewal: | 18 April 2013. |
