ions or any displacement reactions between formoterol and budesonide.
Elimination
The major part of a dose of formoterol is transformed by liver metabolism followed by renal elimination. After inhalation, 8% to 13% of the delivered dose of formoterol is excreted unmetabolised in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min) and the terminal elimination half-life averages 17 hours.
Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are eliminated in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.
Pharmacokinetic/pharmacodynamic relationship(s)
The pharmacokinetics of budesonide or formoterol in children and patients with renal failure are unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.
DuoResp Spiromax pharmacokinetic profile
In pharmacokinetic studies with and without a charcoal blockage, DuoResp Spiromax was eva luated by comparing it with an alternative authorised fixed-dose combination inhaled product containing the same active substances, budesonide and formoterol and has been shown to be equivalent in both systemic exposure (safety) and pulmonary deposition (efficacy).
5.3 Preclinical safety data
The toxicity observed in animal studies with budesonide and formoterol, given in combination or separately, were effects associated with exaggerated pharmacological activity.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant in humans at the recommended doses. Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure and implantation losses as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures than those reached during clinical use. However, these animal experimental results do not seem to be relevant in humans.
6. Pharmaceutical particulars
6.1 List of excipients
Lactose monohydrate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
After opening the foil wrap: 6 months.
6.4 Special precautions for storage
Do not store above 25°C.
Keep the mouthpiece cover closed after removal of the foil wrap.
6.5 Nature and contents of container
The inhaler is white with a semi-transparent wine red mouthpiece cover. The inhaler is made of acrylonitrile butadiene styrene (ABS), polyethylene terephthalate (PT) , and polypropylene (PP). Each inhaler contains 120 doses and is foil-wrapped.
Pack sizes of 1, 2 or 3 inhalers.
Not all pack-sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
8. Marketing authorisation number(s)
EU/1/14/920/001
EU/1/14/920/002
EU/1/14/920/003
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 28 April 2014
10. Date of revision of the text
28 April 2014
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