Consumer medicine information

1 Name of Medicine

Budesonide.
Formoterol fumarate dihydrate.

2 Qualitative and Quantitative Composition

Bufomix Easyhaler is available as a multidose inspiratory flow driven, metered dose dry powder inhaler. For ease of reference, formoterol, formoterol fumarate or formoterol fumarate dihydrate have been used throughout the rest of this document.
The following strengths are registered:
Bufomix Easyhaler 200/6. Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 160 microgram/inhalation and formoterol 4.5 microgram/inhalation.
Bufomix Easyhaler 400/12. Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 320 microgram/inhalation and formoterol 9 microgram/inhalation.
To avoid confusion, Bufomix Easyhaler is labelled as the metered dose of the monotherapy products budesonide and formoterol dry powders for inhalation. The monotherapy products are also labelled as metered doses. Table 1 gives the corresponding dose delivered to the patient.
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/BUFEAS01.gif List of excipients with known effect. Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for inhalation in a multiple dose dry powder inhaler.

4 Clinical Particulars

4.9 Overdose

An overdose of formoterol may lead to effects that are typical for β₂-adrenergic agonists: tremor, headache, palpitations, and tachycardia. Monitoring of serum potassium concentrations may be warranted. Hypotension, metabolic acidosis, hypokalaemia and hyperglycaemia may also occur. Supportive and symptomatic treatment may be indicated. β-blockers should be used with care because of the possibility of inducing bronchospasm in sensitive individuals. A metered dose of 120 microgram administered during three hours in patients with acute bronchial obstruction raised no safety concerns.
Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. However, the plasma cortisol level will decrease, and number and percentage of circulating neutrophils will increase. The number and percentage of lymphocytes and eosinophils will decrease concurrently. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.
Withdrawing Bufomix Easyhaler or decreasing the dose of budesonide will abolish these effects, although the normalisation of the HPA-axis may be a slow process.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.3 Preclinical Safety Data

Genotoxicity. Individually, budesonide and formoterol were not genotoxic in a series of assays for gene mutations (except for a slight increase in reverse mutation frequency in Salmonella typhimurium at high concentrations of formoterol fumarate), chromosomal damage and DNA repair. The combination of budesonide and formoterol has not been tested in genotoxicity assays.
Carcinogenicity. The carcinogenic potential of the budesonide/formoterol combination has not been investigated in animal studies.
In formoterol carcinogenicity studies there was a dose dependent increase in the incidence of uterine leiomyomas in mice dosed orally at 0.1, 0.5 and 2.5 mg/kg/day for two years, and a mesovarian leiomyoma was observed in a female rat dosed by inhalation at 0.13 mg/kg/day for two years. The effects observed are expected findings with high dose exposure to β₂-agonists.
Formoterol carcinogenicity studies performed by other companies used systemic exposure levels 800 to 4800-fold higher than those expected upon clinical use of formoterol (based on an 18 microgram daily dose).
Some carcinogenicity activity was observed in rats and mice. However, in view of the dose levels at which these effects were observed and the fact that formoterol is not mutagenic (except for very weak activity at high concentrations in one test system), it is concluded that the cancer risk in patients treated with formoterol fumarate is no greater than for other beta-adrenoceptor agonists.
The carcinogenic potential of budesonide has been evaluated in the mouse and rat at oral doses up to 200 and 50 microgram/kg/day, respectively. In male rats dosed with 10, 25 and 50 microgram budesonide/kg/day, those receiving 25 and 50 microgram/kg/day showed an increased incidence of primary hepatocellular tumours. In a repeat study this effect was observed in a number of steroid groups (budesonide, prednisolone, triamcinolone acetonide) thus indicating a class effect of corticosteroids.

6 Pharmaceutical Particulars

6.7 Physicochemical Properties

Budesonide. Budesonide is a white to off white crystalline powder. It is freely soluble in methylene chloride, sparingly soluble in ethanol and practically insoluble in water.
Chemical name: 16α, 17α-22 R, S-propylmethylenedioxypregna-1, 4-diene-1β, 21-diol-3, 20-dione.
Chemical structure.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSBUDESO.gif Molecular formula: C₂₅H₃₄O₆. Molecular weight: 430.5.
CAS number. 51333-22-3.
Formoterol fumarate dihydrate. Formoterol fumarate dihydrate is a white or almost white or slightly yellow powder. It is slightly soluble in water, soluble in methanol, slightly soluble in 2-propanol and practically insoluble in acetonitrile.
Chemical name: (R*R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide, (E)-2-butendioate(2:1), dihydrate).
Chemical structure.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSFORFUD.gif Molecular formula: C₄₂H₅₂N₄O₁₂,2H₂O. Molecular weight: 841.
CAS number. 183814-30-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes

https://stagingapi.mims.com/au/public/v2/images/fulltablegif/BUFEASST.gif