Vilanterol and Fluticasone furoate

Studies in subjects with mild, moderate and severe hepatic impairment showed an increase in systemic exposure to fluticasone furoate (both C_max and AUC).

Caution should be exercised when dosing patients with hepatic impairment who may be more at risk of systemic adverse reactions associated with corticosteroids.

For patients with moderate or severe hepatic impairment the maximum dose is 92/22 micrograms.

Caution is advised when co-administering with strong CYP 3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products) as there is potential for increased systemic exposure to both fluticasone furoate and vilanterol. Co-administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid undesirable effects, in which case patients should be monitored for systemic corticosteroid undesirable effects. A repeat dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (184/22 micrograms) and the strong CYP3A4 inhibitor ketoconazole (400mg). Co-administration increased mean fluticasone furoate AUC_(0-24) and C_max by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serum cortisol. Co-administration increased mean vilanterol AUC_(0-t) and C_max 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta₂-agonist related systemic effects on heart rate, blood potassium or QTcF interval.

Beta₂-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists. Concurrent use of both non-selective and selective beta₂-adrenergic blockers should be avoided unless there are compelling reasons for their use.

Fluticasone furoate/vilanterol should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections.

There have been reports of increases in blood glucose levels in diabetic patients and this should be considered when prescribing to patients with a history of diabetes mellitus.

Fluticasone furoate/vilanterol should be used with caution in patients with severe cardiovascular disease or heart rhythm abnormalities, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.

Studies in animals have shown reproductive toxicity at exposures which are not clinically relevant. There are no or limited data from the use of fluticasone furoate and vilanterol trifenatate in pregnant women.

Administration of fluticasone furoate/vilanterol to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

There is insufficient information on the excretion of fluticasone furoate or vilanterol trifenatate and/or metabolites in human milk. However, other corticosteroids and beta₂-agonists are detected in human milk. A risk to breastfed newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue fluticasone furoate/vilanterol therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no fertility data in humans. Animal studies showed no effect of fluticasone furoate/vilanterol trifenatate on fertility.

Fluticasone furoate or vilanterol has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Data from large asthma and COPD clinical trials were used to determine the frequency of adverse reactions associated with fluticasone furoate/vilanterol. In the asthma clinical development programme a total of 7,034 patients were included in an integrated assessment of adverse reactions. In the COPD clinical development programme a total of 6,237 subjects were included in an integrated assessment of adverse reactions.

The most commonly reported adverse reactions with fluticasone furoate and vilanterol were headache and nasopharyngitis. With the exception of pneumonia and fractures, the safety profile was similar in patients with asthma and COPD. During clinical studies, pneumonia and fractures were more frequently observed in patients with COPD.

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class and frequency. The following convention has been used for the classification of frequencies: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

^*,** See below 'Description of selected adverse reactions'

Description of selected adverse reactions

^*Pneumonia

In an integrated analysis of the two replicate one year studies in moderate to severe COPD (mean predicted post-bronchodilator screening FEV1 of 45%, standard deviation (SD) 13%) with an exacerbation in the preceding year (n=3255), the number of pneumonia events per 1000 patient years was 97.9 with FF/VI 184/22 micrograms, 85.7 in the FF/VI 92/22 micrograms and 42.3 in the VI 22 micrograms group. For severe pneumonia the corresponding number of events per 1000 patient years were 33.6, 35.5, and 7.6 respectively, while for serious pneumonia the corresponding events per 1000 patient years were 35.1 for FF/VI 184/22 micrograms, 42.9 with FF/VI 92/22 micrograms, 12.1 with VI 22 micrograms. Finally, the exposure-adjusted cases of fatal pneumonia were 8.8 for FF/VI 184/22 micrograms versus 1.5 for FF/VI 92/22 micrograms and 0 for VI 22 micrograms.

In a placebo-controlled study (SUMMIT) in subjects with moderate COPD (mean percent postbronchodilator screening FEV1 of 60%, SD 6%), and a history of, or an increased risk of cardiovascular disease, the incidence of pneumonia with FF/VI, FF, VI and placebo was: adverse events (6%, 5%, 4%, 5%); serious adverse events (3%, 4%, 3%, 3%); adjudicated on treatment deaths due to pneumonia (0.3%, 0.2%, 0.1%, 0.2%); the exposure adjusted rates (per 1000 treatment years) were: adverse events (39.5, 42.4, 27.7, 38.4); serious adverse events (22.4, 25.1, 16.4, 22.2); adjudicated on-treatment deaths due to pneumonia (1.8, 1.5, 0.9, 1.4) respectively.

In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of pneumonia per 1000 patient years was 18.4 for FF/VI 184/22 micrograms versus 9.6 for FF/VI 92/22 micrograms and 8.0 in the placebo group.

^**Fractures

In two replicate 12 month studies in a total of 3,255 patients with COPD the incidence of bone fractures overall was low in all treatment groups, with a higher incidence in all fluticasone furoate/vilanterol groups (2%) compared with the vilanterol 22 micrograms group (<1%). Although there were more fractures in the fluticasone furoate/vilanterol groups compared with the vilanterol 22 micrograms group, fractures typically associated with corticosteroid use (e.g., spinal compression/thoracolumbar vertebral fractures, hip and acetabular fractures) occurred in <1% of the fluticasone furoate/vilanterol and vilanterol treatment arms.

For the SUMMIT study, the incidence of all events of fracture with FF/VI, FF, VI and placebo were 2% in each arm; fractures commonly associated with ICS use were less than 1% in each arm. The exposure-adjusted rates (per 1000 treatment years) for all fracture events were 13.6, 12.8, 13.2, 11.5 respectively; fractures commonly associated with ICS use were 3.4, 3.9, 2.4, 2.1 respectively. In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of fractures was <1%, and usually associated with trauma.