1. The following text is proposed for section 4.4 of the SPC for single-constituent salmeterol and formoterol products:

Although [product] may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on [product] during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with [product]. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on [product].

[product] should not be used (and is not sufficient) as the first treatment for asthma.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of [product]. Regular review of patients as treatment is stepped down is important. The lowest effective dose of [product] should be used.

2. For fixed combination products containing formoterol or salmeterol with an inhaled steroid, some wording similar to the above agreed wording is already included in the SPCs. To avoid repetition or any confusion regarding steroid use, the following wording is suggested:

Patients should not be initiated on [PRODUCT] during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with [product]. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on [product].

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of [product]. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Seretide should be used (see section 4.2).

(except SERETIDE® – change arising from the Article 6 referral for SERETIDE®)

[product] should not be used as the first treatment for asthma.

(except SERETIDE® – change arising from the Article 6 referral for SERETIDE®)

3. The following text is proposed for section 4.4 of the SPC for salmeterol-containing products:

Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART) suggested African-American patients were at increased risk of serious respiratory-related events or deaths when using salmeterol compared with placebo (see section 5.1). It is not known if this was due to pharmacogenetic or other factors. Patients of black African or Afro-Caribbean ancestry should therefore be asked to continue treatment but to seek medical advice if asthma symptoms remained uncontrolled or worsen whilst using [PRODUCT].

4. The following wording is proposed for inclusion of section 5.1 of the SPC for salmeterol-containing products, to give details of the outcomes from the SMART study:

Safety

The Salmeterol Multi-center Asthma Research Trial (SMART)

SMART was a multi-centre, randomised, double-blind, placebo-controlled, parallel group 28-week study in the US which randomised 13,176 patients to salmeterol (50μg twice daily) and 13,179 patients to placebo in addition to the patients’ usual asthma therapy. Patients were enrolled if ≥12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences.

Key findings from SMART: primary endpoint

Patient group	Number of primary endpoint events /number of patients		Relative Risk (95% confidence intervals)
	salmeterol	placebo
All patients	50/13,176	36/13,179	1.40 (0.91, 2.14)
Patients using inhaled steroids	23/6,127	19/6,138	1.21 (0.66, 2.23)
Patients not using inhaled steroids	27/7,049	17/7,041	1.60 (0.87, 2.93)
African-American patients	20/2,366	5/2,319	4.10 (1.54, 10.90)

(Risk in italics is statistically significant at the 95% level.)

Key findings from SMART by inhaled steroid use at baseline: secondary endpoints

	Number of secondary endpoint events /number of patients		Relative Risk (95% confidence intervals)
	salmeterol	placebo
Respiratory-related death
Patients using inhaled steroids	10/6127	5/6138	2.01 (0.69, 5.86)
Patients not using inhaled steroids	14/7049	6/7041	2.28 (0.88, 5.94)
Combined asthma-related death or life-threatening experience
Patients using inhaled steroids	16/6127	13/6138	1.24 (0.60, 2.58)
Patients not using inhaled steroids	21/7049	9/7041	2.39 (1.10, 5.22)
Asthma-related death
Patients using inhaled steroids	4/6127	3/6138	1.35 (0.30, 6.04)
Patients not using inhaled steroids	9/7049	0/7041	*

(*=could not be calculated because of no events in placebo group. Figures in italics are statistically significant at the 95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The secondary endpoints of combined all-cause death or life-threatening experience, all cause death, or all cause hospitalisation did not reach statistical significance in the whole population.