Key points from the evidence | Inflammatory lesions of papulopustular rosacea: ivermectin 10 mg/g cream | Advice

Summary

In 2 randomised controlled trials (RCTs) ivermectin cream was statistically significantly more effective than vehicle cream (placebo) in improving rosacea severity score and reducing inflammatory lesion count. In another RCT, ivermectin was superior to metronidazole cream at reducing lesion count and improving rosacea severity score. Local adverse events, including skin burning sensation, skin irritation, pruritus and dry skin, are common, although these are mostly transient, mild to moderate in severity and usually decrease when treatment is continued.

Regulatory status: Ivermectin 10 mg/g cream (Soolantra) received a UK marketing authorisation in April 2015. It was launched in the UK in June 2015.

Effectiveness

Statistically significantly more people receiving ivermectin cream were considered treatment successes compared with those using vehicle cream. Success rate, measured using Investigator Global Assessment (IGA), was approximately 39% for ivermectin compared with approximately 15% for vehicle. People treated with ivermectin cream had approximately 8 fewer lesions compared with the vehicle group. Time to onset of efficacy was 4 weeks (2 RCTs, n=1371, 12 weeks).
Ivermectin cream was superior to metronidazole cream at reducing inflammatory lesions, with participants having approximately 10% fewer lesions (1 investigator‑blinded RCT, n=962, 16 weeks).

Safety

In 2 RCTs adverse events were reported by between 32 to 40% of people using ivermectin cream. Adverse events considered to be treatment‑related were reported by about 4% of people receiving ivermectin.
The most commonly reported adverse events were skin burning, skin irritation, pruritus and dry skin.
Adverse events are typically mild to moderate in severity, and usually decrease when treatment is continued.

Patient factors

Over two‑thirds of people treated with ivermectin cream rated their improvement as 'excellent' or 'good', compared with about one‑third of people in the vehicle group.
Ivermectin cream is applied once daily, while other topical treatments for rosacea are applied twice daily.
People with rosacea should be advised to avoid rosacea triggers, for example, sudden exposure to heat, certain foods and excessive sun exposure.

Resource implications

Ivermectin 10 mg/g cream is £18.29 for a 30 g tube (excluding VAT; cost taken from MIMS, December 2015).
Topical metronidazole 0.75% (cream or gel) costs between £6.60 and £22.63 for a 30 g or 40 g tube (excluding VAT; cost taken from MIMS December 2015 or Drug Tariff, December 2015).
Azelaic acid 15% gel costs £7.48 for a 30 g tube (excluding VAT; cost taken from Drug Tariff, December 2015).
In a clinical trial people receiving ivermectin cream used approximately half the amount of cream each day compared with those treated with metronidazole cream. This is because ivermectin is applied once daily and metronidazole twice daily.

Introduction and current guidance

Rosacea is a chronic relapsing disease of the facial skin, characterised by recurrent episodes of facial flushing, persistent erythema, telangiectasia (fine, dilated blood vessels), papules and pustules. Mild or moderate papulopustular rosacea (with a limited number of papules and pustules, and no plaques) is generally treated with a topical drug (metronidazole or azelaic acid). For moderate or severe papulopustular rosacea (with extensive papules, pustules, or plaques), oral tetracycline, erythromycin, doxycycline or lymecycline can be prescribed, although not all of these drugs are licensed for treating rosacea (Clinical Knowledge Summaries: rosacea).

Full text of introduction and current guidance.

Product overview

Ivermectin is a member of the avermectin class of medicines. The mechanism of action for treating the inflammatory lesions of rosacea is not known, but may be linked to the anti‑inflammatory effects of ivermectin, as well as causing the death of Demodex folliculorum mites (Soolantra 10 mg/g Cream [ivermectin] summary of product characteristics).

Full text of product overview.

Evidence review

This evidence summary is based on 2 randomised controlled trials (RCTs) of identical design that compared ivermectin with vehicle (placebo, study 1 [n=683] and study 2 [n=688], Stein Gold et al. 2014a), and a randomised, active‑comparator trial that compared ivermectin cream with metronidazole cream (n=962, Taieb et al. 2015). Information on long‑term safety, efficacy and recurrence rates is supplied by one 36‑week and two 40‑week extension studies.
In 2 RCTs ivermectin was statistically significantly more effective than vehicle at reducing signs and symptoms of papulopustular rosacea:
- For the co‑primary end point of 'treatment success' at 12 weeks, defined as an Investigator Global Assessment (IGA) score of 0 or 1 ('clear' or 'almost clear'), 38.4% and 40.1% of the ivermectin group, and 11.6% and 18.8% of the vehicle group were considered treatment successes (statistically significant difference, both p<0.001, number needed to treat [NNT]=5).
- From a baseline of approximately 32 lesions, people treated with ivermectin had a reduction of about 21 lesions and people treated with vehicle had a reduction of 13 lesions. At 12 weeks this equates to an absolute mean reduction in inflammatory lesion count (second co‑primary end point) of approximately 8.2 fewer inflammatory lesions for ivermectin compared with vehicle (p<0.001 both studies).
- Statistically significantly more people receiving ivermectin reported 'excellent' or 'good' improvements at week 12 compared with vehicle (secondary end point).
- Statistically significant improvements in participant satisfaction and quality of life were reported. Although the minimal clinically important difference in reduction of Dermatology Life Quality Index (DLQI) score was not reached, baseline DLQI scores were not poor, meaning large improvements would not be expected.
A 16‑week randomised, investigator‑blinded study compared the efficacy of ivermectin with metronidazole 0.75% cream (n=962, Taieb et al. 2015).
- The primary end point of this study was mean absolute change in inflammatory lesion count. Participants receiving ivermectin cream experienced an 83.0% reduction in inflammatory lesion count, compared with a reduction of 73.7% in the metronidazole group (p<0.001). This equated to a treatment difference of approximately 4 lesions between ivermectin and metronidazole.
- The secondary efficacy end point was treatment success (defined using IGA score) at week 16, which was achieved by 84.9% in the ivermectin group, compared with 75.4% for metronidazole (p<0.001, NNT=11).
- The incidence of adverse events was similar for ivermectin cream (reported by 32.4% of people) and metronidazole cream (33.1%), as was the incidence of treatment‑related adverse events (2.3% for ivermectin and 3.7% for metronidazole, Taieb et al. 2015).
The most common adverse events reported by people receiving ivermectin cream were skin burning sensation (1.3%), skin irritation (1.0%), pruritus (0.8%) and dry skin (0.7%). No systemic adverse events were reported in the clinical studies (Soolantra PAR).

Full text of evidence review.

Context

Mild or moderate papulopustular rosacea is usually treated with topical metronidazole or azelaic acid, with moderate or severe papulopustular rosacea often managed with oral tetracycline, erythromycin, doxycycline or lymecycline (Clinical Knowledge Summaries: rosacea).

Full text of context.

Estimated impact for the NHS

Local decision makers will need to consider the available evidence on efficacy and safety, as well as cost and individual patient factors, when making decisions about using ivermectin 10 mg/g cream or other topical treatments for papulopustular rosacea. A Cochrane review states that topical ivermectin appeared to be slightly more effective than topical metronidazole for papulopustular rosacea (van Zuuren et al. 2015). There are no published studies that directly compare the efficacy of ivermectin and azelaic acid.

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.