New Medicines Committee Briefing March 2017 Ivermectin 1% Cream for the Topical Treatment of Papulopustular Rosacea in Adults.

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1 Soolantra is to be reviewed for use within: New Medicines Committee Briefing March 2017 Ivermectin 1% Cream for the Topical Treatment of Papulopustular Rosacea in Adults. Summary: 1 Primary Care Secondary Care Whilst it is not a life-threatening condition, rosacea is associated with psychological distress and can severely impair patients quality of life 1 Currently, National Institute of Health and Care Excellence (NICE) Clinical Knowledge Summaries (CKS) recommend topical metronidazole or azelaic acid as first line treatment for papulopustular rosacea 2. Soolantra (ivermectin) is licensed for the topical treatment of inflammatory lesions of papulopustular rosacea in adult patients 3. Soolantra is licensed for once daily administration, unlike topical metronidazole and azelaic acid which are applied twice daily. All Wales Medicine Strategy Group (AWSMG) recommended Soolantra as an option in papulopustular rosacea 4. The Scottish Medicines Consortium (SMC) recommended Soolantra as a treatment option in moderate or severe papulopustular rosacea 5. The Regional Drug and Therapeutic Centre (RDTC) recommend Soolantra as an option in the symptomatic treatment of rosacea 6. Ivermectin cream is applied once daily whereas other rosacea treatments are applied twice daily. In trial data this reflected approximately 50% reduction in the daily quantity of Ivermectin cream applied versus metronidazole (0.72 vs. 1.31) 7. A significantly higher success rate was achieved with Ivermectin cream versus placebo (39% vs. 15%, P<0.001) as well as a significant reduction in the number of lesions (8.2, P<0.001) 8. Ivermectin cream was superior to topical metronidazole cream at reducing inflammatory lesions (10% reduction, P<0.001). Treatment success was achieved by 84.9% in the ivermectin group, compared with 75.4% for metronidazole (p<0.001) 7. Treatment-related adverse effects were numerically lower with Ivermectin cream compared to topical metronidazole (2.3% vs. 3.7%). The most commonly reported adverse events were skin burning, skin irritation, pruritus and dry skin 7. In a Cochrane analysis, the evidence supporting the efficacy of Ivermectin cream was rated as high quality 9. In a meta-analysis of topical treatments for rosacea, Ivermectin cream was the only therapy that showed statistical superiority over vehicle at all time points 10. There was no statistically significant difference in success rate between the interventions, although ivermectin was associated with a higher likelihood of success versus azelaic acid and topical metronidazole 10.

2 Formulary application Consultants submitting application: Dr Nick Craven (Consultant Dermatologist) Clinical Director supporting application: Dr Paul Wilson (Clinical Director for Dermatology) Dr Craven has requested ivermectin 1% cream (Soolantra ) to be considered for inclusion in the North Staffordshire Joint Formulary for the topical treatment of inflammatory lesions of papulopustular rosacea in adult patients. He anticipates that the once daily dosing with ivermectin 1% cream will ensure that it is cost neutral with existing treatment options, which are twice daily. In published studies it has demonstrated superior efficacy to comparators and appears safe. Background Rosacea is a chronic inflammatory cutaneous disorder primarily affecting facial convexities (central forehead, chin, cheeks and nose). The prevalence is poorly characterised but it is reported to affect 1-22% of the population in Europe and the USA 7. Of these, one estimate suggests that 25% are moderate or severe in nature 11. Whilst it is not considered a life-threatening condition it is associated with great psychological distress and facial lesions have been found to significantly reduce health-related quality of life 1. The disease state is characterised by varying combinations of cutaneous signs including: flushing, erythema, telangiectasia, oedema, papules, pustules, ocular symptoms and rhinophyma 12. Given the diverse presentation of rosacea, the National Rosacea Society developed a standard classification system to further define patients (Table 1) 13. 2

3 Table 1 - National Rosacea Society classification of rosacea. Subtype 1 Erythematotelangiectatic rosacea 2 Papulopustular rosacea (PPR) 3 Phymatous rosacea 4 Ocular rosacea Description Flushing and persistent central facial erythema with or without telangiectasia. Other signs include central facial oedema, stinging and burning sensations, and roughness or scaling. Persistent central facial erythema with transient, central facial papules and/or pustules. Thickening skin, irregular surface nodularities and enlargement. May occur on the nose, chin, forehead, cheeks, or ears Foreign body sensation in the eye, burning or stinging, dryness, itching, ocular photosensitivity, blurred vision, telangiectasia of the sclera or other parts of the eye, or periorbital edema. Variant Granulomatous rosacea Non-inflammatory; hard; brown, yellow, or red cutaneous papules; or nodules of uniform size. The pathology of rosacea is complex and poorly characterised. Its aetiology is multifactorial and proposed contributing factors include abnormalities in innate immunity, inflammatory reactions to cutaneous parasites, ultraviolet damage, and vascular dysfunction Error! Bookmark not defined.. In addition, skin affected by rosacea is typically hypersensitive making it difficult to treat Error! Bookmark not defined.. The goal of therapy is to manage the clinical signs and symptoms of rosacea. However, it is important to consider the impact on patients psychological health and quality of life when prescribing treatment for this chronic condition. The National Institute of Clinical Excellence (NICE) Clinical Knowledge Summaries (CKS) provides prescribing guidance for papulopustular acne rosacea (Figure 1) 2. 3

4 Mild/Moderate Papulopustular Acne Rosacea Topical metronidazole 0.75% gel/cream applied twice daily OR Topical azelaic acid 15% gel applied twice daily Moderate/Severe Papulopustular Acne Rosacea Oral oxytetracycline/tetracycline 500mg twice daily OR Oral doxycycline 100mg once daily OR Oral lymecycline 408mg once daily OR Oral erythromycin 500mg twice daily Ivermectin, a member of the avermectin class, provides an alternative for the topical management of rosacea. The mechanism of action has not been characterised in rosacea, but may be linked to antiinflammatory effects as well as causing the death of Demodex folliculorum mites 3. The exact role of Demodex folliculorum in rosacea is unknown, but is thought to be an aggravating, rather than causative, factor 6. Current formulary status Ivermectin is not included in the North Staffordshire Joint Formulary (NSJF). Topical metronidazole has a green status and azelaic acid 15% is not included. 4

5 Therapeutic class and mode of action 3 Ivermectin is a member of the avermectin class. Avermectin is associated with anti-inflammatory effects secondary to inhibition of lipopolysaccharide-induced production of inflammatory cytokines. These anti-inflammatory properties have been replicated with topical ivermectin in animal skin models. Ivermectin also causes death of parasites, primarily through binding selectively and with high affinity to glutamate-gated chloride channels, which occur in invertebrate nerve and muscle cells. The mechanism of action of ivermectin in treating the inflammatory lesions of rosacea is not characterised but may be linked to these anti-inflammatory properties as well as causing the death of Demodex folliculorum which has been reported to be a factor in inflammation of the skin. 5

6 Licensed indications 3 Soolantra is licensed for the topical treatment of inflammatory lesions of papulopustular rosacea in adult patients. The safety and efficacy in children and adolescents aged less than 18 years have not been established. Dosage and administration 3 Soolantra is applied to the face once daily for up to 4 months. A pea-size amount should be applied to each of the five facial convexities (forehead, chin, nose and each cheek) and spread as a thin layer across the face, avoiding the eyes, lips and mucosa. Cosmetics may be applied after the medicinal product has dried. The treatment course may be repeated if required. In case of no improvement after 3 months, the treatment should be discontinued. Safety and adverse effects 3 Contraindications Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use Soolantra has not been studied in patients with renal or hepatic impairment. The following excipients may cause adverse effects: - Cetyl alcohol and stearyl alcohol may cause local skin reactions (e.g. contact dermatitis). - Methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) may cause allergic reactions (possibly delayed). - Propylene glycol may cause skin irritation. Topical ivermeticin is absorbed systemically. However, at steady state conditions the systemic exposure (AUC 0-24hr :36 ±16 ng/hr/ml) was lower than following a single 6-mg oral dose of ivermectin in healthy volunteers (AUC 0-24hr :134 ± 66 ng/hr/ml). Undesirable effects The most commonly reported adverse reactions are skin burning sensation, skin irritation, pruritus and dry skin, all occurring in 1% or less of patients treated with the medicinal product in clinical trials (Table2). Reactions are typically mild/moderate in severity and usually decrease when treatment is continued. 6

7 Table 2 Adverse reactions reported in clinical trials 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), not known (cannot be estimated from the available data) System Organ Class Frequency Adverse reactions Skin and subcutaneous tissue disorders Common Uncommon Skin burning sensation Skin irritation, pruritus, dry skin Drug Interactions 3 Concomitant use of Soolantra with other topical or systemic medicinal products for the treatment of rosacea has not been investigated. In vitro studies have shown that ivermectin is primarily metabolised by CYP3A4. Caution is advised when ivermectin is administered concomitantly with potent CYP3A4 inhibitors as the plasma exposure may be significantly increased. Presentation 3 The cream (Figure 3) is available in the following pack sizes: 2g, 15g, 30g, 45g or 60g. The 15g, 30g, 45g and 60g tubes have a child resistant closure whereas the 2g tube does not. Excipients Glycerol, isopropyl palmitate, carbomer, dimeticone, disodium edetate, citric acid monohydrate, cetyl alcohol, stearyl alcohol, macrogol cetostearyl ether, sorbitan stearate, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), phenoxyethanol, propylene glycol, oleyl alcohol, sodium hydroxide, purified water. Patent Status 14 Medication Patent Expiry Soolantra Date not available (up to 2019) Metronidazole 0.75% cream/gel Date not available (up to 2019) Azelaic acid 15% gel Date not available (up to 2019) 7

8 Guidance and Evidence Summary NICE Guidance No Scottish Medicines Consortium (SMC) 5 Yes Following a full submission, SMC concluded that: Ivermectin (Soolantra ) is accepted for restricted use within NHS Scotland for the treatment of moderate to severe inflammatory lesions of rosacea where a topical treatment is considered appropriate. The submitting company did not submit evidence for SMC assessment for use in patients with mild papulopustular rosacea, therefore SMC cannot recommend ivermectin 10mg/g cream for use in this sub-population. All Wales Medicines Strategy Group (AWMSG) 4 Yes Following a full submission, AWMSG concluded that: Ivermectin (Soolantra ) is recommended as an option for use within NHS Wales for the topical treatment of inflammatory lesions of rosacea (papulopustular) in adult patients. Regional Drug and Therapeutic Centre (RDTC) 6 Yes The RDTC conclude that trials have demonstrated the efficacy of ivermectin versus placebo and metronidazole. Although the clinical significance of reported improvements is not clear, patients may value even small improvements. With the available evidence, topical ivermectin represents an additional option in the symptomatic treatment of rosacea. Theoretically it may be more acceptable than oral tetracyclines or erythromycin. However, more robust comparative data are required to conclusively determine ivermectin s place in therapy. MTRAC No NICE Evidence Summary: New Medicine(ESNM68) 15 Yes The evidence summary is based on 2 randomised controlled trials 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) 7, 8. 8

9 Ivermectin cream was statistically significantly more effective than both placebo and metronidazole in improving rosacea severity score and reducing inflammatory lesion count. Local adverse events (burning sensation, irritation, pruritus and dry skin) are common, although these are mostly transient, mild to moderate in severity and usually decrease with continuation of treatment. 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 (P<0.001). At 12 weeks, there was an absolute mean reduction in inflammatory lesion count of approximately 8.2 fewer inflammatory lesions for ivermectin compared with vehicle (p<0.001). Time to onset of efficacy was 4 weeks (2 RCTs, n=1371, 12 weeks). Safety Adverse events considered to be treatment-related were reported by 2.3% of patients receiving ivermectin and 3.7% receiving metronidazole Error! Bookmark not defined.. 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. Ivermectin cream was superior to metronidazole cream at reducing inflammatory lesions, with participants having approximately 10% fewer lesions (P<0.001). Treatment success (defined using IGA score) at week 16 was achieved by 84.9% in the ivermectin group, compared with 75.4% for metronidazole (p<0.001, NNT=11). 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. Resource implications In a clinical trial people receiving ivermectin cream used approximately half the amount of cream each day compared with those treated with metronidazole cream. Ivermectin is applied once daily, while other topical rosacea treatments are applied twice daily. 9

10 Primary Care Dermatology Society (PCDS) 16 Yes Topical treatments for papulopustular rosacea If symptoms are mild, topical agents should be sufficient as first line eg Soolantra (ivermectin 10 mg/g) cream, Rozex (metronidazole 0.75%) gel or cream, or Finacea (azealic acid 15%) cream. Cochrane Review: Interventions for rosacea 9 Yes Design: A Cochrane review performed to assess the efficacy and safety of rosacea treatments. Randomised controlled trials were identified from searches of the Cochrane Library, MEDLINE (from 1946), EMBASE (from 1974), Science Citation Index and trial registers. Population: A total of 106 studies and 13,631 participants were included in the meta-analysis. Most of the participants in the included studies had papulopustular rosacea, however in 16 of the studies most or all of the participants had subtype 1 (Erythematotelangiectatic) rosacea. The participants were years of age (mean = 48.6 years) and predominately female (8332 women; 3718 males; 1581 unspecified). Intervention: There were 11 categories of interventions within the meta-analysis: topical metronidazole (15); topical azelaic acid (7); topical brimonidine (6); topical ivermectin (2); topical metronidazole, azelaic acid or other topical treatments, or both (35); oral antibiotics (10); oral antibiotics combined with topical treatments (6); oral antibiotics compared with topical antibiotics (5); other systemic treatments (10); laser and light-based therapies (7); and other treatments or combined treatments (3). Results: High quality evidence was available to support the effectiveness of topical azelaic acid, topical ivermeticin and topical brimonidine. Moderate quality evidence was available for topical metronidazole. Two studies showed a statistically significant and clinically important improvement in favour of topical ivermectin versus placebo (high quality evidence). Participants' assessments in these studies showed a risk ratio (RR) of 1.78 (95% CI 1.50 to 2.11) and RR of 1.92 (95% CI 1.59 to 2.32), which were supported by physicians' assessments. One study demonstrated superiority of topical ivermectin versus topical metronidazole for papulopustular rosacea, demonstrating an improvement in quality of life and participant and physician assessed outcomes (high quality evidence). 10

11 The efficacy, safety, and tolerability of ivermectin compared with current topical treatments for the inflammatory lesions of rosacea: a network meta-analysis 10. Design: A systematic review was conducted from January 2011 to June 2015 in order to update the previous meta-analysis (Zuuren et al, 2011) 17. Population: A total of 19 studies were included in the final analysis. The total number of patients was not specified but the population of the individual studies varied from 72 to 1299 patients. The patient population of interest was adults (>19 years of age) of any gender or race who had been diagnosed with moderate-to-severe papulopustular rosacea. Studies which did not meet these criteria were excluded. Intervention: The interventions included in the review were: ivermectin 1 % cream, azelaic acid 15 % gel; azelaic acid 20 % cream; metronidazole 1 % gel/cream/lotion; metronidazole 0.75 % gel/cream/lotion; oral antibiotics; pimecrolimus 1 % cream; silica encapsulated benzoyl peroxide with or without topical antibiotics; sulfacetamide in combination with sulfur. The duration of the studies was 10 to 56 weeks. Endpoints: Outcomes of interest included: Efficacy (success rate, percentage change in inflammatory lesion count). Safety (incidence of any AE, any serious AE [SAE], any treatment-related AE [TRAE], burning/stinging, skin irritation, worsening of erythema, and worsening of rosacea). Tolerability (all-cause withdrawals, withdrawals due to AE). Success rate was defined as either an Investigator Global Assessment (IGA) score of 0 (clear) or 1 (minimal) on a 5-point scale, or 0 (clear), 1 (minimal), or 2 (mild) on a 7-point Likert scale. Percentage change in inflammatory lesion count was defined as the percentage reduction compared to placebo. Outcomes: Success Rate: At 12 weeks, ivermectin 1 % cream QD was the only active treatment to show statistical superiority to vehicle for treatment success at all time points investigated and in both analyses (RR and number needed to treat (NNT)). There was also a higher likelihood of success with ivermectin 1 % cream once daily compared with twice daily applications of azelaic acid 15 % gel and metronidazole 0.75 % gel/cream, with fewer patients needing to be treated in order for one patient to achieve success (Table 3). However, this 11

12 difference did not reach statistical significance. Silica encapsulated benzoyl peroxide 1 or 5 % gel produced a lower RR and a similar NNT, although the difference was not significant. Table 3 - Results of a mixed treatment comparison of success rate for ivermectin 1 % cream once daily versus other available topical treatments and vehicle at 12 weeks. Comparator treatment 12 weeks 12 studies RR (95 % Cl) (vs. ivermectin 1 % cream once daily) Azelaic acid 15 % gel once daily 1.33 (0.99 to 2.20) Azelaic acid 15 % gel twice daily 1.25 (1.14 to 1.37) Metronidazole 0.75 % cream twice daily 1.17 (1.08 to 1.29) Metronidazole 1 % gel once daily 1.18 (0.98 to 1.56) Silica encapsulated benzoyl peroxide 1 % gel once daily 1.09 (0.86 to 1.78) Silica encapsulated benzoyl peroxide 5 % gel once daily 0.94 (0.81 to 1.29) Vehicle 1.56 (1.46 to 1.65) Number needed to Treat (NNT) (95 % CI) (vs. vehicle) Azelaic acid 15 % gel once daily 7 ( 120 to 120) Azelaic acid 15 % gel twice daily 9 (6 to 14) Metronidazole 0.75 % cream twice daily 6 (4 to 13) Metronidazole 1 % gel once daily 6 (3 to 41) Silica encapsulated benzoyl peroxide 1 % gel once daily 4 ( 31 to 44) Silica encapsulated benzoyl peroxide 5 % gel once daily 3 (2 to 9) Ivermectin 1 % cream once daily 3 (3 to 4) Reduction in Inflammatory Lesion Count: At week 12, ivermectin 1 % cream once daily was associated with a significantly greater reduction in inflammatory lesion count than vehicle at all evaluable time points (Table 4). Also, there was a greater percentage reduction in inflammatory lesion count with ivermectin 1 % cream once daily versus to azelaic acid 15 % gel once/twice daily and metronidazole 0.75 % cream twice daily. No significant differences were observed between ivermectin 1 % cream once daily and metronidazole 1 % gel twice daily; metronidazole 1 % gel twice daily + doxycycline 40 mg once daily; sodium sulfacetamide 10 % + sulfur 5 % cream twice daily. 12

13 Table 4 - Results of a mixed treatment comparison of percentage change in inflammatory lesion count between ivermectin 1 % cream QD and comparators at 12 weeks. Comparator treatment Azelaic acid 15 % gel QD Azelaic acid 15 % gel BID Metronidazole 0.75 % cream BID 12 weeks (Absolute difference, 95 % Crl) 14 studies ( to 2.87) 8.04 ( to 3.43) 9.92 ( to 6.35) Metronidazole 1 % gel BID ( 3.63 to 39.95) Metronidazole 1 % gel BID + doxycycline 40 mg QD 0.04 ( to 25.65) Sodium sulfacetamide 10 % + sulfur 5 % cream BID 1.68 ( to 6.85) Vehicle ( to 17.60) Safety There was no significant difference in the rate of discontinuation due to adverse events (AEs) between ivermectin 1 % cream and any of the comparators at 12 weeks (Figure 1). There was a significantly lower risk of treatment-related AEs with ivermectin 1 % cream once daily compared with azelaic acid 15 % foam/gel twice daily [0.47 ( )] and vehicle [0.63 ( )]. There was with no significant difference between ivermectin 1 % cream once daily and all other comparators. 13

14 Figure 1 - Results of meta-analysis between ivermectin 1 % cream and comparators for the incidence of any adverse events (top), serious adverse events (middle), and treatment-related adverse events (bottom) at 12 weeks. Limitations: These conclusions are largely formed by indirect comparisons due to the lack of direct head-to-head data and it is difficult to assess the heterogenicity of the study methods. There was variability in clinical characteristics at baseline: baseline inflammatory lesion counts were higher in studies investigating ivermectin 1 % cream compared with studies evaluating metronidazole 1 % cream or azelaic acid 15 % gel. The heterogenicity of general skin care routines and avoidance of triggers was not reported. Finally, the results should be interpreted with caution as it is not possible to extrapolate beyond week

15 Superiority of ivermectin 1% cream over metronidazole 0 75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial 7. Design: This was a phase 3, investigator-blinded, randomized controlled trial conducted in 64 centres from 10 European countries from April 2012 to April Population: A total of 962 patients (18 years or older) were randomised to the study. Eligible subjects presented with facial inflammatory lesions and moderate or severe PPR; the latter was noted by an Investigator Global Assessment (IGA) score of 3 (several small or large papules/pustules, moderate erythema) or 4 (numerous small and/or large papules/pustules, severe erythema). Demographics and baseline disease characteristics were comparable between the two treatment arms. Intervention: Patients received Ivermectin 1% (IVM) once daily (n=478) or metronidazole 0.75% (MTZ) cream twice daily (n=484) for 16 weeks. The subjects were instructed to maintain a consistent lifestyle throughout the study regarding rosacea triggers (i.e. avoiding known offending environmental factors and foods, and excessive sun exposure). Study visits were as follows: a screening visit, and at baseline, weeks 3, 6, 9, 12 and 16. Primary and Secondary Endpoints: Primary efficacy endpoints were performed at study visits and included: Inflammatory lesion counts (papules and pustules) counted on five facial regions (forehead, chin, nose, right cheek, left cheek). The Investigator's Global Assessment (IGA) of disease severity (Table 5). Grade Score Clinical description Success Clear 0 No inflammatory lesions present, no erythema Almost clear 1 Very few small papules/pustules, very mild erythema present Mild 2 Few small papules/pustules, mild erythema Failure Moderate 3 Several small or large papules/pustules, moderate erythema Severe 4 Numerous small and/or large papules/pustules, severe erythema Table 5 - Investigators Global Assessment (IGA) score Primary safety endpoints included adverse events (AEs) throughout the study, local tolerance parameters (stinging/burning, dryness, itching) at each visit evaluated on a 4-point scale [from 0 (none) to 3 (severe)], and laboratory parameters (at baseline, weeks 9 and 16). Secondary endpoints included the patient's evaluation of rosacea improvement compared to baseline, with a global 5-point scale (worse, no improvement, moderate, good or excellent) and the patient s appreciation questionnaire at the end of the study. The quality of life was measured using a Dermatology Life Quality Index (DLQI), completed at baseline and at week

16 Outcomes: The daily quantity of MTZ applied in the MTZ arm (1.31g) was nearly twice as much as in the IVM arm (0.72g). In the primary outcome of percentage reduction in lesion count from baseline to week 16, IVM was superior to MTZ (reductions of 83.0% vs. 73.7% respectively, P<0.001)(Figure 2). A significant difference began to emerge from week 3 until week 16. The IGA success rate in the IVM group at week 16 was significantly higher than with MTZ (84.9% vs. 75.4%, p<0.001) (Figure 3). At week 16, 34.9% of patients in the IVM group were rated as completely clear compared to 21.7% with MTZ (p value not reported). Figure 2 - Mean percentage change from baseline in inflammatory lesion counts (95% confidence intervals (CI) displayed) Figure 3 - Percentage IGA success based on clear or almost clear. 16

17 The incidence of overall (32.4% with IVM vs. 33.1% with MTZ, P value not reported) and treatment related AEs (2.3% with IVM vs. 3.7% with MTZ, P value not reported) was similar between the two arms. The most common treatment related AE was skin irritation (0.6% with IVM vs. 0.8% with MTZ, P value not reported). There was a higher rate of treatment discontinuation with metronidazole due to treatment related AEs (0.6% with IVM vs. 2.1% with MTZ, P value not reported). In terms of local tolerance, the incidence of worsening from baseline was higher in the MTZ arm: stinging/burning (11.1% with IVM vs. 15.5% with MTZ, P value not reported); dryness (10.8% with IVM vs. 12.8% with MTZ, P value not reported); itching (8.8% with IVM vs. 11.4% with MTZ, p value not reported). At week 16, the percentage of patients who rated their global improvement as excellent or good was higher with IVM (85.5% with IVM vs. 74 8% with MTZ, P value not reported). Furthermore, more subjects receiving IVM 1% reported an excellent improvement (52.3% vs. 37.0% respectively, P value not reported). More patients treated with IVM reported a satisfactory response in the subject's appreciation questionnaire (76.0% with IVM vs. 61.3% with MTZ, P value not reported). In addition, more patients receiving IVM considered the product easy to use, whereas more subjects found MTZ to be irritating (data not reported). Patients treated with IVM showed a higher numerical reduction in their DLQI score than patients treated with MTZ ( 5 18 vs. 3 92; P < 0.01). At the end of the study after 16 weeks of treatment, 71% of patients treated with IVM reported that their disease had no deleterious effect at all on their quality of life compared to 64% with MTZ (P value not reported). Limitations: The patients were not blinded during the study. There is no reporting on how successful the avoidance of rosacea triggers was. Skin care routines, such as cleansing and moisturising, were not standardised in the trial. Concomitant or prior use of other rosacea treatments was not reported in the trial. Patients had moderate to severe rosacea and there is no data on the efficacy or safety of ivermectin cream in patients with mild rosacea. There was no plateau of efficacy at 16 weeks and longterm results cannot be extrapolated. 17

18 Cost analysis Medicine Description IVERMECTIN (SOOLANTRA) CREAM NMC Review February 2017: Usage and Expenditure for Dec15-Nov16 UHNM Expenditure for Dec15-Nov16: Current Price UHNS (incl. VAT) Drug Tariff (excl. VAT) Quantity Royal Stoke Pharmacy (Ascribe) Expenditure (VAT included) Royal Stoke Lloyds Quantity Expenditure (VAT not included) Royal Stoke epact Quantity Based on Total Act Cost (VAT not included) UHNM Royal Stoke TOTAL (VAT applied where appropriate) IVERMECTIN (SOOLANTRA) 10MG/G CREAM (30g) METRONIDAZOLE (ANABACT) 0.75% GEL (15g) METRONIDAZOLE (ANABACT) 0.75% GEL (30g) METRONIDAZOLE (ROZEX) 0.75% GEL (40g) METRONIDAZOLE (ROZEX) 0.75% CREAM (30g) METRONIDAZOLE (NO BRAND) 0.75% CREAM (30g) NA AZELAIC ACID (FINACEA) 15% GEL (30g) TOTAL CCG Expenditure for Dec15-Nov16: Medicine Description Sum of Total (g) Total Cost IVERMECTIN (SOOLANTRA) 10MG/G CREAM 6,150 3, METRONIDAZOLE 0.75% GEL 84,455 35, METRONIDAZOLE 0.75% CREAM 32,970 7, METRONIDAZOLE 0.75% GEL/CREAM TOTAL 117,425 42, AZELAIC ACID (FINACEA) 15% GEL 12,450 2,

19 References 1 Balkrishnan R, McMichael AJ, Hu JY et al. Correlates of health related quality of life in women with severe facial blemishes. Int J Dermatol : National Institute of Health and Care Excellence (NICE). Rosacea Acne. Clinical Knowledge Summaries (CKS). London Available at: (Accessed 13 th Dec 2016). 3 Electronic Medicines Compendium (EMC). Soolantra 10mg/g Cream. Galderma (U.K) Ltd Available at: (Accessed 13 th Dec 2016). 4 All Wales Medicines Strategy Group (AWMSG). Final Appraisal Recommendation: Ivermectin (Soolantra ). AWMSG (Ref No. 1627) Available at: (Accessed 14th Dec 2016). 5 Scottish Medicines Consortium (SMC). Advice: Ivermectin (Soolantra ). SMC (No. 1104/15) Available at: (Accessed 14th Dec 2016). 6 Regional Drug and Therapeutic Centre (RDTC). Ivermectin for the treatment of rosacea. RDTC (Ref No. 146) Available at: (Accessed 14 th Dec 2016). 7 Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0 75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol (4): Stein-Gold L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol Mar;13(3): Van Zuuran EJ, Fedorowicz Z, Carter B, et al. Interventions for rosacea. Cochrane Database of Systematic Reviews Issue 4: CD Siddiqui K, Stein-Gold L, Gill J. The efficacy, safety, and tolerability of ivermectin compared with current topical treatments for the inflammatory lesions of rosacea: a network meta-analysis. Springerplus. 2016; 5(1): Tan J et al. An observational cross-sectional survey of rosacea: clinical associations and progression between subtypes. Br J Dermatol : Wilkin J. Rosacea: pathophysiology and treatment. Arch Dermatol : Wilkin J, Dahl M, Detmar M et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol : UKMI. Prescribing Outlook: New Medicines. SPS National Institute for Health and Care Excellence (NICE). Inflammatory lesions of papulopustular rosacea: ivermectin 10 mg/g cream. Evidence Summary: New Medicine (ESNM 68). London Available at: (Accessed 15th Dec 2016). 16 Primary Care Dermatology Society (PCDS). Rosacea. PCDS Van Zuuren EJ, Kramer S, Carter B, et al. Interventions for rosacea. Cochrane Database Syst Rev (3):CD Produced by Daniel Clarke Specialist Rotational Clinical Pharmacist University Hospital of North Midlands Daniel.clarke@uhnm.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes. 19