New Medicines Committee Briefing March 2016 Review of preparations for treatment of acne

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1 New Medicines Committee Briefing March 2016 Review of preparations for treatment of acne Summary: NICE CKS recommends topical retinoids (e.g. Adapalene (Differin ), adapalene combined with benzoyl peroxide (Epiduo ) and isotretinoin (Isotrex ) as first line agents for treatment of comedonal acne. Adapalene gel was superior to tretinoin gel in reduction of inflammatory lesion counts (32% vs. 17% respectively, P=0.001) and total lesion counts (28% vs. 22% respectively; P=0.042). Adapalene-benzoyl peroxide was significantly more effective than corresponding monotherapies in total success (subjects clear or almost clear ). Isotretinoin had similar efficacy to benzoyl peroxide and significantly reduced non-inflamed lesions at 4 (P=0.05), 8 (P < 0.01) and 12 (P < 0.01) weeks. Azelaic acid (Skinoren ) is an alternative to topical adapalene, benzoyl peroxide and isotretinoin for treatment of comedonal acne. Azelaic acid gel was more effective than the placebo in reducing acne severity index (ASI). NICE CKS recommends fixed dose combinations of topical antibiotic/topical retinoid/benzoyl peroxide (e.g. Duac, Treclin, Epiduo, Aknemycin Plus, Isotrexin gel ) for the treatment of mild popular/pustular acne. No significant difference was noted in terms of efficacy when the effects of topical clindamycin phosphate alone, topical benzoyl peroxide alone and a topical combination of benzoyl peroxide and clindamycin Once-daily treatment with clindamycin 1%-benzoyl peroxide 5% for 11 weeks reduced inflammatory lesions by 53% and non-inflammatory lesions by 25%. Good or excellent global response was experienced in 50% of subjects. Isotrexin gel produced the greatest improvement for all acne assessments at week 12 when compared to erythromycin 2% gel alone, isotretinoin 0.05% gel alone and placebo. In 6500 patients, efficacy of tretinoin-erythromycin was classed as 'very good' (42.8%) or 'good' (43.3%) in 86.1% of all patients treated. Treatment with tretinoin-erythromycin resulted in a reduction of lesions after 2 weeks in 35% of the patients while comedones, papules, and pustules were eliminated at the end of treatment in 47.0%, 58.2% and 74.3% patients respectively. Treclin resulted in a statistically significant reduction in the number of lesions compared to tretinoin, clindamycin and tretinoin vehicle. Failure rates were also statistically significantly lower with Treclin (80%) compared to tretinoin (85%), clindamycin (85%) and tretinoin vehicle (91%) (P < 0.05). For the Global Severity Score (clear/almost clear) at week 12, Treclin had the greatest success (20%) compared to clindamycin (15%), tretinoin (15%) and vehicle (9%) (P < 0.05). 1

2 Systemic antibiotics are recommended for treatment of moderate inflammatory acne. Doxycycline and lymecycline are once daily preparations. No significant difference was found between the available oral tetracyclines in terms of improvement in inflammatory (32 trials, P = 0.898) and non-inflammatory (23 trials, P = 0.429) lesions. Overall reduction in inflammatory lesion count was similar with both lymecycline and minocycline (50.6 % and 52.2%). Formulary application Consultant submitting application: Clinical Director supporting application: Dr N Craven (Consultant Dermatologist) Dr G Rowlands Adapalene (Differin), adapalene with benzoyl peroxide (Epiduo), Isotretinoin (Isotrex) and azelaic acid (Skinoren) are not listed on the formulary but these preparations are licensed for the treatment of comedonal acne. Furthermore, Benzoyl peroxide 3% plus clindamycin 1% (Duac gel ), Tretinoin 0.025% plus clindamycin 1% (Treclin gel ), Tretinoin 0.025% plus erythromycin 4% (Aknemycin plus ) are also not listed on the formulary, yet NICE guidance recommends fixed dose combinations of topical antibiotics/topical retinoids/benzoyl peroxide for the treatment of mild papular/pustular acne. The South Staffordshire Joint Formulary lists a number of the above preparations (Adapalene, adapalene with benzoyl peroxide, azelaic acid and benzoyl peroxide 3% plus clindamycin 1%.) Background Acne is the most common skin condition affecting young people. The treatment of acne is generally determined by the severity and extent of the condition. Mild and moderate acne is generally treated with topical agents including benzoyl peroxide, retinoids and antibiotics either alone or in combination. In moderate acne, oral treatment with antibiotics or anti-androgens may also be needed. Current formulary status Topical preparations for acne Benzoyl peroxide Salicylic acid (cream with sulphur) Topical antibiotics Clindamycin Erythromycin Zineryt Tetracycline (Topicycline topical solution) Topical retinoids Tretinoin Lymecycline and Doxycycline are not listed on the formulary for treatment of acne Oral preparations for acne Oral antibiotics Oxytetracycline Erythromycin Hormone treatment Co-cyprindiol (Dianette ) Oral retinoid Isotretinoin As per skin department formulary 1 st Line Restriction: Initiation on specialist dermatological advice 2

3 Therapeutic class and mode of action Adapalene (Differin ) Step 1: Treatment of comedonal acne Adapalene is a chemically stable, naphthoic acid derivative with retinoid-like activity. Biochemical and pharmacological profile studies have demonstrated that adapalene acts in the pathology of Acne vulgaris: it is a potent modulator of cellular differentiation and keratinisation and it has antiinflammatory properties. Adapalene + Benzoyl peroxide (Epiduo ) As for adapalene plus Benzoyl peroxide has been shown to have antimicrobial activity; particularly against P. acnes, which is abnormally present in the acne-affected pilosebaceous unit. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities. Benzoyl peroxide is also sebostatic, counteracting the excessive sebum production associated with acne. Isotretinoin (Isotrex ) Isotretinoin is structurally and pharmacologically related to vitamin A and is thought that topically applied isotretinoin stimulates mitosis in the epidermis, reduces intercelluar cohesion in the stratum corneum, contests the hyperkeratosis characteristic of acne vulgaris, aids desquamation, preventing the formation of lesions and mediates an increased production of less cohesive epidermal sebaceous cells, which appears to promote the initial expulsion of comedones and their subsequent prevention. In addition, Isotretinoin has topical anti-inflammatory actions through inhibition of leukotriene-b 4 - induced migration of polymorphonuclear leukocytes. Azelaic acid (Skinoren ) The antimicrobial action and a direct influence on follicular hyperkeratosis are assumed to be the basis for the therapeutic efficacy of Skinoren in acne. The mechanism of action is thought to be through the inhibition of hyperactive protease activity that converts cathelicidin into the antimicrobial skin peptide. Azelaic acid belongs to a class of medication called dicarboxylic acids. Step 2: Treatment of mild papular/pustular acne a) First line Clindamycin combinations Benzoyl peroxide 3% plus clindamycin 1% (Duac gel ) As for benzoyl peroxide plus clindamycin. Clindamycin is a lincosamide antibiotic with bacteriostatic action, stopping bacteria involved in acne from reproducing. It is active against Gram-positive aerobes and a wide range of anaerobic bacteria. Lincosamides such as clindamycin bind to the 23S subunit of the bacterial ribosome and inhibit the early stages of protein synthesis. The action of clindamycin is predominantly bacteriostatic although high concentrations may be slowly bactericidal against sensitive strains. Tretinoin 0.025% plus clindamycin 1% (Treclin gel ) Topical tretinoin has both comedolytic and anti-inflammatory effects. Tretinoin decreases cohesiveness of follicular epithelial cells resulting in decreased microcomedone formation. 3

4 Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells, causing extrusion of the comedones. The comedolytic activity is related to a normalisation of the desquamation of the follicular epithelium. Tretinoin exerts anti-inflammatory effect via suppression of toll-like receptors (TLRs). A combination therapy of clindamycin and tretinoin, as in Treclin Gel, not only combines the individual actions of both active agents but also complements their certain actions. There is also evidence in the literature to show that when applied together, tretinoin increases the penetration of clindamycin. Thus, this combination therapy targets multiple pathogenic factors: abnormal follicular keratinization, P.acnes proliferation, inflammation and increased sebum production. b) Second line Erythromycin combinations Tretinoin 0.025% plus erythromycin 4% (Aknemycin plus ) As for Tretinoin above plus erythromycin which is a macrolide antibiotic with bacteriostatic action on all pathogens involved in the development of acne. When applied topically it also effects a reduction in the concentration of skin surface lipids and shows a direct anti-inflammatory effect. There is also evidence in the literature to show that when applied together, tretinoin increases the penetration of erythromycin. Isotretinoin 0.05% with erythromycin 2% (Isotrexin gel) As for Isotretinoin plus erythromycin which is a macrolide antibiotic with bacteriostatic action on all pathogens involved in the development of acne. Step 3: Treatment of moderate inflammatory acne a) First line Tetracyclines (Note: contraindicated in pregnancy and patients under 12 years) Lymeycycline Lymecycline belongs to the Tetracycline class of antibitoics. Tetracyclines provide bacteriostatic action at the available plasma and tissue concentrations and are effective against intracellular and extracellular organisms. Their mechanism of action is based on an inhibition of ribosomal protein synthesis. Tetracyclines block the access of the bacterial aminoacyl-trna to the mrna-ribosome complex by binding to the 30S subunit of the ribosome, thus preventing the addition of amino acids to the growing peptide chain in protein synthesis. When given at therapeutically attainable concentrations their toxic effect is limited to the bacterial cells. Doxycycline As for Lymecycline. Doxycycline belongs to the tetracycline class of antibiotics and blocks ribosomal protein synthesis. Dosage and administration Product Adapalene (Differin ) Adapalene + Benzoyl peroxide (Epiduo ) Isotretinoin (Isotrex ) Azelaic acid (Skinoren ) Frequency of administration Once a day in the evening Once a day in the evening Once or twice a day Apply Twice a day 4

5 Benzoyl peroxide 3% plus clindamycin 1% (Duac ) Tretinoin 0.025% plus clindamycin 1% (Treclin ) Tretinoin 0.025% plus erythromycin 4% (Aknemycin plus ) Isotretinoin 0.05% with erythromycin 2% (Isotrexin ) Oxytetracycline 250mg Tablets Tetracycline 250mg Tablets Lymecycline 408mg Capsules (Tetralysal ) Doxycycline 100mg Capsules Erythromycin 250mg Tablets Trimethoprin (Unlicensed Indication) Once a day Once a day at bedtime Once or twice a day Once or twice a day for 9-12 weeks 500mg twice daily initially for 3 months 500mg twice daily initially for 3 months One daily for at least 8 weeks One daily for six to 12 weeks 500mg twice daily 300mg twice daily NICE Guidance published No NICE Clinical Knowledge Summary NICE Clinical Knowledge Summary for Moderate Acne states: Benzoyl peroxide combined with a topical retinoid has been reported as being a 'very effective' treatment, although CKS identified no good-quality RCTs to support this. This combination may cause an unacceptable rate of adverse effects 1. NICE clinical knowledge summaries recommend that combined topical treatment be considered for people with moderate acne that is at risk of scarring. A topical antibiotic combined with benzoyl peroxide or a topical retinoid is the preferred regimen, as it is proven to be effective and may limit the development of bacterial resistance. Where possible, a topical antibiotic course should be limited to a maximum of 12 weeks. Oral antibiotics are recommended for the treatment of severe acne, or extensive acne that would be difficult to treat with a topical drug. Oral tetracyclines are recommended first-line whilst erythromycin is reserved for use when tetracyclines are contraindicated such as in pregnancy or in patients under 12 years of age. Evidence Adapalene (Differin ) A meta-analysis of five randomised controlled trials (900 patients, 450 treated with adapalene 0.1% gel, 450 treated with tretinoin 0.025% gel) by Cunliffe et al. compared the efficacy and tolerability of 5

6 adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris. 2 Adapalene demonstrated more rapid efficacy, as evident by a significant difference in the reduction of inflammatory and total lesions at week 1. Adapalene also demonstrated considerably greater local tolerability at all evaluation periods. A randomised multi-centre study (105 patients) in patients with mild to moderate acne vulgaris Grosshans et al. compared the efficacy and safety of adapalene 0.1% gel (n=52) with tretinoin 0.025% gel (n=53) for 12 weeks in patients aged between 12 and 30 years of age. 3 Reduction in inflammatory lesion counts following one week of treatment and the impact on quality of life was investigated. Adapalene gel was found to be superior to tretinoin gel in terms of efficacy after one week of treatment, with respect to reduction in inflammatory lesion counts (32% vs. 17% respectively, p=0.001), total lesion counts (28% vs. 22% respectively; P=0.042) and global severity grade found after 12 weeks of treatment for any of these vehicles. Evaluation of facial skin tolerance parameters showed significant differences between the two treatments in favour of adapalene for dryness, erythema, immediate and persistent burning as well as pruritus. Quality of life scores improved more rapidly in the adapalene group than in the tretinoin group with significant differences (P<0.05) appearing at week 1 A study by Shalita et al. in 290 patients, 288 of whom completed 12 weeks of treatment investigated the effect of adapalene vs. tretinoin in reducing non-inflammatory and total lesion counts. 4 The results of the study show that more people in the adapalene group (29%) experienced statistically significant excellent improvement (defined as a 75% reduction in lesions) at week 12 compared to the tretinoin group (18%, P<0.05). There was also statistically significant improvement in non-inflammatory lesions for patients treated with adapalene compared to tretinoin (31% vs. 18%, P<0.05). In terms of adverse events, erythema, scaling, dryness and burning were significantly less frequent and less severe among adapalene treated patients than those treated with tretinoin (P<0.05). Adapalene + benzoyl peroxide (Epiduo ) Gollnick et al. 5 conducted a study in 1670 subjects who were randomized in a double-blind controlled trial to receive adapalene benzoyl peroxide, adapalene, benzoyl peroxide or vehicle for 12 weeks (1 : 1 : 1 : 1 randomization). Evaluations included success rate (subjects clear or almost clear ), percentage change in lesion count from baseline, cutaneous tolerability and adverse events. Adapalene benzoyl peroxide was significantly more effective than corresponding monotherapies, with significant differences in percentage lesion count change observed as early as 1 week. Cutaneous tolerability profile was similar to adapalene. Adverse events were more frequent with the combination therapy (mainly due to an increase in mild-to-moderate dry skin), occurred early in the study, and were transient. Differences between adapalene benzoyl peroxide and all other treatments were statistically significant at week 8, week 12 and endpoint (P < 0.001). Differences between adapalene benzoyl peroxide and adapalene and vehicle were also significant at week 2 and week 4 (at least P < 0.05) The net beneficial effect (active minus vehicle) obtained from adapalene benzoyl peroxide (20%) was greater than the sum of the net benefits obtained from the individual components (3.9% for adapalene plus 8.8% for benzoyl peroxide), thus indicating a synergistic effect of the therapeutic activities of these substances when used in a fixed-dose combination. At week 12, adapalene benzoyl peroxide was significantly superior to adapalene, benzoyl peroxide and vehicle for median percentage change from baseline in inflammatory, non-inflammatory and total lesions (all P < 0.001) 6

7 Overall, the local tolerability of adapalene benzoyl peroxide was comparable with adapalene. Isotretinoin (Isotrex ) A double-blind, randomised study comparing isotretinoin gel, vehicle base and benzoyl peroxide was conducted Hughes et al. on 77 patients with mild to moderate acne vulgaris. 6 The effect of treatment was assessed by acne grade and lesion count. The vehicle base had no effect, but both active groups produced significant improvements. Benzoyl peroxide and isotretinoin significantly reduced noninflamed lesions at 4 (P=0.05), 8 (P < 0.01), 12 (P < 0.01) weeks. Benzoyl peroxide had a more rapid effect on inflamed lesions, their being significant reductions at 4, 8 and 12 weeks (P < 0.01), whereas with isotretinoin there was a significant improvement at 12 weeks (P < 0.01). In addition, compared to placebo, both active treatments significantly reduced inflamed and non-inflamed lesions. Acne grade had improved significantly in the benzoyl peroxide group by 4 weeks (P < 0.01) and in the isotretinoin group by 8 weeks (P < 0.05). No significant change in haematological or biochemical parameters occurred. An irritant dermatitis occurred equally with both treatments but was well tolerated by the patients. Chalker et al. completed a multicenter, double-blind, controlled study comparing isotretinoin 0.05% gel with its vehicle in two hundred and sixty-eight patients with mild to moderate acne vulgaris. 7 Patients were treated twice daily for up to 14 weeks. Efficacy was measured by counting facial inflammatory and non-inflammatory lesions and by grading acne severity initially and at 2- to 3-week intervals throughout the study. The isotretinoin 0.05% gel proved to be statistically more effective than vehicle in reducing inflammatory lesions after 5 weeks and in reducing non-inflammatory lesions and acne severity grade after 8 weeks. Azelaic acid (Skinoren ) A randomised double blind placebo controlled study by Fariba Iraji et al. evaluated the efficacy of 20% azelaic acid gel vs. gel vehicle in the treatment of mild to moderate acne vulgaris. 8 Thirty patients were treated twice daily with topical azelaic acid gel (20%) and thirty controls with the vehicle gel, composed of carbapol 934 (1%), glycerin (5%) and triethanolamine ( %). Both physicians and patients were blinded to the type of treatment. All 60 patients completed the study. Patients were followed up every 15 days for a period of 45 days. The number of lesions and the acne severity index (ASI, ASI = Papules + (2 pustules) + (0.25 x comedones) were recorded and compared using Student's t-test. The results of the study were that total lesion count was reduced by 60.6% and 19.9% by azelaic acid gel and the placebo respectively (P =0.002). ASI was reduced by 65.2% and 21.3% by azelaic acid gel and the placebo respectively (P =0.001). Azelaic acid gel was 3.06 times more effective than the placebo in reducing ASI. Shemer A et al. conducted an open prospective study consisting of 46 patients (19 men and 27 women), aged years, with recurrence of acne or inadequate acne response to other therapies. 9 Acne grading was based on the Cunliffe score (Leeds technique), a photonumeric grading scale. Inclusion criteria for this study were patients over 14 years of age, with acne grades 1 3 (without cystic acne). Follow-up visits were required at the beginning of the study, and then at weeks 3, 9, 15, 24 (end of treatment) and 30 (6 weeks after end of treatment). All patients were examined by the same investigator before the study and throughout the study period. Forty patients (87%) completed the study. 22 patients (85%) had grade 1 2 or 0 1 acne, with mild or no hyperpigmentation where lesions 7

8 had resolved. In resolved lesions, the skin was the same pigmentation as uninvolved skin. Four patients (15%) remained with hyperpigmentation and acne grade 1 3. No serious adverse effects were noted. There were three cases of mild stinging sensation that resolved spontaneously and did not require stopping the trial. Benzoyl peroxide 3% plus clindamycin 1% (Duac ) Tucker et al. compared the effect of administration of topical clindamycin phosphate alone, topical benzoyl peroxide alone with a combination of the two for the treatment of acne vulgaris 10 Patients with moderate to severe acne vulgaris were treated for 10 weeks with either topical clindamycin phosphate twice daily, benzoyl peroxide (5% gel) twice daily, or benzoyl peroxide (5% gel) in the morning and clindamycin phosphate solution in the evening. All treatments lowered the number of comedones, papules, pustules, and cysts by the end of the 10 week period. No specific treatment was found to be significantly better in all categories. All three regimens produced clinical improvements which did not differ significantly from each other. There was no statistically significant difference in the severity index between treatment groups. However, all groups did display a lower severity index by week 10 as compared with week 0 (P<0.05). The irritancy index indicates that benzoyl peroxide had a significantly higher score than either clindamycin phosphate alone or the combination therapy (P<0.01). The subjective rating of the investigators (based on a scale of 1-4) indicated an improvement of acne by all three treatment regimens. At the completion of the study 95%, 82%, and 96%, of the patients using clindamycin phosphate, benzoyl peroxide, and the combination therapy respectively, felt their acne had improved. No statistical difference was noted in the subjective rating between the three treatment groups. Isotretinoin 0.05% & erythromycin 2% (Isotrexin gel) The safety and efficacy of Isotrexin (applied twice daily) were evaluated in a 12-week, double-blind, randomised, placebo-controlled, parallel group study in 161 patients aged years, with mild to moderate acne vulgaris. 11 Isotrexin was compared with an erythromycin 2% gel, isotretinoin 0.05% gel and a placebo gel. Efficacy was assessed by comparison between the groups of the total number of lesions, total number of inflammatory lesions, total number of non-inflammatory lesions, acne severity grade, global change scores (investigator assessment) and the patient's self-rating assessment of their condition. Isotrexin gave the greatest improvement for all acne assessments at week 12. Isotrexin significantly (p<0.05) reduced the mean total lesions (inflammatory and non-inflammatory) when compared with placebo. A study by Clark et al. was conducted to determine if a combined formulation of erythromycin and isotretinoin improved the efficacy and safety in patients with mild/moderate acne. 12 Twice daily application of (isotretinoin 0.05% and erythromycin 2%) Isotrexin gel was compared to application of gels containing the individual components isotretinoin 0.05% (Isotrex ) and erythromycin 2% (Stiemycin ) as well as a gel base. 40 patients per group were randomised to each of the treatments. Lesion counts performed at 0,4,8 & 12 weeks. At most visits the active therapies were significantly superior to placebo. The percentage reduction in total lesions increased with time reaching a maximum of 12 weeks of 29.6% with Isotrexin, 21.5% with Isotrex, 25.2% with Stiemycin; placebo was 10.8%. Between group comparisons demonstrated that combined isotretinoin 0.05% and erythromycin 2% was significantly more effective than 0.05% isotretinoin alone for inflamed lesions at week 4 and acne grade at weeks 4 and 8. There was also a trend of improved efficacy of Isotrexin 8

9 over the 2% erythromycin with mean reduction in total lesions, total non-inflammatory lesions and acne grading being greater for Isotrexin. All products were well tolerated. Tretinoin 0.025% plus clindamycin 1% (Treclin ) Three randomised double-blind clinical studies, including a total of 4550 patients with acne vulgaris with both inflammatory and non-inflammatory lesions were performed. 13 Of these 1853 patients were treated with Treclin Gel, 846 with tretinoin, 1428 with clindamycin phosphate and 423 with Treclin Gel vehicle. Patients with facial acne inflammatory lesions (papules and pustules), facial acne non-inflammatory lesions (open and closed comedones), two or fewer nodules (defined as an inflammatory lesion greater than or equal to 5 mm in diameter) and without cysts were included. Lesions were counted at baseline and at weeks 2, 4, 8 and 12. Primary measurements of efficacy for two studies were (1) mean percent change from baseline at Week 12 in inflammatory lesion counts, (2) mean percent change from baseline at Week 12 in noninflammatory lesion counts, (3) mean percent change from baseline at Week 12 in total lesion counts, and (4) the percent of subjects who were clear or almost clear, at Week 12 as judged by an Evaluator's Global Severity Score (EGSS). Superiority vs. monotherapies was concluded if two of three lesion count variables and dichotomized EGSS were significant. Treatment was applied once daily for 12 weeks and patients were evaluated and lesions counted at week 12. Two studies compared Treclin to both mono treatments (clindamycin phosphate 1.2% gel and tretinoin 0.025% gel) and vehicle using a doubleblind treatment regimen. The third clinical study compared Treclin to clindamycin alone. At week 12, Treclin resulted in the greatest decrease in the number of inflammatory and non-inflammatory lesions compared to clindamycin alone, tretinoin alone and tretinoin vehicle alone. For the Global Severity Score (clear/almost clear) at week 12, Treclin had the greatest success (20%) compared to clindamycin (15%), tretinoin (15%) and vehicle (9%). In terms of failure, Treclin had the lowest percentage (80%) compared to clindamycin (85%), tretinoin (85%) and vehicle (91%). Comparison between Treclin and tretinoin and vehicle was statistically significant in the two studies. In the third study, success and failure rates with Treclin were statistically significant compared to clindamycin. (Success: Treclin 38%, clindamycin 32%. Failure: Treclin 62%, clindamycin 68%. P = 0.002). For adolescents, the median percent change (decrease) in the number of lesions (inflammatory, non-inflammatory and total lesions) at Week 12 was observed with Treclin. The decrease was statistically significant compared for treclin compared to clindamycin, tretinoin and vehicle (P < 0.05). Tretinoin 0.025% plus erythromycin 4% (Aknemycin plus ) A post-marketing surveillance study involving over 6500 patients by Kreusch et al. investigated the efficacy and tolerability of a Topical Erythromycin/Tretinoin Combination Preparation in Acne Treatment. 14 The efficacy was determined by counting the number of comedones, papules and pustules (nodules) per side of the face at the start and at the end of treatment using a five-point score (0 = none, 1 = 1-10, 2 = 10-25, 3 = 25-50, 4 = >50). Tolerability parameters (redness, scaling, dryness, itching) were evaluated in the same way using a four-point score (categories: absent, mild, moderate, severe). Analysis of the intensity of acne efflorescence during the period of investigation showed a clear decline in both non-inflammatory comedones and inflammatory papules and pustules. The score for the comedones decreased during treatment from 1.9 to 0.9; the value for pustules and papules decreased from 1.6 to 0.5. The overall medical assessment of efficacy classified the combination 9

10 preparation as being 'very good' (2793 patients, 42.8%) or 'good' (2828 patients, 43.3%) in 86.1% of all patients treated. Efficacy was assessed as 'mediocre' in 650 patients (10%) and as 'poor' in only 123 patients (1.9%) Excellent efficacy could be demonstrated particularly for acne comedonica and acne papulopustulosa. Tolerability of the test preparation was assessed as being 'very good' (40.6%) or 'good' (47.5%) in 88.1% of cases. It was assessed as being 'mediocre' in 475 patients (7.3%) and 'poor' in 130 patients (2.0%). Patients with seborrhoeic skin tolerated it somewhat better than those with mixed type or sebostatic skin. Local intolerability was documented in a total of 1312 patients (20.1%) and was almost exclusively the known side-effects of redness, scaling, dryness and itching. These were usually only mild. Efficacy and tolerability of a gel preparation with 0.025% tretinoin and 4% erythromycin in acne vulgaris was also evaluated in an open multicentre study by Korting et al of 1337 patients aged 8-68 years. 15 Efficacy was determined by counting the acne lesions (comedones, papules and pustules) before drug administration and every second week during the treatment period. Lesions had diminished after 2 weeks in about 35% of the patients. At the end of the treatment period, comedones were eliminated in 47.0% and improved in another 41.4%. Papules were eliminated and improved in 58.2% and 32.6%, pustules in 74.3% and 18.3% respectively. Side-effects (erythema, burning, pruritus, scaling and dryness of the skin) occurred in 203 patients (15.3%). Treatment was stopped in 25 subjects (1.9%) due to intolerance reactions. Lymecycline (Tetralysal ) A systematic review of the clinical trials ( ) by Simonart et al. investigated oral tetracyclines (oxytetracycline, lymecycline, doxycycline and minocycline) for the treatment of inflammatory acne. 16 Overall, there was no significant difference between the available tetracyclines in terms of efficacy in inflammatory (P = 0.898) and non-inflammatory lesion count (P = 0.429). Neither the duration of the assessment, nor the drug dosage, nor the year of publication had an impact on inflammatory lesions (n = 32, multiple R = 0.139, P = 0.907) or non-inflammatory lesions (n = 23, multiple R = 0.423, P = 0.279). Cunliffe et al undertook a randomised double-blind, double-dummy study to compare the efficacy and safety of lymecycline vs minocycline in moderately severe acne (n=144). 17 Both treatments were similar in efficacy. The overall reduction in inflammatory lesion count (primary endpoint) was similar with both drugs (50.6 % and 52.2% with lymecycline and minocycline respectively). Non-inflammatory lesions were reduced by 40.6% and 32.2 % and global acne severity was reduced by 42.4% and 47.9% respectively. Doxycycline The safety and efficacy of three doses of doxycycline calcium tablets compared with placebo in the treatment of moderate to severe inflammatory facial acne vulgaris was evaluated by Leyden et al. in a randomised, double-blind, phase 2 dose-ranging study. 18 Subjects with moderate to severe inflammatory acne aged 12 years to 45 years were randomised to receive doxycycline calcium tablets 0.6, 1.2, or 2.4 mg/kg/day or placebo. The primary efficacy variables were the dichotomized Investigator's Global Assessment score (success or failure) at week 12 (success defined as 2 score decrease from baseline) and the absolute change from baseline to week 12 in inflammatory lesion count. A dose-response effect was seen with doxycycline calcium formulation in subjects with 10

11 moderate to severe inflammatory acne. The highest dose-group (corresponding to approximately 2.4 mg/kg/day) showed a statistically significant difference from placebo. Moore et al. evaluated the safety and efficacy of sub-antimicrobial, modified-release (MR) Doxycycline 40 mg compared to Doxycycline 100 mg and to placebo for the treatment of inflammatory lesions in moderate and severe acne (n=662). 19 Modified release doxycycline 40 mg was superior to placebo in the mean reduction of the number of inflammatory lesions, median percent reduction in inflammatory and total lesions, and success rate. Modified release doxycycline 40 mg was also comparable to doxycycline 100 mg in the reduction of the number of inflammatory lesions, and percent reduction of total lesions. SMC recommended use within NHS Scotland Product Adapalene (Differin ) Adapalene + Benzoyl peroxide (Epiduo ) Isotretinoin (Isotrex ) Azelaic acid (Skinoren ) Benzoyl peroxide 3% plus clindamycin 1% (Duac gel ) Tretinoin 0.025% plus clindamycin 1% (Treclin gel ) Tretinoin 0.025% plus erythromycin 4% (Aknemycin plus ) Isotretinoin 0.05% & erythromycin 2% (Isotrexin gel) Lymecycline 408mg capsules Doxycycline 100mg capsules Accepted for use (Yes/No) No Yes No No Yes Yes No No No No All Wales Medicines Strategy Group (AWSG) NO Regional Drug and Therapeutic Centre (RDTC): NO MTRAC NO 11

12 Cochrane Review: Adapalene (Differin ) - not reviewed Adapalene + Benzoyl peroxide (Epiduo ) - not reviewed Isotretinoin (Isotrex ) - not reviewed Tretinoin 0.025% plus clindamycin 1% (Treclin gel ) - not reviewed Tetracycline Not reviewed Azelaic acid (Skinoren ) - A cochrane review by Liu et al. found that Azelaic acid 20% cream monotherapy or in combination therapy with glycolic acid, azelaic acid 20% or 15% gel, azelaic acid 5% gel in combination with clindamycin 2% or erythromycin 2% have been found to be effective treatments for acne. 20 Azelaic acid 20% cream can reduce the number of both non-inflammatory and inflammatory lesions and has an effect comparable to the other approved standard treatments, including benzoyl peroxide and erythromycin, as well as tretinoin, but it is better tolerated by people with fewer side effects. Benzoyl peroxide 3% plus clindamycin 1% (Duac gel ) - In a clinical study of 358 subjects with moderate to moderately severe acne vulgaris, once-daily treatment with clindamycin 1%-benzoyl peroxide 5% for 11 weeks reduced inflammatory lesions by 53% and noninflammatory lesions by 25%. Good or excellent global response was experienced in 50% of subjects. Overall tolerance ratings were good to excellent in 99% of subjects, and, except for mild to moderate expected local reactions, there were no adverse events related to treatment. 21 Tretinoin 0.025% plus erythromycin 4% (Aknemycin plus ) - In a multicentre double-blind study, 272 patients were selected and randomised to one of the following three groups: (1) 2.75% erythromycin lauryl sulphate (ELS) (equivalent to 2% erythromycin base) applied in the morning and at night (n = 88); (2) placebo applied in the morning and 0.05% TRT at night (n = 92); (3) placebo applied in the morning and ELS/TRT at night. Treatments were applied for 10 weeks. Clinical assessments were performed at 0, 5 and 10 weeks, ELS/TRT was significantly better than ELS alone in the reduction of total (P < 0.001), open (P < 0.001) and closed comedones (P < 0.025). The efficacy of ELS/TRT was significantly better than that of TRT alone in the reduction of inflammatory lesions (P < 0.01) and pustules (P < 0.025). The mean grade of acne severity at week 10 was significantly lower with ELS/TRT than with ELS (P < 0.05). No serious side-effects were reported. Mild irritative effects were observed in patients treated with TRT, ELS/TRT applied once daily is therefore an effective and well-tolerated treatment for acne vulgaris. This combination significantly enhances the comedolytic action of TRT and the antiinflammatory effect of ELS Lymecycline (Tetralysal ) - Dubertret et al. compared the efficacy and safety of lymecycline 300 mg od vs lymecycline 150 mg bid or placebo in the treatment of moderate to severe acne. 271 patients received either oral lymecycline 300 mg od + placebo od, lymecycline 150 mg bid, or placebo bid, for 12 weeks. Reduction in inflammatory lesion counts at week 12 was the primary efficacy variable (global improvement was a primary efficacy parameter vs placebo) and safety was assessed by adverse events. Lymecycline 300 mg od was non-inferior to lymecycline 150 mg bid at all-time points and superior to placebo throughout the study. Drug-related adverse events were similar for all treatment groups. Lymecycline 300 mg od is as effective and safe as lymecycline 150 mg bid in the treatment of moderate to severe acne. This new, once daily formulation could potentially contribute towards improved compliance rates with oral tetracyclines

13 Cost analysis: The Drug Tariff prices listed for Acne preparations are as follows: Prices of topical drugs for acne, Drug Tariff October 2015, excluding VAT (BNF Sections and ) Current Price Medicine Description (DRUG TARIFF/ BNF excl. VAT) ACNECIDE 5% GEL (BENZOYL PEROXIDE 5%) 5.44 ACNECIDE 5% GEL WASH BRASIVOL PASTE (ALUMINIUM OXIDE 38.09%) 2.76 BREVOXYL 4% CREAM (BENZOYL PEROXIDE 4%) 4.13 DUAC ONCE DAILY (BENZOYL PEROXIDE 3% / CLINDAMYCIN 1% GEL) 30g DUAC ONCE DAILY (BENZOYL PEROXIDE 5% / CLINDAMYCIN 1% GEL) 25g ERYTHROMYCIN 4% GEL - QUERY BRAND FINACEA (AZELAIC ACID 15% GEL) 7.48 PANOXYL 10 AQUAGEL (BENZOYL PEROXIDE 10%) 2.13 PANOXYL 10 GEL (BENZOYL PEROXIDE 10%) 4.00 PANOXYL 10 WASH (BENZOYL PEROXIDE 10%) 4.00 PANOXYL 2.5 AQUAGEL (BENZOYL PEROXIDE 2.5%) 1.76 PANOXYL 5% AQUAGEL (BENZOYL PEROXIDE 5%) 1.92 PANOXYL 5% CREAM (BENZOYL PEROXIDE 5%) 1.89 QUINODERM CREAM 10% 50g (BENZOYL PEROXIDE 10%/ POTASSIUM HYDROXYQUINOLINE 0.5%) 2.55 QUINODERM CREAM 5% 50g (BENZOYL PEROXIDE 5%/ POTASSIUM HYDROXYQUINOLINE 0.5%) 2.43 SALICYLIC AND SULPHUR OINTMENT 3%/3% SKINOREN (AZELAIC ACID 20% CREAM) 3.74 STEIMYCIN (ERYTHROMYCIN 2% SOLUTION) 7.69 ZINDACLIN 1% GEL (CLINDAMYCIN 1%) 8.66 EPIDUO (ADAPALENE 0.1% / BENZOYL PEROXIDE 2.5%) DIFFERIN (ADAPALENE 0.1% CREAM) DIFFERIN (ADAPALENE 0.1% GEL) AKNEMYCIN PLUS (ERYTHROMYCIN 4% / TRETINOIN 0.025% SOLUTION) 25mL 7.05 DALACIN T LOTION (CLINDAMYCIN 1% AQUEOUS LOTION) 5.08 DALACIN T TOPICAL SOLUTION (CLINDAMYCIN 1% ALCOHOLIC SOLUTION) 4.34 TRECLIN 1%/0.025% GEL (CLINDAMYCIN 1%/TRETINOIN 0.025%) ZINERYT LOTION 30mL (ERYTHROMYCIN 40mg/ZINC ACETATE 12mg/Ml) 7.71 FREEDERM 4% GEL (NICOTINAMIDE 4%) ISOTREXIN 0.05%/2% GEL (ISOTRETINOIN 0.05%/ERYTHROMYCIN 2%) 7.47 ISOTREX (ISOTRETINOIN 0.05% GEL) 5.94 NICAM 4% GEL (NICOTINAMIDE 4%) 7.10 TRETINOIN 0.025% GEL - QUERY BRAND Not available SALICYLIC ACID 5% in WHITE SOFT PARAFFIN (100g) - Expenditure on topical drugs for acne, September 2014 to August 2015 (BNF Sections and ) 13

14 Medicine Description UHNS NORTH STAFFS CCG STOKE ON TRENT CCG Total Cost 1 Total Cost 1 ACNECIDE 5% GEL (BENZOYL PEROXIDE 5%) , , ACNECIDE 5% GEL WASH BRASIVOL PASTE (ALUMINIUM OXIDE 38.09%) BREVOXYL 4% CREAM (BENZOYL PEROXIDE 4%) DUAC ONCE DAILY (BENZOYL PEROXIDE 3% / CLINDAMYCIN 1% GEL) 30g , , DUAC ONCE DAILY (BENZOYL PEROXIDE 5% / CLINDAMYCIN 1% GEL) 25g , , ERYTHROMYCIN 4% GEL - QUERY BRAND FINACEA (AZELAIC ACID 15% GEL) , , PANOXYL 10 AQUAGEL (BENZOYL PEROXIDE 10%) PANOXYL 10 GEL (BENZOYL PEROXIDE 10%) PANOXYL 10 WASH (BENZOYL PEROXIDE 10%) PANOXYL 2.5 AQUAGEL (BENZOYL PEROXIDE 2.5%) PANOXYL 5 AQUAGEL (BENZOYL PEROXIDE 5%) PANOXYL 5 CREAM (BENZOYL PEROXIDE 5%) QUINODERM CREAM 10% 50g (BENZOYL PEROXIDE 10%/ POTASSIUM HYDROXYQUINOLINE 0.5%) QUINODERM CREAM 5% 50g (BENZOYL PEROXIDE 5%/ POTASSIUM HYDROXYQUINOLINE 0.5%) SALICYLIC AND SULPHUR OINTMENT 3%/3% SKINOREN (AZELAIC ACID 20% CREAM) STEIMYCIN (ERYTHROMYCIN 2% SOLUTION) ZINDACLIN 1% GEL (CLINDAMYCIN 1%) , EPIDUO (ADAPALENE 0.1% / BENZOYL PEROXIDE 2.5%) , , DIFFERIN (ADAPALENE 0.1% CREAM) , , DIFFERIN (ADAPALENE 0.1% GEL) , , AKNEMYCIN PLUS (ERYTHROMYCIN 4% / TRETINOIN 0.025% SOLUTION) 25mL DALACIN T LOTION (CLINDAMYCIN 1% AQUEOUS LOTION) , , DALACIN T TOPICAL SOLUTION (CLINDAMYCIN 1% ALCOHOLIC SOLUTION) , TRECLIN 1%/0.025% GEL (CLINDAMYCIN 1%/TRETINOIN 0.025%) ZINERYT LOTION 30mL (ERYTHROMYCIN 40mg/ZINC ACETATE 12mg/Ml) , , FREEDERM 4% GEL (NICOTINAMIDE 4%) ISOTREXIN 0.05%/2% GEL (ISOTRETINOIN 0.05%/ERYTHROMYCIN 2%) ISOTREX (ISOTRETINOIN 0.05% GEL) NICAM 4% GEL (NICOTINAMIDE 4%) TRETINOIN 0.025% GEL - QUERY BRAND SALICYLIC ACID 5% in WHITE SOFT PARAFFIN (100g) TOTAL , , VAT not included 14

15 Prices of oral drugs for acne, Drug Tariff January 2016 Drug Pack size Primary care Cost excluding VAT per unit (Drug Tariff /dm+d) Cost per capsule/ tablet excl VAT Pack size Secondary care Cost including VAT ( ) Cost per capsule/ tablet incl VAT DOXYCYCLINE 50MG CAPSULES DOXYCYCLINE 100MG CAPSULES OXYTETRACYCLINE 250MG TABLETS LYMEYCYLINE408 MG CAPSULES MINOCYCLINE MR 100MG CAPSULES MINOCYCLINE 50MG TABLETS MINOCYCLINE 100MG TABLETS TETRACYCLINE 250MG TABLETS ERYTHROMYCIN 250MG TABLETS CLARITHROMYCIN 250MG TABLETS TRIMETHOPRIM 100MG TABLETS TRIMETHOPRIM 200MG TABLETS CO-CYPRINDIOL 2000/35 TABLETS (GENERIC) ISOTRETINOIN 20mg CAPSULES ISOTRETINOIN 10mg CAPSULES

16 Appendix European Guidelines on the Treatment of Acne *1 limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first line therapy (e.g. financial resources/ reimbursement limitations, legal restrictions, availability, drug licensing) *2 in case of more widespread disease/ moderate severity, initiation of a systemic treatment can be recommended *3 adapalene to be preferred over tretinoin/ isotretinoin *4 systemic treatment with corticosteroids can be considered *5 doxycycline and lymecycline *6 low strength of recommendation *7 indirect evidence from a study also including chorhexidine, recommendation additionally based on expert opinion *8 indirect evidence from nodular and conglobate acne and expert opinion *9 indirect evidence from severe papularpustular acne *10 only studies found on systemic AB + adapalene, Isotretinoin and tretinoin can be considered for combination treatment based on expert opinion f.c. fixed combination 23 16

17 REFERENCES: 1 NICE Clinical Knowledge summaries: Acne Vulgaris 2 Cunliffe W J, Poncet M, Loesche C, Verschoore M. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. The British journal of dermatology, vol. 139 Suppl 52, p , (October 1998). 3 Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris, with particular reference to the onset of action and impact on quality of life. British Journal of Dermatology , pp Shalita A, Weiss JS, Chalker DK et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicentre trial. J am Acad Dermatol 1996; 34: Gollnick H.P.M, Draelos Z, Glenn M.J, Rosoph L.A, Kaszuba A, Cornelison R, Gore B, Liu Y, Graeber M. Adapalene benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. British Journal of Dermatology , pp Hughes B.R, Norris J.F.B, Cunliffe W.J. A double-blind evaluation of topical isotretinoin 0.05%, benzoyl peroxide gel 5% and placebo in patients with acne. Volume 17, Issue 3, pages , May Chalker D, Lesher JL, Graham-Smith J, Klauda HC, Pochi PE, Jacoby WS, Yonkosky DM, Voorhees JJ, Ellis CN, Matsuda-John S, Shalita AR, Smith EB, Raimer SS, Knox JM, Kantor II. Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: Results of a multicenter, double-blind investigation. Journal of the American academy of Dermatology. August 1987 Volume 17, Issue 2, Part 1, Pages Iraji F, Sadeghinia A, Shahmoradi Z, Siadat AH, Jooya A. Efficacy of topical azelaic acid gel in the treatment of mild-moderate acne vulgaris. Indian J Dermatol Venereol Leprol [serial online] 2007 [cited 2016 Jan 7];73:94-6. Available from: 9 A Shemer, G Weiss, B Amichai, B Kaplan, H Trau Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Tucker S.B, Tausend R, Cochran R AND Flannigan S.A. Comparison of topical clindamycin phosphate, benzoyl peroxide, and a combination of the two for the treatment of acne vulgaris. British Journal of Dermatology (1984) n o, Summary of product characteristics (SPC): Isotrexin gel Stiefel. Last Updated on emc 19-Dec Clark S.M, Cunliffe W.J, Boorman G.C. Placebo controlled studies of topical isotretinoin/erythromycin gels in acne. Journal of Investigative Dermatology Dréno B, et al. Eur J Dermatol 2014;24: Kreusch I, Bextermöller R. Efficacy and Tolerability of a Topical Erythromycin/Tretinoin Combination Preparation in Acne Treatment: Post-marketing Surveillance Study Involving Over 6500 Patients. Curr Med Res Opin. 2000;16(1) 15 Korting H C,Braun-Falco O. Efficacy and tolerability of combined topical treatment of acne vulgaris with tretinoin and erythromycin in general practice. Drugs under experimental and clinical research, vol. 15, no. 9, p , (1989) 16 T. Simonart, M. Dramaix, V. De Maertelaer. Efficacy of tetracyclines in the treatment of acne vulgaris: a review. British Journal of Dermatology 2008;158: Cunliffe et al. A comparison of the efficacy and safety of lymecycline and minocycline in patients with moderately severe acne vulgaris. European Journal of Dermatology. 1998;8: Leyden, JJ. Bruce, S. Lee, C.S, Ling, M, Sheth PB, Stewart D.M, Werschler WP, Gilbert RD, Kircik L. A randomized, phase 2, dose-ranging study in the treatment of moderate to severe inflammatory facial acne vulgaris with doxycycline calcium. Journal of drugs in dermatology : JDD, vol. 12, no. 6, p , (June 1, 2013) 17

18 19 Moore A, Ling M, Bucko A, Manna V, Rueda M.J. Efficacy and Safety of Subantimicrobial Dose, Modified-Release Doxycycline 40 mg Versus Doxycycline 100 mg Versus Placebo for the treatment of Inflammatory Lesions in Moderate and Severe Acne: A Randomized, Double-Blinded, Controlled Study. Journal of drugs in dermatology : JDD, vol. 14, no. 6, p , (June 2015) 20 Liu H, Yu H, Xia J, Liu L, Liu GJ, Sang H. Topical azelaic acid, salicylic acid, nicotinamide, and sulphur for acne. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD DOI: / CD Fagundes DS, Fraser JM, Klauda HC. New therapy update--a unique combination formulation in the treatment of inflammatory acne. Cutis 72:1 Suppl 2003 Jul pg Dubertret L, Alirezai M, Rostain G, Lahfa M, Forsea D, Niculae BD, Simola M, Horvath A, Mizzi F. The use of lymecycline in the treatment of moderate to severe acne vulgaris: a comparison of the efficacy and safety of two dosing regimens. European journal of dermatology (1) European Guidelines on the Treatment of Acne Produced by Mr Stephen Morrow Specialist Rotational Clinical Pharmacist University Hospital of North Midlands Stephen.Morrow@uhns.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes. 18