Adalain

Pharmacotherapeutic group: Anti-acne preparations for topical use, Retinoids for topical use in acne; ATC code: D10AD53 Mechanism of action and pharmacodynamic effects This medicine combines two active substances, which act through different, but complementary, mechanisms of action. - Adapalene : Adapalene is chemically stable, naphtoic 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 anti-inflammatory properties. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors. Current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation. Adapalene inhibits the chemotactic (directional) and chemokinetic (random) responses of human polymorphonuclear leucocytes in in vitro assay models: it also inhibits the metabolism of arachidonic acid to inflammatory mediators. In vitro studies have shown inhibition of the AP-1 factors and the inhibition of the expression of toll like receptors 2. This profile suggests that the cell mediated inflammatory component of acne is reduced by adapalene. - Benzoyl peroxide (BPO): Benzoyl peroxide has been shown to have antimicrobial activity; particularly against Cutibacterium acnes , which is abnormally present in the acne-affected pilosebaceous unit. The mechanism of action of Benzoyl peroxide has been explained by its highly lipophilic activity, enabling its penetration through the epidermis into bacterial and keratinocyte cell membranes of the pilosebaceous unit. Benzoyl peroxide is recognized as a very effective broad-spectrum antibacterial agent in the treatment of acne vulgaris. It has been demonstrated to exert bactericidal effect by generating free radicals that oxidize proteins and other essential cellular components in the bacterium wall. The minimum inhibitory concentration of benzoyl peroxide is bactericidal and has demonstrated effectiveness on antibiotic-sensitive and antibiotic-resistant C. acnes strains. Additionally, benzoyl peroxide has demonstrated exfoliative and keratolytic activities. Clinical efficacy of fixed combination adapalene/benzoyl peroxide in patients aged 12 years and older The safety and efficacy of fixed combination adapalene/benzoyl peroxide applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicentre, controlled clinical studies of similar design, comparing fixed combination adapalene/benzoyl peroxide to its individual active components, adapalene and benzoyl peroxide, and to the gel vehicle in acne patients. A total of 2185 patients were enrolled in Study 1 and Study 2. The distribution of patients in the two studies was approximately 49% male and 51% female, 12 years of age or older (mean age: 18.3 years; range 12-50), presenting 20 to 50 inflammatory lesions and 30 to 100 non-inflammatory lesions at baseline. The patients treated the face and other acne affected areas as needed once daily in the evening. The efficacy criteria were: (1) Success rate, percentage of patients rated “Clear“ and “Almost Clear“ at week 12 based on the Investigator's Global Assessment (IGA); (2) Change and Percent Change from baseline at week 12 in - inflammatory lesion counts - noninflammatory lesion counts - total lesion count. The efficacy results are presented for each study in Table 1. and combined results in Table 2. Fixed combination adapalene/benzoyl peroxide was shown to be more effective compared to its monads and gel vehicle in both studies. Overall, the net beneficial effect (active minus vehicle) obtained from adapalene/benzoyl peroxide was greater than the sum of the net benefits obtained from the individual components, thus indicating a potentiation of the therapeutic activities of these substances when used in a fixed-dose combination. An early treatment effect of fixed combination adapalene/benzoyl peroxide was consistently observed in Study 1 and Study 2 for inflammatory lesions at Week 1 of treatment. Noninflammatory lesions (open and closed comedones) noticeably responded between the first and fourth week of treatment. The benefit on nodules in acne has not been established. Table 1. Clinical efficacy in two comparative trials Study 1 Study 1 Week 12 LOCF; ITT Adapalene+BPO N=149 Adapalene N=148 BPO N=149 Vehicle N=71 Success (Clear, Almost Clear) 41 (27.5%) 23 (15.5%) p=0.008 23 (15.4%) p=0.003 7 (9.9%) p=0.002 Median Reduction (% Reduction) in Inflammatory Lesion Count 17 (62.8%) 13 (45.7%) p<0.001 13 (43.6%) p<0.001 11 (37.8%) p<0.001 Noninflammatory Lesion Count 22 (51.2%) 17 (33.3%) p<0.001 16 (36.4%) p<0.001 14 (37.5%) p<0.001 Total Lesion Count 40 (51.0%) 29 (35,4%) p<0.001 27 (35.6%) p<0.001 26 (31.0%) p<0.001 Study 2 Study 2 Week 12 LOCF; ITT Adapalene+BPO N=415 Adapalene N=420 BPO N=415 Vehicle N=418 Success (Clear, Almost Clear) 125 (30.1%) 83 (19.8%) p<0.001 92 (22.2%) P=0.006 47 (11.3%) p<0.001 Median Reduction (% Reduction) in Inflammatory Lesion Count 16 (62.1%) 14 (50.0%) p<0.001 16 (55.6%) P=0.068 10 (34.3%) p<0.001 Noninflammatory Lesion Count 24 (53.8%) 22 (49.1%) p=0.048 20 (44.1%) p<0.001 14 (29.5%) p<0.001 Total Lesion Count 45 (56.3%) 39 (46.9%) p=0.002 38 (48.1%) p<0.001 24 (28.0%) p<0.001 Table 2. Clinical efficacy in combined comparative trials Adapalene+BPO N=564 Adapalene N=568 BPO N=564 Gel Vehicle N=489 Success (Clear, Almost Clear 166 (29.4%) 106 (18.7%) 115 (20.4%) 54 (11.1%) Median Reduction (%Reduction) in Inflammatory Lesion Count 16.0 (62.1) 14.0 (50.0) 15.0 (54.0) 10.0 (35.0) Noninflammatory Lesion Count 23.5 (52.8) 21.0 (45.0) 19.0 (42.5) 14.0 (30.7) Total Lesion Count 41.0 (54.8) 34.0 (44.0) 33.0 (44.9) 23.0 (29.1) Clinical efficacy of fixed combination adapalene/benzoyl peroxide in children 9 to 11 years old During a paediatric clinical trial, 285 children with acne vulgaris, aged 9-11 years (53% of the subjects were 11 years old, 33% were 10 years old and 14% were 9 years old) with a score of 3 (moderate) on the IGA scale and a minimum of 20 but not more than 100 total lesions (Non-inflammatory and/or Inflammatory) on the face (including the nose) at baseline were treated with fixed combination adapalene/benzoyl peroxide gel once daily for 12 weeks. The study concludes that the efficacy and safety profiles of fixed combination adapalene/benzoyl peroxide gel in the treatment of facial acne in this specific younger age group are consistent with results of other pivotal studies in subjects with acne vulgaris aged 12 years and older showing significant efficacy with an acceptable tolerability. A sustained early treatment effect of fixed combination adapalene/benzoyl peroxide gel compared to Gel Vehicle was consistently observed for all Lesions (Inflammatory, Non-Inflammatory, and Total) at Week 1 and continuing to Week 12. Study 3 Week 12 LOCF; ITT Adapalene + BPO N=142 Vehicle Gel N=143 Success (Clear, Almost Clear) 67 (47.2%) 22 (15.4%) Median Reduction (% Reduction in Inflammatory Lesion Count 6 (62.5%) 1 (11.5%) Noninflammatory Lesion Count 19 (67.6%) 5 (13.2%) Total Lesion Count 26 (66.9%) (18.4%)