Download Acne NMC Briefing Full Review - Stoke-on

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).
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 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:
Dr N Craven (Consultant Dermatologist)
Clinical Director supporting application:
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
13.6.1
Topical preparations for acne
Benzoyl peroxide
Salicylic acid (cream with sulphur)
As per skin department formulary
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.
13.6.2
Oral preparations for acne
Oral antibiotics
Oxytetracycline
1st Line
Erythromycin
Hormone treatment
Co-cyprindiol (Dianette®)
Oral retinoid
Isotretinoin
Restriction: Initiation on specialist dermatological
advice
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Therapeutic class and mode of action
Step 1: Treatment of comedonal acne
Adapalene (Differin®)
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-B4induced 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.
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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
Frequency of administration
Adapalene (Differin®)
Once a day in the evening
Adapalene + Benzoyl peroxide (Epiduo®)
Once a day in the evening
Isotretinoin (Isotrex®)
Azelaic acid (Skinoren®)
Once or twice a day
Apply Twice a day
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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)
NICE Guidance published
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
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
effects1.
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
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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)
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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 (0.2-0.5%). 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 14–25 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
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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 vulgaris10 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 16-32 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
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 20-50 facial acne inflammatory lesions (papules and pustules), 20-100 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
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 (1962–2006) 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
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
Accepted for use (Yes/No)
Adapalene (Differin®)
No
Adapalene + Benzoyl peroxide (Epiduo®)
Yes
Isotretinoin (Isotrex®)
Azelaic acid (Skinoren®)
No
Benzoyl peroxide 3% plus clindamycin 1% (Duac gel®)
Tretinoin 0.025% plus clindamycin 1% (Treclin gel®)
Tretinoin 0.025% plus erythromycin 4% (Aknemycin plus®)
No
Yes
Yes
No
Isotretinoin 0.05% & erythromycin 2% (Isotrexin® gel)
No
Lymecycline 408mg capsules
Doxycycline 100mg capsules
No
No
All Wales Medicines Strategy Group (AWSG)
NO
Regional Drug and Therapeutic Centre (RDTC):
NO
MTRAC
NO
11
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.22
12
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 13.6.1 and
13.6.2)
Medicine Description
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)
Current Price
(DRUG
TARIFF/ BNF
excl. VAT)
£5.44
£2.76
£4.13
£13.14
£10.95
£7.48
£2.13
£4.00
£4.00
£1.76
£1.92
£1.89
£2.55
£2.43
£3.74
£7.69
£8.66
£17.91
£16.43
£16.43
£7.05
£5.08
£4.34
£11.94
£7.71
£7.47
£5.94
£7.10
Not available
-
Expenditure on topical drugs for acne, September 2014 to August 2015 (BNF Sections 13.6.1 and
13.6.2)
13
Medicine Description
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)
13.06.01 TOTAL
1
£0.00
£0.00
£0.00
£0.00
NORTH
STAFFS
CCG
Total Cost1
£2,863.35
£15.12
£0.00
£7.66
£0.00
£2,789.24
£4,132.59
£35.03
£18,986.28
£23,362.24
£0.00
£7.48
£0.00
£0.00
£0.00
£0.00
£0.00
£0.00
£0.00
£1,675.48
£17.82
£43.54
£0.00
£6.56
£14.29
£22.84
£555.93
£1,474.79
£11.85
£37.00
£11.14
£4.92
£49.90
£12.31
£0.00
£9.48
£29.14
£0.00
£22.56
£11.29
£0.00
£11.22
£0.00
£222.34
£276.62
£28.42
£16.43
£0.00
£679.57
£199.37
£921.56
£5,963.88
£2,843.77
£3,584.88
£313.05
£877.55
£277.69
£1,274.88
£5,765.96
£4,264.61
£3,586.30
£106.08
£606.49
£672.39
£76.60
£2,459.80
£4,036.05
£52.14
£841.07
£2,447.68
£0.00
£99.46
£165.82
£27.74
£20,967.12
£21,446.55
£0.00
£2.88
£36.60
£0.00
£311.19
£179.85
£29.70
£511.59
£0.00
£52.59
£0.00
£0.00
£0.83
£0.00
£890.62 £66,519.44
£429.15
£52.42
£4.89
£0.00
£79,235.74
UHNS
STOKE ON
TRENT CCG
Total Cost1
£3,607.97
£20.14
£33.32
£49.77
VAT not included
14
Prices of oral drugs for acne, Drug Tariff January 2016
Primary care
Drug
DOXYCYCLINE 50MG CAPSULES
DOXYCYCLINE 100MG CAPSULES
Pack size
Secondary care
Cost excluding
Cost per
VAT per unit
capsule/
(Drug Tariff tablet excl
/dm+d)
VAT
Pack size
Cost
including
VAT (£)
Cost per
capsule/
tablet incl
VAT
28
£1.47
£0.05
28
£0.82
£0.03
8
£0.97
£0.12
50
£2.10
£0.04
OXYTETRACYCLINE 250MG TABLETS
28
£1.00
£0.04
28
£0.48
£0.02
LYMEYCYLINE408 MG CAPSULES
28
£8.11
£0.29
28
£6.26
£0.22
MINOCYCLINE MR 100MG CAPSULES
56
£20.08
£0.36
56
£19.19
£0.34
MINOCYCLINE 50MG TABLETS
28
£6.19
£0.22
28
£3.19
£0.11
MINOCYCLINE 100MG TABLETS
28
£14.01
£0.50
28
£5.22
£0.19
TETRACYCLINE 250MG TABLETS
28
£2.22
£0.08
28
£1.62
£0.06
ERYTHROMYCIN 250MG TABLETS
28
£1.50
£0.05
28
£0.96
£0.03
CLARITHROMYCIN 250MG TABLETS
14
£1.48
£0.11
14
£0.92
£0.07
TRIMETHOPRIM 100MG TABLETS
28
£0.93
£0.03
28
£0.17
£0.01
6
£1.29
£0.22
6
£0.28
£0.05
CO-CYPRINDIOL 2000/35 TABLETS (GENERIC)
63
£5.42
£0.09
63
£2.76
£0.04
ISOTRETINOIN 20mg CAPSULES
30
£19.55
£0.65
30
£3.54
£0.12
ISOTRETINOIN 10mg CAPSULES
30
£14.54
£0.48
30
£2.40
£0.08
TRIMETHOPRIM 200MG TABLETS
15
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 combination23
16
REFERENCES:
1
NICE Clinical Knowledge summaries: Acne Vulgaris http://cks.nice.org.uk/acne-vulgaris#!scenario:1
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. 48-56, 0007-0963 (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 1998 139, pp26–33
4
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: 482-485
5
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 2009 161, pp1180–1189
6
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 165–168, May
1992
7
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 251–254 http://www.eblue.org/article/S0190-9622(87)70200-X/pdf
8
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: http://www.ijdvl.com/text.asp?2007/73/2/94/31892
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.
http://onlinelibrary.wiley.com/doi/10.1046/j.1468-3083.2002.00392_6.x/pdf
10
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 , 487-492.
11
Summary of product characteristics (SPC): Isotrexin gel® Stiefel. Last Updated on eMC 19-Dec-2013
https://www.medicines.org.uk/emc/medicine/7495
12
Clark S.M, Cunliffe W.J, Boorman G.C. Placebo controlled studies of topical
isotretinoin/erythromycin gels in acne. Journal of Investigative Dermatology 1997. 108. 3. 393
13
Dréno B, et al. Eur J Dermatol 2014;24:201–9.
14
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) http://www.medscape.com/viewarticle/407765_2
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. 447-451, 0378-6501 (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;158:208-216.
17
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;8:161-166
18
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. 658663, 1545-9616 (June 1, 2013)
2
17
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. 581-586, 1545-9616 (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.: CD011368. DOI:
10.1002/14651858.CD011368.
21
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 16-9.
http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/281/CN-00450281/frame.html
22
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. 2003 13 (1) 44-48
http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/123/CN-00432123/frame.html
23
European Guidelines on the Treatment of Acne 2011 http://www.euroderm.org/edf/index.php/edfguidelines/category/4-guidelines-acne?download=7:guideline-treatment-of-acne
Produced by
Mr Stephen Morrow
Specialist Rotational Clinical Pharmacist
University Hospital of North Midlands
e-mail: [email protected]
Produced for use within the NHS. Not to be reproduced for commercial purposes.
18