COMPASS Therapeutic Notes on the Management of Acne in

14 Pages·2012·1.11 MB·English

COMPASS Therapeutic Notes on the
Management of Acne in Primary Care
In this issue: Glossary of terms
Page Acne Very severe acne where inflammatory lesions predominate and coalesce, often
Introduction, features & conglobata accompanied by exudate or bleeding. This form of acne may cause extensive
1
complications scarring. Systemic symptoms are absent.
Topical treatments of acne 3 Acne A sudden severe inflammatory reaction that precipitates deep nodules and
Oral treatments of acne 6 fulminans erosions, often with systemic effects (such as fever and arthralgia).
Cheilitis Inflammation of the lips
Comedones The basic acne lesion. An enlarged hair follicle plugged with oil and bacteria
Desquamation The shedding of the outer layers of the skin

MHRA Medicines and Healthcare products Regulatory Agency

Papulopustular Presence of comedones (blackheads and whiteheads) and some papules and

acne pustules

Pilosebaceous A unit consisting of one hair and an associated sebaceous gland
unit
RCT Randomised Controlled Trial
SmPC Summary of Product Characteristics

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Introduction, clinical features & complications of acne

Acne vulgaris (common acne) is a chronic inflammatory skin
condition which is notable for open and/or closed comedones Table ONE: Differential diagnosis9
(blackheads and whiteheads) and inflammatory lesions including
Most commonly seen in people over the age of 30
papules, pustules, or nodules.1
Rosacea years and is associated with telangiectasia and

A diagnosis of acne is often quite clear, and laboratory investigations flushing
are unnecessary, except where signs and symptoms suggest Folliculitis Infection of hair follicles; diagnosis could be confirmed
hyperandrogenism.2,3 Acne is rarely misdiagnosed. However, other and boils by taking swabs which usually reveal Staph. aureus
conditions can include some of the features of acne (Table ONE), Sycosis
but the presence of comedones confirms the diagnosis of acne.4 barbae Persistent folliculitis of the beard area

What are the clinical features of acne? Milia Small keratin cysts, most commonly around the eyes
Acne presents with non-inflammatory or inflammatory lesions, or a Peri-oral Erythema and small papules around the mouth,
mixture of the two.5 dermatitis nasolabial folds, and sometimes the lower eyelids
Non-inflammatory lesions are known as “comedones”:5 Acneiform Seen commonly during treatment with endothelial
• blackheads (open comedones) are follicles that have a wider eruption growth factor inhibitors such as cetuximab
than normal opening. They are filled with plugs of sebum and Acne can also occur later in life. Approximately 5% of women and
shed cells. This material has a typical black appearance due to 1% of men aged 25-40 years either continue to get acne lesions or
melanin deposition and lipid oxidation develop acne (late-onset acne) after adolescence.5 Patients with
• whiteheads (closed comedones) are follicles that are filled with persistent acne often have a family history of persistent acne.7 This is
the same material as blackheads but have a much smaller a more demanding, articulate group of patients with high
opening to the skin surface, and therefore appear white expectations for improvement.
Inflammatory lesions mainly consist of:5
Without treatment, acne persists in most sufferers for an average of
• superficial papules (red inflamed lesions, usually less than 5mm 8-12 years.10 Currently, the understanding of acne has been refined
in diameter), and
toward a “chronic disease”, overcoming the misconception of acne
• pustules (small, superficial lesions containing pus) as a simple, self-limiting affliction of adolescents.11
In more severe acne, nodules (deep papular lesions) and cysts
(deep pustular lesions that carry a greater risk of scarring than more
Did you know…?
superficial lesions) may occur. In very severe acne, nodules may
Recent evidence suggests that acne may be linked with smoking
track together and form large, deep sinuses (acne conglobata).
cigarettes, particularly in adult women smokers who were four times
Acne presents in a wide variety of clinical forms depending on the more likely to have acne than non-smoking controls.12 In addition,
type, number and severity of the predominant lesion. In most studies have shown that severe acne increases with smoking.13,14
patients, acne is a spectrum of disease. At one end lies the invisible

microcomedone – the development of which is the first essential step What causes acne?
in acne lesion formation – and at the other end is the deep scarring There are 4 primary pathogenic factors, which interact in a complex
inflammatory nodule.6 Acne principally affects the face (99% of manner to produce acne lesions:7,15
sufferers), the back (60%), and the chest (15%).5 1. Androgen-induced sebum production by the sebaceous gland
2. Abnormal keratinisation resulting in the formation of
Who gets acne?
comedones
Acne affects almost everyone at some point in their life, up to 14% of
people will consult their GP,7 and about 0.3% will require referral to a 3. Colonisation of the pilosebaceous duct with Propionibacterium
dermatologist.8 Peak incidence is seen in females aged 14-17 years acnes. P. acnes is an anaerobic bacterium that forms part of
and males aged 16-19 years.5 Acne varies greatly in severity, and the normal cutaneous flora in adults. Colonisation by P. acnes
leads to visible inflammation with swelling, redness, pain and
the person’s perception of the problem will influence whether they
release of inflammatory mediators into surrounding skin
seek medical help for it. Acne is the presenting problem in 3% of GP
consultations in the 13-25 age group.5 4. Inflammation, resulting from an interaction between biological
changes in the duct, P. acnes colonisation, and the production

of pro-inflammatory cytokines in response
COMPASS Therapeutic Notes on the Management of Acne in Primary Care ● April 2012 1
The formation of an acne lesion is thought to begin with the

microscopic lesion known as the “microcomedo” or Counselling someone with acne:

“microcomedone”. This lesion, which is not yet clinically visible, forms ► Reassure the person that acne is common, will not last forever,
when excess sebum collects in the follicle and abnormal epithelial and effective treatment is available
desquamation occurs along with proliferation of P. acnes. The ► Ask about previous treatments, including over-the-counter
microcomedo is the precursor to all acne lesions.15 products
► Patients should understand how to use their treatment and be
What are the complications of acne?
aware of potential side-effects
Although acne is a common, non-life threatening disease, untreated
► The likely timescale for improvement and duration of treatment
it can have serious, lifelong physical and psychological
consequences16 17 and health professionals should aim to treat it should be explained
effectively.18 ► Dispel common myths
► Advise on good skin care. Skin should not be washed too
Physical complications frequently or vigorously; wash no more than twice a day using a mild
Acne can cause extensive and permanent scarring. Scarring is soap or cleanser and lukewarm water. Do not use vigorous
usually mild and only visible under bright lights. However, significant scrubbing. The use of abrasive soaps, cleansing granules,
scarring (socially noticeable) is estimated to occur in 22% of people astringents, or exfoliating agents should be discouraged (advise use
with acne19 and has been implicated as a risk factor for suicide, of a soft wash-cloth and fingers instead)5
particularly in men.20 The development of post-acne scarring often ► Advise patients to avoid picking spots, this leads to trauma,
represents the failure of adequate and timely medical therapy,21 thus secondary infection, and scarring
early and effective treatment of acne is the most appropriate way to
prevent scarring. Topical and oral corticosteroids, anabolic steroids, androgens,
Psychological complications iodides, bromides, ciclosporin, lithium, halothane, progestogens and
Acne develops at the time when there is already a great deal of vitamin B12 can all cause or aggravate acne.7,33,34
conflict and difficulty for the adolescent, and the presence of
significant acne can make things worse.22 The social, psychological, How can compliance with acne treatments be improved?
Non-compliance is primarily the result of patient dissatisfaction due
and emotional impairment that can result from acne has been
to treatment-related side-effects and the inability of some patients to
reported to be similar to that associated with epilepsy, asthma,
follow what can be complex, multi-product regimens. There are
diabetes, and arthritis.23 In particular, it is the psychosocial distress
several ways in which healthcare professionals can work with a
that acne produces that makes such a powerful argument for its
patient to motivate him/her to comply with prescribed regimens,
timely and adequate treatment.
thereby improving response to treatment:

Even patients with mild to moderate acne have a higher prevalence • treatment may be associated with short-term adverse effects.
of suicidal ideation, comparable to that among patients with far more These may improve with continued use
chronic and disfiguring dermatological problems.24 Other • at the start of treatment, acne may appear to initially worsen. It
psychological consequences include lowered self-esteem and should be explained that this is because medications may be
professional expectations, social inhibition, depression and anxiety.25 working on lesions that were not previously visible
Furthermore, severe acne has been associated with decreased • explain why a specific treatment was chosen. This emphasises
employability in adulthood.26
the individualised benefits and therefore encourages compliance

What are the goals of acne treatment? • suggesting how the recommended therapy can be incorporated
The therapeutic goals in acne are to resolve existing lesions, prevent into the patient’s skin care regimen is important because tailoring
scarring and suppress the development of new lesions.15 Successful treatment recommendations to fit within the patient’s lifestyle will
management of acne involves choosing the right medications and increase the likelihood of compliance
helping the patient to use the medications as directed. The treatment • scheduling an initial follow-up visit between 4 and 8 weeks is
of acne is often hampered by misunderstandings about the condition important to assess response to treatment, as well as to give
(See Table TWO) and unrealistic expectations of treatment. Patients support to the patient
often abandon treatment early because of slowness of response, • at each follow-up visit, ask about the patient’s impression of
skin irritation caused by treatment or inconvenient regimens. It is treatment effectiveness and assess any adverse effects related to
important to recognise that patients want treatment that produces the current treatment.35 Based on the observed response, the
rapid results with minimum inconvenience. Successful treatment treatment plan is maintained, revised, or simplified according to
depends not merely on the provision of efficacious products but also the patient’s specific needs
on support and encouragement to carry on with treatment for months • patients should be aware that long-term treatment is likely to be
rather than just days or weeks. necessary to control their acne

Myths and Frequently Asked Questions Assessing the severity of acne
Healthcare professionals have an important role in giving support to When assessing the severity of acne, consider the distribution (face,
patients, stressing that acne is usually a treatable disease, back, chest, and upper arms), type and number of lesions
particularly if the patient complies with treatment.22 Some questions (comedones, papules, pustules, nodules) and the presence or
that are commonly asked are listed in Table TWO. absence of scarring.1,4 Physically, acne can be categorised as mild,
moderate or severe (see Table THREE).
Are there any drugs that could cause or aggravate acne?

Table TWO: Myths about acne and commonly asked questions22
Patients will often carry beliefs about the cause(s) of their acne, 27-29 and will often blame themselves for the condition. Dispelling popular
myths can have a positive impact on a person’s motivation in coping with acne, improve adherence to treatment, and stop a person adopting
unnecessary or potentially harmful behaviour.18

Is acne caused by poor hygiene?
Acne is not caused by poor hygiene and there is no evidence it is improved by cleaning.30 In fact, excessive washing can aggravate acne. The
black tip of a comedone is deposited melanin and oxidised sebum,16 not dirt, and it cannot be removed by scrubbing. Vigorous washing or
picking spots may actually make things worse.
Can I wear cosmetics?
Yes, especially if they are non-comedogenic but it is best to avoid heavy make-up.
Does diet influence acne?
Diet has little or no effect on acne. No studies have shown a link between acne and diet. In particular, no effect has been established between
chocolate, dairy products, shellfish, or fatty foods.31,32
Does stress aggravate acne?
Patients sometimes report that stress aggravates acne. This possibility is not unreasonable because stress, through its effect on the pituitary-
adrenal axis, may slightly increase the levels of circulating androgens.
Does acne flare before a period?
A premenstrual acne flare occurs in about 60% of females with acne.
Does sunshine help?
Many patients report benefit from sunshine, however, studies show sunlight probably has little benefit in acne.
Is acne infectious?
Acne is not infectious and cannot be passed on to other people. P. acnes is naturally present on skin but colonises follicles in acne.
COMPASS Therapeutic Notes on the Management of Acne in Primary Care ● April 2012 2
Table THREE: Grading of acne severity1,36 Table FOUR: NICE guidelines on referral to specialist services
for acne vulgaris
Mild acne Moderate acne Severe acne
Open and closed Comedones, more Comedones, Referral time Reason for referral
comedones frequent papules and more pustules, Have a severe variant of acne, such as acne
Urgent
(whiteheads and pustules, minimal and pustules plus fulminans or Gram-negative folliculitis
blackheads) a few scarring; can be nodular Have severe or nodulocystic acne that could
papules and subdivided into mainly abscesses with benefit from oral isotretinoin, or
Soon
pustules comedonal or mainly more extensive Have severe social or psychological problems,
inflammatory acne scarring including a morbid fear of deformity
Scarring often indicates previous episodes of severe acne (its Are at risk of, or are developing, scarring despite
presence may warrant more aggressive treatment to prevent primary care therapies
further scarring). Have moderate acne that has failed to respond to
treatment which has included 2 courses of
The psychological impact of acne Routine
antibacterials each lasting 3 months
It is important to recognise that acne can have a substantial impact
Are suspected of having an underlying
on a person’s quality of life, affecting both self-esteem and
psychosocial development.37 Psychological morbidity is not a trivial endocrinological cause for the acne that needs
problem, and it is compounded by multiple factors:38 assessment
Time
• acne affects highly visible skin
discretionary and
• popular culture and societal pressures dictate blemishless skin Have, or develop, features that make the
dependent on
• acne can be dismissed by healthcare professionals as a trivial clinical diagnosis uncertain
self-limiting condition circumstances
• acne peaks in teenage years, a time crucial for building
When should treatment of acne be started?
confidence and self-esteem
Acne medications should be started soon after the appearance of
Studies assessing the effect of acne on psychological health found a
acne lesions to minimise the potential for physical and emotional
range of abnormalities including depression, suicidal ideation, scarring.15,42 This is especially important because the clinical severity
anxiety, psychosomatic symptoms, shame, embarrassment, and
social inhibition,39 which improve with effective treatment.40 of acne does not correlate well with the impact on the patient; thus,
the patient may feel significant embarrassment, anger, or other

Many healthcare professionals and a significant proportion of the lay psychological disturbance even when disease is mild.25
public dismiss acne as a natural part of growing up that has few real
consequences. Yet considerable evidence shows that acne can be a How is it decided which treatment(s) should be used?
psychologically damaging condition that lasts years.26,33 Treatment for acne is largely determined by factors such as severity,
extent and duration of the disease; predisposition to scarring; post-
Acne severity and degree of psychological impairment do not
inflammatory erythema and pigmentation; and patient preference and
necessarily correspond – mild disease in one person can cause high
cost considerations. Response to previous treatment also needs to
degrees of psychological disability, whereas another with more
severe disease can seem less bothered by their acne.41 be considered, bearing in mind that many people will have bought
topical preparations over-the-counter before consulting a healthcare

When is it appropriate to consider referring a person for professional. Patients should be advised of the importance of
specialist treatment? adherence to treatment to minimise the potential for scarring.15
NICE has developed referral advice for acne patients. See Table The Global Alliance to Improve Outcomes in Acne15 has produced
FOUR. useful guidance – this is summarised in Table FIVE.

Table FIVE: Global Alliance Acne Treatment Algorithm15

Mild acne Moderate acne Severe acne*

Comedonal Mixed and papular/pustular Nodular Nodular/conglobate
Oral antibacterial Oral antibacterial
Topical retinoid
First choice Topical retinoid + topical retinoid + topical retinoid Oral isotretinoin
+ topical antibacterial
+/- benzoyl peroxide + benzoyl peroxide
Different topical
Different topical Oral isotretinoin
retinoid High dose oral
retinoid Different oral antibacterial OR
OR antibacterial
Alternatives + topical antibacterial + different topical retinoid Different oral antibacterial
Azelaic acid + topical retinoid
OR +/- benzoyl peroxide + different topical retinoid
OR + benzoyl peroxide
Azelaic acid +/- benzoyl peroxide
Salicylic acid
High dose oral anti-
Oral anti-androgen
Oral anti-androgen androgen
Alternatives + topical retinoid/azelaic
+ topical retinoid + topical retinoid
for females acid +/- topical
+/- oral antibacterial +/- topical
antibacterial
antibacterial
Maintenance
Topical retinoid Topical retinoid +/- benzoyl peroxide
therapy

* Refer all people with severe acne for specialist assessment and treatment (for example with oral isotretinoin), and consider prescribing an oral
antibiotic in combination with a topical drug whilst waiting for an appointment

Topical preparations for the management of acne
There are various topical treatment options for acne and no single same medication in a different vehicle, and less-irritating products
agent has a beneficial effect on all the main factors in the disease may be more likely to “work” because the patient is more compliant
pathogenesis.43 with therapy.44

Formulation issues The choice of formulation should be determined by skin type, acne
The active ingredient of a topical preparation is a very important distribution, and patient preference:45
component of efficacy, but the vehicle also is an important • gels, solutions and washes are non-greasy and have a drying
component of drug tolerability. These factors, in turn affect whether effect, which may be preferable for someone with oily skin
the medication works – not just because of its efficacy but also • creams are moisturising, and may be preferable for someone with
because of any impact it may have on the use of and compliance with dry skin
the medication regimen. Although no difference may exist between • lotions are useful for dry skin and for application to large areas of
generic topical medications in the active ingredient, a difference in skin
the vehicle means that the medication is different. As a result, a • alcoholic bases have a tendency to dry skin and may irritate
patient may have a different response (or lack of response) to the sensitive skin
COMPASS Therapeutic Notes on the Management of Acne in Primary Care ● April 2012 3
How should topiccal agents be uused? Howw should a topiccal retinoid be used?
Thee following advicce should be givven to all peoplee using topical Patieents should apply a thin layer of the agent to any area affectedd by
treaatments:5,33 acnee and continue uuntil lesions cleaar. Without instrruction many
1.. Wash the skiin and leave to ddry for about 200 minutes beforee patieents will apply onnly to inflamed sspots. Applicatioon should be att
applying treaatment. bedtiime because retinoids are inacctivated by light.552
2.. Apply topical agents sparinggly – more is nott better. For Seveeral months of trreatment with a topical retinoid may be neededd to
example, a ppea-sized amounnt of cream shoould be enough to achieeve an optimal rresponse, and ttreatment shouldd be continued until
treat the facee. no neew lesions deveelop.8,42
3.. Apply to all thhe affected areaas, not just to thhe spots. Most toopical
drugs have aa preventative action against neew lesions forming, Wheen are topical reetinoids contraa-indicated?
rather than trreating lesions tthat have alreaddy formed, so arreas Topiccal retinoids shoould be avoidedd in:
that are clearr of acne shouldd also be treatedd until it is likelyy the • pregnancy.42 Woomen of child-bearing age musst use effective
disease is in full remission. coontraception (orral progestogen-only contracepptives not
4.. Avoid the eyees and mouth wwhen applying a topical agent. coonsidered effecttive)42
5.. The person sshould be informmed that topical treatments are • peeople with veryy sensitive skinn (such as people with eczema)).5
effective and are worth persevering with, ass improvementss may CConsider using aadapalene in preeference to tretinoin if sensitivitty is
not occur immmediately, in facct there may be an initial a problem5
deterioration in the conditionn. • peersonal or familial history of cuutaneous epitheelioma

Tollerability issuees with topical ppreparations Whaat are the side-eeffects of usingg a topical retinoid?
Pattients often repoort tolerability prroblems with toppical acne The most common aadverse effect aassociated with topical retinoid
treaatments, for exaample, patients using benzoyl pperoxide prepaarations is locaal irritation. Symmptoms include erythema, scaling,
preeparations may ccomplain that thhe product causses skin drynesss or dryneess, itching, andd burning. Thesse effects often rresolve after abbout
irritation.44 This is pparticularly probblematic early inn the course of 3 weeeks usage,53 buut in the meantimme, if symptomss are troublesomme,
treaatment. To imprrove tolerability of topical agentts, gradual dosinng conssider the followinng measures:
cann be considered. For example, the use of a toppical agent twicee a • addvise the person to persist withh treatment, as iirritation usuallyy
weeek or every otheer day for the firrst few weeks off the regimen mmay suubsides over timme16
be helpful; after thiis time, daily use can be instituted. Moisturiserrs can • appply the agent oon alternate dayys to begin with,, and increase to
alsoo be used to deecrease irritationn.44 daaily application once tolerance has developed,5 or
• inncrease the prodduct strength grradually as tolerrance improves445
Forr how long shoould topical treeatments be ussed?
• swwitch to an alterrnative topical reetinoid. More reecently developeed
In ggeneral, topical treatment should be used for aa period of six
weeeks before respponse is assesssed.46 Some impprovement shouuld reetinoids, such ass adapalene, caause less irritatioon than tretinoinn5
beccome apparent dduring this time period, althouggh maximal respponse • addvise the person to wash off the product after about 20 minutees;
may occur later. OOnce a satisfactoory response haas been achieveed, it mmost people can tolerate topical retinoids applieed in this way
is uuncertain how loong treatment shhould be continuued for. The deccision • coonsider changinng the formulatioon of the drug (iit may be the
shoould be made onn a case by casse basis. Factorss to consider incclude veehicle that is causing the irritatiion)

the original severity of the acne, thhe psychologicaal disability caussed Topiccal retinoids inccrease the skin’ss sensitivity to ultraviolet lighht.
by tthe acne, and thhe adverse effects of treatmentt. This is especially immportant if they aare also taking aa tetracycline. NNight
• benzoyl peroxide and topicall retinoids can be used indefinnitely usagge of the producct and the use off a sunscreen uusually avoids thhis
as long as adveerse effects do nnot occur. It may be possible too problem.54
reduce applicattion to alternate days or less duuring maintenannce Apprroximately 3 weeeks after startinng topical retinoiid therapy, many
• topical antibaccterials should not usually be uused long-term due patieents report a flarre-up of their accne.55 There is tthen a further deelay
to fears of resisstance occurringg (see later) of 2 mmonths before tthe retinoids exeert their maximaal effect.54
• azelaic acid is only licensed foor treatment perriods of 6 monthhs,
although it is freequently used foor longer periodds47 Mainntenance treatmment with topiccal retinoids
The nature of acne aas a “chronic disease”11 requirees the definition of
Most physicians prrobably prescribbe topical therappies indefinitely
proovided the patiennt is respondingg.22 Indeed it woould be wise to ttell mainntenance regimeens to preserve the initial treatmment success annd
preveent frequent relaapses. Topical rretinoids are suitable for
the patient that somme form of topiccal therapy will pprobably be reqquired
mainntenance treatmment due to theirr multifactorial anti-acne efficaccy
for much of the pattient’s acne-life.. This could be aanything from aa few
yeaars up to 10 yeaars or more.22 A small number oof patients (up too 7%) withoout inducing baccterial resistancce during long teerm treatment and
havve acne persisting well up to thee age of 40 yeaars.22 their ability to prevennt microcomedoone formation. Itt has been showwn
that, after cessation of retinoid treattment, the numbber of

Topical reetinoids andd related ppreparationns microocomedones inccreases again,556 which might eexplain the
occurrence of frequeent relapses whhen treatment is withdrawn
• Aknemycin® Pluus ( tretinoin + eerythromycin) followwing successfull initial therapy.
• Differin® (adapaalene)
• Epiduo® (adapaalene + benzoyl peroxide)
Cautioons with the use of topical rettinoids
• Isotrex® (isotrettinoin)
• Isotrexin® (isotrretinoin + erythroomycin) ► Topical retinoids shhould be avoidedd in pregnancy.
• Retin-A® (tretinooin) ►Topiccal retinoids shoould be avoidedd in severe acnee
involvinng large areas.442
Thee topical retinoidds available in the UK are tretinnoin, isotretinooin, ► Coontact with eyess, nostrils, moutth and mucous membranes,
andd adapalene. Thhey are available in a variety off strengths and eczeematous, brokenn or sunburned skin should be aavoided.42
formmulation. The efffectiveness of ttopical retinoidss in the treatmennt of ► Usse with caution in sensitive areeas such as the neck, and
acnne is well docummented,48,49 althoough there is a lack of evidencee accumulation in anggles of the nose should be avoidded.42
fromm trials to show that any particuular topical retinnoid is superior tto ► Exxposure to UV light (including ssunlight, solariums) should be
anoother, although higher-strength products, or prooducts in an avoidded; if sun expoosure is unavoiddable an approppriate sunscreenn or
alcooholic vehicle, mmay irritate the sskin more.1 proteective clothing sshould be used.442

Toppical retinoids should be a founndation in acne ttherapy for virtuually ► Usse of retinoids wwith abrasive cleeansers, comeddogenic or
all ppatients except those with the mmost severe dissease.15 astrinngent cosmeticss should also bee avoided.42
► Alllow peeling (e.gg. resulting fromm the use of otheer irritant
How do topical reetinoids work? treatments) to subside before usingg a topical retinooid.42
Toppical retinoids normalise follicullar keratinisationn, promote drainnage
of ccomedones, andd inhibit new comedone formation.50,51 They have

beeen used historically mainly to treeat comedoness, but they are also

effeective at treatingg inflammatory llesions (if used in the longer term)
by iinhibiting microccomedone formmation.51 This is supported by goood
eviddence from placcebo-controlled trials.10
Toppical retinoids decrease the nummber of comedoones and

inflaammatory lesions by 40-70%.4

COMPASSS Therapeuticc Notes on thee Management of Acne in Primary Care ●● April 2012 4
TTopical benzoyl peroxxide Topical aazelaic acidd (Finacea® andd Skinoren®)
((Acnecide®, Breevoxyl®, PanOxyyl®)
Azelaaic acid is a natturally occurringg decarboxylic aacid that has beeen

Bennzoyl peroxide hhas been a wideely used topical treatment for aacne showwn to be effectivve in reducing booth inflammatorry and non-
sincce the 1960s. AAlthough a poweerful oxidising aggent, benzoyl inflammmatory acne leesions.69 Azelaic acid has moderate antibacterrial
perroxide is non-toxxic to humans aand is used in foood processing tto and kkeratolytic activvity as well as weeak anti-inflammmatory effects.6
bleaach flour and oils and in various industrial appplications.57 For the Cliniccal studies havee shown it to bee as effective as benzoyl peroxide
treaatment of acne, benzoyl peroxidde is available iin a variety of or treetinoin in the treeatment of mild tto moderate acnne and some
streengths and formmulations, both oon prescription aand over-the-coounter patieents prefer it beccause it is less llikely to cause loocal irritation than
fromm pharmacies. TThere is no eviddence from trialss that any one benzzoyl peroxide.73-776 Because it is less irritant than other topical
prooduct is superiorr to another. treatments, it can bee a useful alternnative if benzoyl peroxide or toppical
retinooids are not toleerated.69
How does benzoyyl peroxide actt?

Toppical benzoyl peeroxide has nummerous modes oof activity. It hass Whaat are the adverrse effects of toopical azelaic aacid?
beeen shown to posssess antimicrobial, anti-inflammatory,58 Mild transient erytheema and skin irritation are thee most frequenttly
kerratolytic,59 and wwound-healing aactivity.60,61 reported adverse evvents and these tend to subsidee after 3-4 weekks of
It has been shown that P. acnes iss capable of seccreting protectivve continued use. No aalteration in regimen is usually nnecessary.51
bioffilm polysacchaarides,62 which mmay explain somme of the difficullty of Azelaaic acid can lighhten the colour of the skin, bbut this is rarely
delivering effectivee levels of antimmicrobials within the skin. Benzooyl problematic in practice. Similarly, photosensitivityy can occur but is
perroxide, with its ooxidative properrties, appears too have a role in rare and usually mildd.51
desstroying this bioffilm. This model helps to illustraate the use of
TTopical anttibacterialss
bennzoyl peroxide in facilitating thee delivery of topical antibacteriaals
andd other agents too the targeted bbacteria.62,63 It also explains whhy (Dalacin TT®, Stiemycin®, Zindaclin® and Zineryt®)
bennzoyl peroxide hhas the ability too prevent or elimminate the
Actioon
devvelopment of P.acnes resistancce.64-68 In many years of use in acne
Topiccal antibacterialls, such as clinddamycin and eryythromycin, are
management, bactterial resistancee to benzoyl perroxide has not
bacteeriostatic for P.acnes and havee also been demmonstrated to haave
devveloped.
anti-iinflammatory acctivities through inhibition of lipaase production by
How should benzzoyl peroxide pproducts be applied? P. accnes or inhibition of leukocyte cchemotaxis.71,78
Simmilar to other toppical agents, benzoyl peroxide should be applied to
Efficcacy
the whole of the afffected area, noot just the spotss.69
Topiccal antibacterialls are generally well-tolerated aand have been
Whhat are the adveerse effects offbenzoyl peroxxide? showwn to reduce infllammatory lesioons by 46-70% in several RCTss.4
Bennzoyl peroxide ccan cause skin irritation, erythema, drynesss, and
Placce in therapy
skin peeling. Althoough irritation teends to diminishh as tolerance
Topiccal preparationss of erythromyciin and clindamyycin are used in the
devvelops, it can bee severe enoughh to limit use.5 MMinimise local treatment of mild to moderate inflammmatory acne33,42,51 but appearr to
advverse effects by considering thee following: be noo more effectivee than topical beenzoyl peroxidee or tretinoin.42,799
• use a low strength of benzoyl pperoxide. Evidence suggests thhat Topiccal antibacterialls are probably best reserved foor patients who
2.5% preparatioons are as effecctive as 5% or 10% preparationns,45 wish to avoid oral anntibacterials or wwho cannot toleerate them.42
and they are lesss likely to causse irritation. Thuus, 2.5% is the Seveeral topical antibbacterial produccts are availablee and appear to be
concentration oof choice roughly equivalent inn efficacy.73
• wash off the appplication of bennzoyl peroxide aafter 15 minutes
initially, and inccrease exposuree in increments of 15 minutes uuntil Use
the drug can bee tolerated for 2 hours Where topical antibaacterials are inddicated (such ass in papulopustuular
• use water-baseed products insteead of alcohol-bbased products664 acnee), they must be used in combinnation with a toppical agent that has
anti-rresistance properties (such as benzoyl peroxidde), not as
Alleergic contact ddermatitis is a mmore serious addverse effect
monootherapy, and limited to short-term treatment ((i.e. reviewed att 6-
asssociated with beenzoyl peroxide.. It has been repported in 12 wweeks).43
appproximately 1% to 3% of patients70 and its occuurrence necessitates

disccontinuing the treatment. It usuually resolves when treatment iss Whaat are the adverrse effects of toopical antibactterials?
withhdrawn.45 Mild skin irritation mmay occur with ssymptoms of errythema, peelingg,
dryneess and burningg, and may be ddue to the vehicle used.71 Topiccal
Forr how long shoould benzoyl peeroxide be useed?
antibbacterials rarely cause significant skin irritation unless there is a
Thee response to beenzoyl peroxidee is usually rapidd, with improvemment
hypeersensitivity reacction to the antibbacterial used, iin which case
noted as early as ffive days after trreatment has beegun.71,72 Most
treatment should bee stopped.
clinnical improvemeent with benzoyl peroxide occurrs within the first 6
weeeks, although thhe maximal respponse may takee up to 3 monthss. 5,46 Althoough more commmonly associateed with systemicc clindamycin,
diarrhoea, abdominaal pain, bloody ddiarrhoea, and ccolitis (includingg
Oncce a satisfactoryy response has occurred, the ddecision to contiinue
pseuudomembranouss colitis) have also been associated with topicaal
treaatment should bbe made on an individual basis. Factors to consider clindamycin,79 but thhis is likely to bee very rare in praactice.71
incllude the original severity of the acne, the psychological disabiility

cauused by the acne, and adverse effects of treatmment. Benzoyl Is there a significannt problem witth resistance too topical
perroxide may be uused indefinitelyy (either alone or in combinationn with antibbacterials?
a toopical retinoid) pprovided adversse effects do not occur. It may bbe Resisstance of P. acnnes to topical anntibacterials hass become more
posssible to reduce application to aalternate days oor less frequentlyy prevaalent and may rresult in loss of product efficacyy.70,80,81 In a largge
durring maintenancce. RCTin UK primary ccare, levels of reesistance in P.acnes was founnd
to bee 47% with erythhromycin and 411% with clindammycin.46
Presccribing points –– Benzoyl perooxide The problem of resisstant P. acnesiss most often seen with topical
clindamycin and eryythromycin, with some experts rreporting neitheer of
► Avooid contact with eyes, mouth annd mucus thesee agents usefulunless combineed with benzoyl peroxide.18 Failure
membranes42
to resspond to a topiccal antibacterial within 6 to 8 weeeks should
► BBenzoyl peroxidde may cause bbleaching of hairr, clothing, toweels, autommatically promppt a change in trreatment.18
andd bed-linen.51

► AAvoid excessivee exposure to suunlight.42
► AAvailable as creeam, gel, aquaggel, and wash foormulations.42 Prescribinng point – topical antibacterials

► FFor people with sensitive skin, weaker, aqueouus products may be Monotheraapy with topical aantibacterials shhould not be ussed
preeferred.5 routinely beecause P. acnees may become resistant within
► BBenzoyl peroxidde inactivates toopical retinoid wwhen used one mmonth after dailly treatment hass begun.82 Resisstance can be
conncurrently.54,77 avoidded if a topical aantibacterial is ccombined with bbenzoyl peroxide.83

COMPASSS Therapeuticc Notes on thee Management of Acne in Primary Care ●● April 2012 5
Salicylic acid is available in various preparations for sale direct to
Steps to combat bacterial resistance: the public for the treatment of mild acne.42 Salicylic acid may be an
► Do not use topical antibacterials where other topical acne option for someone who cannot tolerate retinoids.98 Nicotinamide
treatments can be expected to bring the same benefit42,71 (Nicam®) has potent anti-inflammatory activity in vitro, but there is
► Do not use a topical antibacterial alone;71 rather use combined little data to support its efficacy.45
therapy with retinoids or benzoyl peroxide70
► Stop topical antibacterials when there is no further improvement or Using combinations of topical agents
the improvement is only slight71 Given the multiple factors as well as the complex inter-relationship of
►6-8 weeks into treatment might be an appropriate time point at these factors contributing to acne development, combination therapy
which to assess response to a topical antibacterial81 targeted towards simultaneous processes has been increasingly
► Try to avoid continuing topical antibacterials for longer than favoured in practice. This can be done by alternating separate
necessary.71 However, treatment should be used for at least 6 products or using proprietary combination products (see Table SIX).
months42,81 The choice should be made according to patient’s preference bearing
► Do not combine topical and systemic antibacterials71 in mind that combined proprietary products:5
► Check the patient’s compliance with treatment ● do not allow for individual titration of component agents
● are usually formulated with an alcoholic base, which may irritate

Other topical preparations sensitive skin
● may be more convenient for people to use as they reduce the
Abrasive agents and vigorous scrubbing are not beneficial in acne
and should be avoided,42 as they can aggravate acne by promoting numbers of products and applications required and thus may
the development of inflammatory lesions.16,97 Peeling agents such as increase compliance
sulphur-containing preparations and salicylic acid are generally ● are generally more expensive than single products43

considered inferior to the more modern topical treatments for acne.

Table SIX: Practical considerations when combining topical treatments for acne

Proprietary combinations When combining separate
Combination Comments
available products
Benzoyl peroxide + Concomitant use of benzoyl peroxide and topical
clindamycin Apply 12 hours apart (e.g. benzoyl clindamycin or erythromycin is more effective than
(Duac® Once Daily) peroxide at night and topical either component alone67,84-86 and decreases the
Benzoyl peroxide + antibacterial in the morning) risk of resistance68,83
topical antibacterial Benzoyl peroxide + Avoid use of two products that Duac® gel needs to be refrigerated until it is
potassium have an alcoholic base, as this dispensed. After dispensing, it then needs to be
hydroxyquinoline sulphate may increase skin irritation stored below 25oC. Shelf life after dispensing = 2
(Quinoderm®) months
The combination of a topical retinoid plus benzoyl
Apply 12 hours apart (e.g. topical
peroxide is a logical formulation, because it targets
retinoid at night and benzoyl
3 of 4 pathophysiologic factors and the antibacterial
Benzoyl peroxide + Benzoyl peroxide + peroxide in the morning)
topical retinoid adapalene (Epiduo®) Both products may irritate the skin; pwoitrhtioount (ebveidneznocyle p oefr boaxicdtee)r iaisl rraepsiisdtlay nbcaec tericidal
switch to an alternative
Benzoyl peroxide may oxidize a retinoid if they are
combination if this is a problem applied as separate products.77
A combination of topical retinoid and topical
antibacterial is more effective than either agent
Tretinoin + erythromycin used alone.73,87-92 However, the agents should be
(Aknemycin® Plus) Apply 12 hours apart (e.g. topical applied at separate times, unless they are known to
Topical retinoid +
retinoid at night and topical be compatible
topical antibacterial Isotretinoin + erythromycin antibacterial in the morning) Patients on combination therapy show faster signs
(Isotrexin®) of improvement.92-95 This is believed to lead to
greater patient adherence and reduce the risk of P.
acnes resistance
Notes:58,96
► Topical retinoids improve the penetration of other topical medications.
► Topical retinoids may help to improve the hyperpigmentation that is left in darker skin types after the resolution of inflammatory lesions.

Oral preparations for the management of acne
Oral antibacterials Table SEVEN for doses). Minocycline is no longer considered
suitable as a first-line acne treatment (see later). Alternatives to
When topical agents are insufficient or not tolerated, or in cases of tetracyclines include erythromycin, and trimethoprim.
moderate to severe acne, especially when the chest, back and [Trimethoprim is not licensed for acne].
shoulders are involved, systemic antibacterials are often considered
Erythromycin should only be used as a first-line agent when
the next line of treatment.99,100 tetracyclines are contraindicated.66 There is a lack of evidence from
Oral antibacterials are usually reserved for:33,70,101 placebo-controlled trials to verify the efficacy of erythromycin,
• moderate inflammatory acne although evidence from comparative trials indicates it is probably as
• patients who have not responded adequately to topical therapy or effective as tetracyclines. However, there is evidence from
who cannot tolerate it observational and controlled studies that there are particular
• those at greatest risk of scarring problems with the development of bacterial resistance to
• where lesions are predominantly on the chest, back, shoulders erythromycin. Erythromycin can be used as second-line choice
making topical therapy impractical following therapeutic failure of a tetracycline.
Anti-comedonal treatment (e.g. with topical benzoyl peroxide) may No oral antibacterial has been shown to be more effective than any
also be required.42 other,104 but clinical experience indicates that some people respond
Oral antibacterials reduce P. acnes within follicles, thereby inhibiting better to one antibacterial than another. There is no evidence that
production of bacteria-induced inflammatory cytokines.102 Compared higher doses are more effective than lower doses or that controlled-
to topical antibacterials, oral antibacterials are more effective and release preparations are necessary.105,106
have a faster onset of action. Unfortunately, the risk of antibacterial
Which tetracycline?
resistance is significant.103
There is good evidence that tetracyclines are effective in the

Which oral antibacterials are suitable for the treatment of acne? treatment of acne, but there is a lack of good-quality comparative
Of the oral antibacterials, tetracyclines are first-line.73 Tetracycline, trials to show superiority of one tetracycline compared with another in
doxycycline, lymecycline, or oxytetracycline may be used. (See terms of efficacy.106 Therefore the choice of specific tetracycline
COMPASS Therapeutic Notes on the Management of Acne in Primary Care ● April 2012 6
shoould be made acccording to the
TTable SEVEN: OOral antibacterrial therapy forr acne vulgaris42,107
individual's prefereence and cost, bbearing in

minnd the adverse eeffect profile of tthe drugs Cost of 28 days
Antibacterial aand dose Notes
andd the convenience of their dosinng treatment
schhedules (see Taable SEVEN). Contraindicaated in pregnannt women or in
DDoxycycline children undder 12 years of aage
Whhy is minocycliine not consideered to be £3.67
1100mg daily Can be takeen with food
a fiirst-line acne trreatment?
Adverse reaactions: GI upseet, phototoxicity
Minnocycline is NOTT a first-line acnne
treaatment based on the following: EErythromycin TTABLETS Safe in preggnant women annd children
• evidence that mminocycline mighht be 5500mg twice daily £20.38* M42a%y coaf upsaeti eeGGnIt su pmsaeyt show resistance108
more effective tthan other tetraccyclines
is, at best, weak, being limited to a few, LLymecycline Contraindicaated in pregnannt women or in
poor quality triaals with questionnable 4408mg daily £7.77 children undder the age of 122 years
results109,110 Can be takeen with food
• minocycline seeems to be almost unique OOxytetracyclinee Contraindicaated in pregnannt women or in
within tetracycliines in causing potentially 5500mg twice daily £4.40 children undder 12 years of aage
irreversible slatte-grey Needs to bee taken on an emmpty stomach
hyperpigmentattion of the skin. TTetracycline Contraindicaated in pregnannt women or in
Pigmentation off other tissues ((e.g. the 5500mg twice daily £47.88 children undder 12 years of aage
sclera, conjuncttiva) has also been Needs to bee taken on an emmpty stomach
reported111,112 Unlicensed indication
• minocycline is aassociated with a higher TTrimethoprim £5.32 Useful in paatients resistant to other antibiottics
risk of inducing lupus-like synddrome.109 3300mg twice daily Risk of serioous skin reactions, such as
The overall hazzard ratio for thee Stevens-Johhnson syndromee
association of mminocycline to luupus **Prescribe erythrromycin as tabletts; they cost conssiderably less thaan the capsules442
erythematosus was 2.64 (95% Whaat are the adverrse effects of thhe oral antibaccterials used too
confidence interval = 1.51 to 4.66).113 treatt acne?
• minocycline hass been associatted with autoimmmune hepatitis oor The incidence of siggnificant adversee effects with orral antibacterial use
other types of hhepatotoxicity is loww. However, advverse effect proofiles may be heelpful for each orral
Thee SmPC for minnocycline produccts recommendss that if the drugg is antibbacterial used inn the treatment oof acne.
conntinued for over 6 months, patieents should be mmonitored at leaast 3-
Tetraacyclines
monthly for featurees of hepatitis, ssystemic lupus eerythematosus oor
• GGastrointestinal ddisturbances arre the most commmon adverse
unuusual pigmentattion.
efffects associateed with use of teetracyclines orally. Nausea,
Connsidering the noon-superiority off its effects in accne, its specific
voomiting and diaarrhoea are thee most commonn adverse effectss.
advverse effects, itss price and the aalternatives, thee benefits of
Tetracycline and oxytetracyclinee should be takeen on an empty
minnocycline are siggnificantly lowerr than the potenntial risks.114
sttomach, which mmay increase naausea. Doxycyccline, lymecyclinne,
Minnocycline may bbe an effective trreatment for somme patients withh
annd minocycline may be taken wwith food, which may help the
acnne but there is aa lack of evidencce that it is any better than otheer peerson tolerate thhe drug.51
options.104,115
• VVulvovaginal caandidiasis may occur as a resuult of the broad
sppectrum nature of tetracycliness.45
Actions ffor prescriberss: Minocycline
• Tetracyclines cann cause severe oesophagitis, presenting as
The potenntial for serious aadverse reactions with minocyccline buurning pain in thhe lower chest. To counteract this, it is
has led maanufacturers to recommend “peeriodic” monitorring reecommended thhat tetracycliness are taken in ann upright positioon
of blood, rrenal, and liver ffunction. The BNNF recommends wwith plenty of water, without cheewing or breakinng the tablets orr
monitoring for hepaatotoxicity, pigmmentation and syystemic lupus caapsules.42

erythematosus eveery 3 months, if the drug is takeen for 6 months or • Photosensitivityy may also occuur with tetracycline use, especiaally
more.42 dooxycycline. As aa precaution, peeople taking thee drug should bee

Preescribers are advised to review patients currenntly on minocycline addvised to limit thheir exposure too sunlight (cover up with clothes
withh a view to channging to an alterrnative tetracycline if appropriaate. annd use sunblockk), and avoid suun-lamps. Doxyccycline has beeen
reeported to causee photosensitivity in 13 per 1 mmillion prescriptioons
Aftter what time shhould efficacyyof an oral antiibacterial be wwritten.117 Lymeccycline is much less phototoxic than
asssessed and forr how long shoould treatment bbe continued?? dooxycycline.118
Oraal antibacterials usually cause aa rapid and susttained improvemment • BBenign intracranial hypertension is a rare buut important
in aacne; data from a large RCT inddicated that 6-88 weeks is an addverse effect off tetracycline-likee drugs.45 If a person taking a
apppropriate time too assess responnse.105 Howeverr, maximal teetracycline deveelops headache and visual distuurbances, the drug
impprovement may only be apparent after 3-4 monnths, and it has been shhould be stoppeed immediately and advice sought.
recommended thatt treatment shouuld be continuedd for a minimumm of 3 • Tetracyclines as a class should not be used in ppregnant women or
months before it iss assumed to bee ineffective.16 inn patients youngger than 12 yearrs to avoid the rrisks of tooth

If an individual doees not respond tto oral antibacteerials or stops discolouration aand bone growwth retardation in the foetus orr
responding, there is no evidence tthat increasing tthe frequency oor chhild.51 When administered to chhildren, all tetraccyclines induce
dosse is helpful. Such strategies increase the risk of resistance grrey (63%), yelloow (28%), or broown (10%) discooloration of teeth.119
devveloping withoutt increasing efficcacy. The oral aantibacterial shoould Inn adults, only miinocycline inducces tooth discoloouration.
be stopped if no fuurther improvemment is evident;388 a different oral
antibacterial can be tried.42,52 Minoocycline
Minoocycline shares most of the advverse effects thaat occur with othher
If patients respondd well, the oral aantibacterial shoould be continueed for tetraccyclines, but it is also associateed with several adverse effectss
6-88 months in totall and then the ppatient maintaineed on an approppriate that aare rarer but moore severe:
topical regimen.52 OOral antibacterials should NOTT be routinely ussed • DDrug-induced heepatitis is the mmost severe adveerse effect
for maintenance beecause alternatives exist with ssimilar efficacy aand asssociated with mminocycline usee, and this can bbe life-threateninng.
preeventative actionn.66 AAll tetracyclines hhave the potenttial to cause heppatic inflammation;
Whhat happens whhen the coursee of oral antibacterial finishess? hoowever, it seemms to be more coommon with minnocycline.109 This
An oral antibacteriaal can be very hhelpful in bringinng moderate to haas led some phyysicians to sugggest that minocyycline should onnly
sevvere acne underr control. Howevver, once adequuate control is bee offered as a ssecond-line treattment, after other antibacterialss
achhieved, the oral antibacterial maay be discontinuued. Many patieents haave failed to havve a satisfactorry effect.120
do well with subsequent use of a ttopical regimen with a combinaation • MMinocycline can cause vestibular disturbancees. Typically, theese
topical retinoid pluss topical antibiootic or retinoid plus benzoyl perooxide prresent as headaache, dizziness, ataxia, and droowsiness.51 Theese
commbination. Maintenance therapyy with topical reetinoids or retinooid addverse symptomms are usually rreversible, and mmay be decreassed
commbinations may obviate the neeed for long-termm systemic byy starting with aa low dose of miinocycline and increasing
antibiotics.116 grradually.45

COMPASSS Therapeuticc Notes on thee Management of Acne in Primary Care ●● April 2012 7
• Skin discolourration is a posssible adverse reaaction to Commbined oral conntraceptives
minocycline, annd presents as aa grey-blue disccolouration, Therre is good evidence from placebbo-controlled trials that COCs aare
particularly in areas that have bbeen inflamed bby acne.45 This eeffect effecctive in reducingg lesion count, aacne severity, annd the woman'ss
may be related to the cumulativve dose of minoocycline taken aand perceeption of the condition. 34,127-131 Clinical observvation indicates tthat
may be irreverssible.109,111 women with deep-seeated nodules oof the lower facee and neck are aa
group in whom hormmonal treatmentt may be especially useful.82
Eryythromycin
Gasstrointestinal aadverse effectss are common wwith prolonged In geeneral, after 6 too 9 months of usse of a COC, there is a reductioon
erythromycin use, and these may be severe enouugh to limit its use.45 in infflammatory lesioons by 30-60%, an improvemennt of acne in 50-
Howwever, erythrommycin can be takken with food, wwhich may help 90% of patients, andd non-inflammattory facial acne lesions are alsoo
reduce nausea. reducced.33,34 Of notee, hormonal therrapies seem to work best in
women who report aacne flare-up prremenstrually.1322
How significant aa problem is ressistance to oraal antibacterialls in
thee management of acne? Howw do COCs worrkk in the treatmment of acne?
A mmajor problem aaffecting oral anttibacterial use inn acne is bacterrial The beneficial effectts of COCs on aacne have beenn noted for manyy
resistance, which hhas been increaasing.80,121 Resisstance has beenn yearss.97 COCs are uuseful in acne beecause oestrogen inhibits
seeen with all antibaacterials used too treat acne, but is most commmon sebaaceous gland acctivity and supprresses ovarian aand adrenal
withh erythromycin.1 androogen productionn. Androgens arre one of the maain factors in accne
pathoogenesis becauuse they enhancce follicular keraatosis and influeence
How can the channces of developping antibacteerial resistancee be sebuum production.1333-135 There is noo acne without ssebum, which
lowwered? servees as a nutrient source for P. acnes, and androogens are the
In aan attempt to coounteract the deevelopment of antibacterial majoor sebotropic hormones. The increased sebumm production in aacne
resistance, consideer the following::16,122 patieents may be duee to increased ccirculating androogens or a
• stress the impoortance of adherrence to treatmeent hypeerresponsivenesss of the target oorgan (the pilosebaceous unit) to
• prescribe adequuate doses of an oral antibacteerial androogens, or both.11,82
• use antibacteriaals only when thhere is no other option
• avoid concomitant use of oral aand topical antibbacterials42,71,82 Whicch COC?
The eefficacy of COCCs in acne treatmment has been comprehensively
• use antibacteriaals for the minimmum time possibble
revieewed; ethinylesttradiol/drospirennone and

If an oral antibacteerial has failed aand resistance iss suspected, it is ethinnylestradiol/cyprroterone are thee most effective followed by
proobably justified too try another anntibacterial fromm a different classs. ethinnylestradiol/desoogestrel and ethhinylestradiol/geestodene. This is
Howwever, avoid routinely switchingg or rotating anttibacterials, as tthis followwed by ethinylesstradiol/levonorrgestrel and
praactice promotes resistance.122 Iff acne relapses after an antibaccterial ethinnylestradiol/noreethisterone whicch are equally efffective.136-138
is sstopped, restart the regimen if this was originallly effective. Notee: none of the CCOCs are licenssed to treat acne.

Hormonaal treatment
Progestoggens have andrrogenic propertiees. Thus,

Co--cyprindiol (2mmg cyproteronee acetate with 335microgramss progestoogen-only contraaceptives often worsen acne
ethhinylestradiol) and shoould be avoided in acne patients.33,34
Co--cyprindiol is liceensed for the treeatment of seveere acne refracttory

to pprolonged oral aantibacterial treaatment.123 Howeever, it has beenn Oral rettinoids
sugggested that it mmay be more appropriate to usee it in suitable
wommen before antiibacterials are tried, and this is commonly done in Oralisotretinoin is aa synthetic form of vitamin A. Oral isotretinoin is
praactice.5 Co-cyprindiol is also an effective combiined oral indiccated for severe acne such as nnodulocystic andd conglobate accne,
conntraceptive (COCC), but is not liccensed for the sole purpose of ooral but itt is commonly used for severe aacne that has faailed to respondd to
conntraception. Brands include Diaanette®, Acnocinn®, Cicafem®, adeqquate courses of standard oral and topical therrapies.139 It is alsso
Claairette®. particcularly useful inn women who deevelop acne in tthe third or fourtth
decaades of life, sincce late onset acnne is frequently unresponsive too
Whhat are the adveerse effects offco-cyprindiol?? antibbacterials.42
Co--cyprindiol has bbeen found to bbe associated with an increasedd risk
When the use of thiss agent is beingg considered, ann assessment off
of vvenous thrombboembolism (VVTE). The risk off VTE is consideered
the sseverity of diseaase should include the effect of the acne on thee
to bbe 2-4 fold higheer than that asssociated with conventional secoond-
genneration COCs.1124,125 persoon, such as the potential for sccarring.33

Othher adverse effeects associated with co-cyprindiol are similar too Isotreetinoin is a toxicc drug that shouuld be prescribeed only by, or
those of other COCCs and include breast tendernness, mood undeer the supervission of, a consuultant dermatoologist. In Northhern
Irelannd, oral isotretinnoin is on the RED list for specialist medicines.
chaanges, and boddy weight changges.
This means that the responsibility foor prescribing itt remains with thhe
Forr how long shoould co-cyprinddiol be given? conssultant or speciaalist clinician. Suupply of isotretinnoin is via the
A reesponse to hormmonal interventiion may be seen after one relevvant hospital phharmacy. (See wwww.ipnsm.hsccni.net).
menstrual cycle, but 3-6 months aare usually needded to judge thee full
effeect. 33,36 Prescribbing and dispennsing oral retinnoids
Co--cyprindiol shouuld be continuedd for only 3-4 meenstrual cycles after
GPs and other primarry care prescribbers should NOOT
the woman’s acne has resolved, ddue to the risk oof serious adversse
presccribe oral retinooids, even on recceipt of a requeest to do so fromm a
effeects such as VTTE.126 If contraceeptive cover is sstill required afteer the
privaate medical clinic/practice.
couurse of co-cyprinndiol is finished,, the patient shoould change to
anoother oral contraaceptive.Note: oother COCs cann be effective inn Commmunity pharmacists should NNOT dispense ooral retinoids, evven
acnne managementt (although unliccensed) and maay be continued on reeceipt of a private prescription.
indeefinitely.
Privaate medical facillities have arranngements in place to prescribe

Ifaacne recurs afteer co-cyprindiool has been stoopped can it bee re- and ddispense oral reetinoids themselves as patientss must be enrolled
staarted? in a ppregnancy monitoring scheme.
If, oon withdrawal off co-cyprindiol, tthe patient's acnne relapses, theen a

reppeat course of coo-cyprindiol is inndicated. No set interval between Howw effective is orral isotretinoin in the treatmeent of acne?
couurses is suggestted, but in orderr to maintain thee menstrual cyccle, it Oral isotretinoin is thhe most effectivve drug availablee for the treatmeent
is ssuggested leavinng a minimum oof one month beefore restarting of accne. However, ddespite its undenniable effectivenness, isotretinoin is
anoother course. not aa curative drug.1140 After one couurse of oral isotrretinoin:
• 400% of patients wwill be free of accne
• 400% of patients wwill have recurreence of acne of low severity thaat
reesponds to meddications to whicch the acne had been previouslly
Prescribing points – CCo-cyprindiol reesistant

► Brandds include Acnocin®, Cicafem®, Clairette®, • 200% will need repeated treatment with oral isotretinoin at a futuure
Dianette® timme;72 factors linked with relapse are younger aage, female
► VVTE occurs more frequently in women taking cco-cyprindiol thaan geender, pre-pubeertal acne or truncal acne and aa high number oof
those taking a low--dose COC. Preescribers are reminded that co-- innflammatory lesiions at the end of treatment141
cypprindiol should nnot be used soleely for contraception.126

COMPASSS Therapeuticc Notes on thee Management of Acne in Primary Care ●● April 2012 8
How does oral isootretinoin workk in the treatmeent of acne?
Whaat about reportss linking oral issotretinoin witth depression oor
Oraal isotretinoin is thought to treatt all the primaryy aetiologic factoors of
acnne pathogenesiss by: 36,142-151 sBueigciiindnainl gid iena 1ti9o8n3?, tthere were a number of case reeports170-172 as wwell
• decreasing sebbum production (by 70%) as smmall case studiees173,174 suggestting that mood cchange, and
• normalising follicular keratinisaation
particcularly depressiion, can occur inn association wwith treatment wiith
• reducing follicular colonisation with P. acnes oral iisotretinoin. Thee clinical data suupporting a relaationship betweeen
• reducing inflammmation isotreetinoin and moood change are cconflicting, with several small
Thee combination oof these actions explains the effficacy of oral inconnclusive studiess, often with signnificant design ffaults. The curreent
isottretinoin.82,152 literaature does not support nor disprove a causative link between
Whhat are the sidee-effects of oraal isotretinoin? isotreetinoin and depression.175,176 Inn particular it hass not been posssible
Isottretinoin has a ssignificant pattern of adverse efffects. The patteern is to disstinguish accuraately between mmood change duue to the drug and
simmilar to that seenn in hypervitaminosis A. Adversse effects assocciated to thee acne itself (deepression and suicidal ideation occur with seveere
withh isotretinoin range from mild, ttemporary effeccts which resolvee acnee in the absencee of isotretinoin ttreatment177-180)).
afteer the drug is disscontinued, to rrarer potentially fatal conditionss.153 Healthcare professioonals should bee alert to the pottential psychiatrric
Milder side-effectts side--effects which are not restrictedd to depression. When symptomms
Most patients receeiving isotretinoin experience vaariable dryness of havee been describedd, they have moost commonly bbeen fatigue,
skinn and mucous mmembranes including nose, eyees and lips. Theese irritabbility, poor conccentration, sadness, crying spells, loss of
symmptoms are dosse-related, and mmay lead to active inflammationn, motivvation and forgeetfulness. It is esstimated that a physician wouldd
e.g. cheilitis. This ccan usually be mmanaged with thhe regular use oof needd to start 2000 ppatients on oral isotretinoin in a year to see onee
emollients, eye droops and lip balmms. Because of tthese issues addittional suicide atttempt.177 The timme course of onnset of mood
conncurrent adminisstration of isotreetinoin with topiccal keratolytic or alteraation is variablee, but is often latter in treatment, and in some
exfooliative anti-acnne agents shouldd be avoided ass local irritation may casees depressive syymptoms have ooccurred only inn second or even
incrrease.139 Dryingg of the nasal mucosa may leadd to colonisationn with third courses of therrapy. Resolutionn of symptoms is usually rapid,
Staaphylococcus auureus, the potenntial complicatioons of which incllude within days to weekss of discontinuinng the drug, althhough there aree
absscesses, conjunnctivitis, impetigoo, cellulitis, and folliculitis.154 instaances of prolongged illness requiiring antidepressant therapy.1811
Rarrer side-effectss Baseed on the available evidence, thhere is no need to discourage tthe
Rarrer side-effects include:139,154-1566 use oof isotretinoin inn severe acne inn patients who wwill benefit from
• myositis and arrthralgia treatment in terms oof physical and ppsychological immprovement.
• intracranial hyppertension Howeever, the following are recommmended:182
1. A direct enquirry about previouus psychiatric heealth should be
• hair loss
made for all paatients who are being considereed for isotretinooin
• drowsiness, dizzziness and visuual disturbancess (patients shouuld be
and the facts rrecorded in the notes
warned that if thhey experience these effects, they should not drive,
2. All patients, annd their families, should be madde aware of the
or operate macchinery)
possible potenntial for mood chhange
• erythema multifforme, Stevens--Johnson syndrome, and toxic
3. Direct enquiry about psycholoogical symptomss should be madde
epidermal necroolysis (patients should be informmed of the signs and
at each clinic vvisit
symptoms of these serious skin eruptions andd advised to stopp

treatment and ccontact their heaalthcare professsional immediately if Whaat are the cliniccally significant drug interacttions of oral
any of these ariise)157 isotrretinoin?
• elevated liver enzymes Patieents should not take vitamin A concurrently duue to the risk of
• hypercholesteroolaemia and eleevation of serumm triglycerides deveeloping hypervitaaminosis A.139 CCases of benignn intracranial
hypeertension have bbeen reported wwith concomitantt use of isotretinnoin
Hyppertriglyceridaemia, hypercholeesterolaemia annd elevated liverr
and ttetracyclines. TTherefore, conccomitant treatmeent with
enzzymes occur in 15-25% of patieents but are rareely of clinical
tetraccyclines should be avoided.139 Concurrent admministration of
signnificance or sevvere enough to rrequire dose redduction or
isotreetinoin with topical keratolyticc or exfoliative anti-acne agentts
disccontinuation of ttreatment. Lipidds rapidly drop too pretreatment
shouuld be avoided aas local irritationn may increase.1139 Oral isotretinnoin
leveels after cessatiion of therapy. MMonitoring of livver enzymes andd
can rreduce the serum levels of carbbamazepine, concurrent use
lipidds is now recommmended beforee and 1 month aafter starting
treaatment and every 3 months theereafter.139 In thee event of persisstent requires close monittoring.42

clinnically relevant eelevation of trannsaminase levels, reduction of tthe
dosse or discontinuation of treatmeent should be coonsidered.139 Prescribing points – ooral retinoids
Asssociations with uuse of isotretinooin and inflammaatory bowel diseease Althoughh not prescribed in primary caree, healthcare
aree controversial1588,159 as are assoociations with deepression and professioonals in primaryy care should noote:
suiccide160 (see lateer). ► Referrral of patients wwho would beneffit from isotretinnoin
is thee responsibility oof the GP. GPs are in a position not only to maake
Terratogenicity
sugggestions or recommendations too patients regarrding referral forr
Thee most severe ssafety issue concerning oral isootretinoin is
conssideration of isottretinoin treatmeent, but also to eensure patient
teraatogenicity and the consequencces of taking isootretinoin while
decissions are basedd on realistic undderstanding of tthe benefits andd
preegnant are well ddescribed.161 Thhe main abnormmalities found in risks of therapy183
isottretinoin embryoopathy are craniofacial, central nervous systemm,
► Isotretinoin is an efficacious and widely-used therapy for severee
carrdiovascular andd thymic. 162-166 IIn addition, foetaal exposure to acnee184,185 but it is reecognised as haaving a wide rannge of side-effeccts
isottretinoin is assoociated with a high risk of adverrse outcome witth
► Dooses of 0.5 to 1mg/kg per day aare typical. It is given for at least
respect to mental ffunctioning.167 TThe UK Nationall Teratology
16 wweeks; repeat coourses are not nnormally required. Improvementt
Infoormation Servicee estimates that in foetal expossure to isotretinooin, may continue for up to 5 months aftter ending theraapy51
30%% of infants withh no gross malfoormations have mental retardattion,
andd up to 60% havve impaired neuuropsychologicaal function.168 ►de pGreePsss mioany t rfyinindg t htoee malslaeylv tehse iirn p tahteiee mnti’dsd alen xoife tthiees daaeenbda dteo usbutrsro.2u1 nding

Thee MHRA has isssued formal presscribing guidancce for isotretinooin Althoough a causal linnk between isottretinoin use and psychiatric
that is designed to reduce the riskk of pregnancy dduring treatment.169 channges (including ssuicidal ideationn) has not beenn established, thhe
Thee regulations reqquire that womeen are carefully counselled posssibility should bee considered before initiating treeatment; if
regarding the riskss of pregnancy aand should use effective psychiatric changes occur during treeatment, isotrettinoin should bee
conntraception for oone month beforre therapy, durinng therapy and for stoppped, the prescriber informed, and specialist pssychiatric advicee
onee month afterwaards. Two simulttaneous forms oof contraceptionn, shouuld be sought.42A close partnerrship between ddermatologist annd
inclluding a barrier method, shouldd preferably be uused. Pregnanccy GP iss likely to be opptimal in this situuation183
testts are now requuired before treaatment, every foour weeks duringg

treaatment and five weeks afterwarrds.
MHHRA guidance caan be found at tthe following links:

• Doctors guide tto isotretinoin prregnancy prevention programmme:
www.mhra.gov..uk/home/groupps/pl-
p/documents/wwebsiteresourcess/con2031779.ppdf
• Pharmacist’s guuide to isotretinooin pregnancy pprevention
programme: wwww.mhra.gov.ukk/home/groups/ppl-
p/documents/wwebsiteresourcess/con2031781.ppdf
COMPASSS Therapeuticc Notes on thee Management of Acne in Primary Care ●● April 2012 9
evaluation of combination use with a topical retinoid. J.Drugs Dermatol.
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