PBS-listed topical retinoid

Key points | Evidence snapshot | PBS listing | What is it? | Who is it for? | Where does it fit? | How does it compare? | Safety issues | Reason for PBS listing | Dosing issues | Information for patients | References

Evidence snapshot

PBS listing

Restricted benefit

For acute and maintenance treatment of severe acne vulgaris.⁴ Acute treatment is in combination with an oral antibiotic.

May be prescribed by nurse practitioners (continuing therapy only)

Authorised nurse practitioners may prescribe continuing therapy of this medicine after it has been initiated by a medical practitioner. See the PBS website for more in formation on nurse practitioner PBS prescribing.

What is it?

Epiduo is a topical fixed-dose combination gel containing adapalene (0.1%) and benzoyl peroxide (2.5%).

Adapalene is a topical retinoid. It reduces comedone formation and inflammation.³ Benzoyl peroxide is an oxidising agent with antimicrobial activity against Propionibacterium acnes.

Who is it for?

Consider prescribing adapalene–BPO for severe acne when a patient has failed to respond to, or has not tolerated, a first-line treatment option^*, e.g. an over-the-counter product containing benzoyl peroxide. Acute treatment must be in combination with an oral antibiotic, e.g. doxycycline. In clinical trials, acute treatment was for 12 weeks.

Adapalene–BPO can be continued as maintenance therapy without an oral antibiotic (see Benefits are maintained for 6 months with continued adapalene–BPO therapy).

There are no data from children less than 12 years of age.³ As with other topical retinoids, adapalene–BPO should be avoided in pregnant women, women planning a pregnancy, and women using inadequate contraception.^5–7

*Adapalene–BPO is not approved by the TGA for initiating acne therapy.³

Where does it fit?

Adapalene–BPO is a PBS-listed alternative to topical tretinoin; it is an option for both acute and maintenance treatment of severe acne.

Australian guidelines currently recommend a topical retinoid (e.g. ≤ 0.05% tretinoin cream available by private prescription) or benzoyl peroxide (5%) in combination with an oral antibiotic for moderate acne.⁸ A combined oral contraceptive may be used instead of, or in addition to, the topical preparation in female patients.^5,8 For moderate to severe acne, tretinoin 0.05% or 0.1% cream is recommended in combination with an oral antibiotic.⁸

If there is scarring, a family history of scarring, or acne is refractory to topical adapalene–BPO, the patient should be referred to a dermatologist for consideration of further treatment, including oral isotretinoin.⁸ Avoid adapalene–BPO, and other topical anti-acne preparations, in patients receiving oral isotretinoin therapy because of the increased risk of cutaneous adverse effects.⁵

How does it compare?

Adapalene–BPO, combined with oral doxycycline, has been compared with doxycycline monotherapy in the acute treatment of patients with severe acne vulgaris.¹ There are no head-to-head trials comparing the effect of adapalene–BPO with that of other topical or systemic retinoids. Oral isotretinoin is preferred for severe cystic acne, when response to therapy is inadequate or there is a risk of scarring (see Where does it fit?).⁸

Both components of adapalene–BPO contribute to its efficacy.^9–11

Acute treatment with adapalene–BPO and doxycycline reduces acne severity

In patients with severe facial acne vulgaris (≥ 12 years of age; n = 459), the treatment success rate^† at 12 weeks was higher with adapalene–BPO (applied once daily at night) and 100 mg oral doxycycline, than with doxycycline monotherapy (31.5% vs 8.4%, respectively; p < 0.001).¹ Adapalene–BPO and doxycycline reduced comedone, papule and pustule count (total lesion count), the primary efficacy endpoint, by 23% compared with doxycycline alone (Table 1).¹

† Defined as the percentage of patients rated 'clear' or 'almost clear' on the Investigator's Global Assessment scale of acne severity

Table 1: Median reduction (%) in lesion count from baseline to week 12

‡Sum of inflammatory and non-inflammatory lesions. Inflammatory lesions are papules, pustules and nodules/nodulocystic lesions; non-inflammatory lesions are open or closed comedones¹²

§Statistically significant improvement over doxycycline monotherapy (p < 0.001)

Benefits are maintained for 6 months with continued adapalene–BPO therapy

Patients who responded to adapalene–BPO with doxycycline or doxycycline alone (n = 243; acne rated 'moderate' or better on the Investigators Global Assessment scale of acne severity) were eligible to enter a maintenance phase.^1,2

Participants were randomly assigned to adapalene–BPO or gel vehicle (placebo); neither group received oral doxycycline. After 24 weeks, 79% of patients treated with adapalene–BPO maintained their improved total lesion count^¶ compared with 46% who received placebo.

¶Maintenance success was defined as the percentage of subjects maintaining at least 50% of the improvement obtained with prior combination therapy (adapalene–BPO with doxycycline 100 mg or vehicle gel with doxycycline 100 mg), in terms of total lesion count.

Safety issues

The common adverse effects of adapalene–BPO — dry skin, burning sensation and contact dermatitis — are characteristic of topical acne therapies; sunburn and pruritus were uncommon.³ All occurred at the site of application, and the majority were rated as being of mild or moderate severity in clinical trials.^1,3,13 Stinging and burning was most severe after 2 weeks of treatment with adapalene–BPO and doxycycline, and decreased thereafter.¹

Of the 459 patients enrolled in the 12-week acute treatment trial, six withdrew because of adverse events; two receiving adapalene–BPO and doxycycline, and four doxycycline alone (see Antibiotic-related nausea, vomiting and diarrhoea may occur during acute treatment).¹

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Antibiotic-related nausea, vomiting and diarrhoea may occur during acute treatment

In the 12-week trial comparing adapalene–BPO and doxycycline with doxycycline alone, 9.6% of patients (n = 44) experienced gastrointestinal disorders.¹ Three participants discontinued because of these effects.

Tetracyclines, including doxycycline, may also induce phototosensitivity and patients should be advised about protective measures (see Information for patients).⁶

Avoid in pregnancy and women using inadequate contraception

Adapalene is a Category D drug under the Australian (formerly ADEC) pregnancy categorisation. It should not be used during pregnancy because of the potential risk of adverse effects to the foetus.^5,8

Clinical trials of adapalene–BPO excluded women planning a pregnancy.^1,9,10,13 As with other topical retinoids, adapalene should be avoided in women planning to conceive or who are not taking adequate contraceptive precautions.^5–7

Reason for PBS listing

The Pharmaceutical Benefits Advisory Committee recommended a restricted benefit listing for adapalene–BPO for acute (in combination with an oral antibiotic) and maintenance treatment of severe acne on the basis of acceptable cost-effectiveness compared with placebo.⁴

Dosing issues

Adapalene–BPO should be applied once daily,* at night, after washing with a soap-free cleanser. The skin should be allowed to dry before applying a thin film of gel over the entire acne-affected area, taking care to avoid the eyes, lips, cuts, scrapes and sunburnt skin.^5,14

* It may be possible to apply topical retinoids less frequently if maintenance therapy response is adequate.^5,15

Simple dosing strategies may help to reduce skin irritation

Although irritation may improve with time, it can limit topical retinoid use.¹⁵ To help minimise skin irritation and dryness consider advising patients to:^3,5,15,16

• remove residual adapalene–BPO by washing the treated skin with a soap-free cleanser in the morning
• use adapalene–BPO less frequently, e.g. on alternate days
• apply adapalene–BPO for a short period of time, e.g. 15–20 minutes, and then wash from the skin
• use a non-comedogenic moisturiser.

Note that some patients may need to stop using adapalene–BPO because of skin irritation.³

Benzoyl peroxide is present in many topical preparations

Ensure patients and their carers are aware that Epiduo contains two active ingredients.

Advise patients to stop using over-the-counter products containing benzoyl peroxide and/or previously prescribed adapalene (or other topical retinoid), and to return unwanted medicines to their pharmacist for safe disposal.¹⁴

Information for patients

Provide patients and carers with the following information.^3,5,8,15

• Adapalene–BPO should not be used by pregnant women, women planning a pregnancy and women using inadeqate contraception, because there is a potential risk of birth defects.
• Apply a thin film of gel over the entire acne-affected area at night. This will help to prevent acne formation, as well as treat existing acne.
• Skin irritation and/or an apparent worsening of acne may occur during the first few weeks of treatment (see Simple dosing strategies may help to reduce skin irritation).
• Adapalene–BPO can make skin more prone to sunburn. Avoid excess sunlight and protect treated skin with a non-comedogenic, SPF 30+ broad-spectrum sunscreen.
• The full benefit of treatment may not be apparent for several months, so patience is required.
• The antibiotic used during acute treatment may cause gastrointestinal symptoms. It may also increase the risk of photosensitivity.
• Benzoyl peroxide can bleach or discolour hair, clothes and bed linen.
• Do not wash affected skin more than twice a day and use a low-irritant, pH-balanced, soap-free cleanser.
• Picking or squeezing lesions can make acne worse and increase the risk of permanent scarring. Avoid vigorous scrubbing of affected skin, and using astringent or exfoliating agents.

Discuss the Epiduo consumer medicine information (CMI) leaflet with the patient.

Counsel patients about the condition and its course

Acne may have a significant social and emotional impact upon the individual.^6,8,15 Addressing concerns and providing reassurance may be of benefit to some patients.

Counsel patients that:^15,17

• acne is very common among young people, but it will improve with time
• it is not caused by poor hygiene, and excessive washing can make acne worse
• no direct link has been found between diet and acne
• acne is not infectious
• UV light has little benefit in acne. Use appropriate sun protection measures when outside.

References

1. Gold LS, Cruz A, Eichenfield L, et al. Effective and safe combination therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg. Cutis 2010;85:94–104. [PubMed]
2. Adapalene-benzoyl peroxide (BPO) gel in the treatment of acne vulgaris as a 6-month maintenance (ACCESS II). ClinicalTrialsgov 2008. http://clinicaltrials.gov/ct2/show/NCT00687908?term=adapalene&rank=10 (accessed 15 December 2010).
3. Galderma Australia Pty Ltd. Epiduo product information. 4 June 2010.
4. Pharmaceutical Benefits Branch. Adapalene with benzoyl peroxide, gel, 1 mg - 25 mg per g (0.1% - 2.5%), 30 g, Epiduo, November 2010. Canberra: Australian Government Department of Health and Ageing, 2010. http://www.health.gov.au/internet/main/publishing.nsf/Content/public-summary-documents-by-meeting (accessed 10 March 2011).
   
5. Rossi S, ed. Australian Medicines Handbook 2010. Adelaide: Australian Medicines Handbook Pty Ltd.
6. Cook D, Krassas G, Huang T. Acne — best practice management. Aust Fam Physician;39:656–60. [PubMed]
7. Purdy S, Deberker D. Acne vulgaris. Clin Evid (Online) 2008. [PubMed]
8. Dermatology Writing Group. Therapeutic Guidelines: Dermatology. Version 3. Melbourne: Therapeutic Guidelines Ltd, 2009.
9. Thiboutot DM, Weiss J, Bucko A, et al. Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 2007;57:791–9. [PubMed]
10. Gollnick HP, Draelos Z, Glenn MJ, et al. 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. Br J Dermatol 2009;161:1180–9. [PubMed]
11. Gold LS, Tan J, Cruz-Santana A, et al. A North American study of adapalene-benzoyl peroxide combination gel in the treatment of acne. Cutis 2009;84:110–6. [PubMed]
12. US Food and Drug Administration Guidance for Industry. Acne vulgaris: developing drugs for treatment. 2005. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidanc-es/UCM071292.pdf (accessed 4 January 2011).
13. Pariser DM, Westmoreland P, Morris A, et al. Long-term safety and efficacy of a unique fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide 2.5% for the treatment of acne vulgaris. J Drugs Dermatol 2007;6:899–905. [PubMed]
14. Galderma Australia Pty Ltd. Epiduo consumer medicine information. 25 February 2009.
15. National Health Service Clinical Knowledge Summaries. Acne vulgaris. 2009. http://www.cks.nhs.uk/home (accessed 17 December 2010).
16. Goodman G. Managing acne vulgaris effectively. Aust Fam Physician 2006;35:705–9. [PubMed]
17. Goodman G. Acne — natural history, facts and myths. Aust Fam Physician 2006;35:613–6. [PubMed]