Minocycline for acne – an update
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Relevant BNF section: 5.1.3, 13.6.2
Abstract
Minocycline is an oral tetracycline that, unlike some other drugs in its class, is a once-daily treatment and need not be taken on an empty stomach.1 Such potential advantages together with preferential use in secondary care helped to establish minocycline as the oral tetracycline of choice for acne.2,3 However, concerns over the safety of minocycline and the lack of therapeutic advantage over other tetracyclines have challenged this view.1,4,5 Here we consider how trends in prescribing of minocycline have changed in the UK in recent years.
DOES MINOCYCLINE WORK?
Minocycline is an effective treatment for some patients with acne but there is a lack of evidence that it is any better than other options.3,6
One systematic review included 27 randomised controlled trials that compared oral minocycline with placebo or other active treatment in a total of 3,031 patients with inflammatory acne affecting the face or upper trunk.6 Comparators included topical clindamycin, erythromycin plus zinc, or fusidic acid; oral doxycycline, lymecycline, oxytetracycline, or tetracycline; oral co-cyprindiol; and oral isotretinoin. In general, the trials were small and of poor quality. Also, since outcome measures varied markedly between trials and primary data were not available for some, meta-analysis was not attempted. In only two studies was minocycline more effective than the comparator (oxytetracycline or tetracycline). However, both studies were non-blinded and of poor quality, so providing only weak evidence to support the preferential use of minocycline.
A more recent systematic review, which included 57 clinical trials, assessed the relative effectiveness of oral tetracyclines in inflammatory acne and their optimal dose.7 The median duration of the trials was 12 weeks. There was substantial heterogeneity in their design and a variety of outcome measures were reported. The review concluded there was insufficient evidence to support use of one oral tetracycline over another and no apparent effect of antibacterial dose on efficacy across the range of doses studied.
WHAT ABOUT SAFETY?
Like other tetracyclines, minocycline can cause unwanted effects such as gastrointestinal upset, vaginal candidiasis, photosensitivity, hypersensitivity reactions and benign intracranial hypertension, and its use is contraindicated in pregnancy and children aged under 12 years.1 However, minocycline appears to be unique in the group in causing hyperpigmentation, typically slate-grey pigmentation of the skin, although pigmentation of other tissues (e.g. the sclera, conjunctiva) has been reported.8,9 Furthermore, minocycline can cause lupus-like syndrome, arthropathies, autoimmune hepatitis and vasculitis associated with production of a range of autoantibodies.1 Summaries of product characteristics for minocycline products recommend that if the drug is continued for over 6 months, patients should be monitored at least 3-monthly for features of hepatitis, systemic lupus erythematosus or unusual pigmentation.1
In a case-control study using data from the UK General Practice Research Database, the likelihood of lupus-like syndrome with minocycline was 8.5 (95% CI 2.1 to 35) times that in non-users and past users of all other tetracyclines; there was no increased risk with other tetracyclines.10 The overall risk of the syndrome in females was around14 times that in males. Further evidence comes from a more recent retrospective analysis of UK general practice records of 97,694 patients with acne (mean age 22 years, 57.5% female) followed for around 520,000 person-years.11 Minocycline, but not other tetracyclines, was associated with increased likelihood of drug-induced lupus erythematosus (hazard ratio corrected for age and gender 3.11, 95% CI 1.77 to 5.48).
COSTS
At the recommended dose of 100 mg daily, the cost to the NHS of 6 months' treatment with minocycline 100 mg tablets is £55; for modified-release capsules, the cost is £69. By comparison, the cost of oxytetracycline 500 mg twice daily is £26; tetracycline 500 mg twice daily £231; doxycycline 50 mg once daily £12; and lymecycline 408 mg once daily £46.
CHANGES IN PRESCRIBING ADVICE
In an article in 2006, we concluded in 2006 that the use of minocycline for acne could not be justified given the availability of tetracyclines that are as effective, safer and less expensive.1 This message was reiterated in a BMJ Change Page based on the DTB article.3 Advice provided in the British National Formulary has changed to reflect the increased concerns about minocycline's use, particularly the risks of systemic lupus erythematosus and irreversible pigmentation.12
MINOCYCLINE USE
Trend 1996–1997
Minocycline is prescribed mainly for acne. Following publication in January 1996 of a series of case reports of the development of systemic lupus erythematosus or autoimmune hepatitis in patients on minocycline,4 its use fell substantially: in the quarter following publication, the number of defined daily doses* of minocycline dispensed in the UK fell to below 70% of that in the previous quarter.5 Minocycline use continued to fall in the following quarter to around 62% of that before the case reports were published, and stayed at this level during 1996 and the first half of 1997 (the period covered by the analysis).5
*A defined daily dose represents the assumed average maintenance dose per day for a drug used for its main indication in adults.13
Trend 1997–2008
Data from the Prescription Pricing Division of the NHS Business Services Authority shows that minocycline prescribing in England has, overall, continued to follow a downward trend, with use of the drug now below 50% of the level in 1997 (Figure 1), and around 30% of the amount dispensed in 1995.5,14 The greatest rate of decline appears to be since the autumn of 2006, since which, annual use of the drug has fallen by around 20% compared with an annual rate of decline of no more than 10% since 1997 (Figure 1). While the change happens to be since publication of our review in August 2006, the evidence is not sufficient to say whether or not this was a causal factor. Minocycline now accounts for only around 11% of the 2.7 million prescriptions for an oral tetracycline dispensed in England.15 This is less than for doxycycline (36% of total items), oxytetracycline (33%) and lymecycline (16%).15 However, minocycline still accounts for the greatest proportion of the £21 million expenditure for this class of drugs (29% vs. 17% for doxycycline, 22% for oxytetracycline and 25% for lymecycline).15 The fall in use of minocyline has been accompanied by a substantial increase in use of lymecycline, which is licensed only for acne and is now more commonly prescribed than minocycline. The annual rate of growth in lymecycline use appears to be greatest following publication of our review in 2006 but, again, we make no claim that this was a causal factor (Figure 1). Since other tetracyclines are prescribed for indications other than acne, it is more difficult to interpret changes in their prescribing.
ALTERNATIVES TO MINOCYCLINE
Oxytetracycline and tetracycline are often used as first-line oral tetracyclines for acne but need to be taken twice daily on an empty stomach.12 Such limitations are often perceived as a barrier to adherence to treatment in a primarily young population of patients.16 Where once-daily treatment is preferred, doxycycline and lymecycline can be used and need not be taken on an empty stomach.16 However, doxycycline may be more likely to cause photosensitivity.17
CONCLUSION
Use of minocycline fell markedly following reports of systemic lupus erythematous or autoimmune hepatitis with the drug and has followed a downward trend ever since. This decline appears to have accelerated in recent years and in keeping with the availability of other tetracyclines that appear as effective, safer and less expensive. We cannot see a place for minocycline in the management of patients with acne.
