Severe methemoglobinemia due to topical dapsone misuse in a teenage girl

Dapsone gel is a topical treatment for facial acne in adolescents and adults, and while systemic dapsone therapy is known to be associated with methemoglobinemia, once-daily topical dapsone has been well tolerated with few side effects in large randomized controlled trials. We describe the first reported case of severe methemoglobinemia in a healthy adolescent using daily topical dapsone. Although the medication was prescribed for facial use only, the patient reported topical use over her back and chest as well. This case illustrates the potential for significant systemic dapsone absorption even with daily topical dosing and demonstrates the need for clear anticipatory guidance to prevent the potential morbidity and mortality associated with methemoglobinemia from improper topical dapsone use.     

Newer topical therapies for the treatment of acne vulgaris

Newer topical therapies approved by the US Food and Drug Administration (FDA) for the treatment of acne vulgaris are dapsone gel 5% and clindamycin phosphate 1.2% and tretinoin 0.025% combination gel. Both are formulated in aqueous-based gel vehicles. These newer topical acne products have been shown to be effective and safe in pivotal 12-week phase 3 trials and long-term studies completed over 12 months. This article reviews applicable pharmacokinetic, efficacy, and safety data reported with both products.     

Dapsone 5% gel: a new option in topical therapy for acne

Dapsone 5% gel for the topical treatment for acne vulgaris was recently introduced in Canada. It represents the first new anti-acne agent to gain North American regulatory approval in the past decade. Dapsone's utility is attributable to its anti-inflammatory and antimicrobial properties that improve both inflammatory and non-inflammatory acne, with more prominent effects occurring in inflammatory lesions. Short- and long-term safety and efficacy have been demonstrated. Especially for patients exhibiting sensitivities or intolerance to conventional anti-acne agents, topical dapsone is a novel addition to the treatment armamentarium.     

Efficacy and safety of dapsone gel 5% for the treatment of acne vulgaris in adolescents

Two 12-week, randomized, vehicle-controlled. double-blinded pivotal studies and a 12-month. long-term, open-label, noncomparative safety study were conducted to evaluate the efficacy and safety of dapsone gel 5% in patients with acne vulgaris. Of 3516 participants enrolled in the 3 trials, 1306 participants (37%) were adolescents aged 12 to 15 years and comprised the subgroup reported here. Participants randomly were assigned to twice-daily treatment with dapsone gel (n=578) or vehicle gel (n=547) in the pivotal studies and received open-label treatment with dapsone gel in the long-term safety study (n=181). In the pivotal studies, success based on achieving a Global Acne Assessment Score (GAAS) of 0 (none) or 1 (minimal) at week 12 was significantly greater for the dapsone gel-treated adolescent participants (40.1%; 232/578) compared with the vehicle gel-treated adolescent participants (28.2%; 154/547) (P<.001). Treatment with dapsone gel in adolescents also resulted in clinically meaningful improvements in acne lesion counts by week 12 in the pivotal studies and for up to 12 months in the long-term safety study. The incidence of adverse events, including application-site events, was low and similar between treatment groups in the pivotal studies and was similarly low in the long-term safety study. Results from the large number of adolescent participants in these 3 studies show that dapsone gel is an effective and safe topical therapy for the treatment of acne vulgaris in adolescents aged 12 to 15 years for up to 12 months.     

Newer Approaches to the Treatment of Acne Vulgaris

The multifactorial etiology of acne vulgaris makes it challenging to treat. Current treatments include topical retinoids, benzoyl peroxide, topical and systemic antibiotics, azelaic acid, and systemic isotretinoin. Adjunctive and/or emerging approaches include topical dapsone, taurine bromamine, resveratrol, chemical peels, optical treatments, as well as complementary and alternative medications. The purpose of this paper is to discuss the therapies available for acne and their latest developments, including new treatment strategies (i.e. re-evaluation of the use of oral antibiotics and avoidance of topical antibiotic monotherapy, use of subantimicrobial antibiotic dosing, use of low-dose isotretinoin, optical treatments), new formulations (microsponges, liposomes, nanoemulsions, aerosol foams), new combinations (fixed-combination products of topical retinoids and topical antibiotics [essentially clindamycin] or benzoyl peroxide), new agents (topical dapsone, taurine bromamine, resveratrol) and their rationale and likely place in treatment. Acne vaccines, topical natural antimicrobial peptides, and lauric acid represent other promising therapies.     

Acne fulminans and erythema nodosum during isotretinoin therapy responding to dapsone

Acne vulgaris is very common, 85% of teenagers being affected at any one time. In most cases, the disease is mild and patients do not present to the dermatologist. Most are instead treated with over-the-counter products and conventional treatment such as peeling agents or topical and systemic antibiotics. Isotretinoin has revolutionized the treatment of severe acne unresponsive to oral antibiotics. Explosive and very severe acne such as pyoderma faciale, acne conglobata and acne fulminans are rare, the features that distinguish acne fulminans from the other conditions being systemic upset with fever, joint pain, malaise and leucocytosis,^1–3 while there have been two reports of the condition associated with erythema nodosum.^4,5 The recommended treatment for acne fulminans is a combination of oral steroids and systemic antibiotics, isotretinoin probably not being the treatment of choice.⁶ We now report a patient who developed acne fulminans and erythema nodosum within 3 weeks of starting isotretinoin and then responded to dapsone without oral steroids.     

Update on the use of dapsone in dermatology

Dapsone (4,4'-diaminodiphenylsulfone) is the only remaining sulfone used in anthropoid therapeutics and is commercially available as an oral formulation, an inhaled preparation, and a 5% or 7.5% cream. Dapsone has antimicrobial effects stemming from its sulfonamide-like ability to inhibit the synthesis of dihydrofolic acid. It also has anti-inflammatory properties such as inhibiting the production of reactive oxygen species, reducing the effect of eosinophil peroxidase on mast cells and down-regulating neutrophil-mediated inflammatory responses. This allows for its use in the treatment of a wide variety of inflammatory and infectious skin conditions. Currently in dermatology, the US Food and Drug Administration (FDA)-approved indications for dapsone are leprosy, dermatitis herpetiformis, and acne vulgaris. However, it proved itself as an adjunctive therapeutic agent to many other skin disorders. In this review, we discuss existing evidence on the mechanisms of action of dapsone, its FDA-approved indications, off-label uses, and side effects.     

Successful treatment of perifolliculitis capitis abscedens et suffodiens with combined isotretinoin and dapsone

Perifolliculitis capitis abscedens et suffodiens (PCAS) is a rare scalp disease of unknown etiology which is hard to treat.It is often accompanied by scarring alopecia, acne conglobata, and recurrent fluctuant abscesses. PCAS belongs to the family of acne inversa (hidradenitis suppurativa). A 19-year-old man presented with PCAS for 2 years; multiple systemic antibiotic therapies and surgical approaches had shown no effect. Monotherapy with isotretinoin 80 mg daily for 4 weeks had not been successful. Combination therapy with dapsone 100 mg and isotretinoin 80 mg daily produced significant improvement. During 4 weeks of treatment significant clearing was achieved.Dapsone was reduced to 50 mg daily after 6 months, while isotretinoin was discontinued gradu-ally.Now the patient is on dapsone 50 mg every other day and has remained free of recurrences for 6 months.     

Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel

Adapalene 0.1%/benzoyl peroxide 2.5% gel (Epiduo?, Tactuo?) is the only fixed-dose combination product available that combines a topical retinoid with benzoyl peroxide; it targets three of the four main pathophysiologic factors in acne. This article reviews the therapeutic efficacy and tolerability of topical adapalene 0.1%/benzoyl peroxide 2.5% gel in the treatment of patients aged ≥ 12 years with acne vulgaris, as well as summarizing its pharmacologic properties. In three 12-week trials in patients aged ≥12 years with moderate acne, success rates were significantly higher with adapalene 0.1%/benzoyl peroxide 2.5% gel than with adapalene 0.1% gel or benzoyl peroxide 2.5% gel alone, and combination therapy had an earlier onset of action. In addition, significantly greater reductions in total, inflammatory, and noninflammatory lesion counts were seen in patients receiving adapalene 0.1%/benzoyl peroxide 2.5% gel than in those receiving adapalene 0.1% gel or benzoyl peroxide 2.5% gel alone. Adapalene 0.1%/benzoyl peroxide 2.5% gel did not significantly differ from clindamycin 1%/benzoyl peroxide 5% gel in terms of the reduction in the inflammatory, noninflammatory, or total lesion counts in patients with mild to moderate acne, according to the results of a 12-week trial. Twelve-week studies showed that topical adapalene 0.1%/benzoyl peroxide 2.5% gel in combination with oral lymecycline was more effective than oral lymecycline alone in patients with moderate to severe acne, and topical adapalene 0.1%/benzoyl peroxide 2.5% gel in combination with oral doxycycline hyclate was more effective than oral doxycycline hyclate alone in patients with severe acne. In patients with severe acne who responded to 12 weeks’ therapy with topical adapalene 0.1%/benzoyl peroxide 2.5% gel plus oral doxycycline hyclate or oral doxycycline hyclate alone, an additional 6 months’ therapy with adapalene 0.1%/benzoyl peroxide 2.5% gel was more effective than vehicle gel at maintaining response, with further improvement seen in adapalene 0.1%/benzoyl peroxide 2.5% gel recipients. A noncomparative study also demonstrated the efficacy of 12 months’ therapy with adapalene 0.1%/benzoyl peroxide 2.5% gel in patients with acne vulgaris. Topical adapalene 0.1%/benzoyl peroxide 2.5% gel was generally well tolerated in patients with acne. In 12-week trials, the most commonly occurring treatment-related adverse events included erythema, scaling, dryness, and stinging/burning; these dermatologic treatment-related adverse events were usually of mild to moderate severity, occurred early in the course of treatment, and resolved without residual effects. Topical adapalene 0.1%/benzoyl peroxide 2.5% gel was generally well tolerated in the longer term, with dry skin being the most commonly occurring treatment-related adverse event over 12 months of treatment. In conclusion, adapalene 0.1%/benzoyl peroxide 2.5% gel is a valuable agent for the first-line treatment of acne vulgaris.     

Recently approved systemic therapies for acne vulgaris and rosacea

Until recently, with the exception of oral isotretinoin for the treatment of severe recalcitrant nodular acne, systemic therapy for acne vulgaris and rosacea has been based on anecdotal support, clinical experience, and small clinical trials. Tetracycline derivatives are the predominant systemic agents that have been used for both disease states, prescribed in dose ranges that produce antibiotic activity. Anti-inflammatory dose doxycycline, a controlled-release (CR) 40-mg capsule formulation of doxycycline that is devoid of antibiotic activity when administered once daily, was US Food and Drug Administration (FDA)-approved for the treatment of inflammatory lesions (papules and pustules) of rosacea, based on large-scale phase 3 pivotal trials and long-term microbiologic and safety data. Also, an extended-release (ER) tablet formulation of minocycline was approved by the FDA for the treatment of inflammatory lesions of moderate to severe acne vulgaris in patients 12 years and older based on large-scale phase 3 clinical trials that evaluated efficacy and safety, dose-response analysis, and long-term data. This article discusses the studies and clinical applications related to the use of these agents.     

A pilot study of the safety and efficacy of picolinic acid gel in the treatment of acne vulgaris

BACKGROUND: Cost limitations, adverse effects or lack of efficacy limit the use of current topical therapies in mild to moderate acne vulgaris. OBJECTIVES: To determine the safety and efficacy of picolinic acid, a novel zinc finger therapy, in the treatment of mild to moderate acne vulgaris. METHODS: Twenty subjects with mild to moderate acne vulgaris were treated at our centre during an open-label study with 10% picolinic acid gel (PCL-016) twice daily to the face over 12 weeks. RESULTS: Fifteen patients completed the 12-week open-label study. A reduction of 58.2% (P < 0.001) in mean total lesion count, 55.5% (P < 0.001) in mean inflammatory lesion count and 59.7% (P < 0.005) in noninflammatory lesion count was seen in this population. No serious adverse events or clinically significant changes in laboratory values were noted. CONCLUSIONS: Results from this study suggest that 10% picolinic acid gel applied twice daily may be safe and effective in the treatment of mild to moderate acne vulgaris.     

The use of oral antibiotics in treating acne vulgaris: a new approach

Although acne is not an infectious disease, oral antibiotics have remained a mainstay of treatment over the last 40 years. The anti‐inflammatory properties of oral antibiotics, particularly the tetracyclines, are efficacious in treating inflammatory acne lesions. Common prescribing practices in Dermatology exert significant selection pressure on bacteria, contributing to the development of antibiotic resistance. Antibiotic use for acne not only promotes resistance in Propionibacterium acnes, but also affects other host bacteria with pathogenic potential. This review will summarize the commonly used treatments for acne vulgaris, and how they should be combined as rational treatment. The indications for using oral antibiotics in acne will be highlighted. Strategies described in the literature to conserve the utility of oral antibiotics will be summarized. These include limiting the duration of antibiotic therapy, concomitant use of a topical non‐antibiotic agent, use of subantimicrobial dose doxycycline, and the introduction of topical dapsone.     

What's new in acne? New therapeutic approaches

Well-known topical and systemic treatments for acne have advanced little over the last 10 years. However, many therapeutic approaches are being evaluated both in terms of topical and systemic treatments. The purpose of this paper is to show the progress of innovative drug projects in treating acne. The topical use of new formulations using lipid nanoparticles and microspheres could help for new products based on anti-androgens or retinoids more concentrated and better tolerated. New active agents such as topical antimicrobial peptides, inhibitors of ectopeptidase, omiganan pentahydrochloride, antisense oligonucleotides, lauric acid are many original ways to explore for the treatment of acne. New treatment regimens for doxycycline and isotretinoin would increase tolerance. Dapsone has been evaluated for isotretinoin-resistant forms. Phototherapy narrowband light (blue or red) can find its place in the strategy for the management of acne. Finally, acne vaccines could be developed too.     

BENZOYL PEROXIDE GEL THERAPY IN ACNE IN SINGAPORE

ABSTRACT: The results of an open clinical trial of 200 patients in Singapore show that benzoyl peroxide, in a stable gel formulation, both in 2.5% and 5% strengths, was highly efficacious in the topical treatment of acne vulgaris without con-comitant systemic therapy. The series included a small number of Caucasians (13 patients) who were also treated effectively. Side effects noted were generally mild and transient.     

Prospective, open-label, comparative study of clindamycin 1%/benzoyl peroxide 5% gel with adapalene 0.1% gel in Asian acne patients: efficacy and tolerability

Background  Used as individual agents, topical antibiotics and benzoyl peroxide are known to be effective in treatment of acne. Clindamycin phosphate 1% with benzoyl peroxide 5% (CDP/BPO) is a new combination gel, made by rationale, in that combination drug is more effective than either ingredients used alone. Adapalene 0.1% (ADA) is the third-generation retinoid, shown to be as effective as other topical retinoid with well tolerability.
Objectives  To compare the efficacy and tolerability in combination of CDP/BPO in comparison with ADA in Asian patients with mild to moderate acne vulgaris.
Methods  Total of 69 patients, including 31 patients for CDP/BPO group and 38 for ADA group, with mild to moderate acne vulgaris were enrolled for a 12-week prospective, randomized, open-label comparative study of topical agents. Efficacy was assessed by lesion counts, acne grading system, and global improvement. Adverse events were also evaluated in scale of 0 (none) to 3 (severe).
Results  Both CDP/BPO and ADA were effective in reducing lesion counts and acne severity scale and showed significant global improvement. However, CDP/BPO offered greater efficacy against inflammatory lesions than ADA. Both drugs were well tolerated with minimal adverse drug reactions.
Conclusion  Combination formulation of CDP/BPO and ADA were shown to be both effective in decreasing total, inflammatory, and non-inflammatory lesion counts along with well tolerability in Asian patients with mild to moderate acne vulgaris.

Conflicts of interest

None declared     

Treatment of bullous pemphigoid with dapsone, methylprednisolone, and topical clobetasol propionate: a retrospective study of 62 cases

Dapsone has been used successfully as adjuvant therapy for bullous pemphigoid (BP). The effectiveness of dapsone for this indication, however, remains controversial. We evaluated the effectiveness and adverse events of dapsone (1.0-1.5 mg/kg per day) in combination with oral methylprednisolone (tapering doses of 0.5 mg/kg per day) and topical clobetasol propionate (initially applied once daily on lesions only) in the treatment of BP. Sixty-two patients treated with this regimen were analyzed retrospectively. Patients were free of new blisters after a mean (+/- SD) of 22 +/- 13 days (median, 20 days). After 3 and 6 months of treatment, methylprednisolone could be reduced to less than 10 mg/d in 71% and 91% of patients, respectively; after 12 months of treatment, 53% of patients were in complete remission without receiving further therapy. Dapsone-related side effects were usually mild except in 3 patients (5%), 2 patients with anemia (hemoglobin level, <7 g/dL) and 1 with agranulocytosis. Our data suggest that dapsone used in combination with systemic and topical corticosteroids may be a relatively safe and effective treatment option for BP.     

Fractional carbon dioxide (CO2) laser combined with topical tretinoin for the treatment of different forms of cystic acne

Nodulocystic acne is prone to scarring and difficult to treat with treatments other than oral isotretinoin. The aim of this article is to discuss the role of a single session of a fractional carbon dioxide (CO₂) laser combined with a topical treatment with a tretinoin and antibiotic gel for a month as a successful treatment to improve nodulocystic acne and chronic microcystic acne. Two cases were involved: the first with nodulocystic acne lesions that persisted after oral retinoids and the second with chronic microcystic acne resistant to topical treatments. After only one session of treatment with the CO₂ laser and the topical treatment, a complete healing of the nodulocystic acne lesions was observed with minimal secondary effects. The microcystic acne showed great improvement. No other topical or oral treatment was needed. This treatment could be a safe and effective treatment for nodulocystic acne lesions and microcystic acne when other treatments fail. More studies should be performed to confirm our results.     

Optimizing use of oral antibiotics in acne vulgaris

Oral antibiotics are commonly used to treat acne vulgaris, primarily in patients presenting with moderate to severe facial or truncal disease severity. These agents are most appropriately used in combination with a topical regimen containing benzoyl peroxide and a topical retinoid. The most common oral antibiotics for treating acne vulgaris are the tetracycline derivatives, although macrolide agents such as erythromycin have also been used extensively. Over the past 4 decades, as the sensitivity of Propionibacterium acnes to several oral and topical antibiotics has decreased, the efficacy of oral tetracycline and erythromycin has markedly diminished, leading to increased use of doxycycline, minocycline, and other agents, such as trimethoprim/sulfamethoxazole.     

A single centre, open-label, cross-over study of pharmacokinetics comparing topical zinc/clindamycin gel (Zindaclin) and topical clindamycin lotion (Dalacin T) in subjects with mild to moderate acne

Zinc/clindamycin gel (Zindaclin 1%) gel, is a new once-daily topical acne treatment (Strakan Ltd) containing clindamycin phosphate equivalent to 1% clindamycin and zinc acetate in a formulation, which leads to a reduced systemic absorption of clindamycin through the skin. The objective of the study was to compare the systemic absorption of clindamycin from zinc/clindamycin gel and clindamycin lotion (Dalacin T topical lotion, Pharmacia Ltd) after repeated twice-daily topical administration for two periods of 5 days with an intervening gap of 2 weeks in 24 subjects with mild to moderate acne. Plasma Cmax, and AUC0-12 of clindamycin measured after single and multiple applications of zinc/clindamycin gel were between 30% and 50% lower than for clindamycin lotion. As zinc/clindamycin gel is a topical treatment for acne, the lower systemic bioavailability may be beneficial because there may be a correspondingly lower risk of systemic events in zinc/clindamycin gel-treated subjects.     

阿达帕林凝胶治疗寻常痤疮10年回顾

目的 总结阿达帕林凝胶治疗寻常痤疮的临床文献,为临床合理用药提供参考。方法 对阿达帕林凝胶上市10年来国内有关治疗寻常痤疮的疗效及安全性观察的中文文献进行整理和分析。结果 联合用药组疗效高于单用药物组,阿达帕林凝胶组疗效与其他维A酸类药物疗效相当,但高于其他痤疮药物组,不良反应低于其他药物。结论 阿达帕林凝胶治疗轻中度痤疮安全、有效,可单独或联合用药,还可作为维持治疗。