Dapsone (Topical)
Aczone (dapsone gel, 7.5%)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Acne vulgaris (inflammatory and non-inflammatory lesions) | ≥9 years (gel 7.5%) | Monotherapy or adjunctive (topical, once daily) | FDA Approved |
Topical dapsone gel fills a specific niche in acne management as a non-antibiotic, anti-inflammatory topical that does not contribute to antimicrobial resistance. The 7.5% gel formulation (approved February 2016, expanded to ages 9+ in September 2019) replaced the earlier 5% twice-daily formulation by offering once-daily dosing with 50% greater dapsone concentration. In two pivotal phase 3 trials involving 4,340 patients with moderate acne, the 7.5% gel demonstrated statistically significant improvements in both inflammatory and non-inflammatory lesion counts compared with vehicle.
Adult female acne: Subgroup analyses of pivotal trials suggest dapsone gel may have particular efficacy in adult women, with greater treatment differences vs vehicle than in adolescent males. Used as an alternative to hormonal therapy. Evidence quality: Moderate (subgroup analysis of RCTs)
Comedonal acne adjunct: Dapsone gel combined with a retinoid (e.g., tazarotene, adapalene) has been studied for enhanced comedolytic effect. Evidence quality: Moderate (RCT data)
Dosing
Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate acne vulgaris — face (gel 7.5%) | Pea-sized amount to entire face, once daily | Once daily indefinitely | ~2 g/day total (face + trunk if needed) | Wash and pat dry skin before application. Apply thin layer and rub in gently. Reassess if no improvement after 12 weeks. FDA PI (ACZONE 7.5%); ages ≥9 years |
| Moderate acne — trunk involvement (gel 7.5%) | Thin layer to affected areas, once daily | Once daily | As above | Apply to upper chest, upper back, and shoulders in addition to face. PK study used 2 g to all areas combined. FDA PI (ACZONE 7.5%) |
| Acne — combination with retinoid (off-label adjunctive) | Dapsone gel QD + retinoid QD | Apply at different times of day or as tolerated | Standard doses of each | Dapsone gel provides anti-inflammatory benefit without retinoid irritation overlap. Apply dapsone in AM, retinoid in PM for optimal tolerability. Clinical practice; Tanghetti et al. JDD 2011 |
Concurrent or sequential application of dapsone gel with benzoyl peroxide (BPO) may cause temporary yellow or orange discolouration of the skin and facial hair. This is a cosmetic interaction, not a safety concern. To avoid it, apply dapsone gel in the morning and BPO-containing products in the evening, or allow the dapsone gel to dry completely before applying BPO. The 7.5% formulation is specifically designed with reduced potential for this interaction compared to the older 5% gel, though the PI still notes this possibility.
Special Populations
| Population | Recommendation | Key Consideration |
|---|---|---|
| Paediatric (9–11 years) | Approved; same dosing as adults | Supported by open-label PK and safety study (N=100). Steady-state concentration at 10 h post-dose: 20 ± 12.5 ng/mL. Safety profile consistent with adults |
| Paediatric (<9 years) | Safety and efficacy not established | No clinical data in children under 9 years |
| Elderly (≥65 years) | Insufficient data | Clinical trials did not include sufficient numbers of patients ≥65 years |
| G6PD deficiency | Use with caution; monitor for hemolysis | In a cross-over study of 64 G6PD-deficient patients using dapsone 5% gel, some developed laboratory changes suggestive of hemolysis, but no clinically significant hemolytic anaemia was observed |
| Pregnancy | Use only if clearly needed | No human data. Animal studies: embryocidal effects at >400× MRHD in rats and >425× in rabbits (maternally toxic doses) |
Pharmacology
Mechanism of Action
The exact mechanism by which topical dapsone treats acne vulgaris is not fully elucidated (FDA PI). Dapsone is a sulfone compound with both anti-inflammatory and antimicrobial properties. Its anti-inflammatory activity is attributed to inhibition of neutrophil myeloperoxidase, suppression of reactive oxygen species generation, blockade of integrin-mediated neutrophil adhesion, and inhibition of leukotriene B4 and prostaglandin synthesis in the arachidonic acid cascade. These mechanisms reduce the inflammatory component of acne without relying on antibiotic-mediated bacterial suppression, thereby avoiding the selection pressure that drives antimicrobial resistance. While dapsone does have antibacterial activity against some organisms (including historical use against Mycobacterium leprae), no in vivo microbiology studies were conducted during the topical acne programme, and therapeutic resistance to topical dapsone in the context of Cutibacterium acnes has not been characterised.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | After 28 days of 2 g/day (7.5% gel): Cmax 13.0 ± 6.8 ng/mL; AUC0-24h 282 ± 146 ng·h/mL. Systemic exposure ~1% of a 100 mg oral dapsone dose. Steady state reached within 7 days. | Very low systemic exposure relative to oral dosing markedly reduces the risk of haematological side effects, though methemoglobinaemia has been reported at topical doses (postmarketing) |
| Distribution | Oral dapsone: highly distributed (Vd ~1.5 L/kg); ~70–90% protein bound. Topical distribution is primarily local cutaneous. | At topical plasma concentrations (~13 ng/mL), systemic tissue exposure is negligible compared with oral therapeutic levels (~1,000–3,000 ng/mL) |
| Metabolism | N-acetylation (polymorphic NAT2) to monoacetyldapsone (MADDS); CYP-mediated hydroxylation to dapsone hydroxylamine (associated with haemotoxicity). No formal topical metabolism study conducted; data extrapolated from oral dapsone. | Dapsone hydroxylamine is the metabolite responsible for methemoglobinaemia and haemolysis. At topical doses, the amount of hydroxylamine formed is substantially lower than with oral therapy |
| Elimination | Oral dapsone: t½ 20–30 hours; primarily renal excretion. No independent topical elimination data; systemic exposure data show no accumulation over 12 months of use. | The absence of accumulation supports long-term use without dose adjustment. No topical-specific half-life has been determined |
Side Effects
Topical dapsone gel 7.5% has a favourable tolerability profile that closely mirrors vehicle. In two controlled 12-week pivotal trials (N=2,161 treated with dapsone gel, N=2,175 vehicle), the incidence of adverse reactions was low and similar between groups. The safety profile was consistent through an additional 12-month safety study.
| Adverse Effect | Incidence (Dapsone) | Incidence (Vehicle) | Clinical Note |
|---|---|---|---|
| Application site dryness | 1.1% (24/2161) | 1.0% (21/2175) | Very close to vehicle rate; mild, manageable with a non-comedogenic moisturiser |
| Application site pruritus | 0.9% (20/2161) | 0.5% (11/2175) | Mild itching; typically transient and self-limiting with continued use |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Methemoglobinaemia | Rare (postmarketing; mostly 5% gel BID) | Hours after exposure; may be delayed | Immediate discontinuation; seek emergency care if cyanosis (grey-blue lips, nail beds, buccal mucosa); methylene blue IV for severe cases (>20% MetHb) |
| Hemolytic anaemia (G6PD-deficient patients) | Uncommon (laboratory changes suggestive of subclinical haemolysis in 5% gel study) | Days to weeks | Discontinue dapsone gel; urgent haemoglobin, reticulocyte count, haptoglobin, LDH; refer haematology if clinically significant anaemia |
| Facial swelling (including lip and eye swelling) | Very rare (postmarketing) | Days | Discontinue; evaluate for angioedema vs contact reaction; antihistamines; epinephrine if airway compromise |
| Agranulocytosis | Not observed topically (reported with oral dapsone) | Weeks to months (oral) | If unexplained infection or fever during topical dapsone use, obtain urgent CBC; discontinue if neutropaenia detected |
| Peripheral neuropathy | Not observed topically (reported with oral dapsone) | Months (oral) | Report any new motor weakness or sensory changes; these are expected only with systemic dapsone exposure |
Although reported primarily with the 5% twice-daily formulation in postmarketing surveillance, methemoglobinaemia remains a labelled warning for all topical dapsone products. Patients with congenital or idiopathic methemoglobinaemia should avoid dapsone gel entirely. Initial signs include slate-grey cyanosis of the buccal mucosa, lips, and nail beds. The risk is amplified when topical dapsone is used concurrently with other methemoglobin-inducing agents (e.g., benzocaine, nitrates, sulfonamides). The 7.5% once-daily formulation delivers less total daily dapsone exposure than the 5% twice-daily formulation, which may reduce this risk, though direct comparison data are not available.
Drug Interactions
No formal drug-drug interaction studies were conducted with ACZONE Gel 7.5%. However, interaction data from the 5% gel and from oral dapsone inform the following clinically relevant considerations. Systemic exposure from the 7.5% gel is approximately 1% of that from a 100 mg oral dose, even when co-administered with TMP/SMX.
Monitoring
-
Clinical Response
Week 4, then week 12
Routine Assess inflammatory and non-inflammatory lesion counts. Improvement typically begins by week 4. If no response by week 12, reassess treatment (per FDA PI). Long-term use can be continued in responders. -
Methemoglobin Signs
Ongoing during treatment
Trigger-based Counsel patients to watch for slate-grey cyanosis of lips, nail beds, or buccal mucosa. Symptoms may be delayed hours after application. Routine methemoglobin screening is not required but should be measured urgently if cyanosis appears. -
G6PD Status
Before initiation (in at-risk populations)
Routine Consider G6PD testing in patients of African, South Asian, Middle Eastern, or Mediterranean ancestry before starting topical dapsone. G6PD-deficient individuals are more prone to haemolysis and methemoglobinaemia. -
Haemolysis Signs
If G6PD deficient or symptomatic
Trigger-based Monitor for dark urine, back pain, fatigue, pallor, jaundice, or shortness of breath in G6PD-deficient patients. In the dedicated G6PD study (dapsone 5%), subclinical laboratory changes occurred without clinically significant anaemia, but individual risk should be assessed. -
Local Tolerability
First 4 weeks
Routine Assess for application site dryness, pruritus, stinging, or scaling. In pivotal trials, tolerability scores were similar to vehicle, making dapsone gel one of the mildest topical acne treatments available.
Contraindications & Cautions
Absolute Contraindications
- None listed in the FDA prescribing information.
Relative Contraindications (Specialist Input Recommended)
- Congenital or idiopathic methemoglobinaemia: The FDA PI specifically advises avoiding dapsone gel in these patients due to their inherent susceptibility to further methemoglobin elevation.
- Concurrent use with oral dapsone or antimalarial medications: The PI advises avoidance due to additive haemolytic risk.
- Known hypersensitivity to dapsone or gel excipients: Although not listed as a formal contraindication, prior adverse reaction to dapsone (any formulation) should preclude use.
Use with Caution
- G6PD deficiency: Increased risk of haemolysis. Some patients with G6PD deficiency developed subclinical laboratory changes in the dedicated cross-over study. Monitor closely if prescribed.
- Concurrent methemoglobin-inducing agents: Multiple oxidising drugs amplify methemoglobinaemia risk.
- Pregnancy and lactation: Insufficient human data for topical use. Oral dapsone passes into breast milk and may cause haemolytic anaemia and hyperbilirubinaemia in nursing infants, especially those with G6PD deficiency.
- Eyes, mouth, and mucosal surfaces: Not for ophthalmic, oral, or intravaginal use.
Cases of methemoglobinaemia with resultant hospitalisation have been reported in postmarketing experience with topical dapsone (primarily the 5% twice-daily formulation). Patients with G6PD deficiency or congenital/idiopathic methemoglobinaemia are at highest risk. Signs may be delayed several hours after exposure. Initial signs include slate-grey cyanosis of the buccal mucosa, lips, and nail beds. Advise patients to discontinue dapsone gel immediately and seek emergency medical attention if cyanosis develops. Oral dapsone treatment is associated with dose-related haemolysis and haemolytic anaemia; G6PD-deficient individuals are most vulnerable.
Patient Counselling
Purpose of Therapy
Dapsone gel is a once-daily prescription treatment for acne that works by reducing inflammation in the skin. It is not an antibiotic, so it does not promote bacterial resistance the way traditional acne antibiotics can. It treats both the red bumps (papules, pustules) and the non-inflamed lesions (comedones/blackheads) of acne. Results typically begin within 4 weeks, with continued improvement through 12 weeks.
How to Apply
Gently wash and pat dry the face before application. Apply a pea-sized amount of dapsone gel in a thin layer to the entire face once daily, rubbing in gently and completely. Additional affected areas (upper chest, upper back, shoulders) may also be treated. The gel can be applied in the morning, as it is not photosensitising. Wash hands after application.
Sources
- ACZONE (dapsone) Gel, 7.5% — Full Prescribing Information. Almirall, LLC (revised September 2019). accessdata.fda.gov Primary regulatory source for the 7.5% gel; provides approved indication, dosing, adverse reactions (Table 1), PK data, G6PD study results, and clinical efficacy data (Table 2).
- ACZONE (dapsone) Gel, 5% — Full Prescribing Information. Allergan (revised 2015). accessdata.fda.gov Regulatory source for the original 5% twice-daily formulation; includes TMP/SMX interaction data, G6PD cross-over study details, and 12-month safety data.
- Stein Gold LF, Jarratt MT, Bucko AD, et al. Efficacy and safety of once-daily dapsone gel, 7.5% for treatment of adolescents and adults with acne vulgaris: first of two identically designed, large, multicenter, randomized, vehicle-controlled trials. J Drugs Dermatol. 2016;15(5):553–561. First pivotal phase 3 trial (N=2,102) demonstrating GAAS success rate of 29.9% vs 21.2% for vehicle and 55.5% inflammatory lesion reduction at week 12.
- Eichenfield LF, Lain T, Frankel EH, et al. Efficacy and safety of once-daily dapsone gel 7.5% for treatment of adolescents and adults with acne vulgaris: second of two identically designed, large, multicenter, randomized, vehicle-controlled trials. J Drugs Dermatol. 2016;15(8):962–969. Second pivotal trial (N=2,238) with consistent results: GAAS success 30% vs 21%, 54% inflammatory lesion reduction at week 12.
- Draelos ZD, Carter E, Maloney JM, et al. Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. J Am Acad Dermatol. 2007;56(3):439.e1–439.e10. doi:10.1016/j.jaad.2006.10.005 Original pivotal trials for dapsone 5% gel (N=3,010) establishing the topical dapsone platform with twice-daily dosing; foundational safety and efficacy data.
- Eichenfield LF, Hebert AA, Engstrom AM, et al. Once-daily dapsone 7.5% gel for the treatment of acne vulgaris in preadolescent patients: a phase IV, open-label, 12-week study. J Clin Aesthet Dermatol. 2021;14(5):50–56. Postmarketing study (N=100) in patients 9–11 years supporting the age expansion to ≥9 years; demonstrated consistent efficacy and safety with PK data.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945–973.e33. doi:10.1016/j.jaad.2015.12.037 AAD evidence-based acne guidelines positioning topical dapsone as an option for inflammatory acne, particularly in patients seeking non-antibiotic therapy.
- Thiboutot DM, Dréno B, Abanmi A, et al. Practical management of acne for clinicians: an international consensus from the Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2018;78(2 Suppl 1):S1–S23.e1. doi:10.1016/j.jaad.2017.09.078 International consensus on practical acne management including topical anti-inflammatory agents in treatment algorithms.
- Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol. 2009;10(4):221–227. doi:10.2165/00128071-200910040-00002 Review of dapsone’s anti-inflammatory mechanism in acne (neutrophil inhibition, myeloperoxidase suppression, ROS scavenging) and safety profile of the topical gel.
- Wozel G, Blasum C. Dapsone in dermatology and beyond. Arch Dermatol Res. 2014;306(2):103–124. doi:10.1007/s00403-013-1409-7 Comprehensive review of dapsone pharmacology covering anti-inflammatory mechanisms, metabolism to haemotoxic hydroxylamine, and clinical applications across dermatology.
- Draelos ZD, Rodriguez DA, Kempers SE, et al. Treatment response with once-daily topical dapsone gel, 7.5% for acne vulgaris: subgroup analysis of pooled data from two randomized, double-blind studies. J Drugs Dermatol. 2017;16(6):591–598. Subgroup analysis by age, sex, and race from the two pivotal trials showing consistent efficacy across demographics; supports dapsone’s utility in adult female acne.
- Tanghetti E, Harper JC, Oefelein MG. Pooled efficacy, safety, and dermal tolerability of dapsone gel, 7.5% in patients with moderate acne vulgaris: a pooled analysis of two phase 3 trials. J Clin Aesthet Dermatol. 2018;11(4):42–49. Pooled analysis of pivotal data (N=4,340) providing the definitive efficacy figures: GAAS success 29.8% vs 21.1%, inflammatory lesion reduction 54.6% vs 48.1%.