The melasma trials in the sources used here mostly tested a triple-combination cream (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) against dual combinations, hydroquinone 4% cream or placebo. Each trial below ran 8 weeks. Their endpoints differ, so a percentage from one trial is not comparable with a percentage from another. The sources used here report no trial of hydroquinone 8% or of a blend with tretinoin, niacinamide and vitamin C.
The trials at a glance
| Source and comparison | Size and length | Endpoint and reported result |
|---|---|---|
| Cutis report, 2003: tretinoin 0.05%, hydroquinone 4.0% and fluocinolone acetonide 0.01% versus dual-combination agents | Two 8-week, multicenter, randomized, investigator-blind studies | Complete clearing at the end of week 8 in the combined analysis: 26.1% with the triple combination versus 4.6% in the other groups (P<.0001) |
| Prescribing information, fluocinolone acetonide, hydroquinone and tretinoin cream: triple combination versus HQ+RA, FA+RA and FA+HQ (dual-combination strengths are not given in the sources used here) | Two trials, 641 subjects aged 21 to 75 years, Fitzpatrick skin types I-IV, eight-week treatment period | Investigators' assessment of treatment success, defined as the clearing of melasma. Trial 1: 38% versus 15%, 0 and 4%, in that order. Trial 2: 13% versus 4%, 4% and 1% |
| British Journal of Dermatology, 2008: triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) once at bedtime versus hydroquinone 4% cream twice daily, in Asian patients | Randomized, investigator-blinded, multicentre; treated daily for 8 weeks | Global severity score "none" or "mild" at week 8: 77/120 (64.2%) versus 48/122 (39.4%) (P < 0.001) |
| Clinical Drug Investigation, 2015: FAHT cream (fluocinolone acetonide, hydroquinone, and tretinoin) versus placebo, in Chinese patients; the abstract does not state the strengths | 233 subjects allocated 1:1 (n = 117 and n = 116), once nightly for 8 weeks | Integral therapeutic efficacy rate in the full analysis set: 64.60% versus 0.88% for placebo |
Endpoints and adverse events
The prescribing information says primary efficacy was the proportion of subjects with an investigators' assessment of treatment success, defined as the clearing of melasma at the end of the eight-week treatment period. The full analysis set in the Chinese trial includes subjects lost to follow-up who received at least one study treatment.
In the trial in Asian patients, more patients had related adverse events on the triple combination (63/129, 48.8%) than on hydroquinone 4% cream (18/131, 13.7%), but most were mild and none was severe.
What reviews say about these trials
A Cochrane review reported that triple-combination cream was significantly more effective at lightening melasma than hydroquinone alone (RR 1.58, 95% CI 1.26 to 1.97); the abstract text used here does not state strengths for that comparison. The same review found azelaic acid (20%) significantly more effective than 2% hydroquinone (RR 1.25, 95% CI 1.06 to 1.48) but not when compared to 4% hydroquinone (RR 1.11, 95% CI 0.94 to 1.32). It also concluded that the quality of studies evaluating melasma treatments was generally poor and available treatments inadequate, and called for high-quality randomised trials with long-term outcomes.
A network meta-analysis of randomized controlled trials found triple combined cream the most favorable selection among the topical drugs for melasma when both efficacy and safety were considered. An evidence-based review lists heterogeneity of study design, small sample size and lack of long-term follow-up as limitations of the evidence.
What this does not tell you
These trials compared products at 4% hydroquinone or in the triple combination, over 8 weeks. They do not show how a cream behaves over longer courses, and the prescribing information for the triple combination states that melasma usually recurs upon discontinuation. The sources used here report no trial of hydroquinone 8% or of a blend with tretinoin, niacinamide and vitamin C, so these results cannot be assumed to apply to either. Each trial used its own endpoint, and some strengths are unstated in the sources used here. A licensed provider decides what suits a person.