3 Hydroquinone Side Effects You Need to Know About

Melasma is a common acquired skin hyperpigmentation primarily affecting sun-exposed areas of the forehead, cheeks, nose, upper lip, and chin, and occasionally the neck and forearms. Melasma affects all races but are more common in individuals of Hispanic, Latin American, Middle Eastern, Asia and African origin (Fitzpatrick skin types III–V).

Melasma are dark patches that are bilateral and do not have definitive border. It is also difficult to treat with a single modality. Traditionally, hydroquinone, a tyrosinase inhibitor, has been used alone or as “triple combination” therapy and has remained the gold standard treatment for melasma. A formulation of hydroquinone 4%, tretinoin 0.05%, and flucinolone acetonide 0.01% (HTF, Triluma®) remains the only US FDA approved triple combination for melasma therapy. Studies across ethnicities have documented its superior efficacy even in moderate to severe melasma and improved quality of life compared with hydroquinone monotherapy or other combination therapies. This triple combination was more effective than hydroquinone 4% alone from 4 weeks onwards in a comparative study in 120 Brazilian patients with moderate-to-severe melasma.

Chan et al. also demonstrated nearly 70% of 125 South-East Asian patients with moderate to severe melasma achieved complete clearance in triple combination group as compared to 44% of 129 patients in hydroquinone only group. Despite its success rate, the focus has shifted to non-hydroquinone-based medical therapies in recent years. We dissect three side effects of Hydroquinone and how they are misconceived.

#1 - Limited Treatment Duration. "The treatment of melasma can take 6 months or more and I should not be using Hydroquinone long term due to the risk of ochronosis."

Hydroquinone has shown to be safe and effective when used under medical supervision, even beyond three and six months. The risk of ochronosis is only seen in very high doses and when it is applied to large areas and for a long period of time.

#2 - Rebound Hyperpigmentation. "There is a risk of rebound hyperpigmentation when I stop using Hydroquinone."

Just like any other chronic condition, when treatment is ceased, the condition is likely to recur. The same principle applies to diabetes, high blood pressure and any other chronic condition. Hence, it is important to have the right maintenance therapy or treatment protocol in place to prevent melasma from recurring when you stop using Hydroquinone.

The need to taper off Hydroquinone (to avoid rebound hyperpigmentation) is only necessary if therapy has been established for a very long period of time. Extreme long term therapy is more common when it is purchased and used freely without medical supervision.

#3 - Irritation

Hydroquinone has been shown to be well tolerated between 2-4%. Stinging and irritation is common in concentrations of Hydroquinone 10% or more.

What are the treatment options for melasma once I stop Hydroquinone?

Azelaic Acid 20% has been found to be as effective as Hydroquinone 4% for the treatment of melasma. Other non-hydroquinone based therapies include:

  • Alpha arbutin
  • Niacinamide
  • Liquorice Root 
  • Soy Bean
  • Vitamin C 
  • Tretinoin
  • Kojic Acid 
  • Glycolic Acid


Is there such thing as drug resistance when it comes to treating melasma?

Triple combination therapy has shown to be effective in over 90% of cases with moderate to severe melasma. In cases where the patient does not respond to triple combination therapy, the incorporation of Glycolic Acid peel has shown to be beneficial. 






Author: Helen Huynh B. Pharm MPS









1. Doolan, B et al (2021) "Melasma". Australian Journal of General Practice. vol50, issue 12. 

2. Chan R, Park KC, Lee MH, et al. "A randomized controlled trial of the efficacy and safety of a fixed combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinne 4% cream in Asian patients with moderate to severe melasma." Br J Dermatol. 2008; 159: 697-703.

3. Sarka, R et al (2013) "Cosmeceuticals for Hyperpigmentation: What is available?." Journal of Cutaneous and Aesthetic SurgeryJan-Mar; 6(1): 4–11. doi: 10.4103/0974-2077.110089  

4. Navarette-Solis, J (2011) "A Double Blind, Randomised Clinical Trial of Niacinamide 4% vs Hydroquinone 4% in the Treatment of Melasma." Journal of Dermatology Research and Practice. doi: 10.1155/2011/379173

5. Banyopadhayay, D (2009). "Topical Treatment of Melasma." Indian Journal of Dermatology. 2009 Oct-Dec; 54(4): 303–309.

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