Hydroquinone
Systematic reviews of randomized trials found hydroquinone lightened melasma, and the triple cream with tretinoin and a steroid lightened it more than hydroquinone alone. Azelaic acid and tranexamic acid gave similar results. Skin irritation was very common. Case series link long use, mostly above 4% and over years, to permanent blue-black ochronosis, and FDA removed OTC products in 2020.
Add to Bio HackChecked 2026-11-14
- Status
- Not legally sold over the counter in the US since September 23, 2020. FDA states that under the CARES Act, OTC skin lightening products with hydroquinone are unapproved new drugs, and it sent warning letters to 12 companies in 2022. FDA names Tri-Luma (fluocinolone 0.01%, hydroquinone 4%, tretinoin 0.05%) as the only FDA-approved hydroquinone drug, a prescription cream for short-term treatment of moderate to severe facial melasma.
- Also called
- HQ, hydroquinone cream, hydroquinone 2%, hydroquinone 4%, skin lightener, skin bleaching cream, fade cream, dark spot corrector, Tri-Luma, triple combination cream, fluocinolone acetonide, hydroquinone and tretinoin
- Taken for
- melasma, dark spots, age spots, sun spots, acne marks, post-inflammatory hyperpigmentation, uneven skin tone, skin lightening
Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on
Shown to help2
- StrongShown to clear or lighten melasma more than hydroquinone alone or any two-ingredient mix over 8 weeks. Against placebo cream, about 65% responded against 1%.Very common
- ModerateShown to lighten melasma in randomized trials, including against placebo cream. Broad-spectrum sunscreen that also blocks visible light added to its effect.
Reported risks6
- ModerateShown to cause skin irritation often. In a pooled analysis, 50.9% on hydroquinone combinations had irritation, and on Tri-Luma 41% had redness and 38% peeling.Very common
- ModerateFDA states no OTC skin lightening product is legally marketed in the US, after the CARES Act deemed hydroquinone products unapproved new drugs from September 2020.How often is not known
- LimitedCase reports: hydroquinone has been followed by blue-black facial darkening, mostly at concentrations above 4% and after years of use. FDA warns it may be permanent.How often is not known
- LimitedFDA states it has received reports of serious skin rashes and facial swelling from OTC skin lightening products with hydroquinone. It gives no rate.How often is not known
- LimitedThe Tri-Luma label states there are no adequate studies in pregnancy and that its tretinoin component is a teratogen. It gives no data on hydroquinone alone.How often is not known
- LimitedThe Tri-Luma label warns its corticosteroid can be absorbed and suppress the adrenal glands, with possible steroid insufficiency after stopping. It gives no rate.How often is not known
What people take it for, and what was found
Shown to help2
Melasma, hydroquinone alone
Shown to lighten melasma in randomized trials, including against placebo cream. Broad-spectrum sunscreen that also blocks visible light added to its effect.
Compared with placebo cream [1]; before treatment [2]; other topical treatments [3]
The numbers and sources
- Effect
- In a split-face trial in skin types IV to VI, the abstract reports 76.9% improvement on the hydroquinone 4% side compared with the placebo side over 3 months, with side effects in 25% [1]. Pooled before-and-after data showed hydroquinone alone lowered melasma severity scores (SMD -1.3, 95% CI -1.6 to -1.0) [2]. A review of investigator-blinded randomized trials concluded hydroquinone and tretinoin, alone and combined, lightened melasma, and that sunscreen covering visible as well as UV light raised hydroquinone's effect compared with UV-only protection [3].
- Population
- 25 patients completing one split-face trial in Brazil [1]; 2,359 patients in 45 studies [2]; 36 investigator-blinded randomized trials [3].
- Sources
- [1], [2], [3]
- Caveats
- The placebo trial was small [1]. [2] measured change from baseline, not against a control. Most trials are small, short and use varied outcomes [3]. No controlled trial of hydroquinone alone for age spots or acne marks was located in this search.
Melasma, the triple combination cream (Tri-Luma)
Shown to clear or lighten melasma more than hydroquinone alone or any two-ingredient mix over 8 weeks. Against placebo cream, about 65% responded against 1%.
Compared with hydroquinone alone [4]; two-ingredient combinations [4][5]; placebo cream [6]
The numbers and sources
- How common
- Very common: more than 1 in 10 people.
- Effect
- The triple cream lightened melasma more than hydroquinone alone (RR 1.58, 95% CI 1.26 to 1.97) and more than tretinoin plus hydroquinone (RR 2.75) [4]. In the two label trials, melasma cleared at 8 weeks in 38% on Tri-Luma against 15% on hydroquinone 4% plus tretinoin, 0 on fluocinolone plus tretinoin and 4% on fluocinolone plus hydroquinone in trial 1, and in 13% against 4%, 4% and 1% in trial 2 [5]. In a placebo-controlled trial in China, the integral efficacy rate was 64.6% on the triple cream and 0.88% on placebo [6]. The investigator-blinded review also found the triple cream lightened melasma [3].
- Population
- 20 randomized trials, 2,125 participants [4]; 641 adults aged 21 to 75 with skin types I to IV, about 98% women [5]; 233 Chinese adults with moderate to severe melasma [6]; 36 randomized trials [3].
- Sources
- [4], [5], [6], [3]
- Caveats
- The label states melasma usually recurs after stopping Tri-Luma, and it is not indicated for maintenance [5]. The Cochrane review rated study quality as generally poor [4].
Mixed results1
Against azelaic acid, tranexamic acid and other lighteners
Mixed results: azelaic acid 20% lightened melasma about as much as 4% hydroquinone, or slightly more, and tranexamic acid, cysteamine and kojic acid gave comparable results.
Compared with azelaic acid [4][7]; tranexamic acid, cysteamine, kojic acid and others [2][3]
The numbers and sources
- Effect
- Azelaic acid 20% lightened melasma more than 2% hydroquinone (RR 1.25, 95% CI 1.06 to 1.48) and did not differ from 4% hydroquinone (RR 1.11, 95% CI 0.94 to 1.32) [4]. Across 6 trials, azelaic acid lowered melasma severity scores 1.23 points more than hydroquinone (95% CI 0.40 to 2.05), with no difference in objective response or adverse events [7]. In pooled before-and-after data, hydroquinone (SMD -1.3), cysteamine (-1.6), tranexamic acid (-1.5), azelaic acid (-1.3) and kojic acid (-0.9) showed comparable effects [2]. The investigator-blinded review pooled topical tranexamic acid against hydroquinone but found too few comparisons to rank treatments [3].
- Population
- 20 trials [4]; 673 patients in 6 randomized trials [7]; 45 studies [2]; 36 randomized trials [3].
- Sources
- [4], [7], [2], [3]
- Caveats
- Trials were small and short. [2] compared change from baseline across separate studies, not head to head.
Doses studied
Tri-Luma contains fluocinolone acetonide 0.01%, hydroquinone 4% and tretinoin 0.05%, and its trials applied a thin layer nightly for 8 weeks with SPF 30 sunscreen daily [5]. The placebo-controlled hydroquinone trial used 4% cream nightly for 3 months with SPF 25 sunscreen [1]. Trials in the reviews compared hydroquinone 2% and 4% [4]. FDA's 2006 proposed rule notes ochronosis after concentrations as low as 1% to 2% [8].
Risks
Reported risks6
Skin irritation, redness and peeling
Shown to cause skin irritation often. In a pooled analysis, 50.9% on hydroquinone combinations had irritation, and on Tri-Luma 41% had redness and 38% peeling.
The numbers and sources
- How common
- Very common: more than 1 in 10 people.
- Effect
- Irritation occurred in 50.9% on hydroquinone-containing combinations, against 18.7% on azelaic acid, 5.3% on kojic acid and 0.8% on tranexamic acid [2]. On Tri-Luma, 63% had at least one treatment-related adverse event, including erythema in 41%, desquamation 38%, burning 18%, dryness 14% and itching 11% [5]. In a placebo-controlled trial, 30.1% on the triple cream and 2.6% on placebo reported adverse effects, mostly mild [6]. Side effects occurred in 25% on hydroquinone 4% in the split-face trial [1].
- Population
- 4,539 patients in 55 studies [2]; 161 Tri-Luma users in label trials [5]; 226 adults in China [6]; 25 patients [1].
- Sources
- [2], [5], [6], [1]
- Caveats
- Most events were mild to moderate [5][6]. The Tri-Luma rates include effects of tretinoin and the steroid.
Exogenous ochronosis (blue-black skin darkening)
Case reports: hydroquinone has been followed by blue-black facial darkening, mostly at concentrations above 4% and after years of use. FDA warns it may be permanent.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- A systematic review of 56 reports with 126 patients found ochronosis most often in middle-aged women (53.2%), people of African descent (45.2%) and skin types V and VI (52.4%). It was most often reported with concentrations above 4% (35.7%) or unknown (32.5%), after a median 5 years of use. Only 4 cases followed 3 months or less, and 8 a year or less [10]. FDA's 2006 proposal cites ochronosis after concentrations as low as 1% to 2% [8]. FDA's 2022 communication lists ochronosis among serious side effects reported and states it may be permanent [9]. The Tri-Luma label warns of ochronosis, mostly in Black patients but also in white and Hispanic patients [5]. A clinical review describes it as hard to treat, with Q-switched lasers showing the most results [11].
- Population
- 126 patients in published case reports [10]; adverse event reports to FDA [9].
- Sources
- [10], [8], [9], [5], [11]
- Caveats
- Case reports give no rate. Many involved unregulated products of unknown strength [10].
Rashes and facial swelling
FDA states it has received reports of serious skin rashes and facial swelling from OTC skin lightening products with hydroquinone. It gives no rate.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- FDA reports serious side effects including skin rashes, facial swelling and ochronosis, and advises consumers not to use OTC skin lightening products with hydroquinone [9]. The Tri-Luma label lists hypersensitivity to any component as a contraindication [5].
- Population
- Adverse event reports to FDA [9].
- Sources
- [9], [5]
- Caveats
- Spontaneous reports cannot give a rate or prove cause.
Pregnancy
The Tri-Luma label states there are no adequate studies in pregnancy and that its tretinoin component is a teratogen. It gives no data on hydroquinone alone.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- The label lists Pregnancy Category C, states there are no adequate and well-controlled studies in pregnant women, and states tretinoin may cause embryo-fetal death, altered fetal growth and malformations. Pregnant and breastfeeding women were excluded from the trials, and 13 women became pregnant during treatment. Dermal studies in pregnant rats showed malformations of the type expected with tretinoin [5].
- Population
- Label trials and animal studies [5].
- Sources
- [5]
- Caveats
- The pregnancy warning is driven by tretinoin, not shown for hydroquinone itself.
Adrenal suppression with the steroid in Tri-Luma
The Tri-Luma label warns its corticosteroid can be absorbed and suppress the adrenal glands, with possible steroid insufficiency after stopping. It gives no rate.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- The label states systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis suppression, with potential glucocorticosteroid insufficiency after treatment is withdrawn, and that a cosyntropin test may help evaluate it [5].
- Population
- Labeling statement for topical corticosteroids [5].
- Sources
- [5]
- Caveats
- This applies to the fluocinolone in Tri-Luma, not to hydroquinone alone.
FDA removal of OTC products
FDA states no OTC skin lightening product is legally marketed in the US, after the CARES Act deemed hydroquinone products unapproved new drugs from September 2020.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- In 2006 FDA proposed that OTC skin bleaching products are not generally recognized as safe and effective, citing animal carcinogenicity and ochronosis, and said it intended to require an approved application for all skin bleaching products, prescription or OTC [8]. Under the 2020 CARES Act, OTC skin lightening products with hydroquinone are deemed new drugs and misbranded, and had to leave the market from September 23, 2020. In April 2022 FDA sent warning letters to 12 companies still selling them and added some manufacturers to an import alert. FDA states Tri-Luma is the only FDA-approved drug containing hydroquinone, and that many of its concerns also apply to hydroquinone in cosmetics [9].
- Population
- US market [8][9].
- Sources
- [8], [9]
- Caveats
- Products may still be found online or imported despite FDA action [9].
Possible, not studied in people1
Cancer in animal studies
Not studied in people. Animal studies of oral hydroquinone found some evidence of cancer in rats and female mice, and FDA cannot rule out a human risk.
No study in people. This rests on animal studies.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- Oral hydroquinone showed "some evidence" of carcinogenic activity in male and female rats and in female mice in NTP studies. FDA's carcinogenicity committee concurred and asked for more safety studies, which had not been submitted by 2006. FDA stated it could not rule out a carcinogenic risk from topical hydroquinone in humans [8]. In label studies, hydroquinone was quantifiable in plasma in 18% of volunteers after 8 weeks of daily Tri-Luma [5].
- Population
- Rats and mice given oral hydroquinone [8]; 59 healthy volunteers in a label absorption study [5].
- Sources
- [8], [5]
- Caveats
- The animals took hydroquinone by mouth, not on the skin. No human cancer study was located.
Related
Sources
- Haddad AL, Matos LF, Brunstein F, et al. A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma. International Journal of Dermatology. 2003. https://doi.org/10.1046/j.1365-4362.2003.01621.x
- Chang YF, Lee TL, Oyerinde O, et al. Efficacy and safety of topical agents in the treatment of melasma: What's evidence? A systematic review and meta-analysis. Journal of Cosmetic Dermatology. 2023. https://doi.org/10.1111/jocd.15566
- Pennitz A, Kinberger M, Avila Valle G, et al. Self-applied topical interventions for melasma: a systematic review and meta-analysis of data from randomized, investigator-blinded clinical trials. British Journal of Dermatology. 2022. https://doi.org/10.1111/bjd.21244
- Rajaratnam R, Halpern J, Salim A, Emmett C. Interventions for melasma. Cochrane Database of Systematic Reviews. 2010. https://doi.org/10.1002/14651858.cd003583.pub2
- U.S. Food and Drug Administration. TRI-LUMA (fluocinolone acetonide, hydroquinone, and tretinoin) cream, prescribing information. 2024. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a35fa709-5eb5-4429-b38f-f1e0019bf0ee
- Gong Z, Lai W, Zhao G, et al. Efficacy and safety of fluocinolone acetonide, hydroquinone, and tretinoin cream in chinese patients with melasma: a randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Clinical Drug Investigation. 2015. https://doi.org/10.1007/s40261-015-0292-8
- Albzea W, AlRashidi R, Alkandari D, et al. Azelaic Acid Versus Hydroquinone for Managing Patients With Melasma: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus. 2023. https://doi.org/10.7759/cureus.41796
- U.S. Food and Drug Administration. Skin Bleaching Drug Products For Over-the-Counter Human Use; Proposed Rule. Federal Register 71 FR 51146. 2006. https://www.federalregister.gov/documents/2006/08/29/E6-14263/skin-bleaching-drug-products-for-over-the-counter-human-use-proposed-rule
- U.S. Food and Drug Administration. FDA works to protect consumers from potentially harmful OTC skin lightening products. Drug Safety Communication. 2022. https://www.fda.gov/drugs/drug-safety-communications/fda-works-protect-consumers-potentially-harmful-otc-skin-lightening-products
- Ishack S, Lipner SR. Exogenous ochronosis associated with hydroquinone: a systematic review. International Journal of Dermatology. 2022. https://doi.org/10.1111/ijd.15878
- Simmons BJ, Griffith RD, Bray FN, et al. Exogenous ochronosis: a comprehensive review of the diagnosis, epidemiology, causes, and treatments. American Journal of Clinical Dermatology. 2015. https://doi.org/10.1007/s40257-015-0126-8