Hydroquinone and tretinoin together for melasma

Hydroquinone and tretinoin are used together in one FDA-approved product: a prescription cream for melasma that also holds a steroid. The FDA says this cream, sold as Tri-Luma, is "the only FDA-approved drug containing hydroquinone." This guide covers what the cream is approved for, what its trials found, how its label says to use it, and the warnings that come with it. For tretinoin by itself, see the tretinoin guide.

Skinli gives general education and is not a doctor. Melasma is a condition of dark patches on the face, and a dermatologist is the person to confirm it. Both drugs need a prescription in the US, and your prescriber picks the product and how long you use it. For the dark marks that pimples leave behind, which are a different problem, see hyperpigmentation and retinol and tretinoin for dark spots.

What each drug is

The Tri-Luma label is published on DailyMed, the National Library of Medicine's database of drug labels. It describes three drugs in one cream.

Drug	What the label calls it	Amount in each gram
Hydroquinone	"a melanin synthesis inhibitor". Melanin is the skin's pigment, so this drug slows the making of pigment	40 mg (4 percent)
Tretinoin	"a retinoid", a drug related to vitamin A	0.5 mg (0.05 percent)
Fluocinolone acetonide	"a corticosteroid", a type of steroid used to calm inflamed skin	0.1 mg (0.01 percent)

The American Academy of Dermatology (AAD) describes the same cream on its melasma page: it "contains three medications", which are "tretinoin (a retinoid), a corticosteroid to reduce inflammation, and hydroquinone to even out your skin tone." The AAD also lists hydroquinone used alone, and tretinoin with a mild corticosteroid, as other prescriptions a dermatologist may choose.

Tretinoin is a retinoid and belongs to a different drug class from the steroid in this cream. Is tretinoin a steroid? explains the difference.

What the combined cream is approved for

The label says Tri-Luma is "indicated for the short-term treatment of moderate to severe melasma of the face, in the presence of measures for sun avoidance, including the use of sunscreens." It then sets four limits:

• Short-term only. "TRI-LUMA Cream is NOT indicated for the maintenance treatment of melasma." Maintenance means ongoing use to keep a condition away.
• Melasma only. Safety and efficacy, meaning how well the cream works, "in the treatment of hyperpigmentation conditions other than melasma of the face have not been studied." Hyperpigmentation means darker patches of skin. This limit includes marks left by acne.
• Darker skin was not studied. The leaflet says: "It is not known if TRI-LUMA Cream is safe and effective in people with dark brown to black skin color." The trials enrolled people with the four lighter types on the six-step scale doctors use for skin color.
• Medical supervision. The FDA says the cream "should only be used under the supervision of a licensed health care professional."

No source read for this guide covers a store-bought hydroquinone product used beside a tretinoin prescription, and none gives an order for applying two separate products.

What the trials found

Two trials on the label enrolled 641 adults with moderate to severe melasma of the face. Each person used one of four creams every night for 8 weeks, with SPF 30 sunscreen during the day. Success meant that the dark patches had cleared.

Cream	Cleared at 8 weeks, trial 1	Cleared at 8 weeks, trial 2
All three drugs	38 percent (32 of 85)	13 percent (10 of 76)
Hydroquinone with tretinoin	15 percent (12 of 83)	4 percent (3 of 75)
Steroid with tretinoin	0 of 85	4 percent (3 of 76)
Steroid with hydroquinone	4 percent (3 of 85)	1 percent (1 of 76)

Hydroquinone with tretinoin is the pair this page is about. It cleared melasma in fewer people than the three-drug cream in both trials. The label adds that improvement with the three-drug cream was seen "as early as 4 weeks", and that 4 of the 7 people who were clear at 4 weeks did not stay clear after 4 more weeks of treatment.

Two later studies are known here from their abstracts, the short published summaries.

• Against hydroquinone alone. A 2008 trial in the British Journal of Dermatology compared the three-drug cream with hydroquinone 4 percent cream in Asian patients. At week 8, melasma was rated none or mild in 77 of 120 people (64.2 percent) on the three-drug cream and in 48 of 122 (39.4 percent) on hydroquinone. Side effects linked to treatment were more common with the three-drug cream, 48.8 percent against 13.7 percent, and the abstract says most were mild and none was severe.
• Over 12 months. A 2005 report in the Journal of Drugs in Dermatology followed 569 people who used the three-drug cream, with breaks, for up to a year. It reports that 14 patients (2.5 percent) left the study because of side effects, and that "By month 12, 80% of patients had lesions completely cleared or nearly cleared." Lesions here means the dark patches. Its abstract shows no funding line.

The label's own follow-up is less positive. It says the clear periods "appeared to shorten between progressive courses of treatment", and that few people, 1 to 2 percent, kept complete clearing.

How the label says to use the cream

1. Wash. "gently wash your face with a mild cleanser. Rinse your face and pat your skin dry."
2. Apply once a day. The label says "once daily, at least 30 minutes before bedtime."
3. Cover the patch and its edge. Apply a thin layer to the dark patches and to half an inch of normal skin around each one.
4. Keep it off sensitive areas. The label says to keep it "away from the eyes, nose, angles of the mouth, or open wounds because these areas are more sensitive to the irritant effect."
5. Leave the skin uncovered. "Do not bandage or cover the treated skin after applying TRI-LUMA Cream."
6. Daytime. "During the day, use a sunscreen of SPF 30, and wear protective clothing." The label also says: "Patients may use moisturizers and/or cosmetics during the day."
7. Stop when the patches are under control. "Therapy should be discontinued when control is achieved."

The cream is kept cold. The label says: "Store in a refrigerator, 2° - 8°C (36° - 46°F). Protect from freezing."

Sunlight has a strong effect on melasma. The leaflet says: "Melasma can get worse with even a small amount of sunlight." It also says that hormonal birth control "can cause your melasma to become worse", and tells patients to talk with their doctor about other options. The SPF figures from each tretinoin label are in sunscreen with tretinoin.

Warnings on the label

Side effects were common in the trials. Of 161 people who used the cream for 8 weeks, 102 (63 percent) had at least one side effect linked to it.

Side effect	Share of 161 people
Redness	41 percent
Peeling	38 percent
Burning	18 percent
Dryness	14 percent
Itching	11 percent
Acne	5 percent

The label carries four warnings beyond irritation.

• Skin darkening from hydroquinone. The label says hydroquinone "may produce exogenous ochronosis, a gradual blue-black darkening of the skin, the occurrence of which should prompt discontinuation of therapy." It says most people who develop it are Black, and that it may also occur in white and Hispanic people.
• Effects of the steroid. The leaflet says: "Too much TRI-LUMA Cream passing through your skin can cause your adrenal glands to stop working." The adrenal glands make the body's own steroid hormones. The 12-month study reported 2 mild cases of skin thinning.
• Sulfite allergy. The cream "contains sodium metabisulfite, a sulfite that may cause allergic-type reactions".
• Pregnancy. The leaflet says the cream "may cause birth defects or death of the baby if used during pregnancy."

The label also tells patients to avoid "medicated or abrasive soaps and cleansers, soaps and cosmetics with drying effects, products with high concentrations of alcohol and astringents, and other irritants or keratolytic drugs". Keratolytic drugs loosen the outer layer of skin, and salicylic acid is one of them. See salicylic acid with tretinoin.

Hydroquinone sold without a prescription, and mixed creams

The FDA's position on store-bought hydroquinone is plain: "there are no FDA-approved or otherwise legally marketed OTC skin lightening products." OTC means sold without a prescription. A law that took effect on September 23, 2020 required companies to remove such products unless they had FDA approval. The AAD tells patients the same: "Hydroquinone is no longer available in products that you can buy without a prescription."

The FDA "advises consumers not to use" these products. It has received reports of "skin rashes, facial swelling, and ochronosis (discoloration of skin)", and a second FDA warning says the discoloration "may be permanent". That second warning also reports high levels of mercury in some skin lightening products the agency tested.

DailyMed also lists creams that mix tretinoin with hydroquinone and other drugs. Their labels were not read for this guide, and their approval status was not checked. A cream that a pharmacy mixes to order is called a compounded drug. The FDA says: "Compounded drugs are not FDA-approved", and that it "does not verify the safety, effectiveness or quality of compounded drugs before they are marketed." It adds that poor compounding practices can lead to a drug with too much or too little active ingredient. If you are offered a mixed cream, ask your prescriber why it was chosen over the approved one. How to get tretinoin covers safe ways to fill a prescription.

After the cream is stopped

The label says: "Melasma usually recurs upon discontinuation of TRI-LUMA Cream." It also says that after control is reached, "some patients may be managed with other treatments". The leaflet tells patients to keep avoiding sunlight, using sunscreen and wearing protective clothing after treatment ends.

The AAD describes the wider plan. It says the most effective treatment "combines sun protection with medications that you apply to your skin", and that "it usually takes between 3 to 12 months to see results." It adds a point on cost: because melasma treatment is not considered medically necessary, "most insurers will not cover the cost." The Skinli guide to melasma covers the condition itself.

When to see a doctor

Stop the cream and call your doctor if the treated skin turns blue-black, or if it blisters, crusts, swells or burns severely. The leaflet says to get medical help right away for swelling of the face, eyes, lips, tongue or throat, or for trouble breathing, because these are signs of an allergic reaction. Tell your prescriber before you start if you are pregnant or planning a pregnancy.

See a dermatologist before treating any dark patch that has not been diagnosed. The guide on when to see a doctor about a dark spot lists the signs that need a check.