Tretinoin Compounded vs Branded: A Clinical Comparison

What is the difference between compounded and branded tretinoin?

The main difference is regulatory. Compounded drugs are not FDA-approved, which means FDA does not verify their safety, effectiveness or quality before they are marketed [1]. Consumers and health care professionals rely on FDA's drug approval process for that verification [1].

Compounding still has a role. FDA says a drug may be compounded for a patient who cannot be treated with an FDA-approved medication, such as a patient with an allergy to a dye or a patient who cannot swallow a tablet [1]. FDA also says compounded drugs should only be used in patients whose medical needs cannot be met by an FDA-approved drug, and that unnecessary use may expose patients to serious health risks [1].

Branded tretinoin is not one product. Retin-A and Retin-A Micro are indicated for acne vulgaris. Renova 0.02% cream is indicated only as an adjunct, with a comprehensive skin care and sunlight avoidance program, for mitigation of fine facial wrinkles [2]. Its label says it does not eliminate wrinkles, repair sun-damaged skin, reverse photoaging or restore a more youthful skin structure [2]. A compounded preparation has no FDA-approved indication of its own [1].

Is compounded tretinoin as effective as branded tretinoin?

FDA does not verify the effectiveness of compounded drugs before they are marketed [1]. The published tretinoin trials below tested specific formulations, and their results should not be assumed to carry over to a compounded preparation.

In a 24-week randomized, double-blind, vehicle-controlled multicenter study of 251 subjects with mild to moderate photodamaged facial skin, 79% of subjects who received 0.05% tretinoin emollient cream showed overall improvement, compared with 48% of vehicle-treated subjects [3]. Significant reductions were found in fine wrinkling, mottled hyperpigmentation, roughness and laxity [3]. That study tested 0.05% and 0.01% creams, not the 0.02% Renova cream [3]. Two 24-week vehicle-controlled histologic studies involving 533 subjects found increased epidermal thickness, increased granular layer thickness, decreased melanin content and stratum corneum compaction in tretinoin-treated skin; 0.001% tretinoin was not significantly different from vehicle, and no obvious dermal changes were detected in any group [4].

For acne, a retrospective, investigator-blinded, vehicle-controlled photographic assessment rated 577 patients from 12- or 15-week double-blind comparisons of several retinoids [5]. Among evaluations in which pretreatment acne severity was at least mild to moderate, clinically significant improvement was recorded in 21% with tretinoin microsponge (47 patients) versus 7% with vehicle, and the tretinoin 0.025% gel group (39 patients) was statistically similar to vehicle [5]. None of these studies tested a compounded preparation [3][4][5].

What does the Renova label say about use and safety?

Renova 0.02% cream is applied once a day in the evening, using only enough to cover the affected area lightly [2]. The label says to gently wash the face with a mild soap, pat dry, and wait 20 to 30 minutes before applying, and to avoid the eyes, ears, nostrils and mouth [2]. Application of larger amounts has not been shown to lead to more rapid or better results, and may cause marked redness, peeling or discomfort [2].

The label warns that Renova is a dermal irritant [2]. Local reactions include peeling, dry skin, burning, stinging, erythema and pruritus [2]. In double-blind, vehicle-controlled studies involving 339 patients, almost all reported one or more local reactions; 32% had skin irritation that was severe, led to temporary discontinuation, or led to use of a mild topical corticosteroid, and about 4% discontinued because of adverse reactions [2]. The label also says tretinoin has been reported to cause severe irritation on eczematous skin [2].

Photosensitivity is a labeled safety issue. The Renova label says exposure to sunlight, including sunlamps, should be avoided or minimized because of heightened sunburn susceptibility [2]. It recommends sunscreens with a minimum SPF of 15 and protective clothing, and says patients with sunburn should not use the product until fully recovered [2]. The label says Renova should not be used if the patient is also taking drugs known to be photosensitizers, such as thiazides, tetracyclines, fluoroquinolones, phenothiazines or sulfonamides, because of possible augmented phototoxicity [2]. It also says to keep the product out of the eyes, mouth, angles of the nose and mucous membranes [2].

Pregnancy wording varies by tretinoin label. The Renova label says not to use the cream if the patient is pregnant, attempting to become pregnant, or at high risk of pregnancy [2]. It also describes animal data and 30 human cases of temporally associated congenital malformations reported during two decades of clinical use of another topical tretinoin formulation (Retin-A), with no definite pattern of teratogenicity and no causal association established [2]. Renova has no boxed warning [2].

What are the specific risks of compounded tretinoin?

FDA's compounding information addresses quality in general, not tretinoin specifically. The agency says poor compounding practices can result in serious drug quality problems, such as contamination or a drug that contains too much or too little active ingredient, and that this can lead to serious patient injury and death [1].

FDA also describes who oversees compounders. State boards of pharmacy generally have primary responsibility for day-to-day oversight of state-licensed pharmacies that are not registered with FDA as outsourcing facilities; FDA conducts surveillance and for-cause inspections of those pharmacies [1]. Facilities registered with FDA as outsourcing facilities are primarily overseen and inspected by FDA according to a risk-based schedule, and drugs compounded in outsourcing facilities are subject to current good manufacturing practice requirements [1]. By contrast, drugs compounded by a licensed pharmacist in a state-licensed pharmacy under the conditions of federal law are not subject to those CGMP requirements [1].

Side-by-side: what is actually supported

Bottom line

A branded tretinoin product is FDA-approved; a compounded tretinoin preparation is not, and FDA does not verify its safety, effectiveness or quality before marketing [1]. The Renova label gives specific indications, application instructions, irritation rates and sun warnings for that product [2], and the Weinstein, Bhawan and Leyden studies report outcomes for the formulations they tested [3][4][5].