A Comprehensive Review of Clocortolone Pivalate 0.1% Cream: Structural Development, Formulation Characteristics, and Studies Supporting Treatment of Corticosteroid-responsive Dermatoses

James Q. Del Rosso, DO, FAOCD, Dermatology Residency Program Director, Valley Hospital Medical Center, Las Vegas, Nevada; Leon Kircik, MD, Clinical Associate Professor, Mount Sinai Medical Center, New York, New York

Disclosure: Dr. Del Rosso is a consultant, speaker, and/or researcher for Coria/Valeant, Allergan, Galderma, Graceway, Intendis, Medicis, Onset Dermatologics, Obagi Medical Products, Ortho Dermatologics, PharmaDerm/Nycomed, Promius, Ranbaxy, Stiefel/GSK, TriaBeauty, Triax, Unilever, and Warner-Chilcott. Dr. Kircik Dr. Kircik is an advisor, consultant, speaker, and investigator for Promius Pharma and a speaker for Pedia Pharma.

Clocortolone pivalate is a mid-potency topical corticosteroid available as a 0.1% emollient cream approved by the United States Food and Drug Aministration for use in the treatment of corticosteroid-responsive dermatoses. The vehicle is formulated for application to a variety of corticosteroid-responsive skin disorders, including those with inflamed and fissured skin, such as eczematous dermatoses. Hence, the potency of the formulation and its vehicle characteristics are important when treating disorders, such as atopic dermatitis and other eczematous dermatoses, which are prone to cutaneous irritation and skin sensitivity to exogenously applied agents. As both localized and diffuse eczematous dermatoses and seborrheic dermatitis are common in pediatric patients (including infants) as well as in adults, the fact that clocortolone pivalate 0.1% cream has no age restriction related to its use according to United States Food and Drug Aministration-approved product labeling is important to recognize. The chemical structure of clocortolone pivalate is a unique design that provides high lipid solubility. Highly lipophilic topical corticosteroids exhibit augmented penetration through the stratum corneum, which provides higher epidermal concentrations. It has been reported that the structural characteristics of this molecule enhance its potency without increasing the potential for topical corticosteroid-related adverse effects. Clocortolone pivalate 0.1% cream has been studied in randomized, controlled trials of patients with atopic dermatitis and other eczematous dermatoses, psoriasis vulgaris, contact dermatitis, and seborrheic dermatitis. It has been shown to be more effective as monotherapy in the treatment of these corticosteroid-responsive dermatoses than the vehicle. Its efficacy and safety in pediatric patients and patients with facial dermatoses have also been demonstrated. Patients using clocortolone pivalate 0.1% topical cream in clinical trials had a low rate of adverse events, which were primarily minor application-site reactions. Systemic reactions related to the drug were not observed in these trials. Clinical studies of patients with corticosteroid-responsive dermatological conditions have found that clocortolone pivalate 0.1% cream is an effective class 4 topical corticosteroid with a favorable safety profile.  (J Clin Aesthet Dermatol. 2012;5(7):20–24.)

For many years, topical corticosteroids (TCs) have been the mainstay of therapy for a wide variety of corticosteroid-responsive dermatoses, including atopic dermatitis, contact dermatitis, psoriasis vulgaris, and seborrheic dermatitis.[1–6] TCs range in potency from mild to super-potent and are available in a variety of vehicle formulations.[7,8] TC therapy can be individualized by matching the potency and vehicle of the agent to the corticosteroid responsiveness and anatomic site of the condition under treatment.[2,5]

Clocortolone pivalate is a mid-potency TC available as a 0.1% emollient cream approved by the United States Food and Drug Administration (FDA) for use in the treatment of corticosteroid-responsive dermatoses with no age restriction on use specified in approved product labeling.[9] Favorable efficacy and safety have been demonstrated in patients with corticosteroid-responsive dermatoses in vehicle-controlled studies inclusive of more than 2,500 adult and pediatric patients. In some of these trials, subjects were treated with the commercially available formulation of clocortolone pivalate 0.1% cream (Cloderm® Cream, Promius Pharma LLC) or vehicle (n=1,000 collectively), and in other studies, patients were treated with a different vehicle formulation of clocortolone pivalate or vehicle (n=1,529 collectively).[10] The objective of this article is to review the pharmacological properties of topical clocortolone pivalate and the results of clinical trials investigating its efficacy and safety in various corticosteroid-responsive skin diseases.

Structural Considerations and Pharmacology of Topical Corticosteroids
TCs bind to intracellular corticosteroid receptors and regulate transcription of several genes, particularly those that encode for proinflammatory cytokines, and thereby produce anti-inflammatory, antiproliferative, immunosuppressive, and initial vasoconstrictive effects.[5] TC molecules are generally 21-carbon structures with a 2-carbon side chain at C-17.[8,11] All have three 6-carbon rings (A, B, C) and one 5-carbon ring (D). The basic corticosteroid molecule is frequently modified to enhance the inherent potency of a given TC molecule; however, the concentration and the vehicle that a given TC molecule is incorporated into can both independently or collectively alter the relative potency of that final formulation.[11]

Over several years, the most widely utilized and conventionally recognized method for evaluation of corticosteroid potency is the vasoconstrictor assay.[8] Although it is based primarily on relatively immediate vasoconstrictor activity, this test also considers skin penetration, activity at the receptor, and the rate of clearance from the application site. The classification system used to designate TC potency ranges from class 1 (most potent) to class 7 (least potent). Mid-potency TCs (class 4 or 5) are the most commonly prescribed group overall by clinicians, especially for eczematous dermatoses, although there may be some differences among dermatologists for more refractory noneczematous disease states (i.e., chronic plaque psoriasis, lichen planus).[10]

The potential for adverse effects associated with TCs tend to increase in incidence and severity as the potency of the compound increases, especially with more prolonged durations of use, although adverse reactions are uncommon overall with proper use of any TC agent.[12] The most common adverse effects are local application site reactions, which may include atrophy or thinning of the skin, striae, telangiectasia, acneiform eruptions, irritant contact dermatitis (usually vehicle-related), and, less commonly, allergic contact dermatitis. Allergic contact dermatitis from a TC and cross-allergenicity with other TCs are dependent on the structural class of the agent.

Systemic effects may occur when a TC, especially a high-potency agent, is used over a large body surface area for a prolonged period of time. Potential adverse effects of concern reported with use of TCs that are related to prolonged excessive corticosteroid exposure are hypothalamic-pituitary-adrenal (HPA) axis suppression, growth retardation in children, cataract formation, and glaucoma. The latter two may be associated with prolonged or careless periocular use. Fortunately, clinically relevant systemic adverse effects related to HPA axis suppression are rare as most clinicians discontinue TC use or decrease the application frequency after a relatively short course of continuous therapy once the dermatological disorder responds adequately. This allows for the HPA axis to accommodate and revert to normal. Importantly, a laboratory finding of “chemical” HPA axis suppression does not mean the axis is fully inoperative, and there have been very few reports of HPA axis suppression related to use of TCs that has led to clinically evident adverse events.  However, it is important to respect the potential for HPA axis suppression, especially with continuous and/or frequent use of TCs for chronic disease states, especially when large areas are treated, and when TCs are used in children.

Pharmacology of Topically Applied Clocortolone Pivalate
Clocortolone pivalate 0.1% cream is a class 4 (mid-potency) TC formulation. With the development of clocortolone pivalate, the objectives were to modify the basic corticosteroid nucleus to achieve mid-range potency and to create a vehicle that is well tolerated when applied to the skin affected by a variety of disease states, especially eczematous skin that is easily irritated by many exogenous agents. Other goals of structural modification were to optimize the lipophilicity of the molecule itself, as the creation of a TC that inherently achieves good penetration of the stratum corneum (SC) is advantageous. By circumventing the need to add certain “penetration enhancer” ingredients to assist the TC molecule in permeation through the SC, damage to the SC permeability barrier caused by such ingredients could be avoided. This is an important factor in treating many skin disorders, such as atopic dermatitis and other eczematous dermatoses, as epidermal barrier impairment contributes at least partially to the signs and symptoms of many skin diseases such as atopic dermatitis.

Structural modifications completed in the development of clocortolone pivalate include ?-hydroxylation at C-11; methylation at C-16; double bonds at C-1,2; esterification at C-21; and halogenation at C-6 and C-9 (Figure 1).[10] The specific effects of these modifications are shown in Table 1. Esterification at C-21 with substitution of a pivalate group increases the lipophilicity, duration of action, and potency of clocortolone pivalate. Methylation at C-16 also increases lipophilicity.[10]

A common misperception holds that halogenation of the corticosteroid molecule always increases the risk of the formulation causing adverse effects. Although some halogenated high-potency corticosteroids do have a high potential for adverse effects associated with prolonged use, it is the position and nature of the halogen atoms in the structure of the molecule, not halogenation itself, that mediates drug potency and side effect potential.[11] The halogen atoms in clocortolone pivalate are chlorine at C-9 and fluorine at C-6, which affect the efficacy and safety profiles of a mid-potency TC.[10]

The absorption of TCs and their penetration through the SC are determined in part by their lipophilicity.[8] Thus, highly lipophilic agents achieve higher concentrations in viable epidermis and appear to exhibit greater anti-inflammatory potency.[13] Clocortolone pivalate 0.1% has the highest lipophilicity among commonly used mid-potency TCs (Figure 2).[14] Although the large size of the pivalate group may theoretically reduce the glucocorticoid receptor affinity of clocortolone pivalate, halogenation at C-6 and C-9 enhances receptor affinity, which appears to counter the potential effect created by the size of the pivalate moiety.[14–16] It should be noted that independently studied correlations between specific structure-activity characteristics of the clocortolone pivalate molecule and clinical outcomes have not been established in clinical trials. However, data from pharmacological, efficacy, and safety analyses from the multiple studies discussed below support that clocortolone pivalate 0.1% cream is a well-tolerated, effective, and safe mid-potency TC for treatment of corticosteroid-responsive dermatoses in both the adult and pediatric populations.

Formulation Characteristics of the Cream Vehicle
Clocortolone pivalate 0.1% is formulated in a cream containing three ingredients that assist in maintenance of SC permeability barrier integrity. These ingredients are white petrolatum (occlusive), mineral oil (humectant), and stearyl alcohol (long-chain fatty alcohol emollient).[9] In general, emollient creams improve SC permeability barrier function (epidermal barrier function), reduce transepidermal water loss (TEWL), increase SC hydration, and, in some cases, replace lipids in the intercellular region of the SC.[16] Clocortolone pivalate 0.1% cream does not contain lanolin or fragrance, both of which may be problematic in some patients, especially in those with atopic skin. This formulation also does not contain propylene glycol, which can produce cutaneous irritation or contact allergy in some patients when present in higher concentrations. Clocortolone pivalate 0.1% cream is supplied in both tubes and pump bottles, with the latter offering the advantage of delivering a consistent amount of medication with each press of the pump lever.[10]

Clinical Efficacy Data
Atopic dermatitis/eczematous dermatitis. In six parallel, double-blind, placebo-controlled trials, patients with atopic dermatitis/eczematous dermatitis were randomized to treatment with clocortolone pivalate 0.1% topical cream (total n=109) or vehicle (total n=100), applied three times daily over a duration of 14 days.[10] Outcomes after four days, seven days, and 14 days of use were based on physician (investigator) global rating of improvement and assessments of observed clinical symptomatology. According to evaluations completed by the physician investigators, a significantly higher proportion of patients in the clocortolone pivalate group than patients in the vehicle group demonstrated a good or excellent response at Days 4, 7, and 14 (Figure 2). Regarding symptomatology or adverse events noted during the study, dryness and/or skin irritation was reported by four (3.4%) patients using clocortolone pivalate 0.1% cream; dryness, skin irritation, or secondary infection was reported by 11 (10.4%) patients using vehicle. No systemic events were observed or reported in either of the study groups across all of the parallel studies (N=209).

Other inflammatory dermatoses. In two controlled clinical trials, patients with psoriasis or contact dermatitis were randomized to treatment with clocortolone pivalate 0.1% cream or vehicle.[10] At the end of each trial, significantly more patients treated with clocortolone pivalate 0.1% were rated as a good or excellent response based on physicians’ ratings of improvement (Table 2).

Pediatric patients. Clinical trials comparing clocortolone pivalate 0.1% topical cream with vehicle in atopic dermatitis/eczematous dermatitis, psoriasis, and contact dermatitis included pediatric patients (N=44).[10] The mean age of pediatric subjects was 10 years (range 3–14 years). Clocortolone pivalate 0.1% cream was efficacious for the majority (75%) of the pediatric patients in these trials (Table 3). No adverse events occurred in either treatment group. In an open-label study of clocortolone pivalate 0.1% topical cream, 5 of 39 pediatric patients experienced dryness.[10]

Facial dermatoses. In the clinical trials investigating the use of clocortolone pivalate 0.1% cream for atopic dermatitis or seborrheic dermatitis, patients with facial involvement were included in these trials (n=147). Efficacy, tolerability, and safety results were consistent with the overall performance that has been discussed with clocortolone pivalate 0.1% cream for these disorders. In these trails, tolerability and safety were favorable in subjects applying the medication to facial skin when affected. No cases of atrophy, hypopigmentation, or striae were reported.[10]

In another report, patients with facial dermatoses (seborrheic dermatitis, atopic dermatitis, and psoriasis) were treated with clocortolone pivalate 0.1% topical cream three times daily for 21 days (N=38). Overall, good-to-excellent responses were noted by investigators in 66 percent of patients.[10] No cases of atrophy, striae, or telangiectasia were reported. Five cases of mild acne, one case of mild burning, and one case of mild folliculitis were noted.

Tolerability and Safety Considerations
In clinical trials inclusive of 559 treated patients, 4.4 percent experienced adverse events, most of which were local application-site reactions, such as dryness, stinging, burning, or itching.[10]

No systemic adverse effects related to treatment with clocortolone pivalate 0.1% cream have been reported.10 As noted above, in clinical trials involving 147 patients with dermatoses presenting with facial involvement, no cases of cutaneous atrophy, striae, or hypopigmentation have been reported.[10]

Use of longer durations of therapy. Most clinical trials of clocortolone pivalate 0.1% cream evaluated use over 14 to 28 days. However, patients with chronic eczematous disease or psoriasis vulgaris (n=27) underwent continued therapy for a mean of 116.4 days in order to sustain control of the signs and symptoms of the disorder. During that period, no drug-related adverse effects were documented, other than possible mild dryness reported by 1 of the 27 patients. Two patients had mildly elevated serum glutamic oxaloacetic transaminase or blood urea nitrogen levels, but these were not judged to be related to use of clocortolone pivalate. After seven months of use, no systemic, cumulative, or delayed adverse events attributable to clocortolone pivalate were reported.

As with any therapeutic approach, chronic-intermittent use of clocortolone pivalate 0.1% cream as a continued treatment for control of chronic, relapsing dermatoses (i.e., atopic dermatitis, other recurrent eczematous dermatoses, chronic plaque psoriasis, some cases of seborrheic dermatitis) necessitates use for actively present disease coupled with appropriate patient monitoring. In disorders, such as atopic dermatitis, where SC permeability function is innately compromised by the underlying disorder itself, concomitant use of proper skin care (i.e., use of gentle cleansing and moisturization) is an important component of the overall long-term management plan.

HPA axis suppression study. The effect of clocortolone pivalate 0.1% cream application on the HPA axis was investigated in an open-label study in which 10 healthy subjects applied 30g of the product twice daily for 21 days and wore whole-body plastic sweat suits for 12 hours per day. Urine 17-ketosteroid and serum cortisol levels were measured 48 hours before treatment initiation, daily for five days during the treatment phase, and once at completion of therapy. No evidence of HPA axis suppression was found.10

Cutaneous safety studies. In a double-blind study, no skin irritation was observed in 25 healthy subjects who applied clocortolone pivalate 0.1% under patch occlusion for 48 hours.[10] A 21-day double-blind study of eight healthy subjects who applied clocortolone pivalate 0.1% daily noted negligible irritancy.[10]

No phototoxicity was observed in the forearm skin of 10 healthy subjects exposed to clocortolone pivalate 0.1% topical cream.[10] Human Draize sensitization with and without ultraviolet light exposure in 25 healthy subjects who applied clocortolone pivalate 0.1% cream demonstrated no evidence of sensitization or photoallergy.[10]

Multiple clinical trials completed in study subjects with corticosteroid-responsive dermatoses, including atopic dermatitis, contact dermatitis, seborrheic dermatitis, and psoriasis vulgaris, have demonstrated that clocortolone pivalate 0.1% cream is an effective mid-potency class 4 corticosteroid with a favorable safety profile.

Combined safety analysis of clinical trials that included 559 subjects using clocortolone pivalate 0.1% cream, including a large subset with facial dermatoses, found a low incidence of adverse events and no reports of cutaneous atrophy, striae, or hypopigmentation. No evidence of HPA axis suppression or other systemic events related to the drug were reported during therapy with clocortolone pivalate 0.1% cream.

Based on data accumulated from multiple studies of patients with a variety of corticosteroid-responsive dermatoses, clocortolone pivalate 0.1% cream should be considered a viable therapeutic option for such patients when the clinician wishes to treat with a mid-potency TC.

The cream vehicle that is used is adaptable to skin that is eczematous and/or prone to contact irritancy or allergy, including in atopic skin. This is achieved through incorporation of ingredients that provide humectancy and some occlusive benefit, as well as the avoidance of lanolin, fragrances, and propylene glycol in the formulation.

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