Transitioning from brand to generic with topical products and the importance of maintaining the formulation and therapeutic profiles of the original product: focus on clocortolone pivalate 0.1% cream.

Topical corticosteroids (TCSs) are a major part of the foundation of treatment for a wide variety of eczematous and inflammatory skin disorders in both adults and children. Mid-potency TCSs represent an important category as they are often used to treat eczematous dermatoses, such as atopic dermatitis. The TCS product must effectively release the active ingredient and promote cutaneous penetration so that therapeutic activity can occur. As many topical products eventually become available as generic formulations, it is important to recognize that although the active ingredient and its concentration are the same, the vehicle excipients may differ significantly, occasionally leading to potential differences in irritancy, in allergenicity, in effects on epidermal permeability barrier function, and, possibly, in efficacy. Clocortolone pivalate 0.1% cream is a mid-potency TCS formulated in an emollient formulation that has been shown to be effective and well-tolerated in the management of several corticosteroid-responsive dermatoses. This article outlines the pharmacologic and clinical data achieved with the original brand formulation of clocortolone pivalate 0.1% cream, and discusses the establishment of an authorized generic formulation that is identical in formulation to the original brand.

A study to assess the occlusivity and moisturization potential of three topical corticosteroid products using the skin trauma after razor shaving (STARS) bioassay.

Dysfunction of the epidermal barrier is generally considered a precursor of cutaneous inflammation that can directly contribute to the pathogenesis of skin diseases, notably atopic dermatitis (AD). We also know that topical corticosteroids may actually impair the epidermal barrier by interfering with epidermal lipid synthesis. Therefore, it is important to utilize topical corticosteroids in vehicles that will help at least to enhance the already disrupted epidermal barrier in atopic dermatitis patients. Two studies of identical design were conducted to determine and compare the occlusivity and moisturizing potential of three topical corticosteroid products when applied to skin whose barrier integrity has been disrupted by dry shaving. Findings in both studies showed the clocortolone pivalate cream decreased TEWL better than non-treatment or treatment with hydrocortisone butyrate lotion. Skin surface hydration increased significantly (P<0.001) in all three treated sites, compared to the non-treated damaged control and non-treated normal skin. Clocortolone pivalate cream increased skin surface hydration significantly (P<0.001) better than hydrocortisone butyrate lipocream or hydrocortisone butyrate lotion. These studies showed that clocortolone pivalate cream enhances barrier function by providing occlusion. While understanding of the structure and function of the stratum corneum (SC) and epidermal barrier function has evolved tremendously over the last several decades, and especially over the last 15 years,1 confusion and misinformation still persist. Dysfunction of the epidermal barrier is generally considered a precursor of cutaneous inflammation that can directly contribute to the pathogenesis of skin diseases, notably atopic dermatitis (AD).2,3 Topical steroids are standard of care in treatment of atopic dermatitis. However, we also know that topical corticosteroids may actually impair epidermal barrier by interfering with epidermal lipid synthesis.4,5 In addition to that, various penetration enhancers in the topical steroid formulations also contribute to the impairment of the epidermal barrier.4 Therefore, it is important to utilize topical corticosteroids in vehicles that will help at least to enhance the already disrupted epidermal barrier in atopic dermatitis patients. In this regard, these studies were designed to determine the hydrating effects of clocortolone pivalate cream 0.1% (Cloderm Cream, Promius Pharma).

Visual outcome of patients following NAION after treatment with adjunctive fluocortolone.

PURPOSE: Nonarteriitic anterior ischemic optic neuropathy (NAION) is a leading cause of sudden loss of vision, which particularly affects individuals older than 50 years. Up to now there is no treatment that is effective at reversing or limiting the course of this disease. To study the short- and long-term effects of fluocortolone (FC) on the visual outcome of patients with acute NAION compared to standard treatment with pentoxifylline (PFX). METHODS: A prospective, quasirandomized intervention trial was conducted involving 60 patients with acute-onset NAION. Patients in the comparison (PFX) group (n = 30) received PFX intravenously and per os for 7 days and then per os for a further 6 months, which is a standard treatment. Patients in the intervention (PFX + FC) group (n = 30) received the standard treatment plus 1 mg/kg FC for 5 days, with a subsequent stepwise dose reduction over time. As a primary outcome measure, the best corrected visual acuity (BCVA) was determined at the initial baseline consultation (i.e., before treatment), and at 3 days and 6 months after therapy onset. Visual field (VF) was analyzed using standard automated perimetry at the initial baseline examination and at 6 month after therapy onset. Changes in BCVA and visual field in the PFX and PFX + FC groups were compared and analyzed statistically. RESULTS: Treatment with FC resulted in a significant improvement in BCVA. Patients receiving FC in acute NAION were more likely to experience improvement and less likely to have worsened visual acuity (mean BCVA scores: at baseline, 0.22; after 3 days and 6 months of treatment, 0.33 and 0.43, respectively) than PFX patients (mean BCVA scores: at baseline, 0.33; after 3 days and 6 months of treatment, 0.33 and 0.28, respectively; p < 0.002 and 0.001). The beneficial effect was even more marked 6 months after therapy onset. Remarkably, patients with a baseline BCVA score of >=0.05 profited significantly by FC treatment (p < 0.006 and 0.001), whereas those with a baseline BCVA score of <0.05 did not (p < 0.4). PFX did not improve BCVA. However, VF did not show any significant improvement due to FC therapy. CONCLUSION: This is the first prospective randomized intervention trial that demonstrates the distinctive beneficial effects of FC in terms of the visual outcome of patients with NAION compared to standard treatment with only PFX. FC significantly improves both short- and long-term visual acuity in patients with moderate BCVA impairment due to recent onset of NAION, while VF did not show any significant improvement; however, PFX did neither enhance BCVA nor VF. Administration of FC should be seriously considered for the treatment of NAION whenever there are no contraindications.

Clocortolone pivalate: a topical corticosteroid with a unique structure.

As the accumulated clinical evidence and experience to be presented in the next several pages demonstrate, the unique engineering of the clocortolone pivalate molecule balances potency with documented efficacy and a favorable safety profile. Clocortolone pivalate 0.1% cream is a well-formulated and versatile therapeutic option to consider for many of our patients with steroid-responsive dermatoses.

The role of a midpotency topical corticosteroid and the clinical relevance of formulation characteristics in the management of commonly encountered eczematous and inflammatory dermatoses in adults and children: focus on the pharmacologic properties of clocortolone pivalate 0.1% cream.

Midpotency topical corticosteroids (TCSs) are frequently used for the treatment of common eczematous and inflammatory skin disorders in both adults and children. There are several commercially available products in this category, and many vehicles and formulations for the clinician to choose from. Clocortolone pivalate 0.1% cream is a midpotency TCS formulated in an emollient formulation that has been shown to be effective and well tolerated when used appropriately in the management of several corticosteroid-responsive dermatoses. This article discusses the physiochemical properties of the compound; the characteristics of its emollient cream formulation; the functions of individual excipients; and the efficacy, tolerability, and safety data supporting its use in adults and children, including for facial involvement.

Clinical results of 123 femtosecond laser-assisted penetrating keratoplasties.

BACKGROUND: Postoperative astigmatism following penetrating keratoplasty is a major problem after corneal transplantation. The main goal of new trephination techniques such as femtosecond laser or excimer-laser trephination is to improve refractive and visual outcomes. The femtosecond laser technique makes profiled corneal trephinations such as the top hat or mushroom profile possible. We present the postoperative outcome of femtosecond laser-assisted penetrating keratoplasties. METHODS: We performed 123 femtosecond laser-assisted penetrating keratoplasties in 119 patients. The main outcome measures were intraoperative specifics, astigmatism, and irregularity in Orbscan corneal topography, as well as the occurrence of immune reactions and side-effects. RESULTS: All sutures have been removed in 49 of these 123 eyes. Their mean follow-up was 13.9 ± 4.5 months. Time to complete suture removal (n = 49) was 12.0 ± 3.7 months in the mushroom group and 9.8 ± 2.1 months in the top hat group. Mean astigmatism in Orbscan topography was 6.4 ± 3.0 diopters in the mushroom and 5.8 ± 4.6 diopters in the top hat group (all sutures out). CONCLUSIONS: Femtosecond laser-assisted penetrating keratoplasty is a safe surgical technique. Due to the steps in profiled trephinations, the wound area is larger and theoretically the wound healing is, thus, faster and more stable. Complete suture removal is possible at an earlier time point compared to conventional penetrating keratoplasty. However, refractive results are not superior to those following conventional trephination.

The treatment of inflammatory facial dermatoses with topical corticosteroids: focus on clocortolone pivalate 0.1% cream.

OBJECTIVE: Study results evaluating the efficacy and safety of clocortolone pivalate 0.1% cream in the treatment of adults, young children, and infants with inflammatory facial dermatoses are reported in this article. Clocortolone pivalate 0.1% cream, indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, is a mid-potency topical corticosteroid (Class 4) that has been studied and used extensively to treat a variety of corticosteroid-responsive inflammatory dermatoses, many of which often involve facial skin in both adults and children. METHODS: Clocortolone pivalate 0.01% cream was applied to affected facial skin in subjects presenting with seborrheic dermatitis, contact dermatitis, atopic dermatitis, or psoriasis. Application was completed three times daily for 21 days. Assessments of erythema, edema, transudation, lichenification, scaling, pruritus and/or pain were completed at baseline and Days 4, 7, 14, and 21. Overall therapeutic response was assessed at all follow-up visits. Forty-nine subjects were entered, ranging in age from 1 month to 88 years of age. Thirty-eight subjects completed the studies, with 11 subjects lost to follow-up after the first visit. Individuals between the ages of 13 and 19 years were pre-emptively excluded to avoid potential application of a corticosteroid to acne-affected or acne-prone skin. RESULTS: Treatment with clocortolone pivalate 0.1% cream resulted in decreases in erythema, edema, transudation, lichenification, scaling, and pruritus/pain in 76% of treated study subjects. The overall therapeutic response in approximately two-thirds of the subjects (68%) was rated as good to excellent. There were 7 adverse events noted over the course of the study that were judged to be related to treatment, all of which were cutaneous and localized to the site of application (acneiform eruptions, burning, and folliculitis). CONCLUSION: Clocortolone pivalate 0.1% cream was effective in relieving the signs and symptoms of corticosteroid-responsive inflammatory dermatoses involving facial skin, including seborrheic dermatitis, contact dermatitis, atopic dermatitis, and psoriasis. Overall, the safety profile was favorable and devoid of any treatment-related serious adverse events.

Identification and characterization of three impurities in clocortolone pivalate.

Clocortolone pivalate is a synthetic corticosteroid that can be used to cure corticosteroid-responsive dermatoses. Three previously unknown impurities detected by HPLC were isolated by semi-preparative LC. Based on the NMR and MS spectral data, these were identified as (6R,9R,16R)-9-chloro-6ß-fluoro-11ß,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate (Impurity I), (9R,16R)-9-chloro-4-fluoro-11ß,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate (Impurity II) and (9R,16R)-9-chloro-6α-fluoro-11ß,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-11,21-dipivalate (Impurity III). The possible mechanism of the formation of the impurities is discussed.

A retrospective study on the efficacy of total absorbed orbital doses of 12, 16 and 20 Gy combined with systemic steroid treatment in patients with Graves' orbitopathy.

BACKGROUND: Graves' disease (GD) is an autoimmune disease that typically affects the thyroid gland. Thirty to sixty percent of patients also suffer from orbital inflammation. Retrobulbar radiotherapy for Graves' orbitopathy (GO) has been used for decades, though there is no direct evidence for the influence of dose and fractionation schedules on various signs and symptoms. Indeed, optimal fractionation schedules and recommended total irradiation doses are still a matter of discussion. Our aim was to investigate treatment efficacy of retrobulbar irradiation for GO at different total absorbed doses and fractionation schedules. METHODS: A retrospective evaluation of 129 patients who were examined before, as well as 6-8 months after irradiation with different treatment schedules at eight radiotherapeutic departments. Total absorbed doses were 12, 16, or 20 Gy. All patients were additionally treated with systemic application of corticosteroids. Treatment efficacy was evaluated through assessment of proptosis, horizontal and vertical ocular motility and of clinical activity (CAS). Overall group and individual responses were evaluated. Treatment response was defined as inactivation of GO, reduction of proptosis by at least 2 mm, improvement of motility by > or = 8 degrees or unchanged normal parameters. RESULTS: Prior to irradiation, neither age, disease duration, gender distribution, smoking behavior or serologic parameters, nor clinical activity or severity stages varied significantly between groups. Neither did outcome measures, except proptosis, differ significantly. Retrobulbar irradiation led to inactivity of GO in approximately 80% of patients, with no significant group difference. After irradiation with 16 and 20 Gy, vertical motility improved in a significantly higher percentage of patients than after irradiation with 12 Gy. Median improvement of vertical motility in responding patients was excellent in all groups (15 degrees at 12 Gy, 10 degrees at 16 Gy, 10 degrees at 20 Gy). Horizontal motility did not change significantly. CONCLUSION: If the aim of retrobulbar irradiation is primarily to reduce soft-tissue signs, lower doses are sufficient. If a patient also suffers from dysmotility, doses exceeding 12 Gy may be more effective.

[Retinochoroidopathy after intravitreal anti-VEGF treatment]. / Retinochoroidopathie nach intravitrealer Anti-VEGF-Behandlung.

A 74-year-old man presented with persistent metamorphopsias of the right eye 2 weeks after intravitreal injection of bevacizumab to treat choroidal neovascularization due to exudative age-related macular degeneration. The diagnosis reached was retinochoroiditis as an occult manifestation of sarcoidosis, possibly resulting from an intravitreal injection of bevacizumab. The patient received a prescription for 100 mg Ultralan to be taken daily for 3 days and then tapered in 3 day steps. During the further course no deterioration of the condition was observed.

Adherence to clocortolone pivalate cream 0.1% in a pediatric population with atopic dermatitis.

Topical corticosteroids are first-line treatments for atopic dermatitis (AD) and their efficacy is well-established in randomized controlled clinical trials. When corticosteroids fail in clinical practice, it often is attributed to nonresponse. However, poor adherence also should be considered. With the advent of electronic monitoring systems, objective data on adherence can be obtained. The purpose of this study was to determine both self-reported and actual adherence to clocortolone pivalate cream 0.1% in the treatment of AD in a pediatric population. Six participants completed the 4-week study. Self-reported adherence was significantly higher than objectively measured adherence (P = .01). In general, adherence was best during the first week of treatment and tapered off thereafter. Clocortolone pivalate cream 0.1% was generally effective, with rapid improvement over the first week of treatment, even when adherence was limited. This study was limited by the small sample size and the failure of 2 participants to complete the study. Patients overestimate their adherence behavior. While some patients are adherent to treatment, others rapidly discontinue their use of medication over time. Midpotency topical corticosteroids such as clocortolone pivalate cream 0.1% are highly effective treatments for AD. Poor adherence should be considered when AD is not responding to topical corticosteroid treatment.

[Sudden hearing loss in a patient with a 3-mm acoustic tumor]. / Uç milimetrelik akustik tümörü olan bir hastada ani isitme kaybi.

Sudden sensorineural hearing loss (SNHL) accounts for 1% of all SNHL cases. It has been reported that acoustic neuroma may be present up to 47.5% of patients with sudden SNHL. A 55-year-old man presented with sudden hearing loss in his left ear of 45-day history. Audiologic and transient evoked otoacoustic emission tests showed near-total hearing loss and absence of emissions in the left ear, respectively. Electronystagmography showed left canal paralysis and lack of response to the Kobrak test. The interpeak interval I-V latency and interaural amplitude differences in wave V latency were prolonged in auditory brainstem response. Computed tomography showed an increase in the diameter of the left internal acoustic canal, and magnetic resonance imaging (MRI) revealed an intracanalicular mass, 3 mm in size, originating from the left cochlear nerve. Another mass (18x17 mm) was detected that filled the right pontocerebellar cistern, suggesting a meningioma, but this was not thought to exert an obvious shift effect contributing to the development of left-sided hearing loss. Despite treatment with a tapered course of fluocortolone for 18 days the patient's hearing level did not change. He was included in a follow-up with MRI at six-month intervals.

Oral and intralesional steroid therapy in giant cell granuloma.

Giant cell granulomas account for 7% of all benign tumors of the jaw. They are commonly seen as asymptomatic masses. A 4-year-old boy with an exophitic, crusty, hemorrhagic mass on the anterolateral region of the right maxilla was referred to our department. Pathological examination was reported as giant cell granuloma. A mixture of prednisolone, lidocaine and adrenaline was injected intralesionally once a week and oral fluocortone was added to this therapy. A limited surgery could be performed. Intralesional prednisolone and systemic fluocortone therapy seems to be effective, as the lesion stopped growing and increase in bony structures was observed radiologically.

An open prospective pilot study on the use of rapamycin after penetrating high-risk keratoplasty.

BACKGROUND: The purpose of this study was to prove efficacy and safety of systemic immunosuppression with rapamycin following penetrating high-risk keratoplasty. Rapamycin has shown its immunosuppressive potential in the rat keratoplasty model and is a component of several immunosuppressive protocols after solid organ transplantation. In this pilot study, we compared the efficacy and safety of rapamycin and mycophenolate mofetil (MMF). METHODS: Ten patients (group 1) undergoing high-risk keratoplasty were included in this study, receiving rapamycin as postoperative immunoprophylaxis. Rapamycin was administered orally once daily (blood trough level 4-10 ng/ml) for 6 months. Thereafter, it was tapered over 2 weeks. The control group (group 2) consisted of 24 patients who received 1000 mg MMF twice daily for 6 months. All of the patients received postoperative medication with fluocortolone 1 mg/kg/day (tapered over 3 weeks) and prednisolone acetate eyedrops 5 times per day (tapered over 5 months). RESULTS: Mean follow-up of all patients (n=34) was 739 days. No immune reaction was observed in groups 1 and 2 during the first 6 months under immunosuppression. Two immune reactions occurred in group 1, and five in group 2 within a 2-year follow-up. All of the immune reactions were reversible. The side effects observed in both groups were mostly reversible. CONCLUSIONS: Rapamycin and mycophenolate mofetil seem to be similarly efficacious in preventing immune reactions after high-risk keratoplasty, as long as they are administered. However, we observed a broad spectrum of side effects from rapamycin.

Topical FK506 as immunoprophylaxis after allogeneic penetrating normal-risk keratoplasty: a randomized clinical pilot study.

The purpose of this study was to evaluate for the first time the efficacy and safety of topical FK506 in patients undergoing penetrating normal-risk keratoplasty in a prospectively randomized clinical trial. Twenty patients were treated with FK506 0.06% three times per day for 6 months postoperatively. An additional 20 patients received five drops of prednisolone acetate 1% tapered within 6 months. All patients received 1 mg/kg bodyweight/day of systemic fluocortolon tapered within 3 weeks postoperatively. Clear graft survival, ratio of immune reactions and side effects were the main outcome measures. One year postoperatively all patients of the FK 506 group were free from immune reactions, in contrast to 84% in the steroid group (Kaplan-Meier values; P = 0.9 in the log rank test). None of the patients developed irreversible graft failure so far. In eight patients of the FK506 group premature withdrawal of the drug was deemed appropriate because of local side effects. FK506 might turn out to become an effective immunoprophylaxis in subjects undergoing penetrating normal-risk keratoplasty. Local discomfort should be further reduced.

[Ranking of systemic steroids after normal-risk keratoplasty. Results of a randomized prospective study]. / Stellenwert der systemischen Steroidtherapie nach Normalrisikokeratoplastik. Eine randomisierte prospektive Pilotstudie.

BACKGROUND: The aim of this study was to evaluate the efficacy of sole application of topical steroids after normal-risk keratoplasty. PATIENTS AND METHODS: This randomized prospective clinical study assessed 40 patients who had undergone penetrating normal-risk keratoplasty. Twenty patients were treated exclusively with prednisolone acetate 1% eye drops 5x/day for 6 months postoperatively. Another 20 patients additionally received systemic fluocortolone 1 mg/kg body weight per day tapered within 3 weeks postoperatively. The main outcome measures included clear graft survival, ratio of graft rejection, and side effects. RESULTS: The mean postoperative follow-up was 18+/-9 months. Three graft rejections were observed in the group receiving only topical steroids. Two graft rejections were observed in the group administered combined systemic and topical steroid therapy. None of the patients has developed irreversible graft failure so far. CONCLUSION: Sole topical steroid application seems to be an effective immune prophylaxis in patients undergoing penetrating normal-risk keratoplasty.

Clinical results of anti-inflammatory therapy in Graves' ophthalmopathy and association with thyroidal autoantibodies.

OBJECTIVE: Graves' ophthalmopathy (GO) is clinically associated with autoimmune thyroid disease, and autoantibodies to thyroidal antigens, especially to the TSH-receptor (TRAb), might be involved in the disease process. While there is mounting evidence that TRAb are associated with GO at the onset of the disease, so far no studies have looked at the association between thyroidal autoantibodies and the clinical outcome of GO therapy. The aim of this retrospective study was to evaluate whether TSH binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) are still associated with the clinical activity and severity of GO after the completion of anti-inflammatory therapy. In addition, we wanted to elucidate whether thyroid peroxidase (TPO) or thyroglobulin (TG) autoantibodies (TPOAb and TGAb) are in any way related to GO. DESIGN PATIENTS AND MEASUREMENTS: Clinical activity score (CAS) and the severity of GO (modified NOSPECS score) were assessed in 108 patients with GO after steroid therapy and, if indicated, orbital irradiation. Patients were grouped according to their clinical presentation and autoantibody levels (TBII, TSAb, TPOAb and TGAb) were measured. After therapy for hyperthyroidism, all patients were clinically euthyroid but showed clear heterogeneity for GO 4-12 months after the end of anti-inflammatory therapy. Fifty-two patients had inactive GO, 41 had moderately active and 15 still had very active (non-responsive) GO. Concerning severity, 27 patients had mild GO, 64 moderately severe and 17 severe GO. RESULTS: TBII titres were still positive in 14 (93%) of 15 patients in the non-responsive group (CAS > 6) compared to 22 (42%) of 52 patients (P < 0.001) with post-therapeutic inactive GO (CAS