Application Site Adverse Events Research Articles

Pharmacologic properties and results of a clinical study of oxybutynin hydrochloride lotion (APOHIDE® Lotion 20%) as a novel treatment for primary palmar hyperhidrosis

APOHIDE® Lotion 20% is a topical agent for treating primary palmar hyperhidrosis that contains the active ingredient oxybutynin hydrochloride. Oxybutynin hydrochloride has anticholinergic effects and inhibits sweating by binding to the M3 receptor, a subtype of the muscarinic acetylcholine receptor, in eccrine sweat glands. The clinical response to oxybutynin hydrochloride treatment also involves N-desethyloxybutynin, an active metabolite of oxybutynin. A clinical study in Japanese patients with primary palmar hyperhidrosis showed superiority of APOHIDE® Lotion 20% over placebo, i.e., there were significantly more responders (i.e., patients with a reduction in sweat volume ≥50% from baseline) in the APOHIDE® Lotion 20% group (APOHIDE® Lotion 20% group: 52.8%, placebo group: 24.3%; treatment difference: 28.5%; P < 0.001, Fisher's exact test). This and other clinical studies reported some adverse events (AEs) associated with the drug's anticholinergic effects and some application site AEs, but most of the AEs were mild. Clinical response did not decrease with long-term (52-week) treatment, and only a few patients (2 of 125) discontinued treatment because of AEs. Taken together, study results indicate that APOHIDE® Lotion 20% may be an effective and safe new treatment option for patients with primary palmar hyperhidrosis.

Roflumilast Cream 0.3% in Patients With Chronic Plaque Psoriasis: Individual Patient PASI and PASI-HD Responses: Pooled DERMIS-1 and DERMIS-2 Phase 3 Trials

Background: Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 inhibitor approved as a nonsteroidal, once-daily treatment for patients with plaque psoriasis. Pooled efficacy and safety results from two Phase 3 clinical trials (DERMIS-1 and DERMIS-2) have been presented previously. The Psoriasis Area and Severity Index (PASI) is used to assess the severity of plaque psoriasis in clinical trials; however, PASI is not precise when the area of involvement is &lt;10% of a given anatomic region. A modified version of the PASI, the PASI-high discrimination (PASI-HD), allows more precise assessment of psoriasis in body regions where &lt;10% area is affected. We present individual patient responses using PASI and PASI-HD.&#x0D; Methods: Patients aged ≥2 years with at least mild plaque psoriasis involving 2-20% body surface area were randomized 2:1 to apply roflumilast cream 0.3% or vehicle cream once daily for 8 weeks. The primary efficacy endpoint was Investigator Global Assessment (IGA) Success (score of Clear or Almost Clear plus ≥2-grade improvement from baseline) at Week 8. PASI and PASI-HD were used to measure disease severity; individual patient PASI and PASI-HD responses were plotted graphically. Safety and tolerability were also evaluated and were reported previously.&#x0D; Results: Roflumilast- and vehicle-treated patients had similar baseline demographic and disease characteristics. At Week 8, statistically significantly more roflumilast- than vehicle-treated patients achieved IGA Success (39.9% vs. 6.5%; P&lt;0.0001). Statistically significant differences favoring roflumilast were observed at Week 8 for percentages of patients achieving a 50% reduction in PASI (72.1% vs. 25.5%; P&lt;0.0001), 75% reduction (40.3% vs. 6.5%, P&lt;0.0001), 90% reduction (19.7% vs 2.3%; P&lt;0.0001), and 100% reduction (12.3% vs 0.8%; P&lt;0.001). Likewise, statistically significant differences favoring roflumilast were observed at Week 8 for percentages of patients achieving 50% reduction in PASI-HD (79.4% vs. 33.1%; P&lt;0.0001), 75% reduction (59.9% vs. 17.9%, P&lt;0.0001), 90% reduction (39.9% vs 9.1%; P&lt;0.0001), and 100% reduction (12.3% vs 0.8%; P&lt;0.0001). Roflumilast cream demonstrated low rates of application-site adverse events (AEs), treatment-related AEs, and discontinuations due to AEs, comparable to vehicle. At the first application of roflumilast cream 0.3% (day 1), 96% of patients reported no or mild sensation, increasing to 99% of patients at Weeks 4 and 8.&#x0D; Conclusions: Roflumilast cream 0.3% provided greater improvement in IGA Success, PASI, and PASI-HD versus vehicle with favorable safety and tolerability in patients with psoriasis in two Phase 3 trials. PASI-HD provided higher discrimination of effects of treatment in areas with &lt;10% involvement than the traditional PASI.&#x0D; ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389&#x0D; Financial Disclosures: Arcutis Biotherapeutics, Inc.

Roflumilast Cream 0.15% in Patients with Atopic Dermatitis: Individual Patient Response from the Pooled INTEGUMENT-1 and INTEGUMENT-2 Phase 3 Trials

Introduction: Roflumilast cream 0.15% is a highly selective phosphodiesterase 4 inhibitor under investigation as a once-daily, nonsteroidal treatment for atopic dermatitis (AD). Pooled safety and efficacy results of two Phase 3 clinical trials (INTEGUMENT-1 and INTEGUMENT-2) in patients with AD have been presented previously. Here we present individual patient responses on the Eczema Area and Severity Index (EASI), which is used to assess disease severity in clinical trials. Methods: INTEGUMENT-1 and INTEGUMENT-2 were identical, randomized, double-blind, vehicle-controlled, 4-week trials of once-daily roflumilast cream 0.15% in patients aged ≥6 with AD (body surface area [BSA] affected: ≥3%). Patients were randomly assigned 2:1 to roflumilast cream 0.15% or vehicle cream. The primary efficacy endpoint was Validated Investigator Global Assessment for AD (vIGA-AD) Success (score of 0 [Clear] or 1 [Almost Clear] plus ≥2-point improvement from baseline, assessed on a five-point scale ranging from 0 to 4 [Severe]) at Week 4. EASI was assessed as a secondary endpoint. Safety and tolerability were also evaluated. Results: In total, 884 patients received roflumilast 0.15% cream and 453 patients received vehicle cream. Baseline characteristics and demographics were similar between treatment groups. Significantly more roflumilast- than vehicle-treated patients achieved vIGA-AD Success (31.3% versus 14.1%; P&lt;0.0001) and vIGA-AD of Clear or Almost Clear (41.1% vs. 21.4%; P&lt;0.0001) at Week 4. Roflumilast treatment significantly improved itch by 24 hours after first application (P&lt;0.0001). At the first post-treatment timepoint evaluated (Week 1), 84.9% of roflumilast-treated patients had a measurable improvement in EASI. By Week 4, 91.5% of patients had a measurable improvement in EASI. Differences favoring roflumilast were also observed at Week 4 for percentages of patients achieving a 50% reduction in EASI (69.2% vs. 44.4%; P&lt;0.0001), 75% reduction (44.5% vs. 21.2%, P&lt;0.0001), 90% reduction (22.4% vs 8.6%; P&lt;0.0001), and 100% reduction (9.8% vs 4.8%; P&lt;0.002). Roflumilast cream had low rates of application-site adverse events (AEs), treatment-related AEs, and discontinuations due to AEs, comparable with vehicle. On local tolerability assessments, &gt;95% of investigators reported no evidence of irritation at any time point and &gt;90% of patients reported no or mild sensation after applying roflumilast cream on patient-rated local tolerability assessments. Conclusions: Roflumilast cream 0.15% provided greater improvement in vIGA-AD Success, vIGA-AD of Clear or Almost Clear, itch, and EASI versus vehicle in patients with AD in two Phase 3 trials. Among patients treated with roflumilast cream 0.15%, 91.5% demonstrated an improvement in EASI score by Week 4. Safety and tolerability were favorable, with &gt;90% of roflumilast- and vehicle-treated patients reporting no or mild sensation at the application site at any timepoint. Sponsored by Arcutis Biotherapeutics, Inc. ClinicalTrials.gov Identifiers: INTEGUMENT-1 [NCT04773587]; INTEGUMENT-2 [NCT04773600]

Roflumilast Cream 0.3% in Patients with Chronic Plaque Psoriasis: Individual Patient Response from the Pooled DERMIS-1 and DERMIS-2 Phase 3 Trials

Roflumilast cream 0.3% in patients with chronic plaque psoriasis: individual patient response from the pooled DERMIS-1 and DERMIS-2 phase 3 trials&#x0D; &#x0D; James Del Rosso1 on behalf of the authors&#x0D; &#x0D; INTRODUCTION: Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 inhibitor approved as a nonsteroidal, once-daily treatment for patients with plaque psoriasis. The efficacy and safety of the pooled results of two Phase 3 clinical trials (DERMIS-1 and DERMIS-2) in patients aged ≥2 years with plaque psoriasis have been previously presented. We present individual patient responses using the Psoriasis Area and Severity Index (PASI).&#x0D; METHODS: Patients aged ≥2 years with at least mild plaque psoriasis involving 2-20% of body surface area were randomized 2:1 to apply roflumilast cream 0.3% or vehicle cream once daily for 8 weeks. The primary efficacy endpoint was Investigator Global Assessment (IGA) Success (score of Clear or Almost Clear plus ≥2-grade improvement from baseline) at Week 8; IGA of Clear or Almost Clear was a secondary endpoint. PASI was used to measure disease severity; individual patient PASI responses were plotted graphically. Safety and tolerability were also evaluated and have been previously reported.&#x0D; RESULTS: Roflumilast- and vehicle-treated patients had similar baseline demographic and disease characteristics. At Week 8, statistically significantly more roflumilast- than vehicle-treated patients achieved IGA Success (39.9% vs. 6.5%; P&lt;0.0001) and IGA of Clear or Almost Clear (48.0% vs. 9.5%; nominal P&lt;0.0001). Statistically significant differences favoring roflumilast were observed at Week 8 for percentages of patients achieving a 50% reduction in PASI (72.1% vs. 25.5%; P&lt;0.0001), 75% reduction (40.3% vs. 6.5%, P&lt;0.0001), 90% reduction (19.7% vs 2.3%; P&lt;0.0001), and 100% reduction (12.3% vs 0.8%; P&lt;0.001). At the first post-treatment timepoint evaluated (Week 2), 85.7% of roflumilast-treated patients had a measurable improvement in PASI, increasing to 95.0% by the last timepoint (Week 8). Roflumilast cream demonstrated low rates of application-site adverse events (AEs), treatment-related AEs, and discontinuations due to AEs, comparable with vehicle. Approximately 96% of patients reported no or mild sensation after the first application of roflumilast cream 0.3%, improving to more than 99% of patients at Week 4 and Week 8, similar to vehicle.&#x0D; CONCLUSIONS: Roflumilast cream 0.3% provided greater improvement in IGA Success, IGA of Clear or Almost Clear, and PASI versus vehicle with favorable safety and tolerability in patients with psoriasis in two Phase 3 trials.&#x0D; Sponsored by Arcutis Biotherapeutics, Inc.&#x0D; ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389

Long-term study of ropinirole patch in Parkinson's disease patients with/without basal l-dopa

IntroductionA dopamine agonist patch could be an important treatment option for Parkinson's disease. This study evaluated the long-term efficacy and safety of the ropinirole hydrochloride patch. The steady state plasma ropinirole concentration was also assessed. MethodsIn a multicenter, open-label, uncontrolled study, Parkinson's disease patients with/without basal levodopa and with/without prior dopamine agonist therapy (any of these four regimens) received application of a ropinirole patch once daily for up to 52 weeks with unforced titration from 8 to 64 mg. For patients with prior dopamine agonist therapy, the initial dose of ropinirole patch was determined from the prior dopamine agonist dose by using a conversion table. ResultsMost adverse events were mild or moderate. All application site adverse events were mild, except for moderate application site erythema in one patient. In patients with prior dopamine agonist therapy, switching to ropinirole patch did not lead to a significant early increase of adverse events. A change from baseline in the UPDRS Part III total score, the primary efficacy endpoint, showed improvement until Week 16 compared with baseline, followed by little subsequent change until Week 52, indicating maintenance of efficacy. The plasma ropinirole concentration was at steady state throughout the study period and showed a dose-proportional increase. ConclusionOnce-daily application of ropinirole patch showed long-term efficacy and safety (52 weeks) for Parkinson's disease. Switching from other dopamine agonists to ropinirole patch was effective and safe. The plasma ropinirole concentration was at steady state throughout the study period and showed a dose-proportional increase.

Safety of buprenorphine transdermal system in the management of pain in older adults

ABSTRACTObjectives: To evaluate whether buprenorphine transdermal system (BTDS; Butrans®) is an option for the treatment of chronic pain in older adults.Methods: This retrospective analysis of 16 placebo- and active-controlled and uncontrolled studies (N = 6566) evaluated the safety and tolerability profile in patients exposed to BTDS and compared the safety profiles associated with BTDS treatment in older patients ≥ 65 years of age (65 to 98 years) and younger patients < 65 years of age (18 to 64 years). Safety analyses included adverse events (AEs), laboratory values, and electrocardiograms.Results: Overall, the incidence of AEs was similar in the ≥ 65 year patient cohort (N = 1715) and the < 65 year patient cohort (N = 4843) (63.8% and 61.0%, respectively). The older patient cohort experienced more constipation, peripheral edema, and urinary tract infection, but fewer application-site AEs (eg, erythema, irritation, pruritus, rash) and headaches. A statistically significant treatment-by-age interaction was observed for fall, arthralgia, and localized and non-application site-related rash, suggesting a differential increase in the risk of these events among older patients treated with BTDS that cannot be explained by age or treatment alone. A similar trend was observed for accidents and injuries, and for falls, in patients treated with both BTDS and active controls (oxycodone/acetaminophen [OXY/APAP] and hydrocodone/acetaminophen [HCD/APAP]), suggesting an opioid class effect. However, due to small sample sizes of the active control groups, a statistical test of treatment-by-age interaction could not be conducted for the active controls. The incidences of serious AEs and of clinically significant increases in liver enzymes, such as AST, ALT and bilirubin were small, regardless of age.Conclusion: BTDS appears to be a viable option for the management of pain in older adults, but the benefits need to be tempered by potential risks among older adults.

Olumacostat glasaretil, a novel topical sebum inhibitor, in the treatment of acne vulgaris: A phase IIa, multicenter, randomized, vehicle-controlled study

Olumacostat glasaretil (OG) inhibits acetyl-coenzyme A carboxylase, the enzyme responsible for the first, rate-limiting step in de novo fatty acid synthesis. OG inhibited invitro human sebocyte lipid production and reduced invivo sebaceous gland size in hamster ears. Safety and efficacy of OG 7.5% gel were evaluated in patients with moderate to severe facial acne vulgaris. Patients were randomized (1:1) to twice-daily application of OG or vehicle for 12weeks. Efficacy was measured through changes in lesion counts and improvement in acne severity scores. A total of 108 patients received OG (n=53) or vehicle (n=55); these groups had mean baseline counts of 29.7 and 28.6 inflammatory and 40.9 and 38.8 noninflammatory lesions, respectively. At week 12, OG treatment showed greater reductions from baseline in inflammatory lesions (-63.9% vs -45.9%; P=.0006) and noninflammatory lesions (-48.1% vs -28.8%; P=.0025), and more patients with greater than or equal to 2-grade improvement in investigator global assessment score (24.5% vs 7.3%; P=.0070) than vehicle. Application-site adverse events (typically mild or moderate intensity) were more common with OG. Larger trials are needed to optimize OG dosing and confirm the current results. OG was well tolerated and showed evidence of efficacy, suggesting further development is warranted.

Application site adverse events associated with the buprenorphine transdermal system: a pooled analysis

Objective: To characterize the profile of application site reactions (ASRs) for patients treated with the buprenorphine transdermal system (BTDS) in chronic pain studies.Methods: The incidences of ASRs during treatment with BTDS were examined using (a) integrated data from 16 controlled and uncontrolled Phase III chronic pain studies (N = 6566), (b) a subset of integrated data that focused on the double-blind phases of five enriched, placebo-controlled studies (n = 1806) and (c) data from an international postmarketing drug safety database. These data were compared with the ASR data reported in the full prescribing information of other transdermal patches marketed in the US.Results: Among the 6566 patients, the overall incidence of ASRs was 23.4%, of which 98.3% were mild to moderate in intensity, none were serious and 4.4% led to treatment discontinuation. Rates of severe and inflammatory ASRs were low. Among the 1806 patients, ASR rates were higher with BTDS (16.6%) than placebo transdermal system (12.7%). Among the 6566 patients, the 1806 patients, and the postmarketing data, the most common ASRs seen were pruritus, erythema and rash. Incidences of most ASRs for other selected transdermal products were 17% or lower.Conclusion: Incidence rates of ASRs in patients treated with BTDS were low and infrequently led to discontinuation. Severe and inflammatory-type ASRs were not common. The ASR profile of BTDS was comparable with those of other transdermal patches.

4 The Risk of Severe Treatment Related Adverse Events is Significantly Lower in Children Compared to Adults When Treated With Standardized Timothy Grass Allergy Immunotherapy Tablets

BackgroundAllergy immunotherapy tablets (AIT) provides a safer and more convenient alternative to subcutaneous specific immunotherapy treatment. However, severe adverse events occur infrequently. These events are rare and therefore pooled safety data from 1 phase II/III and 6 phase III clinical trials (5 in adults, 2 in children (5–17 years)) with grass AIT (Grazax, Phleum pratense 75,000 SQ-T/2800 BAU, ALK, Denmark) were analysed.MethodAll trials were randomised, double-blind, placebo-controlled multi-centre trials. Subjects suffered from grass pollen induced allergic rhinoconjunctivitis with or without asthma, had positive skin prick test and specific IgE to Phleum pratense. Subjects received once-daily sublingual treatment with grass AIT or placebo for approximately 24 weeks. The 5 adult trials comprised 2095 treated subjects (AIT = 1060, placebo = 1035) and the 2 children trials comprised 597 treated subjects (AIT = 301, placebo = 296). Adverse events were assessed by the investigator as treatment-related (possible or probable) or unlikely related and for seriousness. Application site-related events were defined as adverse events in relation to the oral cavity.ResultsIn the adult trials, 71% of AIT-treated subjects reported treatment-related adverse events compared to 24% for placebo. In the children trials the corresponding numbers were 63% for AIT and 27% for placebo. Of the AIT-treated subjects 2 children (0.7%) and 32 adults (3.0%) experienced severe treatment-related events. The odds for severe events was 4.7 times lower in children compared to adults (odds-ratio with 95% CI, 0.22 [0.025-0.85], P = 0.019). Both AIT-treated children (0.7%) and 18 (1.7%) of the AIT-treated adults experienced severe treatment-related events that were application site-related. The odds for having severe related application site adverse events was 2.6 times lower in children compared to adults (odds-ratio with 95% CI, 0.39 [0.04-1.63], P = 0.27, not statistically significant). No serious treatment-related adverse events were reported.ConclusionThis pooled analysis of over 2000 subjects in 7 clinical trials shows that the risk of experiencing severe treatment-related adverse events was significantly lower in children compared to adults when treated with of Timothy grass allergy immunotherapy tablets. This analysis provides evidence that Timothy grass AIT is an important and safe immunotherapy treatment option in children with grass pollen induced rhinoconjunctivitis.

Application site adverse events of Butrans™ (buprenorphine) transdermal system

Application site adverse events of Butrans™ (buprenorphine) transdermal system

Three Times Weekly Tacrolimus Ointment Reduces Relapse in Stabilized Atopic Dermatitis: A New Paradigm for Use

Paller AS, Eichenfield LF, Kirsner RS, et al. Pediatrics. 2008;122(6). Available at: www.pediatrics.org/cgi/content/full/122/6/e1210PURPOSE OF THE STUDY. To evaluate the safety and efficacy of intermittent topical tacrolimus as maintenance therapy in patients with moderate-to-severe atopic dermatitis.STUDY POPULATION. Subjects 2 to 15 years of age with moderate-to-severe atopic dermatitis.METHODS. Subjects underwent stabilization with either 0.05% aclometasone ointment or 0.03% tacrolimus in a double-blind fashion for 4 days, followed by twice-daily, open-label, 0.03% tacrolimus treatment for all subjects. Subjects who became “clear” or “almost clear” entered phase II (maintenance phase) and underwent double-blind, random assignment to either 0.03% tacrolimus or vehicle applied once daily, 3 times per week, for up to 40 weeks. Emollients were permitted, but corticosteroid use was prohibited; open-label tacrolimus use was permitted to treat relapses.RESULTS. A total of 206 patients were randomly assigned, and 50 subjects completed the study. There were no significant differences between groups at baseline. Aclometasone-treated patients showed more improvement in the acute phase than did tacrolimus-treated patients, and there were no differences in application-site adverse events between groups. During maintenance, tacrolimus-treated patients had a significantly greater number of disease-free treatment days, compared with vehicle-treated patients (mean: 174 vs 107 days; P = .0008), and a longer time to first relapse (median: 116 vs 31 days; P < .04).CONCLUSIONS. Long-term intermittent application of 0.03% tacrolimus to clinically normal-appearing but previously affected skin was significantly more effective than vehicle at maintaining disease stabilization in patients with moderate-to-severe atopic dermatitis. The safety profile of intermittently applied tacrolimus was similar to that of vehicle.REVIEWERS COMMENTS. Atopic dermatitis is a chronic relapsing disease. Prevention of relapse is aimed at skin hydration and avoidance of triggers. Adverse effects of topical steroids limit their long-term use and, although there are concerns that calcineurin inhibitors may carry an increased risk of malignancy, long-term data on the safety of topical calcineurin inhibitors contradict this notion. This study shows promise that intermittent application of 0.03% tacrolimus offers a novel, steroid-sparing approach to maintaining stabilization of atopic dermatitis that seems both safe and efficacious.

Fentanyl buccal tablet for the treatment of breakthrough pain in opioid‐tolerant patients with chronic cancer pain

This study assessed the long-term safety and tolerability of fentanyl buccal tablet (FBT) in opioid-tolerant patients with cancer and breakthrough pain (BTP) who were either naive to FBT or had completed 1 of 2 previous double-blind, placebo-controlled FBT studies (rollover patients). Patients who were FBT-naive underwent titration to find a successful FBT dose. Rollover patients used a previously identified successful dose of FBT. Patients who achieved a successful dose were eligible to enter a maintenance phase (>or=12 months). Safety assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory tests. Two hundred thirty-two patients were enrolled. A total of 112 entered titration; 79 identified a successful FBT dose, and 77 of these patients entered the maintenance phase along with 120 rollover patients (n = 197). AEs resulted in discontinuation of therapy for 33% of patients. The most common AEs were generally typical of opioids administered to cancer patients. All serious AEs were considered to be related to the patients' underlying conditions, except for 1 incident of FBT-related drug withdrawal syndrome. Sixty patients died after enrollment because of disease progression. Fifteen (6%) patients experienced >or=1 application-site AE, all of which were considered by investigators to be related to FBT. FBT was generally well tolerated and had a favorable safety profile in the long-term (>or=12 months) management of patients with persistent cancer pain and BTP. No unexpected AEs occurred. Safety and tolerability was similar to that observed in short-term studies.

Evolution of transdermal oxybutynin in the treatment of overactive bladder

Overactive bladder (OAB) syndrome affects millions of people worldwide. In addition to adversely affecting quality of life, the direct and indirect costs in managing patients with OAB incur a substantial financial burden on health services. Among the approved anticholinergics for treating OAB, oxybutynin is the most extensively studied drug in clinical trials. The principle metabolite of oxybutynin has a higher affinity for muscarinic receptors in salivary glands which lead to significantly high dry mouth rates. This prompted the development of alternative formulations of oxybutynin aiming to achieve better tolerability whilst sustaining efficacy. This editorial examines the efficacy and tolerability of transdermal oxybutynin (OXY-TD) in treating OAB. Articles were retrieved from PubMed between 2000 to the present day relating to OXY-TD. Data is presented from phase I-IV trials. The results from placebo-controlled trials indicate that OXY-TD is efficacious in treating patients with OAB associated with urge urinary or mixed incontinence. Systemic side effects most notably dry mouth, appear to be less with this formulation compared with oral anticholinergics. However, further study is required in different OAB populations. The main limitation appears to be related to application site adverse events such as pruritus and erythema. OXY-TD is likely to find its place as first-line pharmacotherapy in the clinicians' armamentarium in treating OAB.

Absorption profile, safety, and tolerability of a 200 μg dose of fentanyl buccal tablet (FBT) in opioid-tolerant cancer patients with or without oral mucositis

9053 Background: Fentanyl buccal tablet (FBT) is an effervescent formulation of fentanyl indicated for the management of breakthough pain in opioid-tolerant cancer patients. This open-label study investigated the absorption profile, safety, and tolerability of FBT in cancer patients with or without oral mucositis. Methods: Patients self-administered a single 200 μg dose of FBT. Pharmacokinetic assessments, oral mucosal examinations, and measurements of vital signs were performed at intervals of up to 8 hours following FBT placement. Adverse events (AEs) were monitored throughout the study. Results: 16 patients (8 with, 8 without mucositis) received FBT and completed the study. Mucositis was mild (functional/symptomatic grade 1 for 7 patients, grade 2 for 1 patient; clinical grade 1 for all patients). The absorption profile of FBT was similar in patients with and without mucositis. Mean±SD Cmax values were 1.25±0.78 ng/mL and 1.24±0.77 ng/mL in patients with or without mucositis, respectively. Maximum plasma concentrations of fentanyl were achieved rapidly, and were not significantly different in the two groups: median (range) tmax 25.0 (15.0–45.0) min in patients with mucositis, 22.5 (10.0–121.0) min in patients without (p=0.79). FBT was well tolerated; 4 patients experienced =1 treatment-emergent AE. Dizziness (mild) was reported by 1 patient in each group, and resolved. One patient in each group experienced a treatment-related AE (dizziness). There were no deaths, serious AEs, or withdrawals due to AEs. No application site AEs or changes in oral mucosal assessments were reported. Conclusions: The absorption profile of FBT was similar in patients with or without oral mucositis, which suggests that dose adjustment of FBT is not required when mild oral mucositis is present. FBT was generally safe and well tolerated, and not associated with adverse changes in the oral mucosa. Further studies in patients with grade 3–4 mucositis are warranted. No significant financial relationships to disclose.

Absorption of Fentanyl from Fentanyl Buccal Tablet in Cancer Patients With or Without Oral Mucositis

Patients with cancer, particularly those undergoing chemotherapy or radiotherapy, may develop oral mucositis. This is the first study to investigate the absorption profile of fentanyl buccal tablet (FBT) - an effervescent formulation of fentanyl indicated for the management of breakthrough pain in opioid-tolerant cancer patients - in patients with or without oral mucositis. In this open-label study, patients with or without oral mucositis self-administered a single 200 microg dose of FBT by placing the tablet between the upper gum and cheek above a molar tooth. Venous blood samples for measurement of plasma fentanyl concentrations were collected at regular intervals up to 8 hours following FBT administration. Parameters of interest included maximum plasma concentration (C(max)), time to reach C(max) (t(max)), area under the plasma concentration-time curve from time zero to 8 hours (AUC(8)), and AUC from time zero to the median t(max) (AUC(tmax)(')). Adverse events were monitored throughout the study. Oral mucosal examinations and measurements of vital signs were performed at intervals up to 8 hours following FBT administration. Sixteen patients, 8 with and 8 without oral mucositis, received FBT and completed the study. The severity of oral mucositis was mild in the patients exhibiting this condition. Median C(max) values were comparable: 1.14 ng/mL (range 0.26-2.69 ng/mL) in patients with mucositis, and 1.21 ng/mL (range 0.21-2.34 ng/mL) in patients without mucositis. The t(max) was not significantly different in the two groups: median t(max) was 25.0 min (range 15-45 min) in patients with mucositis and 22.5 min (range 10-121 min) in patients without mucositis. Median AUC(tmax') values were 0.17 ng . h/mL (range 0.04-0.52 ng . h/mL) in patients with mucositis, and 0.20 ng . h/mL (range 0.00-0.65 ng . h/mL) in patients without mucositis. The corresponding AUC(8) values were 2.05 ng . h/mL (range 1.16-3.83 ng . h/mL) and 1.55 ng . h/mL (range 0.74-3.07 ng . h/mL), respectively. FBT was generally well tolerated in this small group. No application site adverse events or changes in oral mucosal assessments were reported. The absorption profile of a single dose of FBT 200 microg was similar in patients with or without mild oral mucositis. The compound was generally well tolerated.

New Treatment Modalities for Vitiligo

The development of effective treatment modalities for vitiligo is dependent on an understanding of the events leading to depigmentation. However, the exact pathogenesis of vitiligo is still mostly unknown. Abnormalities in both humoral and cell-mediated immunity have been documented in vitiligo patients and they present a basis for using immunomodulating agents, such as corticosteroids and macrolide immunomodulators, in the treatment of vitiligo. Macrolide immunomodulators, such as tacrolimus and pimecrolimus, which can be used topically, are known as topical immunomodulators (TIMs). TIMs inhibit the action of calcineurin, and consequently inhibit T-cell activation and the production of various cytokines; this is considered the working mechanism of action of TIMs in vitiligo. Several small studies and case reports on the use of TIMs in vitiligo have been published so far. Tacrolimus achieves better results on the face and neck than on other body areas. Particular advantages of TIMs are safety in treating these areas because of lack of skin atrophy and good tolerability. The incidence of application site adverse events in vitiligo seems to be lower than in the treatment of atopic dermatitis. On the face and neck, TIMs may become a useful tool in the treatment of adults and children with vitiligo despite possibly lower efficacy than topical corticosteroids. Further, larger, controlled clinical studies are warranted to determine the definite role of TIMs as monotherapy or in combination with other modalities in the treatment of vitiligo.

Safety and Efficacy of Tacrolimus Ointment 0.1% (Protopic™) in Atopic Dermatitis: A Canadian Open-Label Multicenter Study

Most previously published trials of topical tacrolimus in atopic dermatitis were of relatively short duration and comprised a limited population with moderate-to-severe disease. The goal of the study was to evaluate the safety and efficacy over a 6-month period of tacrolimus 0.1% ointment in children and adults with a broader severity spectrum of atopic dermatitis. An open-label multicenter trial in patients 2 years and older was used. Primary safety and tolerability assessments included skin infection and application site adverse events. Efficacy parameters were body surface area involvement, pruritus score, and overall response. There were 240 patients recruited at 23 study sites. Significant improvement from baseline was noted for all efficacy endpoints in both pediatric and adult patients. Skin infections occurred in 26% of patients. Burning sensation with product application, reported by 38% of patients, was transient and of mild-to-moderate severity in the majority. Tacrolimus 0.1% ointment was safe, well tolerated, and efficacious in treatment of atopic dermatitis in children and adults over six months.

Safety and Efficacy of Tacrolimus Ointment 0.1% (Protopic™) in Atopic Dermatitis: A Canadian Open-Label Multicenter Study

Background: Most previously published trials of topical tacrolimus in atopic dermatitis were of relatively short duration and comprised a limited population with moderate-to-severe disease. Objective: The goal of the study was to evaluate the safety and efficacy over a 6-month period of tacrolimus 0.1% ointment in children and adults with a broader severity spectrum of atopic dermatitis. Methods: An open-label multicenter trial in patients 2 years and older was used. Primary safety and tolerability assessments included skin infection and application site adverse events. Efficacy parameters were body surface area involvement, pruritus score, and overall reponse. Results: There were 240 patients recruited at 23 study sites. Significant improvement from baseline was noted for all efficacy endpoints in both pediatric and adult patients. Skin infections occurred in 26% of patients. Burning sensation with product application, reported by 38% of patients, was transient and of mild-to-moderate severity in the majority. Conclusion: Tacrolimus 0.1% ointment was safe, well tolerated, and efficacious in treatment of atopic dermatitis in children and adults over six months.

Behandlung des atopischen Ekzems mit topischen Calcineurininhibitoren

During the last years the enormous progress in the understanding of the complex pathomechanisms underlying immune-mediated and inflammatory skin diseases has allowed for the development of novel therapeutic strategies. Among several drugs and biologics being investigated for dermatological use currently calcineurin inhibitors such as tacrolimus and pimecrolimus appear to be the most promising. Recently topical preparations of both tacrolimus (Protopic) and pimecrolimus (Elidel) have been developed and are available for the treatment of atopic dermatitis. Since the introduction of topical corticosteroids more than 50 years ago these novel compounds are the first major development in the topical treatment of inflammatory skin diseases. Both drugs exert a potent antiinflammatory activity and the immunosuppressive potential of pimecrolimus in particular is minimal. Both compounds are well tolerated, do not cause skin atrophy and are safe during long-term application. Application site adverse events mainly consist of a transient sensation of burning which more frequently has been observed after the use of Protopic. The risk of systemic exposure after topical application is low and usually transient. In most of the cases blood levels were below the limit of quantification and in particular Pimecrolimus blood levels never reached a range of potential toxicity. In many short- and long-term studies Protopic-ointment as well as Elidel-cream has been shown to be highly effective. The symptoms of atopic dermatitis such as pruritus and eczema were found to improve within a few days. According to first reports both Protopic and Elidel also appear to be highly effective in the treatment of other inflammatory skin diseases. Future studies will reveal whether early and perhaps prophylactic application of topical calcineurin-inhibitors may prevent flare progression and improve long-term disease control.

Safe treatment of head/neck AD with Tacrolimus ointment

background: Atopic dermatitis(AD) with head and neck involvement is common and therapeutically challenging.methods: Efficacy and safety data specific to treatment of head/neck regions with tacrolimus ointment (Protopic®) from three double‐blind, randomized, vehicle‐controlled studies are reported. A total of 631 adult and 352 pediatric patients with moderate to severe atopic dermatitis applied the vehicle, 0.03% or 0.1% tacrolimus ointment twice daily to affected areas for up to 12 weeks.results: Significant improvements from baseline to end of treatment for signs of atopic dermatitis (erythema, edema, excoriation, oozing, scaling, and lichenification) were noted for head/neck and non‐head/neck areas treated with either 0.03% or 0.1% tacrolimus ointment (p<0.001). Within each treatment group, the overall 12‐week adjusted incidence rate of application site adverse events was similar for both head/neck and non‐head/neck areas. The incidence of common adverse events such as pruritus, “skin burning”, erythema, infection, and skin tingling in head/neck areas was comparable to that observed in non‐head/neck areas within each treatment group. The overall prevalence of application site adverse events decreased rapidly during the first few days of treatment.conclusion: Tacrolimus ointment is a safe and effective treatment for atopic dermatitis on the head and neck.