EDITORIAL
Transdermal patches: how common are application site reactions and how severe are they? Linked Comment: Alva et al. Int J Clin Pract 2015; 69: 518–30.
In this issue of the International Journal of Clinical Practice, Alva et al. describe the skin reactions that were observed in patients with Alzheimer’s disease who participated in clinical trials of transdermal rivastigmine (1). This is important because many of these details are not in the manufacturer’s prescribing information for the product (2). Patients may like the rivastigmine patch because it can improve gastrointestinal tolerability, and caregivers may like it because it is relatively easy to administer (3,4). However, skin reactions are common. Alva et al. review the most frequently encountered skin reactions reported with transdermal delivery and these include erythema (localised redness), pruritus (localised itching) and oedema (localised swelling). Mostly observed are skin reactions that are classified as irritant contact dermatitis. Less common are skin reactions that may arise because of a localised allergic reaction to a constituent of the patch and categorised as allergic contact dermatitis. In one of the transdermal rivastigmine studies, approximately 25% of participants receiving the rivastigmine patch at either dose experienced application site reactions. There was no dose–response; the authors calculated a number needed to harm of 333 when comparing the incidence of skin reactions between the higher dose patch (13.3 mg/24 h) vs. the lower dose patch (4.6 mg/24 h). The rate of discontinuation as a result of application site reactions was relatively low (1.7–2.5%). The incidence of application site reactions was similar in the other reported study where a rate of 23% for application site reactions was observed in the initial open-label phase. In that study, approximately 9% of patients discontinued treatment because of application site reactions during the initial open-label treatment period. For the studies reported, the majority of patch application site reaction and irritation episodes experienced by individual patients occurred once and were of ‘mild’ or ‘moderate’ severity, with ‘severe’ reactions accounting for less than 6%. Erythema was the most commonly reported application site reaction. Application site reactions are not unique to transdermal rivastigmine. Another psychotropic transder-
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69, 5, 509–514
mal agent used in adults is the antidepressant selegiline, where application site reactions were reported in 24% of persons randomised to transdermal selegiline vs. 12% for placebo (5,6). Most of these application site reactions were mild or moderate in severity and led to study discontinuation in about 2% of selegiline-treated patients (5,6). Another agent available is transdermal rotigotine, a dopamine agonist indicated for Parkinson’s disease and moderateto-severe primary restless legs syndrome (7). At the maximum recommended dose, the incidence of application site reactions was 32% for transdermal rotigotine and 19% for placebo in patients with earlystage Parkinson’s disease, 36% for transdermal rotigotine and 13% for placebo in patients with advancedstage Parkinson’s disease, and 43% for transdermal rotigotine and 4% for placebo in patients with restless legs syndrome (7). Study discontinuation because of transdermal rotigotine application skin reactions was 2–3% for patients with Parkinson’s disease and 12% for patients with restless legs syndrome (treated with the maximum recommended dose). Alva et al. give important practical advice to minimise skin reactions, such as watching for sweat accumulation and sweat duct occlusion, making sure the skin is clean, dry and free from powder or lotions before patch application, gently removing any residual adhesive on the skin, rotating the application site daily, avoiding skin areas prone to friction from tight clothing or prone to substantial movement or skin folding (upper or lower back, or upper arm is recommended), avoiding application on irritated or broken skin (be mindful that age-related deterioration in skin integrity and mechanical strength increases the risk of skin trauma and irritation in elderly populations), and avoiding hirsute areas (and skin should not be depilated before application of a patch). Additional advice regarding skin tolerability can also be found elsewhere (8–10). In addition to work being done in psychiatry and neurology (11), a quick look at the US National Institutes of Health ClinicalTrials.gov registry reveals 685 clinical trials that include the text-word ‘transdermal’ (and 6792 studies that include the more non-specific word ‘patch’) for a variety of agents and
Skin reactions are common but usually mild in severity
509
510
Editorials
disease states. Many of these studies are ongoing and represent potentially new (or reformulated) therapeutic agents that may eventually become available commercially (12).
References 1 Alva G, Cummings JL, Galvin JE, Meng X, Velting DM. Skin reactions at the application site of rivastigmine patch (4.6 mg/24 h, 9.5 mg/24 h or 13.3 mg/24 h): a qualitative analysis of clinical studies in patients with Alzheimer’s disease. Int J Clin Pract 2015; 69: 518–30. 2 Novartis. EXELON PATCH (rivastigmine transdermal system). Prescribing information. Revised February 2015. http://www.pharma.us.novartis.com/ product/pi/pdf/exelonpatch.pdf (accessed 6 April 2015). 3 Adler G, Mueller B, Articus K. The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer’s disease under daily practice conditions. Int J Clin Pract 2014; 68: 465–70. 4 Citrome L. Formulations: friendly, fast, forgiving and flexible. Int J Clin Pract 2014; 68: 407. 5 Citrome L, Goldberg JF, Portland KB. Placing transdermal selegiline for major depressive disorder into clinical context: number needed to treat, number needed to harm, and likelihood to be
6
7
8
9
10
11
L. Citrome New York Medical College, Valhalla, NY, USA Email: [email protected]
helped or harmed. J Affect Disord 2013; 151: 409–17. Mylan. EMSAM (selegiline transdermal system). Prescribing information. Revised September 2014. http:// www.emsam.com/includes/pdf/EMSAM-PIR12_ Exhibit.pdf (accessed 6 April 2015). UCB. NEUPRO (rotigotine transdermal system). Prescribing information. Revised February 2015. http:// www.neupro.com/pdf/Neupro-PI.pdf (accessed 6 April 2015). Greenspoon J, Herrmann N, Adam DN. Transdermal rivastigmine: management of cutaneous adverse events and review of the literature. CNS Drugs 2011; 25: 575–83. Wohlrab J, Kreft B, Tamke B. Skin tolerability of transdermal patches. Expert Opin Drug Deliv 2011; 8: 939–48. Ale I, Lachapelle JM, Maibach HI. Skin tolerability associated with transdermal drug delivery systems: an overview. Adv Ther 2009; 26: 920–35. Isaac M, Holvey C. Transdermal patches: the emerging mode of drug delivery system in psychiatry. Ther Adv Psychopharmacol 2012; 2: 255–63.
12 Di Filippo P. Transdermal/transmucosal drug delivery. New technologies and outsourcing opportunities. Contract Pharma 2013; Jan–Feb: 54–7. http://www. contractpharma.com/issues/2013-01/view_features/ transdermaltransmucosal-drug-delivery/ (accessed 6 April 2015).
Disclosures No external funding or writing assistance was utilised in the production of this editorial. In the past 36 months, Leslie Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Forest, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant. doi: 10.1111/ijcp.12668
EDITORIAL
Reduction of angiotensin inhibition in older CKD patients with heart failure led to improved renal and mortality outcomes – the results of a Spanish open RCT
Reduction of angiotensin inhibition in older CKD patients with heart failure could be beneficial
We read with fascination and heightened interest the recent reported open randomised control trial that compared the impact of a 50% reduction in angiotensin inhibition in the intervention group of older chronic kidney disease (CKD) patients with heart failure and anaemia, mean age 78 years, on renal function, anaemia and mortality outcomes vs. a control group (1). Pita-Fernandez et al. after 3 months, demonstrated improved haemoglobin levels from 10.62 to 11.47 g/dl, improved creatinine clearance from 32.5 ml/min/1.73 m2 BSA to 42.9 ml/min/1.73 m2 BSA following a simultaneous decrease in serum creatinine from 1.98 to 1.68 mg/dl, and reduced C-reactive protein when compared with controls where the admission dose of angiotensin inhibition was continued (1). This study showed that the global survival rate was 97.9% after 3 months, 80.9% after 6 months and 60.8% after 12 months. Survival in the intervention group vs. the control group was 86.7% vs. 75%
after 6 months, and 69.3% vs. 50% after 12 months (1). Overall, the risk of death was reduced by 43% in the intervention group vs. the control group (1). Furthermore, the clinical relevance of this intervention was highlighted by the demonstration that the relative risk reduction was 0.43 at 6 months and 0.36 at 12 months, whereas the number needed to treat was 10, after 6 months of follow-up, and 6, after 12 months of follow-up in the intervention group (1). It is common knowledge that as a result of the differential physiological effects of angiotensin II on the afferent and efferent glomerular arterioles, angiotensin inhibition generally results in greater efferent glomerular arteriolar dilatation than afferent glomerular arteriolar dilatation, thus resulting in reduced intraglomerular pressure, therefore resulting in an obligatory increase in serum creatinine (2–7). Thus, in the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) Trial, a randomised trial that ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69, 5, 509–514
Transdermal patches: how common are application site reactions and how severe are they? Linked Comment: Alva et al. Int J Clin Pract 2015; 69: 518–30.
In this issue of the International Journal of Clinical Practice, Alva et al. describe the skin reactions that were observed in patients with Alzheimer’s disease who participated in clinical trials of transdermal rivastigmine (1). This is important because many of these details are not in the manufacturer’s prescribing information for the product (2). Patients may like the rivastigmine patch because it can improve gastrointestinal tolerability, and caregivers may like it because it is relatively easy to administer (3,4). However, skin reactions are common. Alva et al. review the most frequently encountered skin reactions reported with transdermal delivery and these include erythema (localised redness), pruritus (localised itching) and oedema (localised swelling). Mostly observed are skin reactions that are classified as irritant contact dermatitis. Less common are skin reactions that may arise because of a localised allergic reaction to a constituent of the patch and categorised as allergic contact dermatitis. In one of the transdermal rivastigmine studies, approximately 25% of participants receiving the rivastigmine patch at either dose experienced application site reactions. There was no dose–response; the authors calculated a number needed to harm of 333 when comparing the incidence of skin reactions between the higher dose patch (13.3 mg/24 h) vs. the lower dose patch (4.6 mg/24 h). The rate of discontinuation as a result of application site reactions was relatively low (1.7–2.5%). The incidence of application site reactions was similar in the other reported study where a rate of 23% for application site reactions was observed in the initial open-label phase. In that study, approximately 9% of patients discontinued treatment because of application site reactions during the initial open-label treatment period. For the studies reported, the majority of patch application site reaction and irritation episodes experienced by individual patients occurred once and were of ‘mild’ or ‘moderate’ severity, with ‘severe’ reactions accounting for less than 6%. Erythema was the most commonly reported application site reaction. Application site reactions are not unique to transdermal rivastigmine. Another psychotropic transder-
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69, 5, 509–514
mal agent used in adults is the antidepressant selegiline, where application site reactions were reported in 24% of persons randomised to transdermal selegiline vs. 12% for placebo (5,6). Most of these application site reactions were mild or moderate in severity and led to study discontinuation in about 2% of selegiline-treated patients (5,6). Another agent available is transdermal rotigotine, a dopamine agonist indicated for Parkinson’s disease and moderateto-severe primary restless legs syndrome (7). At the maximum recommended dose, the incidence of application site reactions was 32% for transdermal rotigotine and 19% for placebo in patients with earlystage Parkinson’s disease, 36% for transdermal rotigotine and 13% for placebo in patients with advancedstage Parkinson’s disease, and 43% for transdermal rotigotine and 4% for placebo in patients with restless legs syndrome (7). Study discontinuation because of transdermal rotigotine application skin reactions was 2–3% for patients with Parkinson’s disease and 12% for patients with restless legs syndrome (treated with the maximum recommended dose). Alva et al. give important practical advice to minimise skin reactions, such as watching for sweat accumulation and sweat duct occlusion, making sure the skin is clean, dry and free from powder or lotions before patch application, gently removing any residual adhesive on the skin, rotating the application site daily, avoiding skin areas prone to friction from tight clothing or prone to substantial movement or skin folding (upper or lower back, or upper arm is recommended), avoiding application on irritated or broken skin (be mindful that age-related deterioration in skin integrity and mechanical strength increases the risk of skin trauma and irritation in elderly populations), and avoiding hirsute areas (and skin should not be depilated before application of a patch). Additional advice regarding skin tolerability can also be found elsewhere (8–10). In addition to work being done in psychiatry and neurology (11), a quick look at the US National Institutes of Health ClinicalTrials.gov registry reveals 685 clinical trials that include the text-word ‘transdermal’ (and 6792 studies that include the more non-specific word ‘patch’) for a variety of agents and
Skin reactions are common but usually mild in severity
509
510
Editorials
disease states. Many of these studies are ongoing and represent potentially new (or reformulated) therapeutic agents that may eventually become available commercially (12).
References 1 Alva G, Cummings JL, Galvin JE, Meng X, Velting DM. Skin reactions at the application site of rivastigmine patch (4.6 mg/24 h, 9.5 mg/24 h or 13.3 mg/24 h): a qualitative analysis of clinical studies in patients with Alzheimer’s disease. Int J Clin Pract 2015; 69: 518–30. 2 Novartis. EXELON PATCH (rivastigmine transdermal system). Prescribing information. Revised February 2015. http://www.pharma.us.novartis.com/ product/pi/pdf/exelonpatch.pdf (accessed 6 April 2015). 3 Adler G, Mueller B, Articus K. The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer’s disease under daily practice conditions. Int J Clin Pract 2014; 68: 465–70. 4 Citrome L. Formulations: friendly, fast, forgiving and flexible. Int J Clin Pract 2014; 68: 407. 5 Citrome L, Goldberg JF, Portland KB. Placing transdermal selegiline for major depressive disorder into clinical context: number needed to treat, number needed to harm, and likelihood to be
6
7
8
9
10
11
L. Citrome New York Medical College, Valhalla, NY, USA Email: [email protected]
helped or harmed. J Affect Disord 2013; 151: 409–17. Mylan. EMSAM (selegiline transdermal system). Prescribing information. Revised September 2014. http:// www.emsam.com/includes/pdf/EMSAM-PIR12_ Exhibit.pdf (accessed 6 April 2015). UCB. NEUPRO (rotigotine transdermal system). Prescribing information. Revised February 2015. http:// www.neupro.com/pdf/Neupro-PI.pdf (accessed 6 April 2015). Greenspoon J, Herrmann N, Adam DN. Transdermal rivastigmine: management of cutaneous adverse events and review of the literature. CNS Drugs 2011; 25: 575–83. Wohlrab J, Kreft B, Tamke B. Skin tolerability of transdermal patches. Expert Opin Drug Deliv 2011; 8: 939–48. Ale I, Lachapelle JM, Maibach HI. Skin tolerability associated with transdermal drug delivery systems: an overview. Adv Ther 2009; 26: 920–35. Isaac M, Holvey C. Transdermal patches: the emerging mode of drug delivery system in psychiatry. Ther Adv Psychopharmacol 2012; 2: 255–63.
12 Di Filippo P. Transdermal/transmucosal drug delivery. New technologies and outsourcing opportunities. Contract Pharma 2013; Jan–Feb: 54–7. http://www. contractpharma.com/issues/2013-01/view_features/ transdermaltransmucosal-drug-delivery/ (accessed 6 April 2015).
Disclosures No external funding or writing assistance was utilised in the production of this editorial. In the past 36 months, Leslie Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Forest, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant. doi: 10.1111/ijcp.12668
EDITORIAL
Reduction of angiotensin inhibition in older CKD patients with heart failure led to improved renal and mortality outcomes – the results of a Spanish open RCT
Reduction of angiotensin inhibition in older CKD patients with heart failure could be beneficial
We read with fascination and heightened interest the recent reported open randomised control trial that compared the impact of a 50% reduction in angiotensin inhibition in the intervention group of older chronic kidney disease (CKD) patients with heart failure and anaemia, mean age 78 years, on renal function, anaemia and mortality outcomes vs. a control group (1). Pita-Fernandez et al. after 3 months, demonstrated improved haemoglobin levels from 10.62 to 11.47 g/dl, improved creatinine clearance from 32.5 ml/min/1.73 m2 BSA to 42.9 ml/min/1.73 m2 BSA following a simultaneous decrease in serum creatinine from 1.98 to 1.68 mg/dl, and reduced C-reactive protein when compared with controls where the admission dose of angiotensin inhibition was continued (1). This study showed that the global survival rate was 97.9% after 3 months, 80.9% after 6 months and 60.8% after 12 months. Survival in the intervention group vs. the control group was 86.7% vs. 75%
after 6 months, and 69.3% vs. 50% after 12 months (1). Overall, the risk of death was reduced by 43% in the intervention group vs. the control group (1). Furthermore, the clinical relevance of this intervention was highlighted by the demonstration that the relative risk reduction was 0.43 at 6 months and 0.36 at 12 months, whereas the number needed to treat was 10, after 6 months of follow-up, and 6, after 12 months of follow-up in the intervention group (1). It is common knowledge that as a result of the differential physiological effects of angiotensin II on the afferent and efferent glomerular arterioles, angiotensin inhibition generally results in greater efferent glomerular arteriolar dilatation than afferent glomerular arteriolar dilatation, thus resulting in reduced intraglomerular pressure, therefore resulting in an obligatory increase in serum creatinine (2–7). Thus, in the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) Trial, a randomised trial that ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69, 5, 509–514
