DIS News. Literature Highlight: Treating Acute and Chronic Plaque-Type Psoriasis Using Atorvastatin. Inside this issue: February 2012

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1 DIS News College of Health Professions and Biomedical Sciences Drug Informa tion Service Literature Highlight: Treating Acute and Chronic Plaque-Type Psoriasis Using Atorvastatin Plaque-type psoriasis is an autoimmune disease that causes inflamed, scaly patches on the epidermis. Atorvastain is a lipid-lowering medication that also has anti-inflammatory and immunomodulatory effects. In a doubleblind, randomized, placebo-controlled trial, atorvastatin was studied for its effectiveness and safety in the treatment of acute and chronic plaque-type psoriasis. Forty-two patients, years old, with a diagnosis of acute or chronic plaque-type psoriasis that involved at least 10% of their body surface area (BSA) were included in the study. Patients with alternative forms of psoriasis or psoriatic arthritis or who were pregnant or had a contraindication to atorvastatin were excluded. Patients were randomized into either the placebo group or the oral atorvastatin 40 mg/day group. Patients were evaluated at baseline and then every four weeks until the end of the 12-week trial. Patients were also allowed to use topical emollients, keratolytics, and class V corticosteroids. To measure effectiveness of therapy, the Psoriasis Area and Severity Index (PASI) was used, and the amount of BSA involvement was measured. Adverse reactions were also monitored during the trial, along with liver function tests. Quality-of-life changes were not evaluated. Only 40 patients completed the study, with 20 patients in both treatment groups. At the end of the 12 weeks, both the placebo and the atorvastatin group significantly improved in both BSA involvement and PASI score (p<0.001). The placebo group experienced a 16.97% decrease in BSA involvement (32.30% baseline, 15.33% week 12), and the treatment group experienced a 14.77% decrease in BSA involvement (31.20% baseline, 16.43% week 12). Seven patients in the placebo group and eight in the treatment group experienced a 75% improvement in PASI score (p=0.204), with an overall improvement of 4.33 points in the placebo group (6.92 baseline, 2.59 week 12), and an improvement of 4.48 points in the treatment group (7.42 baseline, 2.94 week 12). There was, however, no significant difference between the placebo and the atorvastatin group for either outcome (p=0.54 BSA, p=0.72 PASI). No adverse events were reported during this trial. The authors concluded that atorvastatin 40 mg/day was not significantly more effective than placebo in improving PASI scores or BSA involvement in patients with plaque-type psoriasis. The authors believed that any improvement seen was from the effects of the topical therapies used during the trial. The results are limited by the small patient population and the moderate dose of atorvastatin used. In this study, baseline PASI scores and BSA scores were lower than in other psoriasis trials using simvastatin, which might explain the lack of effect. A larger trial with increased doses may be needed to see improvement with atorvastatin. SUMMARY: Treatment of plaque-type psoriasis with atorvastatin 40 mg/day for 12 weeks did not significantly improve PASI scores or BSA involvement when compared to placebo. Faghihi T, Radfar M, Mehrabian Z, Ehsani AH, Hemami MR. Atorvastatin for the treatment of plaque-type psoriasis. Pharmacotherapy 2011;31(11): By Justin Sisney, Pharm.D. Candidate February 2012 Volume 16, Issue 2 Inside this issue: Duexis (ibuprofen and famotidine) Community- Acquired MRSA Guidelines Literature Highlight We welcome any comments and suggestions for future newsletter topics. Editors in Chief Sherrill Brown, DVM, Pharm.D., BCPS Tanner Higginbotham, Pharm.D

2 Table 1. Results of study Duexis % (n/n) Ibuprofen % (n/n) P-value Duexis (ibuprofen and famotidine) and Gastrointestinal Ulcers Ulcers are a common side effect in patients requiring long-term ibuprofen therapy. Duexis (ibuprofen and famotidine) was developed to decrease the risk of ibuprofen-associated upper gastrointestinal (UGI) ulcers (gastric or duodenal) while treating pain and inflammation associated with arthritis. 1 Duexis was approved in April 2011 based on randomized, controlled trials. 1 A randomized, double-blind study examined whether Duexis reduced the rate of ulcers in subjects who required daily use of ibuprofen. 2 Patients were assigned either the combination product (ibuprofen 800 mg/famotidine 26.6 mg; n=380) or ibuprofen 800 mg alone (n=190) three times daily for 24 weeks or until the development of either an endoscopicallydiagnosed UGI ulcer and/or prohibitive toxicity. 1 Patients were years old and had not used an NSAID within 30 days prior to study entry but were expected to receive an NSAID for at least six months for conditions such as osteoarthritis, rheumatoid arthritis, chronic lower back pain, or chronic soft tissue pain. 1 Patients with a history of ulcer perforation, gastric outlet obstruction due to ulcers, gastrointestinal bleeding, uncontrolled diabetes, or erosive esophagitis were excluded. 1 The primary endpoint was the proportion of patients who developed endoscopically-diagnosed UGI ulcers throughout the 24 weeks of treatment. The secondary endpoint was the proportion of patients who developed endoscopically-diagnosed gastric ulcers at any time throughout 24 weeks of treatment. A total of 40 patients (11%) in the combination group developed UGI ulcers, compared to 38 patients (20%) in the ibuprofen-alone group (95% CI , p=0.0018). Over 24 weeks, 37 patients (9.7%) in the combination group developed gastric ulcers, compared to 34 patients (18%) in the ibuprofen-alone group (95% CI , p=0.0051). Adverse events occurred more frequently in the ibuprofen-alone group (4.35% vs. 3.62%). 1 The adverse events in the combination group included acute renal failure, chest pain, and dehydration. The ibuprofen group experienced adverse events such as cardio-respiratory arrest, pneumonia, and dyspnea. 2 Two additional randomized, double-blind, active-controlled studies (study 301 and study 303) were conducted to compare the development of ibuprofenassociated UGI ulcers in patients taking either Duexis or ibuprofen alone. 3 Patients were randomly assigned to treatment with either ibuprofen and famotidine 800 mg /26.6 mg (n=1022) or ibuprofen 800 mg alone three times daily for 24 weeks. 3 The primary endpoint of Study 301 was the proportion of patients who developed at least one endoscopically-diagnosed UGI ulcer over the six-month period. 3 The secondary endpoint in study 301 was gastric ulcer development. Endoscopies were performed at weeks 8, 16, and 24. The results of study 301 are found in Table 1. 3 The primary endpoint of study 303 was the proportion of patients who developed at least one endoscopically diagnosed gastric ulcer, and the secondary endpoint was the development of a UGI ulcer. The results of study 303 are found in Table 2. 1 In both studies, the most common adverse reactions leading to discontinuation of ibuprofen and famotidine were nausea (0.9%) and upper abdominal pain (continued on page 4) Primary endpoint Upper gastrointestinal ulcer** 10.5% (40/380) 20.0% (38/190) Upper gastrointestinal ulcer* 22.9% (87/380) 32.1% (61/190) Secondary endpoint Gastric ulcer** 9.7% (37/380) 17.9% (34/190) Gastric ulcer* 22.4% (85/380) 30.0% (57/190) * Classified patients who early terminated due to an adverse event, were lost to follow-up, discontinued due to the discretion of the sponsor or the investigator, or did not have an endoscopy performed within 14 days of their last dose of study drug as having an ulcer ** Classified early terminated patients as not having an ulcer Duexis % (n/n) Ibuprofen % (n/n) P-value Primary endpoint Gastric ulcer** 8.7% (39/447) 17.6% (38/216) Gastric ulcer* 17.4% (78/447) 31.0% (67/216) < Secondary endpoint Upper gastrointestinal ulcer** 10.1% (45/447) 21.3% (46/216) < Upper gastrointestinal ulcer* 18.6% (83/447) 34.3% (74/216) < * Classified patients who early terminated due to an adverse event, were lost to follow-up, discontinued due to the discretion of the sponsor or the investigator, or did not have an endoscopy performed within 14 days of their last dose of study drug as having an ulcer ** Classified early terminated patients as not having an ulcer Page 2 DIS News

3 Treating Community-Associated Methicillin-Resistant Staphylococcus Aureus Skin and Soft Tissue Infections Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for many infections that are difficult to treat. In recent years, a type of MRSA has emerged in the community that differs from hospital-associated MRSA (HA- MRSA) infections in both genotype and human pathology. 1 Communityassociated MRSA (CA-MRSA) infections often involve people without typical HA- MRSA risk factors (e.g., immunosuppression, catheters). Visiting athletic facilities, dormitories, daycares, and military barracks may place people at greater risk, as CA-MRSA outbreaks are common in these locations; the CDC recommends that at-risk individuals avoid these places. 2 CA-MRSA can cause severe pneumonia in children and skin and soft tissue infections (SSTIs) in adults. Transmission usually occurs from close contact, and risk factors for infection include crowded living conditions, poor hygiene, and cuts or openings in the Table 1. Classification of soft skin and tissue infections 3 Anatomic Structure Infection Description Epidermis Superficial Dermis Deep Dermis Subcutaneous Tissue Impetigo Folliculitis Furuncles Carbuncles Hidradenitis suppurativa Erysipelas Cellulitis Fasciitis skin. 1,2 SSTIs are a common presentation of CA-MRSA infections because the bacteria colonize on the skin. SSTIs are classified based on the anatomic structure involved in the infection and can be caused by Staphylococcus aureus, Streptococcus pyogenes, and in some cases, Pseudomonas aeruginosa. 3 Table 1 describes the general classification of SSTIs. SSTIs can range from (continued on page 4) A superficial infection that mostly affects children on the face and legs. Fluid-filled vesicles rupture and form a yellow and thick crust. Impetigo is highly contagious but generally mild; however, severe infection may need systemic antibiotics. An infection in the hair follicle, folliculitis usually presents as raised, painful, reddish lesions often containing fluid. Also known as boils, furuncles are deeper infections of the hair follicles and present as painful raised lesions usually 1-2 cm in diameter. May be severe enough to cause hemorrhagic pneumonia, especially in children. Infections that involve several hair follicles and can often spread to subcutaneous tissue. An infection of the sweat glands with an appearance similar to furuncles. Presents as red, hot eruptions with systemic symptoms of sepsis and high fever. Infection of the subcutaneous tissue that can cause severe inflammation. Pain and fever are usually present, and bactermia is also common. A severe and very painful infection that needs immediate drainage. Fasciitis can quickly spread and result in the need for amputation. Table 2. Antibiotic treatment of MRSA 3 MRSA Type Drug Dose 3,5 Duration 3 Clindamycin Oral 600 mg every 8 hours 5-10 days CA-MRSA HA-MRSA Trimethoprim- Sulfamethoxazole Oral 160/800 to 320/1600 mg every 12 hours 5-10 days Doxycycline Oral 100 mg every 12 hours 5-10 days Minocycline Oral 200 mg once then 100 mg every 12 hours 5-10 days Linezolid Oral 600 mg every 8 hours 5-10 days Clindamycin IV or oral 600 mg every 8 hours 7-14 days Vancomycin IV mg/kg every 8-12 hours 7-14 days Linezolid IV or oral 600 mg every 12 hours 7-14 days Daptomycin IV 4 mg/kg every 24 hours 7-14 days Telavancin IV 10 mg/kg every 24 hours 7-14 days Volume 16, Issue 2 Page 3

4 (0.9%). 1 Three serious cases of acute renal failure were observed in patients treated with ibuprofen and famotidine tablets. All three patients recovered to baseline levels after discontinuation of the drugs. Additionally, increases in serum creatinine were observed in both treatment groups. Many of these patients were taking concomitant diuretics and/or angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. 1 In both trials, Duexis was associated with a significant reduction in the risk of developing upper gastrointestinal ulcers compared to taking ibuprofen alone. An average of 23% of patients 65 years old who were treated with Duexis developed an upper gastrointestinal ulcer, compared to 27% of patients of the same age who received ibuprofen alone. 1 All three studies are all limited by their duration; outcomes associated with drug use for longer than six months cannot be determined. In addition, analyses were not performed to determine the incidence of Duexis (ibuprofen and famotidine) (from page 2) ulcers based on concomitant medications. 1 Common side effects associated with Duexis in the studies were nausea, upper abdominal pain, and constipation. The recommended dose of Duexis is one tablet (ibuprofen 800 mg and famotidine26.6 mg) orally three times daily. 1 Duexis was associated with fewer gastric and UGI ulcers compared to ibuprofen alone in three randomized, controlled trials. Studies with a longer duration are necessary to determine the potential longterm effects of Duexis. The combination medication may be of benefit in patients taking ibuprofen who are at risk of bleeding or developing ulcers. However, both medications in Duexis are available separately and could be taken together as separate pills at a lower cost than the new combination pill. By Princy Varghese, Pharm.D. Candidate References: 1. Duexis [package insert]. Northbrook, IL: Horizon Pharma USA, Inc.;2011 October. 2. Efficacy and safety study of HZT- 501 in subjects requiring nonsteroidal anti-inflammatory drug (NSAID) treatment (5/17/2011). Clinical Trials Web site. Available at: ct2/show/results/nct Accessed November 10, Center for Drug Evaluation and Research. Duexis: summary review. Application number Orig1s000. US Food and Drug Administration Web site. Available at: drugsatfda_docs/ nda/2011/022519orig1s000sumr. pdf. Accessed November 14, Skin and Soft Tissue Infections (from page 3) superficial infections to life threatening infections in the deep dermal layers of the skin. 3 The Infectious Diseases Society of America (IDSA) has recently published updated guidelines for the treatment of CA- MRSA SSTIs. 4 The IDSA recommends incising and draining the abscess of a CA- MRSA SSTI whenever possible. 4 In many cases, drainage of the abscess is all that is necessary to promote healing of the infection. For minor skin infections, mupirocin 2% topical ointment is recommended, especially for impetigo. Antibiotic therapy may be appropriate if the patient is experiencing severe disease, rapid progression of the infection or systemic illness, is very young or elderly, or has an abscess that is difficult to drain. The IDSA recommends obtaining a culture and treating empirically until the culture results are returned. Table 2 lists the current antimicrobial treatment for CA- MRSA SSTIs in an outpatient setting and also treatment for HA-MRSA. HA- Page 4 MRSA treatments are also effective for CA-MRSA infections; however, CA- MRSA treatments are not recommended for HA-MRSA infections. 4 CA-MRSA differs from HA-MRSA in both genotype and type of infection caused. CA-MRSA is becoming more prevalent and often causes SSTIs in adults. The CDC recommends good hygiene and, when possible, avoidance of sites where outbreaks occur. The recommended first-line therapy is drainage of the infection site, and, when antibiotic therapy is indicated, there are several options to empirically treat while cultures are being completed. By Justin Sisney, Pharm.D. Candidate References: 1. Rybak MJ, LaPlante KL. Community-associated methicillin-resistant Staphylococcus aureus: a review. Pharmacotherapy 2005:25(1): MRSA infections (9/9/2010). Centers for Disease Control Web site. Available at: index.html. Accessed November 7, Moreillon P, Que Y, Glauser MP. Staphylococcus aureus (Including Staphylococcal Toxic Shock). In: Mandell GL, Bennett JE, Dolin R, editors. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia (PA): Elsevier;2005: Liu c, Bayer A, Cosgrove S, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infec Dis 2011;52: Lexi-Comp, Inc. (Infectious Diseases ). Lexi-comp, Inc.: October 25, DIS News

5 Literature Highlight: Effect of Increasing Doses of Saw Palmetto Extract on Lower Urinary Tract Symptoms Benign prostatic hyperplasia (BPH) is a common, non-cancerous enlargement of the prostate gland that usually occurs in elderly men. This enlargement can increase the pressure on the urethra and cause urinary problems. Saw palmetto is an herbal product that has been studied for the treatment of BPH-related symptoms such as nocturia and urinary bother. A recent multicenter, double-blind, placebo-controlled, randomized study assessed the effects of increasing doses of saw palmetto extract on lower urinary tract symptoms (LUTS). The study included men 45 years old with a peak uroflow rate 4 ml/second and a score on the American Urological Assessment Score Index (AUASI) of between 8 and 24 at two different screening visits. An AUASI score of 7 or less represents a urinary condition that is not at all bothersome (the mild group), scores between 8 and 19 are intermediate ratings (the moderate group), and scores of 20 represent a very bothersome urinary condition (the severe group). Patients were ineligible if they had prior invasive treatment for BPH, recent treatment with other medications affecting LUTS, or repeated urinary tract infections. Patients were randomly assigned to receive either increasing doses of saw palmetto [n=151] or matching placebo [n=155] for 72 weeks. Saw palmetto 320 mg daily was given at baseline until week 24. The dose was increased to 640 mg daily at week 24 until week 48. At week 48, the dose was again increased to 960 mg until week 72. The primary endpoint was the change in AUASI scores from baseline to week 72. The secondary endpoints included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostratespecific antigen levels, global assessment and indices of sexual function, continence, sleep quality, and prostatitis symptoms. A similar number of patients in each group dropped out during the trial (21% in the saw palmetto group and 20% in the placebo group). Based on an intent-to-treat analysis, the mean AUASI score decreased from to points (-2.20 points; 95% CI to -0.36) with saw palmetto and from to points (-2.99 points; 95% CI to -2.17) with placebo between baseline and 72 weeks. The mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points, favoring placebo. There were no significant differences between groups in any of the secondary outcomes. The only major adverse effects that occurred more frequently in the saw palmetto group were physical injuries or trauma (24 patients in the saw palmetto group vs. 10 patients in the placebo group; p=0.01). The authors of the study concluded that up to three times the standard daily dose of 320 mg of saw palmetto extract daily had no significant effect in improving LUTS and outcomes related to BPH. Only one extract of saw palmetto was studied, and because the potential active constituents and mechanisms of action of saw palmetto are unknown in BPH treatment, the findings of the study are not generalizable to all saw palmetto extracts. SUMMARY: Increasing doses of saw palmetto (up to three times the standard daily dose) had no greater effect than placebo on improving LUTS or other BPHrelated outcomes. Barry MJ, Meleth S, Lee JY, et al. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA 2011;306(12): By Princy Varghese, Pharm.D. Candidate College of Health Professions and Biomedical Sciences Drug Information Service The University of Montana Skaggs School of Pharmacy 32 Campus Drive Missoula, MT Phone: Fax: druginfo@umontana.edu