® Volume 25, Issue 3 December 2009 active metabolites stimulate sebaceous gland activity, leading to an increase in sebum production. When hyperkeratinization occurs during the natural sloughing MANAGEMENT OF ACNE process, sebum mixes with clumped keratinocytes. This clumping leads to plugging of the follicle, thus VULGARIS: A REVIEW widening the follicle and producing a favorable envi- ronment for bacteria, such as Propionibacterium acnes. Jennifer D. Billman, Pharm.D. Candidate Subsequently, primary acne lesions form, appearing as blackheads, also known as open comedos. After devel- opment of a blackhead, trauma or inflammation to the follicles may ultimately lead to the formation of closed comedos, or whiteheads.1,3 A variety of factors increase the risk for acne vulgaris (Table 1). A cne vulgaris is a common skin disorder caused by abnormal hyperkeratinization and over- TREATMENT OF ACNE production of sebum by the sebaceous gland. Acne first presents early in adolescence and often con- Various therapies are available for the treatment tinues into early adulthood, negatively affecting qual- of acne vulgaris, including topical and oral agents Pre- ity of life. This article will review the current treat- ferred therapies differ based on the severity of disease ment options for acne vulgaris.1 presentation. EPIDEMIOLOGY Mild-to-Moderate Acne: Topical Antibiotics Topical antibiotics including erythromycin and Acne may be psychologically impacting in late ado- clindamycin, are effective and well tolerated for the lescence, leading to depression and diminished quality treatment of acne vulgaris. However, because antibiot- of life. In the United States, acne affects about 40-50 ics may potentially decrease sensitivity of P. acnes, the million people1 – impacting nearly 80% of the popula- use of these agents should be limited.4 Erythromycin is tion between 12-25 years – without gender, ethnicity used alone for inflammatory acne or in combination or race prevalence differences. The onset of acne vul- with zinc, which helps the antibiotic penetrate into the garis varies within age groups, but is more prevalent pilosebaceous units. Clindamycin inhibits P. acnes and during the onset of puberty, and can continue to be a problem throughout early adulthood.2 ETIOLOGY & PATHOPHYSIOLOGY INSIDE THIS ISSUE: The origin of acne vulgaris is complex, but at least four primary factors are associated with its de- MANAGEMENT OF ACNE VULGARIS: A REVIEW velopment, including increased sebum production, sloughing of keratinocytes, bacterial growth and colo- DRONEDARONE: A NEW OPTION FOR ATRIAL nization, and inflammation and immune system re- FIBRILLATION sponse. At puberty, stimulation of androgens, espe- cially testosterone, is enhanced. Testosterone and its 1 PharmaNote V o l u m e 2 5 , Issue 3 December 2009 Table 1: Risk factors for acne vulgaris. Environmental Factors: Physical Factors: High-humidity Occlusive clothing Prolonged sweating Headbands Increase in skin hydration Helmets Exposure to dirt or vaporized cooking oil or certain chemicals Friction-producing devices like petroleum derivatives Medication Use: Cosmetic Use: Phenytoin Moisturizers Isoniazid Tanning oils Phenobarbital Cocoa butter Lithium Ethonamide Hormonal Factors: Steroids Menarche Azathioprine High-androgenic progestin birth control Quinine Emotional Factors: Rifampin Severe/prolonged period of stress Adapted from Haider A, et. al.3 possesses comedolytic and anti-inflammatory proper- most effective when used in combination with topical ties.1 antibiotics or benzoyl peroxide (Brevoxyle ®).1 Topical antimicrobial combination therapy is more A meta-analysis by Leyden and colleagues, evaluat- effective than monotherapy.1,4 A randomized, parallel, ing topical tazarotene in mild to moderate acne, found vehicle-controlled trial by Lookingbill and colleagues that tazarotene was well tolerated and effective for the evaluated 334 patients over an 11-week once-nightly treatment of acne vulgaris, regardless of patient- preparation study. Evaluation was performed on specific factors, including acne severity, skin type, sex weeks 2, 5, 8 and 11 for lesion counts, global response or ethnicity. Six comparative, multicenter, double- rate and irritant effects of clindamycin plus benzoyl blind, randomized studies of monotherapy with ta- peroxide gel, benzoyl peroxide alone, clindamycin zarotene 0.1% gel or cream were analyzed, encom- alone or vehicle gel.5 The combination of clindamycin/ passing 468 patients who exhibited moderate to com- benzoyl peroxide significantly improved patient global plete clearing at 12 weeks. Both inflammatory and non response and reduced inflammatory and non- -inflammatory lesion counts declined substantially inflammatory response compared to clindamycin with both formulations over the treatment period. alone, benzoyl peroxide alone, or the vehicle gel. Furthermore, both formulations were well-tolerated.8 Monotherapy with clindamycin or benzoyl peroxide In a 3-way retrospective, investigator blinded, photo- compared to the vehicle gel resulted in significant im- graphic review, investigators evaluated the efficacy of provement in patient global response and a reduction tazarotene 0.1% gel, adapalene 0.1% gel, tretinoin in inflammatory and non-inflammatory response. All 0.1% microsponge, and tretinoin 0.025% gel for the of the treatment options were well tolerated.5 Table 2 treatment of inflammatory acne. The authors con- summarizes the clinical studies of various products cluded that all formulations showed significant clinical used to treat acne vulgaris, including topical antibiot- improvements compared to tazarotene 0.1% cream ics. (vehicle).7 Mild-to-moderate Acne: Topical Retinoids Mild-to-moderate Acne: Combination therapy The available topical retinoids used for acne vul- Recent guidelines suggest that combination ther- garis include tretinoin (Retin-A®), adapalene apy with topical retinoids and antimicrobial agents (Differin®) and tazarotene (Tazorac®) (Table 3). achieves significantly greater and faster clearing of These agents work by reducing obstruction within the acne compared with antimicrobial therapy alone.2 follicle.4,6,7 Such products are considered first-line for Combination therapies utilize agents with complimen- the treatment of mild-to-moderate inflammatory acne tary mechanisms of action to target multiple etiologi- and comedonal acne.2 Additionally, these agents are cal factors simultaneously.2,8 preferred for maintenance therapy of acne in order to Gollnick and colleagues recently conducted a ran- preserve the use of antibiotics.4 Topical retinoids are domized, double-blind, placebo-controlled study to 2 PharmaNote V o l u m e 2 5 , Issue 3 December 2009 Table 2. Clinical studies summary. STUDY METHODS STUDY GROUPS RESULTS Lookingbill, et 11-week, RCT, PL Study groups: Clindamycin + BPO showed SS (P<0.001) good/excellent al.3 (n=334) Clindamycin + BPO gel PGR, ß in inflammatory and non-inflammatory re- (1997) BPO gel sponse and was significantly superiority to clindamycin, Clindamycin gel BPO, or vehicle gel alone. Placebo (vehicle gel) Clindamycin and BPO alone were SS (P<0.001) vs. vehicle gel in PGR, ß in inflammatory and non-inflammatory response. Leyden, et al.9 6-comparative MC, DB, R Tazarotene 0.1% gel Both groups showed: (2004) studies evaluated 468 Tazarotene 0.1% cream Moderate clearing after 12 weeks patients with mild- Statistical ß in inflammatory and non-inflammatory Meta-analysis moderate acne lesions Well tolerated Leyden, et al.5 3-way RS, IB, photo- Tazarotene 0.1% gel All formulations showed significant clinical improve- (2005) graphic review evaluat- Adapalene 0.1% gel ments in inflammatory acne vs. to vehicle. ing efficacy of topical Tretinoin 0.1% microsponge retinoids Tretinoin 0.025% gel Tazarotene 0.1% cream Gollnick et al.8 DB, RCT evaluating Adapalene 0.1% + BPO 2.5% gel Adapelene + BPO was SS more effective (P<0.001) at (2009) safety and efficacy Adapalene 0.1% weeks 8, 12, and end-point than monotherapy and SS Adapalene 2.5% more effective (P<0.05) at weeks 2 and 4 than vehicle- BPO 2.5% only. Vehicle gel A significant difference in lesion counts from baseline as early as the 1st week. Equal tolerability in all groups. More AEs with adapalene-BPO early in therapy, but only transient. Krunic, et al.12 27 females 18-43 with Spironolactone + 30mcg EE/3mg 85% subjects had complete clearing of lesions or excel- (2008) severe papular or NC DRSP lent improvement facial acne 7.4% had mild improvement 7.4% had no improvement. Palombo-Kinne, MN, MC, 3-arm, DB, RCT, Completed 6 cycles of either: EE/DNG was superior to PL and non-inferior to EE/CPA et al.13 women 16-45 with mild- EE/DNG, (P<0.05). (2009) to-moderate facial acne EE)/ CPA, or Rates of ß in inflammatory lesions were -65.6+/-29.9% PL for EE/DNG, 64.6+/-31.2% for EE/CPA and 49.4+/-41.0% for PL. Percentages of pts with improvement of facial acne were 91.9% for EE/DNG, 90.2% for EE/CPA and 76.2% for PL. Jones, et al.14 RCT, 76 pts with severe Isotretinoin 0.1mg/kg/day to 80% ß in total acne after 4 months. (1983) acne 0.5mg/kg/day 89% ß in total lesions when a 1.0mg/kg/day dose was used. RCT = randomized controlled trial; MN = multinational; MC = multicenter; DB = double-blind; RS = retrospective; IB = investigator-blind; R = randomized; SS = statistically significant; PGR = patient global response; NC = nodulocytic; y/o = years old; PL = Placebo; Pts = Patients. assess the safety and efficacy of adapalene 0.1% + ben- with a faster onset, and had an equivalent safety pro- zoyl peroxide (BPO) 2.5% combination gel and 0.1% file when compared to the monotherapies.8 adapalene, 2.5% BPO, or a vehicle gel. The authors reported that combination therapy was more effective Mild-to-Moderate Acne: Hormonal Therapy (P<0.001) at weeks 8 and 12, and at study end com- Hormonal therapy produces anti-androgen effects, pared with BPO monotherapy and a vehicle gel. More- which leads to a decrease in testosterone circulating in over, combination therapy was more effective the body. Consequently, sebaceous gland stimulation (P<0.05) at weeks 2 and 4 compaed with vehicle-only. is prevented, reducing sebum production.3,10 FDA- A significant difference in lesion counts from baseline approved hormonal therapies consist of oral contra- was reported as early as the 1st week. Adverse effects ceptive agents that contain norgestimate with ethinyl were more prevalent in the early phase of treatment estradiol (Ortho-Tri-Cyclen®) and norethindrone ace- with combination therapy, but these effects were tran- tate with ethinyl estrodial (Estrostep®), as well as the sient. This study showed that combination therapy anti-androgenic agent, spironolactone (Table 4).4 was significantly better, synergistically efficacious Anti-androgens, such as spironolactone or cypro- 3 PharmaNote V o l u m e 2 5 , Issue 3 December 2009 C TSO :mg06 %1 76.84$ = PVA :mg06 %2 99.43 $ = leG 99.41 $ = nloS 99.78$ :hsaW E0R1- 99.492$ :ebut mg06 ,%1.0( ebut mg5499.302$ :)%3.0 99.041$ :mg05 aecaniF 99.881$ :mg05 xelezA )CIRENEG ON( :ebut leg mg06 90.O9 P20B1$-- 98.O2P2 B5$-- :noitol mg792 %945 .O5P5B$- %985 .O7P5B$- :maerc ebut mg06 99 %.25702.0$- 99. 1%912.0$- :leg ebut mg001 99 %.15504.0$- 99. 3%813.0$- :ebut mg54 leg9 %51.609.0$- maerc %9592.205.0$- leg %9592.508.0$- maer9c9 %.15001.0$- maer9c5 %.518.0$- = PVA ;dica cilof = AF ;n ES STCEEFDFI suotamehtnaxe dezilareneg etuca ,sitirurP ,amehtyre ,sisorex ,gninrub ,sisolutsup.gnileep ,ssenilio suotamehtnaxe dezilareneg etuca ,sitirurP ,aehrraid ,gnitimov ,aesuan ,sisolutsup.aixerona dna hcihw ,edimatecaflus ot 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fo tnemtaert eht rof B SDNAR zaY ,®nimsaY ,®allecO-®82 irT ohtrO ,®asseNonoM-ohtrO ,®oL nelcyC-irT ohtrO ,®nelcyC-irT ,®cetnirpS ,®neclyC-irT ,®mefiverP ,®cetnirpS®assenirT ,®mefiverP- -senmA ,®enatuccA-toS ,®siravalC ,®meet®ter ®onoripS ,®enotcadlA ,®kcaP ,axodA ,®axodA-ivA ,®xodirtA ,®xodolA yxoD ,®yxoD ,®yxod ®lyxarO ,®aecarO ,®001arbiV ,®ta t,s®osibreaPT-®nicymarbiV euvareelC ,®nit s,e®rMA- ,®niconiM ®nicanyD®nydoloS ,®caryM a cioniter = RAR ;tsinogatn ;cireneg = G ;ecirp elbaira stn a rov eg ega larO .4 elbaT D GUR lynihtE ;enoneripsorDloidartsE ;loidartsE lynihtEetamitsegroN nionitertosI enotcalonoripS enilcycyxoD )citoibitna( enilcyconiM )citoibitna( tpecer negordna = ARAareva = PVA ;sisolutsup 5 PharmaNote V o l u m e 2 5 , Issue 3 December 2009 terone, and oral estrogens, such as ethinyl estradiol, teratogenicity, men and women of child-bearing age decrease androgen levels in patients with acne. Krunic are asked to register and comply with the FDA ap- et. al., evaluated the safety and efficacy of daily proved iPLEDGE program. This program is a risk man- sprionolactone (SL) 100 mg ,ethinyl estradiol 30 mcg, agement program that prevents isotretinoin exposure and drospirenone (EE/DRSP; Yasmin®) 3 mg. The to the fetus. study found that 85% of subjects had complete clearing of acne lesions or excellent improvement, 7.4% SUMMARY had mild improvement, and 7.4% had no improvement. No significant increase in serum potassium or Many well-tolerated and effective options are other side effects were observed in any subjects. The available for the treatment of acne vulgaris, depending authors concluded that EE/DRSP combination therapy on the type and severity of disease. Topical retinoids, and SL 100 mg daily was well tolerated and efficacious antibiotics and BPO are effective for mild-to-moderate in the treatment of severe papular and nondulocystic acne, while oral isotretinoin and hormonal therapy are acne in women.12 effective for more severe cases. In addition, combina- In a multinational, multicenter, three-arm, double- tion therapy with clindamycin and BPO is more effec- blind, randomized trial, Palombo-Kinne evaluated tive than treatment with either alone. Management of healthy women between the age of 16 and 45 with this common dermatologic disorder may contribute to mild to moderate facial acne. Participants were ran- a better quality of life. domly assigned to ethinylestradiol (EE)/dienogest (DNG), ethinylestradiol (EE)/cyproterone (CPA) or ♦ ♦ ♦ placebo for six cycles. The primary efficacy variables were the percent change from baseline to cycle 6 in REFERENCES inflammation and total lesion count and the percent- age of patients with improvement in acne evaluated by 1. Pharmacotherapy: A Pathophysiological Approach. Joseph T. the Investigator Global Assessment. The study found DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara that EE/DNG was superior to placebo and non-inferior G. Wells, L. Michael Posey (Eds). 7th edition. Chapter 100. Acne Vulgaris: Treatment: Acne Vulgaris. Accesspharmacy. http:// to EE/CPA. The rates of reduction (± SD) in inflamma- www.accesspharmacy.com/content.aspx?aID=3212123 tory lesions were -65.6+/-29.9% for EE/DNG, -64.6+/- 2. Thiboutot D, Gollnick H. New insight into the management of 31.2% for EE/CPA and -49.4+/-41.0% for placebo. The acne: An update from the Global Alliance to Improve Out- percentages of patients with improvement of facial comes in Acne Group. J Am Acad Dermatol 2009;60:S1-50. 3. Haider A, Shaw J. Treatment of Acne Vulgaris. JAMA:2004;292 acne were 91.9% for EE/DNG, 90.2% for EE/CPA and (6):726-35. 76.2% for placebo. The authors concluded that EE/ 4. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care DNG was superior to placebo and as effective as EE/ for acne vulgaris management. J Am Acad Dermatol 2007;56 CPA for treatment of mild to moderate acne.13 (4):651-63. 5. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindaymycin/benzoyl peroxide gel Severe Acne: Oral Isotretinoin compared with clindamycin gel, benzoyl peroxide gel and Isotretinoin (Accutane®) is a naturally occurring vehicle gel: combined results of two double blind investiga- metabolite of Vitamin A, and is indicated for the treat- tions. J Am Acad Dermatol 1997;37:590-5. ment of severe acne. Isotretinoin works by reducing 6. Fox Lindy P, Merk Hans F, Bickers David R. Chapter 62: De- rmatological Pharmacology. Laurence L. Brunton, John S. the size of the sebaceous gland, suppressing sebum Lazo, Keith L. Parker (Eds): Goodman & Gilman's The Pharma- production, and normalizing follicular epithelial des- cological Basis of Therapeutics, 11e: http:// quamation (Table 4).14 Several studies show isotreti- www.accesspharmacy.com/content.aspx?aID=959337 noin to be effective in severe acne. In a randomized 7. Leyden JJ, Shalita A, Thiboutot D, et al. Topical retinoids in controlled trial with 76 patients, isotretinoin showed inflammatory acne: A retrospective, investigator-blinded, vehicle-controlled, photographic assessment. Clin Ther an 80% reduction in total acne after 4 months. Treat- 2005;27:216-24. ment doses ranged from 0.1mg/kg/day to 0.5mg/kg/ 8. Gollnick HPM, Draelos Z, Glenn MJ, et al. Adapelene-benzoyl day. An 89% reduction in total lesions was observed at peroxide, a unique fixed-dose combination topical gel for the the 1.0mg/kg/day dose.10,14 Although the drug is effec- treatment of acne vulgaris: a transatlantic, randomized, double-blind controlled study in 1670 patients, Br J Dermatol tive for severe acne, reported side effects may be se- 2009 [Epub ahead of print]. vere, including inflammation of the lips, which is dose 9. Leyden JJ. Meta-analysis of the topical tazarotene in the treat- related. In addition, xerosis, xerostomia, epitaxis, peel- ment in the treatment of the mild to moderate acne. Cutis ing, pruritus, nausea/vomiting, altered lipid profiles, 2004;74(supp 4):9-15. and most importantly, teratogenesis may occur with 10. George R., Clarke S, et al. Hormonal Therapy in Acne. Semin Cutan Med Surg 2008:27(3):188-96. any amount of isotretinoin ingestion.10 Because of the 11. Gold Standard, Inc. Clinical Pharmacology [database online]. 6 PharmaNote V o l u m e 2 5 , Issue 3 December 2009 Available: http://www.clinicalpharmacology.com. Accessed: rhythm. In the AFFIRM trial, 67% of patients in the July 15, 2009. rhythm control group were started on amiodarone or 12. Krunic A, Ciurea A, Scheman A, et al. Efficacy and tolerance of sotalol; and at the end of the study 66% of the patients acne treatment using both spironolactone and a combined contraceptive containing drospirenone. J Am Acad Dermatol had tried amiodarone at least once.5 An advantage of 2008;58:60-2. amiodarone is the low poarrhythmic risk of in left ven- 13. Paloma-Kinne E, Schellschmidt I, Schumacher U, et al. Efficacy tricular (LV) hypertrophy, heart failure (HF), coronary of a combined oral contraceptive containing 0.030 mg artery disease, and post myocardial infarction.3 How- ethinylestradiol/2 mg dienogest for the treatment of papu- ever, this agent is limited by extra-cardiac toxicities lopustular acne in comparison with placebo and 0.035 mg ethinylestradiol/2 mg cyproterone acetate. Contraception including pulmonary fibrosis, hepatic and thyroid dys- 2009 ;79(4):282-9. function, neurological disorders, blue-gray skin discol- 14. Jones DH, King K, Miller AJ, et al. A dose response study of 13- oration, and corneal deposits. In addition, amiodarone cis retinoic acid in acne vulgaris. Br J Dermatol 1983;108:333- has a complicated dosing schedule and interacts with 43. some cardiovascular (CV) agents including warfarin 15. Lexi-Comp OnlineTM , 2009. Accessed: July 15, 2009. Available: http://www.crlonline.com/crlsql/servlet/crlonline. and digoxin.3,6 Dronedarone (Multaq®) is an amiodarone analogue manufactured by Sanofi-Aventis and recently approved by the FDA in July 2009. The struc- ture of dronedarone differs from amiodarone by the absence of iodine and the presence of a methane- DRONEDARONE: A NEW sulfonyl group that decreases lipophilicity. These TREATMENT OPTION FOR changes were intended to reduce accumulation in tis- ATRIAL FIBRILLATION sues to prevent thyroid and other peripheral adverse effects.7 This article will review the efficacy, safety and tolerability of dronedarone for maintenance of sinus Ana Marquez, Pharm.D. Candidate rhythm in AF. PHARMACOLOGY AND PHARMACOKINETICS (PK) Dronedarone is a benzofuran derivative that has A trial fibrillation (AF) is the most common sus- electrophysiological properties of all Vaughan- tained cardiac arrhythmia affecting approxi- Williams antiarrhythmic drug classes. Specifically, mately 2.2 million people in the US.1 AF is dronedarone blocks sodium and calcium channels, prevalent in <1% of adults younger than 55 and ap- demonstrates noncompetitive antiadrenergic actions proaches 10% in those older than 80.2 AF results in and prolongs the action potential and refractory peri- hemodynamic and thromboembolic complications, ods.8 Oral dronedarone prolongs the PR and QTc inter- and increases the rate of ischemic stroke 5 fold.1,3 val in a dose-dependent manner. Heart rate is not af- Hospitalization rates due to AF have increased by 66% fected by oral administration of 400 mg twice daily during the past 20 years resulting in a significant pub- and is reduced by ~4 beats/min with 800 mg twice lic health burden. This cost will continue to rise due to daily.9 an aging population.3,4 One of every six strokes occurs Dronedarone undergoes extensive first-pass me- in a patient with AF with mortality rates doubled com- tabolism and has a low bioavailability that is increased pared to patients in sinus rhythm. by food. A 2-fold increase in dose results in an ap- Treatment for AF consists of ventricular rate con- proximate 2.5- to 3.0- fold increase in Cmax and AUC, trol or sinus rhythm control with concomitant antico- indicating nonlinear PK. The main active circulating agulation therapy. Use of long term antiarrhythmic metabolite is formed by N-debutylation. This N- therapy may be needed in the majority of patients due debutyl metabolite has one-tenth to one-third the po- to the high rate of recurrence after electrical or phar- tency of dronedarone. Time to peak plasma concen- macological cardioversion. Antiarrhythmic drugs also tration of dronedarone and its primary metabolite is 3 may be started when symptoms are not suppressed to 6 hours under fed conditions. Dronedarone reaches with rate control therapy alone. But the choice of an- steady-state concentrations after 4 to 8 days of oral tiarrhythmic agent must take into account the safety administration of 400 mg twice daily. Steady-state profile of the drug as well as the underlying heart dis- Cmax and AUC are similar for both parent and active ease of the patient.3 metabolite. Dronedarone moderately inhibits CYP3A Amiodarone, a class III antiarrhythmic drug, is ef- and CYP2D6. 10 fective and commonly used for maintenance of sinus Females have an approximate 30% greater expo- 7 PharmaNote V o l u m e 2 5 , Issue 3 December 2009 sure to dronedarone than males. In a cross study, Japa- total of 25 patients (8.1%) died in the dronedarone nese men showed a 2-fold increase in dronedarone group and 12 patients (3.8%) died in the placebo levels compared to Caucasian men after a single dose group. In the dronedarone arm, 24 out of the 25 of 400 mg. Patients > 65 years of age have a 23% deaths were caused by CV events. Ten of these CV higher exposure than younger patients. Dronedarone deaths were caused by worsening HF. In the placebo exposure is increased by 30% and the N-debutyl me- arm, 9 out of the 12 deaths were caused by CV events. tabolite is decreased by about 50% in patients with Two of these deaths were from worsening HF. The moderate hepatic impairment. Dronedarone’s PK have number of patients having a first hospitalization for an not been studied in individuals with severe hepatic acute CV event was more common in the dronedarone impairment. No significant PK differences were ob- group (71 patients) compared to placebo (50 pa- served in patients with mild to severe renal insuffi- tients). Overall, rates of hospitalization due to any CV ciency relative to patients with normal renal func- cause were higher in the dronedarone group. The tion.10 In animal studies, dronedarone distributes main cause of these hospitalizations was worsening widely throughout the body, crosses the placenta and HF (35 patients taking dronedarone vs. 30 taking pla- blood brain barrier, and is excreted into breast milk.9 cebo). The only significant laboratory adverse event These PK properties differ significantly from those of more common with dronedarone was an increase in amiodarone (Table 1). serum creatinine. This increase in serum creatinine was observed immediately after the start of therapy CLINICAL TRIALS and returned to baseline after discontinuation of dronedarone. ANDROMEDA The authors concluded that dronedarone should ANDROMEDA was a randomized, double-blind, not be used in patients with HF and LV systolic dys- placebo-control, parallel-group, multicenter trial con- function, and that further studies were needed to ana- ducted to test the hypothesis that dronedarone 400 lyze the effect of the drug on renal function (Table 2). mg twice daily could decrease hospitalization and sud- den cardiac death caused by arrhythmia in patients EURIDIS/ADONIS with HF.11 Study participants were hospitalized pa- EURIDIS/ADONIS were two identical, randomized, tients with new or decompensated HF who had had double-blind, parallel-group, placebo-controlled, mul- symptoms of NYHA class III/IV HF or paroxysmal noc- tinational trials comparing dronedarone 400 mg twice turnal dyspnea within the month before hospitaliza- daily with placebo in patients with at least one episode tion. The primary end point was death from any cause of AF or atrial flutter (AFL), on sinus rhythm at time of or hospitalization from worsening HF. The study was randomization, and without NYHA class III/IV HF.12 originally planned for 2 years, but was prematurely EURIDIS was conducted in Europe and ADONIS in stopped at 7 months (January 2003) due to excess America, Africa and Australia. The primary endpoint mortality in patients assigned to dronedarone. Partici- was time to first recurrence of AF/AFL. pants were followed for 6 months after discontinua- The combined results of both trials favored drone- tion of the study drug. darone: time to recurrence was 116 days with drone- In the course of a median follow up of 2 months, a darone vs. 53 days with placebo (HR=0.75, p=0.001). Table 1. Pharmacokinetic of dronedarone and amiodarone PROPERTY DRONEDARONE AMIODARONE Oral bioavailability 15% with high fat meal; 4% without meals 35%-65% Protein binding >98% (mainly albumin) ~96% V (steady state) 1400 L (IV) 4936 L d Metabolism CYP3A4 (>84%) CYP3A4 and CYP2C8 Principal active metabolite N-debutyl metabolite N-desethylamiodarone Urine: ~6% mainly as metabolites Urine: negligible Excretion Feces:~84% mainly as metabolites Bile: primary Elimination half life 13-19 hours 15-142 days Effect on CYP450 CYP3A and CYP2D6 moderate inhibitor; CYP3A4, CYP1A2, CYP2C9, CYP2D6 and P-gp potential P-gp inhibitor inhibitor V = volume of distribution; P-gp = P-glycoprotein d 8 PharmaNote V o l u m e 2 5 , Issue 3 December 2009 Table 2. Summary of efficacy and safety trials of dronedarone TRIAL PATIENTS DESIGN PRIMARY ENDPOINT (PE) RESULTS EURIDIS/ADONIS12 Paroxysmal DB RCT Time to 1st recurrence of EURIDIS (2007) or Persistent AF/ AF/AFL PE: 96 days (DRO) vs. 41 days (PCB), p=0.01 AFL DRO 400mg BID Recurrence at 12 mo: 67.1%(DRO) vs. 77.5%(PCB) n=1237 (n=828) vs. PCB HR*=0.78, p=0.01 (n=409) ADONIS PE: 158 days (DRO) vs. 59 days (PCB), p=0.002 Follow up: 12 mo Recurrence at 12 mo: 61.1%(DRO) vs. 72.8% (PCB) HR*=0.73, p=0.002 ANDROMEDA11 Hospitalized pa- DB RCT Death from any cause or PE: 53 events (DRO) vs. 40 (PCB) HR*=1.38 (2008) tients with new DRO 400mg BID hospitalization for wors- p=0.12 or worsening HF, (n=310) vs PCB ening HF n=627 with NYHA class (n=317) Death: 8.1% (DRO) vs. 3.8% (PCB) HR*=2.13%, III/IV HF or parox- p=0.03 ysmal nocturnal Median follow up: dyspnea 2 mo 1st CV Hospitalization 71 Pts (DRO) vs. 50 Pts (PCB) p=0.02, worsening HF was main reason 35 Pts (DRO) vs. 30 Pts (PCB) ATHENA7 Paroxysmal or DB RCT First hospitalization due PE: 31.9% (DRO) vs. 39.4% (PCB) HR*= 0.76 (2009) persistent AF/AFL to CV events or death p<0.001 with recent epi- DRO 400mg BID from any cause n= 4628 sode and risk vs. PCB 1st CV hospitalization: 29.3% (DRO) vs. 36.9% factors (PCB) HR*=0.74 p<0.001, driven by reduction in Mean follow up: hospitalization for AF & ACS 21±5 mo All-cause mortality: 5% (DRO) vs. 6% (PCB) HR*=0.84 p=0.18 CV mortality: 2.7% (DRO) vs. 3.9% (PCB) HR*=0.71 p<0.03 mainly driven by reduction in death from cardiac arrhythmia DIONYSOS13 DRO 400 mg BID Recurrence of AF or dis- PE: 73.9% (DRO) vs. 55.3% (AMIO) p<0.001 (pending) vs. AMIO 600 mg continuation of the study daily X 28 days drug because of lack of AF recurrence: 36.5%(DRO) vs. 24.3%(AMIO) n=504 then 200 mg daily efficacy or intolerance Premature discontinuation: 26 patients (DRO) vs. Duration: mean 7 34 (AMIO). months *HR are for dronedarone group ACS=acute coronary syndromes; ADONIS=American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm; AF=atrial fibrillation; AFL=atrial flutter; AMIO=amiodarone; ANDROMEDA=Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease; ATHENA=A Placebo-Controlled, Double Blind Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg Bid for the Prevention of Cardiovascular Hospitalization or Death from any cause in Patients with AF/AFL; CV=cardiovascular; DB=double blind; DIONYSOS=The Efficacy and Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients with AF; DRO=dronedarone; EURIDIS=European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm; HF=heart failure; NYHA=New York Heart Association; PCB=placebo Pts=patients; RCT randomized-placebo-control trial. The rates of symptomatic first recurrence were 37.7% The authors concluded that dronedarone was bet- in the dronedarone group vs. 46.0% in the placebo ter at reducing rates of first recurrence and sympto- group (p<0.001). In addition, the ventricular rate matic recurrence at 12 months without significant (bpm) during recurrence was lower with dronedarone prolongation of the QT or QTc interval. (117.5 ± 29.1 and 116.6 ± 31.9, in EURIDIS and ADONIS, respectively) compared to placebo (102.3 ± ATHENA 24.7 and 104.6 ± 27.1). Rates of hospitalization or ATHENA was a randomized, double-blind, placebo- death at 12 months were 22.8% with dronedarone controlled, parallel-arm, multinational trial that as- and 30.9% with placebo. More cases of hyperthyroid- sessed the efficacy of dronedarone in the prevention ism and increase in creatinine concentration were of CV hospitalization or death from any cause in pa- seen with dronedarone. tients with AF/AFL.7 Patients included in the study 9 PharmaNote V o l u m e 2 5 , Issue 3 December 2009 had a recent episode (within 6 months) of paroxysmal ferent: 26 with dronedarone and 48 with placebo or persistent AF/AFL and at least one of the following (p=0.01). The prevalence of abnormal liver function risk factor: age ≥ 70, diabetes, taking ≥ 2 antihyperten- tests, endocrine events (hyper- and hypo-thyroidism), sive medications, previous stroke/TIA/systemic em- or interstitial lung disease were not different vs. pla- boli, left atrial (LA) diameter ≥ 50 mm, left ventricular cebo. Side effects more common with dronedarone ejection fraction (LVEF) ≤ 40%. The study excluded were gastrointestinal (GI) disorders, mainly diarrhea patients with recent HF decompensation and NYHA and nausea, bradycardia, QT prolongation, rash, and class IV HF. Patients were randomized to receive ei- increased serum creatinine. GI side effects (12.7%) ther placebo or dronedarone 400 mg twice daily. Ap- were the main reason for discontinuation of therapy proximately 25% of patients entered the study while with dronedarone vs. placebo (8.1%). However, rate of on AF/AFL (patients not on sinus rhythm at enroll- discontinuation of ~30% due to any adverse event ment were expected to be cardioverted); ~21% had were similar in both treatment groups. NYHA classII/III HF; and ~12% had LVEF < 45%. The The authors concluded that dronedarone was as- most common underlying CV disease was hyperten- sociated with a significant reduction in the rate of hos- sion (~85%) and structural heart disease was present pitalization due to CV events or death compared with in ~60% of patients. The primary endpoint was first placebo, without a significant increase in thyroid or hospitalization due to CV events or death from any pulmonary toxicities. However a mean follow up of 21 cause, including death from cardiac arrhythmia, non- months may not have been long enough to see side arrhythmic cardiac causes, noncardiac vascular effects such as pulmonary fibrosis which usually ap- causes, and non-CV causes. pears after 2 years of therapy with amiodarone. The primary endpoint was reached by 734 (31.9%) patients in the dronedarone group vs. 917 DIONYSOS (39.4%) patients in the placebo group (HR=0.76, The finalized results of DIONYSOS are awaiting p<0.001). The rate of first hospitalization due to CV publication. Dronedarone was compared to amiodar- events was 29.3% in the dronedarone group vs. 36.9% one in 504 patients for a mean follow up of 7 in the placebo group (HR=0.74, p<0.001). This reduc- months.13 Preliminary data shows that the primary tion in first CV hospitalization favoring dronedarone, endpoint (recurrence of AF or discontinuation of the was driven by a reduction in hospitalization due to AF drug due to lack of efficacy or intolerance) was higher (HR=0.63, p=<0.001) and ACS (HR=0.70, p=0.03). in the dronedarone group vs. the amiodarone group Death from any cause was not different between treat- (73.9% vs. 55.3%, respectively). Patients in the drone- ment groups (116 with dronedarone and 139 with darone group had greater AF recurrence rates placebo, p=0.18). However, death from CV causes was (36.5%) compared to patients in the amiodarone lower with dronedarone (63 events) vs. placebo (90 group (24.3%). Fewer patients discontinued drone- events; HR=0.71, p=0.03). The difference in number of darone prematurely compared to amiodarone (26 pa- deaths from cardiac arrhythmias was statistically dif- tients vs. 34 patients, respectively). Patients on drone- Table 3. Effects of other drugs on dronedarone. DRUG EFFECT MECHANISM Azole antifungals (ketoconazole,itraconazole) ↑ dronedarone exposure Potent CYP3A4 inhibition Nefazodone (Ketoconazole ↑dronedarone exposure by 17- Ritonavir fold & Cmax by 9-fold) Erythromycin Clarithromycin Grapefruit juice Rifampin ↓ dronedarone exposure CYP3A4 induction Carbamazepine (Rifampin increases dronedarone exposure by Phenobarbital 80%) Phenytoin St. John Wort Verapamil ↑dronedarone exposure by 1.4-to 1.7-fold Moderate CYP3A4 inhibition Diltiazem ↓HR and pharmacodynamic inter- action Grapefruit juice ↑ dronedarone exposure 3-fold and Cmax 2.5- CYP3A inhibition fold 10 PharmaNote V o l u m e 2 5 , Issue 3 December 2009

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