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MANAGEMENT OF ACNE
VULGARIS: A REVIEW
Jennifer D. Billman, Pharm.D. Candidate
A cne vulgaris is a common skin disorder caused
by abnormal hyperkeratinization and over-
production of sebum by the sebaceous gland.
Acne first presents early in adolescence and often con-
tinues into early adulthood, negatively affecting qual-
ity of life. This article will review the current treat-
ment options for acne vulgaris.1
EPIDEMIOLOGY
Acne may be psychologically impacting in late ado-
lescence, leading to depression and diminished quality
of life. In the United States, acne affects about 40-50
million people' impacting nearly 80% of the popula-
tion between 12-25 years without gender, ethnicity
or race prevalence differences. The onset of acne vul-
garis varies within age groups, but is more prevalent
during the onset of puberty, and can continue to be a
problem throughout early adulthood.2
ETIOLOGY & PATHOPHYSIOLOGY
The origin of acne vulgaris is complex, but at
least four primary factors are associated with its de-
velopment, including increased sebum production,
sloughing of keratinocytes, bacterial growth and colo-
nization, and inflammation and immune system re-
sponse. At puberty, stimulation of androgens, espe-
cially testosterone, is enhanced. Testosterone and its
active metabolites stimulate sebaceous gland activity,
leading to an increase in sebum production. When hy-
perkeratinization occurs during the natural sloughing
process, sebum mixes with clumped keratinocytes.
This clumping leads to plugging of the follicle, thus
widening the follicle and producing a favorable envi-
ronment for bacteria, such as Propionibacterium acnes.
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 in-
crease the risk for acne vulgaris (Table 1).
TREATMENT OF ACNE
Various therapies are available for the treatment
of acne vulgaris, including topical and oral agents Pre-
ferred therapies differ based on the severity of disease
presentation.
Mild-to-Moderate Acne: Topical Antibiotics
Topical antibiotics including erythromycin and
clindamycin, are effective and well tolerated for the
treatment of acne vulgaris. However, because antibiot-
ics may potentially decrease sensitivity of P. acnes, the
use of these agents should be limited.4 Erythromycin is
used alone for inflammatory acne or in combination
with zinc, which helps the antibiotic penetrate into the
pilosebaceous units. Clindamycin inhibits P. acnes and
INSIDE THIS ISSUE:
MANAGEMENT OF ACNE VULGARIS: A REVIEW
DRONEDARONE: A NEW OPTION FOR ATRIAL
FIBRILLATION
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PharmaNote
VOLUME 25, ISSUE 3 DECEMBER 2009
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Volume 25, Issue 3 1 December 2009
PharmaNote
Table 1: Risk factors for acne vulgaris.
Environmental Factors:
High-humidity
Prolonged sweating
Increase in skin hydration
Exposure to dirt or vaporized cooking oil or certain chemicals
like petroleum derivatives
Cosmetic Use:
Moisturizers
Tanning oils
Cocoa butter
Hormonal Factors:
Menarche
High-androgenic progestin birth control
Emotional Factors:
Severe/prolonged period of stress
Physical Factors:
Occlusive clothing
Headbands
Helmets
Friction-producing devices
Medication Use:
Phenytoin
Isoniazid
Phenobarbital
Lithium
Ethonamide
Steroids
Azathioprine
Quinine
Rifampin
Adapted from Haider A, et. al.3
possesses comedolytic and anti-inflammatory proper-
ties. 1
Topical antimicrobial combination therapy is more
effective than monotherapy.1,4 A randomized, parallel,
vehicle-controlled trial by Lookingbill and colleagues
evaluated 334 patients over an 11-week once-nightly
preparation study. Evaluation was performed on
weeks 2, 5, 8 and 11 for lesion counts, global response
rate and irritant effects of clindamycin plus benzoyl
peroxide gel, benzoyl peroxide alone, clindamycin
alone or vehicle gel.5 The combination of clindamycin/
benzoyl peroxide significantly improved patient global
response and reduced inflammatory and non-
inflammatory response compared to clindamycin
alone, benzoyl peroxide alone, or the vehicle gel.
Monotherapy with clindamycin or benzoyl peroxide
compared to the vehicle gel resulted in significant im-
provement in patient global response and a reduction
in inflammatory and non-inflammatory response. All
of the treatment options were well tolerated.5 Table 2
summarizes the clinical studies of various products
used to treat acne vulgaris, including topical antibiot-
ics.
Mild-to-moderate Acne: Topical Retinoids
The available topical retinoids used for acne vul-
garis include tretinoin (Retin-A), adapalene
(Differin) and tazarotene (Tazorac) (Table 3).
These agents work by reducing obstruction within the
follicle.4,6,7 Such products are considered first-line for
the treatment of mild-to-moderate inflammatory acne
and comedonal acne.2 Additionally, these agents are
preferred for maintenance therapy of acne in order to
preserve the use of antibiotics.4 Topical retinoids are
most effective when used in combination with topical
antibiotics or benzoyl peroxide (Brevoxyle ).1
A meta-analysis by Leyden and colleagues, evaluat-
ing topical tazarotene in mild to moderate acne, found
that tazarotene was well tolerated and effective for the
treatment of acne vulgaris, regardless of patient-
specific factors, including acne severity, skin type, sex
or ethnicity. Six comparative, multicenter, double-
blind, randomized studies of monotherapy with ta-
zarotene 0.1% gel or cream were analyzed, encom-
passing 468 patients who exhibited moderate to com-
plete clearing at 12 weeks. Both inflammatory and non
-inflammatory lesion counts declined substantially
with both formulations over the treatment period.
Furthermore, both formulations were well-tolerated.8
In a 3-way retrospective, investigator blinded, photo-
graphic review, investigators evaluated the efficacy of
tazarotene 0.1% gel, adapalene 0.1% gel, tretinoin
0.1% microsponge, and tretinoin 0.025% gel for the
treatment of inflammatory acne. The authors con-
cluded that all formulations showed significant clinical
improvements compared to tazarotene 0.1% cream
(vehicle).7
Mild-to-moderate Acne: Combination therapy
Recent guidelines suggest that combination ther-
apy with topical retinoids and antimicrobial agents
achieves significantly greater and faster clearing of
acne compared with antimicrobial therapy alone.2
Combination therapies utilize agents with complimen-
tary mechanisms of action to target multiple etiologi-
cal factors simultaneously.2,8
Gollnick and colleagues recently conducted a ran-
domized, double-blind, placebo-controlled study to
Ph m oeVlue2,Ise3 eebr20
Volume 25, Issue 3 1 December 2009
PharmaNote
*
3-way RS, IB, photo-
graphic review evaluat-
ing efficacy of topical
retinoids
Table 2. Clinical studies summary.
STUDY METHODS
Lookingbill, et 11-week, RCT, PL
al.3 (n=334)
(1997)
Leyden, et al.9 6-comparative MC, DB, R
(2004) studies evaluated 468
patients with mild-
Meta-analysis moderate acne
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 popular 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 R 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% R in total acne after 4 months.
(1983) acne 0.5mg/kg/day 89% R 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 = ran-
domized; 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-
zoyl peroxide (BPO) 2.5% combination gel and 0.1%
adapalene, 2.5% BPO, or a vehicle gel. The authors re-
ported that combination therapy was more effective
(P<0.001) at weeks 8 and 12, and at study end com-
pared with BPO monotherapy and a vehicle gel. More-
over, combination therapy was more effective
(P<0.05) at weeks 2 and 4 compared with vehicle-only.
A significant difference in lesion counts from baseline
was reported as early as the 1st week. Adverse effects
were more prevalent in the early phase of treatment
with combination therapy, but these effects were tran-
sient This study showed that combination therapy
was significantly better, synergistically efficacious
with a faster onset, and had an equivalent safety pro-
file when compared to the monotherapies.8
Mild-to-Moderate Acne: Hormonal Therapy
Hormonal therapy produces anti-androgen effects,
which leads to a decrease in testosterone circulating in
the body. Consequently, sebaceous gland stimulation
is prevented, reducing sebum production.3,10 FDA-
approved hormonal therapies consist of oral contra-
ceptive agents that contain norgestimate with ethinyl
estradiol (Ortho-Tri-Cyclen) and norethindrone ace-
tate with ethinyl estrodial (Estrostep), as well as the
anti-androgenic agent, spironolactone (Table 4).4
Anti-androgens, such as spironolactone or cypro-
Ph ra ot olme25 sse IDcebe 20
Leyden, et al.5
(2005)
STUDY GROUPS
Study groups:
. Clindamycin + BPO gel
. BPO gel
. Clindamycin gel
. Placebo (vehicle gel)
. Tazarotene 0.1% gel
. Tazarotene 0.1% cream
. Tazarotene 0.1% gel
. Adapalene 0.1% gel
. Tretinoin 0.1% microsponge
. Tretinoin 0.025% gel
. Tazarotene 0.1% cream
RESULTS
. Clindamycin + BPO showed SS (P<0.001) good/excellent
PGR, R in inflammatory and non-inflammatory re-
sponse and was significantly superiority to clindamycin,
BPO, or vehicle gel alone.
. Clindamycin and BPO alone were SS (P<0.001) vs. vehi-
cle gel in PGR, R in inflammatory and non-inflammatory
response.
Both groups showed:
. Moderate clearing after 12 weeks
. Statistical R in inflammatory and non-inflammatory
lesions
. Well tolerated
. All formulations showed significant clinical improve-
ments in inflammatory acne vs. to vehicle.
Volume 25, Issue 3 1 December 2009
PharmaNote
Table 3. Topical agents for the treatment of acne vulgaris.11'15
Table 3. Topical agents for the treatment of acne vulgaris.11'15
DHFS = dihydrofolate synthetase; FR = free radical; RAR = retinoic acid receptor; BS = bacteriostatic; BC = bacteriocidal; Al = anti-inflammatory; AK = anti-keratinization; FA = folic acid; AVP =
average variable price
DRUG
Clindamycin
(antibiotic)
Erythromycin
(antibiotic)
Sulfacetamide
(antibiotic)
Dapsone
(antibiotic)
Adapelene
Azelaic Acid
Benzoyl Peroxide
Tazoretene
Trentinoin
BRANDS
Cleocin T, Clindagel
Clindesse, Clinda-derm,
Evoclin
Akne Mycin, E-Mycin,
EMGEL, Ery-Pad, Ery-
geIR
Cetamide, Klaron,
Ovace, RE-10 wash, Ro-
sula NS, Seb-Prev
Aczone
Differing
Azelex, Finacea
Finacea Plus, Finevin
Acne-10, Acne-5
Acneclear, Benoxyl Be-
noxyl, Benprox, Benzac,
Benzac, Benzagel, Ben-
ziq, Brevoxyl, ClearPlex,
Desquam EX, Fostex,
Inova Lavoclen, others
Avage, Tazorac
Altinac, Atralin
Avita, Renova, Retin-A,
Trentin-X, Vesanoid
MECHANISM
Inhibits 50s ribosomal subunit of
bacteria, which inhibits protein
synthesis
Inhibits 50s ribosomal subunit of
bacteria, which inhibits protein
synthesis
Inhibits bacterial DHFS, interfering
with FA synthesis, an essential com-
ponent for bacterial development
Mechanism similar to sul-
facetamide, but for dermatological
disorder; possible immunomodula-
tor
Binds specific nuclear RAR, pene-
trating deep into hair follicles,
modulating cell differentiation and
keratinization. Also has potent Al
and comedolytic properties
Exact mechanism unknown: inhibits
microbial protein synthesis; BS at
lower doses; BC at higher doses.
Also direct Al and AK effects
Releases FR oxygen species oxidizes
bacterial proteins. Also keratolytic
activity
Exact mechanism unknown; Bind
specific nuclear RAR, and exerts
effects on keratinocyte differentia-
tion, proliferation, and inflamma-
tion.
Binds to RAR, modifying gene ex-
pression, thus affecting protein
synthesis, epithelial cell growth and
differentiation. Also has AK effects.
STRENGTH/DOSES
1% (cream, solution,
pads)
Any topical applied on
affected area twice daily.
1.5% 2% (solution, gel,
ointment)
Any topical applied on
affected area twice daily.
10% lotion
Apply on affected area
twice daily.
5% gel
Apply on affected area
twice daily.
0.1% (cream or gel) &
0.3% (gel)
Apply to affected areas
once daily before bed-
time.
15%-20% (gel or cream)
Apply to affected areas
twice daily.
2.5% to 10% (creams, gels
or lotions)
Apply once daily and
gradually increase to four
times daily.
0.1% (creams or gel)
Apply a thin film on the
affected area in the eve-
ning.
0.025%, 0.04%, 0.05%, or
0.1% (cream, liquid, gel)
Apply to affected area
once daily at bedtime.
SIDE EFFECTS
Pruritis, acute generalized exanthematous
pustulosis, burning, xerosis, erythema,
oiliness, peeling.
Pruritis, acute generalized exanthematous
pustulosis, nausea, vomiting, diarrhea,
and anorexia.
Hypersensitivity to sulfacetamide, which
may progress to lupus like syndrome.
Photosensitivity
(Most problems are seen in leprosy pa-
tients)
Erythema, burning, xerosis, skin irritation,
photosensitivity, pruritus.
Contact dermatitis, erythema, hyper-
trichosis, infection, pruritus, rash
(unspecified), skin hypopigmentation, skin
irritation, xerosis.
Contact dermitis, erythema, pruritus, rash
(nonspecific), skin irritation, xerosis
Desquamation, burning/stinging, xerosis,
erythema, pruritus, skin irritation, skin
pain, fissuring, localized edema, and skin
discoloration.
Burning, stinging, xerosis, peeling, ery-
thema, and pruritus. Also, skin hyper- or
hypo-pigmentation, photosensitivity.
COST
1% 60gm:
AVP = $48.67
2% 60gm:
Gel = $ 34.99
Soln = $ 14.99
RE-10 Wash: $87.99
60gm tube: $294.99
45gm tube (0.1%,
0.3%): $203.99
Finacea 50gm: $140.99
Azelex 50gm: $188.99
(NO GENERIC)
60gm gel tube:
BPO-10 $29.09
BPO-5 $22.89
297gm lotion:
BPO 4% $55.59
BPO 8% $57.59
60gm tube cream:
0.05% $272.99
0.1% $291.99
100gm tube gel:
0.05% $451.99
0.1% $383.99
45gm tube:
0.01% gel $96.59
0.025% cream $52.99
0.025% gel $85.99
0.05% cream $101.99
0.1% cream $85.59
Table 4. Oral agents for the treatment of acne vulgaris.11'15
DRUG BRANDS MECHANISM STRENGTH/DOSES SIDE EFFECTS COST
Drospirenone; Ethinyl
Estradiol
Ethinyl Estradiol;
Norgestimate
Isotretinoin
Spironolactone
Doxycycline
(antibiotic)
Minocycline
(antibiotic)
Ocella, Yasmin, Yaz-
28
MonoNessa, Ortho Tri-
Cyclen Lo, Ortho-
Cyclen, Ortho Tri-
Cylcen, Sprintec, Tri-
Sprintec, Previfem, Tri
-Previfem, Trinessa
Accutane, Amnes-
teem, Clavaris, Sot-
ret
Aldactone, Spirono
Adoxa, Adoxa, Pack,
Alodox, Atridox, Avi-
doxy, Doxy, Doxy
100, Oracea, Oraxyl
Periostat, Vibra-Tabs,
Vibramycin
Arestin, Cleeravue-M,
Dynacin Minocin,
Myrac, Solodyn
Some have less/no androgenic
activity, thus preventing TT pro-
duction, and are less likely to
stimulate/aggravate sebaceous
glands.
Shows reversible inhibition of
sebum production by reduction
in sebaceous glands, and possi-
ble inhibition of follicular kerati-
nization. Also might have Al
effects.
Acts as an ARA, competitively
inhibiting TT, a steroid that trig-
gers secretion of oil by sebum
glands, leading to acne. Inhibi-
tion leads to decrease in sebum
production.
Prolonged use (> 2
-4 months) needed
for acne resolu-
tion.
0.5-1 mg/kg/day in
two divided doses
for 15-20 weeks.
50-200 mg/day
100 mg twice daily
on day 1, then
100mg once daily
Reversibly binds to 30s subunit
of bacteria, which blocks mRNA
and tRNA function, thus blocking
protein synthesis.
lmg/kg once daily
given for 12 weeks
Menstrual irregularity, breakthrough
bleeding, spotting in the 1st 3 months,
migraines, venous thrombosis embo-
lism, hypertension, vaginal discharge,
vaginal irritation, mood/personality
changes, ocular disorders, Melasma,
photosensitivity, bleeding of the gums,
rash, urticaria, erythema, alopecia,
hirsutism, can exacerbate acne vulgaris
Cheilitis, xerosis, xerostomia, epistaxis,
peeling, pruritus, acneiform rash,
alopecia, eczema, flushing, hirsutism,
impaired wound healing, infection,
photosensitivity, seborrhea, skin fragil-
ity, skin hyper-, hypopigmentation,
urticaria.
Cardiac arrhythmias, hyperkalemia,
gynecomastia, libido decrease, men-
strual irregularity, post-menopausal
bleeding, breast tenderness, hirsutism,
amenorrhea
Diarrhea, nausea, vomiting, epigastric
distress, anorexia, esophagitis, vaginal
candidiasis, photosensitivity, rashes,
nail discoloration, AGEP, neutropenia
and eosinophilia
AA, anorexia, dyspepsia, enterocolitis,
glossitis, N/V/D, pancreatitis, pseu-
domembranous colitis, and stomatitis,
asthma exacerbation, cough, dyspnea,
bronchospasm, pneumonitis, bone
discoloration, photosensitivity, rash,
nail discoloration alopecia, vaginal,
rectal, or oral candidiasis,
Yaz/Yasmin: $74.59
Ocella: $59.99 (G)
28 tablets (ALL)
MonoNessa: $27.99
Ortho-Tri-Cyclen Lo: $62.59 (B)
Tri-Lo-Sprintec: $54.99 (G)
Ortho-Tri-Cyclen : $47.39 (B)
Tri-Sprintec: $31.39 (G)
Trinessa: $47.39 (G)
Ortho-Cyclen: $48.49
Sprintec: $27.99
40mg
AVP (30 tablets): $272.49
(ALL GENERICS)
Accutane (B) 40mg (30 tablets):
$849.99
25mg (30 tablets): $11.19
(FOR GENERIC)
50mg (30 tablets): $35.79 (G)
50mg (30 tablets): $97.59 (G)
ARA = androgen receptor antagonist; RAR = retinoic acid receptor; TT = testosterone; AA = abdominal pain; N/V/D = nausea, vomiting, diarrhea; AGEP = acute generalized exanthematous
pustulosis; AVP = average variable price; G = generic; B = brand
terone, and oral estrogens, such as ethinyl estradiol,
decrease androgen levels in patients with acne. Krunic
et. al., evaluated the safety and efficacy of daily
sprionolactone (SL) 100 mg ,ethinyl estradiol 30 mcg,
and drospirenone (EE/DRSP; Yasmin) 3 mg. The
study found that 85% of subjects had complete clear-
ing of acne lesions or excellent improvement, 7.4%
had mild improvement, and 7.4% had no improve-
ment No significant increase in serum potassium or
other side effects were observed in any subjects. The
authors concluded that EE/DRSP combination therapy
and SL 100 mg daily was well tolerated and efficacious
in the treatment of severe popular and nondulocystic
acne in women.12
In a multinational, multicenter, three-arm, double-
blind, randomized trial, Palombo-Kinne evaluated
healthy women between the age of 16 and 45 with
mild to moderate facial acne. Participants were ran-
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
inflammation and total lesion count and the percent-
age of patients with improvement in acne evaluated by
the Investigator Global Assessment The study found
that EE/DNG was superior to placebo and non-inferior
to EE/CPA. The rates of reduction ( SD) in inflamma-
tory lesions were -65.6+/-29.9% for EE/DNG, -64.6+/-
31.2% for EE/CPA and -49.4+/-41.0% for placebo. The
percentages of patients with improvement of facial
acne were 91.9% for EE/DNG, 90.2% for EE/CPA and
76.2% for placebo. The authors concluded that EE/
DNG was superior to placebo and as effective as EE/
CPA for treatment of mild to moderate acne.13
Severe Acne: Oral Isotretinoin
Isotretinoin (Accutane) is a naturally occurring
metabolite of Vitamin A, and is indicated for the treat-
ment of severe acne. Isotretinoin works by reducing
the size of the sebaceous gland, suppressing sebum
production, and normalizing follicular epithelial des-
quamation (Table 4).14 Several studies show isotreti-
noin to be effective in severe acne. In a randomized
controlled trial with 76 patients, isotretinoin showed
an 80% reduction in total acne after 4 months. Treat-
ment doses ranged from 0.1mg/kg/day to 0.5mg/kg/
day. An 89% reduction in total lesions was observed at
the 1.0mg/kg/day dose.10,14 Although the drug is effec-
tive for severe acne, reported side effects may be se-
vere, including inflammation of the lips, which is dose
related. In addition, xerosis, xerostomia, epitaxis, peel-
ing, pruritus, nausea/vomiting, altered lipid profiles,
and most importantly, teratogenesis may occur with
any amount of isotretinoin ingestion.10 Because of the
teratogenicity, men and women of child-bearing age
are asked to register and comply with the FDA ap-
proved iPLEDGE program. This program is a risk man-
agement program that prevents isotretinoin exposure
to the fetus.
SUMMARY
Many well-tolerated and effective options are
available for the treatment of acne vulgaris, depending
on the type and severity of disease. Topical retinoids,
antibiotics and BPO are effective for mild-to-moderate
acne, while oral isotretinoin and hormonal therapy are
effective for more severe cases. In addition, combina-
tion therapy with clindamycin and BPO is more effec-
tive than treatment with either alone. Management of
this common dermatologic disorder may contribute to
a better quality of life.
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14. Jones DH, King K, Miller AJ, et al. A dose response study of 13-
cis retinoic acid in acne vulgaris. Br J Dermatol 1983;108:333-
43.
15. Lexi-Comp OnlineTM, 2009. Accessed: July 15, 2009. Available:
http://www.crlonline.com/crlsql/servlet/crlonline.
DRONEDARONE: A NEW
TREATMENT OPTION FOR
ATRIAL FIBRILLATION
Ana Marquez, Pharm.D. Candidate
trial fibrillation (AF) is the most common sus-
tained cardiac arrhythmia affecting approxi-
mately 2.2 million people in the US.1 AF is
prevalent in <1% of adults younger than 55 and ap-
proaches 10% in those older than 80.2 AF results in
hemodynamic and thromboembolic complications,
and increases the rate of ischemic stroke 5 fold.1,3
Hospitalization rates due to AF have increased by 66%
during the past 20 years resulting in a significant pub-
lic health burden. This cost will continue to rise due to
an aging population.3,4 One of every six strokes occurs
in a patient with AF with mortality rates doubled com-
pared to patients in sinus rhythm.
Treatment for AF consists of ventricular rate con-
trol or sinus rhythm control with concomitant antico-
agulation therapy. Use of long term antiarrhythmic
therapy may be needed in the majority of patients due
to the high rate of recurrence after electrical or phar-
macological cardioversion. Antiarrhythmic drugs also
may be started when symptoms are not suppressed
with rate control therapy alone. But the choice of an-
tiarrhythmic agent must take into account the safety
profile of the drug as well as the underlying heart dis-
ease of the patient3
Amiodarone, a class III antiarrhythmic drug, is ef-
fective and commonly used for maintenance of sinus
PharmaNote
rhythm. In the AFFIRM trial, 67% of patients in the
rhythm control group were started on amiodarone or
sotalol; and at the end of the study 66% of the patients
had tried amiodarone at least once.5 An advantage of
amiodarone is the low poarrhythmic risk of in left ven-
tricular (LV) hypertrophy, heart failure (HF), coronary
artery disease, and post myocardial infarction.3 How-
ever, this agent is limited by extra-cardiac toxicities
including pulmonary fibrosis, hepatic and thyroid dys-
function, neurological disorders, blue-gray skin discol-
oration, and corneal deposits. In addition, amiodarone
has a complicated dosing schedule and interacts with
some cardiovascular (CV) agents including warfarin
and digoxin.3,6 Dronedarone (Multaq) is an amiodar-
one analogue manufactured by Sanofi-Aventis and re-
cently 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-
sulfonyl group that decreases lipophilicity. These
changes were intended to reduce accumulation in tis-
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
rhythm in AF.
PHARMACOLOGY AND PHARMACOKINETICS (PK)
Dronedarone is a benzofuran derivative that has
electrophysiological properties of all Vaughan-
Williams antiarrhythmic drug classes. Specifically,
dronedarone blocks sodium and calcium channels,
demonstrates noncompetitive antiadrenergic actions
and prolongs the action potential and refractory peri-
ods.8 Oral dronedarone prolongs the PR and QTc inter-
val in a dose-dependent manner. Heart rate is not af-
fected by oral administration of 400 mg twice daily
and is reduced by ~4 beats/min with 800 mg twice
daily.9
Dronedarone undergoes extensive first-pass me-
tabolism and has a low bioavailability that is increased
by food. A 2-fold increase in dose results in an ap-
proximate 2.5- to 3.0- fold increase in Cmax and AUC,
indicating nonlinear PK. The main active circulating
metabolite is formed by N-debutylation. This N-
debutyl metabolite has one-tenth to one-third the po-
tency of dronedarone. Time to peak plasma concen-
tration of dronedarone and its primary metabolite is 3
to 6 hours under fed conditions. Dronedarone reaches
steady-state concentrations after 4 to 8 days of oral
administration of 400 mg twice daily. Steady-state
Cmax and AUC are similar for both parent and active
metabolite. Dronedarone moderately inhibits CYP3A
and CYP2D6. 10
Females have an approximate 30% greater expo-
Volume 25, Issue 3 I December 2009
sure to dronedarone than males. In a cross study, Japa-
nese men showed a 2-fold increase in dronedarone
levels compared to Caucasian men after a single dose
of 400 mg. Patients > 65 years of age have a 23%
higher exposure than younger patients. Dronedarone
exposure is increased by 30% and the N-debutyl me-
tabolite is decreased by about 50% in patients with
moderate hepatic impairment. Dronedarone's PK have
not been studied in individuals with severe hepatic
impairment No significant PK differences were ob-
served in patients with mild to severe renal insuffi-
ciency relative to patients with normal renal func-
tion.10 In animal studies, dronedarone distributes
widely throughout the body, crosses the placenta and
blood brain barrier, and is excreted into breast milk.9
These PK properties differ significantly from those of
amiodarone (Table 1).
CLINICAL TRIALS
ANDROMEDA
ANDROMEDA was a randomized, double-blind,
placebo-control, parallel-group, multicenter trial con-
ducted to test the hypothesis that dronedarone 400
mg twice daily could decrease hospitalization and sud-
den cardiac death caused by arrhythmia in patients
with HF." Study participants were hospitalized pa-
tients with new or decompensated HF who had had
symptoms of NYHA class III/IV HF or paroxysmal noc-
turnal dyspnea within the month before hospitaliza-
tion. The primary end point was death from any cause
or hospitalization from worsening HF. The study was
originally planned for 2 years, but was prematurely
stopped at 7 months (January 2003) due to excess
mortality in patients assigned to dronedarone. Partici-
pants were followed for 6 months after discontinua-
tion of the study drug.
In the course of a median follow up of 2 months, a
total of 25 patients (8.1%) died in the dronedarone
group and 12 patients (3.8%) died in the placebo
group. In the dronedarone arm, 24 out of the 25
deaths were caused by CV events. Ten of these CV
deaths were caused by worsening HF. In the placebo
arm, 9 out of the 12 deaths were caused by CV events.
Two of these deaths were from worsening HF. The
number of patients having a first hospitalization for an
acute CV event was more common in the dronedarone
group (71 patients) compared to placebo (50 pa-
tients). Overall, rates of hospitalization due to any CV
cause were higher in the dronedarone group. The
main cause of these hospitalizations was worsening
HF (35 patients taking dronedarone vs. 30 taking pla-
cebo). The only significant laboratory adverse event
more common with dronedarone was an increase in
serum creatinine. This increase in serum creatinine
was observed immediately after the start of therapy
and returned to baseline after discontinuation of
dronedarone.
The authors concluded that dronedarone should
not be used in patients with HF and LV systolic dys-
function, and that further studies were needed to ana-
lyze the effect of the drug on renal function (Table 2).
EURIDIS/ADONIS
EURIDIS/ADONIS were two identical, randomized,
double-blind, parallel-group, placebo-controlled, mul-
tinational trials comparing dronedarone 400 mg twice
daily with placebo in patients with at least one episode
of AF or atrial flutter (AFL), on sinus rhythm at time of
randomization, and without NYHA class III/IV HF.12
EURIDIS was conducted in Europe and ADONIS in
America, Africa and Australia. The primary endpoint
was time to first recurrence of AF/AFL.
The combined results of both trials favored drone-
darone: time to recurrence was 116 days with drone-
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%
Vd (steady state) 1400 L (IV) 4936 L
Metabolism CYP3A4 (>84%) CYP3A4 and CYP2C8
Principal active metabolite N-debutyl metabolite N-desethylamiodarone
Urine: ~6% mainly as metabolites Urine: negligible
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
Vd = volume of distribution; P-gp = P-glycoprotein
n6 iai I-*--I ** 0 Xf
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ra ma ote
Table 2. Summary of efficacy and safety trials of dronedarone
TRIAL PATIENTS DESIGN PRIMARY ENDPOINT (PE) RESULTS
EURIDIS/ADONIS2 Paroxysmal DB RCT Time to 1' recurrence of
or Persistent AF/
AFL
ANDROMEDA"
(2008)
n=627
ATHENA7
(2009)
n= 4628
Hospitalized pa-
tients with new
or worsening HF,
with NYHA class
Ill/IV HF or parox-
ysmal nocturnal
dyspnea
Paroxysmal or
persistent AF/AFL
with recent epi-
sode and risk
factors
AF/AFL
n=1237
DRO 400 mg BID
vs. AMIO 600 mg
daily X 28 days
then 200 mg daily
Duration: mean 7
months
DRO 400mg BID
(n=828) vs. PCB
(n=409)
Follow up: 12 mo
DB RCT
DRO 400mg BID
(n=310) vs PCB
(n=317)
Median follow up:
2 mo
DB RCT
DRO 400mg BID
vs. PCB
Mean follow up:
215 mo
First hospitalization due
to CV events or death
from any cause
Recurrence of AF or dis-
continuation of the study
drug because of lack of
efficacy or intolerance
(2007)
*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%
in the dronedarone group vs. 46.0% in the placebo
group (p<0.001). In addition, the ventricular rate
(bpm) during recurrence was lower with dronedarone
(117.5 29.1 and 116.6 31.9, in EURIDIS and
ADONIS, respectively) compared to placebo (102.3
24.7 and 104.6 27.1). Rates of hospitalization or
death at 12 months were 22.8% with dronedarone
and 30.9% with placebo. More cases of hyperthyroid-
ism and increase in creatinine concentration were
seen with dronedarone.
The authors concluded that dronedarone was bet-
ter at reducing rates of first recurrence and sympto-
matic recurrence at 12 months without significant
prolongation of the QT or QTc interval.
ATHENA
ATHENA was a randomized, double-blind, placebo-
controlled, parallel-arm, multinational trial that as-
sessed the efficacy of dronedarone in the prevention
of CV hospitalization or death from any cause in pa-
tients with AF/AFL.7 Patients included in the study
Pha rma Note Volume 25, Issue 3 I December 2009
EURIDIS
PE: 96 days (DRO) vs. 41 days (PCB), p=0.01
Recurrence at 12 mo: 67.1%(DRO) vs. 77.5%(PCB)
HR*=0.78, p=0.01
ADONIS
PE: 158 days (DRO) vs. 59 days (PCB), p=0.002
Recurrence at 12 mo: 61.1%(DRO) vs. 72.8%
(PCB)
HR*=0.73, p=0.002
PE: 53 events (DRO) vs. 40 (PCB) HR*=1.38
p=0.12
Death: 8.1% (DRO) vs. 3.8% (PCB) HR*=2.13%,
p=0.03
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)
PE: 31.9% (DRO) vs. 39.4% (PCB) HR*= 0.76
p<0.001
1st CV hospitalization: 29.3% (DRO) vs. 36.9%
(PCB) HR*=0.74 p<0.001, driven by reduction in
hospitalization for AF & ACS
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
PE: 73.9% (DRO) vs. 55.3% (AMIO) p<0.001
AF recurrence: 36.5%(DRO) vs. 24.3%(AMIO)
Premature discontinuation: 26 patients (DRO) vs.
34 (AMIO).
Death from any cause or
hospitalization for wors-
ening HF
DIONYSOS13
(pending)
n=504
Volume 25, Issue 3 1 December 2009
PharmaNote
had a recent episode (within 6 months) of paroxysmal
or persistent AF/AFL and at least one of the following
risk factor: age _> 70, diabetes, taking _> 2 antihyperten-
sive medications, previous stroke/TIA/systemic em-
boli, left atrial (LA) diameter 50 mm, left ventricular
ejection fraction (LVEF) <: 40%. The study excluded
patients with recent HF decompensation and NYHA
class IV HF. Patients were randomized to receive ei-
ther placebo or dronedarone 400 mg twice daily. Ap-
proximately 25% of patients entered the study while
on AF/AFL (patients not on sinus rhythm at enroll-
ment were expected to be cardioverted); ~21% had
NYHA classll/III HF; and -12% had LVEF < 45%. The
most common underlying CV disease was hyperten-
sion (-85%) and structural heart disease was present
in ~60% of patients. The primary endpoint was first
hospitalization due to CV events or death from any
cause, including death from cardiac arrhythmia, non-
arrhythmic cardiac causes, noncardiac vascular
causes, and non-CV causes.
The primary endpoint was reached by 734
(31.9%) patients in the dronedarone group vs. 917
(39.4%) patients in the placebo group (HR=0.76,
p<0.001). The rate of first hospitalization due to CV
events was 29.3% in the dronedarone group vs. 36.9%
in the placebo group (HR=0.74, p<0.001). This reduc-
tion in first CV hospitalization favoring dronedarone,
was driven by a reduction in hospitalization due to AF
(HR=0.63, p=<0.001) and ACS (HR=0.70, p=0.03).
Death from any cause was not different between treat-
ment groups (116 with dronedarone and 139 with
placebo, p=0.18). However, death from CV causes was
lower with dronedarone (63 events) vs. placebo (90
events; HR=0.71, p=0.03). The difference in number of
deaths from cardiac arrhythmias was statistically dif-
ferent: 26 with dronedarone and 48 with placebo
(p=0.01). The prevalence of abnormal liver function
tests, endocrine events (hyper- and hypo-thyroidism),
or interstitial lung disease were not different vs. pla-
cebo. Side effects more common with dronedarone
were gastrointestinal (GI) disorders, mainly diarrhea
and nausea, bradycardia, QT prolongation, rash, and
increased serum creatinine. GI side effects (12.7%)
were the main reason for discontinuation of therapy
with dronedarone vs. placebo (8.1%). However, rate of
discontinuation of ~30% due to any adverse event
were similar in both treatment groups.
The authors concluded that dronedarone was as-
sociated with a significant reduction in the rate of hos-
pitalization due to CV events or death compared with
placebo, without a significant increase in thyroid or
pulmonary toxicities. However a mean follow up of 21
months may not have been long enough to see side
effects such as pulmonary fibrosis which usually ap-
pears after 2 years of therapy with amiodarone.
DIONYSOS
The finalized results of DIONYSOS are awaiting
publication. Dronedarone was compared to amiodar-
one in 504 patients for a mean follow up of 7
months.13 Preliminary data shows that the primary
endpoint (recurrence of AF or discontinuation of the
drug due to lack of efficacy or intolerance) was higher
in the dronedarone group vs. the amiodarone group
(73.9% vs. 55.3%, respectively). Patients in the drone-
darone group had greater AF recurrence rates
(36.5%) compared to patients in the amiodarone
group (24.3%). Fewer patients discontinued drone-
darone prematurely compared to amiodarone (26 pa-
tients vs. 34 patients, respectively). Patients on drone-
Table 3. Effects of other drugs on dronedarone.
DRUG
. Azole antifungals (ketoconazole,itraconazole)
. Nefazodone
. Ritonavir
. Erythromycin
. Clarithromycin
. Grapefruit juice
. Rifampin
. Carbamazepine
. Phenobarbital
. Phenytoin
. St. John Wort
. Verapamil
. Diltiazem
. Grapefruit juice
EFFECT
t dronedarone exposure
(Ketoconazole tdronedarone exposure by 17-
fold & Cmax by 9-fold)
,l, dronedarone exposure
(Rifampin increases dronedarone exposure by
80%)
tdronedarone exposure by 1.4-to 1.7-fold
,,HR
t dronedarone exposure 3-fold and Cmax 2.5-
MECHANISM
Potent CYP3A4 inhibition
CYP3A4 induction
Moderate CYP3A4 inhibition
and pharmacodynamic inter-
action
CYP3A inhibition
Pharm NteVoum 2, Isu 3I ecmbr 00
Volume 25, Issue 3 1 December 2009
PharmaNote
Table 4. Effects of dronedarone on other drugs.9
DRUG EFFECT MECHANISM
Digoxin t concentration 2.5-fold P-glycoprotein
Simvastatin level t 4- & 2-fold, respectively CYP3A4 inhibition
Metoprolol level t 1.6-fold CYP2D6 inhibition
Propranolol level t 1.3-fold CYP2D6 inhibition
13-blockers, TCAs, SSRIs t plasma concentration CYP2D6 inhibition
Verapamil, Diltiazem or Nifedipine level t 1.4-to 1.5-fold CYP3A4
Cyclosporine, Sirolimus, Tacrolimus t plasma concentration CYP3A4 inhibition
SSRIs=selective serotonin reuptake inhibitors; TCA= tricyclic antidepressants.
darone had fewer thyroid and neurologic side effects.
Dronedarone was correlated with fewer occurrences
of bradycardia, and QT prolongation than amiodarone.
GI side effects such as diarrhea, vomiting, and nausea,
were more common with dronedarone.12 The small
sample size and limited duration of follow up make it
difficult to statistically interpret the findings from this
superiority trial.
SAFETY
Results from the ANDROMEDA trial led to a box
warning from the FDA that discourages dronedarone
use in patients with NYHA class IV HF and in NYHA
class II/III HF with a recent decompensation that re-
quires hospitalization. Patients need to be advised to
contact their physician at any signs of weight gain,
edema, or shortness of breath.10
The effect of dronedarone on renal function was
assessed in 15 healthy individuals. Dronedarone re-
duced renal creatinine clearance by about 18% with-
out reducing renal sinistrin clearance compared to
placebo. This indicates no effect on glomerular filtra-
tion rate but a partial inhibition of tubular organic
cation transporters that lead to a potential interaction
with cationic drugs.13 The increase in serum creatinine
(SrCr) concentration happens quickly, reaches a pla-
teau after 7 days and reverses after discontinuation.
The plateau SrCr concentration should be used as the
patient's new baseline.10
Dronedarone should not be given with drugs that
are strong CYP3A inhibitors or those that have the po-
tential to prolong the QT interval, such as class I and
III antiarrhythmics (e.g. ibutilide, quinidine, procaina-
mide, dofetilide, amiodarone), fluoroquinolones, or
ritonavir to avoid the risk of developing Torsade de
Points (Tables 3 & 4). Dronedarone is contraindi-
cated in patients with second- or third-degree AV
block, sick sinus syndrome (if not on pacemaker), bra-
dycardia < 50 bpm, PR interval > 280 ms, and should
be stopped if the QTc interval is 500 ms. The drug is
classified in pregnancy category X and should be
avoided in nursing women because its excretion in
human milk is unknown. Safety and efficacy have not
been studied in people under the age of 18 and in se-
vere hepatic impairment.10
Dronedarone has the potential to cause hypo-
kalemia and hypomagnesemia; therefore, monitoring
is warranted when potassium- or magnesium-
depleting diuretics are used concomitantly. Also use
caution when coadministering with drugs that de-
crease AV node conduction such as beta-adrenergic
antagonists and non-dihydropyridine calcium-channel
blockers.10
The most common adverse events are diarrhea,
nausea, vomiting, abdominal pain and asthenia (Table
5). Photosensitivity reactions have been reported in
<1%.10
Table 5. Adverse effects of dronedarone in clinical trials.
ADVERSE EFFECT DRONEDARONE PLACEBO
Diarrhea 9% 6%
Nausea 5% 3%
Abdominal Pain 4% 3%
Vomiting 2% 1%
Dyspepsia 2% 1%
Asthenia 7% 5%
Bradycardia 3% 1%
Skin (rash, pruritus, eczema, dermatitis) 5% 3%
Serum creatinine increase 10% after 5 days of treatment 51% 21%
QTc prolongation (>450 ms in males >470 ms in females) 28% 19%
n6 N W-1 nr I -nnnn
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U1110 00U0 OL10111 01
INDICATION, DOSAGE AND COST
The approved indication, based on the
ATHENA study, is to reduce the risk of CV hospitaliza-
tions in patients with paroxysmal or persistent AF,
with a recent episode of AF/AFL and CV risk factors
(age > 70, hypertension, diabetes, prior cerebrovascu-
lar accident, LA diameter > 50 mm or LVEF < 40%)
who are in sinus rhythm or will be cardioverted. 10 The
recommended dose is 400 mg twice daily by the oral
route. This dose should be administered with the
morning and evening meals to increase bioavailabil-
ity.10 Dronedarone is available as 400 mg oral tablets
and the average retail price of a 30-day supply is
$274.32, ranging from $265.99 to $286.99.
SUMMARY
Dronedarone significantly decreases time to
AF/AFL recurrence, CV hospitalizations, and death due
to CV events compared to placebo. No reports of seri-
ous extra cardiac toxicities, such as thyroid and pul-
monary diseases, have been noted with dronedarone
in clinical trials. Emphasis should be placed on using
dronedarone in the appropriate patient and avoiding
its use in patients with NYHA Class IV HF as well as
those with NYHA class III/IV HF with recent decom-
pensation that required hospitalization.
5. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of
rate control and rhythm control in patients with atrial
fibrillation. N Engl J Med 2002;347(23):1825-33.
6. MICROMEDEX Health Care Series online. Accessed Au-
gust 10, 2009.
7. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of
dronedarone on cardiovascular events in atrial fibrilla-
tion. N Engl J Med 2009;360(7):668-78.
8. Hohnloser SH, Connolly SJ, Crijns HJ, et al. Rationale and
design of ATHENA: A placebo-controlled, double-blind,
parallel arm Trial to assess the efficacy of dronedarone
400 mg bid for the prevention of cardiovascular Hospi-
talization or death from any cause in patiENts with
Atrial fibrillation/atrial flutter. J Cardiovasc Electro-
physiol 2008;19(1):69-73.
9. Hoy SM, Keam SJ. Dronedarone. Drugs. 2009;69
(12):1647-63.
10. Sanofi-Aventis. Multaq (dronedarone) package insert.
Bridgewater, NJ; 2009.
11. K0ber L, Torp-Pedersen C, McMurray JJV, et al. In-
creased mortality after dronedarone therapy for severe
heart failure. N Engl J Med 2008;358(25):2678-87.
12. Singh BN, Connolly SJ, Crijns HGJM, et al. Dronedarone
for maintenance of sinus rhythm in atrial fibrillation or
flutter. N Engl J Med 2007;357:987-99.
13. Howard PA. Dronedarone: Emergence of a new thera-
peutic option for the treatment of atrial fibrillation.
Hospital Pharmacy 2009:44(7):562-568.
14. Tschuppert Y, Buclin T, Rothuizen LE, et al. Effect of
dronedarone on renal function in healthy subjects. Br J
Clin Pharmacol 2007;64(6):785-91.
REFERENCES
1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart dis-
ease and stroke statistics--2009 update: a report from
the American Heart Association Statistics Committee
and Stroke Statistics Subcommittee. Circulation
2009;119(3):480-6.
2. Alan S. Go, MD. The Epidemiology of Atrial Fibrillation
in Elderly Persons: The Tip of the Iceberg. Am J Geriatr
Cardiol 2005;14(2):56-61.
3. Fuster V, Ryd6n LE, Cannom DS, et al. ACC/AHA/ESC
2006 guidelines for the management of patients with
atrial fibrillation: full text: a report of the American Col-
lege of Cardiology/American Heart Association Task
Force on practice guidelines and the European Society
of Cardiology Committee for Practice Guidelines
(Writing Committee to Revise the 2001 guidelines for
the management of patients with atrial fibrillation) de-
veloped in collaboration with the European Heart
Rhythm Association and the Heart Rhythm Society. Cir-
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4. Wattigney WA, Mensah GA, Croft JB. Increasing trends
in hospitalization for atrial fibrillation in the United
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prevention. Circulation 2003;108(6):711-6.
U -
Pha rma Note Volume 25, Issue 3 I December 2009
The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacotherapy and Translational
Research
University of Florida
John G. Gums Editor
PharmD, FCCP
R. Whit Curry, MD Associate Editor
Steven M. Smith Assistant Editor
PharmD
* JW
Volume 25, Issue 3 1 December 2009
PharmaNote
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