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Publication Date: November 2007
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ROTIGOTINE (NEUPRO):
THE FIRST TRANSDERMAL
DOPAMINE AGONIST FOR
PARKINSON'S DISEASE

Stacy Salmon, Pharm. D. Candidate


Approximately 1.5 million Americans cur-
rently have Parkinson's disease (PD) with about
60,000 new cases diagnosed every year. Parkinson's
disease is uncommon in people younger than 40, and
the incidence of the disease increases rapidly over 60
years, with a mean age at diagnosis of 70.5 years.1
The increasing elderly population and the high
prevalence of PD within this group create a large
economic burden. The approximate annual service
costs including formal healthcare and informal care
from friends and family accounted for an estimated
$25,000 yearly per individual with PD.2
Control of PD symptoms remains inadequate
in many patients despite the availability of several
classes of drugs. Current treatment options include
levodopa preparations, dopamine agonists, MAO-B
inhibitors, COMT inhibitors, NMDA antagonists,
and anticholinergics. Although effective initially, as
the disease progresses the effect of levodopa begins
to wear off after approximately four hours leaving
the patient experiencing motor fluctuations known as
"on" and "off' periods. Dopamine agonists, how-
ever, provide the benefit of delaying levodopa-
induced dyskinesia in early PD, and decreasing mo-
tor fluctuations in advanced PD.3 The use of this
class of drugs, however, has been limited by early
morning "off' symptoms due to lack of continuous
dopaminergic stimulation.4


Rotigotine (Neupro) is a new, transdermal,
non-ergolinic dopamine agonist manufactured by
Schwarz Biosciences and was approved by the FDA
in May 2007. Unlike any other treatment options for
PD, the dosage form is transdermal allowing once
daily application and providing a benefit to patients
who have difficulties swallowing and maintaining
stable plasma levels. It is indicated for the treatment
of the signs and symptoms of early-stage idiopathic
PD.5 This article will review the pharmacology,
pharmacokinetics, clinical trials, dosing, toxicity, and
cost of rotigotine.

Pharmacology and Pharmacokinetics
Rotigotine works similarly to other dopamine
agonists by stimulating dopamine receptors in the
brain. It is a non-ergolinic, D3/D2/D1 dopamine ago-
nist with its major effects thought to be due to its
ability to stimulate D2 receptors in the caudate-
putamen. (PI) It is eliminated in the urine as inactive
conjugates. There is about a 3 hour lag time until
rotigotine is detected in the plasma after initial use.
There is, however, no characteristic peak concentra-
tion observed, but dose-proportionality over 2 mg/24
hours to 8 mg/24 hours. In the clinical trials the ap-
plication sites varied amongst 6 different sites
(abdomen, thigh, hip, flank, shoulder, and upper


INSIDE THIS ISSUE:
ROTIGOTINE (NEUPRO): THE FIRST
TRANSDERMAL DOPAMINE AGONIST FOR
PARKINSON'S DISEASE
AND
PHARMACOTHERAPY OF ONYCHOMYCOSIS:
A Focus ON TERBINAFINE
l. I r


mm
PharmaNote Volume 23, Issue 2 November 2007


SPharmaNote


VOLUME 23, ISSUE 2 NOVEMBER 2007


Volume 23, Issue 2 November 2007


PharmaNote







arm), and were rotated from day to day. The resulting
bioavailability varied, with the biggest difference be-
tween the shoulder and thigh (64%) with the shoul-
der showing higher bioavailability. Because roti-
gotine is administered transdermally, it is not af-
fected by food. Steady state concentrations were
reached within 2 to 3 days. It is approximately 90%
bound to plasma proteins. Rotigotine's metabolism is
primarily mediated via conjugation and N-
dealkylation with CYP isoensymes, sulfotrans-
ferases, and 2 UDP-glucoronosyltransferases catalyz-
ing the metabolism. Due to the multiple pathways of
metabolism, drug interactions are unlikely based
upon one pathway. For example, if one CYP isoform
is inhibited the other isoforms could catalyze the me-
tabolism. There are no known drug interactions, but
dopamine antagonists such as metoclopramide and
antipsychotics could diminish the effects of roti-
gotine. The terminal half-life upon removal of the
patch is 5 to 7 hours. The initial half-life is 3 hours
with biphasic elimination. Rotigotine is excreted in
the urine (71%) and feces (11%). No changes in
dose are indicated based upon moderate hepatic or
mild to severe renal dysfunction. The pharmacoki-
netics of rotigotine did not differ significantly based
upon gender or ethnicity. Rotigotine had similar
steady state concentrations for individuals 40 to 80
years old. However, steady state concentrations may
be higher in the elderly (>80 years) due to skin


changes with aging. It has not been studied in pa-
tients less than 18 years old.5

Clinical Trials
Three clinical trials were submitted to the
FDA to demonstrate the effectiveness of rotigotine.
All three studies were randomized, double-blind, pla-
cebo controlled involving patients with idiopathic
early-stage PD not on any other PD medications.6

North American Study
Watts and colleagues evaluated the efficacy
of rotigotine in a randomized, double-blind, multina-
tional study using early-stage idiopathic PD patients.
The primary outcome of the study was change in the
combined Parts II and III of Unified Parkinson's Dis-
ease Rating Scale (UPDRS) from baseline to end of
treatment at week 27. Patients were titrated up
weekly from a starting dose of 2 mg/24 hours up to a
maximum dose of 6 mg/24 hours. Of the 277 patients
who participated in the study, 96 were randomly as-
signed placebo while 181 received rotigotine. A sta-
tistically significant difference was observed be-
tween the placebo and rotigotine with a mean differ-
ence from placebo of -5.3 on the UPDRS
(p<0.0001). (Figure 1) The most common adverse
event was application site skin reactions. Other ad-
verse events experienced were similar to other dopa-
mine agonists used to treat PD.7


Figure 1. Mean change in Unified Parkinson's Disease Rating Scale subtotal (parts II and III) by visit (full analysis set with
last observation carried forward). Adapted from Watts RL, et al.7


M 0
C


toC
CL
0~


Visit 2 3 4 5
Sraion
Phase


6 7 8 9 10 11


Maintenance Phase


Phama~teVolme23,Isse Noemerm00


om


Volume 23, Issue 2 November 2007


PharmaNote







Table 1. Mean change in UPDRS from baseline at end of
treatment for intent-to-treat population
Rotigotine nominal dose Difference from placebo

2 mg/24 hours -2.1

4 mg/24 hours -3.1*

6 mg/24 hours -4.9*

8 mg/24 hours -5.0*
UPDRS = Unified Parkinson's Disease Rating Scale
*p <0.05

Dose-Response Study
An international, randomized, double-blind
trial was conducted by the Parkinson Study Group on
242 early-stage PD patients to compare dosing of
rotigotine. The primary outcome of the study was a
mean change in the sum of scores in the UPDRS. Of
a total of 242 patients, 47 were randomized to re-
ceive placebo and 49, 47, 48, and 51 received one of
several fixed doses of respectively 2 mg/24 hours, 4
mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours for up
to 11 weeks. Mean changes in Parts II and III of
UPDRS are shown in Table 1. The mean changes of
the 4 mg/24 hours, 6 mg/24 hours, and 8 mg/24
hours doses were statistically significant. The mini-
mum effective dose was established to be 4 to 6
mg/24 hours. Nine serious adverse events occurred
during the study including one patient suddenly fal-
ling asleep while driving.8


Figure 2. Mean changes from baseline to the end of week 24
in absolute daily "off time in the PREFER trial.9


0

-0.5

-1 --0.9

-1.5

-2-
-2.1
-2.5

-2.7
-3

-3.5


8 mg/24 hour 12
rotigotine r
n=113
*p < 0.001 vs placebo


ng/24 hour Placebo
otigotine n=119
n=109


Foreign Multinational Study
A multinational, double-blind, randomized
trial was conducted with 561 early stage PD patients.
Patients were randomly assigned to placebo, roti-
gotine, or comparator for 39 weeks. All rotigotine
patients received a weekly dose escalation of patch
by 2 mg/24 until a maximal dose of 8 mg/24 hours or
until a maximum effective and tolerable dose was
met. The comparator group dose was also escalated
to maximum efficacy. Rotigotine patients experi-
enced a mean change of -6.83 from baseline to end
of treatment compared to placebo with a mean
change of -2.33. The mean difference from placebo
for the 8 mg/24 hour dose was -4.5 which was statis-
tically significant.5

Pooled Trials Studying Rotigotine in Advanced PD
The PREFER and CLEOPATRA-PD trials
were done to study the safety and efficacy of roti-
gotine in advanced PD.9-10 Advanced PD was de-
fined as motor fluctuations of the wearing-off type
with an average of at least 2.5 h per day in patients
with PD for more than 3 years and currently taking
stable doses of levodopa and other antiparkinsonian
medications for at least 4 weeks. Dual primary effi-
cacy parameters were mean change in total daily
hours "off" time and percent responders defined as
patients with 30% or more reduction in absolute off
time from baseline to end of maintenance in both
studies. In the PREFER trial, there were significant

Figure 3. Responder rates in the PREFER trial.9


40

S30

20

10

0


S' C.


8 mg/24 hour 12 mg/24 hour
rotigotine rotigotine
n=113 n=109


naceno
u=119


aPatients with 30% reduction in absolute off time; *p < 0.001 vs placebo


PharmaNote Volume 23, Issue 2 November 2007


Volume 23, Issue 2 November 2007


PharmaNote







Figure 4. Changes from baseline to end of maintenance pe-
riod for the three treatment groups in the CLEOPATRA-
PD trial.10


Pramipexole Rotigotine Placebo
n=201 n=204 n=101


*p < 0.0001 vs placebo

decreases in mean "off time of 2.7 hours/day for
the rotigotine 8 mg/24 hours group and 2.1 hours/day
for the 12 mg/24 hours group compared to 0.9 for
placebo.9 (Figure 2) For rotigotine 8 and 12 mg/24
hours groups, responder rates were 56.6% and 55.1%
compared to 34.5% for placebo. (Figure 3) Poewe
and colleagues found in the CLEOPATRA-PD trial
that mean absolute change in off time from baseline
was -2.5 0.2 h with rotigotine (maximum of 16
mg/24 h as a transdermal patch), -2.8 0.2 h with
pramipexole (maximum of 4.5 mg/day orally), and -
0.9 0.29 h with placebo (p<0.0001 for pramipexole
and rotigotine vs placebo).10 (Figure 4) Responder
rates were 67% for pramipexole, 59.7% for roti-
gotine, and 35% for placebo (p<0.0001 for
pramipexole and rotigotine vs placebo) (Figure 5).
Noninferiority was met for mean change in off time,
however, rotigotine was inferior to pramipexole for
the responder rate endpoint (-7.3% difference). In
both trials, adverse events were typical of dopa-
minergic agents of mild-to-moderate intensity with
the addition of patch site reactions for rotigotine.

Dosing and Administration
Rotigotine is available in 2 mg, 4 mg, and 6
mg transdermal systems with the rotigotine content
per system being 4.5 mg, 9 mg, and 13.5 mg respec-
tively. The starting dose should be 2 mg/24 hours
with weekly titration by 2 mg/24 hours if therapeuti-


Figure 5. Responder rates for the three treatment groups
in the CLEOPATRA-PD trial.10


0 -


80

70

60

50

4 40

30
20
N 20

10

0


ri101cuu
n=101


aPatients with >30% reduction in absolute off time; *p < 0.0001 vs placebo

cally needed and tolerated. Rotigotine doses ranging
from 4 mg/24 hours to 6 mg/24 hours have been
evaluated in clinical trials with higher doses demon-
strating an increase in adverse reactions and no clini-
cal benefit in early-stage PD patients.8 Although
higher doses have been studied in patients with ad-
vanced PD, no dosing recommendations are avail-
able at this time. When discontinuing rotigotine, the
daily dose should be decreased by 2 mg/24 hour
every other day until complete withdrawal to prevent
neuroleptic malignant syndrome. Application of
rotigotine should be done on clean, dry, intact,
healthy skin on the abdomen, thigh, hip, flank, shoul-
der, or upper arm, rotating these sites daily. The
same application site should not be used more than
once every 14 days. No dose adjustment is warranted
in patients with renal or hepatic insufficiencies.5

Toxicity and Safety
The safety of rotigotine has been evaluated in
approximately 1200 patients with early-stage PD.
Investigators found that 13% of patients experienced
an adverse event related to the study drug. Applica-
tion site reactions were reported most frequently, fol-
lowed by gastrointestinal adverse events such as nau-
sea and vomiting. Other adverse events reported in-
cluded somnolence, dizziness, headache, and insom-
nia. Side effects that occurred in > 2% of patients in
the studies are presented in Table 2. Clinical trials


PharmaNote Volume 23, Issue 2 November 2007


Pramipexole Rotigotine
n=201 n=204


-0.9


Volume 23, Issue 2 November 2007


PharmaNote







Table 2. Treatment-related adverse events with a 2% or
greater incidence
Placebo Rotigotine
Body system/preferred term N=289 N=649
(%) (%)


N = number of patients; NOS = not other


14 37


Application site reactions
Autonomic nervous system
Sweating increased
Mouth dry
Body as a Whole
Fatigue
Accident NOS
Cardiovascular
Extremity edema
Hypertension
Central and peripheral nerv-
ous system
Dizziness
Headache
Vertigo
Gastrointestinal system
Nausea
Vomiting
Constipation
Dyspepsia
Anorexia
Musculoskeletal system
Back pain
Arthralgia
Psychiatric
Somnolence
Insomnia
Dreaming abnormal
Hallucination
Respiratory system Sinusitis
Skin and appendage erythema-
tous rash
Urinary tract infection
Vision abnormal


have also shown an increase in adverse events with
higher doses. These adverse events are shown in Ta-
ble 3 for placebo and doses up to 8 mg/24 hours,
even though the 8 mg/24 hours dose is not recom-
mended therapy for early-stage PD. Laboratory
changes included an average decrease in blood he-
moglobin levels of about 2% or 0.3 g/dL and a con-
comitant decline in serum albumin. Also, patients on
rotigotine had an increase of blood urea nitrogen lev-
els of 3.7% or 0.21 mg/dL. Subjects had a greater
likelihood of low blood glucose (< 50 mg/dL) at 7%
compared to 4% with placebo. Warnings for roti-
gotine include sulfite sensitivity and falling asleep
during daily activities. The latter includes excessive
drowsiness with reports of patients falling asleep in
motor vehicles leading to accidents. Rotigotine
should be used with caution in patients using sedat-
ing medications or having sleep disorders.5

Cost
As of August 2007, the average retail price of
Neupro is $91 ($83 $100) for a 30 day supply of
the 2 mg/24 hour strength and $290 ($282 $305)
for a 30 day supply of either the 4 mg/24 hour or 6
mg/24 hour strength. Patches may be purchased in 7
or 30 day supplies.

Summary
Rotigotine is a new transdermal, non-
ergolinic dopamine agonist that stimulates D2 recep-
tors. It is indicated for early-stage PD without con-
comitant treatment with antiparkinsonian drugs.
Rotigotine offers a valuable therapeutic alternative
for early-stage treatment differing from other dopa-
mine agonists by providing constant blood levels
over a 24 hour period. This could possibly lower the


Table 3. Incidence (%) of rotigotine dose-related treatment-emergent adverse events
Daily rotigotine dose
Placebo 2 mg/24 h 4 mg/24 h 6 mg/24 h 8 mg/24 h
Adverse Event
N = 64 N = 67 N = 63 N = 65 N = 70
Application site reaction 19 24 21 34 46
Nausea 11 34 38 48 41
Vomiting 3 10 16 20 11
Weight decrease 0 0 0 2 3
Myalgia 0 0 2 2 3
Somnolence 3 13 16 19 21
Insomnia 8 6 13 14 14
Dreaming abnormal 0 2 5 3 7
Hallucination 2 0 2 3 3
Rash erythematous 2 2 6 3 3

PharmaNote Volume 23, Issue 2 November 2007


16
5
<1
1
2
1
1
1
ise specified






on-off symptoms experienced in advanced PD by
delaying the time until levodopa treatment is needed.
There are no known drug interactions of rotigotine
due to multiple pathways of metabolism. The ad-
verse event profile includes similar side effects to
other dopamine agonists including nausea, dizziness,
vertigo, insomnia and somnolence. Adverse events
specific to rotigotine include application site reac-
tions.

References
1. National Parkinson Foundation. http://
www.parkinson.org (Accessed August 2, 2007).
2. McCrone P, Allcock LM, Bum DJ. Predicting
the cost of Parkinson's disease. Mov Disord
2007; 22: 804-12.
3. Kenney C, Jankovic J. Rotigotine transdermal
patch in the treatment of Parkinson's disease and
restless legs syndrome. Expert Opin Pharmaco-
ther 2007; 8: 1329-35.
4. Metman LV, Gillespie M, Farmer C, et al. Con-
tinuous transdermal dopaminergic stimulation in
advanced Parkinson's disease. Clin Neurophar-
macol 2001; 24: 163-9.
5. Neupro (rotigotine) [Package Insert]. Mequon,
WI; Scwarz Pharma, LLC; 2007.
6. FDA news May 9, 2007. FDA approves Neupro
patch for treatment of early Parkinson's disease.
www.fda.gov/bbs/topics/NEW S/2007/
NEW01631.html (Accessed August 10, 2007).
7. Watts RL, Jankovic J, Waters C, et al. Random-
ized, blind, controlled trial of transdermal roti-
gotine in early Parkinson disease. Neurology.
2007; 68: 272-6.
8. The Parkinson Study Group. A controlled trial of
rotigotine monotherapy in early Parkinson's dis-
ease. Arch Neurol 2003; 60: 1721-8.
9. LeWitt PA, Lyons KE, Pahwa R; SP 650 Study
Group. Advanced Parkinson disease treated with
rotigotine transdermal system: PREFER Study.
Neurology 2007; 68: 1262-7.
10. Poewe WH, Rascol O, Quinn N, et al.; SP 515
Investigators. Efficacy of pramipexole and trans-
dermal rotigotine in advanced Parkinson's dis-
ease: a double-blind, double-dummy, randomised
controlled trial. Lancet Neurol 2007; 6: 475-6.
11. Naidu Y, Chaudhuri KR. Transdermal rotigotine:
a new non-ergot dopamine agonist for the treat-
ment of Parkinson's disease. Expert Opin Drug
Deliv 2007; 4: 111-8.


PharmaNote


PHARMACOTHERAPY OF
ONYCHOMYCOSIS: A FOCUS
ON TERBINAFINE

Allison Cammarata, Pharm.D. Candidate


Onychomycosis, also known as tinea un-
guium, is responsible for up to 50% of nail disorders
and affects as much as 8% of the general popula-
tion.1'2 A fungal infection of the fingernails and toe-
nails, onychomycosis is characterized by nail thick-
ening and discoloration. While it is often regarded
as simply a cosmetic problem, it can cause pain, irri-
tation and disfigurement. Additionally, it can lead to
complications in immunocompromised individuals,
including systemic infection, if left untreated.3
Dermatophytes, yeasts and molds are all po-
tential causative agents of onychomycosis.4 Der-
matophytes are responsible for the majority of infec-
tions, particularly Trichophyton rubrum and Tricho-
phyton mentagrophytes.1 Diagnosis of onychomyco-
sis involves evaluation of clinical presentation, direct
microscopy and fungal culture. Direct microscopy
utilizes a 20% potassium hydroxide preparation
(KOH) in dimethyl sulfoxide (DMSO) to rule out
presence of fungi, while fungal culture is used to de-
termine the specific pathogen involved.3
Terbinafine tablets (Lamisil) are indicated
for treatment of onychomycosis and became avail-
able as a generic formulation on July 2, 2007. This
article will review the pharmacokinetics, efficacy
and safety of terbinafine, as well as its role in the
treatment of fungal nail infections.

Pharmacology and Pharmacokinetics
Terbinafine is a synthetic allylamine that has
fungicidal activity against dermatophytes, including
T. rubrum and T mentagrophytes and fungistatic ac-
tivity against some non-dermatophyte yeasts and
molds.5 Terbinafine's antifungal activity is due to its
inhibition of the enzyme squalene monooxygenase, a
major enzyme in fungal sterol biosynthesis.6 Inhibi-
tion of this enzyme prevents conversion of squalene
to 2,3-oxidosqualene, creating a deficiency in ergos-
terol and leading to weakened cell membranes in
sensitive fungi.7
Pharmacokinetic properties of terbinafine af-


Volume 23, Issue 2 November 2007






Table 1. Overview of the pharmacokinetic properties of oral terbinafine in healthy adult volunteers after administration of
a single 250mg dose.7
Parameter Range
Cmx (mg/L)a 0.8 1.5
tmax (h)b 1.3 -2
AUC (mg h/L) 3.55 4.74
Bioavailability (%) 40 50%
Vd,, (L)d 947.5
Serum protein binding (%) 94
tl/2abs (h)e 0.8 1.2
t1/2p (h) 16-26
tl/2y (h) 90
CL (L/h)h 76
Excretion 80% urine; 20% feces
aCmax maximum serum concentration; btm time to Cm,; CAUC = area under the plasma concentration-time curve; dVdss = volume of distribution at steady state;
Ctl/2abs absorption half-life; ftl/ = initial elimination half-life; gt1/2, terminal elimination half-life; hCL = plasma clearance


ter a single 250mg dose are summarized in Table 1.
Terbinafine's mean peak plasma concentration (Cmax)
is reached within approximately 2 hours following
oral administration. Concomitant food intake in-
creases the area under the plasma concentration-time
curve (AUC) by approximately 20%, resulting in
small delays in time to Cmax (tmax) and slight Cmax ele-
vations. Terbinafine is highly protein bound (94-
99%), but also widely distributed in nail beds, hair,
stratum corneum and breast milk. Bioavailability is
approximately 40-50%, due to extensive hepatic
first-pass metabolism. No identified metabolites of
terbinafine have antifungal activity. Between 70-
80% of terbinafine is eliminated in the urine as me-
tabolites, while approximately 20-30% is eliminated
in feces.7 At steady state, peak concentration in-
creases by 25% and AUC increases 2.5-fold. Addi-
tionally, the elimination half-life of terbinafine in-
creases to 36 hours, and the terminal half-life ranges
from 200 to 400 hours. This long terminal half-life
may represent the slow elimination of the drug from
skin and adipose tissue.8 Terbinafine is a potent in-
hibitor of the hepatic enzyme CYP2D6, and as a re-
sult, may potentiate the effects of other medications
metabolized by this enzyme.6

Clinical Trials
Two randomized, double-blind, pla-
cebo-controlled trials were conducted comparing ter-
binafine and placebo.9-10 Data from these trials, as
well as several other trials evaluating the efficacy of
terbinafine versus active treatment options, are sum-
marized in Table 2. In Drake et al., 358 patients in
the United States and Canada were randomized to
one of three groups: oral terbinafine 250 mg/day for
12 weeks, followed by placebo for 12 weeks


(n=142), oral terbinafine 250 mg/day for 24 weeks
(n=145), or placebo for 24 weeks (n=71).9 This treat-
ment phase was followed by 24 weeks of blinded
follow-up, with patients not receiving any treatment.
A cohort of patients with negative mycologic find-
ings (negative culture and microscopy) and at least 5
mm of unaffected new nail growth by week 48 were
selected for an additional 48 weeks of follow-up. The
purpose of this cohort was to examine long-term effi-
cacy and relapse rates of patients taking terbinafine.
At week 48, there was a significant difference in
negative mycology between the terbinafine and pla-
cebo group (70% of the 12-week terbinafine group
and 87% of the 24-week terbinafine group versus 9%
of the placebo group; p<0.001). Clinical success, de-
fined as the percentage of patients with at least 90%
clear nail at week 48, was significantly higher in the
terbinafine groups versus the placebo group (60% of
the 12-week terbinafine group and 75% of the 24-
week terbinafine group versus less than 10% of the
placebo group; p <0.001). A total of 167 terbinafine
treated patients were included in the cohort selected
for 48 weeks of additional follow-up. Of those pa-
tients, 95% of the terbinafine 12-week group and
88% of the terbinafine 24-week group still had nega-
tive mycologic findings at the end of the extended
observation period. Based on these results, terbi-
nafine was considered to be effective for treatment of
onychomycosis.
In Goodfield et al., 99 patients in the United
Kingdom were randomized to receive oral terbi-
nafine 250 mg daily for 12 weeks (n=70) or placebo
(n=29) to treat toenail onychomycosis.10 Addition-
ally, 18 patients were randomized to receive oral ter-
binafine 250 mg daily for 6 weeks (n=13) or placebo
(n=5) to treat fingernail onychomycosis. Mycologi-


PharmaNote Volume 23, Issue 2 November 2007


Volume 23, Issue 2 November 2007


PharmaNote







Table 2. Results from clinical trials with terbinafine

Author N Design Study drug Comparator Results Conclusions
dose


358 RDB


TERB 250mg/
day x 12 wks
(OR)
x 24 wks


TERB 250 mg/
day x 12 wks for
99 RDB toenails (OR)
x 6 wks for fin-
gernails


372 RDB


Brautigam'2 195 RDB


TERB 250mg/
day x 12 wks


TERB 250mg/
day x 12 wks


TERB 250mg/
70 RSB
day x 12 wks








TERB 250mg/
137 RDB wks
day x 12 wks


PLA x 24 wks


PLA
x 12 wks (OR)
x 6 wks


ITRA 200mg/
day x 12 wks


ITRA 200mg/
day x 12 wks


ITRA "pulse"
200mg twice
daily (1 wk on,
3 wks off) x 12
wks





FLUC 150mg
once wkly x 12
wks (OR) x 24
wks


Drake,
et al.9


Oral TERB ef-
fective for treat-
ment of ONY


At week 48:
MYC = 70% TERB 12-wk gp and 87%
TERB 24-wk gp vs 9% PLA gp

Overall response rate of both treatment
gps was comparable: 71% for TERB
12-wk gp vs 77% for TERB 24-wk gp


At 48 wks ITT:
MYC = 73% TERB gps vs 6% PLA
gps (p<0.007)

CLIN = 69% and 71% for TERB
groups (toenail and fingernail) vs 0%
for PLA

At week 48:
MYC = 73% TERB gp vs 45.8%
ITRA group (p<0.0001)

MYC with cleared/min clinical sxs =
64.2% TERB gp vs 37.5% ITRA gp
(p<0.0001)

MYC with cleared clinical sxs = 37.7%
TERB gp vs 23.2% ITRA gp (p=0.004)

At week 52:
MYC = 81.4% TERB gp vs 63.1%
ITRA gp (2p<0.01)

Unaffected area of target nail =
9.44mm TERB gp vs 7.85mm ITRA gp
(2p<0.05)

At week 48:
MYC = 79.3% TERB gp vs 88.2%
ITRA gp (p not significant)

MYC with less than 10% nail plate
involvement = 51.7% TERB gp vs
52.9% ITRA gp (p not significant)


At week 60:
MYC = 89% TERB gp vs 51% FLUC
12-wk gp and 49% FLUC 24-wk gp
(p<0.001)

Complete CLIN of target nail = 67%
TERB gp vs 21% FLUC 12-wk gp and
32% FLUC 24-wk gp (p<0.0001)


Compared with
ITRA, TERB
produced higher
rates of MYC
and CLIN at F/
U


Compared with
ITRA, TERB
produced higher
rates of MYC
and unaffected
nail growth at F/
U

Both continuous
TERB and pulse
ITRA are effec-
tive for the man-
agement of toe-
nail ONY in
diabetic patients

TERB 250mg/
day for 12 wks
significantly
more effective
for treatment of
ONY than
FLUC 150mg
once wkly for
12 or 24 wks


RDB = randomized, double-blind trial design; RSB = randomized, single-blind trial design; TERB = terbinafine; PLA = placebo; ITRA = itraconazole; FLUC = flu-
conazole; ONY = onychomycosis; MYC = mycologic cure; CLIN = clinical cure; ITT = intention-to-treat analysis; gp = group; wk = week; F/U = follow-up

Pharma__oVolume__23, Issue_2_NovemAber 2007


Oral TERB ef-
fective for treat-
ment of ONY


Goodfield,
et al.10


De Backer,
et al.1


Gupta,
et al.13








Havu,
et al.4


Volume 23, Issue 2 November 2007


PharmaNote






Table 3. Most frequently reported adverse events observed in three placebo-controlled trials.8
A e E t Terbinafine (%) Placebo (%)
Adverse Eventn=465n=137
n=465 n=137
Headache 12.9 9.5
Gastrointestinal:
Diarrhea 5.6 2.9
Dyspepsia 4.3 2.9
Abdominal pain 2.4 1.5
Nausea 2.6 2.9
Flatulence 2.2 2.2
Dermatologic:
Rash 5.6 2.2
Pruritus 2.8 1.5
Urticaria 1.1 0.0
Liver enzyme abnormalities* 3.3 1.4
Taste disturbance 2.8 0.7
Visual disturbance 1.1 1.5
* Liver enzyme abnormalities > 2x the upper limit of the normal range


cal cure was defined as negative findings on micros-
copy and culture, with trial endpoints of 12 weeks
(end of treatment period) and 48 weeks (end of fol-
low-up period). Clinical cure was defined as full, un-
affected, normal nail growth. At the end of the treat-
ment period, the mycological cure rates for patients
with toenail and fingernail infections were 29% and
71% respectively for the terbinafine groups versus
12% and 31% for the placebo groups. On an inten-
tion to treat basis, the mycological cure rates for toe-
nail infection at the end of the follow-up period sig-
nificantly favored treatment with terbinafine over
placebo (73% vs 6%, p<0.007). Clinical cure rates at
the end of follow-up were 69% for patients with toe-
nail infection and 71% for patients with fingernail
infection treated with terbinafine. No patients receiv-
ing placebo achieved clinical cure.

Toxicity and Safety
The prescribing information for terbinafine
specifically warns that rare cases of liver failure have
occurred with its use, in patients with and without
pre-existing liver disease, some leading to death or
liver transplant.8 As a result, assessing liver function
is recommended prior to prescribing terbinafine. In
addition, the prescribing information recommends
treatment discontinuation if progressive skin rash
occurs, as there have been isolated reports of serious
skin reactions (including Stevens-Johnson Syndrome
and toxic epidermal necrolysis) with its use. For pa-
tients with known or suspected immunodeficiency
and taking terbinafine for longer than 6 weeks, the


manufacturer recommends monitoring complete
blood counts, as transient decreases in absolute lym-
phocyte counts have been observed in clinical trials.8
Several studies have evaluated the safety of
terbinafine.8'9'11'15 The most common adverse reac-
tions experienced in clinical trials were headache,
diarrhea and rash (Table 3). Generally, adverse re-
actions were found to be transient and mild-to-
moderate in severity.

Dosing and Administration
Terbinafine tablets may be taken with food if
desired. Standard dosing of terbinafine is 250 mg
daily for 6 weeks for treatment of fingernail onycho-
mycosis and 250 mg daily for 12 weeks for treatment
of onychomycosis.6 Two identical trials (n=2005)
were conducted to compare efficacy, safety and tol-
erability of the standard dosing regimen with an in-
termittent dosing regimen. Intermittent dosing con-
sisted of 3 cycles of 350 mg daily for 2 weeks fol-
lowed by 2 weeks of no treatment. Response rates
for mycological and clinical cure were significantly
lower for the intermittent dosing regimen in both
Trial 1 (-5.8%; 95% CI -11.8, 0.07) and Trial 2 (-
5.9%; 95% CI -12, 0.1). Continuous therapy with
terbinafine 250 mg was determined to be more effi-
cacious than intermittent dosing.16

Cost
Prices for a 30 day supply of terbinafine 250
mg vary widely between pharmacies. The median
retail cost from 7 different pharmacies is $231.55


Phara~oe Vlume23,Isse 2 oveber200


Volume 23, Issue 2 November 2007


PharmaNote







(range $4 to $444). Thus, a 12-week course of terbi-
nafine 250 mg is expected to cost $12 $1332.
Median retail cost from 7 different pharma-
cies for Lamisil 250 mg is $435 (range $418.62 to
$502.97). Thus, a 12-week course of Lamisil 250
mg is expected to cost $1674 $2012.

Summary
Terbinafine is a synthetic allylamine ap-
proved for the treatment of onychomycosis that re-
cently became available as a generic formulation. It
demonstrates fungicidal activity against dermato-
phytes and fungistatic activity against some non-
dermatophyte yeasts and molds. Pharmacokinetic
data suggests significant distribution into nail beds
and a long half-life at steady state concentrations,
which contributes to its efficacy. Clinical trials indi-
cate terbinafine is safe and effective treatment option
for onychomycosis. Generally, adverse reactions
were found to be transient and mild-to-moderate in
severity, with headache, diarrhea and rash being the
most common adverse reactions experienced.

References
1. Ghannoum MA, Hajjeh RA, Scher R, et al. A
large-scale North American study of fungal isolates
from nails: the frequency of onychomycosis, fungal
distribution, and antifungal susceptibility patterns. J
Am Acad Dermatol 2000; 43: 641-8.
2. Finch J, Warshaw E. Toenail onychomycosis: cur-
rent and future treatment options. Dermatol Ther
2007; 20: 31-46.
3. Elewski BE. Onychomycosis: pathogenesis, diag-
nosis, and management. Clin Microbiol Rev 1998;
11: 415-29.
4. Mfigge C, Haustein UF, Nenoff P. Causative agents
of onychomycosis--a retrospective study. J Dtsch
Dermatol Ges 2006; 4: 218-28.
5. Debruyne D, Coquerel A. Pharmacokinetics of an-
tifungal agents in onychomycoses. Clin Pharma-
cokinet 2001; 40: 441-72.
6. Clinical Pharmacology [database online]. Tampa,
FL: Gold Standard, Inc.; 2007. URL: http://
www.clinicalpharmacology.com. Updated October,
2007.
7. Darkes MJ, Scott LJ, Goa KL. Terbinafine: a re-
view of its use in onychomycosis in adults. Am J
Clin Dermatol 2003; 4: 39-65.
8. Terbinafine Prescribing Information. Watson Phar-
maceuticals, Inc. Retrieved 10 October 2007. http://
pi.watson.com/data_stream.asp?
product_group=1602&p=pi&language=E


9. Drake LA, Shear NH, Arlette JP, et al. Oral terbi-
nafine in the treatment of toenail onychomycosis:
North American multicenter trial. J Am Acad Der-
matol 1997; 37: 740-5.
10. Goodfield MJ, Andrew L, Evans EG. Short term
treatment of dermatophyte onychomycosis with
terbinafine. BMJ 1992; 304: 1151-4.
11. De Backer M, De Vroey C, Lesaffre E, et al.
Twelve weeks of continuous oral therapy for toe-
nail onychomycosis caused by dermatophytes: a
double-blind comparative trial of terbinafine 250
mg/day versus itraconazole 200 mg/day. J Am
Acad Dermatol 1998; 38: S57-63.
12. Brautigam M. Terbinafine versus itraconazole: a
controlled clinical comparison in onychomycosis of
the toenails. J Am Acad Dermatol 1998; 38: S53-6.
13. Gupta AK, Gover MD, Lynde CW. Pulse itracona-
zole vs. continuous terbinafine for the treatment of
dermatophyte toenail onychomycosis in patients
with diabetes mellitus. J Eur Acad Dermatol
Venereol 2006; 20: 1188-93.
14. Havu V, Heikkila H, Kuokkanen K, et al. A dou-
ble-blind, randomized study to compare the effi-
cacy and safety of terbinafine (Lamisil) with flu-
conazole (Diflucan) in the treatment of onychomy-
cosis. Br J Dermatol 2000; 142: 97-102.
15. Chang CH, Young-Xu Y, Kurth T, et al. The safety
of oral antifungal treatments for superficial der-
matophytosis and onychomycosis: a meta-analysis.
Am J Med 2007; 120: 791-8.
16. Sigurgeirsson B. Intermittent versus continuous
terbinafine in the treatment of toenail onychomyco-
sis: a randomized, double-blind comparison. J Der-
matolog Treat 2006; 17: 38-44.


The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor
Pharm.D.
i:e] nm'e!


- i


Volume 23, Issue 2 November 2007


PharmaNote




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