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Advances in levodopa therapy for

Parkinson disease
Review of RYTARY (carbidopa and levodopa) clinical efficacy
and safety
Rohit Dhall, MD
David L. Kreitzman, MD

Correspondence to
Dr. Dhall:
drdhall@gmail.com

ABSTRACT

Parkinson disease (PD) is a slowly progressive, incurable, neurodegenerative disorder with progressive
motor symptoms that can be managed with treatments. Levodopa is generally recognized as the most
effective and widely used treatment for PD. It improves function and quality of life, morbidity, and mortality, and therefore reduces individual and societal costs. Levodopa has a relatively short half-life, however, and is quickly metabolized in the plasma, leading to fluctuations, including wearing-off of effect
and inconsistent symptomatic relief as well as development of dyskinesias, with both wearing off and
dyskinesias worsening with advancing disease. Immediate-release and controlled-release formulations
have been used with success, but motor fluctuations remain a problem. RYTARY (levodopa and carbidopa, IPX066) is an oral extended-release therapy composed of carbidopalevodopa microbeads
designed to dissolve at various rates that allows for quick absorption and sustained levodopa release
over an extended period. In development studies, RYTARY improved symptoms in patients with both
early and advanced PD and offered significantly improved Unified Parkinson Disease Rating Scale
scores and on times, without worsening troublesome dyskinesias when compared to other levodopa
formulations. Tolerability and safety were comparable to other formulations. This section reviews the
data that support the use of RYTARY in the treatment of PD. Neurology 2016;86 (Suppl 1):S13S24
GLOSSARY
ADVANCE-PD 5 A Study to Evaluate the Safety and Efficacy of IPX066 in Advanced Parkinsons Disease; AE 5 adverse
event; APEX-PD 5 A Study to Evaluate the Safety and Efficacy of IPX066 in Subjects with Parkinsons Disease; ASCENDPD 5 Comparison of IPX066, a Novel Carbidopa-Levodopa Extended-Release Formulation, and CD-LD-Entacapone in
Advanced Parkinsons Disease; CD 5 carbidopa; CGI-C 5 Clinician Global Impression of Change; CLE 5 carbidopa-levodopa
1 entacapone; CR 5 controlled release; DDC 5 dopa decarboxylase; EQ-5D 5 EuroQoL 5-dimension quality of life scale;
FDA 5 Food and Drug Administration; IR 5 immediate release; LD 5 levodopa; PDQ-39 5 39-item Parkinsons Disease
Questionnaire; PD 5 Parkinson disease; PGI-C 5 Patient Global Impression of Change; PK 5 pharmacokinetics; SAE 5
serious adverse event; SF-36 5 Short Form Health Survey; UPDRS 5 Unified Parkinsons Disease Rating Scale.

Parkinson disease (PD) is the second most common neurodegenerative disorder in the United
States. PD pathology in the form of Lewy bodies is found in the brain and spinal cord, as well
as in the peripheral nervous system, and presents a wide range of clinical manifestations, both motor
and nonmotor. Dopamine modulated circuits are at the core of motor dysfunction in PD. Motor
symptoms of rigidity and bradykinesia respond well to dopaminergic treatment in early PD, with
levodopa (LD) being one of the most effective and widely used treatments for PD.14 The use of LD
therapy for PD is supported by the American Academy of Neurology Practice Guidelines5 because
it improves function and quality of life, reduces morbidity and mortality, and, therefore, reduces
individual and societal costs. Patients with early PD can derive significant benefits from simple
regimens initially, but treatment regimens become more complex with advancing PD, and there is
progressive increase in disability from motor and nonmotor impairment as well as complications of
dopaminergic therapy including development of motor fluctuations in advanced PD.6
LD has a relatively short half-life (;1.5 hours), however, and is quickly and extensively
metabolized in plasma.7,8 A number of formulations have been developed that combine LD with
From the Parkinsons Institute and Clinical Center (R.D.), Sunnyvale, CA; and Parkinsons Disease and Movement Disorder Center of Long Island
(D.L.K.), Commack, NY.
Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
This Neurology supplement was not peer-reviewed. Information contained in this Neurology supplement represents the opinions of the authors. These
opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology.

2016 American Academy of Neurology

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2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

a dopa decarboxylase (DDC) inhibitor, such


as carbidopa (CD), which inhibits peripheral
LD metabolism and allows an increase in LD
CNS availability.7 Combining LD with a
DDC inhibitor improves tolerability by reducing nausea and other adverse effects from
peripheral decarboxylation, making oral use
of LD practical. A number of wellcontrolled, large-scale, long-term clinical trials
have consistently demonstrated symptomatic
control of PD with the CD-LD formulation.911
Many of these CD-LD formulations have
limitations. Immediate release (IR) CD-LD
has a short half-life so it must be taken frequently, and at regular intervals, to be effective.
Although effective, over time there is a shortening of clinical response and higher, more frequent dosing to compensate for the change in
pharmacodynamics of CD-LD is required.8,12,13
As PD progresses, the conversion of LD to
dopamine, as well as its subsequent storage
and release, becomes unpredictable.8 The short
half-life of LD coupled with more frequent dosing causes intermittent or pulsatile release of
dopamine in the striatum, producing changes
in the postsynaptic receptors. These downstream changes due to intermittent LD use,
as well as progression of disease severity, lead
to motor complications and dyskinesias.8,12,14,15
Many patients (between 40% and 100%)
have been reported to develop fluctuating
motor and nonmotor symptoms (wearing-off
and on-off phenomena) and dyskinesias with
continued use of LD.1620 Motor fluctuations
can be noted as soon as 56 months after treatment initiation, particularly with large doses
($600 mg/d).21 After 2 years of CD-LD therapy, as few as 20% of patients experience sustained benefits.22 More than 70% of patients
experience on-off fluctuations and dyskinesias
after 5 years.20,23 As wearing-off becomes more
frequent, LD doses need to be given in
increasing frequency to achieve a sufficient
clinical response. The fluctuation of pharmacodynamic response to LD between wearingoff and LD-induced dyskinesias leads to a
narrower optimal therapeutic window with
increasing probability of overdosage and
underdosage.12 Thus, research has focused on
an oral PD drug that provides a rapid onset of
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Neurology 86 (Suppl 1)

effect and more stable plasma LD levels, resulting in less off time and more on time.
Controlled-release (CR) or sustainedrelease formulations of CD-LD that use a
degradable polymer matrix to slow the release
of LD into the gut have been developed as alternatives to IR formulations. However, a
5-year comparison study noted no difference
in the degree of motor fluctuations and dyskinesias between CR and IR formulations in
patients with moderate to severe motor fluctuations.24 Patients transferred to CR CD-LD
from an IR formulation have not consistently
experienced significant off time reduction.2529 Absorption is delayed (46 hours)30
and symptom relief is less predictable with CR
than with IR.3133 This often requires coadministration of IR with CR, particularly for
the first morning dose, and increases the burden or complexity of the medication schedule
for patients.34,35 CR use is often restricted to
nighttime administration.
CD-LD1 entacapone (CLE) increases total
exposure of IR by 35%40% and prolongs
LD half-life to 2.4 hours. Entacapone inhibits
peripheral LD metabolism and allows more
LD to enter the CNS.36 However, CLE has
been shown to produce LD plasma profiles
similar to CR CD-LD, with higher LD
fluctuations.37
RYTARY (IPX066),
an oral formulation of CD-LD that received US
Food and Drug Administration (FDA) approval in
early 2015, was designed to meet the need for
better LD pharmacokinetics (PK) over existing
preparations. Each RYTARY capsule contains CDLD microbeads designed to dissolve at various rates,
allowing for release and absorption of LD over a
longer timeframe. The CD:LD ratio is 1:4.
Summaries of the key clinical trials for RYTARY
are provided in the sections below.
INTRODUCTION TO RYTARY

Phase 1 research. A key phase 1 study38 in healthy

volunteers assessed the PK of RYTARY vs IR, CR,


and CLE formulations using a randomized, singledose, open-label, crossover design in 24 individuals.
The mean plasma concentration of both LD and CD
were greater and more sustained with RYTARY than
with the other treatments. An initial LD plasma peak
occurred at 1 hour, with a median Tmax of 4.5 hours.
Unlike the plasma concentrations of the other
formulations, which decreased to ,10% of peak at
57.5 hours, RYTARY plasma concentrations

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remained above 10% of peak until 10.1 hours (figure


1A). The PK profile for CD was similarly extended
(figure 1B). Another study utilized a randomized
open-label, crossover design to assess the dose
proportionality of 4 doses of RYTARY in 28
subjects. Statistical analysis of the PK parameters
demonstrated that the Cmax and AUC0N values for
LD and CD increased in an approximately doseproportional manner over the range of doses studied.39
The effects of a high-fat, high-calorie meal, as well
as sprinkling the capsule contents on applesauce on
the PK of RYTARY, were examined in a randomized,
single-dose, open-label, 3-sequence, 3-treatment,
crossover study39 in healthy volunteers. Subjects were
randomized to receive 2 capsules of RYTARY 61.25
245 mg (CD-LD) 30 minutes after ingestion of an
FDA-standardized, high-fat, high-calorie breakfast.
They were asked to swallow, without chewing and
in a fasted state, 2 tablespoons of applesauce onto

Figure 1

Mean levodopa and carbidopa plasma concentration profile38

Mean levodopa (A) and carbidopa (B) plasma concentration time profiles following a single
dose of 2 capsules of extended-release (ER) carbidopa-levodopa (CD-LD) (total dose 97.5
mg CD390 mg LD), immediate-release (IR) CD-LD (25100 mg), controlled-release (CR)
CD-LD (25100 mg), and CD-LD-entacapone (25100200 mg) under fasting conditions.
Source: Hsu A, et al. J Clin Pharmacol 2015;55:9951003.

which the contents of 2 capsules of RYTARY


61.25245 mg (CD-LD) had been sprinkled, or were
asked to take 2 capsules of RYTARY 61.25245 mg
in a fasted state. No dose dumping was noted with
the high-fat, high-calorie breakfast; however, the meal
increased LD AUC0N by ;13% and decreased Cmax
by ;21% relative to values in the fasted state. Sprinkling the RYTARY capsule contents on applesauce
did not affect the PK of LD compared with the intact
capsule.39
Phase 2 research. A single phase 2 study examined the
effects of RYTARY in 27 patients with advanced PD
experiencing motor fluctuations while on IR CD-LD
therapy.40 Patients were Hoehn & Yahr stages IIV
during on time, with a Mini-Mental State
Examination score $26, and had predictable
wearing-off with at least 3 hours of off time per
day. In this randomized, open-label, crossover
study, patients received either RYTARY followed by
IR CD-LD or IR CD-LD followed by RYTARY. PK
and motor evaluations were performed for 8 hours on
day 1 (single-dose evaluation) and for 12 hours on
day 8 (multiple-dose evaluation) during each
treatment period. Mean daily LD doses were 816.7
mg with IR CD-LD and 2,054.4 mg with RYTARY.
Mean daily dosing frequency decreased from 5.4
doses to 3.5 doses during RYTARY treatment, but
were unchanged with IR CD-LD.40
LD plasma concentrations reached 50% of Cmax at
approximately the same rate; 50% of Cmax was 0.78
hours for RYTARY and 0.76 hours for IR CD-LD
(p 5 0.90). However, LD plasma concentration was
sustained above 50% of Cmax for 4 hours with
RYTARY compared with 1.4 hours with IR
CD-LD (p , 0.0001). During multiple-dose administration (day 8), RYTARY had a significantly lower
fluctuation index (1.5 vs 3.2; p , 0.0001) and Cmax/
Cmin ratio (p , 0.0001) compared with IR CD-LD
(12.0 vs 82.2). LD bioavailability of RYTARY was
74.5% relative to IR CD-LD (table).40
On day 1, motor symptoms improved rapidly for
the first 2 hours following both treatments. After 3, 4,
5, and 6 hours, motor disability as measured by Unified Parkinsons Disease Rating Scale (UPDRS) part
III motor score was reduced significantly (p , 0.05)
more with RYTARY compared with IR CD-LD
treatment. Even after 6 hours, 68% of RYTARYtreated patients were reported to be on without
troublesome dyskinesia compared with 4% following
IR CD-LD treatment; the average amount of time
spent in the off state after RYTARY was significantly less than with IR CD-LD (1.9 vs 4.4 hours;
p , 0.0001). The amount of on time with troublesome dyskinesia did not significantly differ
between the treatment groups.40
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Table

LD PK values (mean 6 SD)40

Day 1 single-dose data, mg

RYTARY

IR CD-LD

664

165

p Value

Cmax, ng/mL

3,000 6 1,300

2,360 6 1,100

Tmax, h

2.0 6 1.1

0.87 6 0.5

Time to reach 50% of Cmax, h

0.78 6 0.40

0.76 6 0.47

Duration LD plasma concentration


above 50% of Cmax, h

4.0 6 2

1.4 6 0.7

Relative bioavailability, % (90% CI)

74.5 (60.192.2)

NA

Day 8 multiple-dose data, mg

1,248

482

Accumulation index (90% CI)

1.23 (0.981.55)

1.07 (0.871.27)

Fluctuation indexa

1.5 6 0.4

3.2 6 1.3

,0.0001

Cmax/Cmin

12.0 6 18.5

82.2 6 67.5

,0.0001

0.0034
,0.0001
0.8998
,0.0001

0.19

Abbreviations: CD-LD 5 carbidopa-levodopa; CI 5 confidence interval; Cmax 5 peak levodopa plasma concentration; Cmin 5 minimum levodopa plasma concentration; IR 5 immediate release; LD 5 levodopa; NA 5 not available; PK 5 pharmacokinetics; Tmax 5 time to Cmax.
Source: Hauser RA, et al. Mov Disord 2011;26:22462252.
a
Fluctuation index 5 (Cmax 2 Cmin)/Cavg (where Cavg is the average concentration over the
12-hour interval on day 8).

After repeated dosing (day 8), Cmax for RYTARY was


30% higher and LD AUC was 87% higher than for IR
CD-LD. Walking times (predose and postdose on day 8,
p , 0.02), UPDRS part III scores (predose and postdose
day 8, p # 0.03), and on time without troublesome
dyskinesias (p 5 0.04) were significantly improved with
RYTARY, as well. Patient diaries noted a 2.11-hour
improvement in off time for RYTARY compared with
0.11 for IR CD-LD (p , 0.0001). On time without
troublesome dyskinesia was also significantly (p 5
0.002) greater for RYTARY (1.38 vs 0.43 hours). There
were no serious adverse events (SAEs) and few drugrelated adverse events (AEs). Five subjects reported a
total of 9 mild or moderate treatment-emergent AEs,
approximately equally split between treatment groups.40
The authors concluded that RYTARY was rapidly
absorbed and provided more sustained plasma LD
concentrations with less fluctuation compared with
IR CD-LD. Consistent with its PK profile, RYTARY
produced a similar clinical onset and had a longer duration of reduced motor symptoms (less off time).40
Phase 3 research. Five phase 3 studies (1 in early PD, 3
in advanced PD, and 1 open-label extension in both
early and advanced PD) examined the safety and
efficacy of RYTARY in patients with PD.
A STUDY TO EVALUATE THE SAFETY AND
EFFICACY OF IPX066 IN SUBJECTS WITH
PARKINSONS DISEASE (APEX-PD) APEX-PD was

a randomized, double-blind, fixed-dose, placebocontrolled study that examined the safety and efficacy
of RYTARY in 381 LD-naive patients with early
PD.41 Patients were not to have been exposed to LD
for .30 days, or have received LD within 4 weeks of
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study entry. Treatment with dopamine agonists was


also an exclusion criterion. Patients were initiated
onto RYTARY using a fixed titration schedule,
starting with 95 mg RYTARY 3 times/day (TID).
Patients were increased to their randomized RYTARY
dose (145 mg TID, 245 TID, or 390 mg TID) over the
4-week titration period. RYTARY or placebo was
administered 3 times/day and patients were followed
for a total of 30 weeks. The primary efficacy
endpoint was the change from baseline at week 30 in
the sum of the UPDRS parts II and III.41
All 3 doses of RYTARY significantly (p , 0.0001)
improved UPDRS part II 1 III scores by study end
(figure 2).41 Decreases from baseline in UPDRS were
also significantly (p , 0.0001) greater at each week for
all RYTARY doses relative to placebo. Concordance
was seen in the individual parts of the UPDRS (except
part IV; p , 0.0001), changes in the 39-item Parkinsons Disease Questionnaire (PDQ-39) total scores
(p # 0.034), and the Patient Global Impression of
Change (PGI-C) and Clinician Global Impression of
Change (CGI-C) scores (p , 0.0001), with all indicating significant improvement for all 3 doses of
RYTARY compared with placebo. AEs were reported
in 56.3% of 145 mg, 72.1% of 245 mg, 71.4% of 390
mg RYTARY treatment groups compared with 72.8%
in the placebo group. The most commonly reported
AEs (.5%) across all treatment groups were nausea
(15.7%), headache (12.1%), dizziness (11.8%), and
insomnia (5.2%). None of the 14 SAEs were attributed to study treatment; the number of patients experiencing SAEs was similar across all treatment groups.
Discontinuations due to AEs were higher in the 245and 390-mg treatment groups.41
RYTARY at 145, 245, and 390 mg of LD was safe
and well-tolerated, as well as effective for improving
PD symptoms in LD-naive patients with PD as measured by UPDRS, PDQ-39, and patient and clinician
global impressions. The best balance between efficacy
and safety among LD-naive patients in this trial was
achieved with 145 mg of RYTARY 3 times daily.41
A STUDY TO EVALUATE THE SAFETY AND
EFFICACY OF IPX066 IN ADVANCED PARKINSONS
DISEASE (ADVANCE-PD) The ADVANCE-PD42 study

was a randomized, double-blind, parallel-group trial


comparing RYTARY to IR CD-LD in patients with
advanced PD. Patients were required to have Hoehn &
Yahr stage IIV in the on state, Mini-Mental State
Examination score $26, predictable off time, and
be on a stable ($4 weeks) treatment regimen with
IR CD-LD. Patients initially underwent a 3-week
adjustment period to maximize the treatment
response to IR CD-LD, followed by a 6-week
RYTARY dose-conversion period; 95.5% (n 5 450)
completed the 3-week open-label adjustment period

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Figure 2

Mean (SE) Unified Parkinsons Disease Rating Scale (UPDRS) II 1 III over 30 weeks41

TID 5 3 times daily. Source: Pahwa R, et al. Parkinsonism Relat Disord 2014;20:142148.

and 83.4% (n 5 393) completed the 6-week openlabel RYTARY dose conversion. The initial dose of
RYTARY was based on each patients total daily dose
of IR CD-LD at the end of the IR dose adjustment
period. Patients were to start on 3 times/day dosing
with RYTARY, but the dose and dose frequency could
be adjusted by the investigator, with the intention of
reducing off time and minimizing adverse effects.
After the 6-week dose conversion period, patients
were randomly assigned to double-blind treatment
with either RYTARY (186 patients completed) or IR
CD-LD (183 patients completed) for 13 weeks. Four
dose strengths of RYTARY were available for use.42
The 471 patients enrolled in this study had a mean
age of 63.2 years, PD duration of 7.4 years, and mean
daily off time of 5.97 hours.42 The primary efficacy
endpoint, off time as percent of waking hours, was
significantly (p , 0.0001) reduced with RYTARY
(1.17 hours greater reduction) compared with the IR
formulation by study end. Mean daily IR CD-LD dose
was 825.4 mg/d and the mean RYTARY dose was
1,621 mg/d; the mean dosing frequency was 5.2 doses
per day for IR CD-LD and 3.6 doses per day for
RYTARY. Sixty percent of patients required higher
doses of and 16% required lower doses of RYTARY
compared to the dose at the start of conversion; the
dose ratio of RYTARY to IR CD-LD was 2.05. Mean
daily off time is shown in figure 3 for the duration of
the study. Mean on time without troublesome

dyskinesia was increased with RYTARY. Mean


changes in PGI-C, CGI-C, UPDRS parts II and III,
PDQ-39 total score and mobility subscores, modified
Rankin Scale, components of the Short Form Health
Survey (SF-36), EuroQoL 5-dimension quality of life
scale (EQ-5D), and Scales for Outcomes in Parkinsons DiseaseSleep Scale favored RYTARY.42
During the 13-week double-blind period, 43%
and 40% of patients taking RYTARY and IR CDLD, respectively, reported AEs, mostly insomnia,
nausea, falls, dizziness, and dyskinesia. In the
RYTARY treatment group, 15 (7%) patients withdrew from the study, compared with 10 (5%) in
the IR CD-LD group. Five percent of RYTARY
and 3% of IR CD-LD patients reported an SAE. Four
patients overall, 3 taking RYTARY and 1 taking
IR CD-LD, developed impulse control disorders,
none of whom were taking concomitant dopamine
agonists.
Overall, ADVANCE-PD showed that patients
could be safely switched from standard IR CD-LD
to RYTARY with reduced off time and improved
motor function and quality of life.42
COMPARISON OF IPX066, A NOVEL CARBIDOPALEVODOPA EXTENDED-RELEASE FORMULATION,
AND CD-LD-ENTACAPONE IN ADVANCED
PARKINSONS DISEASE (ASCEND-PD) ASCEND-

PD43 was a randomized, double-blind, crossover


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Figure 3

Mean daily off time was significantly (p < 0.0001) reduced with RYTARY42

ANCOVA 5 analysis of covariance; CD-LD 5 carbidopa-levodopa; DB 5 double-blind; EOS 5 end of study; IR 5 immediate
release; OL 5 open-label; V 5 visit. Source: Hauser RA, et al. Lancet Neurol 2013;12:346356. *p 5 0.0004 vs IR CD-LD
group, ANCOVA. **p , 0.0001 vs IR CD-LD group, ANCOVA.

study comparing RYTARY with CLE in patients with


advanced PD previously treated with a stable dose of
CLE ($4 times/day dosing frequency) and having
mean off time $2.5 h/d. After screening, there
was an open-label, 6-week dose conversion period
(from CLE to RYTARY), during which the
RYTARY dose and dose frequency could be adjusted
to the maximum benefit of the patient. As with the
ADVANCE-PD trial,42 the initial RYTARY dose was
based on each patients baseline LD dose (from CLE).
Dosing with RYTARY was not to exceed 5 times/day.
After dose conversion, patients were randomized and
underwent two 2-week crossover treatment periods
where they received either active RYTARY with
placebo CLE or active CLE with placebo RYTARY,
separated by a 1-week open-label RYTARY washout
period. Due to the crossover design, all patients were to
receive both active treatments, one during each
period.43
Eighty-four patients completed both crossover periods. Mean daily LD dosage was 1,723 mg for
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RYTARY and 652 mg for CLE, which reflects an


approximately 22% higher daily LD exposure with
RYTARY and accounts for the differences in bioavailability. Patients taking RYTARY received a mean of
3.5 daily doses compared with 4.7 for CLE.43
Thirty-one percent of patients had no change in their
daily LD dose, 56% increased, and 13% decreased
compared to the dose at the start of conversion.44
Mean percent off time during waking hours (based
on patient diaries) during the last 3 days of each
double-blind treatment period (primary efficacy endpoint) was significantly (p , 0.0001) lower during
RYTARY treatment (24.0%) relative to CLE treatment (32.5%; figure 4A).43 Mean off time during
waking hours per day was significantly (p , 0.0001)
lower for RYTARY (3.8 hours) compared with CLE
(5.2 hours; figure 4B), with a comparable increase in
mean on time without troublesome dyskinesia during waking hours per day for RYTARY (11.4 vs 10.0;
p , 0.0001; figure 4C). There was no significant
increase in on time with troublesome dyskinesia

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Figure 4

Mean percent off time during waking hours, mean off time during
waking hours/day, and mean on time without troublesome dyskinesia
during waking hours/day43

period with RYTARY (n 5 12). SAEs occurred in 4


RYTARY-treated patients while none occurred with
CLE. No SAEs were considered treatment-related.
The more common AEs (reported in at least 2 patients) with RYTARY were nausea (7.3%), vomiting
(2.7%), fall (2.7%), and upper respiratory tract infections (2.7%) during dose conversion; dyskinesia
(4.5%), insomnia (3.4%), and confusional state
(3.4%) were reported during double-blind treatment.
Only falls were reported in at least 2 patients (n 5 2)
taking CLE.43
RYTARY was well-tolerated and demonstrated
improved symptom reduction (decreased percent
off time by 34% and increase in on time by 1.4
hours) without increasing troublesome dyskinesia
compared with CLE in patients with advanced PD.
This improvement was achieved with reduced dosing
frequency. The findings were clinically meaningful as
indicated by the higher percentage of patients showing preference for RYTARY.43
Conversion from CR CD-LD. One study45 examined

(A) Mean percent off time during waking hours. (B) Mean off time during waking hours/day.
(C) Mean on time without troublesome dyskinesia during waking hours/day. CLE 5 carbidopa-levodopa 1 entacapone. Source: Stocchi F, et al. Parkinsonism Relat Disord
2014;20:13351340.

during treatment with RYTARY compared to CLE,


and no treatment period effect was observed.43
At study end, UPDRS II 1 III scores in the on
state were significantly lower with RYTARY (p 5
0.023), and patients reported a significant (p 5
0.0008) preference for RYTARY (52.4%) vs CLE
(27.4%) or no preference (20.2%). The anxiety/
depression scale of the EQ-5D, visual-analog scale,
and the SF-36 Physical Component Summary score
all favored RYTARY over CLE.43
More AEs occurred during the dose conversion
period with RYTARY (n 5 34) compared with the
crossover treatment period with RYTARY (n 5 18)
or CLE (n 5 12) or during the open-label washout

the conversion to RYTARY from CR CD-LD,


followed by long-term treatment with RYTARY in
advanced PD. Patients had been previously treated
with CR CD-LD alone or in combination with IR
CD-LD. The study design included a 6-week openlabel conversion to RYTARY, followed by 6 months
(extension 1) of open-label treatment with RYTARY
and a possible second 6-month period of open-label
RYTARY treatment (extension 2). As with the
previously described studies in advanced PD,
conversion to RYTARY was based on the total daily
dose of LD that patients were taking at study entry.
Initial RYTARY dosing was 3 times/daily and the
RYTARY dose and dosing schedule could be
adjusted with the goal of minimizing off time
without causing troublesome dyskinesia. The
suggested initial total daily LD dose from RYTARY
was approximately 2 to 1; RYTARY was generally
taken at 4- to 6-hour intervals during the patients
waking day.45
Participants had a mean age of 58.4 years at PD
onset and a mean disease duration of 8 years; 65%
were Hoehn & Yahr stage I or II and 35% were stage
III and IV. Mean years of LD treatment was 6.6. Of
the 46 patients screened, 33 completed dose conversion, 25 completed extension 1, and 12 completed
extension 2 (of 12 enrolled). For the total period
under study, 35 patients (81.4% of the 43 treated
patients) reported AEs including urinary tract infection, nausea, anxiety, fall, dyskinesia, viral upper respiratory tract infection, hallucination, orthostatic
hypotension, and tremor (each reported by
$7.0%). Of the 12 patients remaining in the study
at completion (58 weeks), 9 reported AEs (1 each
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anxiety and tremor; 2 each fall, viral upper respiratory


tract infection, and orthostatic hypotension).45 AEs
during long-term treatment with RYTARY were consistent with that of an older population receiving dopaminergic pharmacotherapy for advanced PD and were
similar to those reported previously in patients with
advanced PD receiving RYTARY or IR CD-LD.46,47
PGI-C and CGI-C scales were used to determine
patient and clinical perception of improvement.45 At
the end of initial 6-week dose conversion period,
60.5% (26 of 43) of all enrolled patients and
78.8% (26 of 33) of conversion completers rated
themselves as being at least minimally improved.
Clinicians gave similar ratings to 67.4% (29 of 43)
of all enrolled and 84.8% (28 of 33) of conversion
completers. At the end of the extension 1, 68.8% (22
of 32) of all patients enrolled in the extension rated
themselves as being at least minimally improved.
Clinicians gave such ratings to 75.0% of these patients. More than half of the patients were rated much
improved or very much improved by both scales. No
significant differences in PDQ-8 mean total score
were noted at either time point.45
Of the 33 patients who completed the initial
6-week dose conversion period, 78.8% preferred
RYTARY to their previous treatment, 9.1% preferred
their previous treatment, and 12.1% had no preference. Of the 25 completers of the first 6-month
extension period, 80.0% preferred RYTARY to their
previous treatment, 4.0% preferred their previous
treatment, and 16.0% had no preference (figure 5).
The authors concluded that patients with advanced
PD using CR CD-LD, alone or with IR CD-LD, can
be safely switched to a stable RYTARY dosing regimen within 6 weeks, with an overall patient and clinician perception of clinical improvement.45

S20

Figure 5

Patient preference of treatment45

Source: Tetrud J, et al. Mov Disord 2014;29:727 (poster).

Integrated safety data analyses from RYTARY clinical


trials. An integrated analysis (N 5 978) summarized

led to discontinuation, occurred only in the highdose group.49 Sex (higher rates in females), weight
(higher rates in lighter patients),50 and age (greater
AE rates in patients $75 years of age)51 may also
play a role in rate of AE incidence.

the AE profile of patients with advanced and early PD


treated with RYTARY in phase 2 and 3 trials, which
revealed that a greater proportion of patients with
advanced PD experienced AEs and withdrew from
the studies compared with patients with early PD.48
The most common AEs in patients with early PD
were nausea, dizziness, and headache, compared with
dyskinesias, nausea, and falls in patients with
advanced PD. With the exception of dyskinesias
and falls, AEs tended to decrease with duration of
RYTARY exposure.48 Another analysis49 compared
low- and high-dose groups across 2 studies:
ADVANCE-PD42 and ASCEND-PD.43 Dose
appeared to affect AE occurrence as well.
Dyskinesias were reported more often in high-dose
groups, whereas insomnia was reported more
frequently in low-dose groups. Dyskinesias, which

Long-term safety and efficacy of RYTARY. The last


study covered in this review52 reported the longterm safety and efficacy of RYTARY in patients
with early and advanced PD. The 9-month, openlabel extension study enrolled patients with early
PD from APEX-PD and patients with advanced PD
from ADVANCE-PD and the open-label crossover
study comparing RYTARY and IR CD-LD.
Patients with early PD were titrated by the
investigator to an appropriate RYTARY dose, while
patients with advanced PD started with regimens
established in the previous studies. Patients
RYTARY dose and dose frequency could be
adjusted during the extension study at the
investigators discretion. A total of 617 patients
were enrolled and 567 completed the study.52

Neurology 86 (Suppl 1)

April 5, 2016

2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Patients had a mean age of 64.1 years, with mean


PD duration of 2.7 for early and 7.9 years for
advanced PD. The majority of patients had a Hoehn
& Yahr stage II rating. For patients with early PD,
53.4% experienced at least one AE, most often nausea
(5.6%), insomnia (5.6%), headache (3.7%), back
pain (3.4%), falls (3.4%), dizziness (3.4%), and
tremor (3.0%). Dyskinesia was reported by 1.9% of
patients in the early PD group. In the advanced PD
group, 210 (60.2%) experienced at least one AE,
most often dyskinesia (6.9%), falls (6.6%), pain in
the extremity (3.7%), hallucinations (3.4%), arthralgia (3.2%), urinary tract infections (3.2%), and nausea (2.9%).52
Clinical efficacy, as measured by UPDRS II 1 III
scores in patients with early PD, indicated maintenance of improvement in the extension study to
month 9 regardless of previous treatment with placebo (24.9) or RYTARY (24.0). In patients with
advanced PD, no difference in mean scores was noted
between patients previously treated with IR CD-LD
(28.1) and RYTARY (28.2) at 9 months. The majority of patients with early PD (83.4%) and patients
with advanced PD (80%) were satisfied with
RYTARY treatment at 9 months as indicated by
PGI ratings. PDQ-39, SF-36, and EQ-5D values
were maintained at 9 months.52
Tolerability and efficacy were sustained with
extended treatment with RYTARY in this study, both
in early and advanced PD. No new safety signals were
noted during the extension. In early PD, most patients
took RYTARY 3 times/day with a median dose of 720
mg/d equivalent to 500 mg/d of IR LD doses.52 The
patients with advanced PD who completed the extension most commonly took RYTARY 34 times/day
with a median daily dose of 1,450 mg/d.52
DISCUSSION RYTARY, a formulation of CD-LD
containing both immediate-release and extendedrelease components, has been shown to produce an
onset of clinical effect similar to IR CD-LD while
prolonging the duration of LDs symptomatic
benefits. Plasma LD levels were maintained for up
to 6 hours, which resulted in sustained
improvements in patients with PD and motor
fluctuations.42 Studies included in this review
support the use of RYTARY as initial choice of LD
therapy, as well as to reduce the off time without a
significant increase in troublesome dyskinesias in
patients with advanced PD.4244

Summary of efficacy and safety findings. As indicated by

measures of clinical improvement, RYTARY led to


significant improvement in UPDRS II 1 III, PGIC, and CGI-C in patients with early PD compared to
placebo.39,51 Among patients with advanced PD,
RYTARY resulted in similar improvements in

measures of motor disability and global outcomes,


along with significantly greater reductions in off
time and increases in on time compared with IR
formulations.42,43,53 Patients with advanced PD
reported a significant preference for RYTARY over
CLE.53 The safety profile of RYTARY is consistent
with the known effects of CD-LD in the treatment of
PD.53,54 The most frequent AEs noted with RYTARY
were nausea, dizziness, dyskinesias, falls, headache,
and insomnia,48 which tended to be dose-dependent
in patients with PD in low-dose groups.49 AEs, except
for dyskinesias and falls, tended to decrease over
time45 and were generally consistent between
RYTARY and IR CD-LD.54
Summary of PK findings. PK data from Hsu et al.38 in

healthy adults indicated that the profile for RYTARY


is substantially different from other LD products such
as IR CD-LD, CR CD-LD, and CLE. Following oral
dosing, a sustained concentration defined as .50% of
Cmax was attained and maintained for 1.92.5 hours
longer than other CD-LD products. Due to its
formulation, RYTARY did not require supplemental
IR doses to quickly reach the on state. The variability
in the LD plasma concentration as measured by the
percent coefficient of variation was lower with
RYTARY (64.9%) than with IR CD-LD (121.4%),
CR CD-LD (101.7%), and CLE (92.4%).
Additionally, the slower decline in LD plasma
concentration from peak to 6 hours (Cmax/C6 hr),
lower dose-normalized LD Cmax values, and smaller
deviation from average LD concentration compared
with other agents suggests RYTARY could offer
more constant LD CNS concentrations. This may
result in longer on periods without an increase in
the incidence of dyskinesias compared with the
frequent cycles of on and off periods seen with
the existing IR and CR formulations.
Summary of open-label conversion to RYTARY findings.

The ADVANCE-PD42 and ASCEND-PD43 studies


in advanced PD reported that RYTARY significantly
decreased off time and increased on time without
troublesome dyskinesia, while a long-term open-label
study45 showed conversion to RYTARY from CR
CD-LD with or without IR improved PGI-C and
CGI-C ratings. Patients preferred RYTARY relative
to other LD agents. However, because RYTARY has a
substantially different LD plasma profile, changes in
LD dose and dosing schedules are required when
switching from standard forms of CD-LD to
RYTARY. The initial total daily LD dose from
RYTARY was approximately 2 to 1; RYTARY was
generally taken at 4- to 6-hour intervals during the
patients waking day.4244
Both ADVANCE-PD and ASCEND-PD showed
that the majority of patients required a higher daily
Neurology 86 (Suppl 1) April 5, 2016

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2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

dose of RYTARY than indicated in the dose conversion.42,43 However, adjusting for bioavailability, the
total systemic LD exposure (AUC) was 30%40%
higher with RYTARY than IR CD-LD.40 The
median dosing frequency was 3 times/day after conversion compared with 5 times daily before conversion. In Nausieda et al.,44 the only AE with $5%
incidence was nausea, which was mild or moderate.
There were few discontinuations due to AEs. At the
end of the studies, 86.4% of patients were successfully and safely converted to a stable RYTARY dosage
within a 6-week conversion period.44
Potential role of RYTARY among marketed oral LD
formulations. These clinical results demonstrated that

RYTARY produced significant improvements in


motor disability as well as activities of daily living
and quality of life in early PD vs placebo, and reduced
off time compared with other LD formulations,
while reducing the frequency of dosing, in patients
with advanced PD not adequately controlled by other
LD formulations. Incidence and prevalence of
troublesome dyskinesias remained low in the initial
clinical trials4143 and throughout the open-label
extension study.52 In early PD, a low dose (145 mg
TID) provided the best balance between efficacy and
safety in the initial study.41 For patients with
advanced PD on IR CD-LD, the majority (.85%)
completed the 6-week open-label RYTARY dose
conversion,42 suggesting that a similar conversion
period may be appropriate in clinical practice.
Optimization of therapy can be effectively obtained
in patients with PD with motor fluctuations due to
RYTARYs rapid onset and prolonged action.
AUTHOR CONTRIBUTIONS
R. Dhall: drafting/revising the manuscript for content, contribution of
vital reagents/tools/patents, and acquisition of data. D.L. Kreitzman:
drafting/revising the manuscript for content, including medical writing
for content, and acquisition of data.

ACKNOWLEDGMENT
Editorial assistance was provided by Maria B. Vinall of The Curry Rockefeller Group, LLC, Tarrytown, NY, and was funded by Impax Laboratories, Inc. All authors contributed substantially to the analysis and
interpretation of data and/or the drafting and critical revision of the manuscript. All authors gave final approval for submission.

DISCLOSURES
Dr. Dhall has been an investigator in clinical trials sponsored by Impax
Laboratories, Inc. and has been a consultant for Impax, Merz, Teva,
and Acadia Pharmaceuticals. He has participated on speakers bureaus
for Impax, Teva Pharmaceuticals, and UCB. Dr. Kreitzman has been a
principal investigator (PI) for several IPX066 trials and has served on
one Impax Laboratories, Inc., advisory board, for which he received compensation by the sponsor for these activities. He currently is a PI, and has
been so over the past 5 years, for several ongoing clinical trials sponsored
by Adamas Pharmaceuticals, Teva Pharmaceuticals, Pharma Two B Ltd.,
Impax Laboratories, Inc., Neuraltus Pharmaceuticals, Inc., Chelsea Therapeutics, US WorldMeds, LLC, Ipsen Biopharmaceuticals, and ACADIA
Pharmaceuticals Inc. In addition, he currently is a speaker and consultant, and has been so over the past 5 years, for several pharmaceutical
S22

Neurology 86 (Suppl 1)

companies, including Teva Pharmaceuticals, Impax, US WorldMeds,


LLC, XenoPort, Boehringer Ingelheim, Novartis, and UCB.

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2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Advances in levodopa therapy for Parkinson disease: Review of RYTARY (carbidopa


and levodopa) clinical efficacy and safety
Rohit Dhall and David L. Kreitzman
Neurology 2016;86;S13-S24
DOI 10.1212/WNL.0000000000002510
This information is current as of April 4, 2016
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