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BYETTA: A NEW
PHARMACOLOGICAL OPTION
FOR PATIENTS WITH DIABETES
MELLITUS


Ira Schatten, Pharm.D. Candidate


The prevalence of diabetes is increasing glob-
ally. In 2002, the number of Americans affected by
diabetes reached 18.2 million. Diabetes is responsi-
ble for substantial morbidity and mortality. Compli-
cations of diabetes include heart disease, amputa-
tion, blindness, stroke, neuropathy, and nephropa-
thy. Diabetes was the sixth leading cause of death
listed on U.S. death certificates in 2000.1
Maintaining tight control of blood glucose
slows the progress of microvascular complications
of diabetes, allowing the patient to live a healthier,
more active lifestyle. The United Kingdom Pro-
spective Diabetes Study (UKPDS) confirmed the
value of tight control in type 2 diabetes mellitus
(T2DM).2 However, unresponsiveness to oral anti-
hyperglycemic agents is high. Primary sulfonylurea
failure affects 20% to 25% of patients.3 After five to
seven years of therapy with sulfonylureas, 50% of
these patients will require insulin therapy.4
Exenatide (pyetta) is the first drug in a new
class of antidiabetic medication called incretin mi-
metics. Exenatide was approved on April 29, 2005


and is marketed by Amylin Pharmaceuticals, Inc.,
and Eli Lilly and Co. It is indicated as adjunctive
therapy to improve glycemic control in patients with
T2DM who have not achieved adequate control with
metformin and/or a sulfonylurea. It is expected that
the Food and Drug Administration will also consider
approval of exenatide as monotherapy for patients
with T2DM. Incretin hormones are peptides released
from cells in the gastrointestinal tract in response to
nutrient stimuli. These peptides lead to glucose-
dependent insulin release from the pancreas. Gluca-
gon-like peptide 1 (GLP-1) is a naturally occurring
incretin hormone found in humans. Release of GLP-
1 potentiates glucose-dependent insulin secretion by
stimulating 0-cell growth and differentiation, pro-
moting insulin gene expression, and inhibiting p-cell
death in human islets cultured in vitro.5 Exenatide is
a synthetic form of the 39-amino acid GLP-1 agonist
exendin-4, which was originally isolated from the
salivary secretions of the Gila monster.6 This article
will review the pharmacokinetics and pharmacody-
namics, clinical trials, dosing and administration,
toxicity and safety, and cost of the first available in-
cretin mimetic.
ri.IU


U. 0


PharmaNote


VOLUME 21, ISSUE 4 JANUARY 2006
Lir


INSIDE THIS ISSUE:
BYETTA: A NEW PHARMACOLOGICAL OPTION
FOR PATIENTS WITH DIABETES MELLITUS
REQUIP: THE FIRST FDA-APPROVED DRUG FOR
RESTLESS LEG SYNDROME







Table 1. Summary of Clinical Trials with Exenatide.


Reference


Buse JB, et al.
(2004)9

Fineman MS, et al.
(2004)10

Fineman MS, et al.
(2003)1


Heine RJ, et al.
(2005)13


Sample
Type 2 diabetics
treated with sulfony-
lureas (n = 377)
Type 2 diabetics (n=
123)

Type 2 diabetics (n=
116)


Type 2 diabetics (n
551)


Study Type
RCT, DB, PC, Parallel
group

RCT, DB, PC


RCT, DB, PC, Parallel
group


RCT, OL


Dose
5 and 10 tg twice
daily or placebo

Titrated to 0.24 [tg/kg
TID


0.08 [tg/kg BID


Exenatide 10 [tg BID
versus insulin
glargine


Clinical Response
Improved overall HbAlc (p
< 0.001)
Gradual dose-escalation of
exenatide reduced N/V inci-
dence (p < 0.001)
Decreased fructosamine (p <
0.004), HbA1o (p < 0.006),
PPPG (p < 0.004), increased
P1-cell function
Both exenatide and insulin
reduced HbA1 by 1.11%;
postprandial glucose excur-
sions and weight gain were
less profound with exenatide


RCT = randomized controlled trial; DB = double blind; PC = placebo controlled; N/V
BID= twice daily; TID= three times daily.

Mechanism of Action
Exenatide, a synthetic incretin mimetic, is a
GLP-1 analog.6 GLP-1 is rapidly secreted by the L
cells of the intestine in response to food ingestion.
Release of GLP-1 potentiates glucose-dependent in-
sulin secretion by stimulating P-cell growth and dif-
ferentiation and insulin gene expression. GLP-1 in-
hibits P-cell death in human islets cultured in vitro.
The mechanism of action involves GLP-1-induced
expression of a transcription factor called islet duo-
denum homeobox-1 (IDX-1), which is a master regu-
lator of pancreatic development and P-cell function.
IDX-1 stimulates progenitor cells in the pancreatic
ducts to develop into p-cells. These pancreatic pro-
genitor cells have been isolated in humans. This sug-
gests GLP-1 may improve P-cell differentiation, in-
crease d P-cell mass, and increased P-cell lifespan.
GLP-1 also inhibits glucagon secretion, delays gas-
tric emptying, and acts through the central nervous
system to decrease appetite, increase sensation of
satiety, and promote weight loss.8'12

Pharmacokinetics and Pharmacodynamics
Kolterman, et al. reported that subcutaneous
(SC) doses of exenatide increased plasma concentra-
tions of the drug in a dose-dependent manner. Peak
concentrations were reached within 2-3 hours.7 Simi-
lar exposure was achieved with SC administration of
exenatide in the abdomen, thigh, or arm. Subcutane-
ous injections of exenatide yield a fairly predictable
plasma concentration and lower BG rapidly. The vol-
ume of distribution of exenatide following SC ad-


= nausea and vomiting; PPPG = postprandial plasma glucose; OL = open-label


ministration is 28.3 L, which means that this drug is
highly tissue bound.
Exenatide is predominantly eliminated by glome-
rular filtration with subsequent proteolytic degrada-
tion.12 Mean half-life values ranged 3.3 to 4 hours.
The dose must be reduced in chronic kidney disease
to prevent accumulation and hypoglycemia.8
In two studies by Kolterman, et al., all doses of
exenatide effectively blunted the initial rise in post-
prandial plasma glucose.4 Baseline plasma insulin
concentrations were similar for the placebo and ex-
enatide groups. Within 1.5 to 2 hours following drug
administration, plasma glucose concentrations in all
exenatide groups decreased. In contrast, 5 hours
passed before postprandial plasma glucose concen-
trations decreased in the placebo group. Postprandial
plasma insulin concentrations peaked by 2 hours in
all treatment groups. Baseline plasma glucagon con-
centrations were similar across treatment groups.
There was a dose-dependent slowing of gastric emp-
tying.8

Clinical Trials
Several clinical trials have been conducted to as-
sess the role of exenatide in the care of diabetic pa-
tients. Table 1 includes a summary of clinical trials
with exenatide. Four randomized controlled trials
have helped to establish the safety and efficacy of
exenatide.9-11, 13
One trial studied the effects of exenatide on gly-
cemic control and body weight over a 30-week pe-







Table 2. Incidence of Adverse Effects with Exenatide.12

Adverse effect Placebo BID (%) Exenatide BID (%)*
Nausea 18 44
Vomiting 4 13
Diarrhea 6 13
Feeling Jittery 4 9
Dizziness 6 9
Headache 6 9
Dyspepsia 3 6

* This column includes exenatide at both 5 mcg BID and 10 mcg BID.

riod in patients with T2DM treated with sulfony-
lureas.9The trial enrolled 377 adults at 101 sites in
the U.S. with sulfonylurea-treated T2DM. This ran-
domized, double-blind, placebo-controlled, parallel
group clinical study was designed to evaluate glyce-
mic control, as assessed by HbAlc and safety. The
study commenced with a 4-week, single-blind, lead-
in period with SC injection of placebo twice daily
(BID). Thereafter, subjects were randomized to one
of four treatment arms. Secondary objectives of the
study included examining the effects of exenatide on
fasting plasma glucose concentrations, body weight,
and fasting concentrations of circulating insulin, pro-
insulin, and lipids. Long-term use of exenatide at
fixed doses of 5 and 10 mcg BID improved HbAlc
in patients failing sulfonylurea therapy. Long-term
use of exenatide at fixed SC doses of 5 and 10 mcg
BID appears to have potential for the treatment of
patients with T2DM not adequately controlled with
sulfonylurea agents, with 41% able to reach and
maintain an HbAlc less than 7% in the 10 mcg BID
arm at the end of 30 weeks.
Another trial studied the effectiveness of progres-
sive dose escalation of exenatide in reducing dose-
limiting side effects, such as nausea and vomiting, in
type 2 diabetics. A total of 123 patients with T2DM
were recruited at 31 sites in the United States. This
randomized, placebo-controlled, double-blind, multi-
center study was designed to compare the proportion
of subjects experiencing nausea and vomiting after
receiving a target dose of exenatide that was known
to cause nausea and vomiting (0.24 [g/kg), delivered
either in a dose-escalation regimen (exenatide-
primed arm) or as a first-time exposure (exenatide-
naive arm). The exenatide-primed arm experienced a


lower incidence of nausea and vomiting compared
with the treatment naive group (27% vs 56%, p <
0.001). Gradual dose-escalation of exenatide did not
compromise glucoregulatory activity, thus demon-
strating the value of gradual dose-escalation in miti-
gating the gastrointestinal side effects of exenatide.10
Exenatide added to metformin and/or sulfony-
lureas in type 2 diabetic patients was evaluated to
determining the effect on glycemic control. A total of
116 patients with T2DM were recruited from 24 sites
throughout the U.S. This randomized, double-blind,
parallel-group, placebo controlled study was de-
signed to assess glucose control and evaluate safety
in patients receiving subcutaneously injected ex-
enatide (0.08 .g/kg injection) or placebo for 28 days.
After a two-week, single-blind, placebo lead-in, pa-
tients were randomly assigned to one of three ex-
enatide treatment groups: BID (breakfast and din-
ner); BID (breakfast and bedtime); thrice daily
(TID); or placebo TID. All exenatide groups had re-
ductions in HbAlc ranging from 0.7% to 1.1%. An
end-of-study HbAlc less than 7% was achieved by
15% of exenatide patients versus 4% of placebo pa-
tients (p < 0.006), confirming the effects of exenatide
on overall glycemia. An analytical method used to
measure insulin secretion, P-cell index homeostasis
model assessment (HOMA), was utilized. On days
14 and 28, the P-cell index HOMA for patients
treated with exenatide was 50% to 100% higher than
baseline. The p-cell index HOMA was unchanged in
the placebo arm.11 This indicates an increase in p-cell
function when exenatide is administered.
Most recently, exenatide was compared with in-
sulin glargine in T2DM patients who were subopti-
mally controlled with metformin and a sulfonylurea.
A total of 551 patients were recruited from 82 outpa-
tient study centers in 13 countries. This open-label,
randomized, noninferiority trial was designed to
compare the effects of exenatide and insulin glargine
on HbAlc over 26 weeks in patients with T2DM.
The exenatide arm received 5 [g BID for 4 weeks
followed by 10 pg BID for the remainder of the
study. The insulin glargine arm received an initial
dosage of 10 units/day; then, using a fixed dose algo-
rithm to adjust the dose, the patients self-titrated their
dose in 2 unit increments every 3 days to achieve
fasting blood glucose of less than 100 mg/dL on
daily glucose monitoring. HbAlc was reduced by
1.11% in both arms. The difference in HbAlc be-
tween arms was 0.017 % (CI, -0.123 to -0.157 %).







Table 3. Average Retail Cost of Frequently Used Agents for the Treatment of Diabetes.*

Drug Dose One month of therapy ($)
5 mcg $194.49
Exenatide (ByettaTm)
10 mcg $220.19

Metformin 850 mg $28.09 (generic)
Glipizide 10 mg $28.19 (generic)
Insulin Glargine (LantusT) 1 vial $73.79
*Prices reflect the average retail cost from 3 community pharmacies in Gainesville, FL 32601.


Both arms reduced fasting plasma glucose levels,
although the reduction was significantly greater (p <
0.001) in the insulin glargine arm.13 However, this
was an open-label trial, the long-term impact of ex-
enatide on HbAlc was not assessed, and the attrition
rates were high in the exenatide arm due to adverse
effects.

Dosing and Administration
The initial dose of exenatide is 5 mcg SC BID
within an hour of morning and evening meals. After
one month of therapy, the dose can be increased to
10 mcg SC BID. Exenatide should be injected into
the abdomen, arm, or thigh; these sites should be ro-
tated to prevent lipodystrophy. Exenatide should not
be administered after a meal due to increased risk of
gastroparesis. Exenatide is not recommended in pa-
tients with severe renal impairment (creatinine clear-
ance less than 30 mL/min) or with severe gastroin-
testinal disease due to increased gastroparesis. No
dosage adjustments are needed based on age, race,
gender, or body mass index. No data are available on
the safety or efficacy of intravenous or intramuscular
injection of exenatide.12


Toxicity and Safety
Contraindications to exenatide include known
hypersensitivity to exenatide or any of its compo-
nents, usage in type 1 diabetes, or for the treatment
of diabetic ketoacidosis. Caution is warranted with
the concurrent usage of insulin, thiazolidinediones,
D-phenylalanine derivatives, meglitinides, and al-
pha-glucosidase inhibitors due to a lack of data when
exenatide is used with these drug classes and the po-
tential for increased hypoglycemia. Other precau-
tions include severe renal impairment, gastrointesti-


nal disease (due to the potential for gastroparesis),
and an increased risk of hypoglycemia when used
with a sulfonylurea. Exenatide is not a substitute for
insulin in insulin-requiring patients. 12
Adverse effects associated with exenatide in-
clude hypoglycemia, diarrhea, nausea/vomiting, gas-
troparesis, and postural hypotension. Table 2 in-
cludes the incidence of various side effects. Fineman,
et al. noted that there were no changes in body
weight, lipids, vital signs, hematological parameters,
or cortisol concentrations in type 2 diabetic patients.
Approximately 20% of patients treated with ex-
enatide develop low-titer antibodies to the drug with
no effect on therapeutic results. Mild to moderate
nausea develops in 31% of exenatide-treated pa-
tients; most cases occur in the initial days of therapy.
Only 13% of patients had persistent nausea. Fifteen
percent of patients experienced hypoglycemia. Those
taking concurrent sulfonylureas were at highest
risk.11,12

Cost/How Supplied
Exenatide is available as a 60-dose prefilled pen
in either 5 mcg per dose or 10 mcg per dose. Table 3
depicts the cost of exenatide and other frequently
used antidiabetic medications. 12

Summary
Exenatide, a new therapeutic modality for use in
type 2 diabetics, has a limited role in the care of dia-
betic patients at this point in time. This medication
has a role as an adjuvant for patients who have failed
metformin and/or sulfonylureas. Since no long term
trials have been conducted to date, more studies are
required to assess the long term efficacy and safety.
It remains unclear whether exenatide provides
greater blood glucose control than combinations of






oral treatments. Until further studies are conducted,
exenatide's place in therapy is for short term use in
patients who remain uncontrolled despite sulfony-
lureas and/or metformin but do not require insulin.
Whether exenatide will delay the time to insulin use,
and the accompanying metabolic consequences, re-
mains to be seen.

References
1. Centers for Disease Control and Prevention,
Diabetes public health resources. cdc.gov/
diabetes/pubs/estimates.htm (accessed 2005
Sept 29).
2. United Kingdom Prospective Diabetes Study
(UKPDS) Group. Intensive blood glucose con-
trol with sulphonylureas or insulin compared
with conventional treatment and risk of compli-
cations in patients with type 2 diabetes. Lancet
1998; 352:837-853.
3. Luna B, Feinglos MN. Oral Agents in the Man-
agement of Type 2 Diabetes Mellitus. Am Fam
Physician 2001;63:1747-56.
4. Scheen AJ, Lefebvre PJ. Insulin versus insulin
plus sulfonylureas in type 2 diabetic patients
with secondary failure to sulfonylureas. Diabe-
tes Res Clin Pract 1989;6(suppl):S33-43.
5. Li Y, Hansotia T, Yusta B et al. Glucagon-like
peptide-1 receptor signaling modulates beta cell
apoptosis. J Biol Chem 2003;278:471-8.
6. Kolterman OG, Kim DD, Shen L et al. Pharma-
cokinetics, pharmacodynamics, and safety of
exenatide in patients with type 2 diabetes melli-
tus. Am J Health-Syst Pharm 2005;62:173-81.
7. Kolterman OG, Buse JB, Fineman MS et al.
Synthetic Exendin-4 (Exenatide) Significantly
Reduces Postprandial and Fasting Plasma Glu-
cose in Subjects with Type 2 Diabetes. J Clin
Endocrinol Metab 2003;88:3082-89.
8. Joy SV, Rodgers PT, Scates AC. Incretin Mi-
metics as Emerging Treatments for Type 2 Dia-
betes. Ann Pharmacother 2005;39:110-8.
9. Buse JB, Henry RR, Han J et al. Effects of Ex-
enatide (Exendin-4) on Glycemic Control Over
30 Weeks in Sulfonylurea-Treated Patients With
Type 2 Diabetes. Diabetes Care 2004;27:2628-
35
10. Fineman MS, Shen LZ, Taylor K et al. Effec-
tiveness of progressive dose-escalation of ex-
enatide (exendin-4) in reducing dose-limiting
side effects in subjects with type 2 diabetes.


Diabetes Metab Res Rev 2004; 20:411-417.
11. Fineman MS, Bicsak TA, Shen LZ et al. Effect
on Glycemic Control of Exenatide (Synthetic
Exendin-4) Additive to Existing Metformin and/
or Sulfonylurea Treatment in Patients With
Type 2 Diabetes. Diabetes Care 2003;26:2370-
77.
12. Product Information: BYETTA injection, ex-
enatide injection. Amylin Pharmaceuticals, Inc.,
San Diego, CA, USA, April 2005.
13. Heine RJ, Van Gaal LF, Johns D et al. Ex-
enatide versus Insulin Glargine in Patients with
Suboptimally Controlled Type 2 Diabetes. Ann
Intern Med 2005;143:559-569.





ROPINIROLE: THE FIRST FDA-
APPROVED DRUG FOR REST-
LESS LEGS SYNDROME




Brittany Still, Pharm.D. Candidate


Restless legs syndrome (RLS) is a debilitating
disorder that continually disrupts sleep and dimin-
ishes quality of life. It is a neurological condition
characterized by unpleasant sensations in the legs
with an uncontrollable urge to move when at rest.
These symptoms become worse during rest, particu-
larly at night, and are usually relieved by activity.
Patients frequently describe the feelings in their legs
as burning, creeping, tugging, or like insects crawl-
ing inside the legs. The abnormal sensations, or
paresthesias, can range in severity from uncomfort-
able to irritating but can deteriorate in some patients
and cause pain.1
The leg discomfort associated with RLS is worse
at night. The symptoms demonstrate a circadian
rhythm becoming worse in the late evening and are
usually less severe or absent during the day.2 Relax-
ing or lying down can activate or worsen the symp-
toms. Most people with RLS have difficulty falling







asleep and trouble staying asleep during the night.
This results in daytime fatigue and exhaustion, which
in turn can affect patients' quality of life. Even nor-
mal activities of daily living can be adversely af-
fected since many people are unable to concentrate,
have impaired memory, or fail to complete daily
tasks.1
RLS is underdiagnosed and sometimes even mis-
diagnosed. The exact prevalence is unknown and
may be higher than currently reported. Some re-
searchers have estimated that RLS affects as many as
12 million Americans, and others have reported a
prevalence of 10% in the general population.1,2 Rea-
sons contributing to an under reporting include pa-
tients not seeking medical attention since they do not
believe their condition is treatable or the symptoms
are too mild, or physicians may wrongly attribute
their symptoms to be associated with other condi-
tions such as nervousness, insomnia, stress, or arthri-
tis. RLS occurs in both genders, however the inci-
dence is slightly higher in women. The syndrome can
begin at any age; however it is more common and
more severe in patients middle-aged or older.'
Periodic limb movement disorder (PLMD) is a
common condition that usually accompanies RLS. It
is characterized by involuntary leg twitching or jerk-
ing movements during sleep. These movements typi-
cally occur every ten to sixty seconds and sometimes
persist throughout the night. In PLMD, the leg move-
ments are involuntary and the patient has no control
over them, unlike the movements associated with
RLS, which are usually initiated by the patient in or-
der to relieve the discomfort. More than 80% of pa-
tients with RLS also develop PLMD, however most
people who have PLMD will not necessarily experi-
ence RLS.
RLS is in most cases considered to be idiopathic;
no causes have been identified. Family history is pre-
sent in approximately 50% of cases. Other predispos-
ing conditions that are associated with RLS include:
low iron levels or anemia; chronic diseases such as
kidney failure, diabetes, Parkinson's disease, and pe-
ripheral neuropathy; and pregnancy, particularly in
the last trimester. In addition, certain medications
such as antiemetics, antipsychotics, anticonvulsants,
and cold and allergy drugs can aggravate symptoms.
Dietary factors for aggravation of RLS include: caf-
feine, alcohol, and tobacco. Usually elimination of
the underlying disorder or discontinuing the medica-
tion or substance involved can relieve symptoms.1


Table 1: Dose Titration Schedule of Ropinirole for RLS.


Day/Week
Days 1 and 2

Days 3-7


Dosage to be taken once daily, 1-3
hours before bedtime
0.25 mg

0.5 mg


1 mg


Week 2

Week 3

Week 4

Week 5

Week 6
Week 7


1.5 mg

2 mg

2.5 mg


3 mg
4 mg


Other than treating the underlying disorders caus-
ing RLS, or eliminating potential substances that ag-
gravate symptoms, there are very few treatment op-
tions currently available. Some studies have shown
that maintaining a regular sleep pattern, or a regular
moderate exercise program may help to reduce
symptoms. Other non-pharmacologic treatment op-
tions include taking hot baths, massaging the legs, or
using heating pads or ice packs. Pharmacologic op-
tions include: dopaminergics, benzodiazepines,
opioids, and anticonvulsants. Dopaminergic agents,
commonly used to treat Parkinson's disease, reduce
RLS symptoms and are considered the treatment of
choice. Short-term treatment with levodopa/
carbidopa may cause disease augmentation in which
symptoms eventually become more severe. Another
treatment option includes dopamine agonists such as
pergolide mesylate, pramipexole, and ropinirole hy-
drochloride. These agents are effective in treating the
symptoms of RLS and are less likely to cause aug-
mentation.1
Ropinirole hydrochloride (Requip) is the first
FDA-approved drug for the treatment of moderate-
to-severe primary RLS. Ropinirole is indicated for
patients who experience fifteen or more episodes of
RLS per month.3 The purpose of this article is to re-
view available data on the pharmacokinetics and
pharmacodynamics, clinical trials, dosing and ad-
ministration, toxicity and safety, and cost of ropini-
role.

Mechanism of Action
Ropinirole is a non-ergoline dopamine agonist
with high relative in vitro specificity and full intrin-







Table 2: Results of TREAT RLS 1 and TREAT RLS 2. 2,4

TREAT RLS 1 TREAT RLS 2
Ropinirole Placebo Ropinirole Placebo
END POINTS (n=146) (n=137) (n=131) (n=134)
Mean adjusted change in
-M a c i 11.04 points -8.03 points -11.2 points -8.7 points
IRLS score
CGI-I Scale Response (%) 78 (53.4) 56 (40.9) 78 (59.5%) 53 (39.6%)


sic activity at the D2 and D3 dopamine receptor sub-
types. It binds with higher affinity to D3 than to D2 or
D4 receptor subtypes. Ropinirole has moderate in
vitro affinity for opioid receptors. The exact mecha-
nism of action for RLS is unclear since the patho-
physiology of RLS is also largely unknown. How-
ever, evidence suggests primary dopaminergic sys-
tem involvement in RLS. Some studies show a mild
striatal presynaptic dopaminergic dysfunction that
may be involved in the pathogenesis of RLS.3

Pharmacokinetics and Pharmacodynamics
Ropinirole is rapidly absorbed after oral admini-
stration and reaches peak concentration in 1-2 hours.
Absolute bioavailability is 55%, and the drug under-
goes a first-pass effect. Ropinirole is extensively me-
tabolized by the liver to inactive metabolites. The
major metabolic pathways include N-despropylation
and hydroxylation through the CYP1A2 isoenzyme.
This enzyme is stimulated by smoking; therefore to-
bacco use can decrease the concentration of ropini-
role. In addition, CYP1A2 inhibitors, such as fluvox-
amine, mexiletine, ciprofloxacin, and norfloxacin,
can increase the serum concentration of ropinirole.
Steady-state concentrations are usually achieved
within two days of dosing. Since the dose of ropini-
role is individually titrated to a clinical response, a
dosage adjustment is not necessary in the elderly
even though their oral clearance is reduced by 30%
compared to younger patients. Furthermore, no dos-
age adjustment is necessary in renal dysfunction
since no difference in clearance was found in pa-
tients with moderate renal impairment. Ropinirole
should be titrated with caution in patients with he-
patic impairment since it is metabolized by the liver.3

Clinical Trials
Two major clinical studies assessed the role of
ropinirole in the treatment of RLS. These trials,
TREAT RLS 1 and TREAT RLS 2, were 12-week,
randomized, double-blind, placebo-controlled stud-


ies. TREAT RLS 1 was conducted in 10 European
countries, and TREAT RLS 2 enrolled patients in the
United States, Europe, and Australia.
Both studies used similar methods of measure-
ment for the primary outcome. The primary endpoint
in both trials was the change in the International
Restless Legs Scale (IRLS) score at week 12, com-
pared to baseline. The IRLS is a disease-specific, 10-
item scale that reflects the frequency and intensity of
sensorimotor features, associated sleep problems,
and the impact on mood and daily activities. The
maximum severity score is 40, and patients were re-
quired to have a score of at least 15 to enroll in the
studies. Another scale used for measurement was the
Clinical Global Impression (CGI) scale. CGI is a
seven-point scale ranging from 1, which is equiva-
lent to "very much improved", to 7 or "very much
worse". A response on this scale was defined as a
score of 1 (very much improved) or 2 (much im-
proved).2
TREAT RLS 1 was conducted in 43 hospi-
tals, sleep centers, and neurology clinics in 10 Euro-
pean countries. Patients were randomly assigned to
receive ropinirole or placebo for twelve weeks. Pa-
tients were initiated on ropinirole 0.25 mg once daily
between one and three hours before bedtime. The
dose was titrated upwards during weeks 1 to 7 until
patients received a maximum of 4 mg/day or until
they reached their optimal dose (Table 1). This study
included 146 patients in the ropinirole arm, and 137
patients taking placebo.4
The primary end point was the mean IRLS score
at week 12 compared to baseline. The mean IRLS
score at week 12 was lower in the ropinirole group
(13.5 points) than with the placebo group (17.1
points). The adjusted mean improvement in the IRLS
total score at week 12 was also significantly greater
for the ropinirole group (-11.04 points) than for pla-
cebo (-8.03 points), p value = 0.0036. Significantly
more patients showed a "much improved" or "very
much improved" score on the CGI-I scale at week 12







Table 3: Incidence of Adverse Effects with Ropinirole.2-4


TREAT RLS 1 Study TREAT RLS 2 Study
Ropinirole (n=146) Placebo Ropinirole Placebo
Adverse Events (n=138) (n=131) (n=136)
Nausea (n, %) 55 (37.7) 9 (6.5) 52 (39.7) 11(8.1)
Vomiting (n, %) 19 (13.0) 2 (1.4) 16 (12.2) 3 (2.2)
Headache (n, %) 29 (19.9) 23 (16.7) 29 (22.1) 35 (25.7)
Fatigue/Somnolence (n, %) 18 (12.3) 12 (8.7) 20 (15.3) 9 (6.6)
Upper Respiratory Infection (n, %) 14(9.6) 15 (10.9) 18(13.7) 11(8.1)
Dizziness (n, %) Not Reported Not Reported 20 (15.3) 6 (4.4)
Abdominal Pain (n, %) 18 (12.3) 12 (8.7) Not Reported Not Reported


in the ropinirole group than in the placebo group (p
value = 0.0416). This study also observed several
secondary endpoints including effects on sleep dis-
turbance, sleep quantity, somnolence, mental-health,
and social functioning. Overall, TREAT RLS 1
found that ropinirole was significantly more effective
than placebo in alleviating symptoms of RLS, im-
proving sleep quantity and adequacy, reducing sleep
disturbance and daytime somnolence, and improving
health related quality of life.4
TREAT RLS 2 was conducted in 46 centers in
Australia, Europe, and North America. Patients were
randomly assigned to placebo or ropinirole with an
initial dose of 0.25 mg/day taken one to three hours
before bedtime. The titration schedule was the same
as the one used in TREAT RLS 1. (Table 1) The
study included a total of 265 patients with 131 as-
signed to the ropinirole group and 134 to placebo.2
The primary and secondary end points were the
same as in TREAT RLS 1. The mean adjusted
change in IRLS score between baseline and week 12
was significantly greater for ropinirole (-11.2 points)
than placebo (-8.7 points), p value = 0.0197. More
patients in the ropinirole group (59.5%) were classi-
fied as "much improved" or "very much improved"
on the CGI-I scale compared with the placebo group
(39.6%), p value = 0.001. The results of TREAT
RLS 2 demonstrated that ropinirole effectively treats
the symptoms of moderate-to-severe RLS.2 The re-
sults of these two trials are summarized in Table 2.

Dosage and Administration
The initial dose of ropinirole is 0.25 mg once
daily to be taken 1-3 hours before bedtime. After two
days, the dose can be increased to 0.5 mg daily and
to 1 mg once daily at the end of the first week. Table


1 illustrates the titration schedule approved for the
treatment of RLS. Ropinirole can be taken with or
without food; however food may reduce the occur-
rence of nausea. In the treatment of RLS, the safety
and effectiveness of doses greater than 4 mg once
daily have not been established.3

Toxicity and Safety
The only contraindication to ropinirole is a
known hypersensitivity to the agent. Ropinirole may
increase the risk of patients falling asleep while en-
gaged in daily activities, including driving vehicles,
which reportedly has resulted in automobile acci-
dents. Many patients reported somnolence before
they fell asleep, while a few patients claimed they
had no warning signs. Somnolence is common in
Parkinson's disease patients where it is more fre-
quent than in RLS. Other adverse effects, which
were more frequent in Parkinson's patients, include
syncope, symptomatic hypotension, hallucinations,
dyskinesia, and melanoma. In RLS, augmentation,
defined as an earlier onset of symptoms, increase in
symptoms, and spread of symptoms to involve other
extremities, has been reported with dopaminergic
agents. Rebound, a worsening of symptoms in the
early morning hours, has also been reported among
patients receiving dopaminergic drugs. These phe-
nomena have not been evaluated in controlled clini-
cal trials with ropinirole for patients with RLS.3
The most common adverse events were nausea
and headache. Other adverse events reported were
vomiting, fatigue, somnolence drowsiness, and upper
respiratory tract infection. Table 3 displays the most
frequent adverse events experienced in the two major
clinical trials on ropinirole in RLS.







Table 4: Cost of a One Month Supply of Ropinirole.*

Requip* Price of one month of therapy
0.25mg $65.11

0.5mg $65.11

1mg $63.94

2mg $67.81

3mg $83.91

4mg $88.61

5mg $88.61

*Prices reflect the average retail cost from 3 community pharmacies in Gaines-
ville, FL 32601.

Cost
Ropinirole is a pentagonal film-coated tablet
and is available in several different strengths includ-
ing 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, and 5
mg. Table 4 includes prices for ropinirole in each of
the dosage strengths available3. A dose greater than 4
mg/day is not indicated for the treatment of RLS;
however patients taking 2.5 mg/day could take half
of a 5 mg tablet instead of taking two different
strength tablets.

Summary
Ropinirole is an effective and well tolerated ther-
apy for RLS. The results from two major clinical tri-
als support its first-line use in the treatment of RLS.
Ropinirole is particularly indicated for the treatment
of moderate-to-severe RLS in patients who experi-
ence fifteen or more episodes per month. Clinical
studies of ropinirole did not find an association with
worsening of RLS symptoms. Further studies are re-
quired to confirm that the efficacy and the lack of
augmentation are maintained with long-term use.
Additional studies should investigate earlier dosing
schedules, especially for patients who experience
symptoms before bedtime. Ropinirole is an effective
option for patients who suffer from moderate-to-
severe RLS. Ropinirole alleviates symptoms of RLS,
improves sleep quantity and adequacy, reduces sleep
disturbance and daytime somnolence, and improves
overall health related quality of life.


References
1. Restless Legs Syndrome Fact Sheet: National
Institute of Neurological Disorders and Stroke.
National Institutes of Health. Bethesda, MD.
NIH Publication No. 01-4847. April 2001.
2. Walters AS, Ondo WG, Dreykluft T et al.
Ropinirole is effective in the treatment of restless
legs syndrome. TREAT RLS 2: a 12-week, dou-
ble-blind, randomized, parallel-group, placebo-
controlled study. Movement Disorders
2004;12:1414-1423.
3. Product Information: Requip, ropinirole hydro-
chloride tablets. GlaxoSmithKline, Research Tri-
angle Park, NC. July 2005.
4. Trenkwalder C, Garcia-Borreguero D, Montagna
P et al. Ropinirole in the treatment of restless
legs syndrome: results from the TREAT RLS 1
study, a 12 week, randomized, placebo controlled
study in 10 European countries. J Neurol Neuro-
surg Psychiatry 2004;75;92-97.
5. Bliwise DL, Freeman A, Ingram CD et al. Ran-
domized, double-blind, placebo-controlled, short-
term trial of ropinirole in restless legs syndrome.
Sleep Medicine 2005;6:141-147.
6. Adler CH, Hauser RA, Sethi K et al. Ropinirole
for restless legs syndrome: a placebo-controlled
crossover trial. Neurology 2004;62:1405-1407.


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
Pharm.D. Editor

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D., BCPS


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