Title: PharmaNote
ALL VOLUMES CITATION PDF VIEWER THUMBNAILS PAGE IMAGE ZOOMABLE
Full Citation
STANDARD VIEW MARC VIEW
Permanent Link: http://ufdc.ufl.edu/UF00087345/00039
 Material Information
Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: March 2006
 Record Information
Bibliographic ID: UF00087345
Volume ID: VID00039
Source Institution: University of Florida
Rights Management: All rights reserved by the source institution and holding location.

Downloads

This item has the following downloads:

March2006 ( PDF )


Full Text


















INSULIN DETEMIR: A NEW TOOL TO
FIGHT DIABETES MELLITUS


Anthony Menezes, Pharm.D. Candidate


Diabetes is a major global health problem. There
are currently 20.8 million people in the United States
with diabetes, of which about 6.8 million are not
aware that they have the disease.1 Diabetes is a con-
dition in which the body either does not produce in-
sulin in sufficient concentrations to maintain eugly-
cemia, referred to as Type 1, or does not utilize insu-
lin properly, referred to as Type 2. Poor glycemic
control can lead to numerous microvascular and
macrovascular complications, which ultimately lead
to a shorter lifespan and decreased quality of life.
The treatment of Type 1 diabetes is insulin.
There are numerous types of insulins that have dif-
ferent pharmacokinetic properties. Type 2 diabetes
treatment consists of oral medications as well as in-
sulin in selected patients.
While treatment of diabetes may lead to better
glycemic control, it may increase the risk of hypo-
glycemia and other side effects including weight gain
and skin/injection site reactions. Hypoglycemia can
be a devastating consequence of insulin therapy, with
consequences for both the patient and the people
around them. Patients with diabetes can also develop
nocturnal hypoglycemia, which may result in low
blood sugars in the morning or a type of rebound hy-


perglycemia (the "Dawn Effect").
Most type I diabetic patients require some form
of basal insulin which works throughout the day to
keep glucose levels normal. Most of these basal in-
sulins are subcutaneously injected, and form a crys-
talline substance which delays absorption. However,
these insulins are inconsistently absorbed leading to
variability in duration of action and time to onset.
Basal insulins may also cause hypoglycemic epi-
sodes.
A new type of basal insulin has been approved in
the United States. Levemir (Insulin Detemir) is a
long-acting basal insulin that may offer consistent
glycemic control while minimizing the risks of hy-
poglycemia and weight gain generally associated
with insulin replacement. The objective of this arti-
cle is to describe the efficacy and safety of insulin
detemir.

Pharmacology
Insulin detemir is produced using recombinant
DNA technology. The amino acid residue at posi-
tion B30 has been omitted and a 14-carbon fatty acid
chain has been added to position B29. The fatty acid
chain increases lipophilicity and the addition of zinc
stabilizes the compound. The formation of insulin



INSIDE THIS ISSUE:

INSULIN DETEMIR: A NEW TOOL TO FIGHT
DIABETES MELLITUS

PHARMACOTHERAPY OF GOUT: AN UPDATE

* l *


mm


SPharmaNote


VOLUME 21, ISSUE 6 MARCH 2006
Lir


Volume 21, Issue 6, March 2006


PharmaNote







Table 1. Efficacy of insulin detemir and NPH in adults, adolescents and children with diabetes mellitus.
Baseline Baseline Mean Mean FPG Mean Change
Mean FPG HbAlc at (mmol/L) in Bodyweight
Duration Type Treatment HbAlc (mmol/ end of at end of From
Reference (weeks) (1 or 2) (no. of pts) (%) L) study (%) study Baseline (kg)
ID bid 8.48 8.83 7.88*** 7.58
8.48 8.83 7.88*** 7.58 -0.95***


neriiansen et
al.b


Home et al.




Russell-Jones
et ald.



Vague et al.



Haak et al.



Raslova et al.



De Leeuw et
al.10




Pieber et al.5


( Lz6)
NPH bida
(297)
ID bidc
(137)
ID bida
(139)
NPH bida
(132)
ID qde
(491)
NPH qde
(256)
ID bidf
(301)
NPH bidf
(146)
ID qd/bidg
S (341)
NPH qd/
bidg (164)
ID qd/bidg
S (195)
NPH qd/
bidd (199)
ID bidf
(216)
NPH bidf
(99)
ID bidh
(139)
ID bida
(132)
NPH bida
(129)


a Administered in the morning and at bedtime. b Bolus insulin requirements in the NPH group were provided by regular human insulin. c Administered at 12-hour
intervals. d Bolus insulin requirements were provided by regular human insulin. e Administered at bedtime. f Administered before breakfast and at bedtime. g
Frequency of administration according to previous treatment. h Administered in morning and pre-dinner. p<0.05, ** p = 0.004, ***p < 0.001 vs NPH, ft p
0.02 vs NPH, p p< 0.001 vs baseline, p< 0.02, p = 0.038, p <0.006 vs NPH.


hexamers at the site of injection results in delayed
dissociation of insulin molecules and slow systemic
absorption.2
The mechanism of action of insulin detemir is the
same as that of human insulin. It promotes the stor-
age and inhibits the breakdown of glucose, fat, and
amino acids. It facilitates the uptake of glucose in
muscle and adipose tissue. It inhibits glycogenolysis
and gluconeogenesis and enhances the storage of fat
and inhibits mobilization of fat for energy in adipose
tissue. Insulin is also involved in the regulation of

PharmaNote 4


protein metabolism.3

Pharmacokinetics
Insulin detemir is administered by subcutane-
ous injection only. It is 98-99% reversibly bound to
albumin. The effect of detemir on plasma glucose is
dose-dependent. Insulin detemir provides a meta-
bolic effect for up to 24 hours, depending on the dose
administered. There is a between-subject variability
in the duration of action for insulin detemir, but it is
significantly lower than that of NPH insulin.34 Peak

Volume 21, Issue 6, March 2006


8.29

8.55
8.74

8.52



8.35
8.35


8.18

8.11

7.89

7.77

8.16

8.08


8.18
8.03


8.01
8.13
8.08


9.17

11.57
11.65

12.20



11.88
11.55


11.60

11.60

10.11

10.42


11.85
11.51



10.00
10.63
10.65


8.11


7.75
7.78

7.94


8.30
8.41


7.60

7.64

7.63

7.48

7.465

7.525


7.53
8.03



7.67
7.65
7.73


8.10


9.75**
8.94***

11.24


10.27***
11.40


9.9

9.73

9.61

7.28

7.32


10.7
10.8


9.83***
9.15
11.14


0.07


0.02*
0.24*

0.86


-0.23*
0.31


0.7

0.9tt

1.6

0.51+

1.135


-0.1
1.2



-0.6***
0.01
0.7







plasma concentrations are reached within 6-8 hours
of injection. More than 50% of the maximum effect
occurs between 3-4 hours to 14 hours after injection
for doses ranging from 0.2-0.4 units/kg.3 Detemir
exhibits slightly higher plasma AUC and Cmax in
children compared to adolescents and adults(10%
higher, and 24% higher respectively). No dosage
adjustment is necessary in children because admini-
stration is patient-specific.3 For patients with hepatic
impairment, there are no recommendations available.
Dosage should be modified depending on clinical
response and degree of hepatic impairment. Renal
impairment does not appear to alter the pharmacoki-
netics of insulin detemir, however pharmacodynamic
differences occur in insulin sensitivity as renal func-
tion declines which result in increased responses to a
given dosage.3 As with treatment in individuals with
hepatic impairment, dosage should be based on clini-
cal response.3

Clinical Trials
Several clinical trials have assessed the efficacy
of insulin detemir. (Table 1) Detemir has been com-
pared to NPH in patients with Type 1 and 2 diabetes.
Most regimens included insulin aspart or regular in-
sulin as the meal-time insulin. Most trials demon-
strate that insulin detemir provides glycemic control
that is similar to or better than NPH insulin in pa-
tients with type 1 and type 2 diabetes. Patients on
insulin detemir achieved fasting plasma glucose lev-
els that were similar to or lower than those of pa-
tients on NPH insulin.
Pieber et al investigated the safety and efficacy
of two different administration time regimens with
insulin detemir and NPH insulin. Insulin detemir
was administered in the morning and pre-dinner or in
the morning and at bedtime. The NPH regimen was
given in the morning and before bedtime. All sub-
jects were given insulin aspart before meals. All
three treatment groups had comparable HbAlc levels
after 16 weeks, with reductions of 0.39-0.49%.
Lower fasting plasma glucose was recorded with in-
sulin detemir morning and dinner and morning and
bedtime compared to the NPH -based regimen.
There was significantly less within-person variation
in self-measured fasting plasma glucose for the insu-
lin detemir regimens. The overall and nocturnal rate
of hypoglycemia was similar among all three groups.
Mean bodyweight was lower in the insulin detemir
regimens compared to NPH after 16 weeks, suggest-


ing a lesser propensity to induce weight gain with
detemir.5
De Leeuw et al compared the long term efficacy
and safety of a twice-daily insulin detemir regimen
with a NPH regimen in type 1 diabetic patients. The
HbAlc decreased by 0.64% and 0.56%, respec-
tively. This difference was not statistically signifi-
cant. Nocturnal hypoglycemia during months 2-12
was 32% lower in the detemir group than the NPH
group (p = 0.02). Baseline-adjusted mean body
weight was lower in the detemir group after 12
months. There was a between-group difference of
1.44 kg (p = 0.0002), favoring detemir.10
Haak, et al. compared the safety and efficacy of
an insulin detemir regimen with that of NPH-based
therapy in type 2 diabetic patients. Both regimens
resulted in significant reductions in HbAlc levels.
(detemir HbAlc: 0.2, p= 0.004; NPH HbAlc: 0.4,
p= 0.0001). Reductions in fasting plasma glucose
(FPG) as well as self-monitored blood glucose
(SMBG) profiles were similar for both groups.
Within-subject day to day variation in fasting SMBG
was significantly less with insulin detemir (p=0.021).
The detemir regimen resulted in less body weight
gain than the NPH regimen (1.0 kg vs. 1.8 kg, p=
0.017).11
Raslova, et al. compared the safety and efficacy
of an insulin detemir regimen to that of a NPH regi-
men in type 2 diabetic patients. Both regimens re-
sulted in comparable reductions in HbAlc (p=
0.515). A significantly lower within-person varia-
tion in SMBG (SD: 1.2 mmol/L vs. 1.54 mmol/L,
p<0.001), and a lower degree of weight gain was
seen in the detemir regimen. (0.51kg vs. 1.13 kg,
p=0.038).12

Adverse Effects
Hypoglycemia is the most common adverse
event associated with detemir. However, the risk of
total hypoglycemia is comparable between insulin
detemir and NPH insulin. Some studies suggest a
lower incidence of nocturnal hypoglycemia with de-
temir. Within-person variation in SMBG levels are
significantly lower in detemir regimens compared to
NPH.5,6
Other adverse events reported in clinical tri-
als are headache, upper respiratory tract infection,
dizziness, and rhinitis. Most of these adverse events
are considered mild and are no considered drug-
related. Some patients experience minor local skin


PharmaNote Volume 21, Issue 6, March 2006


Volume 21, Issue 6, March 2006


PharmaNote







reactions around the injection site.5,6,7 Weight gain is
a consequence of insulin administration regardless of
the specific product. Weight gain associated with
insulin detemir is generally less pronounced com-
pared with NPH.7

Contraindications and Precautions
Contraindications to treatment include hyper-
sensitivity to detemir or any of its constituents, as
well as current hypoglycemia.8 Insulin detemir is not
intended to be used with an insulin pump. Caution
should be used when changing insulin doses. Other
precautions include change in physical activity or
diet, hepatic or renal impairment, and periods of ill-
ness or stress. Detemir should be used in pregnancy
and breast-feeding patients only if the benefit out-
weighs the risks.

Dosing
For once-daily use, detemir should be admin-
istered in the evenings or at bedtime. For twice-daily
use, the second dose should be administered with
dinner, at bedtime, or 12 hours after the first dose.
When patients are switching from NPH insulin,
higher doses of detemir may be required to reach the
same glycemic control. However, switching should
be done on a unit-for-unit basis. It should then be
titrated to reach target glucose levels. For insulin-
naive patients, who are inadequately controlled by
oral antidiabetic drugs alone, insulin detemir should
be dosed at 0.1-0.2 units/kg once daily in the eve-
ning, or 10 units once or twice daily. The starting
dose should then be titrated to reach glycemic tar-
gets.8

Pricing
Levemir was FDA approved in June 2005
and should be available in 2006. No pricing infor-
mation is available at this time.

Summary
Insulin detemir is a new type of insulin for
use in both type 1 as well as type 2 diabetics. It has a
comparable safety and efficacy profile to NPH insu-
lin with less weight gain. It shows value in patients
who have questionable compliance due to increased
weight gain. Future studies should attempt to com-
pare insulin detemir with insulin glargine to clarify
the role of these agents as basal insulin products in
patients with diabetes.


References:
1. American Diabetes Association. www.diabetes.org. Ac-
cessed: 11/27/05.
2. Hordern, S.V.M.; Russel-Jones, D.L. "Insulin Detemir,
Does a New Century Bring a Better Basal Insulin?" Int J
Clin Pract 2005;59:730-739.
3. Insulin Detemir. Clinical Pharmacology Online. Gold
Standard.
4. Plank, Johannes MD, et al. A double-blind, randomized,
dose-response study investigating the pharmacodynamic
and pharmacokinetic properties of the long-acting insulin
analog detemir. Diabetes Care 2005;28:1107-1112.
5. Pieber, TR, Draeger E, et al. Comparison of three multiple
injection regimens for type 1 diabetes: morning plus
dinner or bedtime administration of insulin detemir vs.
morning plus bedtime NPH insulin. Diabetic Medicine
2005;22:850-857.
6. Chapman, Therese M, Perry Caroline M. Spotlight on
insulin detemir in type 1 and 2 diabetes mellitus. Biodrugs
2005;19:67-69.
7. Goldman-Levine, Jennifer D, Lee, Karen W. Insulin de-
temir- a new basal insulin analog. Ann of Pharmacother
2005;39:502-507.
8. Insulin Detemir. Thompson MICROMEDEX. Thompson
Healthcare Inc. 2005.
9. Chapman, Therese M. Perry, Caroline M. Insulin Detemir:
a review of its use in the management of type 1 and 2 dia-
betes mellitus. Drugs 2004;64;2577-2595.
10. De Leeuw, I; et al. Insulin detemir used in basal-bolus ther-
apy in people with type 1 diabetes is associated with a
lower risk of nocturnal hypoglycemia and less weight gain
over 12 months in comparison to NPH insulin. Diabetes
Obesity and Metabolism 2005;7:73-82.
11. Haak T, et al. Lower within-subject variability of fasting
blood glucose and reduced weight gain with insulin de-
temir compared to NPH insulin in patients with type 2 dia-
betes. Diabetes Obesity and Metabolism2005;7:56-64.
12. Raslova K, et al. Insulin detemir and insulin aspart: a
promising basal-bolus regimen for type 2 diabetes. Diabe-
tes Research and Clinical Practice 2004;66:193-201.






PHARMACOTHERAPY OF GOUT: AN
UPDATE



Adrianna Natoli, Pharm.D. Candidate


Uric acid is an end product of purine nucleo-


PharmaNote Volume 21, Issue 6, March 2006


Volume 21, Issue 6, March 2006


PharmaNote







tide metabolism. It exists as the urate ion at physio-
logical pH and has a narrow window of solubility.
The enzyme, xanthine oxidase converts xanthine to
urate. Humans do not express the enzyme uricase
responsible for uric acid degradation to allantoin.
Once urate has been formed, it can be eliminated via
the gastrointestinal tract, kidneys, or can be depos-
ited in tissues. The limit of solubility of monosodium
urate (MSU) in serum is 6.4 mg/dL at 370Celsius.
Hence, the "normal" uric acid level in men (7 mg/
dL) is at the limits of urate solubility in vitro, and the
levels in premenopausal women (6 mg/dL) approach
saturation as well, imposing a fragile physiologic
urate balance. Hyperuricemia, usually defined as a
serum uric acid (SUA) level >7 mg/dL, can be
caused by overproduction of urate, or more com-
monly by insufficient renal excretion.1,2,3
Gout is a systemic rheumatic disease, recog-
nized for centuries, which results from an inflamma-
tory response provoked by deposition of MSU crys-
tals in the articular cartilage and synovial membrane.
Demonstration of MSU crystals in the synovial fluid
is essential for a definitive diagnosis of gouty arthri-
tis. Left untreated, these crystals can aggregate in
joint spaces, causing crippling damage to cartilage
and bone and, when deposited in organs such as the
kidney, eventually lead to organ dysfunction, par-
ticularly renal impairment. The single most impor-
tant risk factor for the development of gout is an ele-
vated SUA level. Although hyperuricemia is central
to gout, by itself it is insufficient to cause the dis-
ease, since a substantial number of patients with hy-
peruricemia never experience an acute flare.
This article will examine the epidemiology
and impact of gout as a common clinical problem,
followed by the goals of treatment and a review of
various options for the pharmacological management
of acute gouty attacks, hyperuricemia and chronic
gout, as well as prophylactic strategies.

Epidemiology
Gout is an increasingly prevalent medical
problem, affecting greater than 1 percent of men in
Western countries, with a male:female ratio between
7:1 and 9:1.1 Gouty arthritis is, in fact, the most com-
mon inflammatory joint disease affecting men over
40 years of age.2 The incidence of gout increases
with age and it is has been found to be more preva-
lent in African Americans than in Caucasians.4 A
review of the self-reported incidence of gout from


the National Arthritis Data Workgroup estimates that
gout affects 2.1 million US citizens. The annual eco-
nomic burden for new cases of acute gout among US
men is $27.4 million. As the disease progresses it
markedly impairs quality of life and ability to work,
and its long-term management leads to substantial
health care costs, both direct and indirect (e.g., lost
productivity).4
Treatment Overview
Gout has four stages: (i) asymptomatic hype-
ruricemia; (ii) acute gouty arthritis; (iii) intercritical
gout (intervals between acute attacks) and (iv)
chronic tophaceous gout.2 The classic symptoms of
gouty arthritis are recurrent attacks of acute, ex-
tremely painful monoarticular or oligoarticular in-
flammation; although, polyarthritis can occur as
well.
Management of gout involves not only treat-
ing acute arthritic inflammation, but also preventing
recurrent attacks and disease progression.1 Hence,
there are three stages in the management of gout: (i)
treating the acute attack; (ii) lowering urate levels to
prevent flares of gouty arthritis and prevent tissue
deposition of MSU crystals; and (iii) prophylactic
therapy to prevent recurrent attacks and progression.2
Current treatment for acute and chronic gout, is
based more on practitioners' experience and prefer-
ences than on evidence based medicine.1,2

Treatment of Acute Gouty Arthritis
Acute gout is spontaneous and self-limited in
nature. The primary goal of therapy in acute gout is
to quickly and safely resolve pain and restore func-
tioning. Nonsteroidal anti-inflammatory drugs
(NSAIDs) are the preferred treatment in acute gout,
unless there are risk factors for their use, i.e. age >65
years; creatinine clearance (CrC1) <50 mL/min;
poorly controlled congestive heart failure; history of
peptic ulcer disease; anticoagulation therapy; or he-
patic dysfunction. These patients are at higher risk of
adverse effects associated with use of NSAIDs such
as gastropathy, nephropathy and liver dysfunction.
Therapeutic success with NSAIDs lies not in which
NSAID is chosen, but rather how soon NSAID ther-
apy is initiated after onset of an attack. NSAIDs pro-
vide significant symptom relief within 24 hours.
NSAIDs should be initiated immediately after the
onset of symptoms at maximal doses and then ta-
pered quickly after complete resolution of the at-
tack.1'2 A head-to-head comparison of etoricoxib and


PharmaNote Volume 21, Issue 6, March 2006


Volume 21, Issue 6, March 2006


PharmaNote







indomethacin in patients with acute gout showed
similar efficacy suggesting that selective COX-2 in-
hibitors may provide a reasonable alternative for pa-
tients at high risk of gastrointestinal bleeding.6
(Table 1). However, COX-2 inhibitors should be
used with caution in patients at high risk of cardio-
vascular disease, and they are no safer than conven-
tional NSAIDs with regard to renal function, blood
pressure, or heart failure.
Colchicine is an alternative for the manage-
ment of inflammation in acute gout. The mechanism
of action in gout is interference with formation of
tubulin dimers and subsequent leukocyte function,
including diapedesis, lysosomal degranulation, and
chemotaxis.3 Because it is poorly tolerated, it is not
the preferred drug for the treatment of acute gout. An
as needed supply of colchicine can be provided to
treat acute attacks rapidlyat the onset of symptoms.
Its effectiveness is highest during the first 12-24
hours of symptoms. In a placebo-controlled trial, ap-
proximately two-thirds of patients with acute gout
responded to colchicine within hours when the drug
was initiated in the first 24 hours of the attack.!
However, greater than 80% of patients suffered gas-
trointestinal adverse effects including nausea, vomit-
ing, diarrhea and abdominal pain with administration
of oral colchicine before experiencing complete
clinical improvement. This narrow benefit to adverse
effect ratio limits the use of colchicine. Colchicine
exhibits the poorest ratio of benefit to toxicity of all
the agents used in the management of gout. 1,2 (Table
1).
While intravenous colchicine can quickly
abort a gouty attack, its use is discouraged because it
has been associated with severe complications, in-
cluding fatalities. Serious adverse effects include
granulocytopenia, disseminated intravascular coagu-
lation, renal failure, hepatocellular toxicity, seizures
and shock. These adverse events can occur even at
low doses in patients who have impaired elimination
of colchicine including those with renal insuffi-
ciency, hepatic dysfunction, biliary obstruction and
the elderly. Colchicine is not dialyzable and treat-
ment of colchicine intoxication is largely suppor-
tive.1'2 The maximum recommended intravenous
dose of colchicine per flare is 4 mg in adults,
whereas in the elderly 2 mg is should not be ex-
ceeded. Furthermore, additional colchicine should
not be administered within 7 days.
Corticosteroids can be considered in those


PharmaNote


patients in whom NSAIDs and colchicine are not ap-
propriate. Corticosteroids can be given orally, intra-
venously, intramuscularly, or intrarticularly. Intrar-
ticular injections of depot corticosteroids are consid-
ered beneficial in gouty attacks when only one or
two large joints are affected. In this setting, the effi-
cacy of corticosteroids can be secured, while the sys-
temic adverse effects are avoided. It is crucial to en-
sure that the joint is not infected prior to injecting
intra-articular corticosteroids. Systemic corticoster-
oids must be given at relatively large doses to treat
acute gout effectively (i.e. 40-60 mg of prednisone
daily initially) and then tapered slowly to prevent
rebound flares. (Table 1) Use of parenteral corticos-
teroids confers no advantage over oral administration
unless the patient is unable to tolerate oral medica-
tions. Corticotropin has been shown to be effective
within hours for both monoarticular and polyarticular
gout. Its peripheral anti-inflammatory effects medi-
ated by local activation of the melanocortin type 3
receptor, as well as, the induction of adrenal corti-
costeroid release are believed to contribute to corti-
cotropin's rapid, marked efficacy in treating acute
gouty attacks. Corticotropin is administered as a sin-
gle SC or IM injection; however, some patients may
require a second dose if response is incomplete. Ad-
junctive treatment with low-dose colchicine has been
advocated for the management of rebound flares as-
sociated with use of systemic corticosteroids and cor-
ticotropin in acute gouty attacks.

Long-Term Treatment of Gout
Gout is not always progressive in nature and
attacks are often infrequent, self-limited and easily
treated. In patients with hyperuicemia, SUA levels
may return to normal when risk factors are modified,
such as minimizing alcohol use, discontinuing thi-
azides diuretics, or losing weight. The primary indi-
cations for chronic uric acid-lowering therapy are
macroscopic subcutaneous tophi, frequent gouty at-
tacks (>3 per year), or documented uric acid overpro-
duction. Urate-lowering therapy has been found to be
cost effective in patients with greater than 2 attacks
per year.4 When indicated, long-term management of
hyperuricemia is crucial to preventing recurrent
gouty attacks and the consequences of chronic hype-
ruricemia such as chronic tophaceous gout, urate
nephropathy and urolithiasis. Optimal treatment
maintains SUA level below 6 mg/dL rather than just
within the "normal" range. Initiation of uric-acid


Volume 21, Issue 6, March 2006








Table 1. Systemic pharmacological therapy for acute gouty arthritis.

Drug Dose Adverse Events Comments Cost
NSAIDS


Naproxen



Indomethacin





Cedlecoxib


750-1000mg PO daily x 3 days, then
500-750mg daily x 4-7 days (in 2
divided doses)

150-200mg PO daily x 3 days, then
100mg daily x 4-7 days (in 2 -4 di-
vided doses)



400mg PO on day 1, then 200mg
daily x 6-10 days (in 2 divided doses)


40-60mg PO daily x 3days, then de-
Prednosinoe crease by 10-15mg/day every 3 days


60mg IM x 1


25 USP units SQ for small joints or
monoarticular gout
40 USP units IM/IV x 1 for large
joints or polyarticular gout




In acute episodes of gout within the
first few hours: 0.6mg PO every hour
up to 3 hours (max 3 pills)
For prophylaxis against acute gout,
particularly before initiation of anti-
hyperuricemic therapy:
CrCl 50ml/min: 0.6mg PO BID
CrCl 35-49ml/min: 0.6mg PO daily
CrCl 10-34ml/min: 0.6mg PO every
2-3 days
Avoid if CrCl <10ml/min or on
hemodialysis
Reduce doses by 1/2 if > 70 years old


Gastropathy, renal insuffi-
ciency
nephropathy, hepatic dys-
function, CNS dysfunction,
reversible platelet dysfunc-
tion, fluid overload in CHF
patients


Fluid retention, mood
changes, insomnia, lethargy,
appetite stimulation, weight
gain, increased BP, acne hy-
perglycemia.





Similar to corticosteroids, but
less pronounced





Oral: nausea, vomiting, diar-
rhea, abdominal pain,
myopathy (more likely with
concomitant cyclosporine or
station therapy and in patients
with renal insufficiency
IV: tissue necrosis, dissemi-
nated intravascular coagula-
tion, granulocytopenia, renal
failure, hepatic necrosis,
death


Cost saving; avoid in
patients with renal or
hepatic
failure and patients at
risk for major GI
events, hemorrhage
CHF or asthma; inter-
acts with warfarin
Avoid in patients with
renal or hepatic
failure and patients at
risk for cardiovascular
events, CHF or asthma;
aspirin counteracts
gastroporotective effect



Avoid if joint sepsis
not excluded
Avoid in patients sub-
ject to hyperglycemia



Not universally avail-
able
Less effective in pa-
tients receiving long-
term steroids


Not recommended
long-term due to lower
benefit to toxicity ratio
compared to other
treatments
Less effective after
first day of acute attack
Avoid IV administra-
tion
Drug interactions with
erythromycin, stations
and cyclosporine can
increase risk of toxic
effects


$0.27/250
mg tablet


$0.32/50
mg cap-
sule



$3.17/200
mg
capsule


$0.20/ 10
mg tablet








$3.17/unit











$0.18/0.6
mg tablet


lowering therapy should be avoided during the in- Overproduction occurs when daily urinary urate ex-
flammatory phase of acute gout, as it is could poten- creation exceeds 800-1000 mg. Such a diagnostic pro-
tially worsen arthritis. The urate-lowering medica- cedure also helps identify patients in whom urico-
tions used to treat chronic gout include the uricosuric suric drugs would be contraindicated due to a height-
drugs and xanthine oxidase inhibitors.1'2 ened risk of urolithiasis. However, the test cannot
Determining 24-hour urinary urate excretion identify patients in whom hyperuricemia is a result
can help identify patients who overproduce urate. of a combination of urate overproduction and under-


PharmaNote Volume 21, Issue 6, March 2006


Corticosteroids


Triamcinolon
acetonide




Corticotropin











Colchicine







excretion, and cannot reliably identify urate overpro-
duction in patients with creatinine clearance below
60 mL/minute. Despite these limitations, it is advis-
able to collect and evaluate a 24-hour urine test to
identify urate overproduction in the absence of an
obvious cause of hyperuricemia, such as diuretic use
or renal failure.1,2 However, 24-hour urine urate lev-
els are infrequently evaluated since >90% of patients
with hyperuricemia underexcrete uric acid and be-
cause SUA will respond to allopurinol regardless of
the etiology.
Uricosuric Drugs
Uricosuric drugs are considered first-line therapy in
patients with hyperuricemia due to renal urate under-
excretion. Uricosuric drugs inhibit post-secretory
renal proximal tubule reabsorption of uric acid, in-
creasing its renal clearance, and, thus, reducing SUA.
Upon the initiation of uricosuric drugs, intense urico-
suria can result in urolithiasis and worsening renal
function. Hence, uricosuric drugs are initiated at low
doses and gradually titrated over 2-6 weeks. The risk
of urolithiasis can also be minimized by having pa-
tients stay well hydrated and alkalinizing the urine
with administration of sodium bicarbonate.
Probenecid is an effective uricosuric agent in
patients with normal renal function and no history of
renal stones or massive tophi. Sulfinpyrazone is not
universally available and is not considered a first-line
uricosuric agent secondary to its adverse effect pro-
file, including increased risk of bleeding and bone
marrow suppression.
Use of low doses (<500 mg) of aspirin can
interfere with the uricosuric effect of these agents
and should be addressed before starting a uricosuric.
Fenofibrate, a fibric acid derivative, has been shown
to have a uricosuric effect independent of its lipid-
lowering effect and is associated with a SUA reduc-
tion of 20-35%. It may be beneficial in patients with
gout who also have dyslipidemia. Losartan, an angio-
tensin II receptor antagonist, reduces SUA levels,
but, unlike other uricosurics, it simultaneously in-
creases urine pH, thereby, reducing the risk of uro-
lithiasis. Losartan's uricosuric effect is independent
of its hypertensive effects through angiotensin recep-
tor antagonism. It may be particularly beneficial in
patients with gout who have hypertension. (Table 2)
Uricostatic Drugs
Xanthine oxidase inhibitors are uricostatic drugs,
which inhibit uric acid synthesis. Xanthine oxidase
inhibitors interfere with the conversion of hypoxan-


thine to xanthine and of xanthine to uric acid, caus-
ing a decrease in SUA and uric acid levels, and an
increase in serum and urinary hypoxanthine and xan-
thine levels.2
Allopurinol is a structural analogue of hy-
poxanthine. Its uric acid-lowering effect is dose-
dependent. Although most patients are maintained on
a fixed dose of allopurinol, it should be titrated as
tolerated to the SUA level to ensure that SUA levels
are kept low enough to help prevent further attacks.
Allopurinol is dosed once daily and is effective irre-
spective of the cause of hyperuricemia, making it the
most commonly prescribed urate-lowering agent.
However, one of its disadvantages is that it has sev-
eral important drug interactions. For instance, al-
lopurinol may interfere with hepatic metabolism of
oral anticoagulants, and its administration with
agents such as mercaptopurine and azathioprine may
result in serious hematologic complications if the
dose of these medications is not reduced, as they are
inactivated by xanthine oxidase. Furthermore, up to
5% of patients are unable to tolerate allopurinol due
to its adverse effects (Table 3).2 Of greatest concern
is the potential for severe, life-threatening rash,
which is more common in patients with renal dys-
function when the dose is not adjusted.
Oxypurinol is the active metabolite of al-
lopurinol, the agent primarily responsible for al-
lopurinol's clinical effect of inhibiting xanthine oxi-
dase. Its most significant role is in patient's who are
allergic to allopurinol. Though oxypurinol is not
commercially available in the US, it can be obtained
through the manufacturer (ILEX Oncology, San An-
tonio, TX) for compassionate use (Table 2). 2
Febuxostat is a novel, orally administered,
nonpurine selective inhibitor of xanthine oxidase
currently in phase III studies as a potential alterna-
tive to allopurinol for patients with hyperuricemia
and gout. Though it is a potent inhibitor of xanthine
oxidase, it has minimal effects on other enzymes in-
volved in purine and pyrimidine metabolism. The
recently published Febuxostat versus Allopurinol
Controlled Trial (FACT), a large, phase 3, random-
ized, double-blind, multi-center, non-inferiority trial
compared febuxostat and allopurinol with regard to
safety, urate-lowering efficacy, and incidence of
flares and number of tophi in adult subjects with hy-
peruricemia and gout. Investigators showed that at
all ranges of initial urate levels, the primary efficacy
endpoint, serum urate level below 6 mg/dL, was


m:m
PharmaNote Volume 21, Issue 6, March 2006


Volume 21, Issue 6, March 2006


PharmaNote











Good GI absorption; t/2 of
6-12 hours; 40% renal excre-
tion within 48 hours


Short t/2 requires BID dos-
ing; congener of phenylbuta-
zone (can induce peptic ul-
cer and bone marrow sup-
pression)


Micronized 30% more bioavailable than
Fenofibrate non-micronized; meals in-
crease absorption


Losartan

Xanthine Oxi-
dase Inhibitors
Allopurinol




Oxypurinol


Febuxostat


Metabolite E 3174 inhibits
renal tubular absorption of
uric acid


Short t/2 of 40 minutes; me-
tabolized to oxypurinol by
xanthine oxidase; maximum
SUA lowering within 14
days
Active metabolite of al-
lopurinol; t /29-15 times
longer than allopurinol
Metabolism primarily he-
patic, renal impairment does
not impact serum urate low-
ering effect


Uricosuric Drugs

Probenecid




Sulfinpyrazone


Starting dose: 250mg PO BID,
gradually increased to 1000mg
BID (maximal dose to target
SUA level <6mg/dL in patients
with normal renal function)
Starting dose: 50mg PO BID;
gradually increased to 100-
400mg PO daily (in 2 divided
doses); Maximal dose to target
SUA level <6mg/dL in patients
with normal renal function


Precipitation of acute gout,
urolithiasis, impairment of
renal function


Precipitation of acute gout,
urolithiasis, impaired renal
function; inhibits platelet func-
tion (increased risk of bleeding
with warfarin); use limited by
adverse events

Nausea, vomiting, constipa-
tion, flatulence, dyspepsia;
cholelithiasis; elevated serum
transaminases, myopathy

Diarrhea, dyspepsia, dizziness,
cough, upper respiratory infec-
tions


GI irritation, bone marrow
suppression, precipitation of
acute gout, pruritis; hypersen-
sitivity syndrome (skin rash to
life-threatening)
Toxicity similar to allopurinol
in 30% patients

Diarrhea, headache, nausea,
liver function test abnormali-
ties


50mg PO daily




50-300mg PO daily
CrCl>90ml/min: 300mg daily
CrCl>60ml/min: 200mg daily
CrCl>30ml/min: 100mg daily
CrCl<30ml/min: 50-100mg daily
Not available compassionate
use only

80 or 120mg PO daily


reached by significantly higher proportions of sub-
jects receiving daily febuxostat (80 or 120 mg) than
subjects receiving allopurinol (300 mg). This differ-
ence was sustained at all visits through the 52 weeks
of the study. There was no significant difference
among the groups in incidence of acute gouty flares
or reduction in the number of tophi. One limitation in
this study was that the dose of allopurinol was fixed
and patients were not titrated to target SUA levels.
The incidence of adverse events was similar
among treatment groups, and most adverse events
were mild to moderate in severity. The rates of dis-
continuation were similar in the 80 mg febuxostat
and the allopurinol groups, but significantly higher in
the 120 mg febuxostat group (p=0.003) due to a
higher incidence of gout flares and adverse events in
this group. The study concluded that febuxostat, at a


daily dose of 80 mg or 120 mg was more effective
than allopurinol at the fixed daily dose of 300 mg in
lowering SUA levels. FACT also demonstrated that
maintaining the SUA concentration below 6 mg/dL
resulted in a greater reduction in gouty flares and to-
phi, supporting a subsaturating range of less than 6
mg/dL as the target for management of hyperurice-
mia. Though treatment-related adverse events were
similar for all groups in this study, long-term studies
are ongoing to provide further data on the safety pro-
file of febuxostat.6
Uricolytic Drugs
Humans lack urate oxidase, the enzyme responsible
for oxidation of urate into the highly soluble and
readily excreted allantoin. Unlike, xanthine oxidase
inhibitors that inhibit uric acid synthesis, urate oxi-
dase also breaks down pre-existing uric acid. Ras-


Pharm~oteVolue 21 Isse 6,Marc 200


Table 2. Pharmacological treatments for hyperuricemia and chronic gout.
Drug Pharmacokinetics Adverse events Dose Cost


200mg PO daily


$0.58/
500mg
tablet


$0.60/
100mg
tablet


$3.13/
200mg
capsule


$1.83/
50mg
tablet


$0.14/
100mg
tablet


N/A


Not yet
available


Volume 21, Issue 6, March 2006


PharmaNote







buricase (Elitek) is a recombinant form of urate oxi-
dase. Rasburicase catalyzes enzymatic oxidation of
uric acid into allantoin, thus lowering elevated SUA
levels. Rasburicase has been primarily studied in pe-
diatric patients with hematological malignancies or
solid tumors receiving anti-cancer agents that in-
crease the risk for tumor lysis syndrome (TLS).
Long-term urate oxidase treatment in gout has not
been studied. The use of urate oxidase preparations
in patients with chronic gout is limited by the need
for parenteral administration, as well as the inherent
antigenicity of this product. Production of anti-urate
oxidase antibodies and decreased effectiveness has
been documented following its administration.2

Prophylactic Therapy
Colchicine is commonly used as prophylaxis
against recurrent acute gout, as such episodes are
common during initial treatment with uric acid-
lowering treatment. A standard approach is to use
low-dose oral colchicine (0.6 mg orally twice a day)
for the first six months of anti-hyperuricemic therapy
in patients with normal renal function. Lower doses
are required to adjust for renal dysfunction and in
elderly patients. However, even low doses of daily
colchicine may be associated with severe adverse
effects such as myopathy and myelosuppression.
Furthermore, the effectiveness of colchicine as a sin-
gle-drug therapy for prophylaxis of acute gouty ar-
thritis has not been confirmed by placebo-controlled
trials. Another option for prophylaxis is administra-
tion of low-dose NSAIDs. However, data supporting
this practice are sparse, and there are no comparative
studies with colchicine.1'2 Nevertheless, NSAIDs
may be used as prophylaxis in patients who do not
tolerate or are not candidates for colchicine.

Summary
The goal of therapy in acute gout is rapid, safe reso-
lution of pain and inflammation. NSAIDs are consid-
ered first-line therapy for the treatment of acute gout
in patients without contraindications to their use nor-
mal renal function and who have low risk for gastro-
intestinal or cardiac toxicity. Colchicine is an alter-
native to NSAIDS. Corticosteroids, corticotrophin,
and selective COX-2 inhibitors are options in select
patients.
Long-term uric-acid lowering therapy is ap-
propriate in patients with tophi, frequent attacks of
gouty arthritis (>2 per year), or documented overpro-


duction of urate, though it should not be initiated
during an acute attack. The target uric acid level for
uric-acid lowering therapy is less than 6 mg/dL. Al-
lopurinol is the drug of choice for initial uric-acid
lowering therapy. Uricosurics such as probenecid,
micronized fenofibrate, and losartan may be used in
allopurinol-allergic patients with uric acid underex-
cretion and normal renal function. If there are no
contraindications, colchicine or NSAIDs can be con-
sidered for short-term concomitant prophylaxis
against gouty attacks during the initiation of uric-
acid lowering therapy. Non-pharmacological meas-
ures are an important adjunct to pharmacotherapy
and should include limiting alcohol intake, maintain-
ing a low-purine diet and treating comorbid condi-
tions such as obesity, hypertension, hyperlipidemia,
and coronary artery disease.

References
1. Terkeltaub RA. Clinical practice: gout. N Engl J Med
2003;349:1647-55.
2. Schlesinger N. Management of acute and chronic gouty
arthritis: present state of the art. Drugs 2004;24:2399-
2416.\
3. Cannella AC, Mikuls TR. Understanding treatments for
gout. Am J Manag Care 2005;11:S451-58.
4. Brixner DI, Ho MJ. Clinical, humanistic, and economic
outcomes of gout. Am J Manag Care 2005;11:S459-64.
5. Ahem MJ, Reid C, Gordon TP, et al. Does colchicine
work? The results of the first controlled study in gout. Aust
NZJ Med 1987;17:301-4.
6. Schumacher HR Jr, Boice JA, Daikh DI, et al. Randomized
double blind trial of etoricoxib and indomethacin in treat-
ment of acute gouty arthritis. BMJ 2002;324:1488-92.
7. Becker MA, Schumacher HR Jr, Wortmann RL, et al.
Febuxostat compared with allopurinol in patients with
hyperuricemia and gout. N Engl J Med 2005; 353:2450-61.


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


John G. Gums
Pharm.D. Editor

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D., BCPS
N-1 SK W ^ S^ W W W W^ V


M- I


Volume 21, Issue 6, March 2006


PharmaNote




University of Florida Home Page
© 2004 - 2010 University of Florida George A. Smathers Libraries.
All rights reserved.

Acceptable Use, Copyright, and Disclaimer Statement
Last updated October 10, 2010 - - mvs