Title: PharmaNote
Full Citation
Permanent Link: http://ufdc.ufl.edu/UF00087345/00002
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Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: August 2002
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Bibliographic ID: UF00087345
Volume ID: VID00002
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Rights Management: All rights reserved by the source institution and holding location.


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DeArcy E. Campbell, Pharm.D./MBA Candidate


Hyperlipidemia significantly contributes to
the development of heart disease, the leading cause
of death in the United States.1 According to the Na-
tional Health and Nutrition Examination Survey
and the Adult Treatment Panel III, 52 million
Americans are candidates for dietary therapy and
approximately 12.7 million Americans are candi-
dates for drug therapy for their high cholesterol. Of
these 12.7 million, 4 million have already been di-
agnosed with coronary heart disease.2 Although
dietary therapy is the recommended initial therapy,
many patients require pharmacotherapy to control
their lipid disorder. On December 18, 2001, the
FDA approved Advicor (extended-release niacin,
immediate-release lovastatin) the first dual-
component medication for cholesterol modulation
in the United States. Advicor is marketed by KOS
Advicor is indicated for the treatment of pri-
mary hypercholesterolemia and mixed dyslipide-
mia. It is not intended for first line therapy, but
only after the patient has tried lovastatin or niacin
and still needs further triglyceride-lowering and/or
HDL-raising.3 This article will address the pharma-
cology, clinical trials, adverse effects, costs, and
prescribing considerations of Advicor.


Lovastatin is an HMG-CoA (3-hydroxy-3-
methylglutaryl coenzyme-A) reductase inhibitor. It
is a pro-drug that is hydrolyzed to the active me-
tabolite mevinolinic acid in vivo. The mevinolinic
acid competes with HMG-CoA for HMG-CoA
reductase, a hepatic microsomal enzyme. This
competition reduces the quantity of mevalonic acid,
a cholesterol precursor, thereby reducing the pro-
duction of cholesterol.4 Lovastatin also enhances
the clearance of LDL since cholesterol can be
taken up from LDL by endocytosis. Lovastatin
works mainly on LDL and total cholesterol, al-
though it does have small effects on HDL and
Niacin, also known as nicotinic acid or 3-
pyridinecarboxylic acid, reduces total cholesterol,
LDLs, VLDLs, and triglycerides and increases
HDLs. However, the precise mechanism of action
for its antilipemic effects is unknown.3
Lovastatin is not completely absorbed from
the gastrointestinal tract. It undergoes first-pass ex-
traction by the liver, its main site of action. Less
than 5% of the dose reaches the systemic circula-
tion. After oral administration, lovastatin reaches
its peak concentration in 2-4 hours. Food in the
gastrointestinal tract will increase the oral absorp-
tion. Consumption of grapefruit juice can increase
absorption 30% or more. Lovastatin is most effec-
tive when given as a single dose in the evening be-
fore bedtime due to the diurnal variation in choles-
terol synthesis. Lovastatin is highly lipophillic and
thus can cross the blood-brain barrier, the placental
barrier, and distribute into the breast milk. Lovas-
tatin and its beta-hydroxy acid metabolite are
highly plasma protein bound (> 95%). Lovastatin
is metabolized in the liver by the hepatic isoen-

Pha rma Note Volume 17, Issue 10 August 2002


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Volume 17, Issue 10 August 2002

Table 1. Mean percentage change from baseline at endpoint for LDL-C, HDL-C, TG by gender4
Extended-release Niacin/Lovastatin Extended-release Niacin Lovastatin
2000mg/40mg 2000mg 40mg
Women Men Women Men Women Men
(n=22) (n=30) (n=28) (n=28) (n=21) (n=38)
LDL-C -47% -34% -12% -9% -31% -31%
HDL-C +33% +24% +22% +15% +3% +7%
TG -48% -35% -25% -15% -15% -23%

zyme, CYP3A4, to mevinolinic acid and other ac-
tive metabolites. Mevinolinic acid has a plasma
half-life of 1.1-1.7 hours. Eighty-three percent of
the dose is excreted in the feces as both active and
inactive metabolites and 10% of the drug is elimi-
nated really as inactive drug. In patients with
CrCl = 10-30 mL/min, plasma concentrations were
found to be two-fold higher than those of healthy
Peak concentrations of niacin are reached in
5 hours. Oral nicotinic acid is well-absorbed
(approximately 72% based on urinary excretion
data). Presence of food in the GI tract maximizes
the bioavailability of niacin and minimizes stomach
upset. The sustained-release form of niacin helps
to reduce the onset and severity of peripheral vaso-
dilatation, although it has a higher incidence of
hepatoxicity when compared to the immediate-
release dosage form. Niacin concentrates in the
spleen, liver and adipose tissue and is widely dis-
tributed throughout the body. Niacin undergoes
first-pass metabolism via several pathways. One
pathway is conjugation with glycine to form nico-
turic acid, which is then excreted in the urine. An-
other pathway results in the formation of NAD
(nicotinamide adenine dinucleotide) which is used
in the liver and intestines for other body processes.
About 12% of niacin is excreted unchanged in the
urine at dosages of 1000mg/day, as larger dosages
are given more nicotinic acid will be excreted un-
changed in the urine. Steady state concentrations
of niacin are usually higher in females, although the
absorption, metabolism, and excretion of the drug
appears to be the same in both men and women.
There appears to be no information available about
the pharmacokinetics in patients with renal impair-
Clinical Trials

In a clinical trial organized by the manufac-
turer, the extended-release niacin/lovastatin product
was compared to each of its individual components
(extended-release niacin and lovastatin) in a multi-
center, randomized, double-blind, parallel, 28-
week, active comparator study in patients with
Type IIa or IIb hyperlipidemia. Each patient re-
ceived each dose for at least 4 weeks, using a
forced dose-escalation study design. Patients who
were randomly assigned to the extended-release
niacin/lovastatin treatment group initially received
500mg/20mg. Then half of these patients were ti-
trated up to 1000mg/20mg at 4 week intervals,
while the other half were titrated up to 2000mg/
40mg. The extended-release niacin-only group
started at 500mg and were titrated at 4 week inter-
vals to 2000mg. The lovastatin-only group re-
ceived 20mg for 12 weeks titrated up to 40mg for
up to 16 weeks. In this study, extended-release nia-
cin/lovastatin decreased LDL-C, TG, Lp(a), and in-
creased HDL-C in a dose-dependent manner. Fur-
thermore, the extended-release niacin/lovastatin
lowered LDL-C significantly greater (p<0.0001)
than lovastatin 40mg, extended-release niacin
2000mg and extended-release niacin/lovastatin at
doses of 1000mg/20mg after 28 weeks of titration
to 2000mg/40mg (Table 1). Also, extended-release
niacin/lovastatin was better at raising HDL and re-
ducing TG at doses of 1000mg/20mg or greater
when compared to lovastatin or extended-release
niacin individually. Finally, the Lp(a) lowering ef-
fects of extended-release niacin were superior to
extended-release niacin/lovastatin and both were
superior to lovastatin alone.
In a separate study, Kashyap et al investi-
gated the long-term safety and efficacy of ex-
tended-release niacin/lovastatin in 818 enrolled pa-
tients over 52 weeks in a multi-center, open-label
study.5 The researchers used 4 escalating doses of

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Volume 17, Issue 10 August 2002

Table 2: Mean % Change in Lipids with Extended-release Niacin/Lovastatin5
Baseline 814 195 +/- 1.4 48+/-0.4 199 +/- 3.3
4 753 500/10 -25% 11% -16%
8 705 1000/20 -34% 18% -27%
12 676 1500/30 -41% 26% -34%
16 655 2000/40 -47% 30% -41%
28 604 2000/40 -46% 35% -40%
52 226 2000/40 -45% 41% -42%
N*= number of patients remaining in the trial at each time point. Observed values (mean +/- SE) in milligrams per deciliter

extended-release niacin/lovastatin: 500/10 for the
first 4 weeks, 1000/20 for weeks 5-8, 1500/30 for
weeks 9-12, and 2000/40 for week 13-52. They
found that dose-dependent effects were seen for all
of the lipid parameters (Table 2). At week 16, the
medication reached its maximum effect on LDLs
(47%) and triglycerides (41%). Also, HDLs were
increased by 30% at week 16 with the effects per-
sisting as HDLs were increased to 41% by week 52
(all p <0.001).


Extended-release niacin/lovastatin is not
indicated for first-line therapy of hyperlipidemia.
Before initiation of this combination therapy, each
of the individual products (extended-release niacin
and lovastatin) should first be titrated up. The
manufacturer recommends titration with the niacin
supplement, Niaspan, as this is bioequivalent to the
extended-release niacin in Advicor. For patients
already titrated with Niaspan, they can be immedi-
ately switched over to Advicor, otherwise begin
with Niaspan 500mg once daily at bedtime and
then titrate upward in increments of 500mg every 4
weeks up to a maximum of 2000mg/day as toler-
ated to achieve the target NCEP-ATP III goals. Ad-
vicor is available in three strengths 500/20, 750/20,
and 1000/20, each containing 20mg of lovastatin
with varying amounts of extended-release niacin.
The tablet should be taken once daily at
bedtime as cholesterol production is highest in the
early morning hours. It should be taken with a
small low-fat snack to limit GI side effects, flush-
ing, and increase the bioavailability of lovastatin.

The patient should avoid drinking grapefruit juice
with their dose to avoid drastic increases in the
lovastatin concentration. The tablet should not be
crushed or broken, nor taken with hot beverages or
alcohol. If the niacin-induced flushing is bother-
some the patient may take 325mg of aspirin (if ap-
propriate) or another non-steroidal anti-
inflammatory 30 minutes before their dose to lessen
this side effect.
This drug is not recommended for children
or adolescents, patients with elevated hepatic en-
zymes or hepatic disease, and should be used with
caution in patients with renal disease. For patients
with CrCl > 30mL/min no dosage adjustment is
needed, below CrCl < 30mL/min, doses of lovas-
tatin > 20mg per day should be carefully consid-
ered. As of yet, the dialyzability of niacin and
lovastatin are unknown.
Patients on extended-release niacin/
lovastatin will require monitoring. The patient's
lipid levels should be evaluated at baseline and then
at intervals no less than 4 weeks after initiation of
drug therapy or dosage change.4 Once the patient
has reached their NCEP-ATP III goals for lipids
then monitor their lipids every 4 to 6 months there-
after.2 Liver function tests and serum transaminase
levels, including AST and ALT (SGOT and SGPT),
should be performed on all patients treated with ex-
tended-release niacin/lovastatin. Levels should be
evaluated at baseline, then every 6-12 weeks for the
first 6 months and every 6 months thereafter. If
levels elevate to 3 times the upper limit of normal
the drug should be discontinued.4 Occasional
creatine kinase (CK) levels may be considered in at
risk patients. If the level is 10 times the upper limit

Pha rma Note Volume 17, Issue 10 August 2002


Volume 17, Issue 10 August 2002

Table 3. Treatment-emergent adverse effects in > 5% of patients4'5
ER Niacin/ ER Niacin/ a
Adverse Event a ER Niacina Lovastatina
Lovastatina Lovastatinb

Total no. of patients 214 814 92 94
Cardiovascular 163 (76%) -- 66 (72%) 24 (26%)
Flushing 152 (71%) -- 60(65%) 17(18%)
Body as a whole 104 (49%) -- 50 (54%) 42 (45%)
Asthenia 10 (5%) -- 6 (7%) 5 (5%)
Flu syndrome 12 (6%) -- 7 (8%) 4 (4%)
Headache 20 (9%) 57 (7%) 12 (13%) 5 (5%)
Infection 43 (20%) -- 14 (15%) 19 (20%)
Pain 18(8%) -- 3 (3%) 9(10%)
Pain, abdominal 9 (4%) -- 1 (1%) 6 (6%)
Pain, back 10 (5%) -- 5 (5%) 5 (5%)
Digestive system 51 (24%) 195 (24%) 26 (28%) 16 (17%)
Diarrhea 13 (6%) 65 (8%) 8 (9%) 2 (2%)
Dyspepsia 6 (3%) 65 (8%) 5 (5%) 4 (4%)
Nausea 14 (7%) 65 (8%) 11(12%) 2 (2%)
Vomiting 7 (3%) -- 5 (5%) 0
Metabolic and nutrition system 37 (17%) -- 18 (20%) 13 (14%)
Hyperglycemia 8 (4%) 41 (5%) 6 (7%) 6 (6%)
Musculoskeletal system 19 (9%) -- 9 (10%) 17 (18%)
Myalgia 6(3%) -- 5(5%) 8(9%)
Skin and appendages 3 (2%) -- 19 (21%) 11 (12%)
Pruritus 14 (7%) 130 (16%) 7(8%) 3 (3%)
Rash 11(5%) 73 (9%) 11(12%) 3 (3%)
a Adverse events as reported by manufacturer4; b Adverse events as reported by Kashyap et al study5; -- Not reported

of normal and the patient is experiencing unex-
plained muscle pain, myopathy is likely. The pa-
tient should stop the medication immediately if
myopathy, rhabdomyolysis, or elevations in
creatine kinase are present.3 Niacin may cause a
dose-related elevation in fasting blood glucose.
Close monitoring of blood glucose in patients with
diabetes is advised and adjustment of hypoglyce-
mic medication may be necessary.

Adverse Effects

Flushing episodes (warmth, redness, itch-
ing, and/or tingling) due to niacin were the most
common adverse effects in controlled clinical stud-
ies occurring in up to 71% of patients. Flushing
caused 8% of patients to discontinue the KOS study
and 10% to discontinue the Kashyap et al study.4'5
Table 3 lists the adverse effects that occurred in
greater than 5% of patients.

Advicor is absolutely contraindicated in
children and adolescents, patients with a hypersen-
sitivity to niacin or lovastatin, active peptic ulcer
disease, active hepatic disease (including cholesta-
sis, hepatic encephalopathy, hepatitis, jaundice, ele-
vations in liver enzymes, etc), rhabdomyolysis, ar-
terial bleeding, and patients who are pregnant or
breast feeding. Extended-release niacin/lovastatin
should be used with caution in patients with renal
disease or renal failure.

Retail Cost of Therapy

Three different pharmacies (one supermar-
ket pharmacy, one discount pharmacy, and one ma-
jor chain pharmacy) were asked for their prices for
Advicor # 30 in three different strengths. Table 4
lists the prices charged. The average prices for 30
tablets were $49.87 for 500/20, $58.63 for 750/20,
and $63.45 for 1000/20.

Pha rma Note Volume 17, Issue 10 August 2002


Volume 17, Issue 10 August 2002

Table 4. Prices for Advicor #30 at assorted pharmacies

Strength Pharmacy Pharmacy Pharmacy Average
500/20 $52.95 $45.99 $50.68 $49.87
750/20 $62.95 $55.59 $57.34 $58.63
1000/20 $66.95 $59.49 $63.92 $63.45

Advicor, marketed by KOS pharmaceuti-
cals, is the first combination oral antilipemic agent
to be introduced in the United States. It is indicated
for the treatment of primary hypercholesterolemia
and mixed dyslipidemia for patients who have not
effectively responded to lovastatin or niacin alone.
This combination product is available to practitio-
ners as another option in treating hyperlipidemia
for the purposes of preventing coronary heart dis-


1. Talbert RL. Hyperlipidemia. In: Dipiro JT,
Talbert, RL, Hayes PE, Yee GC, Matzke GR,
Posey LM, editors. Pharmacotherapy. Fourth
edition. Englewood Cliffs, New Jersey: Apple-
ton & Lange; 1999: 350-371.
2. Executive Summary of the Third Report of the
National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III). JAMA
2001; 285:2486-2497.
3. Clinical Pharmacology 2000 [monograph on-
line]. Reents S, Seymour J. Gold Standard
Multimedia, last revised February 27, 2002.
4. Advicor product information. KOS Pharma-
ceuticals, Inc. November 2001.
5. Kashyap ML, McGovern ME, Berra K, Guyton
JR, Kwiterovich PO, Harper WL, et al. Long-
Term Safety and Efficacy of a Once-Daily Nia-
cin/Lovastatin Formulation for Patients with
Dyslipidemia. The American Journal of Cardi-
ology 2002 March 15; 89:672-678.



Bradley Howard, Pharm.D. Candidate

Based on the 58th annual American Diabetes
Association Scientific Session there are 3.5 million
users of injected insulin in the United States. It is
estimated that 16 million Americans would benefit
from exogenous insulin but refuse to do so because
of painful injections. These patients run a high risk
of developing complications caused by diabetes
since they are not optimizing therapy to control
their glycemic levels.1
Since the first insulin injection was given in
1922, researchers have sought to develop a less in-
vasive route of administration. With recent ad-
vances in the development of administration de-
vices and the manipulation of the insulin molecule,
insulin-dependent diabetics may finally have a less
invasive alternate route of administration. This ar-
ticle will focus on three such products that have
shown promise in clinical trials.
Many types of dosage forms have been con-
sidered, however, because of the size of the insulin
molecule, it is nearly impossible to attach it to a
carrier system. Dermal insulin application is not
possible. An oral tablet is not feasible because the
molecule would be denatured in the stomach and
there is not a specific peptide carrier in the stomach
for insulin.2 As far back as 1935, the idea of intra-
nasal administered insulin was considered. How-
ever, low bioavailability and variability in absorp-
tion made this route less practical for insulin ad-
These inhalation insulin products have ad-
vantages and disadvantages. Advantages include a
completely painless delivery of insulin, delivery is
uncomplicated and well tolerated by patients, less
hypoglycemic events occurred in trials than with
subcutaneous (subcutaneous) insulin, and the lung
is capable of absorbing insulin in a reproducible,
dose-dependent manner.4 This is in contrast with
insulin injections, which are affected by factors
such as the site of injection, the depth of injection,
the temperature and vascularity of the tissue, and

PharmaNot Voume17,Isse 1 Auust200


Volume 17, Issue 10 August 2002

Table 1. HbAlc comparisons between trials for Inhance System

HbAlc HbAlc
Author # patients Patient type SC insulin dose Inhalation insulin dose p.
(pre-trial) (post-trial)

Skyler6 35 Type 1 -- 12.2 mg 8.5% 7.9%
Skyler6 36 Type 1 24.8 U -- 8.5% 7.7%
Cefalu 26 Type 2 35.7 U 14.6 mg 8.7% 8.0%

Milligram and Units are given as average daily dose during the trials

whether the underlying muscle is exercising or not.
Disadvantages and concerns stem from the fact
that, if approved, the drugs are new and thus, exten-
sive and long-term studies have not been con-
ducted. Clinicians point out that the growth-
promoting properties of insulin and the effect of pa-
tients that smoke and/or have pulmonary diseases
has not been studied. Furthermore, since inhalable
insulin requires larger doses than subcutaneous in-
sulin, cost may be a factor as well.5


Exubera is an inhaled insulin product co-
developed by Aventis and Pfizer. The delivery of
insulin is via the Inhance System by Inhale Thera-
peutic Systems. Dry-powdered insulin is blister
packed into different dosages. A special delivery
system generates a pulse of compressed air and the
insulin forms a white fog in a 210 milliliter trans-
parent chamber that can be inhaled by deep breath-
ing.4 This enables patients to view the aerosol be-
fore inhalation to ensure proper dosing. This
method also eliminates the need for coordination
between inhalation and actuation. The insulin par-
ticles produced are small (1-3 micrograms) and
reach the alveoli in the lungs, which is the site of
A number of phase II studies were per-
formed evaluating the efficacy of the insulin-
Inhance system. The first study consisted of 71 pa-
tients with type 1 diabetes and was conducted over
three months. The study was an open-label, paral-
lel group trial. One group continued a conventional
insulin regimen with subcutaneous injections of ul-
tralente and regular insulin while the other group
was treated with ultralente subcutaneous injections
and inhaled insulin.6 The second study consisted of
26 patients with type 2 diabetes. Patients were

treated with inhaled insulin before each meal and a
bedtime subcutaneous dose of ultralente insulin.
Prior to being treated, the patients were on stable
insulin schedules of two or three injections a day.7
Evaluation of HbAl levels demonstrated that for
both studies the inhaled insulin was equivalent, if
not superior, to subcutaneous insulin (see Table 1).
Preliminary data found that the inhaled insulin was
well tolerated, caused no increase in hypoglycemic
events or changes in pulmonary function tests.
Exubera has completed phase III testing and
submission for regulatory approval is expected at
the end of 2002.


AERx iDMS inhaled insulin was developed
by Aradigm and NovoNordisk. This product uses
the AERx System designed by Aradigm to deliver
insulin from single-use dosage forms by extruding
the pre-packaged solution through hundreds of pre-
cisely laser-drilled holes in a single use nozzle.
This system emits a controlled, aerosolized release
of insulin. The drug is delivered to the lungs at the
correct flow rate as the patient breathes. The AERx
senses the inspiratory flow rate, notifies the patient
when to deliver the drug, the patient activates the
device, then a small piston drives the insulin
through the tiny holes. The aerosol particles are
between two to three microns. Like Exubera, the
site of action is the alveoli.
Pharmacokinetic trials were performed us-
ing AERx iDMS. A total of 18 type 1 diabetics
participated in the trial. The study was a random-
ized, open-label, 5-period crossover trial.8 Human
regular insulin was administered subcutaneous or
inhaled by AERx iDMS at different doses. Results
of the study showed that inhaled insulin provided a
dose-response relation that was close to linear for

Pha rma Note Volume 17, Issue 10 August 2002


Volume 17, Issue 10 August 2002

Table 2. Comparisons of Products

Exubera AERx iDMS Oralin

Dosage form insulin powder Aerosolized liquid insulin Dry insulin powder
converted to a fog
Site of action Alveoli Alveoli Buccal cavity
Portability/convenience Moderate Moderate High
Cost $$ $$$ $
$ least expensive, $$$ most expensive

insulin (AUC, Cmax) and glucose infusion rate
(AUC, Cmax). The researchers also found that in-
haled insulin had a more rapid onset and shorter du-
ration of action than subcutaneous administered in-
sulin. The authors concluded that AERx iDMS is
feasible, provides a clear dose-response, and may
work best for patients who need short-acting insulin
to cover prandial requirements.
NovoNordisk and Aradigm have completed
phase II trials. Phase III trials should commence in
late 2002.


Oralin is being developed by Generex Bio-
technology based in Toronto, Canada. This product
is administered by RapidMist, a metered dose in-
haler (MDI), which is also developed by Generex
and uses a dry insulin powder. Unlike the previous
two examples, this device's site of action is the
buccal cavity. The RapidMist System propels the
aerosolized particles much faster than conventional
MDIs, allowing deposition in the buccal cavity
where it is absorbed into the bloodstream within 10
minutes. Attributes of this system over subcutane-
ous insulin include: rapid absorption, simple ad-
ministration, precise dosing control, and bolus de-
livery of insulin. The insulin itself is combined
with absorption enhancers, which encapsulate and
protect the insulin molecule.
There have been numerous studies on Or-
alin at the University of Toronto and the National
Research Institute in Los Angeles.9 These studies
have focused on both patients with type 1 and type
2 diabetes. The type 1 study was a double-blind,
crossover study consisting of ten subjects given
subcutaneous regular insulin, Oralin, or a placebo.
Glucose levels were higher in the placebo group

while glucose levels were comparable between the
regular insulin and Oralin groups. The researchers
also found that Oralin plasma concentrations in-
creased faster than did subcutaneous regular insulin
injections. However, after four hours, glucose lev-
els were higher for subjects on Oralin due to rapid
clearance from plasma when compared to subcuta-
neous insulin.
The type 2 study was a double-blind, cross-
over study that involved 16 subjects. Oralin was
given in place of regular mealtime insulin injec-
tions. It concluded that Oralin can be used safely in
place of insulin injections in subjects with type 2
diabetes to control postprandial hyperglycemia.
Additional sub-studies were conducted with
Oralin. One study compared pre-prandial Oralin
plus metformin 850 milligrams (mg) vs. placebo
and metformin 850 mg. The researchers found that
Oralin in combination with metformin was useful
in subjects with secondary sulfonylurea failure.
Another study compared 15 subjects, failing diet
and exercise, with Oralin or placebo. Results sug-
gest that Oralin can be introduced early in the treat-
ment of recently diagnosed patients failing diet and
exercise regimens. The diet and exercise study
also concluded that exogenous administered Oralin
can be used safely in type 2 diabetics without in-
ducing the pancreas to produce more insulin and
create down-regulation of insulin receptors. The
authors hypothesized that the early introduction of
Oralin may actually help preserve beta-cell function
and avoid future diabetic complications.
Oralin is currently in phase III trials in Can-
ada. Generex Biotechnology has submitted an In-
vestigational New Drug Application (IND) to the
FDA in the United States.
Oralin is the most portable and convenient
of the three products discussed. The insulin is de-

Ph ra ot Vlue 7,Isue10Auus 20


Volume 17, Issue 10 August 2002

livered through an MDI-styled device. The cost
should not be much more than other new drugs us-
ing MDIs in the market. Exubera uses a slightly
larger and more complicated device than an MDI,
which might increase its cost over Oralin. AERx
iDMS predictably would have the highest cost as-
sociated with their product because of the sophisti-
cation of the delivery device which is about the size
of a camera. Table 2 provides a comparison of the
three products.


Within the next couple of years, healthcare
providers and patients can expect to see new prod-
ucts offering alternatives to subcutaneous insulin
injections. Clinical trials have demonstrated that
alternate forms of administering insulin are feasi-
ble. Patient satisfaction surveys indicate that sub-
jects were pleased with the convenience, ease of
use, and lack of social stigma of the products.10
These products are short-acting only and should
eliminate the total number of injections a day but
not eliminate the need for long-acting insulin injec-


1. Medicine and Behavior website, visited May 29,
2002: http://www.medinfosource.com/mb/
2. Rave KM, Heise T, Pfutzner A, Steiner S, Heine-
mann L. Result of a dose-response study in ith a
new pulmonary insulin formulation and inhaler.
Diabetes, 2000; (Suppl 1): A305.
3. Saudek CD. Novel forms of insulin delivery.
Endocrinol Metab Clin North Am, 1997; 26: 599-

4. Harsubcutaneoush I, Hahn E, Konturek P. Sy-
ringe, pen, inhaler -the evolution of insulin ther-
apy. Medical Science Monitor, 2001; 7(4): 833-
5. Zinman B. Insulin regimens and strategies for
IDDM. Diabetes Care, 1993; 16 (Suppl 3): 24-38.
6. Skyler JS, Cefalu W, Kourides IA et al. Efficacy
of inhaled human insulin in type 1 diabetes melli-
tus: a randomised proof-of-concept study. Lancet,

2001; 357: 331-335.
7. Cefalu W, Skyler JS, Kourides IA et al. Inhaled
human insulin treatment in patients i/ih type 2 dia-
betes mellitus. Annals of Internal Medicine, 2001;
134: 203-207.
8. Brunner GA, et al. Dose-response relation of
liquid aerosol insulin in type 1 diabetic patients.
Diabetologia, 2001; 44: 305-308.
9. Modi P, Mihic M, Lewin A. The evolving role of
oral insulin in the treatment of diabetes using a
novel RapidMist System. Diabetes Metabolism Re-
search and Reviews, 2002; 18 (Suppl 1): S38-S42.
10. Weiss SR, Berger S, Cheng S-L, Kourides IA,
Landsubcutaneoushulz WH, Gelfand RA, et al.
Adjunctive therapy in ith inhaled insulin in type 2
diabetic patients failing oral agents: a multicenter
phase II trial. Diabetes, 1999; 48 (Suppl 1): A12.

Pha rma Note Volume 17, Issue 10 August 2002

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

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor



Volume 17, Issue 10 August 2002

Table 2. LDL-C mean percent change from baseline4

Extended-release Niacin/Lovastatin Extended-release Niacin Lovastatin
Week N* Dose LDL N* Dose LDL N* Dose LDL
(mg/mg) (mg) (mg)

Baseline 57 190.9 mg/dL 61 189.7 mg/dL 61 185.6 mg/dL
12 47 1000/20 -30% 46 1000 -3% 56 20 -29%
16 45 1000/40 -36% 44 1000 -6% 56 40 -31%
20 42 1000/40 -37% 43 1500 -12% 54 40 -34%
28 42 2000/40 -42% 41 2000 -14% 53 40 -32%
N* = number of patients remaining in the trial at each time point.

Table 3. HDL-C mean percent change from baseline4

Extended-release Niacin/Lovastatin Extended-release Niacin Lovastatin
Week N* Dose HDL N* Dose HDL N* Dose HDL
(mg/mg) (mg) (mg)

Baseline 57 45 mg/dL 61 47 mg/dL 61 43 mg/dL
12 47 1000/20 +20% 46 1000 +14% 56 20 +3%
16 45 1000/40 +20% 44 1000 +15% 56 40 +5%
20 42 1000/40 +27% 43 1500 +22% 54 40 +6%
28 42 2000/40 +30% 41 2000 +24% 53 40 +6%
N* = number of patients remaining in the trial at each time point.

Table 4. TG median percent change from baseline4

Extended-release Niacin/Lovastatin Extended-release Niacin Lovastatin
Week N* Dose TG N* Dose TG N* Dose TG
(mg/mg) (mg) (mg)

Baseline 57 174 mg/dL 61 186 mg/dL 61 171 mg/dL
12 47 1000/20 -32% 46 1000 -22% 56 20 -20%
16 45 1000/40 -39% 44 1000 -23% 56 40 -17%
20 42 1000/40 -44% 43 1500 -31% 54 40 -21%
28 42 2000/40 -44% 41 2000 -31% 53 40 -20%
N* = number of patients remaining in the trial at each time point.

Table 5. Lp(a) median percent change from baseline4

Extended-release Niacin/Lovastatin Extended-release Niacin Lovastatin
Week N* Dose Lp(a) N* Dose Lp(a) N* Dose Lp(a)
(mg/mg) (mg) (mg)

Baseline 57 34 mg/dL 61 41 mg/dL 61 42 mg/dL
12 47 1000/20 -9% 46 1000 -8% 56 20 +8%
16 45 1000/40 -9% 44 1000 -12% 56 40 +8%
20 42 1000/40 -17% 43 1500 -22% 54 40 +6%
28 42 2000/40 -22% 41 2000 -32% 53 40 0%
N* = number of patients remaining in the trial at each time point.

Pha rma Note Volume 17, Issue 10 August 20026


Volume 17, Issue 10 August 2002

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