Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00005
 Material Information
Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: November 2002
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Bibliographic ID: UF00087345
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Trinh Kieu, Pharm.D. Candidate

Migraine headaches are characterized by at-
tacks of intense throbbing head pain which is typi-
cally unilateral. In addition, nausea, vomiting, or
sensitivity to light, sound or movement often ac-
company the headache. When untreated, these at-
tacks typically last 4 to 72 hours. Migraine's preva-
lence worldwide is estimated at 12%, with a higher
prevalence in women (15%-18%) compared to men
(6%). It is estimated that in the United States there
are about 28 million people who suffer from mi-
graine headaches.1 Unfortunately, a significant
number of these people have not been adequately
In the last decade, elucidation of the neuro-
chemical etiology of vascular headaches, particu-
larly migraine attacks, has led to the development
of the "triptan" family of antimigraine agents.3
Frovatriptan (Frova) is the newest addition to the
triptan class. It is manufactured by Elan Pharma-
ceuticals Inc., and was approved by the FDA in
November 2001 for the acute treatment of mi-
graine attacks with or without aura in adults. Perti-
nent pharmacology, pharmacokinetics, clinical tri-
als, adverse drug reactions, drug interactions, dos-
age, and cost of frovatriptan will be reviewed in
this article.

Pharmacology/ Pharmacokinetic
Similar to other members of the triptan fam-

ily, frovatriptan is a serotonin (5-HT) receptor ago-
nist that binds with high affinity to the 5-HT1B and
5-HT1D receptors. Pharmacological actions that
have been implicated in the antimigraine effect of
the triptans include: stimulation of presynaptic 5-
HT1D receptor (which serves to inhibit both dural
vasodilatation and inflammation), and direct inhibi-
tion of trigeminal nuclei cell excitability via 5-
HT1B/iD receptor agonism in the brainstem. More
importantly, frovatriptan causes vasoconstriction of
meningeal, dural, and cerebral vessels after binding
to the 5-HT1B receptor.1 Unlike the other triptans,
frovatriptan is a partial agonist to the 5-HTIB recep-
tor, and it is the most potent triptan in producing
contraction of human basilar arteries.4
Frovatriptan demonstrates a distinct functional
selectivity for cerebral circulation causing an in-
crease in cerebrovascular resistance with little or no
peripheral effects.' The oral bioavailability of
frovatriptan varies from 22% to 30%. Although the
time to maximum concentration is 2-3 hours after
oral administration, approximately 60-70% of the
plasma maximum concentration is achieved within
1 hour of dosing. Frovatriptan is 15% bound to
plasma proteins. It distributes into erythrocytes
with binding that is reversible and time dependent.
Importantly, frovatriptan has a half-life of approxi-
mately 26 hours, which is substantially longer than
any of the other triptans developed to date. Me-
tabolism of frovatriptan is mediated primarily by
the hepatic isoenzyme CYP1A2, and is cleared by
both the kidneys and the liver. Although renal
elimination contributes significantly to frovatriptan
clearance (50%), renal impairment does not have a
significant effect on the pharmacokinetics of frova-
triptan since the liver has sufficient capacity to
compensate. Frovatriptan can be taken without re-
gard for food, and there is no need for dosage ad-

Pha rma Note Volume 18, Issue 2 November 2002




Volume 18, Issue 2 November 2002

Table 1. Review of Frovatriptan Clinical Studies

Reference Study Design N Results

Frovatriptan was well tolerated throughout the dose range of 0.5 to
Rapoport et al 6 R, PC, DB, PG, 1453 40 mg. The 2.5-mg dose gives the optimal balance of efficacy and
tolerability for the acute treatment of migraine.
The 2.5-mg dose of frovatriptan offers optimal tolerability and
Goldstein et al R, DB, PC, PG, MC 635 efficacy the treatment of acute migraine. Higher doses do not appear
to confer greater efficacy and are associated with an increased
incidence of adverse effects.
n et al P, DB, P, M 26 Frovatriptan represents a consistently effective acute treatment for
migraine and accompanying symptoms.
Geraud et al 9 R, OL, PC, DB, PG, MC 2392 Frovatriptan 2.5 mg was well tolerated by a wide variety of patients.
Adverse events profile was found similar to that of placebo.
R=randomized; DB double-blind; MC=multicenter; PC placebo-controlled; PG parallel group; OL open label.

justment in the elderly, or in women taking a com-
bined oral contraceptive.4

Clinical Trials
Limited number of clinical trials are avail-
able which evaluate the efficacy, tolerability and
safety of frovatriptan. Table 1 summarizes some of
the clinical trials reviewed in this paper.
Rapoport et al.6 evaluated the optimum dose
of frovatriptan for the acute treatment of migraine.
The study was a double-blind, randomized, pla-
cebo-controlled, 2 dose parallel-group trial. Patients
(n=1453) were randomly assigned to frovatriptan or
placebo. The dose studied ranged from 2.5 to 40
mg in the high-dose study and 0.5 to 5 mg in the
low-dose study. In the high-dose study, patients
were randomized to take placebo or frovatriptan 2.5
mg, 5 mg, 10 mg, 20 mg, or 40 mg. Patients in the
low-dose study were to take placebo or frovatriptan
0.5 mg, 1 mg, 2.5 mg. The medication was taken at
the onset of a moderate or severe migraine. Pa-
tients were evaluated in the clinic on two occasions,
at screening and at a follow-up visit within 5 work-
ing days following the treatment. Efficacy and tol-
erability were measured based on a 4-point scale
according to International Headache Society crite-
ria.6 Frovatriptan 2.5 mg was observed as the low-
est effective dose with an approximate two-fold
magnitude of effect compared to placebo (40% ver-
sus 23%; P<.001).
A separate study was conducted to investi-
gate the efficacy and tolerability of 0.5, 1, 2.5, or 5

mg doses of frovatriptan compared to placebo in
patients with acute onset of moderate or severe
headache attacks. This randomized, double-blind,
parallel-group, placebo-controlled trial was con-
ducted in various centers throughout the United
States. Patients suffering from migraines with or
without an aura were randomized to receive pla-
cebo, 0.5, 1, 2.5, or 5 mg of frovatriptan. Patients
received the study medication at the onset of a
moderate or severe migraine headache and recorded
headache intensity, functional impairment, and mi-
graine-associated symptoms over 24 hours. The
primary efficacy parameter was headache relief at 2
hours, defined as the proportion of patients in
whom headache severity changed from moderate/
severe to mild or no headache. Secondary efficacy
measures included: headache response at 4 and 6
hours. Out of 695 randomized patients, 635 patients
completed the study. Headache response 2 hours
postdose in patients who took frovatriptan 2.5 mg
(38%) was significantly higher than in the placebo
group (25%; P<0.05). Headache response with
frovatriptan 5 mg (37%) was also superior to pla-
cebo at 2 hours postdose. The response with frova-
triptan 0.5 and 1 mg were comparable to placebo
(26% and 20%, respectively). The author con-
cluded that frovatriptan 2.5 mg is the lowest effec-
tive dose for the treatment of acute migraine. Also,
higher doses did not appear to offer greater effi-
cacy and were associated with an increase in the
incidence of adverse effects.7
To confirm the clinical efficacy of frovatrip-

Pha rma Note Volume 18, Issue 2 November 2002


Volume 18, Issue 2 November 2002

tan 2.5 mg, three randomized, placebo-controlled,
double-blind, parallel-group trials were performed
by Ryan et al.8 The studies were carried out
throughout Europe and North America. Of the total
of 2194 patients, 740 (27.6%) were randomized to
receive placebo and 1454 (72.3%) were random-
ized to receive frovatriptan 2.5mg. Up to three at-
tacks were treated with the study medication and a
consistent response was achieved among patients
on frovatriptan 2.5 mg compared with placebo. The
difference between frovatriptan and placebo was
approximately two-fold (P<0.001). Frovatriptan 2.5
mg provided significant pain relief over placebo at
2, and 4 hours postdose. Frovatriptan was also sig-
nificantly superior to placebo at rendering patients
pain-free, (9%-14%) compared with 2% to 3% for
placebo (P<0.001). One-third of the patients ex-
perienced relief from the headache within 1.3 to 1.7
hours, and in the majority of the patients this relief
did not cease. Migraine related symptoms were re-
lieved faster with frovatriptan compared with pla-
cebo. Fifty-seven percent to 64% of patients with
frovatriptan had no or mild functional impairment
compared with 35% to 43% of patients in the pla-
cebo group. The results of the studies indicate that
frovatriptan 2.5 mg provides reliable and effective
acute treatment for migraines and accompanying
Geraud et al.9 reviewed four short-term
studies that evaluated the tolerability and safety of
frovatriptan 2.5mg in a total of 2392 patients.
These double-blinded, randomized, placebo-
controlled, open-label trials, randomized 1554 pa-
tients to frovatriptan and 838 patients to placebo.
The incidence of adverse events was higher in the
frovatriptan-treated patients versus placebo (47%
versus 34% respectively). However, the vast ma-
jority of the adverse events in both treatment
groups were rated by the patients as mild or moder-
ate in severity. The types of symptoms experienced
by the patients taking frovatriptan was similar to
those in the placebo group. The author concluded
that frovatriptan was well tolerated by the patients
regardless of their age, gender, race, concomitant
medication, or the presence of cardiovascular risk
In a separate study, also reviewed by
Geraud et al.,9 the tolerability and safety of frova-
triptan 2.5mg was compared with sumatriptan 100

mg. This randomized, double-blind, parallel-group
trial was conducted in various centers throughout
Europe and in the United States. Nine hundred and
sixty two patients were divided into two groups:
480 (49.9%) were assigned to receive frovatriptan
2.5 mg and 482 (50.1%) were assigned to receive
sumatriptan 100mg. The study reported that signifi-
cantly fewer patients experienced adverse events
following frovatriptan than sumatriptan treatment
(36% versus 43%). The total number of adverse
events reported was approximately 50% higher in
the patients who took sumatriptan (.91 events per
patient) than in those who took frovatriptan (.62
events per patient). Three of the 480 patients who
took frovatriptan 2.5 mg withdrew due to adverse
events after attack 1 compared with 5 of the 482 su-
matriptan treated patients. The author concluded
that frovatriptan 2.5mg was better tolerated than su-
matriptan 100mg.

Dosage and Administration
Frovatriptan is available as 2.5 mg tablets.
The recommended dose is a single tablet of Frova
(frovatriptan 2.5 mg) taken orally. If the headache
recurs after initial relief, a second tablet may be
taken, providing that there is an interval of a least 2
hours between doses. The total daily dose of frova-
triptan should not exceed 3 tablets (7.5 mg daily).
There is no evidence that a second dose of frova-
triptan is effective in patients who do not respond
to a first dose of the drug for the same headache.
The safety of treating an average of more than 4
migraine attacks in a 30-day period has not been

Adverse Effects
The most common adverse effects associ-
ated with the use of frovatriptan at the recom-
mended dose of 2.5mg were dizziness, dry mouth,
chest pain, paresthesias, and flushing (Table 2).
Other more serious reported adverse effects include
cardiac failure; however, these events are extremely
rare and most have been reported in patients with
risk factors predictive of CAD. Events reported
have included coronary artery vasospasm, transient
myocardial ischemia, and ventricular fibrillation.5

Drug Interactions
There is a potential interaction between

Pha rma Note Volume 18, Issue 2 November 2002


Volume 18, Issue 2 November 2002

Table 2. Adverse Effects Associated with Frovatriptan Use9
Common Adverse Frovatriptan Placebo
Effects (%) (%)
Dizziness 8 5
Dry mouth 3 1
Paresthesia 4 2
Chest pain 2 1
Flushing 4 2
Hot or cold sensation 3 2

frovatriptan and other medications such as
propranolol, moclobemide, ergotamine and/or
fluvoxamine.5 Since ergotamine is a potent central
and peripheral vasoconstrictor, its coadministration
with 5-HT agonists is generally not recommended
due to the theoretical risk of additive
vasoconstriction. On the other hand, fluvoxamine,
a selective serotonin reuptake inhibitor (SSRI), and
combined oral contraceptives are potent inhibitors
of several CYP450 isoenzymes including CYP1A2;
thus coadministration of these medications with
frovatriptan should be avoided. This may result in
weakness, hyperflexia, and incoordiation. Finally,
since moclobemide selectively and reversibly
inhibits MAO-A, it is contraindicated in patients
receiving triptans.5

The mean retail price based on 3 commu-
nity pharmacies for a blister card of 9 tablets of
frovatriptan 2.5 mg is $142.88. The price range is
between $140.99-$144.69.

The Food and Drug Administration (FDA)
has approved Frova (frovatriptan succinate) for
the acute treatment of migraine attacks with or
without aura in adults. Frovatriptan works by bind-
ing to and stimulating serotonin (5-HT) receptors
causing vasoconstriction of human basilar arteries.
It is well tolerated by patients regardless of their
age, gender, race, concomitant medication, and/or
presence of cardiovascular risk factors. Unlike
other triptans, frovatriptan has a slow onset of ac-
tion and long half-life (26 hours). Frovatriptan
2.5mg provides reliable and effective acute treat-
ment for migraine and accompanying symptoms in

1. Comer, M.B. Pharmacology of the Selective 5-HT 1B/1D
Agonist Frovatriptan. Headache 2002; 42 Suppl 2:S47-53.
2. Goadsby PJ, Lipton RB, Ferrari MD. Migraine-Current
Understanding and Treatment. N Engle J Med, 346(4)
3. Lance JW, Goadsby PJ. Mechanism and management of
headache. 6th ed. Boston:Butterworth-Heinemann, 1998.
4. Brown AM, Ho M, Thomas DR, Parsons AA. Compari-
son of functional effects of frovatriptan (VML 251), suma-
triptan, and naratriptan on human recombinant 5-HT1 and
5-HT7 receptors [abstract]. Headache. 1998;38:376.
5. Buchan P, Keywood C, Wade A, Ward C. Clinical phar-
macokinetics of Frovatriptan. Headache. 2002;42[supple
6. Rapoport A, Ryan, et al. Dose Range-Finding Studies
With Frovatriptan in the Acute Treatment of Migraine.
Headache 2002; 42 Suppl 2:S74-83.
7. Goldstein J, Keywood C. Frovatriptan for the Acute
Treatment of Migraine: A Dose-Finding Study. Headache.
8. Ryan R, Geraud G, Goldstein J, Cady R, Keywood C.
Clinical Efficacy of Frovatriptan: Placebo-Controlled
Studies. Headache. 2002;42[suppl 2]:S84-S92.
9. Geraud G, Spierings E, Keywood C. Tolerability and
Safety of Frovatriptan With Short- and Long-term Use for
Treatment of Migraine and in Comparison With Sumatrip-
tan. Headache. 2002;42[supple2]:S93-S99.
10. Frova Package Insert, 2001.

Lexapro (escitalopram) is the pure S-
enantiomer of the racemic derivative
citalopram. It has recently been approved for
the treatment of major depressive disorder.
The initial adult dose is 10mg once daily. A
fixed dose trial failed to demonstrate a
greater benefit of 20mg over 10mg.

The indications for Prozac (fluoxetine) have
been expanded to include the treatment of
panic disorder with or without agoraphobia
and the long-term treatment of bulimia. Prior
to this approval, the maximum treatment
period for fluoxetine in the treatment of
bulimia was 16 weeks.

Pha rma Note Volume 18, Issue 2 November 2002


Volume 18, Issue 2 November 2002


Tammy Calloway, Pharm.D. Candidate

Gastroesophageal reflux disease (GERD)
accounts for a variety of abnormalities in the eso-
phageal mucosa and duodenum with gastric acid
being central to the development of mucosal injury
and resultant esophagitis. The degree and length of
acid suppression are important factors in the man-
agement of GERD and duodenal ulcer. In GERD,
for example, symptom severity correlates well with
the degree of acid exposure. Therefore, the control
of esophageal acidity remains the major therapeutic
approach in the management of erosive esophagi-
tis. Proton pump inhibitors (PPIs) are the most ef-
fective class of drugs for acid suppression.2 Cur-
rently there are five PPIs on the market. Table 1 is
a summary of their dosage forms and their FDA
approved indications. This article will focus on
comparing the pharmacology/pharmacokinetics,
clinical trials, dosing, drug interactions, adverse ef-
fects and costs of the PPIs in the treatment of

The PPIs belong to a class of drugs known
as the substituted benzimidazoles and act by sup-
pressing gastric acid secretion by specific inhibi-
tion of the H+/K+ ATPase, the proton pump, in the
gastric parietal cell. The PPIs undergo acid-
catalyzed conversion into active derivatives in the
parietal cell, bind to cysteine residues on proton
pumps, and inhibit acid production. These drugs
block the final step of acid production. The degree
of acid suppression appears to be dose related lead-
ing to inhibition of both basal and stimulated acid
secretion irrespective of the stimulus.1,15,17,18,19
With the possible exception of rabeprazole, the
binding of PPIs to proton pumps is irreversible.23
Therefore, the life of proton pumps along with the
time required to produce more pumps are the pri-
mary factors controlling the duration of the phar-
macodynamic effect of this class of drugs. Regen-

eration of proton pumps generally requires approxi-
mately 96 hours in humans.9
Pantoprazole differs from omeprazole and
lansoprazole in that it binds to specific cysteine
residues, which are believed to have a greater
specificity for inhibition of the parietal cells, com-
pared with other sites. This may be advantageous
because many other tissues express proton pumps
including the distal colon, kidney, biliary tract, vas-
cular smooth muscle, and the heart, among others.6
Pantoprazole is also more slowly activated at a
moderately acidic pH (pH 4-6). In vitro chemical
experiments at pH 5 have demonstrated that 20% of
pantoprazole was activated after 1 hour, compared
with 50% of lansoprazole and omeprazole. Slower
activation at a moderately acidic pH may prevent
unwanted effects on other tissues or cell organelles
that express proton pumps. The clinical signifi-
cance of these findings is unknown.9
Rabeprazole has a significantly quicker on-
set of acid inhibition than omeprazole, lansopra-
zole, and pantoprazole but not extent of acid inhibi-
tion. It also has a shorter duration of action because
it dissociates from the ATPase enzyme more rap-
idly than the other PPIs.12
All PPIs undergo extensive hepatic metabo-
lism and conjugation mainly through CYP2C19
and 3A4 isoenzymes of the cytochrome P450 en-
zyme system. They all are highly protein bound
(95-98%).1,15,17,18,19 The high pH-sensitive granules
of omeprazole that dissolve only at pH 7 affects the
bioavailability of the first oral dose which is 30%
to 40% but rises with further doses. It should be
taken 30 minutes prior to meals, preferably in the
morning.18 Lansoprazole also has high pH-
sensitive granules and should also be administered
30 minutes prior to meals. The absolute bioavail-
ability is 80%, which may be reduced by 50% if
given after food.17 Rabeprazole has an absolute
bioavailability of 52%. Food delays the rate but
not the extent of absorption, therefore rabeprazole
can be administered without regard to meals.1 Pan-
toprazole undergoes little first-pass metabolism re-
sulting in an absolute bioavailability of 77%. Food
delays the rate but not the extent of absorption,
therefore pantoprazole can also be administered
without regard to meals.18 After a single dose of
esomeprazole, the bioavailability is 64% and in-
creases with repeated administration to 90%. Food

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Volume 18, Issue 2 November 2002

Table 1. FDA approved indications and dosage forms of the PPIs7
Product Name Dosage Forms Indications
Prilosec Delayed-Release Capsules Active duodenal ulcer (DU), gastric ulcer (GU), GERD,
(omeprazole) (10mg, 20mg, 401ng) maintenance of DU/GU, hypersecretory conditions.
Prevacid Delayed-Release Capsules and Suspension Maintenance of DU/GU, gastric ulcer, NSAID-associated GU,
(lansoprazole) (15mg, 30mg) GERD, erosive esophagitis, hypersecretory conditions.
Aciphex Delayed-Release Tablets GERD, GERD maintenance, duodenal ulcer, hypersecretory
(rabeprazole) (20mg) conditions.
Protonix Delayed-Release Tablets and Intravenous Erosive esophagitis with GERD.
(pantoprazole) (401ng)
Nexium Delayed-Release Capsules Erosive esophagitis (EE), maintenance of (EE), GERD.
(esomeprazole) (20mg, 401ng)

decreases the extent of absorption by 33-53%,
therefore esomeprazole should be taken at least one
hour before meals.15

Clinical Trials
The degree of acid suppression that is nec-
essary for healing gastric acid disorders has not
been well defined; however, maintaining the pH
above 3 is believed to be an important objective
for the healing of duodenal ulcers. The use of 24-
hour intragastric pH monitoring is an accepted
method for this assessment. Most of the studies
evaluate this method in determining the degree and
length of acid suppression of each of the PPIs
(Table 2).
In a double-blind, crossover study by Meyer
and Meier14, the effects on intragastric acidity was
compared using low-dose omeprazole (10mg and
20mg) and lansoprazole 15mg in 12 healthy H. py-
lori negative subjects for 5 days. The authors con-
cluded there was no significant difference between
the intragastric acidity measurements and the time
period above pH 4 for omeprazole and lansopra-
zole. Seensula et al.22 noted similar reductions in
24-hour intragastric acidity with omeprazole and
lansoprazole. This double-blind, randomized, cross-
over study involved 16 healthy volunteers who re-
ceived either omeprazole 40mg or lansoprazole
60mg, with a washout period of at least 2 weeks be-
tween each treatment. Twenty-four hour intragas-
tric acidity was measured at baseline and on day 5
of each treatment period. Median pH on day 5 for
omeprazole 40mg was pH 4.15 and lansoprazole
60mg was pH 3.79. The authors concluded that

omeprazole 40mg and lansoprazole 60mg had a
similar effect on 24-hour intragastric acidity.
In a double-blind, crossover study, Hart-
mann et al.2 compared the effect of pantoprazole
40mg and omeprazole 20mg on intragastric pH in
16 healthy subjects. Subjects underwent a 2 week
washout period prior to crossover. The median 24-
hour pH for pantoprazole 40mg was significantly
higher than omeprazole 40mg, pH 3.15 vs. pH 2.05
(p<0.01). The authors stated that intragastric pH is
a surrogate marker and does not necessarily corre-
late to clinical effect. Another study by Koop et
al.2, measured the effect of pantoprazole 40mg and
omeprazole 40mg on intragastric pH of a 7 day
regimen in 7 healthy volunteers. The intragastric
pH was taken on the final day and measurements
for pantoprazole and omeprazole were 4.2 and 4.0
respectively. Both pantoprazole and omeprazole
displayed similar effects on intragastric pH.
Studies investigating esomeprazole with the
other PPIs have all shown that esomeprazole pro-
vides significantly more effective acid control than
the other PPIs when 24-hour intragastric pH was
measured. However, the clinical relevance of these
differences has not yet been defined.2
Data have shown that omeprazole 20mg
daily is highly effective in the management of ero-
sive esophagitis.18 Studies with lansoprazole have
reported a similar level efficacy and confirmed the
role of the PPIs in the pharmacologic management
of erosive esophagitis.17 Table 3 summarizes the
efficacy of short-term treatment using PPIs. Mee et
al.2 compared the healing rates of omeprazole and
lansoprazole in 565 patients. Patients were random-

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Volume 18, Issue 2 November 2002

Table 2. Summary of Clinical Trials Using 24-hour Intragastric acid monitoring.
Duration Median % Time
Author (N) Study Design Drugs Studied Duration M ian % Te P-value
(Days) 24-hr pH pH >4
Omeprazole 20mg qd 53
sa (16) R, IB, Omeprazole 20mg bid 78 <0.0
Lansoprazole 30mg qd 46
Lansoprazole 30mg bid 70 <0.05
Omeprazole 20mg qd 4.2
Williams et al (16) R, DB, CO Rabeprazole 20mg qd 8 4.7 NA 0.0001 vs
Placebo 1.5 placebo
Omeprazole 40mg qd 82.8
Brunner et al (12) R, DB, CO Pantoprazole 40mg qd NA NA 86.9 NA
Esomeprazole 40mg qd 57.2
Thomson et al (28) O, R, 2-way CO Lansoprazole 30mg qd 10 NA 51.8 <0.05

Esomeprazole 40mg qd 4.7 66
Wilder-Smith et al2 (31) O, R, 2-way CO Pantoprazole 40mg qd 5 3.7 44 0.001
Esomeprazole 40mg qd 61
Wilder-Smith et al2 (23) 0, R, 2-way CO Rabeprazole 20mg qd 5 NA 45 0.005

Esomeprazole 20mg qd 5 4.1 53
Nexium & Prilosec Omeprazole 20mg qd (N=38) 3.6 44 0.01
Prescribing Information Esomeprazole 40mg qd 5 68 0.01
Omeprazole 40mg qd (N=114) 62
R=Randomized, IB=Investigator Blind, CO=Crossover, DB=Double-Blind, NA=Not Available

ized to either receive omeprazole 20mg daily or
lansoprazole 30mg daily. Healing rates were as-
sessed at 4 and 8 weeks. At week 4 omeprazole
and lansoprazole had healing rates of 57% and 62%
respectively. At week 8 the healing rate for ome-
prazole was 71% vs. 75% for lansoprazole. No sig-
nificant differences were observed. Pilotto et al.16
compared the efficacy of omeprazole, lansoprazole,
and pantoprazole in 146 elderly patients with
esophagitis diagnosed by endoscopy. Patients were
randomized to receive omeprazole 20mg, lansopra-
zole 30mg, or pantoprazole 40mg daily for 8
weeks. Results showed complete healing of
esophagitis in 83% (omeprazole), 88%
(lansoprazole), and 92% (pantoprazole) of patients.
The investigators concluded that all three are
equally effective in healing esophagitis in elderly
Esomeprazole has only been studied against
omeprazole for the short-term treatment of gastric
disorders. Richter et al.20 compared the efficacy of
esomeprazole 40mg to omeprazole 20mg daily.
The study was a double-blind, randomized, US,
multicenter study (n=2425), with H. pylori negative

patients and photo documented erosive esophagitis.
The primary endpoint was the number of patients
healed at week 8. At week 4, healing rates were
81.7% with esomeprazole 40mg and 68.7% with
omeprazole 20mg daily (p=0.001). Esomeprazole
40mg had an eight-week healing rate of 93.7%
compared to 84.2% for omeprazole 20mg daily
(p<0.001). The authors concluded that esomepra-
zole at week 4 has a similar healing rate as omepra-
zole at week 8. Esomeprazole showed significant
clinical advantages over omeprazole in healing ero-
sive esophagitis. However, esomeprazole 40mg has
not been compared with omeprazole 40mg.
Omeprazole has recently received a patent
extension from the FDA to look at its use in chil-
dren and infants. There has been one randomized
trial that compares ranitidine (Zantac) with ome-
prazole in the treatment of children with refractory
erosive esophagitis. Cucchiara et al. randomized
32 patients with refractory esophagitis, aged 6
months to 13 years, to receive either omeprazole 40
mg/1.72m2 or high dose ranitidine (10 mg/kg) twice
daily. All patients underwent 24-hour intraesophag-
eal and intragastric pH monitoring and endoscopy

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Volume 18, Issue 2 November 2002

Table 3. Summary of Clinical Trials for the Short-term Treatment of GERD
Author (N) Study Design Drugs Studied Remissn Duration Comments
Rates (%)
Omeprazole 20mg (n=431) 82a-91a OME was
Castell et a145 R Lansoprazole 30mg (n=422) 83c-91 to 8 wks significantly
(1284) Lansoprazole 15mg (n=218) 75b-79b better than
Placebo (n=213) 33-40 LAN & placebo
Dekkers et al2 R, Omeprazole 20mg (n=102) 81-94 4 to 8 wks Not significantly
(202) RDB, MC Rabeprazole 20mg + Placebo (n= 100) 81-92 towk different
Corinaldesi et a12 Omeprazole 20mg (n=105) 79-91 Not significantly
(208) R,DB, MC, P Pantoprazole 40mg (n=103) 79-94 towks different
12 Omeprazole 20mg (n=650) 64.7-86.9 EOME was
Kahrilas et a R, DB, MC, P Esomeprazole 20mg (n=656) 70.5d89.9e 4 to 8 wks significantly
(n=1960) Esomeprazole 40mg (n=654) 75.9e-94.1e better than OME

R=Randomized, DB=Double-Blind, MC Multicenter, P Parallel, LAN Lansoprazole, OME Omeprazole, EOME Esomeprazole
a= omeprazole vs. placebo and lansoprazole 15 mg I' '- 5), b= lansoprazole vs. placebo (p<0.05), c= lansoprazole 30 mg vs. placebo and lansoprazole 15 mg
(p<0.05), d= esomeprazole 40 mg vs. omeprazole 20mg (p<0.05), e= esomeprazole 20 mg vs. omeprazole 20 mg (p=0.09)

with biopsy. Esophageal healing occurred in 9 of
12 (75%) of omeprazole treated children and in 8
of 13 (62%) of ranitidine treated children. These
differences were not significantly different.24 Other
published information consists of case reports and
series describing omeprazole use in pediatric pa-
tients refractory to conventional therapy. Gun-
asekaran and Hassall studied 15 children aged 10
months to 17 years who failed H2-receptor antago-
nist and prokinetic agents. Children 3 years of age
and older were given omeprazole 20 mg in the
morning, given in orange juice, cranberry juice, or
yogurt. Children younger than 3 years where given
omeprazole 10 mg in the same vehicles. Doses
were adjusted until the esophageal pH was less
than 4.0 for less than 6% of the time. The omepra-
zole dose required to control esophageal pH was
20-60 mg (0.7-3.3 mg/kg). The children received
omeprazole treatment continuously for 5.5 to 26
months. All of the children where free of symptoms
after 4-6 months of therapy. Nine of the patients
underwent endoscopy all had esophageal healing.24

Because of the chronic nature of GERD,
long-term maintenance therapy is generally re-
quired. GERD relapse within 6-12 months has
been reported in 50-80% of patients in whom an-
tisecretory therapy was stopped. Long-term treat-
ment with PPIs remains the method of choice for
the medical treatment of severe GERD to maintain
remission.12 Patients requiring long-term therapy

with PPIs will not develop tolerance to the PPIs.6
Table 4 contains a summary of dosage and admini-
stration recommendations for the PPIs.
Dosing adjustments may be needed due to
genetic polymorphism of CYP2C19, which results
in slow or fast metabolizers. Omeprazole showed
an increase in the AUC of approximately four-fold
in Asian subjects compared to Caucasians.18 This is
less significant in the other PPIs. In patients with
chronic hepatic disease, the bioavailability of the
PPIs increases, reflecting decreased first pass ef-
fect, and/or an increase in the plasma half-life.
Therefore, a dosage decrease may be warranted in
this patient population, especially if long-term ther-
apy is required. In the elderly population, clearance
is decreased and the elimination half-life is in-
creased but no accumulation is seen with the PPIs
with once-a-day dosing, therefore no dosing adjust-
ments are necessary. Since these drugs are not
eliminated via the kidney as unchanged drug, no
dosing adjustments are needed in renal impair-

Drug Interactions
Since all PPIs inhibit gastric acid secretion,
they may decrease the absorption of drugs where
gastric pH is an important determinant of bioavail-
ability such as ketoconazole, itraconazole, ampicil-
lin, and iron salts.1'15'17'18'19 PPIs may also enhance
the absorption of drugs where a higher pH facili-
tates absorption. Pantoprazole is the exception. It
does not increase the absorption of digoxin. The

Pha rma Note Volume 18, Issue 2 November 2002


Volume 18, Issue 2 November 2002

Table 4. Dosage and Administration for the PPIs1,15,17,18,19
PPI Indication Dose Frequency
Active Duodenal Ulcer (DU) 20 mg qd 4 to 8 weeks
Gastric Ulcer (GU) 40 mg qd 4 to 8 weeks
Prilosec GERD 20 mg qd 4 to 8 weeks
(omeprazole) Maintenance of DU/GU 20 mg qd
Hypersecretory Conditions 60-360 mg/d >/= 5 years
Maintenance of DU/GU 15 mg qd
Gastric Ulcer 30 mg qd Up to 8 weeks
Prevacid NSAID-Associated GU 15 mg qd Up to 12 weeks
(lansoprazole) GERD 15 mg qd Up to 8 weeks
Erosive Esophagitis 30 mg qd Up to 8 weeks
Hypersecretory Conditions 60-120 mg/d >/= 4 years
GERD 20 mg qd 8 to 16 weeks
SGERD Maintenance 20 mg qd
Aciphex (rabeprazole) Duodenal Ulcer 20 mg qd 4 weeks or longer
Hypersecretory Conditions 60-120 mg/d >/= 1 year
Pato ) Erosive Esophagitis with GERD 40 mg qd 8 to 16 weeks
Erosive Esophagitis (EE) 20 40 mg qd 4 to 8 weeks
Nexiumr Maintenance of (EE) 20 mg qd
(esomeprazole) GERD 20 mg qd Up to 4 weeks

other PPIs likely increase the absorption of digoxin
by decreasing the degradation by gastric acid. Ant-
acids do not affect pantoprazole absorption but do
decrease the absorption of lansoprazole.9
The differences in drug interactions among
the PPIs lie in their difference in metabolism and
effects on specific hepatic enzymes. Omeprazole
and lansoprazole induce CYP1A4, though lanso-
prazole is considered a weaker inducer of this
isoenzyme. Omeprazole and lansoprazole to a
lesser extent are significant CYP2C9 inhibitors and
weak CYP3A4 inhibitors.17'18 Pantoprazole, ra-
beprazole, and esomeprazole have a lower potential
for interactions with the cytochrome P450 enzyme
system because of a lower affinity for the P450 en-

Adverse Effects
Short-term side effects of the PPIs are simi-
lar. The most commonly occurring short-term (<12
wks) adverse effects reported include headache, ab-
dominal pain, diarrhea, constipation, nausea, and
pruritis. Adverse effects associated with long-term
(>12 wks) use are generally similar to those ob-
served with short-term therapy. The suppression of
gastric acid is dose-dependent among the PPIs and
typically results in modest elevations of serum gas-

trin above pretreatment levels. However, only a
small fraction of patients receiving PPI therapy will
have serum gastrin concentrations above the nor-
mal range. Hypergastrinemia contributes to the de-
velopment of gastric tumors, gastric cancer, colonic
polyps, and gastric enterochromaffin cell hyperpla-
sia. However, neither omeprazole nor lansoprazole
has been associated with an increased risk of gas-
tric cancer in patients receiving long-term therapy.
Pantoprazole, rabeprazole, and esomeprazole are
likely to have similar long-term safely profiles.15,23

Table 6. Monthly retail costs of the PPIs
PPI Dose Average (range)
Prilosec 10 mg $113.98 (104.02-123.95) $122.37
20 mg (115.80-128.95) $184.87
40 mg (171.07-197.95)
Prevacid 15 mg $120.95 (112.95-128.95) $123.32
30 mg (113.70-132.95)
Aciphex 20 mg $121.83 (111.72-131.95)
Protonix 20 mg $105.00 (94.05-115.95)
40 mg $105.00 (94.05-115.95)
Nexium 20 mg $124.23 (115.51-132.95)
40 mg $124.23 (115.51-132.95)
Prices obtained from a retail chain store, discount source, and an internet

Pha ma Nte Vlume18, ssue2 NoembeL200


Volume 18, Issue 2 November 2002

The costs of the different PPIs are summa-
rized in Table 6.

Based on the superior efficacy profiles,
PPIs are the drugs of choice in managing symp-
toms of GERD, healing and maintaining healing of
duodenal and gastric ulcers, and treating hyper-
secretory conditions including Zollinger-Ellison
syndrome. All of the PPIs provide similar efficacy
rates in gastric acid disorders. The decision to se-
lect one PPI over the other is based on the agents'
cost, formulations, FDA-labeled indications, and
overall safety profiles. Intravenous or parenteral
pantoprazole may be the preferred antisecretory
agent for patients unable to take oral medications.
Head to head studies comparing esomeprazole
40mg to omeprazole 20mg suggest that esomepra-
zole may be more effective or at least have a faster
healing rate in patients with erosive esophagitis.
However, studies have not been done comparing
esomeprazole 40mg with omeprazole 40mg daily.

1. Aciphex. Package Insert. December 2000.
2. AstraZeneca, Data on file.
3. Brunner G, et al. Comparison of pantoprazole (40mg
QD) versus omeprazole (40mg QD) on intragastric pH
and serum gastrin in healthy volunteers. Can J Gastroen-
terology. 1997; 11:41A {abstract}.
4. Castell DO, Richter JE, et al. Efficacy and safety of lan-
soprazole in the treatment of erosive reflux esophagitis.
American Journal of Gastroenterology. 1996;91(9):1749-
5. Castell DO, Richter JE, et al. Large trial compares lanso-
prazole to omeprazole {abstract}. Gastroenterology.
6. DiPalma JA. Management of Severe Gastroesophageal
Reflux Disease. Journal of Clinical Gastroenterology.
2001:32 (1):19-26.
7. www.fda.gov
8. Geus WP, et al. Acid-inhibitory effects of omeprazole
and lansoprazole in Helicobacter pylori negative healthy
subjects. Alimentary Pharmacology & Therapeutics.
9. Jungnickel PW. Pantoprazole: A New Proton Pump In-
hibitor. Clinical Therapeutics. 2000;22:1268-1293.
10. Klinkenberg-Knol EC, et al. Long-term Omeprazole
Treatment in Resistant Gastroesophageal Reflux Disease:
Efficacy, Safety, and Influence on Gastric Mucosa. Gas-
troenterology. 2000;118:661-669.
11. Klinkenberg-Knol EC, et al. Long-term treatment with
omeprazole for refractory reflux esophagitis: Efficacy
and safety. Annuals of Internal Medicine. 1994;121:161-

12. Lanza F, et al. Efficacy of Rabeprazole Once Daily for
Acid-Related Disorders. Digestive Diseases and Sci-
ences, Vol. 46, No 3 (March 2001), pp. 587-596.
13. Maton PN, Burton ME. Proton Pump Inhibitors. Clini-
cian's Manual on Drug Interactions in Gastroenterology.
2000 pp18-22.
14. Meyer M, Meier R. Effect of low-dose lansoprazole and
omeprazole on gastric acidity in Helicobacter pylori
negative healthy volunteers. Gastroenterology. 1998;114
supplyl 4): A227{abstract}.
15. Nexium. Package Insert. January 2000.
16. Pilotto A, Franceschi M, et al. Comparison of omepra-
zole, lansoprazole and pantoprazole in the treatment of
elderly patients with esophagitis {abstract}. Gastroen-
terology. 1999;116(4):A283.
17. Prevacid. Package Insert. November 2000.
18. Prilosec. Package Insert. April 2000.
19. Protonix. Package Insert. March 2000.
20. Richter JE, et al. Efficacy and safety of esomeprazole
compared with omeprazole in GERD patients with ero-
sive esophagitis: a randomized controlled study. Ameri-
can Journal of Gasterology. 2001; 96:656-665.
21. Rohss K, et al. Esomeprazole 40mg provides more effec-
tive acid control than lansoprazole 30 mg. Gastroenterol-
ogy 2000;118:A22.
22. Seensalu, R et al. Dose-response comparison of lanso-
prazole and omeprazole on 24-hour gastric acidity and
plasma gastrin in healthy volunteers. Gastroenterology.
23. Welage LS, et al. Evaluation of omeprazole, lansopra-
zole, pantoprazole, and rabeprazole in the treatment of
acid-related diseases. J Am Pharm Assoc. 2000;40:52-62.
24. Walters KJ, et al. The Use of Omeprazole in the Pediat-
ric Population. The Annuals of Pharmocotherapy. 1998
April, Volume 32.

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 18, Issue 2 November 2002

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