Aliment Pharmacol Ther 2001; 15: 1571±1577.
Effectiveness and safety of nizatidine, 75 mg, for the relief
of episodic heartburn
K. PAU L, C. M. REDMAN & M. CHEN
Clinical Research Department, Whitehall-Robins Healthcare, Madison, NJ, USA
Accepted for publication 28 May 2001
SUMMARY
Background: The most frequent cause of episodic
heartburn is food and beverage ingestion. Nizatidine,
an H2-receptor antagonist, is currently approved for
non-prescription use in the prevention and relief of
heartburn at a dose of 75 mg up to twice a day.
Methods: Two identical studies were carried out to
evaluate the ef®cacy of nizatidine, 75 mg, compared
with placebo in treating heartburn in an `at-home'
setting. The studies were multicentre, multiple-dose,
placebo-controlled, randomized, parallel group design.
A total of 994 subjects were randomized to treatment.
Adequate relief of heartburn was assessed at 15, 30 and
45 min and 1, 2 and 3 h following a treatment dose. A
subject's responses with respect to time to relief and
attainment of adequate relief were combined into a
derived response pro®le, the sustained adequate relief
score. Adverse experiences were noted throughout the
study period.
INTRODUCTION
Nizatidine is a histamine H2-receptor antagonist. Its
mechanism of action, like other drugs in its class, is the
inhibition of histamine-mediated gastric acid secretion
through competitive inhibition of histamine at
H2-receptors.1, 2 Oral doses as low as 75 mg have been
shown to inhibit caffeine-stimulated and meal-stimula-
ted gastric acid secretion.3, 4 Nizatidine is currently
Correspondence to: Dr C. M. Redman, Clinical Research Department,
Whitehall-Robins Healthcare, 5 Giralda Farms, Madison, NJ 07940, USA.
E-mail: redmanc@ahp.com
Ó 2001 Blackwell Science Ltd
Results: The individual and combined study results
showed that nizatidine, 75 mg, relieved heartburn
faster and/or more consistently than placebo. The mean
sustained adequate relief score, calculated over a
subject's ®rst four episodes, was 2.43 in the nizatidine-
treated group compared with 2.14 in the placebo group
(P < 0.001). Nizatidine-treated subjects attained sus-
tained adequate relief in a signi®cantly (P < 0.001)
larger percentage (75%) of their heartburn episodes
than did subjects treated with placebo (66%). No serious
adverse experiences were associated with nizatidine
treatment.
Conclusion: Nizatidine, 75 mg, is a safe and effective
treatment for episodic heartburn. The results showed
that subjects taking nizatidine had heartburn relief that
was achieved faster and/or more reliably than did
subjects taking placebo.
approved for non-prescription use in the prevention and
relief of heartburn at a dose of 75 mg up to twice a day.
The most frequent cause of episodic heartburn is food
and beverage ingestion.5 Heartburn is also the most
common symptom of gastro-oesophageal re¯ux dis-
ease.6 Symptoms are often associated with re¯ux of
acidic gastric contents into the oesophagus,7 producing
a burning sensation. Suppression of acid secretion and
neutralization of excess acid are the current mainstays
of therapy.8 Nizatidine has a serum half-life of 1±2 h; a
75 mg oral dose is largely cleared from the body within
5 h.4 Nizatidine is well absorbed, with an oral bioavail-
ability of greater than 70%. After oral dosing, peak
1571
1572 K. PAUL et al.
plasma concentrations occur within 30 min to 3 h.9 In
clinical pharmacology studies, a 75 mg dose of nizati-
dine taken before a test meal increased the gastric pH
above 4 and maintained it there for over 2 h after
eating, the time frame in which most post-prandial
gastro-oesophageal re¯ux occurs.10 Nizatidine has been
shown to be effective in the complete prevention of
heartburn.11 Because an oral dose of nizatidine, 75 mg,
lowers post-prandial acidity, raises gastric pH and can
prevent heartburn caused by food and beverages, it was
reasonable to evaluate the ef®cacy of this same dose in
relieving episodic heartburn.
SUBJECTS AND METHODS
Subjects
Men and women, 16 years of age or older, who had a
3-month history of episodic heartburn of at least
moderate severity, were recruited. Preliminary screen-
ing of prospective subjects was carried out by tele-
phone. Suitable subjects were invited to report to the
clinic for formal screening. Subjects who recorded and
treated at least three heartburn episodes of moderate or
greater severity during a 1-week, single-blind antacid
qualifying period, and for whom at least 50% of the
treated episodes responded to antacid, were eligible to
enrol in the double-blind treatment period. Moderate
heartburn was de®ned as heartburn that bothered the
subject but did not interfere with daily activities.
Subjects were excluded from the study if they had a
history of gastrointestinal or oesophageal disease or
surgery, serious systemic disorders, unexplained weight
loss or melaena, were currently being treated with a
regular, multiple-times-a-day regimen of aspirin or
NSAID therapy or had a history of substance abuse.
Use of other gastrointestinal medications was consid-
ered a reason for exclusion if taken within 7 days
(prokinetic or anticholinergic agent, sucralfate or his-
tamine H2-receptor antagonist) or 30 days (proton
pump inhibitor or investigational agent) of the start of
the study. Subjects were also excluded for a history of
hypersensitivity to, signi®cant adverse experience
with or contraindication to any histamine H2-receptor
antagonist or antacid. Pregnancy, lactation or reliance
on inadequate contraception were also exclusion
criteria. Approval from the institutional review board
was obtained for each site, and each subject provided
written informed consent before participating.
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1571±1577
Study design
Two identical studies were conducted to evaluate the
ef®cacy of nizatidine, 75 mg, compared with placebo in
an `at-home' setting where subjects treated heartburn
that occurred in the course of their normal daily
activities and diet. The studies were multiple-dose,
placebo-controlled, randomized, parallel group design
trials with a 1-week single-blind antacid qualifying
period and a 2-week double-blind treatment period.
These studies were conducted at 46 sites.
Quali®ed subjects were randomized to receive either
nizatidine, 75 mg, or placebo to treat up to two
heartburn episodes daily during the double-blind treat-
ment period. Treatments were randomly assigned using
a block of size 4. Subjects treated their heartburn at
home and recorded their assessments of adequacy of
relief in a diary at speci®ed time points for 3 h after each
treatment episode. At each episode, adequate relief of
heartburn was assessed at 15, 30 and 45 min and 1, 2
and 3 h following a dose, using a `Yes/No' response to
the question: `Has your heartburn been adequately
relieved?'. At the 3-h assessment, subjects also indicated
whether they had obtained complete relief. Subjects
were permitted to take rescue antacid after the 2-h
assessment if their relief was inadequate. Subjects were
interviewed to determine if any adverse experiences had
occurred and subject diaries were reviewed by study
personnel to identify adverse experiences. For economy
of presentation, the data from both studies in a
combined analysis are reported here, although results
for key parameters within the separate studies are also
shown.
Derived response pro®le
Because ef®cacy in the relief of heartburn can be
perceived in more than one way by the consumer, a
response scale was developed by combining two com-
ponents of ef®cacy into a response pro®le including:
(i) whether adequate relief was attained and sustained
until the 3-h time point; and (ii) the rapidity with which
relief was attained. Using the results of the adequate
relief of heartburn assessments for each episode, a
sustained adequate relief score was assigned a value on
a 5-point categorical scale, as follows: 4, sustained
adequate relief initially attained at 15 or 30 min after
double-blind medication; 3, sustained adequate relief
initially attained at 45 or 60 min after double-blind
 NIZATIDINE, 75 MG, FOR EPISODIC HEARTBURN
medication; 2, sustained adequate relief initially
attained 2 h after double-blind medication; 1, sustained
adequate relief initially attained 3 h after double-blind
medication; 0, no sustained adequate relief attained
within 3 h after double-blind medication or rescue
medication used any time during the 3-h assessment
period.
Any inadequate relief assessments invalidated previous
adequate relief assessments for the purposes of this
derived parameter, as the relief was required to be
sustained until the end of the 3-h assessment period.
Statistical analysis
The primary analysis for establishing ef®cacy used data
from the intention-to-treat population, which consisted
of randomized subjects who took at least one dose of
study medication and provided ef®cacy data for that
dose. The responses over several episodes for an
individual subject were averaged to provide a more
accurate assessment of the response pro®le over time
than could be obtained from the results of a single
episode. The use of the ®rst four episodes as the primary
ef®cacy variable, rather than results from all episodes,
was intended to ensure that there was no dispropor-
tionate representation of some subjects compared with
others due to disparate numbers of treated episodes.
The primary variable was the sustained adequate relief
score averaged over the ®rst four episodes for each
subject. More than 90% of the subjects within each trial
had at least four episodes. Other ef®cacy parameters
included the proportion of each subject's episodes with
adequate relief, the proportion of each subject's episodes
with complete relief reported at 3 h and the proportion
of each subject's episodes for which rescue medication
was consumed. An additional parameter, proportion of
subjects with complete relief at all episodes, was a post
hoc end-point. It nevertheless represents a valid treat-
ment effect assessment, because the reliability of a
product in producing complete relief is important to
consumers. These end-points evaluated the ef®cacy of
nizatidine, 75 mg, in terms of speed, consistency and
completeness of response to medication, which are
relevant consumer issues. In order to ensure that there
was no carry-over effect between episodes, treatment
effects were also assessed using only episodes separated
by at least 12 h.
An appropriate sample size was planned to achieve
80% power for a two-sided hypothesis test at the 0.05
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1571±1577
1573
level in the individual studies. Each of the ef®cacy
parameters was signi®cant at that level in both studies.
The data from the two studies were then combined to
determine whether the effects of nizatidine compared
with placebo were consistent across trials. The weighted
averages of the within-study treatment estimates
(Cochran±Mantel±Haenszel estimates) were computed
across the two studies with weights equal to the
reciprocal variance of the Cochran±Mantel±Haenszel
estimate. These weighted averages were used to test
differences between nizatidine and placebo across the
two studies; 95% con®dence intervals using standard
errors based on within-group standard deviations were
provided for these differences. Chi-squared tests for
homogeneity of treatment effects across the two studies
were also performed.
In each study, small sites, de®ned a priori as those with
fewer than ®ve intention-to-treat subjects per treatment
group, were combined for all analyses.
RESULTS
Subject characteristics
A total of 1423 subjects were enrolled in the screening
phase of the studies. Of these, 994 were randomized and
received double-blind treatment medication. The
remaining 429 subjects either failed to qualify, with-
drew prior to randomization or were randomized but
never took a dose of study medication. Subject charac-
teristics were similar within the individual studies and
the combined analysis.
There were no signi®cant differences between the
treatment groups for any demographic characteristic,
although women slightly outnumbered men (Table 1).
The mean subject age was approximately 43 years.
Ef®cacy
The results showed that nizatidine, 75 mg, relieved
heartburn faster and/or more consistently than did
placebo. The mean sustained adequate relief score,
calculated over a subject's ®rst four episodes, was 2.43
in the nizatidine-treated group compared with 2.14 in
the placebo group (P < 0.001).
The 95% con®dence intervals for the treatment
differences were (0.109, 0.482), (0.053, 0.51) and
(0.145, 0.434) for the ®rst study, the second study and
the studies combined, respectively, showing that the
1574 K. PAUL et al.

Table 1. Summary of subject demographic

Treatment group
Demographic Overall characteristics: combined studies
characteristic (n = 994) Placebo (n = 496) Nizatidine, 75 mg (n = 498)

Gender
Male 455 (46%) 234 (47%) 221 (44%)
Female 539 (54%) 262 (53%) 277 (56%)
Race
Caucasian 809 (81%) 404 (81%) 405 (81%)
Black 107 (11%) 46 (9%) 61 (12%)
Asian 12 (1%) 9 (2%) 3 (1%)
Hispanic 57 (6%) 32 (6%) 25 (5%)
Other 9 (1%) 5 (1%) 4 (1%)
Age (years)
Mean 42.9 43.5 42.3
Range (16±81) (16±81) (16±81)
Weight (lb)
Mean 186.5 186.7 186.4
Range (92±384) (92±384) (100±334)
Height (in)
Mean 66.9 67.0 66.9
Range (52±80) (54±80) (52±76)

advantage of nizatidine over placebo was obvious in Subjects treated an average of 10 episodes during the
each study and not merely a result of combining them. study. The analyses, i.e. mean sustained adequate relief
In addition, the results were consistent between the two score, the proportion of episodes with sustained
studies. adequate relief and the proportion of episodes with
Nizatidine-treated subjects attained sustained adequate adequate relief at each time point, were repeated using
relief in a signi®cantly (P < 0.001) larger percentage data from all episodes, rather than only the ®rst four.
(75%) of their heartburn episodes than did subjects Subjects treated with nizatidine still had signi®cantly
treated with placebo (66%). The 95% con®dence inter- better scores than did placebo-treated subjects.
vals for the treatment differences were (0.05, 0.151), In keeping with the ®nding that nizatidine-treated
(0.016, 0.14) and (0.052, 0.13) for the ®rst study, the subjects attained sustained relief more frequently,
second study and the studies combined, respectively, nizatidine-treated subjects used rescue antacid at
again showing the ef®cacy of nizatidine within the
studies and the similarity of outcome across them.
When the proportion of episodes with adequate relief is
shown by time (Figure 1) for the ®rst four episodes,
nizatidine-treated subjects had signi®cantly more epi-
sodes adequately relieved than did placebo-treated
subjects at 60 min through 180 min. At the 3-h
assessment, nearly three-quarters (74%) of nizatidine-
treated subjects' episodes were scored as complete relief
compared with 64% of placebo-treated subjects' epi-
sodes, a signi®cant difference (P < 0.001), thus show-
ing that nizatidine provides not only adequate relief
more frequently, but also complete relief more fre-
quently. In addition, a signi®cantly larger percentage of
nizatidine-treated subjects (37% vs. 24%, P < 0.001) Figure 1. Proportion of episodes with adequate relief at each time
reported complete relief at all episodes. point based on the ®rst four episodes: combined studies.

Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1571±1577

 NIZATIDINE, 75 MG, FOR EPISODIC HEARTBURN
roughly 20% of their treated heartburn episodes, com-
pared with placebo-treated subjects who used rescue
antacid for 27% of their treated heartburn episodes, a
statistically signi®cant difference (P < 0.001).
Nizatidine has a serum half-life of 1±2 h; thus drug
carry-over between episodes was pharmacologically
possible. In order to ensure that there was no carry-
over effect between episodes, treatment effects were
alternately assessed using only episodes separated by at
least 12 h. Nizatidine's effectiveness was undiminished
in this analysis. The sustained adequate relief score
calculated for the nizatidine-treated subjects was 2.40
compared with 2.12 for placebo-treated subjects
(P < 0.001).
Safety
All 994 (498 nizatidine-treated, 496 placebo-treated)
subjects who took study medication and provided any
follow-up data were included in the analysis of safety.
There were no deaths or serious adverse experiences
among nizatidine-treated subjects.
The study protocols allowed a maximum of two doses
(150 mg) per day or 28 doses (2100 mg) during the
2 weeks of the trial. The average number of nizatidine
75 mg doses taken during these trials was 10; the range
was 1±28.
Nizatidine was well tolerated in the study population
as a whole and in the elderly (³ 65 years) as well. There
was no signi®cant difference between treatment groups
within any body system or individual adverse experi-
ence with the exception of ¯atulence, which occurred
more often among placebo-treated subjects. There were
no statistically signi®cant differences between nizati-
dine-treated men and women in the percentage of
adverse experiences.
There were ®ve adverse experiences that occurred in
1% or more of the nizatidine-treated subjects. Eighty-
three (16.7%) subjects in the nizatidine-treated group
reported at least one of these compared with 73 (14.7%)
in the placebo-treated group. These adverse experiences
were: headache, reported in 22 (4.4%) placebo-treated
subjects vs. 32 (6.4%) nizatidine-treated subjects;
diarrhoea, reported in 10 (2.0%) placebo-treated sub-
jects vs. 15 (3.0%) nizatidine-treated subjects; dyspep-
sia, reported in eight (1.6%) placebo-treated subjects vs.
nine (1.8%) nizatidine-treated subjects; nausea, repor-
ted in ®ve (1.0%) placebo-treated subjects vs. seven
(1.4%) nizatidine-treated subjects; and back pain,
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1571±1577
1575
reported in four (0.8%) placebo-treated subjects vs. ®ve
(1.0%) nizatidine-treated subjects.
No pattern of adverse experiences suggesting drug
interaction was found among subjects who were taking
commonly used chronic medications, such as anti-
hypertensives, beta-adrenergic antagonists, inhaled cor-
ticosteroids, theophylline and selective serotonin
reuptake inhibitors.
DISCUSSION
Heartburn is a common disorder. More than 60 million
American adults suffer from heartburn at least once a
month, and approximately 25 million adults suffer daily
from heartburn.12 While heartburn is not a serious
malady, it can have a decidedly negative impact on the
quality of life of those who suffer from it. Nizatidine,
75 mg, has been shown to be effective in the prevention
of episodic heartburn.11 The clinical studies reported
here established the ef®cacy of nizatidine in the relief of
meal-induced heartburn.
The primary ef®cacy variable, the sustained adequate
relief score, is a derived response pro®le that combines
measures of speed, adequacy and sustaining of relief,
thus providing a single measure of a combination of
characteristics of importance to the consumer suffering
from heartburn. In these analyses, the sustained
adequate relief score was averaged over a subject's ®rst
four episodes to give a more precise estimate of the
subject's response than could be obtained from a single
episode. Using this parameter to assess ef®cacy, nizati-
dine demonstrated superiority to placebo in providing
sustained, adequate relief in episodic heartburn.
For some subjects, nizatidine's effectiveness was not
limited to simply adequate relief of heartburn. It also
provided complete relief signi®cantly more often than
did placebo, both in terms of the mean proportion of
episodes completely relieved, 74% for nizatidine-treated
subjects compared with 64% for placebo-treated sub-
jects, and in the proportion of subjects with complete
relief at all their episodes. Over one-third (37%) of the
nizatidine-treated subjects experienced complete relief at
all episodes, while this was true for less than one-
quarter (24%) of placebo-treated subjects, also a
signi®cant difference. To ensure that the results were
not in¯uenced by a carry-over effect between episodes,
treatment effects were assessed on episodes 12 h apart.
Nizatidine's effectiveness was undiminished. Galmiche
et al.13 compared the ef®cacy of over-the-counter doses
 1576 K. PAUL et al.
of cimetidine (200 mg) and ranitidine (75 mg) with
placebo in the relief of heartburn among subjects similar
to those in these studies. Their primary ef®cacy end-
point was the proportion of subjects who experienced
relief of at least 75% of their heartburn episodes. The
difference observed between each active treatment and
placebo was about 10%. This appears to be comparable
to the differences noted in these studies for the mean
proportion of episodes completely relieved, suggesting
that this is the range of symptom relief available with
over-the-counter doses of H2-receptor antagonists.
A rather marked placebo effect was noted in these
studies, especially compared with that seen in a nizati-
dine prevention study.10 Factors contributing to this
placebo effect could be the different ef®cacy assessments,
i.e. prevention vs. relief, and the study setting. While
these studies were carried out at home, the prevention
study was conducted in a controlled, clinical setting,
probably using more heartburn-provoking meals.
The ef®cacy of treatment with another H2-receptor
antagonist, famotidine, was evaluated in a similar
1 at-home study.14 Simon et al. conducted a double-
blind, randomized, placebo-controlled, parallel group
study of self-directed treatment for episodic heartburn
comparing famotidine, 5, 10 or 20 mg, and antacid
2 (11 mmol ANC [acid neutralizing capacity]) with
placebo. Treatment in an at-home setting was allowed
as needed, up to two episodes daily. After treating an
episode, subjects assessed heartburn relief hourly and
recorded the use of backup antacid. The 10 mg dose
(the over-the-counter dose) is that of greatest interest
with respect to our studies. Comparison of the studies
3 reported here with that of Simon et al. is made
problematic by the fact that the ef®cacy scoring was
different. In the famotidine study, the analysis that
incorporated time used complete relief as the scoring
assessment. In contrast, in the nizatidine studies, the
analysis that incorporated time used sustained ad-
equate relief (Figure 1). This may explain the some-
what higher scores reported for nizatidine. Forty per
cent of episodes were relieved at 1 h, 55% at 2 h and
70% at 3 h in the famotidine study. In the nizatidine
studies, 70% were relieved at 1 h, 77% at 2 h and
76% at 3 h.
Twenty-six per cent of treated episodes required
backup antacid in the famotidine study compared with
20% of treated episodes in the nizatidine studies. In the
famotidine study, subjects were permitted to use antacid
if relief was inadequate at any time after 1 h, in contrast
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1571±1577
to the nizatidine studies in which antacid was allowed
only after 2 h. This difference in timing may account for
the difference in antacid use.
The previously established safety of nizatidine, 75 mg,
was con®rmed by the studies reported here. A summary
of adverse experiences over the dose range of nizatidine
administered in the over-the-counter development pro-
gramme underscores the tolerability of this product.
Furey et al.15 summarized the adverse experiences of
nizatidine-treated subjects across 11 trials (1679 sub-
jects) that evaluated nizatidine, 25, 75 or 225 mg, in
the prevention of meal-related heartburn. One hundred
and seventy-eight nizatidine-treated subjects (10.6%)
and 84 (15.1%) placebo-treated subjects reported an
adverse experience in these studies. Headache was the
most frequently reported adverse experience among
both nizatidine-treated subjects (2.6%) and placebo-
treated subjects (3.8%).
These studies evaluated the ef®cacy and safety of
nizatidine, 75 mg, in relieving episodic heartburn,
when taken as needed up to twice daily, compared
with placebo. The results demonstrated that subjects
taking nizatidine had heartburn relief that was achieved
faster and/or more reliably and more completely than
did subjects taking placebo. The safety pro®le associated
with the use of nizatidine for the treatment of heartburn
was similar to that seen in studies for the prevention of
heartburn. In these studies, nizatidine was used safely
and was not associated with any serious adverse
experiences, contraindications or drug interactions.
ACKNOWLEDGEMENTS
These studies were supported by a grant from White-
hall-Robins Healthcare, Madison, NJ, USA.
We gratefully acknowledge the assistance of Elizabeth
C. Foulds with the statistical analyses.
REFERENCES
1 Evans DC, Ruffolo RR, Warrick MW, Lin TM. Speci®c hista-
mine (H2-receptor) antagonist actions of nizatidine. Fed Proc
1984; 43: 1074.
2 Lin TM, Evans DC, Warrick MW, Ruffolo RR, Jr. Actions of
nizatidine on the rat uterus, dog stomach and experimentally
induced gastric lesions. J Pharmacol Exp Ther 1986; 239:
400±5.
3 Linscheer WG, Raheja KL, Hirose N. A double-blind controlled
study proves nizatidine to be much more potent than cimeti-
dine (Abstract). Gastroenterology 1985; 88(5): 1478.
 NIZATIDINE, 75 MG, FOR EPISODIC HEARTBURN
4 Vargas R, Ryan J, McMahon FG, Regel G, Offen WW,
Matsumoto C. Pharmacokinetics and pharmacodynamics of
oral nizatidine. J Clin Pharmacol 1988; 28: 71±5.
5 Nebel O, Fornes MF, Castell DO. Symptomatic gastroesopha-
geal re¯ux disease: incidence and precipitating factors. Am J
Digest Dis 1976; 21(11): 953±6.
6 Robinson MD. Gastroesophageal re¯ux diseaseÐselecting
optimal therapy. Postgrad Med 1994; 92(2): 88±94, 99±102.
7 Baldi F, Ferranini F, Longanest A, Ragazzini M, Barbara L.
Acid gastroesophageal re¯ux and symptom occurrence. Digest
Dis Sci 1989; 34: 1890±3.
8 Bell NJV, Hunt RH. Role of gastric acid suppression in the
treatment of gastro-esophageal re¯ux disease. Gut 1992; 33:
118±24.
9 Product Information Axid. Physicans' Desk Reference, 52nd
4 edn. Montvale, NJ: Medical Economics, 1998: 1439.
10 Lynn RB, Norry EC, Katz LC, Spiegel JE, Castell DO. Nizatidine
reduces meal induced gastroesophageal re¯ux (GER): a ran-
domized, placebo controlled, double-blinded, 4-way crossover
study. Gastroenterology 1995; 108(Suppl.): A-154790.
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1571±1577
1577
11 Spiegel JE, Thoden WR, Pappas K, Fratarcangelo P, Furey SA.
A double-blind, placebo-controlled study of the effectiveness
and safety of nizatidine in the prevention of postprandial
heartburn. Arch Intern Med 1997; 157: 1594±9.
12 Gastroesophageal re¯ux disease (hiatal hernia and heart-
burn). National Institutes of Health Publication no. 94-882.
Bethesda, MD: National Institute of Diabetes and Digestive and
5 Kidney Diseases, 1994.
13 Galmiche JP, Shi G, Simon B, Casset-Semanaz F, Slama A.
On-demand treatment of gastro-oesophageal re¯ux symptoms:
a comparison of ranitidine 75 mg with cimetidine 200 mg or
placebo. Aliment Pharmacol Ther 1998; 12: 909±17.
14 Simon TJ, Berlin RB, Gardner AH, et al. Self-directed treatment
of intermittent heartburn: a randomized, multicenter, double-
blind, placebo-controlled evaluation of antacid and low doses
of an H2-receptor antagonist (famotidine). Am J Ther 1995; 2:
6 304±3.
15 Furey SA, Thoden WR, Spiegel JE. Side-effect pro®le of non-
prescription nizatidine in the prevention of meal-related
heartburn. J Clin Pharmacol 1997; 37(9): 861(Abstract).