ORIGINAL RESEARCH ARTICLE

Efficacy, Safety, and Tolerability of Pantoprazole Magnesiumin the Treatment of Reflux Symptoms in Patientswith Gastroesophageal Reflux Disease (GERD): A Prospective,Multicenter, Post-Marketing Observational Study

Jose Marıa Remes-Troche • Sergio Sobrino-Cossıo • Julio Cesar Soto-Perez •

Oscar Teramoto-Matsubara • Miguel Morales-Arambula • Antonio Orozco-Gamiz •

Jose Luis Tamayo de la Cuesta • Gualberto Mateos

Published online: 18 December 2013

� Springer International Publishing Switzerland 2013

Abstract

Background To improve proton pump inhibitor effects,

pharmacological modifications have been developed such

as the use of enantiomer molecules (e.g., S-omeprazole,

S-pantoprazole, or dexlansoprazole), or addition of

NaHCO3 (for an immediate release) or magnesium (with a

lower absorption for a more sustained effect).

Objective The objective of this study was to assess the

efficacy, safety, and tolerability of pantoprazole magne-

sium 40 mg once daily for 4 weeks, on the relief of reflux

symptoms in gastroesophageal reflux disease (GERD)

patients.

Methods A phase IV, open-label, prospective, multicen-

ter study was designed. Patients included were prescribed

pantoprazole magnesium 40 mg orally once daily for

28 ± 2 days. All patients had a history of persistent or

recurrent heartburn and/or acid regurgitation for at least

3 months. Effectiveness and tolerability data obtained from

patients who completed a minimum of 4 weeks of pan-

toprazole magnesium treatment were considered for

analysis.

Results The account of baseline characteristics and

demographics of GERD symptom intensity was made by

analyzing the group of 4,343 patients that fulfilled all

inclusion criteria; 54 % were females (n = 2,345) and

46 % (n = 1,998) males, with a mean age of

36.2 ± 7.5 years. Severity of symptoms, assessed by the

physician using the 4-point Likert scale, reduced by at least

80 % from baseline intensity after treatment in the per

protocol population. In the case of the intention-to-treat

population, the improvement in symptom intensity was

73 %. The number of patients that experienced any adverse

events was 175/5,027 (3.48 %).

Conclusions Pantoprazole magnesium is a safe, effective,

and well-tolerated drug that significantly improves GERD

symptoms.

J. M. Remes-Troche (&)

Digestive Physiology and Motility Lab, Instituto de

Investigaciones Medico Biologicas, Universidad Veracruzana,

Iturbide SN. Col Centro, Veracruz, VER 91400, Mexico

e-mail: jose.remes.troche@gmail.com; joremes@uv.mx

S. Sobrino-Cossıo

Hospital Angeles del Pedregal, Servicio de Endoscopia, Instituto

Nacional de Cancerologıa, Mexico City, Mexico

J. C. Soto-Perez

Clınica de Fisiologıa Digestiva del Hospital Metropolitano,

Servicio de Gastroenterologıa y Endoscopia del Hospital Central

Sur de Alta Especialidad PEMEX, Mexico City, Mexico

O. Teramoto-Matsubara

Unidad de Gastroenterologıa y Motilidad Palmas, Mexico City,

Mexico

M. Morales-Arambula

Unidad de Gastroenterologıa Hospital Privado, Guadalajara,

JAL, Mexico

A. Orozco-Gamiz

GastroLab, Guadalajara, Jalisco, Mexico

J. L. Tamayo de la Cuesta

Hospital Civil de Culiacan CIDOCS, Hospital Angeles Culiacan,

Culiacan, Sinaloa, Mexico

G. Mateos

Hospital Angeles del Pedregal, Mexico City, Mexico

Clin Drug Investig (2014) 34:83–93

DOI 10.1007/s40261-013-0135-4

1 Introduction

Gastroesophageal reflux disease (GERD) is one of the most

frequent causes for seeking medical care, both in general

and gastroenterology practice [1, 2]. The significance of

this illness is based on its high prevalence and on the

potential consequences that it may have both in the short-

and long-term. Proton pump inhibitors (PPIs), which are

benzimidazole and imidazopyridine derivatives, have

changed the natural history of acid-related disorders (peptic

ulcer, erosive gastropathy, and GERD) [3, 4]. During the

last two decades, the superiority of PPIs over other drugs

(antacids, prokinetics, and histamine H2-receptor antago-

nists) has been established beyond doubt by many phar-

macological studies and large clinical trials [5, 6].

Today, PPIs are considered to be the mainstay of anti-

reflux medical therapy and are extensively prescribed, not

only by gastroenterologists but also by non-gastrointestinal

specialists such as cardiologists, pneumologists, or otorhi-

nolaryngologists [5–7]. While all of the PPIs are effective

in the long-term, studies have shown variable rates in

intragastric pH control and symptomatic response in the

short-term [8–10]. The decision of choosing a PPI should

be based on efficacy, safety, tolerability, quality of life,

pharmacogenomics, and cost effectiveness [8–11].

In the evolution of PPIs, omeprazole was the first PPI

molecule available (1989) [12]. Lansoprazole (1995), rab-

eprazole (1999), and pantoprazole (2000) were subse-

quently introduced in the market [13]. With the objective

of improving PPI effects, pharmacological modifications

have been developed such as the use of enantiomer mole-

cules (e.g., S-omeprazole, S-pantoprazole, or dexlansop-

razole), or addition of NaHCO3 (for an immediate release)

or magnesium (with lower absorption for a more sustained

effect) [14]. Delayed-release formulations such as encap-

sulated enteric-coated granules or tablets (omeprazole,

pantoprazole, rabeprazole, and dexlansoprazole) have also

been used for a more prolonged effect by making them dual

or multiple formulations so that the active substance,

irrespective of the dose, is available for absorption for an

extended period of time [12, 14, 15].

Pharmacokinetic analyses indicate that the elimination

half-life of pantoprazole magnesium is 23 % longer than

that of pantoprazole sodium [16]. These differences in

pharmacokinetic parameters are likely due to the slow

dissolution of the magnesium-containing tablets in the

stomach, resulting in reduced solubility. In a double-blin-

ded, randomized, controlled multicentric trial (n = 636),

Hein [17] found that pantoprazole magnesium is clinically

as effective and well-tolerated as pantoprazole sodium in

the treatment of GERD stages I–III, demonstrating non-

inferiority for esophageal healing at 8 weeks and superior

healing rates at 4 weeks associated with high levels of

symptomatic relief.

Although there are slight differences in the pharmaco-

kinetics of pantoprazole sodium and pantoprazole magne-

sium, their pharmacodynamic features and safety profiles

are similar, and showed no apparent qualitative or quanti-

tative differences in the toxicity or drug–drug interaction

profiles of the two formulations [17]. It is important to

remark that, recently, several studies have reported the

possible interaction of clopidrogel and PPIs leading to a

decrease in the antiplatelet efficacy of clopidrogel [18].

However, pantoprazole is a PPI not associated with the

decrease in the antiplatelet efficacy of clopidrogel [19].

The primary objective of this study was to assess the

efficacy, safety, and tolerability of Tecta� (Nykomed,

Mexico City, Mexico) [pantoprazole magnesium 40 mg

orally, once daily for 4 weeks] on the relief of reflux

symptoms (i.e., heartburn, acid regurgitation, epigastric

pain, night-time epigastric discomfort, etc.) in GERD

patients. Also, as part of the study, the usefulness of the

self-administered reflux symptom questionnaire ReQuest�

(Spanish version) was assessed in Mexican patients

[20, 21].

2 Methods

A phase IV, open-label, prospective, observational,

descriptive, multicenter study was designed. It was carried

out according to the observational or non-interventional

clinical study definition described in Directive 2001/20/EC

[22], and its follow-up was carried out in accordance with

the good clinical and epidemiological practice guidelines.

The main feature of this kind of study is that all patients

receive the study medication, which allows investigation of

what happens in daily practice. This study was approved by

the Ethical Committee of Research of the Dr. Maximiliano

Ruiz Castaneda General Hospital of Naucalpan, and the

Center of Bioethics of the Medicine Faculty of the Uni-

versity of Guanajuato, Mexico.

The study medication was pantoprazole magnesium

40 mg (Tecta�), which was given according to the product

prescribing information approved by the local health

authorities. Patients participating in this study were pre-

scribed pantoprazole magnesium 40 mg orally once daily

for 28 ± 2 days. As shown in Table 1, the study comprised

two visits in total: V0—in which patients were screened

and enrolled in the study; and V1—the study’s final visit.

The procedures performed on each visit are described in

Table 1.

84 J. M. Remes-Troche et al.

2.1 Patient Population

2.1.1 Inclusion Criteria

Prior to their inclusion in the study, patients signed and

dated the informed consent together with two witnesses

and the investigator. In order to participate in the study,

male and female outpatients, between the ages of 18 and

50 years old, fulfilling the following clinical criteria were

included: (a) history of persistent or recurrent episodes

(three or more episodes per week) of heartburn and/or acid

regurgitation for at least 3 months, not necessarily con-

secutive, within the last 12 months, and with one or more

of the following related symptoms: burping, belching,

water brash, globus (feeling of a lump in the esophagus),

dysphagia, odynophagia, retching, early satiety, nausea,

retrosternal pain, dysphonia or hoarseness; and (b) found to

have no evidence of structural disease likely to explain

their symptoms, using the alarm signs referred to below

and/or according to endoscopy findings. Endoscopy was

performed in patients according to the investigator criteria

to exclude organic disease or in cases with long-standing

symptoms (more than 5 years).

2.1.2 Exclusion Criteria

The following exclusion criteria were applied during the

patients’ initial visit: (a) patients with suspected or con-

firmed alarm signs related to their illness (e.g., progressive

and/or chronic dysphagia, persistent odynophagia, invol-

untary weight loss, anorexia, anemia, palpable nodules or

mass, fever of unknown etiology, gastrointestinal bleeding,

etc.) within 3 months prior to study start; (b) suspected or

confirmed esophageal strictures, grade C or D esophagitis

from the Los Angeles classification, diverticula or varices,

achalasia or Barrett’s esophagus; (c) patients with a history

of peptic ulcer and/or its complications (e.g., bleeding,

strictures, etc.); (d) patients with previous esophageal/

upper gastrointestinal surgery (exception: cholecystec-

tomy); (e) patients with a history of Zollinger-Ellison

syndrome or other gastric hypersecretory condition;

(f) cardiovascular (e.g., angina pectoris, myocardial

infarction, ventricular extrasystoles), pulmonary, endo-

crine, renal or hepatic disease, hematological disorders, or

any other medical condition that could increase the risk to

participating patients; (g) malignant disease of any kind in

any system or organ; (g) pregnant or nursing women; and

(h) women of childbearing potential who had not been

using a reliable and clinically acceptable birth control

method (e.g., intrauterine contraceptive device, oral or

injectable contraceptives) within at least 3 months.

The following restrictions were applied regarding pre-

vious medications: (a) PPIs within 14 days prior to study

start; (b) H2-receptor antagonists or prokinetics within

7 days prior to study start; and (c) history of treatment for

Helicobacter pylori eradication within 28 days prior to

study start.

2.2 Dosing Regimen

All patients participating in the study received two boxes of

pantoprazole magnesium 40 mg during their initial visit

(V0), each containing two cardboard wallets scheduled for

every day of the week, each of them wrapped an aluminum

blister which in turn contained seven tablets of pantop-

razole magnesium 40 mg.

Table 1 Study schedule and

recorded parameters

CRF clinical research form,

GERD gastroesophageal reflux

disease

Parameter Visit 0 (day 0) Visit 1 (day

28 ± 2 days)

Verification of the inclusion/exclusion criteria X

Signed informed consent X

Demographic data X

Complete medical history X X

GERD symptom assessment by the investigator X X

Complete general physical examination X X

Concomitant medications X X

Endoscopic procedure (optional/at the discretion of the investigator) X

Dispensing of study medication to the patient X

Dispensing of the ReQuest� and use instructions to the patient X

Treatment compliance evaluation X

Complete evaluation of adverse events X

Collection of boxes and blisters of study medication X

Return of CRF and questionnaires X

Pantoprazole Magnesium in Symptomatic GERD 85

2.3 Study Protocol

During the initial visit (V0), participating physicians

assessed the inclusion and exclusion criteria so as to decide

whether or not a patient should be invited to participate in

the study. Once a patient was assessed as eligible, the

investigator explained the Informed Consent contents to

the patient who voluntarily agreed to participate by signing

and dating the Informed Consent. Complete medical his-

tory and physical examination were performed, and

patients were asked if they had any illnesses concomitant to

the current disease and if they were or had been receiving

any treatment. All of the information provided by patients

was recorded in a clinical research form (CRF).

Regarding the current disease, which was the reason for

participating in this study, investigators asked questions on

the occurrence of typical and related GERD symptoms,

using a 4-point Likert scale (0 = none, 1 = mild or hardly

perceptible symptoms, with only slight general discomfort,

2 = moderate or clearly perceptible symptoms, but toler-

able without demanding immediate relief, and 3 = severe

or overwhelming discomfort, urging immediate relief).

To record the patient personal assessment of their

symptoms, they received and were instructed on the use of a

ReQuest� (‘‘Reflux Questionnaire’’) notebook for symptom

self-assessment. The questionnaire was completed at the

end of the day, daily from day 1 to 7 after the first dose, and

then at days 14, 21, and 28. Any doubts patients had were

clarified so properly assessed and recorded data could be

obtained. Investigators emphasized how important it was

that patients returned the notebook on their next visit.

ReQuest� is a self-administered questionnaire developed

and validated to assess the treatment effect on GERD

symptom evolution. This symptom measurement tool was

developed after countless reviews of the medical literature

on GERD and its symptoms, re-analyses of clinical trials,

participation of several worldwide expert gastroenterolo-

gists, and extensive interviews of GERD patients [21, 22]. A

total of 67 descriptions of typical and atypical gastroesoph-

ageal reflux symptoms were grouped in six different GERD

categories or dimensions: (1) dimension of acid-related

symptoms or complaints; (2) dimension of upper abdominal/

stomach symptoms or complaints; (3) dimension of lower

abdominal/digestive symptoms or complaints; (4) dimen-

sion of nausea; (5) dimension of sleep disturbances; and (6)

dimension of other symptoms or complaints [23]. To these

six dimensions, a last dimension was added: the general well-

being dimension. Each dimension was evaluated to validate

the frequency (by means of a 7-point Likert scale) and

intensity (by means of a 100-mm visual analog scale) of

every corresponding symptom, except for the general well-

being dimension, which was only evaluated for intensity.

Study medication was dispensed to patients and how and

for how long it was to be taken was explained. Patients

took their first dose in the presence of the investigator and

were asked to come back for their next visit (V1), during

which they had to return all boxes and blisters with any

remaining tablets, along with their ReQuest� symptom

assessment notebook.

During the patient final visit (V1), within 28 ± 2 days,

the following was performed: (a) complete general physi-

cal examination (including anthropometrics); (b) questions

on concomitant medication intake; (c) GERD symptom

assessment by the investigator (4-point Likert scale);

(d) treatment compliance evaluation through collection and

accountability of unused study medication; and (e) review

of the ReQuest� filled in by the patient.

2.4 Outcome Measurements

Effectiveness and tolerability data obtained from patients

who completed a minimum of 4 weeks of pantoprazole

magnesium treatment were considered for analysis. The

treatment response rate after 4 weeks was measured by

comparing symptom assessment (4-point Likert scale) and

ReQuest� scores at the end of treatment with baseline

scores.

An adverse event was defined as any untoward medical

occurrence in a patient, regardless of whether it was

considered to be causally related to use of the treatment.

An adverse event could therefore be any unfavorable and

unintended sign (including an abnormal laboratory find-

ing), symptom, or disease temporally associated with the

use of a medicinal product. Among laboratory findings,

liver function tests, glucose and creatinine determinations

were performed according to the physician criteria.

Adverse events data were collected throughout the study

and until 30 days after the last dose. At the end of the

study the medication was stopped All adverse events,

including symptoms, signs, or diseases, were evaluated.

Information recorded concerning the adverse events

occurring during the trial period included their nature,

whether serious or not, their intensity, any treatment

given, the outcome, and an opinion about the causal

relationship with the study medication. The incidence (%)

of adverse events was calculated and analyzed according

to the guidelines for statistical analysis issued by the Drug

Safety Department in Mexico (COFEPRIS, Mexico City,

Mexico). The seriousness of the adverse event and its

causal relationship with treatment were also tabulated.

Furthermore, information on adverse reactions, defined as

adverse events considered to be causally related to use of

the study drug, was recorded in detail. A list of all

adverse events was compiled.

86 J. M. Remes-Troche et al.

2.5 Statistical Analysis

Sample demographic characteristics were summarized

using descriptive statistics; for this purpose, percentages,

odds ratios (ORs), and 95 % confidence intervals were

calculated. The efficacy analysis was performed using a

multivariate analysis of covariance (MANCOVA) for

repeated samples; time was considered as the principal

related (nested) factor and fitted variables were patient sex,

age, body mass index (BMI), and place of residence.

Epsilon calculations were made in each model to determine

whether or not the assumption of sphericity was met, and if

not met the degrees of freedom were corrected using the

Huynh–Feldt or Greenhouse–Geisser method [24]. Cook’s

distances and leverage points were also analyzed to detect

multivariate outlier values. The correlation between

heartburn and regurgitation scores recorded on the Likert

scale (assessed by physicians/investigators) and those

recorded on the ReQuest� notebook (assessed by patients)

was calculated using two different approaches: Somer’s

d asymmetric measure of association between two vari-

ables and Spearman’s rho.

The software used for data management was SAS�

(Statistical Analysis Software, SAS Statistical Institute

Inc., Cary, NC, USA) version 9.1. For statistical analysis,

the software used was SPSS� (Statistical Package for

Social Sciences, IBM, Chicago, IL, USA) version 15 and

StatisticaTM (Statsoft, Tulsa, OK, USA) version 6.0.

3 Results

3.1 Population

A total of 5,092 patients were enrolled in the study from

1,306 practices around the country. Sixty-five subjects

were removed because they did not sign their Informed

Consent authorizing the use of collected data (Fig. 1).

The inclusion criteria to define this analysis population

was that patients had taken at least one dose of study

medication. This population included a total of 5,027

patients that were analyzed to obtain safety data and it was

designated the ‘‘safety intention-to-treat (ITT) population’’.

During analysis, 684 patients from this group were found to

be protocol violators as they had at least one exclusion

criterion in the enrollment visit (V0), e.g., the patient did

not have heartburn and/or regurgitation, the patient’s age

was outside of the protocol-defined age range, or the

patient had esophageal mucosal breaks grade C or D

according to the Los Angeles classification, as evidenced

by endoscopy data recorded on the CRF. After removing

the 684 patients classified as protocol violators, the efficacy

ITT population was conformed resulting in a total of 4,343

patients. These patients fulfilled all of the inclusion criteria,

but some had missing data. The last recorded observation

was used as if it had remained unchanged throughout the

study [last observation carried forward (LOCF) approach].

This was the ITT population used to measure the study

medication efficacy.

From the 4,343 patients included in the efficacy ITT

population, 678 (15.6 %) patients were removed from the

efficacy ITT analysis, leaving 3,665 in the efficacy per

protocol (PP) analysis (Fig. 2).

Fig. 1 Depletion of the database sample to form the safety and

efficacy intention-to-treat populations. ITT intention-to-treat

Fig. 2 Depletion of the efficacy intention-to-treat population to form

the efficacy per protocol population. Some patients were excluded for

more than one reason. ITT intention-to-treat, PP per protocol

Pantoprazole Magnesium in Symptomatic GERD 87

3.2 Demographics

The baseline characteristics and demographics of GERD

symptom intensity for the study sample were determined

by analyzing the group of 4,343 patients that fulfilled all

inclusion criteria. There were 54 % females (n = 2,345)

and 46 % (n = 1,998) males with a mean [± standard

deviation (SD)] age of 36.2 ± 7.5 years, and a BMI above

normal for both sexes (26.3 ± 4.3 kg/m2). At the time of

the clinical interview 6 % (n = 260) were smokers, while

4.1 % were declared to be ex-smokers.

3.3 Baseline Symptoms

Among atypical and extra-esophageal GERD symptoms,

upper abdominal/epigastric pain showed the highest prev-

alence (90.6 %) and was not sex-related. The second most

prevalent symptom was burping/belching (88.3 %), being

slightly predominant in men (OR = 1.32; p \ 0.003).

Subsequent symptoms that showed a lower but clinically

significant prevalence are shown in Table 2. Men showed a

higher probability of having chronic cough than women,

while women showed a higher probability of having globus

and retching than men.

The maximum number of GERD-related symptoms a

patient could have according to the CRF was 16 (sum of all

GERD-related symptoms), and approximately 7 % of the

patients had all these symptoms. On the other hand, 7 % of the

patients had only three or fewer GERD-related symptoms.

3.4 Endoscopy Findings

Endoscopy was performed in 917 patients (21 %), and

54 % were females (n = 495). The mean (± SD) age was

36.6 ± 7 years for males and 37.2 ± 7.2 (p \ 0.228) for

females. The BMI for males was higher than for females

(26.8 ± 3.5 vs. 25.2 ± 4.5; p \ 0.001), and males were

prone to have a BMI greater than 30 (OR = 1.94, 95 % CI

1.3–2.9). According to the Los Angeles classification, 197

(21 %) had non-erosions, 435 (47 %) had grade A esoph-

agitis, 235 (28 %) had grade B esophagitis, and 32 (4 %)

grades C–D.

3.5 Efficacy Analysis

Severity of symptoms assessed by the physician using the

4-point Likert scale had a reduction of at least 80 % from

baseline intensity after treatment in the PP population

(Table 3). In the case of the ITT population, the average

improvement for symptom intensity was 73 %.

Using the ReQuest�, percentage changes in improve-

ment of symptom intensity were highest at the end of the

first week: between 51 and 58 % for the PP population, and

between 37 and 45 % for the ITT population. From week 2

on, there was an additional improvement of 15–19 % for

the PP group, and 10–12 % for the ITT group (Table 4;

Figs. 3 and 4). These findings suggest that when a subject

complies with the treatment, a 71.56 % reduction is

expected in symptom intensity as measured by the

Table 2 Gastroesophageal reflux disease symptom frequency and sex-related odds ratio

Symptom Frequency [n (%)] M/F (n) OR for men 95 % CI p value

Burping 4,015 (88.3) 1,879/2,136 1.32* 1.10–1.59 0.003

Sialorrhea 2,164 (47.6) 974/1,190 0.93 0.83–1.04 0.204

Globus 2,553 (56.2) 1,115/1,438 0.81* 0.72–0.91 \0.001

Dysphagia 2,242 (49.3) 1,012/1,230 0.93 0.83–1.05 0.252

Odynophagia 1,718 (37.8) 762/956 0.90 0.80–1.01 0.083

Retching 1,727 (38.0) 734/993 0.80* 0.71–0.90 \0.001

Halitosis 2,663 (58.6) 1,231/1,432 1.02 0.91–1.15 0.712

Epigastric pain/discomfort 4,118 (90.6) 1,876/2,242 0.83 0.68–1.01 0.065

Early satiety 2,945 (64.8) 1,284/1,661 0.76* 0.67–0.86 \0.001

Nausea 3,088 (67.9) 1,280/1,808 0.57* 0.50–0.64 \0.001

Flatulence 2,830 (62.3) 1,315/1,515 1.05 0.93–1.19 0.414

Non-cardiac retrosternal pain/tightness 3,024 (66.5) 1,363/1,661 0.90 0.79–1.01 0.078

Dyspnea 1,136 (25.0) 501/635 0.90 0.79–1.03 0.139

Chronic cough 1,498 (33.0) 723/775 1.15* 1.01–1.30 0.031

Dysphonia 1,655 (36.4) 766/889 1.02 0.90–1.15 0.769

Sleep disturbances 2,902 (63.8) 1,316/1,586 0.93 0.82–1.05 0.244

ORs with an asterisk were statistically significant. If an OR value is\1 it means that women are at higher odds of having that symptom than men;

meanwhile, if an OR value is [1, men are at higher odds of having that symptom than females

F female, M male, OR odds ratio

88 J. M. Remes-Troche et al.

ReQuest�. Instead, a subject for whom it is unknown if he/

she will have treatment compliance of at least 85 %, will

have a 52 % reduction in symptom intensity as measured

by the ReQuest�.

The agreement between physician and patient assess-

ments of heartburn was analyzed. Since both scales are

asymmetric, Somer’s d (0.2; p \ 0.001) and Spearman’s

rho (q = 0.21; p \ 0.001) coefficients were used to ana-

lyze agreement correlation. Both measurements suggest a

poor correlation between these two variables.

3.6 Safety Analysis

The ITT population was considered for the safety analysis

as all of these patients took at least one dose of the study

medication. The number of patients that experienced any

events during the study was 175/5,027 (3.48 %) patients

with 232 adverse events. The most common adverse events

were diarrhea (0.57 %, n = 29), nausea (0.51 %, n = 26),

dizziness (0.33 %, n = 17), headache (0.31 %, n = 16),

and constipation (0.21 %, n = 11). The 232 reported

Table 3 Change in gastroesophageal reflux disease symptom severity from baseline to day 28 of the study, as assessed by physicians using an

ordinal Likert scale

Symptom n Baseline Day 28 p value Change (%)

Mean SEM Mean SEM

Heartburn 4,295 2.25 0.01 0.63 0.01 \0.0001 -72.03

Acid regurgitation 4,254 2.17 0.01 0.57 0.01 \0.0001 -73.70

Burping/belching 4,019 1.68 0.01 0.49 0.01 \0.0001 -70.75

Water brash/sialorrhea 3,442 0.91 0.02 0.22 0.01 \0.0001 -75.46

Globus 3,524 1.09 0.02 0.30 0.01 \0.0001 -72.48

Dysphagia 3,495 0.89 0.02 0.22 0.01 \0.0001 -74.87

Odynophagia 3,278 0.70 0.02 0.15 0.01 \0.0001 -78.38

Retching 3,299 0.70 0.02 0.18 0.01 \0.0001 -74.73

Halitosis 3,601 1.17 0.02 0.37 0.01 \0.0001 -68.19

Epigastric pain/discomfort 4,164 1.98 0.01 0.55 0.01 \0.0001 -72.18

Early satiety 3,655 1.35 0.02 0.37 0.01 \0.0001 -72.37

Nausea 3,775 1.23 0.02 0.31 0.01 \0.0001 -74.91

Flatulence 3,597 1.34 0.02 0.46 0.01 \0.0001 -65.84

Non-cardiac chest pain/tightness 3,672 1.37 0.02 0.32 0.01 \0.0001 -76.34

Dyspnea 3,157 0.50 0.02 0.14 0.01 \0.0001 -72.61

Chronic cough 3,320 0.66 0.02 0.18 0.01 \0.0001 -72.86

Dysphonia 3,315 0.69 0.02 0.18 0.01 \0.0001 -73.65

Sleep disturbances 3,726 1.35 0.02 0.38 0.01 \0.0001 -71.60

SEM standard error of the mean

Table 4 Change in the

ReQuest� dimensions from

baseline to day 7 and day 28 of

the study

Symptoms Evaluation period (days) Per protocol Intention-to-treat

General well-being 7 -56.36 -43.11

28 -75.20 -56.25

Acid complaints 7 -58.99 -45.23

28 -76.71 -57.23

Upper abdominal complaints 7 -57.96 -44.04

28 -75.01 -55.38

Lower abdominal complaints 7 -51.36 -37.78

28 -68.20 -49.07

Nausea 7 -52.33 -37.61

28 -67.62 -47.29

Sleep disturbances 7 -51.83 -37.49

28 -67.83 -47.99

Pantoprazole Magnesium in Symptomatic GERD 89

adverse events were classified into four categories: unre-

lated to treatment (n = 106), unlikely related to treatment

(n = 34), likely related to treatment (n = 72), and defini-

tively related to treatment (n = 20). The physician’s clin-

ical criterion was the most important factor for patient

classification. For study report purposes, only those adverse

events and patients with a likely and definitive relation are

described. From the evaluation of definitive and likely

causal relation, only 70/5,027 (1.39%) patients experienced

92 events that were causally related to study medication.

The most common related adverse effects were diarrhea

(0.27 %, n = 14), nausea (0.18 %, n = 10), constipation

(0.15 %, n = 8), dizziness (0.13 %, n = 7), and headache

(0.13 %, n = 7).

4 Discussion

In this large, multicentric, observational study we found

that pantoprazole magnesium 40 mg once daily for

4 weeks is effective, safe, and well-tolerated in GERD

patients. Furthermore, patients experienced a significant

relief of both typical and atypical GERD symptoms, and

this symptomatic relief was obtained during the first 7 days

of treatment and sustained during the following weeks.

Today, although the efficacy of PPIs with a once-daily

dosing regimen is well-recognized and widely recom-

mended, one-quarter to one-third of GERD patients remain

symptomatic [25, 26]. Several factors are associated to PPI

failure, some of them related to the patient (inappropriate

taking of the dose or psychological co-morbidity) and

others related to the drugs [25, 27]. For example, persistent

symptoms may be in part because there is effectively no

circulating PPI present at the end of the 24-h interval,

which may lead to breakthrough symptoms, most notably

nocturnal heartburn, which can be difficult to treat with the

standard once-daily dosing of conventional PPIs [28]. In

our study, at baseline up to 64 % of patients with GERD

had sleep disturbances and one-third at least one of the

extra-esophageal manifestations of GERD such as chronic

cough or dyspnea.

Fig. 3 Changes in the general well-being score for per protocol and

intention-to-treat populations; the lower the value, the greater the

well-being. The Y axis shows symptom intensity score by ReQuest�.

The graph shows mean scores. ITT intention-to-treat, PP per protocol

Fig. 4 Changes in a acid

complaints, b upper and c lower

abdominal complaints, and

d nausea scores for per protocol

and intention-to-treat

populations; the lower the

value, the greater the well-

being. The Y axis shows

symptom intensity score by

ReQuest�. The graph shows

mean scores. ITT intention-to-

treat, PP per protocol

90 J. M. Remes-Troche et al.

One of the strategies to increase PPI efficacy include use

of magnesium formulations such as in esomeprazole,

omeprazole or, more recently, pantoprazole [17]. Pantop-

razole magnesium has a prolonged elimination half-life

compared with pantoprazole sodium; these differences in

their pharmacokinetic parameters are likely due to the slow

dissolution of the magnesium-containing tablets in the

stomach, resulting in reduced solubility which may result

in longer gastric acid suppression for day-time and night-

time symptom control, as is shown in our study. In the

study by Hein [17], pantoprazole magnesium was as

effective as pantoprazole sodium for healing esophageal

erosions at 8 weeks but better at 4 weeks. Also, in this

study more patients experienced relief across a broad range

of symptoms, like in our study.

Because of the large sample size and the multicentric

nature of our study, assessment of healing was very diffi-

cult. However, we decided to use symptomatic relief as our

main goal based in the fact that up to 60 % of patients had

non-erosive GERD and, most importantly, we wanted to

show the effect of pantoprazole magnesium in a real-life

setting. Also, it is important to remark that effectiveness

was based on symptomatic relief using well-validated

methods: severity of symptoms assessed by the physician

and changes in the ReQuest� [21–23]. This provides

independent scores for symptom severity changes. It is

important to stress that there was no correlation between

the symptom intensity assessed by physicians/investigators

and that assessed by patients, and despite this lack of

agreement, both assessing groups showed improvement in

symptom severity. This fact reinforces that the use of

pantoprazole 40 mg once daily significantly reduces

symptom intensity.

Using both the ReQuest� and physician assessments we

found that the average improvement for symptom intensity

ranged between 70 and 80 % for global assessment as well

as for acid complaints, upper and lower abdominal symp-

toms, nausea, and sleep disturbances. It should be noted

that using the ReQuest�, percentage changes in improve-

ment of symptoms intensity were highest at the end of the

first week; thus, it seems that pantoprazole magnesium

provided a rapid but sustained effect for control of GERD-

related symptoms. These results are similar to those

reported by Hein [17].

The high rates of early symptom relief observed with

pantoprazole magnesium in the current study make it a

good alternative to other PPIs for the successful manage-

ment of GERD and important for maintaining patient sat-

isfaction, especially when night-time symptoms are present

[17, 29]. Our findings support that the waning of acid

inhibition at night is due to the prolonged elimination half-

life reported for pantoprazole magnesium.

PPIs are widely used in clinical practice. However,

recently several concerns have been expressed about their

long-term use, particularly with regard to bone health,

hypomagnesaemia, Clostridium difficile infections, and

drug interactions with platelet aggregation inhibitors [18,

30–33]. Among all of the side effects and interaction of

PPIs, the clopidrogel–PPI interaction is the more contro-

versial and life-threatening. Rising evidence suggests that

the bleeding reduction benefit outweighs the possible

adverse cardiovascular risk in patients with an indication

for PPI treatment taking dual antiplatelet treatment [30,

33]. However, in vitro and in vivo studies have provided

direct evidence that PPIs inhibit clopidrogel metabolic

activation and suggest that cytochrome P450 (CYP) 2C19

inhibition is the main cause of drug–drug interaction

between clopidrogel and PPIs [32, 33]. Most retrospective

cohort studies and studies using platelet markers found a

significant association between PPI use, especially ome-

prazole, and decreased efficacy of clopidrogel, while few

comparative trials using clinical outcomes found no asso-

ciation between the same [30–33]. Among all of the PPIs,

pantoprazole is a weak inhibitor of CYP2C19 and has less

effect on the pharmacological activity of clopidrogel than

omeprazole, and has not been associated with a decrease in

the antiplatelet efficacy of clopidrogel. Thus, pantoprazole

is considered the safest PPI.

In this study, we found that pantoprazole magnesium is

a well-tolerated and safe drug, with no unexpected adverse

drug reactions and a safety profile similar to that expected

from preclinical data [17]. Also, given its pharmacody-

namics and pharmacokinetic profile, its safety profile is

similar to pantoprazole sodium. A definitive and likely

causally related adverse effect was reported in 1.39 % of

patients and these were those also reported with pantop-

razole sodium and other PPIs: diarrhea, nausea, constipa-

tion, dizziness, and headache.

Recently, hypomagnesemia has been reported in adult

patients taking PPIs for at least 3 months, but most cases

occurred after a year of treatment [30, 31]. No cases of

hypomagnesemia have been reported in our database to

date.

A main limitation of our study was that in only 21 % of

the cases was endoscopy performed according to the

investigator criteria, thus a selection bias is obvious.

However, as mentioned previously, our main goal was to

assess the efficacy of pantoprazole magnesium in symp-

tomatic GERD, and not the healing rates for erosive

GERD. Also, even when endoscopy was not performed, the

probability for structural disease in the absence of alarm

signs in a cohort with a mean age of\50 years (mean age

37 years) is very low [34]. Another limitation of our study

was the short duration of treatment, because an 8-week

Pantoprazole Magnesium in Symptomatic GERD 91

course of a PPI is the therapy of choice for symptom relief

and healing of esophagitis [34].

5 Conclusion

In this study we found that pantoprazole magnesium

dehydrate 40 mg once daily for 4 weeks significantly

improves GERD symptoms. The effectiveness was

observed during the first 7 days and was sustained along

the 4 weeks of treatment. Treatment effects were not

restricted to acid complaints but occurred in all dimensions

evaluated. We also found that pantoprazole magnesium is

safe and well-tolerated in GERD patients.

Acknowledgments The current study was sponsored by Nykomed,

Mexico. Nykomed did not participate in the writing of this article or

in the decision to submit the article for publication. Jose M. Remes-

Troche has received consultancy honoraria from Takeda, Janssen, and

AstraZeneca. Antonio Orozco-Gamiz has worked as a speaker for

Takeda, GlaxoSmithKline, and Bristol-Myers Squibb. Julio Cesar

Soto-Perez, Oscar Teramoto-Matsubara, Gualberto Mateos, Sergio

Sobrino-Cossıo, Miguel Morales-Arambula, and Jose Luis Tamayo de

la Cuesta have no conflicts of interest that are directly relevant to the

content of this study.

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Pantoprazole Magnesium in Symptomatic GERD 93