MODULE 5

TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

REGISTRATION DOSSIER
OF
TAHAZOLE
(Pantoprazole Sodium Delayed-Release
Tablets USP 40 mg)
FOR
Zanzibar Food And Drugs Agency

SUBMITTED BY
TAHA HEALTHCARE PHARMACY
NO 7, OPP TO CHUKWANI BUS STOP,
CHUKWANI ZANZIBAR UNGUJA (W)
TANZANIA

MANUFACTURER
East African (India) Overseas
Plot No. 1, Pharmacity,
Selaqui, Dehradun, India
www.earindia.com
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

MODULE - 5

TAHAZOLE
CLINICAL STUDY REPORTS
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.1 TABLE OF CONTENTS

SECTION TITLE Page No.

Module 5 : CLINICAL STUDY REPORTS
5.1 Table of Contents of Module 5
5.2 Tabular Listing of All Clinical Studies
5.3 Clinical Study Reports
5.3.1 Reports of Biopharmaceutic Studies
Reports of Studies Pertinent to Pharmacokinetics using
5.3.2
Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.4 Reports of Human Pharmacodynamic (PD) Studies
5.3.5 Reports of Efficacy and Safety Studies
5.3.6 Reports of Post-Marketing Experience if available
5.3.7 Case Report Forms and Individual Patient Listings
5.4 Literature References
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.2 TABULAR LISTING OF ALL CLINICAL STUDIES

CLINICAL STUDY REPORT

TITLE OF STUDY FINDING
Bioavailability of mycophenolate In contrast, pantoprazole does not change the
mofetil and enteric-coated pharmacokinetics of enteric-coated mycophenolate
mycophenolate sodium is sodium. Given that mycophenolic acid exposure correlates
differentially affected by with the incidence of biopsy-proven acute rejections in
pantoprazole in healthy volunteers.(1) renal transplant recipients, these findings may have
clinical implications. Administration of pantoprazole in
combination with mycophenolate mofetil could possibly
result in an insufficient mycophenolic acid exposure,
increasing the risk of treatment failure..
Proton pump inhibitor pantoprazole The addition of PPZ reduced the relative expression of
inhibits the proliferation, self ‑ CSC markers and anti-drug markers accompanied by a
renewal and of decrease in proliferation, 5-FU chemoresistance and
chemoresistance
gastric cancer stem cells via the self-renewal capacity via epithelial-mesenchymal

EMT/β‑catenin pathways (2 transition (EMT)/β-catenin pathways. The study suggests

that PPZ could be a promising novel specific therapeutic
strategy for targeting GC CSCs.
Bioavailability of a crushed the crushed tablet buffered with sodium
pantoprazole tablet after buffering hydrogencarbonate was shown to be bioequivalent with
with sodium hydrogencarbonate or the intact tablet (point estimates for AUC or Cmax: 0.93 or
magaldrate relative to the intact 1.10). For the crushed tablet buffered with magaldrate
enteric coated pantoprazole tablet.(3) (point estimates for AUC or Cmax: 0.88 or 1.12)
bioequivalence with the intact tablet could not be formally
demonstrated, although the lower confidence limit for
AUC of 0.78 was only slightly below the lower limit of
the equivalence range of 0.80
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

Oral bioavailability of pantoprazole The suspension yielded pantoprazole Cmax values similar
suspended in sodium bicarbonate to those of the tablet formulation, but the drug was 25%
solution.(4) less bioavailable. There was no lag time for the
suspension. The suspension was stable for up to two
weeks at 5 degrees C and up to three months at -20
degrees C. A suspension of pantoprazole in sodium
bicarbonate solution yielded a Cmax similar to that of the
tablet formulation, and the drug was quickly absorbed.
However, bio-availability was slightly lower with the
suspension than with the tablet
Twenty-four-hour intragastric pH As compared to the first dose, repeated administration of
profiles and pharmacokinetics both drugs markedly increased the effect on intragastric
following single and repeated oral pH. With pantoprazole, steady-state serum concentrations
administration of the proton pump were obtained after the first dose, but not with omeprazole.
inhibitor pantoprazole in comparison Both drugs were well tolerated without relevant changes in
to omeprazole.(5) vital signs of clinical laboratory parameters
Bioequivalence of two enteric coated However, the data for lnCmax (0.51-0.76) and lnAUC(0-
formulations of pantoprazole in t) (0.68-0.90) under fed condition were not within the
healthy volunteers under fasting and bioequivalence range. The postprandial study
fed conditions (6) demonstrated a high intra-subject variability and in some
subjects pantoprazole could not be detected for up to 24
h, although the dissolution profile of reference and test
formulations presented a similar disposition in FaSSIF
and FeSSIF as confirmed by the values of f2 higher than
50
Comparative bioavailability study The limit of quantification was 5 ng/mL for plasma
with two pantoprazole delayed- pantoprazole analysis. The geometric mean and 90%
released tablet formulations confidence interval CI of test/reference percent ratios
administered with and without food were, without and with food, respectively: 104.6540%
in healthy subjects. (7) (90.8616%-120.5401%) and 99.9708% (90.9987%-
109.8275%) for C(max), 95.6634% (85.2675%-
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

107.3267%) and 89.3500% (83.6630%-95.4237%) for

AUC(last).
Comparison of the coating process The increase in the pantoprazole release rate occurred not
and in vitro dissolution of 3 mm only due to the application of a thinner film but also due to
gastro-resistant minitablets and 5 the reduction in the size of the core independent of the
mm gastro-resistant tablets with coating apparatus that was used. In contrast to minitablets,
pantoprazole.(8) the thin film's thickness was insufficient for 5 mm tablets
and a loss of gastro-resistance was observed. The insertion
of minitablets into a hard gelatine capsule did not affect
drug release from the minitablets under in vitro conditions
Validation of a novel, fully automated The chromatographic run time was set at 1.8 min with a
high throughput high-performance flow rate of 0.6 mL/min on a Nucleosil octylsilyl (C8)
liquid chromatographic/tandem mass analytical column. The method was proven to be sensitive,
Spectrometric method for specific, accurate, and precise for the determination of
quantification of pantoprazole in pantoprazole in human plasma. The method was applied to
human plasma.(9) a bioequivalence study after per os administration of a 40
mg pantoprazole gastric retentive tablet.
Differential pulse anodic The limit of detection and limit of quantitation were found
voltammetric determination of to be 4.0 x 10(-7) and 9.0 x 10(-7)M, respectively.
pantoprazole in pharmaceutical Rapidity, precision, and good selectivity were also found
dosage forms and human plasma for the determination of pantoprazole in pharmaceutical
using glassy carbon electrode.(10) dosage forms and human plasma. For comparative
purposes high-performance liquid chromatography with a
diode array and UV/VIS detection at 290.0 nm
determination also was developed
Pharmacokinetics and tolerance of The means of Cmax, AUC and t1/2 for these 2 PMs were
pantoprazole, a proton pump 1.6, 6.7, and 6.8 times higher than those of the extensive
inhibitor after single and multiple metabolizers (EMs). The pharmacokinetic parameters such
oral doses in healthy Japanese as Cmax, AUC, and t1/2 after the 7th oral dose were not
volunteers.(11) significantly different from those after the 1st dose both in
the PMs and the EMs, which indicated that there was
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

virtually no drug accumulation

Pharmacokinetics of pantoprazole in Lack of interaction was also demonstrated with a

man.(12) coadministered antacid. The absence of inductive effects
on metabolism after chronic administration was first
shown by using antipyrine as a probe for mixed functional
oxidative cytochrome P450 enzymes. Absence of
CYP1A2 induction was confirmed using the specific probe
caffeine. As sensitive probes for CYP3A enzyme
induction, urinary excretion of D-glucaric acid and 6 beta-
hydroxycortisol were also unchanged.
Effects of Genetic Polymorphisms of The MDR1 genetic polymorphisms did not affect plasma
Cytochrome P450 Enzymes and pantoprazole concentrations. MDR1 3435CC-2677GG-
MDR1 Transporter on Pantoprazole 1236CC haplotype carriers had lower H. pylori eradication
Metabolism and Helicobacter pylori rate (60%) than the remaining subjects (84.9%) while the
Eradication.(13) difference was not statistically significant (p = 0.07). In
conclusion, while CYP2C19 genetic polymorphisms
significantly affected plasma pantoprazole concentrations,
polymorphisms of CYP2C19, CYP3A4 and MDR1 did not
affect H. pylori eradication rates.
The proton pump inhibitor MPA concentrations and IMPDH activities did not reveal
pantoprazole and its interaction with any significant difference during PPI treatment and after
enteric-coated mycophenolate sodium withdrawal. MPA AUC, MPA C(max) (maximal MPA
in transplant recipient.(14) concentration), the time until C(max) was reached
(T(max)) and IMPDH activity AUC all showed no
significant difference
Pharmacokinetics, Bioequivalence, The 90% confidence intervals of the least squares
and Safety Studies of Pantoprazole geometric mean ratio of Cmax , area under the
Sodium Enteric-Coated Tablets in concentration-time curve from time zero to the last
Healthy Subjects .(15) measurable concentration (AUC0-t ), and AUC0-∞ of 36
subjects in the fasting trial and of 40 of 41 subjects in the
postprandial trial (Cmax [41], AUC0-t [41], and AUC0-∞
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

[40]) were in accordance with the bioequivalence criteria.

No severe adverse effects were detected. The generic and
branded pantoprazole sodium enteric-coated tablets were
considered bioequivalent with similar safety profiles
Population pharmacokinetic The effect of age on allometrically scaled CL was best
modeling of pantoprazole in pediatric described by a sigmoid Emax model with the age effect
patients from birth to 16 years.(16) reaching an asymptote approximately equal to the adult
CL by 1 year. CYP2C19 poor metabolizers exhibited
reduced CL with the point estimate and 95% CI more than
70% lower than the typical value. Simulations from the
final model indicated that the 1.2-mg/kg dose provides the
best comparison to adults.
Single-dose, multiple-dose, and Pantoprazole did not accumulate following multiple-dose
population pharmacokinetics of administration. The two patients with the CYP2C19 poor
pantoprazole in neonates and metabolizer genotype had a substantially higher AUC than
preterm infants with a clinical extensive metabolizers. No safety-related discontinuations
diagnosis of gastroesophageal reflux occurred.
disease (GERD).(17)
CYP2C19 polymorphism affects A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ±
single-dose pharmacokinetics of oral 0.23 h, p < 0.05) in carriers of CYP2C19*17/*17 vs
pantoprazole in healthy CYP2C19*1/*1 genotypes was observed. Population
volunteers.(18) modeling confirmed the influence of *1/*2, *2/*2, and
*17/*17 genotypes on the pharmacokinetics of
pantoprazole. The lowest population oral clearance was
assessed in the carriers of genotype *2/*2 (3.68 L/h) and
the highest value in subjects with genotype *17/*17 (31.13
L/h).
Efficacy and safety of a fixed-dose After 14 days of therapy, the difference was 0.45 mm
combination of (95% CI, -3.29 to 4.19 mm). The most common adverse
nimesulide/pantoprazole compared to events in the pooled group were abdominal discomfort,
naproxen/esomeprazole for pain abdominal distention, dyspepsia, and nausea, but none of
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

relief in patients with osteoarticular these was deemed to be clinically meaningful.

diseases and dyspeptic symptoms.(19)

On-demand therapy with The discontinuation rate due to insufficient control of

pantoprazole 20 mg as effective long- heartburn was significantly lower in both pantoprazole
term management of reflux disease in groups compared to placebo (placebo: 10.9, pantoprazole
patients with mild GERD: the 20 mg: 2.8, pantoprazole 40 mg: 0.9, ITT)
ORION trial.(20)
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3 CLINICAL STUDY REPORTS

5.3.1 Reports of Biopharmaceutic Studies
Bioavailability of mycophenolate mofetil and enteric-coated mycophenolate
sodium is differentially affected by pantoprazole in healthy volunteers.(1)
Korbinian Rupprecht , Christoph Schmidt, Anne Raspé,, et al,
J Clin Pharmacol. 2009 Oct;49(10):1196-201. doi: 10.1177/0091270009344988.
Abstract
The influence of pantoprazole 40 mg twice daily on the bioavailability of a single
dose of mycophenolate mofetil 1000 mg or enteric-coated mycophenolate sodium is
investigated in healthy volunteers. The plasma concentrations of mycophenolic acid
and of the inactive metabolite mycophenolic acid glucuronide are measured by
high-performance liquid chromatography. The pharmacokinetic parameters
following sole administration are similar for mycophenolate mofetil and enteric-
coated mycophenolate sodium except for the time to peak concentration, which is
longer in the enteric-coated mycophenolate sodium group. Concomitant treatment
with pantoprazole significantly (P < .001) lowers the mycophenolic acid exposure
following administration of mycophenolate mofetil. The peak concentrations drop
by 57%, and area under the curve decreases from 0 to 12 hours by 27%. In contrast,
pantoprazole does not change the pharmacokinetics of enteric-coated
mycophenolate sodium. Given that mycophenolic acid exposure correlates with the
incidence of biopsy-proven acute rejections in renal transplant recipients, these
findings may have clinical implications. Administration of pantoprazole in
combination with mycophenolate mofetil could possibly result in an insufficient
mycophenolic acid exposure, increasing the risk of treatment failure.
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

Proton pump inhibitor pantoprazole inhibits the proliferation, self‑renewal

and chemoresistance of gastric cancer stem cells via the EMT/β ‑ catenin
pathways (2)
Shuitu Feng , Zhigao Zheng , Lihua Feng et al.
Oncol Rep . 2016 Dec;36(6):3207-3214. doi: 10.3892/or.2016.5154. Epub 2016
Oct 7.
Abstract
The cancer stem cell (CSC) model suggests that a small subset of cancer cells
possess stem cell properties and plays a crucial role in tumor initiation, metastasis
and resistance to anticancer therapy. Exploration of the specific therapies targeting
at CSCs has been a crucial issue in antitumor research. Gastric cancer (GC) cells
often exist in an ischemic microenvironment with acidic conditions in vivo, thus
maintenance of cellular pH homeostasis is important for the survival and function
of GC cells. Proton pump inhibitors (PPIs) may prevent intracellular proton
extrusions which consequently reduce cancer cell survival under acidic conditions.
The effects of PPIs on the suppression of the viability and invasiveness of GC cells
have been reported, but the functional role of pantoprazole (PPZ) in GC cells
remains unknown. In this study, we found that when cells were treated with PPZ,
the 5-fluorouracil (5-FU) chemosensitivity was upregulated, meanwhile the sphere
formation ability and the relative expression levels of stem cell markers CD44,
CD24, ABCG2, EpCAM and Lgr5 were significantly decreased. It was
hypothesized that PPZ inhibits the GC CSCs. Successively a sphere formation
culture was performed to establish CSC models and the effect of PPZ on GC CSCs
from SGC-7901 and HGC-27 cells was explored. The addition of PPZ reduced the
relative expression of CSC markers and anti-drug markers accompanied by a
decrease in proliferation, 5-FU chemoresistance and self-renewal capacity via
epithelial-mesenchymal transition (EMT)/β-catenin pathways. The study suggests
that PPZ could be a promising novel specific therapeutic strategy for targeting GC
CSCs.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.1.1 Bioavailability Study Reports

Bioavailability of a crushed pantoprazole tablet after buffering with sodium
hydrogencarbonate or magaldrate relative to the intact enteric coated
pantoprazole tablet.(3)
L M Ley , B Stahlheber-Dilg, P Sander, et al.
Methods Find Exp Clin Pharmacol . Jan-Feb 2001;23(1):41-5. doi:
10.1358/mf.2001.23.1.619179.
Abstract
The aim of this study was to determine the bioavailability of orally administered,
crushed pantoprazole tablets after buffering with either 1.4% sodium
hydrogencarbonate or 1600 mg magaldrate relative to the intact enteric coated
pantoprazole tablet. A single dose, three-period crossover study was performed with
18 healthy male volunteers. The crushed pantoprazole suspension, together with
either sodium hydrogencarbonate or magaldrate, was administered via a nasogastral
tube. Tmax of crushed pantoprazole was earlier as compared to the intact tablet (0.5
h vs. 3 h) and Cmax was approximately 10% higher due to faster absorption. The
bioavailability of the crushed pantoprazole tablet relative to the intact pantoprazole
tablet was 93% when using sodium hydrogencarbonate as the buffering agent, and
88% when using magaldrate. Based on the internationally approved confidence
intervals for AUC (0.80-1.20) and Cmax (0.70-1.43), the crushed tablet buffered
with sodium hydrogencarbonate was shown to be bioequivalent with the intact
tablet (point estimates for AUC or Cmax: 0.93 or 1.10). For the crushed tablet
buffered with magaldrate (point estimates for AUC or Cmax: 0.88 or 1.12)
bioequivalence with the intact tablet could not be formally demonstrated, although
the lower confidence limit for AUC of 0.78 was only slightly below the lower limit
of the equivalence range of 0.80.
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

Oral bioavailability of pantoprazole suspended in sodium bicarbonate

solution.(4)
Geraldine M Ferron , Sherry Ku, Madelyn Abell,, et al.
Am J Health Syst Pharm . 2003 Jul 1;60(13):1324-9.

Abstract
The bioavailability of pantoprazole when administered as a suspension in sodium
bicarbonate solution and as the oral tablet was studied. In an open-label,
randomized, two-period crossover study, healthy fasting subjects received either
one enteric-coated 40-mg pantoprazole tablet by mouth with 240 mL of water or 20
mL of a suspension prepared from one crushed pantoprazole tablet and 840 mg of
sodium bicarbonate solution and administered via a nasogastric tube. Treatments
were separated by a 48-hour washout period. Blood samples were collected at
intervals up to 24 hours after drug administration for measurement of pantoprazole
concentration by high-performance liquid chromatography (HPLC) and estimation
of pharmacokinetic values. A separate study was conducted to determine
pantoprazole's stability in the suspension for up to three months at 25, 5, and -20
degrees C; concentrations were measured by HPLC. Twelve subjects completed the
study. The suspension yielded pantoprazole Cmax values similar to those of the
tablet formulation, but the drug was 25% less bioavailable. There was no lag time
for the suspension. The suspension was stable for up to two weeks at 5 degrees C
and up to three months at -20 degrees C. A suspension of pantoprazole in sodium
bicarbonate solution yielded a Cmax similar to that of the tablet formulation, and
the drug was quickly absorbed. However, bio-availability was slightly lower with
the suspension than with the tablet.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports

Twenty-four-hour intragastric pH profiles and pharmacokinetics following
single and repeated oral administration of the proton pump inhibitor
pantoprazole in comparison to omeprazole.(5)
M Hartmann , U Theiss, R Huber, et al.
Aliment Pharmacol Ther . 1996 Jun;10(3):359-66.
ABSTRACT
Background: Pantoprazole is a proton pump inhibitor characterized by a low
potential to interact with the cytochrome P450 enzyme system in man. Its effect on
intragastric pH following single and repeated oral intake was investigated in
comparison to omeprazole by continuous intragastric pH-metry at doses
recommended for treatment of peptic ulcer disease.
Methods: Sixteen healthy male subjects underwent two dosing periods. From day 1
to day 7, they were given once daily by mouth 40 mg pantoprazole in one period
and 20 mg omeprazole in the other period, according to a double-blind randomized
crossover design. Twenty-four-hour intragastric pH was recorded and frequent
blood samples for pharmacokinetic analysis were taken on day 1 and day 7. A
placebo pH profile was obtained prior to each treatment period.
Results: Pantoprazole was significantly more effective than omeprazole with
regard to increase in 24-h and daytime pH, following both single (median 24-h pH:
1.45 vs. 1.3, P < 0.05; median daytime pH: 1.6 vs. 1.3, P < 0.01) and repeated
(median 24-h pH: 3.15 vs. 2.05, P < 0.01; median daytime pH: 3.8 vs. 2.65, P <
0.05) oral intake. As compared to the first dose, repeated administration of both
drugs markedly increased the effect on intragastric pH. With pantoprazole, steady-
state serum concentrations were obtained after the first dose, but not with
omeprazole. Both drugs were well tolerated without relevant changes in vital signs
of clinical laboratory parameters.
Conclusion: Pantoprazole 40 mg is significantly more effective than omeprazole
20 mg in raising intragastric pH
.
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

Bioequivalence of two enteric coated formulations of pantoprazole in healthy

volunteers under fasting and fed conditions (6)
Daniel Rossi de Campos , Nelson Rogério Vieira, Gilberto Bernasconi, et al.
Arzneimittelforschung. 2007;57(6):309-14. doi: 10.1055/s-0031-1296624.
Abstract
Purpose: To compare the bioavailability of two pantoprazole (CAS 102625-70-7)
formulations (40 mg pantoprazole enteric coated tablets) under fasted and fed
conditions as well as to evaluate the dissolution profile in biorelevant media.
Methods: The subjects received either 40 mg of the reference or of test formulation
in fasting (n = 28) and fed (n=70) condition. The studies were conducted according
to a single dose and randomized crossover design. Blood samples were collected up
to 12 h after drug administration in fasting condition and up to 48 h in fed condition.
Plasma concentrations of pantoprazole were determined by LC-MS/MS.
Pharmacokinetic parameters were calculated from the observed plasma
concentration-time profiles. Bioequivalence between the formulations in fasting and
fed condition was assessed considering 90% confidence intervals for the ratio of
means for lnCmax and lnAUC(0-t) within 0.8-1.25. Dissolution profiles were
evaluated in biorelevant media [Fasting State Simulating Intestinal Fluid (FaSSIF)
and Fed State Simulating Intestinal Fluid (FeSSIF)]. The sameness of the dissolution
curves was assessed by f2 values between 50 and 100.
Results: Under fasting condition the 90% confidence interval for the ratio of means
for the lnCmax, (0.94-1.03) and lnAUC(0-t) (0.89-0.99) was within the guideline
range of bioequivalence (0.80-1.25). However, the data for lnCmax (0.51-0.76) and
lnAUC(0-t) (0.68-0.90) under fed condition were not within the bioequivalence
range. The postprandial study demonstrated a high intra-subject variability and in
some subjects pantoprazole could not be detected for up to 24 h, although the
dissolution profile of reference and test formulations presented a similar disposition
in FaSSIF and FeSSIF as confirmed by the values of f2 higher than 50.
Conclusion: The results demonstrated that the test formulation was bioequivalent to
the reference in fasting condition but not in postprandial state. The dissolution
profile in FaSSIF indicates that this biorelevant medium was more adequate to
discriminate the in vivo disposition of pantoprazole than FeSSIF. Furthermore, the
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

fed condition study had shown a pronounced influence of food in the absorption of
pantoprazole after single oral dose administration.

Comparative bioavailability study with two pantoprazole delayed-released

tablet formulations administered with and without food in healthy subjects. (7)
Fabiana D Mendes , Anil K Patni, Simrit Reyer et al.
Arzneimittelforschung . 2008;58(3):141-8. doi: 10.1055/s-0031-1296484.
Abstract
Objective: To assess the comparative bioavailability of two formulations (40 mg
delayed-released [DR] tablet; test and reference) of pantoprazole (CAS 102625-70-
7) in healthy volunteers of both sexes, with and without food.
Methods: The study was conducted using an open, randomized, two-period
crossover design with a 1-week washout interval, in two groups, with and without
food. Plasma samples were obtained for up to 24 h post dose. Plasma pantoprazole
concentrations were analyzed by liquid chromatography coupled to tandem mass
spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple
reactions monitoring (MRM). From the pantoprazole plasma concentration vs. time
curves, the pharmacokinetic parameters AUC(last) and C(max) were obtained, with
and without food.
Results: The limit of quantification was 5 ng/mL for plasma pantoprazole analysis.
The geometric mean and 90% confidence interval CI of test/reference percent ratios
were, without and with food, respectively: 104.6540% (90.8616%-120.5401%) and
99.9708% (90.9987%-109.8275%) for C(max), 95.6634% (85.2675%-107.3267%)
and 89.3500% (83.6630%-95.4237%) for AUC(last).
Conclusion: Since the 90% CI for AUC(last) and C(max) ratios were within the 80-
125% interval proposed by the US FDA, it was concluded that pantoprazole 40 mg
DR tablet (test formulation) with and without food was bioequivalent to the
reference 40 mg DR tablet for both the rate and extent of absorption.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.1.3 In vitro-In vivo Correlation Study Reports

Comparison of the coating process and in vitro dissolution of 3 mm gastro-
resistant minitablets and 5 mm gastro-resistant tablets with pantoprazole .(8)
M Szczepanska, M Sznitowska
Pharmazie . 2019 Aug 1;74(8):467-470.doi: 10.1691/ph.2019.8180.

ABSTRACT
Minitablets are solid oral forms, which, due to their size (1-3 mm), may be easily
swallowed by children. The administration of minitablets in a certain number of
units allows for flexible dosing for a broad age group of paediatric patients, which is
particularly important for modified-release drugs. In this study, enteric-coated
minitablets (3 mm) with pantoprazole were developed and compared to
conventional tablets (5 mm). Eudragit L 30D 55® and Acryl Eze II® films, which
were 50 and 80 μm thick, respectively, were applied using two different fluid bed
systems. The increase in the pantoprazole release rate occurred not only due to the
application of a thinner film but also due to the reduction in the size of the core
independent of the coating apparatus that was used. In contrast to minitablets, the
thin film's thickness was insufficient for 5 mm tablets and a loss of gastro-resistance
was observed. The insertion of minitablets into a hard gelatine capsule did not affect
drug release from the minitablets under in vitro conditions.
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.1.4 Reports of Bioanalytical and Analytical methods for Human Studies

Validation of a novel, fully automated high throughput high-performance
liquid chromatographic/tandem mass Spectrometric method for
quantification of pantoprazole in human plasma.(9)
Yannis Dotsikas , Constantinos Apostolou, Stefanos Soumelas, et al.
J AOAC Int . Jul-Aug 2010;93(4):1129-36..

Abstract
An automated high-throughput HPLC/MS/MS method was developed for the
quantitative determination of pantoprazole in human plasma. Only 100 microL
plasma was placed in 2.2 mL 96 deep-well plates, and both pantoprazole and
omeprazole (IS) were extracted from human plasma by liquid-liquid extraction,
using diethyl ether-dichloromethane (70:30, v/v) as the organic solvent. Robotic
liquid-handling workstations were used for all liquid transfer and solution
preparation steps and resulted in a short sample preparation time. After vortexing,
centrifugation, and freezing, the supernatant organic solvent was evaporated and
reconstituted in a small volume of reconstitution solution. Sample analysis was
performed by utilizing the combination of RP-HPLC/MS/MS, with positive-ion
electrospray ionization and multiple reaction monitoring detection. The
chromatographic run time was set at 1.8 min with a flow rate of 0.6 mL/min on a
Nucleosil octylsilyl (C8) analytical column. The method was proven to be
sensitive, specific, accurate, and precise for the determination of pantoprazole in
human plasma. The method was applied to a bioequivalence study after per os
administration of a 40 mg pantoprazole gastric retentive tablet.
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

Differential pulse anodic voltammetric determination of pantoprazole in

pharmaceutical dosage forms and human plasma using glassy carbon
electrode.(10)
Nevin Erk .
Anal Biochem. 2003 Dec 1;323(1):48-53.doi: 10.1016/j.ab.2003.08.023.

Abstract
Pantoprazole is used as an anti-ulcer drug through inhibition of H(+), K(+)-
adenosine 5(')-triphosphatase in gastric parietal cells. It reduces the gastric acid
secretion regardless of the nature of stimulation. The use of differential pulse
voltammetry for the determination of pantoprazole in pharmaceutical dosage forms
and human plasma using a glassy carbon electrode has been examined. The best
voltammetric response was reached for a glassy carbon electrode in Britton-
Robinson buffer solution of pH 5.0 submitted to a scan rate of 20.0 mVs(-1) and a
pulse amplitude of 50.0 mV. This electroanalytical procedure was able to determine
pantoprazole in the concentration range 6.0 x 10(-6)-8.0 x 10(-4)M. Precision and
accuracy of the developed method was checked with recovery studies. The limit of
detection and limit of quantitation were found to be 4.0 x 10(-7) and 9.0 x 10(-7)M,
respectively. Rapidity, precision, and good selectivity were also found for the
determination of pantoprazole in pharmaceutical dosage forms and human plasma.
For comparative purposes high-performance liquid chromatography with a diode
array and UV/VIS detection at 290.0 nm determination also was developed..
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.2 Reports of Studies Pertinent To Pharmacokinetics Using Human Biomaterials

Pharmacokinetics and tolerance of pantoprazole, a proton pump inhibitor
after single and multiple oral doses in healthy Japanese volunteers.(11)
M Tanaka , H Yamazaki, Y Ryokawa, et al.
Int J Clin Pharmacol Ther . 1996 Oct;34(10):415-9.

Abstract
The pharmacokinetics and tolerance of pantoprazole were investigated after single
(20, 40, 80, and 120 mg) and multiple (80 mg once a day for 7 days) oral
administration as enteric-coated tablet formulation to healthy male Japanese
volunteers. Pantoprazole was well tolerated with no serious adverse events at all
doses. Pantoprazole was rapidly absorbed in the fasted state. The mean maximum
concentration in serum (Cmax) ranged from 1.77-9.25 micrograms/ml for the 20-
120 mg dose and the mean time to reach Cmax (tmax) ranged from 1.92-2.42 h. The
half-life (t1/2) ranged from 0.74-1.16 h. A good linear correlation was found
between the administered doses (20-120 mg) and the resulting area under the
concentration-time curve (AUC) and Cmax with the correlation coefficients of
0.9088 and 0.9263, respectively. Within 24 h, pantoprazole was excreted into urine
as the unchanged drug to a negligible extent. In the multiple dose study, 2 apparent
poor metabolizers (PMs) of pantoprazole were observed. The means of Cmax, AUC
and t1/2 for these 2 PMs were 1.6, 6.7, and 6.8 times higher than those of the
extensive metabolizers (EMs). The pharmacokinetic parameters such as Cmax,
AUC, and t1/2 after the 7th oral dose were not significantly different from those
after the 1st dose both in the PMs and the EMs, which indicated that there was
virtually no drug accumulation.
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

Pharmacokinetics of pantoprazole in man.(12)

R Huber , M Hartmann, H Bliesath,.et al.
Int J Clin Pharmacol Ther . 1996 May;34(1 Suppl):S7-16.
Abstract.
The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide
for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis,
duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated
tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not
change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is
approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(0,inf.) is approximately 5
mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral
administration. Pantoprazole is extensively metabolized in the liver, has a total
serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an
apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum
proteins. Elimination half-life, clearance and volume of distribution are independent
of the dose. The main serum metabolite is formed by demethylation at the 4-
position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of
an oral or intravenous dose is excreted as metabolites in urine; the remainder is
found in feces and originates from biliary secretion. The pharmacokinetics of
pantoprazole are unaltered in patients with renal failure. In patients with severe liver
cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The
clearance of pantoprazole is only slightly affected by age, its half-life being
approximately 1.25 h in the elderly. Concomitant intake of food had no influence on
the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450
interaction with concomitantly administered drugs in any of the studies conducted
to date. Lack of interaction was also demonstrated with a coadministered antacid.
The absence of inductive effects on metabolism after chronic administration was
first shown by using antipyrine as a probe for mixed functional oxidative
cytochrome P450 enzymes. Absence of CYP1A2 induction was confirmed using the
specific probe caffeine. As sensitive probes for CYP3A enzyme induction, urinary
excretion of D-glucaric acid and 6 beta-hydroxycortisol were also unchanged.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.2.1 Plasma Protein Binding Study Reports

Effects of Genetic Polymorphisms of Cytochrome P450 Enzymes and MDR1
Transporter on Pantoprazole Metabolism and Helicobacter pylori
Eradication.(13)
R Ozgur Karaca , Said Kalkisim , Akif Altinbas, et al.
Basic Clin Pharmacol Toxicol. 2017 Feb;120(2):199-206. doi: 10.1111/bcpt.12667.
Epub 2016 Nov 2.
Abstract
Pantoprazole is a proton pump inhibitor that is commonly used in the treatment of
peptic ulcer disease (PUD) and metabolized by cytochrome P450 (CYP) enzymes
CYP2C19 and CYP3A4. Pantoprazole is a substrate for multi-drug resistance
protein 1 (MDR1). Single nucleotide polymorphisms (SNPs) in CYP2C19, CYP3A4
and MDR1 affect enzyme activity or gene expression of proteins and may alter
plasma pantoprazole concentrations and treatment success in PUD. In this study, we
aimed to investigate the association between genetic polymorphisms in CYP2C19,
CYP3A4 and MDR1 and pharmacokinetics of pantoprazole and therapeutic outcome
in patients with either Helicobacter pylori-associated [H.P.(+)]-PUD or [H.P.(+)]-
gastritis. The plasma pantoprazole concentrations were determined by using an
HPLC method at the third hour after a 40-mg tablet of pantoprazole administration
in 194 newly diagnosed patients with either [H.P.(+)]-PUD or [H.P.(+)]-gastritis.
Genotyping was performed by using PCR-RFLP and DNA sequencing. Among
patients appearing for follow-up examination (n = 105), the eradication rate for H.
pylori was 82.8% (n = 87). The median pantoprazole plasma concentrations in poor
metabolizers (PM), rapid metabolizers (RM) and ultrarapid metabolizers (URM)
were 2.07, 1.69 and 1.28 μg/ml, respectively (p = 0.04). CYP3A4*1G and *22
polymorphisms did not affect plasma pantoprazole concentrations and H. pylori
eradication rate. The MDR1 genetic polymorphisms did not affect plasma
pantoprazole concentrations. MDR1 3435CC-2677GG-1236CC haplotype carriers
had lower H. pylori eradication rate (60%) than the remaining subjects (84.9%)
while the difference was not statistically significant (p = 0.07). In conclusion, while
CYP2C19 genetic polymorphisms significantly affected plasma pantoprazole
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

concentrations, polymorphisms of CYP2C19, CYP3A4 and MDR1 did not affect H.

pylori eradication rates.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies

The proton pump inhibitor pantoprazole and its interaction with enteric-
coated mycophenolate sodium in transplant recipients.(14)
Sieglinde Kofler 1 , Christine Wolf, Natalija Shvets, et al.
J Heart Lung Transplant. 2011 May;30(5):565-71. doi:
10.1016/j.healun.2010.12.003. Epub 2011 Jan 21.
Abstract
Background: In this prospective study we investigated the impact of the proton
pump inhibitor (PPI) pantoprazole on the bioavailability of mycophenolic acid
(MPA) after oral administration of enteric-coated mycophenolate sodium (EC-
MPS; Myfortic) in heart or lung transplant recipients. Previously we demonstrated
that pantoprazole reduces the MPA exposure of mycophenolate mofetil (MMF;
CellCept) by 34% in area under the concentration-time curve (AUC). Because
gastrointestinal side-effects are common after organ transplantation, we
investigated the effect of PPI on MPA levels in patients receiving EC-MPS.
Methods: MPA plasma concentrations and inosine monophosphate dehydrogenase
(IMPDH) activity at baseline, 30 minutes and 1, 2, 3 and 4 hours were obtained
from 21 patients. These patients were treated with pantoprazole 40 mg once daily
and EC-MPS twice daily at a mean dose of 960 mg. Measurements were repeated
after pantoprazole withdrawal.
Results: MPA concentrations and IMPDH activities did not reveal any significant
difference during PPI treatment and after withdrawal. MPA AUC, MPA C(max)
(maximal MPA concentration), the time until C(max) was reached (T(max)) and
IMPDH activity AUC all showed no significant difference.
Conclusion: We did not find an influence of pantoprazole on EC-MPS
pharmacokinetics such as we did for MMF in our previous investigation. A further
prospective, large, cross-over study is planned to support these preliminary results.
Given that MPA exposure by AUC correlates with the incidence of acute rejection
episodes and transplant vasculopathy, the present findings may have clinical
implications
.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.2.3 Reports of Studies using other Human Biomaterials

===Not available==
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.3 Report of Human Pharmacokinetic Studies

5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
Pharmacokinetics, Bioequivalence, and Safety Studies of Pantoprazole Sodium
Enteric-Coated Tablets in Healthy Subjects.(15)
Zhimin Chen , Fangliang Gan , Xiali Rao et al.
Clin Pharmacol Drug Dev . 2021 May;10(5):502-509. doi: 10.1002/cpdd.888.
Epub 2020 Oct 31.
Abstract
This study aimed to evaluate the bioequivalence of 2 pantoprazole sodium enteric-
coated tablet formulations, a generic formulation and a branded formulation, and to
investigate their pharmacokinetic and safety profiles. The study was designed as a
single-center, randomized, open-label, single-dose, dual-period, and 2-sequence
crossover trial, and was divided into fasting and postprandial human bioequivalence
trials. In the first trial, 36 subjects were fasted overnight before they were given
generic or branded tablets (during 2 separate administration periods). Separately, 42
subjects were provided a high-fat meal 1 hour before the drugs were administered.
Blood specimens of each subject were obtained up to 24 hours after drug
administration. No significant differences were observed between the
pharmacokinetic profiles of the generic and branded pantoprazole sodium enteric-
coated tablets. Bioequivalence was evaluated using 90% confidence intervals for the
ratio of test/reference log area under the concentration-time curve over 24 hours, log
area under the concentration-time curve to infinity (AUC0-∞ ), and log peak
concentration (Cmax ). The 90% confidence intervals of the least squares geometric
mean ratio of Cmax , area under the concentration-time curve from time zero to the
last measurable concentration (AUC0-t ), and AUC0-∞ of 36 subjects in the fasting
trial and of 40 of 41 subjects in the postprandial trial (Cmax [41], AUC0-t [41], and
AUC0-∞ [40]) were in accordance with the bioequivalence criteria. No severe
adverse effects were detected. The generic and branded pantoprazole sodium
enteric-coated tablets were considered bioequivalent with similar safety profiles.
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

Population pharmacokinetic modeling of pantoprazole in pediatric patients

from birth to 16 years.(16)
W Knebel , B Tammara, C Udata, et al.
J Clin Pharmacol. 2011 Mar;51(3):333-45. doi: 10.1177/0091270010366146. Epub
2010 May 19.

Abstract
The population pharmacokinetics of pantoprazole was characterized in pediatric
patients from birth to 16 years using NONMEM and evaluated via bootstrap and
predictive check. Data were described using a 2-compartment model with a typical
parameterized in terms of clearance (CL) (95% CI) of 1.93 L per hour (1.53, 2.61),
given the reference covariates (female, full term, extensive/unknown CYP2C19
metabolizer status, non-African American, 10 kg weight, intravenous or tablet
administration). Pantoprazole pharmacokinetic parameters appear to be similar in
pediatric patients compared to adults when allometrically scaled. The effect of age
on allometrically scaled CL was best described by a sigmoid Emax model with the
age effect reaching an asymptote approximately equal to the adult CL by 1 year.
CYP2C19 poor metabolizers exhibited reduced CL with the point estimate and 95%
CI more than 70% lower than the typical value. Simulations from the final model
indicated that the 1.2-mg/kg dose provides the best comparison to adults.
.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.3.2 Patient PK and Initial Tolerability Study Reports

==Not available==
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.3.3 Intrinsic Factor PK Study Reports

==== Not available ===

 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.3.4 Extrinsic Factor PK Study Reports

=== Not available ===

 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.3.5 Population PK Study Reports

===Not Applicable===
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.4 Report of Human Pharmacodynamic Studies

5.3.4.1 Healthy Subject PD and PK/PD Study Reports

===Not Available===
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.4.2 Patient PD and PK/PD Study Reports

Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole
in neonates and preterm infants with a clinical diagnosis of gastroesophageal
reflux disease (GERD).(17)
Robert M Ward , Brinda Tammara, Sandra E Sullivan, et al.
Eur J Clin Pharmacol. 2010 Jun;66(6):555-61 doi: 10.1007/s00228-010-0811-8.
Epub 2010 Mar 20..

Abstract
Purpose: The pharmacokinetic profile of pantoprazole granules was assessed in
neonates and preterm infants with gastroesophageal reflux disease (GERD) in a
multicenter, randomized, open-label trial.
Methods: Patients were randomly assigned to either the pantoprazole 1.25 mg
(approx. 0.6 mg/kg) or 2.5 mg (approx. 1.2-mg/kg) group and treated for > or =5
consecutive days. Blood was sampled either at 0, 2, 8, and 18 h postdose or at 0, 1,
4, and 12 h postdose on day 1 and at 3 and 6 h postdose after > or =5 consecutive
doses. Cytochrome P450 2C19 (CYP2C19) and CYP3A4 genotypes were
determined. Safety was monitored. Population pharmacokinetics (popPK) analyses
were conducted using nonlinear mixed-effects modeling.
Results: The popPK modeling of the pantoprazole 1.25 mg and 2.5 mg groups
obtained mean (+/-standard deviation) estimates for the area under the plasma
concentration versus time curve (AUC) of 3.54 (+/-2.82) and 7.27 (+/-5.30) microg
h/mL, respectively, and mean estimates for half-life of 3.1 (+/-1.5) and 2.7 (+/-1.1)
h, respectively. Pantoprazole did not accumulate following multiple-dose
administration. The two patients with the CYP2C19 poor metabolizer genotype had
a substantially higher AUC than extensive metabolizers. No safety-related
discontinuations occurred.
Conclusions: In preterm infants and neonates, pantoprazole granules were
generally well tolerated, mean exposures with pantoprazole 2.5 mg were slightly
higher than that in adults who received 40 mg. While the half-life was longer,
accumulation did not occur
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

CYP2C19 polymorphism affects single-dose pharmacokinetics of oral

(18)
pantoprazole in healthy volunteers
I Nilsson-Ehle, H Fellner, S A Hedström
Eur J Clin Pharmacol. 2012 Sep;68(9):1267-74. doi: 10.1007/s00228-012-1252-3.
Epub 2012 Mar 15..
Abstract
Objectives: Pantoprazole is metabolized by cytochrome P450 2 C19, which shows
genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose
pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated.
Methods: Pantoprazole pharmacokinetics was determined in 32 healthy volunteers
after a 40-mg single oral dose of the drug.
Results: Carriers of CYP2C19*2/*2 (n = 2) were characterized by higher, starting
from 3.5 h post dose, plasma concentrations of pantoprazole in comparison to wild-
type (CYP2C19*1/*1, n = 6) volunteers. In subjects with CYP2C19*17/*17
genotype (n = 6) significantly lower plasma concentrations of the drug vs
CYP2C19*1/*1 carriers, were observed from 3.0 h after oral pantoprazole
administration. Carriers of CYP2C19*1/*17 (n = 6) and CYP2C19*2/*17 (n = 6)
displayed concentration-time profiles comparable to wild-type subjects.
CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant
(λ(z)) by 83.3%, prolongation of terminal half-life (t(½)) by 572%, a rise in area
under the concentration-time curve (AUC) and mean residence time (MRT) by
506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs
CYP2C19*1/*1 were characterized by higher AUC (4.38 ± 1.00 mg·h/L vs 3.00 ±
1.02 mg·h/L, p < 0.05) and C(max) (2.13 ± 0.42 mg/L vs 1.61 ± 0.35 mg/L, p <
0.05) respectively. A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ± 0.23 h, p
< 0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed.
Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17
genotypes on the pharmacokinetics of pantoprazole. The lowest population oral
clearance was assessed in the carriers of genotype *2/*2 (3.68 L/h) and the highest
value in subjects with genotype *17/*17 (31.13 L/h).
Conclusion: These data suggest that CYP2C19 polymorphism is an important
determinant of pantoprazole pharmacokinetics.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.5 Report of Efficacy and Safety Studies

Efficacy and safety of a fixed-dose combination of nimesulide/pantoprazole
compared to naproxen/esomeprazole for pain relief in patients with
osteoarticular diseases and dyspeptic symptoms.(19)
Morton Scheinberg , Henrique Pott Júnior , Eduardo de Almeida Macêdo. et al.
Drug Des Devel Ther. 2018 Sep 6;12:2775-2783. doi: 10.2147/DDDT.S172068.
eCollection 2018.

Abstract
Purpose: This study investigated the safety and efficacy of fixed-dose combination
tablets of naproxen/esomeprazole magnesium and nimesulide/pantoprazole to
determine if both regimens are equally suited to relieve pain in patients with
osteoarticular diseases and dyspeptic symptoms.
Methods: Patients were randomly assigned to receive either
nimesulide/pantoprazole (100 mg/20 mg) twice daily or naproxen/esomeprazole
magnesium (500 mg/20 mg) twice daily for 14 days. The primary endpoint was
defined as the mean change in modified Western Ontario and McMaster
Universities Osteoarthritis Index pain subscale. Secondary endpoints were mean
visual analog scale score of dyspeptic symptoms (nausea, abdominal
discomfort/pain, epigastric burning, postprandial fullness), mean visual analog
scale score of individual dyspeptic symptoms, and individual score of dyspeptic
symptoms according to patient diary. This study is registered at ClinicalTrials.gov:
NCT01670552.
Results: A total of 490 patients were enrolled and randomized, and 399 completed
treatment (naproxen/esomeprazole, n=201; nimesulide/pantoprazole, n=198). The
difference in mean change in the modified Western Ontario and McMaster
Universities Osteoarthritis Index pain score after 7 days of treatment between the
two treatment groups was 2.33 mm (95% CI, -1.22 to 5.89 mm). After 14 days of
therapy, the difference was 0.45 mm (95% CI, -3.29 to 4.19 mm). The most
common adverse events in the pooled group were abdominal discomfort, abdominal
distention, dyspepsia, and nausea, but none of these was deemed to be clinically
meaningful.
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

Conclusion: The present study demonstrated noninferiority of a 14-day regimen

with a fixed-dose combination of nimesulide/pantoprazole compared to
naproxen/esomeprazole for the treatment of osteoarticular pain.

On-demand therapy with pantoprazole 20 mg as effective long-term

management of reflux disease in patients with mild GERD: the ORION trial
(20)

T Scholten , C P M Dekkers, K Schütze et al.

Digestion. 2005;72(2-3):76-85. doi: 10.1159/000087661. Epub 2005 Aug 19.
Aims: To compare safety and efficacy of on-demand pantoprazole 20 mg/40 mg
versus placebo in the long-term management of patients with mild
gastroesophageal reflux disease (GERD) after heartburn relief.
Methods: A total of 634 patients with endoscopically confirmed GERD grade 0/I
and heartburn were included. During the acute phase, patients were treated with
pantoprazole 20 mg once daily for 4 weeks. Those patients relieved from heartburn
entered the long-term phase, and were randomly assigned to either treatment group
pantoprazole 20 mg, 40 mg or placebo. Over 6 months, patients took study
medication on demand (antacids as rescue medication) and discontinued the drug
once symptoms abated.
Results: After 4 weeks a total of 87.1%/90.0% of patients were free of heartburn
(ITT/PP), and entered the subsequent long-term phase. The perceived average daily
symptom load (placebo: 3.93, pantoprazole 20 mg: 2.91, pantoprazole 40 mg: 2.71,
ITT) and the number of antacid tablets taken (average number, placebo: 0.68,
pantoprazole 20 mg: 0.45, pantoprazole 40 mg: 0.33, ITT) were significantly higher
in the placebo than in both pantoprazole groups (p<0.0001), with no statistically
significant difference between the two pantoprazole groups. The discontinuation
rate due to insufficient control of heartburn was significantly lower in both
pantoprazole groups compared to placebo (placebo: 10.9, pantoprazole 20 mg: 2.8,
pantoprazole 40 mg: 0.9, ITT).
Conclusions: Our findings favor on-demand treatment with pantoprazole 20 mg for
the long-term management of heartburn in patients with uncomplicated GERD
(grade 0/I) with superiority to placebo.
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.6 Reports of Post-Marketing Experience If Available

===Not Available==
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.3.7 Case Report Forms and Individual Patient Listings

===Not Applicable===
 MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

5.4 LITERATURE REFERENCES

1) Korbinian Rupprecht , Christoph Schmidt, Anne Raspé,, et al, “Bioavailability of

mycophenolate mofetil and enteric-coated mycophenolate sodium is
differentially affected by pantoprazole in healthy volunteers” J Clin Pharmacol.
2009 Oct;49(10):1196-201. doi: 10.1177/009127000934498,
2) Shuitu Feng , Zhigao Zheng , Lihua Feng et al. “Proton pump inhibitor
pantoprazole inhibits the proliferation, self‑renewal and chemoresistance of
gastric cancer stem cells via the EMT/β‑catenin pathways” Oncol Rep . 2016
Dec;36(6):3207-3214. doi: 10.3892/or.2016.5154. Epub 2016 Oct.
3) L M Ley , B Stahlheber-Dilg, P Sander, et al “Bioavailability of a crushed
pantoprazole tablet after buffering with sodium hydrogencarbonate or
magaldrate relative to the intact enteric coated pantoprazole tablet” Methods
Find Exp Clin Pharmacol . Jan-Feb 2001;23(1):41-5. doi:
10.1358/mf.2001.23.1.619179
4) Geraldine M Ferron , Sherry Ku, Madelyn Abell,, et al. “Oral bioavailability of
pantoprazole suspended in sodium bicarbonate solution” Am J Health Syst
Pharm . 2003 Jul 1;60(13):1324-9
5) M Hartmann , U Theiss, R Huber, et al., " Twenty-four-hour intragastric pH
profiles and pharmacokinetics following single and repeated oral
administration of the proton pump inhibitor pantoprazole in comparison to
omeprazole "; Aliment Pharmacol Ther . 1996 Jun;10(3):359-66.
6) Daniel Rossi de Campos , Nelson Rogério Vieira, Gilberto Bernasconi, et al;
Bioequivalence of two enteric coated formulations of pantoprazole in healthy
volunteers under fasting and fed conditions.; Arzneimittelforschung.
2007;57(6):309-14. doi: 10.1055/s-0031-1296624
7) Fabiana D Mendes , Anil K Patni, Simrit Reyer et al “Comparative
bioavailability study with two pantoprazole delayed-released tablet
formulations administered with and without food in healthy subjects;
Arzneimittelforschung . 2008;58(3):141-8. doi: 10.1055/s-0031-1296484.
8) M Szczepanska, M Sznitowska; “Comparison of the coating process and in vitro
dissolution of 3 mm gastro-resistant minitablets and 5 mm gastro-resistant
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

tablets with pantoprazole” Pharmazie . 2019 Aug 1;74(8):467-470.doi:

10.1691/ph.2019.8180.
9) Yannis Dotsikas , Constantinos Apostolou, Stefanos Soumelas, et al; Validation
of a novel, fully automated high throughput high-performance liquid
chromatographic/tandem mass Spectrometric method for quantification of
pantoprazole in human plasma '; J AOAC Int . Jul-Aug 2010;93(4):1129-36
10) Nevin Erk “Differential pulse anodic voltammetric determination of
pantoprazole in pharmaceutical dosage forms and human plasma using glassy
carbon electrode” Anal Biochem. 2003 Dec 1;323(1):48-53.doi:
10.1016/j.ab.2003.08.0232
11) M Tanaka , H Yamazaki, Y Ryokawa, et al; Pharmacokinetics and tolerance of
pantoprazole, a proton pump inhibitor after single and multiple oral doses in
healthy Japanese volunteers; Int J Clin Pharmacol Ther . 1996 Oct;34(10):415-9.
12) R Huber , M Hartmann, H Bliesath,.et al. “Pharmacokinetics of pantoprazole in
man '; Int J Clin Pharmacol Ther . 1996 May;34(1 Suppl):S7-16.
13) R Ozgur Karaca , Said Kalkisim , Akif Altinbas, et al; Effects of Genetic
Polymorphisms of Cytochrome P450 Enzymes and MDR1 Transporter on
Pantoprazole Metabolism and Helicobacter pylori Eradication; Basic Clin
Pharmacol Toxicol. 2017 Feb;120(2):199-206. doi: 10.1111/bcpt.12667. Epub
2016 Nov 2
14) Sieglinde Kofler 1 , Christine Wolf, Natalija Shvets, et al.; The proton pump
inhibitor pantoprazole and its interaction with enteric-coated mycophenolate
sodium in transplant recipients; J Heart Lung Transplant. 2011 May;30(5):565-
71. doi: 10.1016/j.healun.2010.12.003. Epub 2011 Jan 21.
15) Zhimin Chen , Fangliang Gan , Xiali Rao et al; Pharmacokinetics,
Bioequivalence, and Safety Studies of Pantoprazole Sodium Enteric-Coated
Tablets in Healthy Subjects '; Clin Pharmacol Drug Dev . 2021 May;10(5):502-
509. doi: 10.1002/cpdd.888. Epub 2020 Oct 31.
16) W Knebel , B Tammara, C Udata, et al “Population pharmacokinetic modeling
of pantoprazole in pediatric patients from birth to 16 years” J Clin Pharmacol.
2011 Mar;51(3):333-45. doi: 10.1177/0091270010366146. Epub 2010 May 19
MODULE 5
TAHAZOLE
(Pantoprazole Sodium Delayed-Release Tablets USP 40 mg)

17) Robert M Ward , Brinda Tammara, Sandra E Sullivan, et al “Single-dose,

multiple-dose, and population pharmacokinetics of pantoprazole in neonates
and preterm infants with a clinical diagnosis of gastroesophageal reflux disease
(GERD); Eur J Clin Pharmacol. 2010 Jun;66(6):555-61 doi: 10.1007/s00228-010-
0811-8. Epub 2010 Mar 20
18) I Nilsson-Ehle, H Fellner, S A Hedström “CYP2C19 polymorphism affects
single-dose pharmacokinetics of oral pantoprazole in healthy volunteers” Eur J
Clin Pharmacol. 2012 Sep;68(9):1267-74. doi: 10.1007/s00228-012-1252-3. Epub
2012 Mar 15.
19) Morton Scheinberg , Henrique Pott Júnior , Eduardo de Almeida Macêdo. et al
“Efficacy and safety of a fixed-dose combination of nimesulide/pantoprazole
compared to naproxen/esomeprazole for pain relief in patients with
osteoarticular diseases and dyspeptic symptoms; Drug Des Devel Ther. 2018 Sep
6;12:2775-2783. doi: 10.2147/DDDT.S172068. eCollection 2018
20) T Scholten , C P M Dekkers, K Schütze et al; On-demand therapy with
pantoprazole 20 mg as effective long-term management of reflux disease in
patients with mild GERD: the ORION trial; Digestion. 2005;72(2-3):76-85. doi:
10.1159/000087661. Epub 2005 Aug 19.