PANTOLOC
(Pantoprazole sodium)
20 and 40 mg Enteric-Coated Tablet
THERAPEUTIC CLASSIFICATION
H+, K+-ATPase Inhibitor
Note: As with all proton pump inhibitors, when PANTOLOC is prescribed in combination with clarithromycin, amoxicillin or metronidazole for the eradication of an H. pylori infection, the Product Monograph for the antibiotics used should be consulted and followed.
ACTION AND CLINICAL PHARMACOLOGY
PANTOLOC (pantoprazole
sodium) is a specific inhibitor of the gastric H+, K+-ATPase
enzyme (the proton pump) that is responsible for acid secretion by the parietal
cells of the stomach.
Pantoprazole sodium is a substituted benzimidazole that accumulates in the acidic
environment of the parietal cells after absorption. Pantoprazole sodium is then
converted into the active form, a cyclic sulphenamide, which binds to the H+,
K+-ATPase, thus inhibiting both the basal and stimulated gastric
acid secretion. Pantoprazole sodium exerts its effect in an acidic environment
(pH < 3), and it is mostly inactive at higher pH. Its pharmacological and
therapeutic effect is achieved in the acid-secretory parietal cells.
In clinical studies investigating intravenous (i.v.) and oral administration,
pantoprazole sodium inhibited pentagastrin-stimulated gastric acid secretion.
With a daily oral dose of 40 mg, inhibition was 51% on Day 1 and 85% on Day
7. Basal 24-hour acidity was reduced by 37% and 98% on Days 1 and 7, respectively.
Fasting gastrin values increased during pantoprazole treatment, but in most
cases the increase was only moderate. An extensive evaluation of clinical laboratory
results has not revealed any clinically important changes during pantoprazole
sodium treatment (except for gastrin which increased to 1.5- fold after 4 to
8 weeks).
Treatment with pantoprazole alone has a limited effect on infections of Helicobacter
pylori, a bacterium implicated as a major pathogen in peptic ulcer disease.
Approximately 90- 100% of patients with duodenal ulcers, and 80% of patients
with gastric ulcers, are H. pylori positive. Preclinical evidence suggests
that there is a synergistic effect between pantoprazole and selected antibiotics
in eradicating H. pylori. In infected patients, eradication of the
infection with pantoprazole and appropriate antibiotic therapy leads to ulcer
healing, accompanied by symptom relief and a decreased rate of ulcer recurrence.
In single dose clinical pharmacology studies, pantoprazole was administered
concomitantly with combinations of amoxicillin, clarithromycin, and/or metronidazole.
When a single dose of pantoprazole was administered to healthy volunteers in
combination with metronidazole plus amoxicillin, with clarithromycin plus metronidazole,
or with clarithromycin plus amoxicillin, lack of interaction between any of
the medications was shown.
Pantoprazole sodium alone is absorbed rapidly following administration of a
40 mg enteric coated tablet. Its oral bioavailability compared to the i.v. dosage
form is 77% and does not change upon multiple dosing. Following an oral dose
of 40 mg, C max is approximately 2.5 mg/mL
with a t
max
of 2 to 3 h. The AUC is approximately 5 mg.h/L. Pantoprazole sodium shows linear
pharmacokinetics after both i.v. and oral administration. Therefore, elimination
half-life, clearance and volume of distribution are independent of the dose.
Concomitant intake of food has no influence on the bioavailability of pantoprazole
sodium.
Studies with pantoprazole sodium in humans reveal no inhibition or activation
of the cytochrome P450 (CYP 450) system of the liver.
Pantoprazole sodium is 98% bound to serum proteins. It is almost completely
metabolized in the liver. Renal elimination represents the major route of excretion
(about 82%) for the metabolites of pantoprazole sodium, the remaining metabolites
are excreted in feces. The main metabolite in both the serum and urine is desmethylpantoprazole
as a sulphate conjugate. The half-life of the main metabolite (about 1.5 hours)
is not much longer than that of pantoprazole sodium (approximately 1 hour).
INDICATIONS AND CLINICAL USE
PANTOLOC (pantoprazole sodium) is indicated for the treatment of conditions where a reduction of gastric acid secretion is required, such as the following:
| | Duodenal ulcer |
| | Gastric ulcer |
| | Reflux esophagitis |
| | Symptomatic
gastro-esophageal reflux disease (such as, acid regurgitation and heartburn). In a US placebo-controlled study involving 538 patients, a significantly greater proportion of patients taking Pantoloc 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation starting from the first day of treatment compared with placebo. Patients taking Pantoloc consumed significantly fewer antacid tablets per day than those taking placebo. In a second US study involving 215 patients, a significantly greater proportion of the patients in the Pantoloc treatment groups experienced complete relief of nighttime heartburn and regurgitation starting on the first day and of daytime heartburn on the second day compared with those taking nizatidine 150 mg twice daily. Patients taking Pantoloc consumed significantly fewer antacid tablets per day than those taking nizatidine. |
| | Helicobacter
pylori associated duodenal ulcer Pantoprazole, in combination with clarithromycin and either amoxicillin or metronidazole, is indicated for the treatment of patients with an active duodenal ulcer who are H. pylori positive. Clinical trials using combinations of pantoprazole with appropriate antibiotics have indicated that such combinations are successful in eradicating H. pylori |
Results of studies in patients with active duodenal ulcer who were H. pylori positive
Treatment |
Eradication
Rate (ITT + kpa analysis) |
95%
CI |
Ulcer
Healing Rate after therapy cessation (MITT analysis) |
95%
CI |
|
Pantoprazole 40 mg + clarithromycin 500 mg + metronidazole 500 mg, all twice daily for 1 week (PCM) |
Study
1 |
83% |
75-90% |
88%
|
80-93% |
Study
2 |
96% |
91-98% |
Not
assessed |
||
Pantoprazole
40 mg + amoxicillin 1000 mg + clarithromycin 500 mg, all twice daily for 1 week (PAC) |
Study
2 |
93% |
88-97% |
Not
assessed |
|
Study
3 |
86% |
68-96% |
88% |
72-97% |
|
Study
4 |
86% |
74-94% |
92% |
82-97% |
|
| ITT
+ kpa: Patients who were H. pylori positive at the initial examination and
had complete and valid results for the requisite (based on the study) number
of tests at the appropriate follow-up visit. In study 1, 3 of 4 H. pylori
tests must be complete and valid. Study 1: Patients with active duodenal ulcer, were assessed for H. pylori status by UBT, histology, culture and rapid urease, n=213 (ITT + kpa) Study 2: Patients with active duodenal ulcer, were assessed for H. pylori status by UBT and rapid urease pretreament and by UBT post-treatment, n=283 (ITT + kpa) Study 3: Patients with active duodenal ulcer, were assessed for H. pylori status by rapid urease and UBT pretreatment and by UBT and histology post-treatment, n=62 (ITT + kpa) Study 4: Patients with active duodenal ulcer, were assessed for H. pylori status by rapid urease, culture and histology pre-treatment and culture and histology post-treatment, n=57 (ITT + kpa) |
For the maintenance treatment of patients with reflux esophagitis and the rapid resolution of symptoms associated with reflux esophagitis, such as heartburn, regurgitation and dyspepsia, 20 mg pantoprazole once daily in the morning has been used for up to 12 months in controlled clinical trials, and in continuous maintenance treatment, in a limited number of patients for up to eight years.
CONTRAINDICATIONS
PANTOLOC (pantoprazole
sodium) is contraindicated in patients with a history of hypersensitivity to
pantoprazole sodium or to any constituents of the medication (see PHARMACEUTICAL
INFORMATION).
WARNINGS
When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with PANTOLOC (pantoprazole sodium) is instituted since treatment with pantoprazole sodium may alleviate symptoms and delay diagnosis.
Use in Pregnancy
There are no adequate or well-controlled studies in pregnant women. Pantoprazole sodium should not be administered to pregnant women unless the expected benefits outweigh the potential risks to the fetus (see also information under REPRODUCTION AND TERATOLOGY).
Use in Nursing Mothers
It is not known whether pantoprazole sodium is secreted in human milk. Pantoprazole sodium should not be given to nursing mothers unless its use is believed to outweigh the potential risks to the infant.
Use in Children
The safety and effectiveness of pantoprazole sodium in children has not yet been established.
PRECAUTIONS
Carcinogenicity
Effects of long-term treatment relate to hypergastrinemia, possible enterochromaffin-like
(ECL) cell hyperplasia and carcinoid formation in the stomach, adenomas and
carcinomas in the liver and neoplastic changes in the thyroid.
In a 24 month carcinogenicity study, Sprague-Dawley (SD) rats were treated orally
with PANTOLOC ( pantoprazole sodium) at 0.5, 5, 50, and 200 mg/kg/day.
Pantoprazole sodium produced gastric (ECL) cell hyperplasia and ECL cell carcinoid
at doses of 50 mg/kg/day and above in males and at 0.5 mg/kg/day and above in
females (first finding after 17 months treatment). In a 24 month carcinogenicity
study in Fischer rats (treated orally with pantoprazole sodium at 5, 15, and
50 mg/kg/day), no metastases from any gastric neuroendrocrine cell tumours was
detected. The mechanism leading to the formation of gastric carcinoids is considered
to be due to the elevated gastrin level occurring in the rat during chronic
treatment. Similar observations have also been made after administration of
other acid secretion inhibitors.
ECL-cell neoplasms were not observed in a 24 month carcinogenicity study in
mice which were treated orally with pantoprazole sodium at 5, 25, and 150 mg/kg/day.
In clinical studies with treatment of 40 to 80 mg of pantoprazole for 1 year,
ECL-cell density remained almost unchanged. (For further details, see TOXICOLOGY).
In the liver of the rat and female mouse, hepatocellular tumor formation was
seen with pantoprazole sodium. In rats, slightly increased liver tumor incidences
were found at 50 mg/kg and above, and in the female mouse at 150 mg/kg. Hepatocellular
tumors are common in mice, and the incidence found for the female 150 mg/kg
group was within historical control ranges for this strain. The liver tumor
incidences in rats treated with 50
mg/kg and in the male rats treated with 200 mg/kg were also within historical
control incidences for the SD rat. These tumors occurred late in the life of
the animals and were primarily benign. The nongenotoxic mechanism of rodent
liver tumor formation after prolonged treatment with pantoprazole sodium is
associated with enzyme induction leading to hepatomegaly and centrilobular hypertrophy
and is characterized by tumor induction in
low incidences at high doses only. Clinical pharmacological studies with pantoprazole
sodium show no induction or inhibition of human liver enzymes. Hepatocellular
tumors in rodents exposed to high levels of pantoprazole sodium are not indicative
of human carcinogenic risk.
A slight increase in neoplastic changes of the thyroid was observed in rats
receiving pantoprazole sodium at 200 mg/kg/day. The incidences of these thyroid
tumors were within the historical control ranges for this rat strain. The effect
of pantoprazole sodium on the thyroid is secondary to the effects on liver enzyme
induction, leading to enhanced metabolism of thyroid hormones in the liver.
As a consequence, increased TSH is produced, having a trophic effect on the
thyroid gland. Clinical studies have demonstrated that neither liver enzyme
induction nor changes in thyroid hormonal parameters occur in man after therapeutic
doses of pantoprazole sodium. (For further details, see TOXICOLOGY).
Short-term and long-term treatment with PANTOLOC (pantoprazole sodium)
in a limited number of patients up to 6 years have not resulted in any significant
pathological changes in gastric oxyntic exocrine cells.
Use
in the elderly
A slight increase in AUC (12%) and Cmax (7%) for pantoprazole sodium
occurs in elderly volunteers when compared to younger volunteers. The daily
dose used in elderly patients, as a rule, should not exceed the recommended
dosage regimens.
Hepatic
insufficiency
The half-life increased to between 7 and 9 h, the AUC increased by a factor
of 5 to 7, and the Cmax increased by a factor of 1.5 in patients
with liver cirrhosis compared with healthy subjects following administration
of 40 mg pantoprazole. Similarily, following administration of a 20 mg dose,
the AUC increased by a factor of 5.5 and the Cmax increased by a
factor of 1.3 in patients with severe liver cirrhosis compared with healthy
subjects. Considering the linear pharmacokinetics of pantoprazole, there is
an increase in AUC by a factor of 2.75 in patients with severe liver cirrhosis
following administration of a 20 mg dose compared to healthy volunteers following
administration of a 40 mg dose. Thus, the daily dose in patients with severe
liver disease should, as a rule, not exceed 20 mg pantoprazole.
Renal
insufficiency
No dose reduction is required when pantoprazole sodium is administered to patients
with impaired kidney function as the difference in AUCs between patients who
are dialyzed and those who are not is 4%.
Drug
interactions
Pantoprazole sodium is metabolized in the liver via the CYP 450 system. Pharmacokinetic
drug interaction studies in man did not demonstrate the inhibition of the oxidative
metabolism of the drug. Pantoprazole sodium does not interact with carbamazepine,
caffeine, diclofenac, ethanol, glibenclamide, metoprolol, antipyrine, diazepam,
phenytoin, nifedipine, theophylline, warfarin, digoxin, or oral contraceptives.
Concomitant use of antacids or consumption of food does not affect the pharmacokinetics
of pantoprazole sodium. Changes in absorption should be taken into account when
drugs whose absorption is pH dependent, e.g., ketoconazole, are taken concomitantly.
Clinical studies have shown that there is no pharmacokinetic interaction between
pantoprazole and the following antibiotic combinations: metronidazole plus clarithromycin,
metronidazole plus amoxicillin, amoxicillin plus clarithromycin.
In a preclinical study, pantoprazole in combination therapy with various antibiotics
(including tetracycline, clarithromycin, and amoxicillin) was shown to have
a potentiating effect on the elimination rate of Helicobacter pylori
infection. (See MICROBIOLOGY)
Other
Generally, daily treatment with any acid-blocking medicines over a long time
(e.g. longer than 3 years) may lead to malabsorption of cyanocobalamin caused
by hypo- or achlorhydria. Rare cases of cyanocobalamin deficiency under acid-blocking
therapy have been reported in the literature and should be considered if respective
clinical symptoms are observed.
ADVERSE REACTIONS
PANTOLOC (pantoprazole sodium) is well tolerated. Most adverse
events have been mild and transient showing no consistent relationship with
treatment. Adverse events have been recorded during controlled clinical investigations
in 2082 patients exposed to pantoprazole sodium as the single therapeutic agent
for treatment of conditions requiring acid suppression.
The following adverse events (at a rate of at least 0.5%) have been reported
in individuals receiving pantoprazole therapy (40 mg once daily) in controlled
clinical situations: diarrhea (1.5%), headache (1.3%), dizziness (0.7%), pruritus
(0.5%) and asthenia (0.3%).
The following adverse events were reported in clinical trials and/or post-marketing
reports:
Skin and Subcutaneous Tissue Disorders: Allergic reactions such as skin
rash. Angioedema, severe skin reactions such as Stevens-Johnson Syndrome, erythema
multiforme, and photosensitivity. Isolated cases of alopecia, acne, maculopapular
rash, urticaria, exfoliative dermatitis.
Nervous System Disorders: Disturbances in vision (blurred vision). Rare
cases of somnolence, insomnia; in isolated cases vertigo, tremor, tinnitus,
paresthesia, nervousness, photophobia.
Gastrointestinal Disorders: Occasionally upper abdominal pain, flatulence;
rare cases of increased appetite, dry mouth, nausea, constipation, dyspeptic
symptoms, acid eructation.
Urogenital: Isolated cases of hematuria and impotence.
Laboratory Parameters: In rare cases, increased liver enzymes (transaminases,
g-GT ), elevated triglycerides.
Hematologic: Isolated cases of eosinophilia.
General Disorders: Peripheral edema subsiding after termination of therapy,
increased body temperature subsiding after termination of therapy.
Hepatobillary Disorders: Severe hepatocellular damage leading to jaundice
with or without hepatic failure.
Immune System Disorders: Anaphylactic reactions including anaphylactic
shock.
Musculoskeletal, Connective Tissue and Bone Disorders: Myalgia subsiding
after termination of therapy.
Psychiatric Disorders: Mental depression subsiding after termination
of therapy.
Other: In isolated cases malaise.
A total of 1217 patients were treated with triple combination therapy including
pantoprazole and two antibiotics. Adverse events noted at a frequency of greater
than or equal to 1% when pantoprazole was used in combination with antibiotics
for the eradication of an H. pylori infection included the following:
In combination with clarithromycin and metronidazole (n=725):
Body as a Whole: headache (1.8%), tiredness (1.1%)
Central and Peripheral Nervous System: dizziness (1.4%)
Gastrointestinal: diarrhea (4.8%), nausea (3.7%), upper abdominal pain
(1.9%), tongue pain (1.2%), loose stools (1.0%), buccal inflammation (1.0%)
Liver/Biliary: hepatic enzymes increased (1.2%)
Special Senses: bitter taste (4.0%), metallic taste (2.1%)
In combination with amoxicillin and clarithromycin (n=492):
Body as a Whole: headache (1.8%), pain (1.0%)
Skin and Appendages: exanthema (1.2%)
Gastrointestinal: diarrhea (10.0%), bitter taste (3.0%), upper abdominal
pain (1.4%), nausea (1.2%)
Regardless of the combination regimen, the most frequently reported events were
gastrointestinal system disorders, followed by autonomic nervous system disorders
and body as a whole, or generalized disorders.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
Some reports of overdosage
with pantoprazole have been received. No consistent symptom profile was observed
after ingestion of high doses of pantoprazole. Doses of up to 240 mg i.v. were
administered and were well tolerated.
Treatment should be supportive and symptomatic. Pantoprazole is not removed
by hemodialysis.
DOSAGE AND ADMINISTRATION
Duodenal Ulcer
The recommended adult dose of PANTOLOC (pantoprazole sodium) for
the oral treatment of duodenal ulcer is 40 mg as pantoprazole given once daily
in the morning. Healing usually occurs within 2 weeks. For patients not healed
after this initial course of therapy, an additional course of 2 weeks is recommended.
Gastric Ulcer
The recommended adult oral dose of pantoprazole for the oral treatment of gastric
ulcer is 40 mg given once daily in the morning. Healing usually occurs within
4 weeks. For patients not healed after this initial course of therapy, an additional
course of 4 weeks is recommended.
Helicobacter Pylori Associated Duodenal Ulcer
Pantoprazole/Clarithromycin/Metronidazole Triple Combination Therapy:
The recommended dose for H. pylori eradication is treatment for seven
days with PANTOLOC 40 mg together with clarithromycin 500 mg and
metronidazole 500 mg, all twice daily.
Pantoprazole/Clarithromycin/Amoxicillin Triple Combination Therapy: The
recommended dose for H. pylori eradication is treatment for seven days
with PANTOLOC 40 mg together with clarithromycin 500 mg and amoxicillin
1000 mg, all twice daily.
Symptomatic Gastro-Esophageal Reflux Disease (Gerd)
The recommended adult oral dose for the treatment of symptoms of GERD, including
heartburn and regurgitation, is 40 mg once daily for up to 4 weeks. If significant
symptom relief is not obtained in 4 weeks, further investigation is required.
Reflux Esophagitis
The recommended adult oral dose of pantoprazole is 40 mg, given once daily in
the morning. In most patients, healing usually occurs within 4 weeks. For patients
not healed after this initial course of therapy, an additional 4 weeks of treatment
is recommended.
For the prevention of relapse in patients with reflux esophagitis, the recommended
adult oral dose is 20 mg pantoprazole given once daily in the morning, increased
to 40 mg once daily in the morning in the case of recurrence.
Pantoprazole sodium is formulated as an enteric-coated tablet. A whole tablet
should not be chewed or crushed, and should be swallowed with fluid in the morning
either before, during or after breakfast.
PHARMACEUTICAL INFORMATION
DRUG SUBSTANCE
| Proper Name: | pantoprazole sodium |
| Chemical Name: | Sodium-[5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyri-dinyl)-methyl]-sulfinyl]-1H-benzimidazolide sesquihydrate |
| Molecular Formula: | C16 H14 F2 N3 NaO4 S × 1.5 H2 O |
| Structural Formula: |  |
| Molecular Weight: | 432.4 |
| Physical Form: | White to off-white powder |
| Solubility: | Pantoprazole sodium
is freely soluble in ethanol, soluble in water, and slightly soluble in hexane. |
| pKa: | 3.92 pyridine; 8.19 benzimidazole |
| pH: | 1% aqueous solution:
10.05 10% aqueous solution: 10.85 |
| Melting point: | Because of gradual
degradation of pantoprazole sodium during heating, the melting point cannot be determined |
|
COMPOSITION |
|
| Active Ingredient: | Pantoprazole sodium
sesquihydrate 45.1 mg pantoprazole sodium sesquihydrate (corresponds to 40 mg pantoprazole /tablet) 22.6 mg (corresponds to 20 mg pantoprazole /tablet) |
| Nonmedicinal: | Calcium stearate, crospovidone,
ferric oxide, mannitol, methylhydroxypropyl cellulose, poly(ethylacrylate, methacrylic acid), polysorbate 80, polyvidone, propylene glycol, anhydrous sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate. |
STABILITY AND STORAGE CONDITIONS
Store at 15°C to 30°C in the recommended packaging.
AVAILABILITY OF DOSAGE FORMS
PANTOLOC (pantroprazole sodium) is available as enteric-coated
tablets for oral administration. PANTOLOC
40 mg tablets are yellow, oval, biconvex tablets marked P 40 on one side and
contain 40 mg pantoprazole (45.1 mg pantoprazole sodium sesquihydrate). PANTOLOC
20 mg tablets are yellow, oval, biconvex tablets marked P 20 on one side and
contain 20 mg pantoprazole (22.6 mg pantoprazole sodium sesquihydrate). PANTOLOC
tablets are available in bottles of 100 tablets.
Information for the Patient:
PANTOLOC (Pantoprazole sodium) Enteric Coated Tablets
Please read the following information carefully.
This (booklet/leaflet/sheet) contains general information about PANTOLOC. If
you need more specific information, ask your doctor or pharmacist. It is important
for you to follow carefully your doctor's instructions regarding how and when
to take PANTOLOC.
What is PANTOLOC used for and how does it work?
PANTOLOC is the brand name for the medication, pantoprazole sodium.
PANTOLOC is used to treat acid-related stomach problems such as stomach ulcers
(also known as gastric ulcers), duodenal ulcers (including ulcers that are associated
with a bacterium called Helicobacter pylori), reflux esophagitis (a
severe form of heartburn) and symptoms of gastro-esophageal reflux disease (heartburn
and acid regurgitation). Pantoloc works by reducing the amount of acid made
in your stomach.
Your doctor will have explained why you need to be treated with PANTOLOC and
will have told you what dose to take. Follow your doctors directions
carefully as they may be different from the information provided in this leaflet.
What is in PANTOLOC?
Each PANTOLOC tablet contains pantoprazole sodium as the active ingredient.
Other non-medicinal ingredients are: calcium stearate, crospovidone, ferric
oxide, mannitol, methylhydroxypropyl cellulose, poly(ethylacrylate, methacrylic
acid), polysorbate 80, polyvidone, propylene glycol, anhydrous sodium carbonate,
sodium lauryl sulfate, titanium dioxide, and triethyl citrate.
Check with your doctor if you think that you might be allergic to any of the
above ingredients.
What should I tell my doctor before taking PANTOLOC?
Tell your doctor:
- about all health problems you have now or have had in the past;
- about all other medicines you take, including ones you can get without a prescription;
- if you are allergic to "non-medicinal" substances which may be present
in "PANTOLOC" (See "What is in PANTOLOC?");
- if you are pregnant, plan to become pregnant or are breastfeeding.
How do I take PANTOLOC properly?
Your doctor has recommended you take PANTOLOC tablets for a specific number
of weeks. Keep taking PANTOLOC until you have finished all your tablets, as
recommended by your doctor. Do not stop even when you start to feel better.
If you stop taking PANTOLOC too soon, your symptoms may return.
If you forget to take one dose of PANTOLOC, take a tablet as soon as you remember,
unless it is almost time for your next dose. If it is, do not take the missed
tablet at all. Never double-up on a dose to make up for the one you have missed,
just go back to your regular schedule.
PANTOLOC may be taken in the morning, with or without food. Swallow the tablet(s)
whole, with water. Do not crush or chew the tablet(s).
PANTOLOC may be used in combination with two antibiotics to treat ulcers associated
with Helicobacter pylori. Doses of PANTOLOC and each of the antibiotics
should be taken twice a day, or as prescribed by your doctor.
Are there any side effects?
Like any medication, PANTOLOC may cause side effects in some people. When side
effects have been reported, they have been generally mild and did not last a
long time. Headache and diarrhea are the most common side effects; less often
rash, itchiness and dizziness can occur. If any of these become troublesome,
consult your doctor. If you experience any unusual or unexpected symptoms while
using PANTOLOC, consult your doctor.
What should I do in case of overdose?
If you or someone you know takes a lot more than the recommended dose (an overdose)
you should contact a doctor or pharmacist immediately. However, no severe symptoms
have been seen up to now in cases of overdose, or in patients following administration
of doses up to 240 mg.
Where should I keep PANTOLOC?
Keep your tablets at room temperature (15 to 30°C)
and in a safe place, where children cannot reach them.
Important Note:
This information is intended to alert you to some of the times when you should
call your doctor. Other situations which cannot be predicted may arise while
you are taking medicines. Nothing should stop you from calling your doctor with
any questions or concerns you have about using PANTOLOC.
PHARMACOLOGY
ANIMAL PHARMACOLOGY
Pharmacodynamics
Pantoprazole is a proton pump inhibitor. It inhibits H+,K+-ATPase,
the enzyme responsible for gastric acid secretion in the parietal cells of the
stomach, in a dose-dependent manner.
The drug is a substituted benzimidazole that accumulates in the acid canaliculi
of parietal cells after absorption. There, pantoprazole is converted into the
active form, a cyclic sulphenamide that binds selectively to the proton translocating
region of the H+,K+-ATPase. Pantoprazole's selectivity
is due to the fact that it only exerts its maximal effect in a strongly acidic
environment (pH < 3). Pantoprazole remains mostly inactive at higher pH values.
As pantoprazole action is distal to the receptor levels, it can inhibit gastric
acid secretion irrespective of the nature of the stimulus (acetylcholine, histamine,
gastrin).
In vivo, pantoprazole produced marked and long-lasting inhibition of
basal and stimulated gastric acid secretion with median effective dose ( ED50)
values ranging from 0.2 -2.4 mg/kg in rats and dogs. In addition to the administration
of single doses, pantoprazole has been tested upon repeated oral administration
(e.g. during 24-h pH-metry in dogs performed under pentagastrin stimulation).
While a dose of 1.2 mg/kg did not significantly elevate pH on Day 1, pH rose
to values between 4 and 7 after a 5-day dosing regimen. This effect was no longer
observed 18 hours after the last drug administration. In various gastric ulcer
models in the rat, pantoprazole showed antiulcer activity.
In parallel to the profound inhibition of gastric acid secretion, pantoprazole
induced a dose-dependent increase in serum gastrin levels up to values above
1000 pg/mL from a control level of about 100 pg/mL. As a consequence of persisting
hypergastrinemia in rats after high/doses of pantoprazole, hyperplastic changes
were observed in the fundic mucosa with an increased density of enterochromaffin-like
(ECL) cells. These changes were reversible during drug-free recovery periods.
In a battery of standard high-dose pharmacology tests, no influence of pantoprazole
was detected on the central and peripheral nervous system. In conscious dogs
as well as anaesthetized cats receiving single i.v. doses up to 10 mg/kg pantoprazole,
no consistent changes with respect to respiratory rate, ECG, EEG, blood pressure
and heart rate were observed. Higher doses led to modest and transient reductions
in blood pressure and variable changes in heart rate. No influence of pantoprazole
was found on renal function and on autonomic functions, such as pancreatic and
bile secretion, gastrointestinal motility and body temperature.
No consistent changes in the effects of ethanol, pentobarbitone, or hexobarbitone
were induced by pantoprazole; only doses over 300 mg/kg prolonged the effects
of diazepam.
Pharmacokinetics:
Absorption and Distribution
Pantoprazole is absorbed rapidly in both rat and dog. Peak plasma levels are
attained within 15 to 20 minutes in the rat and after about 1 hour in the dog.
Oral bioavailability is 33% in the rat and 49 % in the dog. Following absorption,
autoradiography and quantitative tissue distribution experiments have shown
that pantoprazole is rapidly distributed to extravascular sites. Following administration
of pantoprazole, distribution of radioactivity in the blood and most organs
is found to be uniform initially. After 16 hours, radiolabelled pantoprazole
is predominantly detected in the stomach wall. After 48 hours, all the administered
radioactivity is found to have been excreted. Penetration of the blood-brain
barrier by radiolabelled pantoprazole is very low. Protein binding in the rat
and dog is 95% and 86%, respectively.
Metabolism and Excretion
Pantoprazole is extensively metabolized. Oxidations and reductions at different
sites of the molecule, together with Phase II reactions (sulphation and glucuronidation)
and combinations thereof result in the formation of various metabolites. In
rats and dogs, 29-33% of the dose is excreted as urinary metabolites, and the
remainder as biliary/fecal metabolites. Almost no parent compound can be found
in the excreta.
Mammoglandular passage and transplacental transport has been investigated in
the rat using radiolabelled pantoprazole. A maximum of 0.23% of the administered
dose is excreted in the milk. Radioactivity penetrates the placenta with 0.1-0.2%
of the dose /g fetal tissue on the first day after oral administration.
HUMAN PHARMACOLOGY
Pharmacodynamics:
Pantoprazole is a potent inhibitor of gastric acid secretion. This was demonstrated
by use of a gastric acid aspiration technique as well as by continuous intragastric
pH monitoring. Using the aspiration technique it was also shown that pantoprazole
caused a dose-dependent reduction of secreted gastric acid volume.
| Table 1: Percent inhibition of pentagastrin-stimulated acid output (PSAO) in healthy volunteers following single oral doses of Pantoprazole vs. placebo during 4 to 7 hours post dosing. |
Dose |
Mean % Inhibition
of PSAO |
6 mg |
13% |
10 mg |
24% |
20 mg |
27% |
40 mg |
42% |
60 mg |
54% |
80 mg |
80% |
100 mg |
82% |
Time
of Day |
Median
pH |
||
Placebo |
Pantoprazole 40 mg |
Ranitidine
300 mg |
|
08.00-08.00
(24h) |
1.6 |
4.2* |
2.7 |
08.00-22.00 (Day Time) |
1.8 |
4.4* |
2.0 |
22.00-08.00 (Night Time) |
1.3 |
3.1 |
3.7 |
| * p<0.05 vs ranitidine |
40
mg |
80
mg |
|
3.8 |
3.85
|
n.s. |
| n.s. = not significant |
Metronidazole |
Clarithromycin |
Pantoprazole |
|
AUC0-¥
|
1.02
(0.99, 1.06) |
1.16
(1.04, 1.28) |
1.11
(0.98, 1.25) |
Cmax |
1.08
(0.99, 1.14) |
1.15
(0.91, 1.45) |
1.21
(1.06, 1.39) |
| * Ref = drug alone Test = combination |
Amoxicillin |
Clarithromycin |
Pantoprazole |
|
AUC0-¥
|
0.93
(0.85, 1.02) |
1.14
(1.00, 1.31) |
1.10
(1.03, 1.18) |
Cmax |
0.97 (0.86, 1.10) |
1.18
(1.00, 1.40) |
1.11
(0.94, 1.31) |
| * Ref = drug alone Test = combination |
SPECIES |
SEX |
ROUTE |
ca.
LD50* (mg/kg) |
Mouse |
M |
p.o. |
>100 |
F |
p.o. |
747 |
|
Mouse |
M |
i.v. |
399 |
F |
i.v. |
395 |
|
Rat |
M |
p.o. |
1343 |
F |
p.o. |
1037 |
|
Rat |
M |
i.v. |
330 |
F |
i.v. |
343 |
|
Dog |
M/F |
p.o. |
300-1000** |
M/F |
i.v. |
150-300 |
| * Doses refer to the
sodium salt administered in solution ** sodium salt as dry powder in gelatine capsules |
The symptoms seen after lethal oral or i.v. doses were similar in rats and mice:
the animals displayed ataxia, reduced activity, hypothermia and prostration.
Surviving animals recovered uneventfully. Salivation, tremor, lethargy, prostration
and coma were seen in dogs at lethal oral doses, with death occurring on the
following day. Ataxia, tremor and a prone position were noted at sublethal oral
and i.v. doses, but the survivors recovered quickly and appeared fully normal
after the 2-week observation period.
Chronic toxicity
Daily oral doses of pantoprazole in the 1- and 6-month SD rat repeated-dose
studies were 1, 5, 20, and 500 mg/kg and 0.8, 4, 16 and 320 mg/kg, respectively;
doses for the 1 month rat pantoprazole i.v. study were 1, 5, and 30 mg/kg.
A 12-month toxicity study in SD rats was conducted using daily oral doses of
5, 50, and 300 mg/kg. Daily oral doses in the 1- and 6 month (beagle) dog studies
were 7.5, 15, 30, and 100 mg/kg and 5, 15, 30, and 60 mg/kg respectively. In
the 12-month oral study in dogs, 2.5, 15, and 60 mg/kg were administered daily.
Hypergastrinemia was dose-related and was observed at all doses investigated
in the studies mentioned above, but was reversible upon cessation of treatment.
Drug-related effects on the stomach included increased stomach weights and morphologic
changes of the mucosa. In the 6-month rat study, increased stomach weight and
some cellular changes were detected at all doses. In the 1-month rat study,
gastric changes were detected at 5 mg/kg but not at 1 mg/kg. In dogs, increased
stomach weight was observed at all doses studied. There were no gastric cellular
changes detected at oral doses of 7.5 or 5 mg/kg in the 1- and 6-month dog studies,
respectively. In both species, most gastric effects were reversible after a
4- or 8-week recovery period. Hypergastrinemia and gastric changes were considered
to be the consequence of the pharmacological action of the compound, namely
prolonged and profound inhibition of acid secretion.
Increased liver weight in the rat experiments was considered to be a consequence
of the induction of hepatic drug metabolizing systems and was found to be associated
with centrilobular hepatocellular hypertrophy at 320 mg/kg in the 6-month study
and at 50 and 300 mg/kg after 12 months of treatment. Increased liver weights
were also detected at a dose of 16 mg/kg in male rats in the 6-month study and
at 500 mg/kg, but not 20 mg/kg, in the 1-month study. Increased liver weight
was noted in male dogs of all dose groups in the 1-month study, though only
at 100 mg/kg in females on the same study. Both males and females had increased
liver weights after 6 months administration of 30 or 60 mg/kg, but not of 15
mg/kg. In the 12-month study, liver weights were increased only in the female
dogs dosed with 60 mg/kg. There were no hepatic lesions that correlated with
increased liver weight in the dog studies. In dogs, the increase in liver weight
was attributed to an activation of hepatic drug metabolizing systems as mentioned
for rats.
Thyroid activation in animal experiments is due to the rapid metabolization
of thyroid hormones in the liver and has been described in a similar form for
other drugs. Thyroid weights were increased in both sexes at 500 mg/kg in the
1-month rat study and at 320 mg/kg in the rat 6-month study. Thyroid follicular
cell hypertrophy was noted in females at these doses, in rats treated with 50
and 300 mg/kg in the 12 month study and also in a few females at 16 mg/kg in
the 6 month study. There were no thyroid effects in rats at or below an oral
dose of 5 mg/kg even after 1 year. In the dog, no effects were seen on the thyroid
after 4 weeks. Only slight, but not dose-dependent, increases in thyroid weights
were seen after 6 months, but no changes were observed histologically. In the
12 month study, the relative thyroid weights in the 60 mg/kg group were only
slightly higher than those of the control dogs, and changes were detected histologically
in only a few animals under 15 and 60 mg/kg. In both species, changes were reversible.
Increased serum cholesterol values were noted in all groups in the 6- and 12
month dog studies and in all groups in the 12 month rat study. The increases
were slight and were reversible after cessation of treatment.
In dog studies, oral doses of pantoprazole of 15 mg/kg or above caused a transient
pulmonary edema in a proportion of naive dogs during the first week of drug
administration. Pulmonary edema caused death in a few dogs after repeated oral
doses of 15 mg/kg or above. There is strong evidence that the pulmonary toxicity
is due to a thiol metabolite which does not occur in man. No evidence of pulmonary
edema was detected in dogs at an oral dose of 7.5 mg/kg nor at 60 mg/kg when
administered daily for 6 or 12 months after a 1 week dose escalation phase.
In a four week oral toxicity study, Beagle dogs were given daily oral doses
of encapsulated commercial products including pantoprazole, clarithromycin,
metronidazole, and amoxicillin. Groups of three male and three female dogs received
the following daily doses of pantoprazole and/or antibiotics:
Group 1 - pantoprazole 16 mg/kg
Group 2 - clarithromycin 75 mg/kg + metronidazole 50 mg/kg
Group 3 - pantoprazole 16 mg/kg + amoxicillin 120 mg/kg + metronidazole 50 m/kg
Group 4 - pantoprazole 16 mg/kg + amoxicillin 120 mg/kg + clarithromycin 50
mg/kg
Group 5 - pantoprazole 16 mg/kg + clarithromycin 75 mg/kg + metronidazole 50
mg/kg
Histomorphological investigations indicated that treatment with clarithromycin
and metronidazole alone (Group 2) induced an atrophic gastritis, which was not
seen when these products were given concomitantly with pantoprazole. In Group
5, however, the total mucosal appearance was diagnosed as quite normal, and
the height of the mucosa was not decreased. In the recovery dogs, the mucosae
were also judged to be normal.
In all groups dosed with clarithromycin (Groups 2, 4, 5), inflammation and hyperplasia
of the gallbladder, together with degeneration of the renal papillawere noted.
These changes were absent from the Group 5 recovery dogs (only tubular swelling,
increased tubular pigment noted), indicating reversibility. A low centrilobular
hypertrophy was observed in the liver of most animals.
In dogs which had positive 13C-urea breath tests prior to treatment,
the Helicobacter-like organism responsible was eliminated in Groups 2 through
5, and remained eradicated in the Group 5 recovery animals.
Based on the results of this study, it was concluded that no additional toxic
effects were observed during concomitant administration of different antibiotics
with pantoprazole.
Carcinogenicity
Three carcinogenicity studies had been conducted:
- A 24 month oral study was conducted at doses of 0.5, 5, 50 and 200 mg/kg/day
in SD rat.
- A 24 month oral study was conducted at doses of 5, 15 and 50 mg/kg/day in
Fischer- 344 rats.
- A 24 month oral study was conducted at doses of 5, 25 and 150 mg/kg/day in
B6C3F1 mouse.
Pantoprazole, dissolved in distilled water, was administered once a day by oral
gavage to groups of 50 male and 50 female B6C3F1 mice at doses of 5, 25, or
150 mg/kg. An identical control group was dosed with distilled water (pH 10),
while a second identical control group received no treatment at all. In the
first rat study, pantoprazole was administered once a day by oral gavage to
groups of 70 male and 70 female SD rats at doses of 0.5, 5, 50, and 200 mg/kg.
A control group of 70 males and 70 females received the vehicle. In the second
rat study, pantoprazole was administered once a day by oral gavage to groups
of 50 male and 50 female Fischer-344 rats at doses of 5, 15, and 50 mg/kg. A
control group of 50 males and 50 females received the vehicle, while another
group remained untreated.
In the first 2 year carcinogenicity study in rats, which corresponds to a lifetime
treatment for rats, neuroendocrine neoplasms were found in the stomach at doses
of 50 mg/kg/day and above in males and at 0.5 mg/kg/day and above in females.
Tumor formation occurred late in the life of the animals (only after 17 months
treatment), whereas no tumors were found in rats treated with an even higher
dose for 1 year. The mechanism leading to the formation of gastric carcinoids
by substituted benzimidazoles has been carefully investigated, and it is considered
to be due to high levels of serum gastrin observed in the rat during chronic
treatment. In the second rat carcinogenicity study, neuroendocrine cell tumors
in the stomach were found in all treated female groups and in the male 15 and
50 mg/kg groups.
ECL-cell neoplasms were not observed in either the carcinogenicity study in
the mouse (24 months) or in the chronic studies in the dog. In clinical studies,
where pantoprazole was administered at doses up to 80 mg, ECL-cell density remained
almost unchanged.
Microscopy of the rat (first carcinogenicity study) and mouse tissues gave evidence
for an increase in liver tumors. In the rat experiment, the incidence of benign
liver tumors in the 50 and 200 mg/kg groups and the incidence of hepatocellular
carcinoma was increased in the males and females of the 200 mg/kg group. There
was a slightly higher incidence of hepatocellular adenomas and carcinomas in
the female mice of the 150 mg/kg group than in either of the 2 control groups.
Other changes in the liver morphology were present as well. Centrilobular hepatocellular
hypertrophy increased in incidence and severity with increasing dose, and hepatocellular
necrosis was increased in the highest dose in the rat and mouse studies. Hepatocellular
tumors are common in mice, and the incidence found for the female 150 mg/kg
group was within historical control ranges for this strain. The liver tumor
incidences in rats treated with 50 mg/kg and in the male rats treated with 200
mg/kg were also within historical control incidences for the rat. These tumors
occurred late in the life of the animals and were primarily benign. The nongenotoxic
mechanism of rodent liver tumor formation after prolonged treatment with pantoprazole
is associated with enzyme induction leading to hepatomegaly and centrilobular
hypertrophy and is characterized by tumor induction in low incidences at high
doses only. As pantoprazole acts in a similar fashion to phenobarbital, causing
reversible centrilobular hepatocellular hypertrophy and enzyme induction in
short-term studies, it is probable that the mechanism of action for induction
of the liver tumors seen in long-term rodent studies is also the same. Hepatocellular
tumors at high doses in rodents are not indicative of human carcinogenic risk.
A slight increase in neoplastic changes of the thyroid was observed in rats
receiving pantoprazole at 200 mg/kg/day. The incidences of these tumors were
within the historical control ranges for this rat strain. No thyroid neoplasms
were observed in the 12-month study. The no-effect dose for both male and female
rats is 50 mg/kg, which is 100 times the human dose. The effect of pantoprazole
on the thyroid is secondary to the effects on liver enzyme induction, which
lead to enhanced metabolism of thyroid hormones in the liver. As a consequence,
increased TSH is produced, which has a trophic effect on the thyroid gland.
Clinical studies have demonstrated that neither liver enzyme induction nor changes
in thyroid hormonal parameters occur in man after therapeutic doses of pantoprazole.
Tumors induced in rats and mice by pantoprazole were the result of nongenotoxic
mechanisms which are not relevant to humans. Tumors were induced in rodents
at dosages that provide higher exposure than with human therapeutic use. Based
on kinetic data, the exposure to pantoprazole in rats receiving 200 mg/kg was
22.5 times higher than that found in humans receiving 40 mg oral doses. In mice
receiving 150 mg/kg, exposure to pantoprazole was 2.5 times higher than that
in humans.
Mutagenicity
Pantoprazole was negative in eight mutagenicity studies: Ames test, chromosome
aberration test in human lymphocytes in vitro, in vivo chromosome
aberration assay in rat bone marrow, mouse lymphoma test, two gene mutation
tests in Chinese hamster ovary cells in vitro and two micronucleus
tests in mice in vivo. The three in vitro tests were conducted both
in the presence and absence of metabolic activation. In addition, the potential
of pantoprazole to induce DNA repair synthesis was tested in vitro
in an assay using rat hepatocytes. None of the tests indicated genotoxic activity.
In addition, two in vitro cell transformation assays using different
cell types were performed to aid in the interpretation of the rodent carcinogenicity
studies; in neither test did pantoprazole enhance the morphologic transformation
of the cell types used.
A bacterial mutation assay conducted with the degradation product B8810-044,
gave no indication of a mutagenic potential.
Reproduction and teratology
Pantoprazole was not teratogenic to rats or rabbits at doses up to 450 and 40
mg/kg/day (gavage), 20 and 15 mg/kg/day (i.v. injection), respectively.
Treatment of male rats with pantoprazole up to 500 mg/kg p.o. for 127 days did
not affect fertility. Treatment of pregnant rats induced dose-dependent fetotoxic
effects: increased pre and postnatal deaths (450 mg/kg/day), reduced fetal weight
and delayed skeletal ossification (150 mg/kg/day), and reduced pup weight (15
mg/kg/day). These results may be explained by maternal toxicity of pantoprazole
at high dose and/or placental transfer of pantoprazole.
Penetration of the placenta was investigated in the rat and was found to increase
with advanced gestation. As a result, concentration of pantoprazole in the fetus
is increased shortly before birth regardless of the route of administration.
In humans, there is no experience with the use of pantoprazole during pregnancy.
MICROBIOLOGY
In vivo Studies
Female mice were infected with Helicobacter felis on Days 1, 3, and
5 by gavage with 108 - 109 bacteria per animal. Starting
on Day 8, the mice were treated three times daily with placebo or active drug
(pantoprazole and/or amoxicillin, clarithromycin, tetracycline) for four days.
One day after the last treatment, the mice were sacrificed and a biopsy of the
antrum was subjected to a urease test, with only those tests showing a dark
violet colour considered to contain urease-positive Helicobacter.
Doses of the active agents, the number of infected animals per group, and resulting
elimination rates for the H. felis infection were as follows:
Active
Dosing Groups |
Elimination
Rates |
Pantoprazole
100 mg/kg tid (n=10) |
0% |
Amoxicillin
0.5 mg/kg tid (n=10) |
40% |
Amoxicillin
3.0 mg/kg tid (n=10 ) |
100% |
Clarithromycin
0.5 mg/kg tid (n=10) |
10% |
Clarithromycin
3.0 mg/kg tid (n=10) |
70% |
Tetracycline
3.0 mg/kg tid (n=20) |
55% |
Tetracycline
15.0 mg/kg tid ( n=10) |
90% |
Pantoprazole
100 mg/kg tid + amoxicillin 0.5 mg/kg tid (n=10) |
100% |
Pantoprazole
100 mg/kg tid + clarithromycin 0.5 mg/kg tid (n=10) |
90% |
Pantoprazole
100 mg/kg tid + tetracycline 3.0 mg/kg tid (n=20) |
80% |
In the infected, placebo
dosed positive control group, 24 of the 25 mice had positive urease tests, while
the negative control group (not infected, placebo dosed) all had negative urease
tests.
Pantoprazole alone was without effect on Helicobacter pylori infection,
while in combination therapy with the antibiotics, pantoprazole had a potentiating
effect on the elimination rate of Helicobacter pylori infection. The
results show a potentiation by a factor of about six, i.e., pantoprazole plus
the low dose antibiotic achieved an infection elimination rate greater than
or approximately equal to the higher dose of antibiotic given alone, which was
dosed at five to six times higher than the low dose.
REFERENCES
1. Gugler R., Hartmann M., Rudi J., Brod I., Huber R., Steinijans V.W., Bliesath
H., Wurst W., Klotz U.; Lack of pharmacokinetic interaction of pantoprazole
with diazepam in man; Br J Pharmacol 1996;42(2):249-252.
2. Hanauer G., Graf U., Meissner T.; In vivo cytochrome P-450 interactions
of the newly developed H+, K+-ATPase inhibitor Pantoprazole
(BY1023/SK&F96022) compared to other antiulcer drugs; Meth Find Exp
Clin Pharmacol 1991;13(1):63-67
.
3. Hannan A., Weil, J., Broom C., Walt RP.; Effects of oral Pantoprazole
on 24 hour intragastric acidity and plasma gastrin profiles; Aliment Pharmacol
Ther 1992; 6:373- 380.
4. Hartmann M., Theiß U., Bliesath H., Kuhn I., Lühmann R., Huber
R., Wurst W., Postius S., Lücker P.; 24 h intragastric pH following
oral intake of Pantoprazole and omeprazole; Hellenic J. Gastroenterol 1992;5(suppl.):112
(A No. 451).
5. Huber R, Hartmann M, Bliesath H, Luhmann R, Steinuans VW, Zech K. Pharmacokinetic
of pantoprazole in man; Internal J Clin Pharmacol Therap 1996;34:185-194.
6. Huber R, Kohl B, Sachs G, Senn-Bilfinger J, Simon WA, Sturm E. Review
article: the continuing development of proton pump inhibitors with particular
reference to pantoprazole; Aliment Pharmacol Ther 1995;9;363-378.
7. Judmaier G., Koelz H.R., Pantoprazole-duodenal ulcer-study group; Comparison
of pantoprazole and ranitidine in the treatment of acute duodenal ulcer;
Aliment Pharmacol Ther 1994;8:81-86.
8. Kliem V., Bahlmann J., Hartmann M., Huber R., Lühmann R., Wurst W.
Pharmacokinetics of pantoprazole with end-stage renal failure. Nephrol
Dial Transplant 1998;13:1189-1193.
9. Kohl B. et al.; (H+,K+)-ATPase inhibiting - 2-[(2-pyridylmethyl)suftinyl]
benzimidazoles. A novel series of dimethoxypyridyl-substituted inhibitors with
enhanced selectivity. The selection of Pantoprazole as a clinical candidate;
J Medicinal Chem 1992;35:1049-1057.
10. Mossner J., Holscher A.H., Herz R., Schneider A.; A double-blind study
of pantoprazole and omeprazole in the treatment of reflux oesophagitis: a multicentre
trial; Aliment Pharmacol Ther 1995;9:321-326.
11. Müller P., Simon B., Khalil H., Lühmann R., Leucht U., Schneider
A.; Dose-range finding study with the proton pump inhibitor Pantoprazole
in acute duodenal ulcer patients; Z Gastroenterol 1992;30:771-775.
12. Pue M.A., Laroche J., Meineke I., de Mey C.; Pharmacokinetics of Pantoprazole
following single intravenous and oral administration to healthy male subjects;
Eur J Clin Pharmacol 1993;44:575-578.
13. Report 305E/92; Pantoprazole and B8401-026. Effects on selected hepatic
drugmetabolizing enzyme activities following oral administration to female rats
for 4 weeks; Data on file, Byk Gulden.
14. Sachs G.; Gastric H, K-ATPase as therapeutic target; Ann Rev Pharmacol
Toxicol 1988;28:269-284.
15. Schulz H.-U., Hartmann M., Steinijans, V.W., Huber R., Luhrmann B., Bliesath
H., Wurst W.; Lack of influence of Pantoprazole on the disposition kinetics
of theophylline in man; Int J Clin Pharmacol Ther 1991;29(9):369-375.
16. Simon B., Müller P., Bliesath H., Lühmann R., Hartmann M., Huber
R., Wurst W.; Single intravenous administration of the H+,K+-ATPase inhibitor
BY1023/SK&F96022 - inhibition of pentagastrin-stimulated gastric acid secretion
and pharmacokinetics in man; Aliment Pharmacol Therap 1990a;4:239-245.
17. Simon B., Müller P., Hartmann M., Bliesath H., Lühmann R., Huber
R., Bohnenkamp W., Wurst W.; Pentagastrin-stimulated gastric acid secretion
and pharmacokinetics following single and repeated intravenous administration
of the gastric H+,K+-ATPase inhibitor Pantoprazole (BY1023/SK&F96022) in
healthy
volunteers; Z Gastroenterol 1990;28:443-447.
18. Simon B., Müller P., Marinis E., Lühmann R., Huber R., Hartmann
M., Wurst W.; Effect of repeated oral administration of BY1023/SK&F96022
- a new substituted benzimidazole derivative - on pentagastrin-stimulated gastric
acid secretion and pharmacokinetics in man; Aliment Pharmacol Therap 1990c;4:373-379.
19. Steinijans VW, Huber R, Hartmann M, Zech K, Bliesath H, Wurst W, Radtke
HW. Lack of pantoprazole drug interactions in man: an updated review;
Internal J Clin Pharmacol Therap 1996;34:S31-S50.
Date of Preparation: September
23, 1996
Revision Date: October 23, 2002
