PrPANTO®
IV (Pantoprazole sodium for Injection)
40 mg pantoprazole/vial
THERAPEUTIC CLASSIFICATION
H+, K+-ATPase Inhibitor
TABLE OF CONTENTS
ACTION AND CLINICAL PHARMACOLOGY
INDICATIONS AND CLINICAL USE
CONTRAINDICATIONS
WARNINGS
Use
in pregnancy
Use
in nursing mothers
Use
in children
PRECAUTIONS
Patient
monitoring
Use
in the elderly
Hepatic
insufficiency
Renal
insufficiency
Drug
interactions
Carcinogenicity
ADVERSE REACTIONS
SYMPTOMS AND TREATMENT OF OVERDOSAGE
DOSAGE AND ADMINISTRATION
PHARMACEUTICAL INFORMATION
DRUG
SUBSTANCE
COMPOSITION
STABILITY AND STORAGE RECOMMENDATIONS
PARENTERAL PRODUCTS
AVAILABILITY OF DOSAGE FORMS
PHARMACOLOGY
ANIMAL PHARMACOLOGY
Pharmacodynamics
Pharmacokinetics
HUMAN PHARMACOLOGY
Pharmacodynamics
Pharmacokinetics
TOXICOLOGY
Acute
toxicity
Local
tolerance
Chronic
toxicity
Carcinogenicity
Mutagenicity
Reproduction
and teratology
REFERENCES
ACTION AND CLINICAL PHARMACOLOGY
PANTO® IV
(pantoprazole sodium for injection) 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.
Pantoprazole sodium 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/L with a tmax
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
PANTO®IV (pantoprazole sodium for injection) is indicated for the treatment of conditions where a rapid reduction of gastric acid secretion is required, such as reflux esophagitis in hospitalized patients who cannot tolerate oral medication.
CONTRAINDICATIONS
PANTO® IV (pantoprazole sodium for injection) is contraindicated in patients with a history of hypersensitivity to pantoprazole sodium.
WARNINGS
When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with PANTO® IV (pantoprazole sodium for injection) 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
Patient monitoring
Critically ill patients should be monitored carefully for any unexpected side
effects.
Use in the elderly
A slight increase in AUC (12%) and Cmax (7%) for oral 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 food consumption 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.
Carcinogenicity
Effects on 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 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 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.
ADVERSE REACTIONS
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 2,082 patients exposed to oral pantoprazole sodium and in two clinical trials in 286 patients who received pantoprazole i.v..
The following adverse events
(at a rate of at least 0.5%) have been reported in individuals receiving oral
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%).
No unexpected adverse events have been reported with pantoprazole sodium.
In two pantoprazole i.v. studies 16 of the 286 patients (6%) spontaneously reported
a total number of 16 adverse events during the i.v. treatment period. The following
adverse events classified by the investigators as likely related to the administration
of 40 mg pantoprazole i.v. were reported most frequently and judged by the clinical
expert of the report as already known possible side effects: diarrhea (0.3%),
headache (0.7%).
In addition, the following adverse events were reported in oral clinical trials:
Skin: Isolated cases of alopecia, acne, edema, maculopapular rash,
urticaria, exfoliative dermatitis.
Central and Peripheral Nervous System: Rare cases of somnolence, insomnia;
in isolated cases depression, vertigo, tremor, tinnitus, paresthesia, nervousness,
photophobia.
Sensory Organs: Isolated cases of blurred vision.
Gastrointestinal: 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.
Hepatic: In rare cases, increased liver enzymes.
Hematologic: Isolated cases of eosinophilia.
Other: In isolated cases, malaise, fever, myalgia and anaphylactic
shock.
Clinical Laboratory Findings: 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).
SYMPTOMS AND TREATMENT OF OVERDOSAGE
There are no known reports
or experiences of PANTO® IV (pantoprazole sodium for injection)
overdosage in man. Doses of up to 240 mg pantoprazole i.v. were administered
and were well tolerated.
Treatment should be supportive and symptomatic.
Hemodialysis does not influence the exposure.
DOSAGE AND ADMINISTRATION
The recommended adult dose
of PANTO®IV (pantoprazole sodium for injection) is one vial (40
mg pantoprazole) per day, administered either by slow intravenous injection
over 2 to 5 minutes, or by intravenous infusion over 15 minutes . Patients should
be switched to PANTOLOC† (pantoprazole sodium) tablet when feasible.
In switching, the same dose mg per mg should be administered. Divided doses
of up to 240 mg pantoprazole i.v. were administered and were well tolerated.
PANTO® IV has been administered for up to 7 days in clinical
trials.
For intravenous injection, a ready-to-use solution is prepared by injecting
10 mL of physiological sodium chloride solution into the vial containing the
dry substance. The resulting potency is 4 mg/mL of pantoprazole.
For intravenous infusion, the ready-to-use solution should be prepared as described
above. The ready-to-use solution should then be further diluted with 90 mL 0.9%
Sodium Chloride Injection USP, or 90 mL of 5% Dextrose Injection. The resulting
potency of the diluted solution is 0.4 mg/mL of pantoprazole.
After preparation, the reconstituted (ready-to-use) solution or the further
diluted solution for intravenous infusion must be used within six hours of initial
puncture of the stopper. As with all parenteral admixtures, the reconstituted
or further diluted solution should be examined for change in colour, precipitation,
haziness or leakage. Discard unused portion.
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: | Each vial
contains 40 mg pantoprazole (42.3 mg antoprazole sodium). The lyophilization process removes most of the water of hydration from the sesquihydrate starting material. |
| Nonmedicinal: | There are no non-medicinal ingredients. |
STABILITY AND STORAGE RECOMMENDATIONS
Store at 15°C to 30°C and protect from light. The reconstituted (ready-to-use)
solution must be used within six hours of initial puncture of the stopper.
PARENTERAL PRODUCTS
Intravenous Injection
0.9% Sodium Chloride Injection USP
Vial
Size (mL) |
Volume
of Diluent to be Added to Vial (mL) |
Approximate Available Volume |
Nominal
Concentration per mL |
12 |
10 |
10 |
4
mg |
For intravenous injection, a ready-to-use solution is prepared by injecting 10 mL of physiological sodium chloride solution into the vial containing the dry substance. The resulting potency is 4 mg/mL of pantoprazole.
Intravenous Infusion
Prepare as above; then,
1) 0.9% Sodium Chloride Injection USP
| Volume of ready-to- use solution (mL) |
Volume of Diluent (mL) |
Approximate Available Volume |
Nominal Concentration per mL |
10 |
90 |
100 |
0.4 mg |
2) 5% Dextrose Injection, USP
| Volume of ready-to- use solution (mL) |
Volume of Diluent (mL) |
Approximate Available Volume |
Nominal Concentration per mL |
| 10 |
90 |
100 |
0.4 mg |
For intravenous infusion: the solution is prepared by injecting
10 mL of physiological sodium chloride solution into the vial containing the
dry substance. The ready-to-use solution should then be further diluted with
90 mL of 0.9% Sodium Chloride Injection USP, or 90 mL of 5% Dextrose Injection
USP.
Both the ready-to-use solution and the further diluted solution must be used
within 6 hours of preparation. As with all parenteral admixtures, the reconstituted
or further diluted solution should be examined for change in colour, precipitation,
haziness or leakage. Discard unused portion.
When preparing the intravenous infusion, polyvinyl chloride (PVC) infusion bags
can be used. Incompatibilities of pantoprazole reconstituted solution in infusion
bags made with copolymer of ethylene and propylene have been observed. Therefore
these bags cannot be used in preparing pantoprazole intravenous infusion.
AVAILABILITY OF DOSAGE FORMS
PANTO®IV is available as 10 mL vials containing 40 mg pantoprazole
(42.3 mg pantoprazole sodium) as a lyophilized powder. Available in bundles
of 10 vials.
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.
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 |
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.
Local tolerance
Local tolerance of pantoprazole lyophilisate after a single intravenous, paravenous
or intra arterial injection in the rabbit or a single intramuscular injection
in the rat showed no evidence of toxicity.
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 as 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.
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.
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Date of Preparation: February
10, 1999
Revision Date: July 30, 2002
