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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.

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%

With 40 mg administered orally, effective inhibition of gastric acid secretion was achieved. Pantoprazole 40 mg was significantly superior to standard H2-blocker therapy (300 mg ranitidine at night) with regard to median 24-hour and daytime pH; however, not for nighttime measurements.

Table 2: Effects of one week oral treatment in healthy volunteers with placebo, Pantoprazole 40 mg in the morning, and standard ranitidine therapy with 300 mg in the evening
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

Increasing the once daily dose from 40 mg to 80 mg pantoprazole did not result in a significantly higher median 24-hour pH.

Table 3: Effect of oral Pantoprazole in healthy volunteers on median 24 hour pH on Day 7 (40 vs 80 mg).
40 mg
80 mg
3.8
3.85
n.s.
n.s. = not significant

Hence, once daily administration of 40 mg pantoprazole should be sufficient for the treatment of most patients with acid-related diseases.

Pharmacokinetics:
After oral intake, pantoprazole is absorbed with a bioavailability of 77% relative to i.v. dosing. Maximum serum concentrations of pantoprazole are reached within approximately 2.5 hours after oral intake. Following a dose of 40 mg pantoprazole, mean maximum serum concentrations of approximately 2
mg/mL and 3 mg/mL are reached after 2 to 3 hours. There is no food effect on AUC (bioavailability) and Cmax. However, time to reach maximum serum concentrations is slightly increased when the drug is given together with a high caloric breakfast. Taking into account the long duration of action of pantoprazole, which by far exceeds the time period over which serum concentrations are measurable, this observed variation in tmax is considered to be of no clinical importance.

Pantoprazole is approximately 98% bound to serum protein.

Despite its relatively short elimination half-life of approximately 1 hour, the antisecretory effect increases during repeated once daily administration, demonstrating that the duration of action markedly exceeds the serum elimination half-life. This means that there is no direct correlation between the serum concentrations and the pharmacodynamic action.

Morning administration of pantoprazole was significantly superior to evening dosing with regard to 24 hour intragastric pH, hence morning dosing should be recommended for the treatment of patients. Since the intake of the drug before a breakfast did not influence Cmax and AUC, which characterize rate and extent of absorption, no specific requirements for intake of pantoprazole in relation to breakfast are necessary.

Pantoprazole undergoes metabolic transformation in the liver. Approximately 82% of the oral dose is removed by renal excretion, and the remainder via feces. The main serum metabolites (M1-M3) are sulphate conjugates formed after demethylation at the pyridine moiety, the sulphoxide group being either retained (M2, main metabolite), or oxidized to a sulphone (M1), or reduced to a sulphide (M3). These metabolites also occur in the urine (main metabolite M2). Conjugates with glucuronic acid are also found in the urine.

Pantoprazole shows linear pharmacokinetics, i.e., AUC and Cmax increase in proportion with the dose within the dose-range of 10 to 80 mg pantoprazole after both i.v. and oral administration. Elimination half-life, clearance and volume of distribution are considered to be dose-independent. Following repeated i.v. or oral administration, the AUC of pantoprazole was similar to a single dose.

A slight increase in AUC (12%) and Cmax (7%) for pantoprazole occurs in elderly volunteers when compared with younger volunteers. The daily dose in elderly patients, as a rule, should not exceed the recommended dosage regimens.

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 pantopraozle.

No dose reduction is required when pantoprazole is administered to patients with impaired kidney function, because the difference in AUC between patients who underwent dialysis and those who did not is 4%. No induction of the CYP 450 system by pantoprazole was observed during chronic administration with antipyrine as a marker. Also, no inhibition of metabolism was observed after concomitant administration of pantoprazole with either diazepam, phenytoin, nifedipine, theophylline, digoxin or oral contraceptives. Concomitant administration of pantoprazole with warfarin has no influence on the anticoagulatory effect of warfarin.



TOXICOLOGY

Acute toxicity

In acute toxicity studies in mice the mean lethal dose (LD50) values for pantoprazole were found to be around 390 mg/kg bodyweight for i.v. administration and around 700 mg/kg bodyweight for oral administration.

In the rat the corresponding values were around 250 mg/kg for i.v. administration and > 1000 mg/kg for oral administration.

Acute toxicity studies were conducted on B8810-044, the major degradation product of pantoprazole. The approximate LD50 values for mice (119-167 mg/kg) and rats (73-82 mg/kg) were lower than those for pantoprazole itself, after intravenous injection, but the toxic symptoms were similar to those noted for the drug. A 4-week repeat dose study was also conducted using this degradation product using the intravenous route in rats. Rats received 5 and 25 mg of B8810-044/kg, while a comparison group received 25 mg/kg of pantoprazole. Muscle twitches were observed immediately after injection in rats receiving 25 mg/kg of the degradation product, but not in the pantoprazole-treated animals. Otherwise the compounds were comparable.

Table 4: Acute toxicity studies of Pantoprazole
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.

REFERENCES

Gugler R., Hartmann M., Rudi J., Bliesath H., Brod I., Klotz U., Huber R., Steinijans V.W., Wurst W.; Lack of interaction of pantoprazole and diazepam in man; Gastroenterol. 1992; 102 (suppl.):A77.

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. C. in Pharmacol. 1991; 13(1):63-67.

Hannan A., Well, J.; Effects of oral Pantoprazole on 24 hour intragastric acidity and plasma gastrin profiles; Aliment. Pharmacol. Ther. 1992; 6:373-380.

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).

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.

Huber R, Hartmann, M, Bliesath H, Luhmann R, Steinuans VW, Zech K. Pharmacokinetis of pantoprazole in man. Internal J Clin Pharmacol Therap 1996;34:185-194.

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.

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.

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.

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.

Report 104/92; Clinical efficacy and tolerability of 40 mg Pantoprazole once daily versus 20 mg omeprazole once daily in out-patients with Stage II or III reflux esophagitis; Data on file, Byk Gulden.

Report 75/92K1; Clinical efficacy and tolerability of Pantoprazole versus ranitidine in patients with florid duodenal ulcer - a binational multicenter randomized double-blind study; Data on file, Byk Gulden.

Sachs G.; Gastric H, K-ATPase as therapeutic target; Ann. Rev. Pharmacol. Toxicol. 1988; 28:269-284.

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. Toxicol. 1991; 9:369-375.

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.

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. 1990b; 9:443-447.

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.

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: February 10, 1999
Revision Date: July 30, 2002

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