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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 doctor’s 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%

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.

In single dose clinical pharmacology studies, pantoprazole was administered to fasting healthy volunteers concomitantly with combinations of amoxicillin, clarithromycin, and/or metronidazole. Pharmacokinetic characteristics of each of the subject medications administered alone were also evaluated as a reference point. Equivalence between the test (i.e., in combination regimen) and the respective reference was concluded when the 90% confidence interval was within the equivalence range of 0.67 to 1.50 for the AUC0-¥ and Cmax.

The potential influence of the concomitant administration of pantoprazole 40 mg with clarithromycin 500 mg and metronidazole 500 mg on pharmacokinetic characteristics was evaluated following a single oral dose administered to fasted healthy volunteers. A lack of interaction was shown for each of the drugs (see Table 4 below).

Table 4: Point estimates and 90% CIs for the respective ratios of Test/Ref*
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

Concomitant administration was well tolerated, with no clinically relevant changes in vital signs, ECG, or clinical laboratory parameters noted.

The potential influence of the concomitant administration of pantoprazole 40 mg with clarithromycin 500 mg and amoxicillin 1000 mg on pharmacokinetic characteristics was also evaluated following a single oral dose administered to fasted healthy volunteers. A lack of interaction was shown for each of the drugs (see Table 5 below).

Table 5: Point estimates and 90% CIs for the respective ratios of Test/Ref*
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

Concomitant administration was well tolerated, with no clinically relevant changes in vital signs, ECG, or clinical laboratory parameters noted.

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 6: 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.

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.

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Date of Preparation: September 23, 1996
Revision Date: October 23, 2002

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