Pantoloc (Pantoprazole)

PANTOLOC™

Solvay Pharma/Byk Canada

Pantoprazole

H KATPase Inhibitor

Action And Clinical Pharmacology: Pantoprazole is a specific inhibitor of the gastric H KATPase enzyme (the proton pump) that is responsible for acid secretion by the parietal cells of the stomach.

Pantoprazole is a substituted benzimidazole that accumulates in the acidic environment of the parietal cells after absorption. Pantroprazole is then converted into the active form, a cyclic sulfenamide, which binds to the H KATPase, thus inhibiting both the basal and stimulated gastric acid secretion. Pantoprazole exerts its effect in an acidic environment.
In clinical studies investigating i.v. and oral administration, pantoprazole 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.

Pharmacokinetics: Pantoprazole 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, Cmax is approximately 2.5 mg/L with a tmax of 2 to 3 hours. The AUC is approximately 5 mg.h/L. Pantoprazole 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.

Studies with pantoprazole in humans reveal no inhibition or activation of the cytochrome P450 (CYP 450) system of the liver.

Pantoprazole 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, the remaining metabolites are excreted in feces. The main metabolite in both the serum and urine is desmethylpantoprazole as a sulfate conjugate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole (approximately 1 hour).

Indications And Clinical Uses: For the treatment of conditions where a reduction of gastric acid secretion is required, such as the following: duodenal ulcer, gastric ulcer and reflux esophagitis.

Pantoprazole is not indicated for maintenance therapy. Until adequate long-term clinical data are available, pantoprazole should be prescribed only at the recommended dosage regimen (see Dosage).

Contra-Indications: Patients with a history of hypersensitivity to pantoprazole or to any constituents of the medication (see Supplied). It is also contraindicated in patients with cirrhosis of the liver and in cases of severe liver disease (see Precautions).

Manufacturers’ Warnings In Clinical States: When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with pantoprazole is instituted since treatment with pantoprazole may alleviate symptoms and delay diagnosis.

Pregnancy: There are no adequate or well-controlled studies in pregnant women. Pantoprazole should not be administered to pregnant women unless the expected benefits outweigh the potential risks to the fetus.

Lactation: It is not known whether pantoprazole is secreted in human milk. Pantoprazole should not be given to nursing mothers unless its use is believed to outweigh the potential risks to the infant.

Children: The safety and effectiveness of pantoprazole in children have not yet been established.

Precautions: 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 at 1.5, 5, 50, and 200 mg/kg/day. Pantoprazole 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). 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 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.

In the liver of the rat and female mouse, hepatocellular tumor formation was seen with pantoprazole. 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 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 show no induction or inhibition of human liver enzymes. Hepatocellular tumors in rodents exposed to high levels of pantoprazole 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 thyroid tumors were within the historical control ranges for this rat strain. The effect of pantoprazole 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.

The clinical implication of the above observations made in animal studies is not known. Until adequate long-term clinical data are available, pantoprazole should not be prescribed beyond the recommended dosage regimens.

Geriatrics: A slight increase in AUC (12%) and Cmax (7%) for pantoprazole 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 hours, 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. Pantoprazole should not be administered to patients with mild to moderate liver impairment unless the expected benefits outweigh the potential risks.

Renal Insufficiency: No dose reduction is required when pantoprazole 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 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 does not interact with 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.

Adverse Reactions: Pantoprazole 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 pantoprazole.

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%). No unexpected adverse events have been reported with pantoprazole.

In addition, the following adverse events were reported in clinical trials: Skin: isolated cases of alopecia, acne, edema, maculopapular rash, urticaria, exfoliative dermatitis.

Central and Peripheral Nervous Systems: rare cases of somnolence, insomnia; in isolated cases, depression, vertigo, tremor, tinnitus, paresthesia, nervousness, photophobia.

Sensory Organs: isolated cases of blurred vision.

Gastrointestinal: rare cases of increased appetite, dry mouth, nausea, constipation, dyspeptic symptoms, acid eructation; in one case, gastrointestinal carcinoma.

Urogenital: isolated cases of hematuria and impotence.

Hepatic: in rare cases, increased liver enzymes.

Hematologic: isolated cases of eosinophilia.

Other: in isolated cases, malaise.

An extensive evaluation of clinical laboratory results has not revealed any clinically important changes during pantoprazole treatment (except for gastrin which increased to 1.5-fold after 4 to 8 weeks).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There are no known reports or experiences of pantoprazole overdosage in man. Doses of up to 240 mg i.v. were administered and were well tolerated.

Treatment should be supportive and symptomatic.

Dosage And Administration: Duodenal Ulcer: The recommended adult oral dose is 40 mg 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 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.

Reflux Esophagitis: The recommended adult oral dose 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.

Pantoprazole is not indicated for maintenance therapy. Until adequate long-term clinical data are available, pantoprazole should be prescribed only according to the recommended dosage regimens.

Pantoprazole is formulated as an enteric-coated tablet. A whole tablet should not be chewed or crushed, and should be swallowed with water in the morning either before, during or after breakfast.

Availability And Storage: Each enteric-coated, yellow, oval, biconvex tablet, marked P 40 on one side, contains: pantoprazole 40 mg (pantoprazole sodium sesquihydrate 45.1 mg). Nonmedicinal ingredients: 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. Bottles of 14 and 28. Store at 15 to 30°C in the recommended packaging.

PANTOLOC Solvay Pharma/Byk Canada Pantoprazole H KATPase Inhibitor

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