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).

  
  

• Prevention of gastrointestinal lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs) in patients with a need for continuous NSAID treatment, who have increased risk to develop NSAID-associated upper gastrointestinal lesions.

  
  

• H. 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.

  
  

 

For the maintenance treatment of patients with reflux esophagitis and the resolution of symptoms associated with reflux esophagitis, such as heartburn, regurgitation and dyspepsia, 20 mg or 40 mg pantoprazole once daily have been used for 3 years in controlled clinical trials. In continuous maintenance treatment 20 mg pantoprazole has been used in a limited number of patients for up to eight years.

No dose adjustment is recommended based on age. The daily dose used in elderly patients, as a rule, should not exceed the recommended dosage regimens.

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

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

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.

Effects of long-term treatment include 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 the rat, the mechanism leading to the formation of gastric carcinoids is considered to be due to the elevated gastrin level occurring during chronic treatment. Similar observations have also been made after administration of other acid secretion inhibitors.

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.

The daily dose in patients with severe liver disease should, as a rule, not exceed 20 mg pantoprazole. See Action and Clinical Pharmacology, Special Populations and Conditions.

The daily dose used in renal insufficient patients, as a rule, should not exceed the recommended dosage regimens. See Action and Clinical Pharmacology, Special Populations and Conditions.

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.

Limited data is available around pantoprazole in nursing women. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose. The clinical relevance of this finding is not known. Pantoprazole sodium should not be given to nursing mothers unless its use is believed to outweigh the potential risks to the infant.

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

No dose adjustment is recommended based on age. The daily dose used in elderly patients, as a rule, should not exceed the recommended dosage regimens.

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 over 13 000 patients exposed to pantoprazole sodium as the single therapeutic agent for treatment of conditions requiring acid suppression.

The following adverse events (the most frequently reported) have been reported in individuals receiving pantoprazole therapy (40 mg once daily) in controlled clinical trials of at least 6 months duration: headache (2.1%), diarrhea (1.6%), nausea (1.2%).

The following adverse reactions considered possibly, probably, or definitely related by the investigator have been reported in individuals receiving pantoprazole therapy (20 mg or 40 mg once daily) in long-term clinical trials (duration of at least 6 months). There were a limited number of H. pylori positive patients in these studies and therefore, definitive conclusions with regard to long-term consequences of H. pylori infection and acid suppressive treatment on gastric inflammation in this sub-group cannot be made. See Table 1.

Table 1: PANTOLOC

Adverse Drug Reactions With a Frequency of ≥1%, Related to 40 mg Pantoprazole Assessed as Possibly, Probably or Definitely Related by the Investigator

Preferred term	Number of patients	Percentage of patients
Headache	24	2.137
Diarrhea	18	1.603
Nausea	13	1.158

For long-term treatment with 20 mg, no such events were reported with a frequency of more than 1%.

diarrhea, flatulence, abdominal pain, abdominal pain upper, abdominal distension, gastric polyps, loose stools, frequent bowel movements, eructation, dyspepsia, nausea, vomiting, constipation.

fatigue.

alanine aminotransferase increased, aspartate aminotransferase increased, liver function tests abnormal, transaminases increased.

hyperglycaemia.

headache, dizziness, vertigo.

pruritus, rash.

visual disturbance.

libido decreased.

blood pressure increased, hypertension, ECG abnormal.

flatulence, abdominal distension, abdominal pain, abdominal pain upper, loose stools, esophageal reflux aggravated, gastric polyps, abdominal discomfort, abdominal tenderness, constipation, eructation, vomiting, dyspepsia, gastroesophageal reflux, esophagitis.

fatigue, peripheral edema, pyrexia.

alanine aminotransferase increased, aspartate aminotransferase increased, liver function tests abnormal, transaminases increased.

hypertriglyceridaemia.

appetite decreased, weight increase.

dysgeusia, dizziness, migraine, vertigo.

cough.

pruritus, rash.

mouth dry, vision blurred.

neoplasm.

The following adverse reactions considered possibly, probably, or definitely related by the investigator have been reported in individuals receiving pantoprazole therapy (20 mg or 40 mg once daily) in short-term clinical trials (duration of up to 3 months).

diarrhea, flatulence, nausea, constipation, abdominal pain.

headache, dizziness.

pruritus.

In addition, the following adverse events considered unrelated, or unlikely related by the investigator have been reported in individuals receiving pantoprazole therapy (20 mg or 40 mg once daily) in short-term and long-term clinical trials.

influenza like illness, headache, diarrhea.

bronchitis, nausea, back pain, abdominal pain upper, upper respiratory tract infection, nonaccidental injury, sinusitis, abdominal pain, dizziness, arthralgia, vomiting, pharyngitis, chest pain, gastroenteritis, dyspepsia, urinary tract infection, eructation, pyrexia, cough, depression, hypertension, pain in limb, constipation, fatigue, operation, neck pain, nasopharyngitis, alanine aminotransferase increased, hemorrhoids, pain, flatulence, viral infection, hypertriglyceridaemia, toothache, hypersensitivity, rash, abdominal pain lower, pneumonia, abdominal distension, dyspnoea, muscle cramp, rhinitis, peripheral edema, tonsillitis, angina pectoris, cholelithiasis, sinus congestion, influenza, vertigo, insomnia, infection, osteoarthritis, hypercholesterolaemia, pruritis, eczema, sleep disorder, migraine, aspartate aminotransferase increased, hyperglycemia, musculoskeletal discomfort, blood triglycerides increased, myocardial infarction, tendonitis, weight increased, rectal hemorrhage, cystitis, nasal congestion, arthritis, contusion, abdominal discomfort, enteritis.

The following Serious Adverse Events regardless of causality were reported with a frequency of <0.1% in either 20 mg or 40 mg: sepsis.

A total of 1217 patients were treated with triple combination therapy including pantoprazole sodium and two antibiotics. Adverse events noted at a frequency of greater than or equal to 1% when pantoprazole sodium 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):

headache (1.8%), tiredness (1.1%).

dizziness (1.4%).

diarrhea (4.8%), nausea (3.7%), upper abdominal pain (1.9%), tongue pain (1.2%), loose stools (1.0%), buccal inflammation (1.0%).

hepatic enzymes increased (1.2%).

bitter taste (4.0%), metallic taste (2.1%).

In combination with amoxicillin and clarithromycin (n=492):

headache (1.8%), pain (1.0%).

exanthema (1.2%).

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.

Please refer to the Hepatobiliary Disorders and the Laboratory Parameters portions of the Adverse Reaction; Action and Clinical Pharmacology, Special Populations and Conditions; and Warnings and Precautions, Hepatic/Biliary/Pancreatic.

The following adverse events were reported in post-marketing use and causal relation to pantoprazole sodium treatment could not be ruled out:

allergic reactions such as skin rash. Very rare cases of angioedema, severe skin reactions such as Stevens-Johnson Syndrome, erythema multiforme, toxic epidermal necrolysis, and photosensitivity. Isolated cases of alopecia, acne, maculopapular rash, urticaria, exfoliative dermatitis.

hypokinesia, disturbances in vision (blurred vision). Rare cases of somnolence, insomnia; in isolated cases vertigo, tremor, tinnitus, paresthesia, nervousness, photophobia.

anterior ischemic optic neuropathy.

occasionally upper abdominal pain, flatulence; rare cases of increased appetite, dry mouth, nausea/vomiting, constipation, dyspeptic symptoms, acid eructation, pancreatitis, increased salivation.

isolated cases of hematuria and impotence. Interstitial nephritis.

in rare cases, increased liver enzymes (transaminases, γ-GT), elevated triglycerides.

pancytopenia, isolated cases of eosinophilia. Very rare cases of leukopenia, and thrombocytopenia.

speech disorder, very rare cases of peripheral edema, increased body temperature.

very rare cases of severe hepatocellular damage leading to jaundice with or without hepatic failure.

anaphylactic reactions including anaphylactic shock.

elevated creatine phosphokinase, in rare cases, myalgia and arthralgia. In very rare cases rhabdomyolysis.

confusion, very rare cases of mental depression.

in isolated cases malaise.

Pantoprazole undergoes extensive hepatic metabolism via cytochrome P450-mediated oxidation followed by sulphate conjugation via a Phase II reaction (non-saturable, non-cytochrome P450 dependent). Pharmacokinetic drug interaction studies in man did not demonstrate the inhibition of the oxidative metabolism of the drug. No induction of the CYP 450 system by pantoprazole was observed during chronic administration of pantoprazole sodium with antipyrine as a marker. Changes in absorption should be taken into account when drugs whose absorption is pH dependent, e.g., ketoconazole, are taken concomitantly.

Pantoprazole sodium does not interact with carbamazepine, caffeine, diclofenac, naproxen, piroxicam, ethanol, glibenclamide, metoprolol, antipyrine, diazepam, phenytoin, nifedipine, theophylline, digoxin, oral contraceptives, or cyclosporine. Concomitant use of antacids does not affect the pharmacokinetics of pantoprazole sodium.

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 sodium in combination therapy with various antibiotics (including tetracycline, clarithromycin, and amoxicillin) was shown to have a potentiating effect on the elimination rate of H. pylori infection.

Although no interaction during concomitant administration of warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in INR have been reported during concomitant treatment in the post-marketing period. Therefore, in patients being treated with coumarin anticoagulants, monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

Consumption of food does not affect the pharmacokinetics (AUC and C_max) of pantoprazole sodium.

There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results.

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.

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.

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.

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.

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.

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.

Both 20 mg and 40 mg once daily have been demonstrated to be effective in the maintenance of healing of reflux esophagitis. If maintenance therapy fails when using 20 mg once daily, consideration may be given to the 40 mg daily dose as maintenance therapy.

The recommended adult oral dose of pantoprazole is 20 mg, given once daily in the morning.

If a dose is forgotten, the missed dose should be taken as soon as possible unless it is close to the next scheduled dose. Two doses should never be taken at one time to make up for a missed dose; patients should just return to the regular schedule.

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.

Not applicable.

Some reports of overdosage with pantoprazole have been received. No consistent symptom profile was observed after ingestion of high doses of pantoprazole. Daily doses of up to 272 mg pantoprazole i.v., and single doses of up to 240 mg i.v. administered over 2 minutes, have been administered and were well tolerated.

Treatment of overdosage should be supportive and symptomatic. Pantoprazole is not removed by hemodialysis.

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.

In long-term international studies involving over 800 patients, a 2 to 3 fold mean increase from the pre-treatment fasting serum gastrin level was observed in the initial months of treatment with pantoprazole at doses of 40 mg per day during GERD maintenance studies and 40 mg or higher per day in patients with refractory GERD. Fasting serum gastrin levels generally remained at approximately 2 to 3 times baseline for up to 4 years of periodic follow-up in clinical trials.

Treatment with pantoprazole alone has a limited effect on infections of H. 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 sodium and selected antibiotics in eradicating H. pylori. In infected patients, eradication of the infection with pantoprazole sodium 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 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 sulfenamide 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).

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, C_max is approximately 2.5 µg/mL with a t_max of 2 to 3 hours. The AUC is approximately 5 µg·h/mL. There is no food effect on AUC (bioavailability) and C_max.

Pantoprazole is 98% bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose.

Pantoprazole is almost completely metabolized in the liver. Studies with pantoprazole in humans reveal no inhibition or activation of the cytochrome P450 (CYP 450) system of 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 (approximately 1 hour).

Pantoprazole shows linear pharmacokinetics, i.e., AUC and C_max increase in proportion with the dose within the dose-range of 10 to 80 mg 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.

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

An increase in AUC (35%) and C_max (22%) for pantoprazole occurs in elderly volunteers when compared to younger volunteers after 7 consecutive days oral dosing with pantoprazole 40 mg. After a single oral dose of pantoprazole 40 mg , an increase in AUC (43%) and C_max (26%) occurs in elderly volunteers when compared to younger volunteers. No dose adjustment is recommended based on age. 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 C_max 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 C_max 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.