Abbott-Pantoprazole: Indications, Dosage, Precautions, Adverse Effects
Россия
  • Россия
  • Украина

Abbott-Pantoprazole - Product Information

Manufacture: Abbott Laboratories
Country: Canada
Condition: Barrett's Esophagus, Duodenal Ulcer, Erosive Esophagitis, Gastritis (Gastritis/Duodenitis), GERD, Helicobacter Pylori Infection, Peptic Ulcer, Stress Ulcer Prophylaxis, Stomach Ulcer (Gastric Ulcer), Zollinger-Ellison Syndrome
Class: Proton pump inhibitors
Form: Tablets
Ingredients: Pantoprazole Sodium

Summary Product Information

Route of Administration Dosage Form / Strength All Nonmedicinal Ingredients
oral Delayed Release Tablet 20 mg and 40 mg pantoprazole Calcium stearate, crospovidone, ferric oxide yellow, hydroxy propyl cellulose, hypromellose, mannitol, methacrylicacid-ethylacrylate copolymer (1:1) dispersion 30%, propylene glycol, purified water, sodium carbonate anhydrous, talc, titanium dioxide, and triethyl citrate. Composition of the brown ink: Shellac Glaze ~45% (20% Esterified) in Ethanol, N- Butyl Alcohol, Isopropyl Alcohol, Iron Oxide Black, Iron Oxide Red, Propylene Glycol, Iron Oxide Yellow and Ammonium Hydroxide 28%.

Note: As with all proton pump inhibitors, when Abbott-Pantoprazole (pantoprazole sodium sesquihydrate) 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.

Indications and Clinical Use

Abbott -Pantoprazole (pantoprazole sodium sesquihydrate) 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
  • 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.

For the maintenance treatment of patients with reflux esophagitis and the resolution of symptoms associated with reflux esophagitis, such as heartburn with or without regurgitation, 20 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.

Geriatrics (> 65 years of age)

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. See PHARMACOLOGY.

Pediatrics

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

Contraindications

Patients who are hypersensitive to pantoprazole, substituted benzimidazoles or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

Warnings and Precautions

General

In the presence of any alarm symptom (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia, or melaena) and when gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with Abbott-Pantoprazole (pantoprazole sodium sesquihydrate) is instituted since treatment with pantoprazole sodium may alleviate symptoms and delay diagnosis.

Further investigation should be considered if symptoms persist despite adequate treatment.

In long-term treatment, patients should be kept under regular surveillance.

Co-administration of atazanavir with proton pump inhibitors is not recommended (see DRUG INTERACTIONS). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g., virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir. A pantoprazole dose of 20 mg per day should not be exceeded.

Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile.

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. A temporary withdrawal of the PPI may be considered in some patients receiving treatments with high dose methotrexate.

Bone Fracture

Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines (see Dosage and Administration and Adverse Reactions).

Antibiotic Combination Therapy

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

Carcinogenesis and Mutagenesis

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 (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.

Hepatic/Biliary/Pancreatic & Renal

The daily dose in patients with severe liver disease should, as a rule, not exceed 20 mg pantoprazole. See ACTION & CLINICAL PHARMACOLOGY, Special Populations & Conditions.

The daily dose used in renal insufficient patients, as a rule, should not exceed the recommended dosage regimens. See ACTION & CLINICAL PHARMACOLOGY, Special Populations & Conditions.

Pantoprazole should not be used in combination treatment for the eradication of H. pylori in patients with severe hepatic or renal dysfunction since currently no data are available on the efficacy and safety of pantoprazole in combination treatment of these patients.

Endocrine and Metabolism

Hypomagnesaemia

Hypomagnesaemia, symptomatic and asymptomatic, has been reported in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesaemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.

The chronic use of PPIs may lead to hypomagnesaemia. Moreover, hypokalemia and hypocalcemia have been reported in the literature as accompanying electrolyte disorders.

Special Populations

Pregnant Women

There are no adequate or well-controlled studies in pregnant women. Studies in animals have shown reproductive toxicity; the potential risk for humans is unknown. Pantoprazole sodium should not be administered to pregnant women unless the expected benefits outweigh the potential risks to the fetus. See REPRODUCTION and TERATOLOGY.

Nursing Women

Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Pantoprazole sodium should not be given to nursing mothers unless its use is believed to outweigh the potential risks to the infant.

Pediatrics

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

Geriatrics (> 65 years of age)

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. See PHARMACOLOGY. Benefits of use of PPIs should be weighed against the increased risk of fractures as patients in this category (> 71 years of age) may already be at high risk for osteoporosis-related fractures. If the use of PPIs is required, they should be managed carefully according to established treatment guidelines (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).

Adverse Reactions

Adverse Drug Reaction Overview

Pantoprazole sodium is well tolerated. Most adverse events have been mild and transient showing no consistent relationship with treatment.

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%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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 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.

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
Diarrhoea 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%.

Adverse drug reactions with a frequency of 0.1 to 1% related to 20 mg pantoprazole

Gastrointestinal Disorders: Diarrhea, Flatulence, Abdominal pain, Abdominal pain upper, Abdominal distension, Gastric polyps, Loose stools, Frequent bowel movements, Eructation, Dyspepsia, Nausea, Vomiting, Constipation.

General Disorders: Fatigue

Hepatobiliary Disorders: Alanine aminotransferase increased, Aspartate aminotransferase increased, Liver function tests abnormal, Transaminases increased.

Laboratory Parameters: Hyperglycaemia

Nervous System Disorders: Headache, Dizziness, Vertigo.

Skin and Subcutaneous Tissue Disorders: Pruritus, Rash.

Special Senses: Visual disturbance

Other: Libido decreased

Adverse drug reactions with a frequency of 0.1 to 1% related to 40 mg pantoprazole

Cardiovascular System: Blood pressure increased, Hypertension, ECG abnormal

Gastrointestinal Disorders: 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.

General Disorders: Fatigue, Peripheral edema, Pyrexia

Hepatobiliary Disorders: Alanine aminotransferase increased, Aspartate aminotransferase increased, Liver function tests abnormal, Transaminases increased

Laboratory Parameters: Hypertriglyceridaemia

Metabolic and Nutritional: Appetite decreased, Weight increase

Nervous System Disorders: Dysgeusia, Dizziness, Migraine, Vertigo

Respiratory System: Cough

Skin and Subcutaneous Tissue Disorders: Pruritus, Rash

Special Senses: Mouth dry, Vision blurred

Other: 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).

Adverse drug reactions with a frequency of 0.1 to 1% related to pantoprazole, 20 or 40 mg

Gastrointestinal Disorders: Diarrhea, Flatulence, Nausea, Constipation, Abdominal pain

Nervous System Disorders: Headache, Dizziness

Skin and Subcutaneous Tissue Disorders: 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.

Adverse Events with a frequency of ≥ 1 %, 20 or 40 mg

Influenza like illness, Headache, Diarrhea

Adverse Events with a frequency of 0.1 to 1%, 20 or 40 mg

Bronchitis, Nausea, Back pain, Abdominal pain upper, Upper respiratory tract infection, Non-accidental 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):

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%)

Hepatobiliary: 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.

Abnormal Hematological & Clinical Chemistry Findings

Please refer to the Hepatobiliary Disorders and the Laboratory Parameters portions of the ADVERSE REACTION section, the ACTION & CLINICAL PHARMACOLOGY Special Populations & Conditions section, and the WARNINGS & PRECAUTIONS Hepatic/Biliary/Pancreatic section.

Post-Market Adverse Drug Reactions

The following adverse events were reported in post-marketing use and causal relation to pantoprazole sodium treatment could not be ruled out. As the events were reported spontaneously, no exact incidences can be provided:

Interstitial nephritis; Stevens-Johnson syndrome; Erythema multiforme; Toxic epidermal necrolysis (Lyell syndrome); Photosensitivity; Hyponatraemia; Hypomagnesaemia; Hepatocellular injury; Jaundice; Hepatocellular failure; Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in the case of pre-existence), Hypokinesia, Anterior ischemic optic neuropathy; Pancreatitis; Increased salivation;, Speech disorder; Elevated creatine phosphokinase; Rhabdomyolysis; Alopecia; Acne; Exfoliative dermatitis; Nervousness; Tremor; Tinnitus; Paresthesia; Photophobia;, Vertigo; Increased appetite; Hematuria; Impotence; Eosinophilia; Osteoporosis and osteoporosis-related fractures.

In addition the following identified adverse drug reactions have been reported in oral pantoprazole sodium clinical trials in any indication and in any dosage:

Uncommon: Headache; Dizziness; Nausea/vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort; Rash/exanthema/eruption; Pruritus; Asthenia; Fatigue and malaise; Liver enzymes increased (transaminases, γ-GT); Sleep disorders.

Rare: Agranulocytosis; Disturbances in vision/blurred vision; Urticaria; Angioedema; Myalgia; Arthralgia; Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes; Body temperature increased;, Oedema peripheral; Gynaecomastia; Hypersensitivity (including anaphylactic reactions and anaphylactic shock); Bilirubin increased; Depression (and all aggravations); Taste disorder.

Very rare: Thrombocytopenia; Leukopenia; Pancytopenia; Disorientation (and all aggravations).

Withdrawal of long-term PPI therapy can lead to aggravation of acid related symptoms and may result in rebound acid hypersecretion.

Drug Interactions

Overview

Pantoprazole undergoes extensive hepatic metabolism via cytochrome P450-mediated oxidation. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways which include oxidation by CYP3A4. This is 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. Pantoprazole causes long lasting inhibition of gastric acid secretion. Therefore, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of the bioavailability (e.g. ketoconazole, itraconazole, posaconazole, erlotinib).

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and might impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir is not recommended (see WARNINGS AND PRECAUTIONS).

Drug-Drug Interactions

Pantoprazole sodium does not interact with carbamazepine, caffeine, diclofenac, naproxen, piroxicam, ethanol, glibenclamide, metoprolol, antipyrine, diazepam, phenytoin, nifedipine, theophylline, digoxin, oral contraceptives containing (levonorgestrel and ethinyl oestradiol), 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 Helicobacter pylori infection. (See Microbiology)

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.

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

Drug-Food Interactions

Consumption of food does not affect the pharmacokinetics (AUC and Cmax) of pantoprazole sodium. See Human Pharmacology.

Drug-Laboratory Interactions

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

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.

Dosage and Administration

Recommended Dose and Dosage Adjustment

Duodenal Ulcer

The recommended adult dose of Abbott-Pantoprazole (pantoprazole sodium sesquihydrate) 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 Abbott-Pantoprazole 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 Abbott-Pantoprazole 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.

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.

Prevention of Gastrointestinal Lesions Induced by Nsaids

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

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Missed Dose

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.

Administration

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.

Reconstitution

Not applicable

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

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.

As pantoprazole is extensively protein bound, it is not readily dialyzable. In the case of overdosage with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

Action and Clinical Pharmacology

Mechanism of Action

Abbott-Pantoprazole (pantoprazole sodium sesquihydrate) is a specific inhibitor of the gastric H+, K+- ATPase enzyme (the proton pump) that is responsible for gastric 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. Pantoprazole is then converted into the active form, a cyclic sulphenamide, which binds selectively to the proton translocating region of the H+, K+- ATPase, thus inhibiting both the basal and stimulated gastric acid secretion. Pantoprazole 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. 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 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 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 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.

Pharmacodynamics

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.

Pharmacokinetics

Absorption

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 μg/mL with a tmax of 2 to 3 hours. The AUC is approximately 5 μg.h/mL. There is no food effect on AUC (bioavailability) and Cmax.

Distribution

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

Metabolism

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.

Excretion

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 Cmax 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.

Special Populations and Conditions

Pediatrics

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

Geriatrics

An increase in AUC (35%) and Cmax (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 Cmax (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.

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

In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects. No dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis, as the difference in AUCs between patients who are dialyzed and those who are not is 4%.

Storage and Stability

Store at 15ºC to 30ºC in the recommended packaging.

Special Handling Instructions

None.

Dosage Forms, Composition and Packaging

Abbott-Pantoprazole (pantoprazole sodium sesquihydrate) is available as delayed-release (enteric-coated) tablets for oral administration.

Abbott - Pantoprazole 20 mg: Yellow coloured, oval shape, biconvex, enteric coated tablets, plain on one side and "96" printed with brown ink on the other side.

Abbott -Pantoprazole 40 mg: Yellow coloured, oval shape, biconvex, enteric coated tablets, plain on one side and “97” printed with brown ink on other side.

Tablets are available in bottles of 100 tablets for 20 mg and in bottles of 100 and 500 tablets for 40 mg.

Non-medicinal Ingredients: Calcium stearate, crospovidone, ferric oxide yellow, hydroxy propyl cellulose, hypromellose, mannitol, methacrylicacid-ethylacrylate copolymer (1:1) dispersion 30%, propylene glycol, purified water, sodium carbonate anhydrous, talc, titanium dioxide, and triethyl citrate.

Composition of the brown ink: Shellac Glaze ~45% (20% Esterified) in Ethanol, N- Butyl Alcohol, Isopropyl Alcohol, Iron Oxide Black, Iron Oxide Red, Propylene Glycol, Iron Oxide Yellow and Ammonium Hydroxide 28%.