Symptomatic improvement and healing of the following gastrointestinal diseases which require a reduction in acid secretion:

• Duodenal ulcer.
• Gastric ulcer.
• Gastroesophageal reflux disease (GORD). Symptomatic GORD: the treatment of heartburn and other symptoms associated with GORD.
• Reflux oesophagitis.
• Gastrointestinal lesions refractory to H 2-blockers.
• Zollinger-Ellison syndrome.

 

Patients whose gastric or duodenal ulceration is not associated with ingestion of NSAIDs require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation or on recurrence.

Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.

For eradication of Helicobacter pylori, treatment with pantoprazole and one of the following combinations of antibiotics: clarithromycin and amoxycillin or clarithromycin and metronidazole or amoxycillin and metronidazole is recommended in cases of duodenal ulcer and gastric ulcer with the objective of reducing the recurrence of duodenal and gastric ulcers caused by this microorganism (see DOSAGE AND ADMINISTRATION).

Pantoprazole in combination with bismuth, metronidazole and tetracycline is indicated for the eradication of H. pylori associated with peptic ulcer disease with the objective of reducing the recurrence of peptic ulcers caused by this organism.

Prevention of gastroduodenal lesions and dyspeptic symptoms associated with nonselective NSAIDs in increased risk patients with a need for continuous nonselective NSAID treatment.

Pantoprazole tablets should not be chewed or crushed, but swallowed whole with a little water.

 

Helicobacter pylori Positive Patients

In H. pylori positive patients with gastric and duodenal ulcers, eradication of this microorganism by combination therapy should be achieved. One of the following combinations of pantoprazole with antibiotics is effective.

• Pantoprazole 40 mg twice daily plus amoxycillin 1,000 mg (2 x 500 mg) twice daily plus clarithromycin 500 mg twice daily.
• Pantoprazole 40 mg twice daily plus metronidazole 400 mg in the morning and 600 mg at night plus clarithromycin 500 mg twice daily.
• Pantoprazole  40  mg  twice  daily  plus  amoxycillin  1,000  mg  (2  x  500  mg)  twice  daily  plus metronidazole 400 mg in the morning and 600 mg at night.
• Pantoprazole 40 mg twice daily plus bismuth subcitrate 108 mg four times a day plus metronidazole

200 mg three times a day and 400 mg at night plus tetracycline 500 mg (2 x 250 mg) four times a day.

In combination therapy for eradication of H. pylori infection, the second tablet should be taken before the evening meal.

The duration for combination therapy is seven days. If further treatment with pantoprazole is indicated to ensure ulcer healing, dosage recommendations as listed below for duodenal and gastric ulcers should be followed.

 

Helicobacter pylori Negative Patients

In H. pylori negative patients,The following dosage guidelines apply for monotherapy with pantoprazole:

 

Duodenal Ulcer

Pantoprazole 40 mg (one tablet) should be given once a day. In most patients, freedom from symptoms is achieved rapidly and healing generally occurs within two weeks. If a two week period of treatment is not sufficient, healing will be achieved in almost all cases within a further two weeks.

 

Gastric Ulcer

Pantoprazole 40 mg (one tablet) should be given once a day. In most patients, freedom from symptoms is achieved rapidly and healing usually takes four weeks. If a four week period of treatment is not sufficient, healing will usually be achieved in a further four weeks.

 

Lesions Refractory to H2-Receptor Antagonists

Pantoprazole 40 mg (one tablet) should be given once a day. In most patients, freedom from symptoms is achieved rapidly and healing usually takes four weeks. If a four week period of treatment is not sufficient, healing is achieved in the majority of patients in a further four weeks. In a small group of patients, there may be benefit in extending pantoprazole therapy to a total of 12 weeks.

 

Zollinger-Ellison Syndrome

The number of pantoprazole 40 mg tablets should be individually adjusted, so that the acid output remains below 10 mmol/L. No fixed period of time is proposed for treatment of Zollinger-Ellison syndrome.

 

Gastroesophageal Reflux Disease

Symptomatic Gastroesophageal Reflux Disease (Treatment of Symptomatic Reflux)

The recommended dosage is one pantoprazole 20 mg tablet/day. If symptom control has not been achieved after four weeks treatment with pantoprazole 20 mg tablets daily, further investigation is recommended, for example, endoscopy.

 

Treatment of Reflux Oesophagitis

The recommended oral dosage is one pantoprazole 20 or 40 mg tablet/day. A four week period is usually required for healing, however, if this is not sufficient, healing will usually be achieved within a further four weeks. This dosage may be increased up to pantoprazole 80 mg/day.

 

Maintenance of Healed Reflux Oesophagitis in Patients Previously Treated for Moderate to Severe Reflux Oesophagitis

For long-term management, a maintenance dose of one pantoprazole 20 or 40 mg tablet/day is recommended, dependent upon patient response.

 

Prevention of Gastroduodenal Lesions and Dyspeptic Symptoms Associated with Non-Selective Non- Steroidal Anti-Inflammatory Drugs in Increased Risk Patients with a Need for Continuous Non-Selective Non-Steroidal Anti-Inflammatory Drug Treatment

The recommended oral dosage is one pantoprazole 20 mg tablet/day.

 

Use in Children

There are no data currently available on the use of pantoprazole in children.

 

Use in the Elderly

The usual daily dose of 20 or 40 mg can be given. During combination therapy for the eradication of H. pylori, elderly patients should receive the recommended pantoprazole dose of 40 mg twice daily for a one week treatment period.

 

Impaired Renal Function

The usual daily dose of 20 or 40 mg can be given. Combination therapy for eradication of H. pylori should not be used in patients with moderate to severe renal dysfunction as no data are available on efficacy and safety in this population.

 

Impaired Hepatic Function

Combination therapy for eradication of H. pylori should not be used in patients with moderate to severe hepatic dysfunction as no data are available on efficacy and safety in this population.

Pantoprazole is contraindicated in patients with cirrhosis or severe liver disease (see CONTRAINDICATIONS).

With milder forms of liver disease, the minimum effective dose has not been determined and the initial dose should be reduced.

Known hypersensitivity to any components of the formulation; cirrhosis or severe liver disease. Combination therapy for eradication of H. pylori is contraindicated in patients with known hypersensitivity to any of the antibiotics proposed for combination therapy for eradication of H. pylori or in patients with moderate to severe hepatic or renal dysfunction. The product information for the individual components of the combination H. pylori eradication therapy should be consulted for any further contraindications. Pantoprazole, like other proton pump inhibitors, should not be coadministered with atazanavir (see Interactions).

Check the Following Before Use:

In the case of combination therapy for the eradication of H. pylori, the product information for the antibiotics used in the combination should be observed. In the presence of any alarm symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. Further investigation is to be considered if symptoms persist despite adequate treatment.

Pantoprazole, as all acid blocking medicines, may reduce the absorption of cyanocobalamin (vitamin B12) due to hypochlorhydria or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy and in patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment if respective clinical symptoms are observed. Rare cases of cyanocobalamin deficiency following acid blocking therapy have been reported.

Use of pantoprazole 20 mg for prevention of gastroduodenal lesions and dyspeptic symptoms associated with nonselective NSAIDs should be restricted to patients who require continued nonselective NSAID treatment and have an increased risk of developing gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (> 65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.

 

Monitoring

In long-term treatment, especially when exceeding a treatment period of one year, patients should be kept under regular surveillance.

Patients being treated for symptomatic GORD with pantoprazole 20 mg who do not respond after four weeks should be investigated.

 

General Toxicity

Gastrointestinal System

Treatment with pantoprazole causes dose dependent hypergastrinaemia as a result of inhibition of gastric acid secretion. Gastrin has a trophic effect on the gastric mucosa, and increases in gastric weight have been observed in rats and dogs to be dependent upon both dose and duration of treatment. Accompanying histopathological changes in the gastric mucosa were increased height, dilatation of fundic glands, chief cell hyperplasia and/or atrophy and parietal cell hyperplasia or vacuolation/ degeneration. Increased density of enterochromaffin-like (ECL) cells was observed after 12 months treatment at dose levels from 5 mg/kg/day in rats and 2.5 mg/kg/day in dogs; all changes were reversible after various recovery periods. Since these gastric effects are a consequence of the pharmacological effect of acid secretion inhibition, no effect doses were not established in all instances.

Although rats might be more susceptible to this effect than other species because of their high ECL cell density and sensitivity to gastrin, ECL cell hyperplasia occurs in other species, including mice and dogs, and has been observed in one of two clinical trials in which ECL cell density was measured (a two-fold increase was observed in study RR126/97 after up to five years of treatment with regular and high doses, but no increase was observed in study RR125/97). No dysplastic or neoplastic changes were observed in gastric endocrine cells in either study.

 

Ocular Toxicity and Dermal Phototoxicity/Sensitivity

Studies have shown that pantoprazole is retained in low levels in the eyes and skin of pigmented rats. It is likely that the retention reflects a reversible association with melanin. Animal studies investigating the potential for phototoxicity/ photosensitivity have not been conducted.

A two week dog study, conducted specifically to investigate the effects on the eye and ear, did not reveal any changes relating to pantoprazole treatment, but the doses chosen were relatively low (40 and 160 mg (about 4 and 15 mg/kg) orally and 60 mg (about 6 mg/kg) IV). No ophthalmological changes or changes in electroretinographs were observed in cynomolgus monkeys at IV doses of up to 15 mg/kg/day for four weeks.

 

Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity

A number of in vitro and in vivo genotoxicity assays covering mutagenicity, clastogenicity and DNA damage endpoints were conducted on pantoprazole and the results were generally negative. Exposures achieved in the in vivo tests in mice and rats were well in excess of exposures expected clinically. However, pantoprazole was clearly positive in carefully conducted cytogenetic assays in human lymphocytes in vitro, both in the presence and absence of metabolic activation. Omeprazole was also positive in a comparable test conducted in the same laboratory, suggesting a possible class effect. A minute amount of radioactivity was bound to rat hepatic DNA after treatment with pantoprazole 200 mg/kg/day for 14 days. However, no distinct DNA adduct has been detected.

 

Mutagenesis

Pantoprazole was found to be negative in the following studies: in vivo chromosome aberration assay in rat and bone marrow (126E/95), mouse lymphoma test (222E/95) and a gene mutation test in Chinese hamster ovary cells (in vitro) (188E/95). In addition, toxicokinetic studies were conducted in rats at the doses used in the bone marrow assay (50 to 1,200 mg/kg) (56E/96) and in mice at the high dose from the earlier micronucleus test (710 mg/kg) (89E/96). In both species, pantoprazole exposure was high with the AUCs being 26 to 30 times higher in the rat or mouse, respectively, than in humans using the 20 mg tablet.

 

Carcinogenicity

A two year oral carcinogenicity study in Sprague-Dawley rats at doses up to 200 mg/kg/day showed gastric carcinoids after pantoprazole treatment at doses greater than 0.5 mg/kg/day in females and greater than 5 mg/kg/day in males, with none observed in controls. The development of gastric tumours is attributed to chronic elevation of serum gastrin levels with associated histopathological changes in the gastrointestinal system. In both male and female rats the development of hepatocellular adenomas was increased at doses greater than 5 mg/kg/day and development of hepatocellular carcinomas was increased at doses greater than 50 mg/kg/day. Hepatocellular tumours, which were also observed in female mice at oral doses greater than 25 mg/kg/day, may be associated with pantoprazole induced increases in hepatic enzyme activity.

Treatment with pantoprazole at doses greater than 50 mg/kg/day also increased the development of thyroid follicular cell adenomas in male and female rats. Several studies in rats were conducted to investigate the effect of pantoprazole on the thyroid, the results of which suggested that the effect may be secondary to the induction of enzymes in the liver.

In a more recent carcinogenicity study, Fischer rats were studied using lower doses (5, 15 and 50 mg/kg). Gastric carcinoids were detected at all doses in females and at the 15 and 50 mg/kg doses in males, and none were detected in controls. No metastases of these carcinoids were detected. There was no increase in the incidence of liver tumours. The dose of 15 mg/kg is seen to be the no effect level for liver tumours in rodents. Consideration of the possible mechanisms involved in the development of the above drug related tumour types suggests that it is unlikely that there is any carcinogenic risk in humans at therapeutic dose levels of pantoprazole for short-term treatment.

Pantoprazole is metabolised in the liver via the cytochrome P450 enzyme system. A study using human liver microsomes suggested that the P450 enzymes CYP2C19 and CYP3A4 are involved in its metabolism. In addition, CYP2D6 and CYP2C9-10 were implicated in another study. An interaction of pantoprazole with other drugs or compounds which are metabolised using the same enzyme system cannot be excluded. However, no clinically significant interactions were observed in specific tests with a number of such drugs or compounds, namely carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline and the low dose oral contraceptive Triphasil (levonorgestrel and ethinyloestradiol). There was also no interaction with a concomitantly administered antacid (aluminium hydroxide and magnesium hydroxide).

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in international normalised ratio (INR) have been reported during concomitant treatment in the postmarketing 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.

Treatment of dogs with IV famotidine shortened the duration of the pH elevation effect of pantoprazole.

As with all acid suppressant medications, the absorption of drugs whose bioavailability is pH dependent (e.g. ketoconazole) might be altered due to the decrease in gastric acidity.

Four crossover pharmacokinetic studies designed to examine any interactions between pantoprazole and the drugs clarithromycin, amoxycillin and metronidazole, conducted in 66 healthy volunteers, showed no interactions.

It has been shown that coadministration of atazanavir 300 mg/ ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg single dose) to healthy volunteers resulted in a substantial reduction in the bioavailability of atazanavir. The absorption of atazanavir is pH dependent. Therefore, proton pump inhibitors, including pantoprazole, should not be coadministered with atazanavir (see CONTRAINDICATIONS).

Effects on Fertility

Pantoprazole at oral doses up to 500 mg/kg/day in male rats and 450 mg/kg/day in female rats (estimated exposure at least 60-fold the clinical exposure from the 40 mg tablet) was found to have no effect on fertility and reproductive performance.

 

Use in Pregnancy (Category B)

Teratological studies in rats and rabbits gave no evidence of a teratogenic potential for pantoprazole. In oral studies in rats, dose dependent toxic effects were observed on fetuses and pups: increased prenatal and postnatal deaths (450 mg/kg/day), reduced fetal weight (greater than or equal to 150 mg/kg/day) and delayed skeletal ossification and reduced pup growth (greater than or equal to 15 mg/kg/day). For the latter, a no effect dose was not established. Doses of 450 mg/kg/day were maternotoxic and may have been associated with dystocia and incomplete parturition. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentrations of pantoprazole in the foetus are increased shortly before birth regardless of the route of administration. The significance of these findings in humans is unclear. As there is no information on the safety of the drug during pregnancy in women, pantoprazole should not be used during pregnancy unless the benefit clearly outweighs the potential risk to the foetus.

 

Use in Lactation

A perinatal/postnatal study in rats found that treatment with pantoprazole at doses of 10 mg/kg/day or greater decreased pup growth. A transient effect on one of a series of development tests (startle response) was only evident in the 30 mg/kg/day group at an age when male and female offspring showed lower bodyweights, paralleled with lower brain weight, than the controls. The significance  of  these findings for humans is unknown, and there is currently no information on the safety of pantoprazole during breastfeeding in humans. Therefore, pantoprazole should only be used during lactation if the benefits clearly outweigh the risks.

No or negligible influence.

Pantoprazole is well tolerated. Most of the adverse reactions seen  with  treatment  were  of  mild  or moderate intensity. The following adverse reactions have been reported in patients receiving pantoprazole alone or in combination with antibiotics for H. pylori eradication in clinical trials and postmarketing surveillance.

 

Body as a Whole

Fatigue, asthenia and increased sweating.

Rare reports of fever, anaphylactic reactions including anaphylactic shock and peripheral oedema.

Very rare reports of substernal chest pain and hot flushes.

 

Cardiovascular Disorders, General

Rare reports of hypertension.

Very rare reports of circulatory collapse.

 

Central and Peripheral Nervous System Disorders

Headache.

Uncommon reports of dizziness.

Very rare reports of reduced movement and speech disorder.

 

Gastrointestinal System Disorders

Diarrhoea, severe eructation, constipation or flatulence, dry mouth and upper abdominal pain.

Uncommon reports of nausea and vomiting.

Rare reports of rectal disorder and colonic polyp.

Very rare reports of faecal discolouration and increased saliva.

 

Hearing and Vestibular Disorders

Very rare reports of tinnitus.

 

Liver and Biliary System Disorders

Very rare reports of increased liver enzymes (transaminases, gamma-GT), hepatic failure, cholestatic hepatitis, bilirubinaemia and jaundice.

The occurrence of severe hepatocellular damage leading to jaundice or hepatic failure having a temporal relationship to the intake of pantoprazole has been reported with a frequency of approximately one in a million patients.

 

Metabolic and Nutritional Disorders

Rare reports of hypertriglyceridaemia.

 

Hypomagnesaemia:

Reported rarely usually with prolonged PPI use of >3 months (most cases>1 year of therapy ) may be symptomatic or asymptomatic ; severe cases may cause tetany seizures , and cardiac arrhythmias. Consider obtaining serum magnesium concentrations prior to beginning long-term therapy especially if taking concomitant digoxin, diuretics, or other drugs known to cause hypomagnesaemia; and periodically thereafter. Hypomagnesaemia may be corrected by magnesium supplementation, although discontinuation of pantoprazol may be necessary; magnesium levels typically return to normal within 1 week of stopping.

 

Musculoskeletal

Rare reports of myalgia and arthralgia.

Very rare reports of pain including skeletal pain.

 

Renal and Urinary Disorders

Very rare reports of interstitial nephritis.

 

Platelet, Bleeding, Clotting Disorders

Very rare reports of thrombocytopenia and increased coagulation time.

 

Psychiatric Disorders

Rare reports of onset of depression, hallucination, disorientation and confusion, especially in predisposed patients, as well as aggravation of these symptoms in the case of pre-existence.

Very rare reports of anxiety.

 

Red and white blood cell disorders

Rare reports of anaemia.

Very rare reports of leucopenia.

 

Resistance mechanism disorders

Rare reports of sepsis.

 

Respiratory system disorders

Very rare reports of dyspnoea.

 

Skin and appendages

Uncommon reports of allergic reactions such as pruritus and skin rash.

Very rare reports of angioedema, urticaria,,severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, Lyell syndrome and photosensitivity.

 

Special senses, other disorders

Metallic taste.

Very rare reports of changes to the senses of smell and taste.

 

Vascular (extracardiac) disorders

Very rare reports of flushing.

 

Vision disorders

Uncommon reports of disturbances in vision (blurred vision).

Very rare reports of conjunctivitis.

See Tables 1 and 2.

 

Pantoprazole Table 1

Incidence (%) of Common (> 1%) and Uncommon (< 1%) Adverse Events in Clinical Trials of Triple Therapy Containing Pantoprazole in Combination with Two Antibiotics for H.pylori Eradication

 

Event	Incidence
	PCM/T* (n = 725)	PAC (n = 492)	PAM (n = 146)
Diarrhoea	4.8	10.0	7.5
Bitter taste	4.0	3.0	0
Nausea	3.7	1.2	1.4
Metallic taste	2.1	0.2	0
Upper abdominal pain	1.9	1.4	0
Headache	1.8	1.8	0
Dizziness	1.4	0.6	0
Tongue pain	1.2	0.8	0
Liver enzymes increased	1.2	0.2	0
Tiredness	1.1	0	0.7
Loose stools	1.0	0.8	0
Oral moniliasis	1.0	0.4	0
Buccal inflammation	1.0	0	0
Exanthemata	0.4	1.2	0.7
Heartburn	0.4	0.4	2.7
Dyspepsia	0.1	0.6	1.4
Rash	0.1	0.6	1.4
At least one of the above	34	29	20

*T = tinidazole, used in place of metronidazole in one clinical study

P = pantoprazole; C = clarithromycin; A = amoxycillin; M = metronidazole

 

Pantoprazole Table 2

Adverse Events (≥ 1%) Reported in Clinical Trial Comparing Quadruple and Triple Therapies for H pylori Eradication Regardless of Causality

 

Adverse event	PBMT (n = 422)	BMT (n = 600)	PAC (n = 368)
Skin & appendages disorders
Rash	7 (1.7%)	16 (2.7%)	4 (1.1%)
Pruritus ani	-	7 (1.2%)	-
Central & peripheral nervous system disorders
Headache	49 (11.6%)	65 (10.8%)	38 (10.3%)
Dizziness	30 (7.1%)	38 (6.3%)	25 (6.8%)
Special senses other, disorders
Taste perversion	45 (10.7%)	65 (10.8%)	67 (18.2%)
Psychiatric disorders
Anorexia	11 (2.6%)	19 (3.2%)	17 (4.6%)
Somnolence	-	8 (1.3%)	-
Depression	-	-	4 (1.1%)
Gastrointestinal disorders
Diarrhoea	49 (11.6%)	56 (9.3%)	37 (10.1%)
Nausea	38 (9.0%)	58 (9.7%)	34 (9.2%)
Abdominal pain	27 (6.4%)	37 (6.2%)	24 (6.5%)

 

Adverse event	PBMT (n = 422)	BMT (n = 600)	PAC (n = 368)
Vomiting	7 (1.7%)	12 (2.0%)	8 (2.2%)
Faeces discoloured	7 (1.7%)	18 (3.0%)	-
Tongue discolouration	10 (2.4%)	11 (1.8%)	-
Mouth dry	-	13 (2.2%)	4 (1.1%)
Constipation	-	-	8 (2.2%)
Dyspepsia	-	6 (1.0%)	-
Respiratory system disorders
Pharyngitis	8 (1.9%)	9 (1.5%)	7 (1.9%)
Body as a whole – general disorders
Influenza-like symptoms	15 (3.6%)	12 (2.0%)	14 (3.8%)
Chest pain	5 (1.2%)	-	4 (1.1%)
Resistance mechanism disorders
Moniliasis	6 (1.4%)	-	5 (1.4%)

---- Events reported by < 1%

 

-  To report any side effect(s):

Saudi Arabia: The National Pharmacovigilance and Drug Safety Centre (NPC) Fax: +966‐11‐205‐7662 Call NPC at +966‐11‐2038222, Exts: 2317‐2356‐2353‐2354‐2334‐2340. Toll free phone: 8002490000 E‐mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc

 

Other GCC States: Please contact the relevant competent authority.

Symptoms

There are no known symptoms of overdosage in humans. In individual cases 240 mg has been administered IV or orally and was well tolerated. As pantoprazole is extensively protein bound, it is not readily dialyzable. As in any case of overdosage, treatment should be symptomatic and supportive measures should be utilised.

 

Treatment

Standard detoxification procedures apply.

 

Contact the Poison Information Centre on your region for advice on the management of over dosage.

Pantoprazole inhibits specifically and dose proportionately H+/K+-ATPase, the enzyme which is responsible for gastric acid secretion in the parietal cells of the stomach. The substance is a substituted benzimidazole which accumulates in the acidic environment of the parietal cells after absorption. There, it is converted into the active form, a cyclic sulfenamide which binds to the H +/K+-ATPase, thus inhibiting the proton pump and causing potent and long lasting suppression of basal and stimulated gastric acid secretion. As pantoprazole acts distal to the receptor level it can influence gastric acid secretion irrespective of the nature of the stimulus (acetylcholine, histamine, gastrin). Pantoprazole's selectivity is due to the fact that it only exerts its full effect in a strongly acidic environment (pH < 3), remaining mostly inactive at higher pH values. As a result, its complete pharmacological, and thus therapeutic, effect can only be achieved in the acid secretory parietal cells. By means of a feedback mechanism this effect is diminished at the same rate as acid secretion is inhibited.

 

As with other proton pump inhibitors and H2-receptor inhibitors, treatment with pantoprazole causes a reduced acidity in the stomach and thereby an increase in gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible.

 

Helicobacter pylori is associated with duodenal and gastric ulcer disease in about 95 and 70% of patients, respectively. H. pylori is the major factor in the development of gastritis and ulcers in such patients. Recent evidence also suggests a causative link between H. pylori and gastric carcinoma. An attempt to eradicate H. pylori is recommended in most patients with duodenal and gastric ulcer where the latter is not caused by nonsteroidal anti-inflammatory drug (NSAID) ingestion (see DOSAGE AND ADMINISTRATION). In an experimental study in mice, pantoprazole at a dose of 100 mg/kg three times daily increased the inhibitory potency of amoxycillin, clarithromycin and tetracycline against Helicobacter felis.

Pantoprazole is rapidly absorbed and the maximal plasma concentration appears after one single oral dose. After single and multiple oral doses, the median time to reach maximum serum concentrations was approximately 2.5 hours, with a Cmax of approximately 1.2 microgram/mL. Terminal half-life is approximately one hour. Volume of distribution is approximately 0.15 L/kg and clearance is approximately 0.1 L/hour/kg. Pharmacokinetics do not vary after single or repeated administration. The plasma kinetics of pantoprazole are linear (in the dose range of 10 to 80 mg) after both oral and intravenous (IV) administration. Pantoprazole is completely absorbed after oral administration. The absolute bioavailability of the tablet is approximately 77%. Concomitant intake of food had no influence on area under the curve (AUC), maximum serum concentrations and thus bioavailability.

The serum protein binding of pantoprazole is approximately 98%. Pantoprazole is rapidly eliminated from serum and is almost exclusively metabolised in the liver. Renal elimination represents the most important route of excretion (approximately 80%) for the metabolites of pantoprazole; the rest are excreted with the faeces. The main metabolite in both the serum and urine is desmethyl-pantoprazole which is conjugated with the sulfate. The half-life of the main metabolites (approximately 1.5 hours) is not much longer than that of pantoprazole.

Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C 19 displays a known genetic polymorphism due to its deficiency in some sub- populations (e.g. 3% of Caucasians and African-Americans and 17-23% of Asians). Although these sub- populations of slow pantoprazole metabolizers have elimination half-life values of 3.5 to 10.0 hours, they still have minimal accumulation (8 23%) with once daily dosing.

In patients with liver cirrhosis given a single 40 mg tablet, the half-life increases to between seven and nine hours and the AUC values are increased by a factor of six to eight but the maximum serum concentration increases only slightly by a factor of 1.5 in comparison with healthy subjects. After a single 20 mg tablet, AUC increased threefold in patients with mild hepatic impairment and fivefold in patients with severe hepatic impairment compared with healthy controls. Mean elimination half-life was 3.3 hours in mild hepatic impairment and six hours in severe hepatic impairment compared with 1.1 hours in controls. The maximum serum concentration only increased slightly by a factor of 1.3 compared with healthy subjects.

In patients  with renal  impairment (including  those undergoing dialysis) no dose reduction  is required.

Although the main metabolite is moderately increased, there is no accumulation. The half-life of pantoprazole is as short as in healthy subjects. Pantoprazole is poorly dialysable.

The slight increase in AUC and Cmax in elderly volunteers compared with their younger counterparts is also not clinically relevant.

Not Available

Name of the excipients(s)

Lactose

Mannitol

Crospovidone

Microcrystalline Cellulose

Magnesium Stearate

Hypromellose

Polyethylene Glycol 8000

Anhydrous Sodium Carbonate

Methacrylic Acid Copolymer Type C

Triethyl Citrate

Talc Titanium Dioxide

Iron Oxide Yellow

Not applicable.

18 months.

Store below 30°C. Protect from light and moisture.

Primary packaging: Blister (Alu/Alu)

Secondary packaging: Carton

If your doctor or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.