Pansa 40 Tablets

Pantoprazole Gastro-resistant Tablets IP 40 mg

Each Gastro-resistant tablet contains :

Pantoprazole Sodium IP

equivalent to Pantoprazole 40 mg

Excipients q.s.

Colours : Yellow Oxide of Iron &

Titanium Dioxide IP

Gastro-resistant Tablet 40 mg

4.1 Therapeutic indication

For the treatment of gastric ulcer, duodenal ulcer, moderate and severe reflux oesophagitis.

4.2 Posology and method of administration Adults and adolescents 12 years of age and above Reflux oesophagitis

One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Treatment of gastric ulcer

One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets of Pantoprazole daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Treatment of duodenal ulcer

One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets of Pantoprazole daily) especially when there has been no response to other treatment. A duodenal ulcer generally heals within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Special populations

Patients with hepatic impairment

A daily dose of 20 mg Pantoprazole (1 tablet of 20 mg Pantoprazole) should not be exceeded in patients with severe liver impairment.

Patients with renal impairment

No dose adjustment is necessary in patients with impaired renal function

Elderly

No dose adjustment is necessary in the elderly

Paediatric population

Pantoprazole is not recommended for use in children below 12 years of age because of limited data on safety and efficacy in this age group.

Method of administration

Oral use. The tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water

4.3 Contraindications

Hypersensitivity to the active substance, substituted Benzimidazoles, or to any of the excipients listed in the formulation

4.4 Warning and precautions

Hepatic impairment

In patients with severe liver impairment, the liver enzymes should be monitored regularly during treatment with Pantoprazole, particularly on long-term use. In the case of a rise of the liver enzymes, the treatment should be discontinued.

Gastric malignancy

Symptomatic response to Pantoprazole may mask the symptoms of gastric malignancy and may delay diagnosis. 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 or present, malignancy should be excluded. Further investigation is to be considered if symptoms persist despite adequate treatment.

Co-administration with HIV protease inhibitors

Co-administration of Pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as Atazanavir, due to significant reduction in their bioavailability.

Long-term treatment

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance

Gastrointestinal infections caused by bacteria

Treatment with Pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

Hypomagnesaemia

Severe hypomagnesaemia has been rarely reported in patients treated with proton pump inhibitors (PPIs) like Pantoprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia. In most affected patients, hypomagnesaemia (and hypomagnesaemia associated hypocalcaemia and/or hypokalaemia) improved after magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Bone fractures

Proton pump inhibitors, especially if used in high doses and over long durations (> 1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in the presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10 - 40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium

Sub-acute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping Pantoprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Pantoprazole treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin

levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

4.5 Drug interactions

Medicinal products with pH-dependent absorption pharmacokinetics

Because of profound and long-lasting inhibition of gastric acid secretion, Pantoprazole may interfere with the absorption of medicinal products where gastric pH is an important determinant of oral bioavailability, e.g. some azole antifungals such as Ketoconazole, Itraconazole, Posaconazole and other medicines such as Erlotinib.

HIV protease inhibitors

Co-administration of Pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as Atazanavir due to significant reduction in their bioavailability. If the combination of HIV protease inhibitors with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended. A Pantoprazole dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitor may need to be adjusted.

Coumarin anticoagulants (Phenprocoumon or Warfarin)

Co-administration of Pantoprazole with Warfarin or Phenprocoumon did not affect the pharmacokinetics of Warfarin, Phenprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and Warfarin or Phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with Pantoprazole and Warfarin or Phenprocoumon may need to be monitored for increase in INR and prothrombin time.

Methotrexate

Concomitant use of high-dose Methotrexate (e.g. 300 mg) and proton pump inhibitors has been reported to increase Methotrexate levels in some patients. Therefore, in settings where high-dose Methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of Pantoprazole may need to be considered.

Other interactions studies

Pantoprazole is extensively metabolised in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4. Interaction studies with medicinal products also metabolised with these pathways, like Carbamazepine, Diazepam, Glibenclamide, Nifedipine, and an oral contraceptive containing Levonorgestrel and Ethinyl Oestradiol, did not reveal clinically significant interactions

An interaction of Pantoprazole with other medicinal products or compounds, which are metabolised using the same enzyme system, cannot be excluded.

Results from a range of interaction studies demonstrate that Pantoprazole does not affect the metabolism of active substances metabolised by CYP1A2 (such as Caffeine, Theophylline), CYP2C9 (such as Piroxicam, Diclofenac, Naproxen), CYP2D6 (such as Metoprolol), CYP2E1 (such as Ethanol), or does not interfere with p-glycoprotein related absorption of Digoxin.

There were no interactions with concomitantly administered antacids. Interaction studies have also been performed by concomitantly administering Pantoprazole with the respective antibiotics (Clarithromycin, Metronidazole, Amoxicillin). No clinically relevant interactions were found.

Medicinal products that inhibit or induce CYP2C19

Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of Pantoprazole. A dose reduction may be considered for patients treated long-term with high doses of Pantoprazole, or those with hepatic impairment. Enzyme inducers affecting CYP2C19 and CYP3A4 such as Rifampicin and St John´s wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs that are metabolised through these enzyme systems.

4.6 Special populations

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or fetal/ neonatal toxicity of Pantoprazole. Animal studies have shown reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of Pantoprazole during pregnancy.

Breast-feeding

Animal studies have shown excretion of Pantoprazole in breast milk. There is insufficient information on the excretion of Pantoprazole in human milk but excretion into human milk has been reported. A risk to the new-borns / infants cannot be excluded. Therefore, a decision on whether to discontinue breast-feeding or to discontinue/abstain from Pantoprazole therapy taking into account the benefit of breast-feeding for the child, and the benefit of Pantoprazole therapy for the woman.

Fertility

There was no evidence of impaired fertility following the administration of Pantoprazole in animal studies

4.7 Effects on ability to drive and use machines

Pantoprazole has no or negligible influence on the ability to drive and use machines. Adverse drug reactions, such as dizziness and visual disturbances may occur. If affected, patients should not drive or operate machines.

4.8 Undesirable effects

1. Hypocalcemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia in association with hypomagnesemia.

2. Muscle spasm as a consequence of electrolyte disturbance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There are no known symptoms of overdose in man. Systemic exposure with up to 240 mg administered intravenously over 2 minutes, were well tolerated. As Pantoprazole is extensively protein bound, it is not readily dialysable. In the case of an overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

5.1 Mechanism of action

Pantoprazole is a substituted Benzimidazole which inhibits the secretion of Hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells. Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with Pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since Pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (Acetylcholine, Histamine, Gastrin). The effect is the same whether the product is given orally or intravenously.

5.2 Pharmacodynamic properties

The fasting gastrin values increase under Pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments have not been observed in humans. An influence of a long term treatment with Pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies. During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.

5.3 Pharmacokinetic properties

Absorption

Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40 mg oral dose. On average at about 2.5 h p.a. the maximum serum concentrations of about 2 - 3 µg/mL are achieved, and these values remain constant after multiple administration. Pharmacokinetics does not vary after single or repeated administration. In the dose range of 10 to 80 mg, the plasma kinetics of Pantoprazole are linear after both oral and intravenous administration. The absolute bioavailability from the tablet was found to be about 77%. Concomitant intake of food had no influence on AUC, maximum serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.

Distribution

Pantoprazole's serum protein binding is about 98%. Volume of distribution is about 0.15 L/kg.

Biotransformation

The substance is almost exclusively metabolised in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation; other metabolic pathway includes oxidation by CYP3A4.

Elimination

Terminal half-life is about 1 hour and clearance is about 0.1 L/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of Pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion). Renal elimination represents the major route of excretion (about 80%) for the metabolites of Pantoprazole, the rest is excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of Pantoprazole.

6.1 Animal toxicology or pharmacology

Non-clinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the fore stomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted Benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment. In the two-year rodent

studies an increased number of liver tumours was observed in rats and in female mice and was interpreted as being due to Pantoprazole's high metabolic rate in the liver. A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected. In a peri-postnatal rat reproduction study designed to assess bone development, signs of offspring toxicity (mortality, lower mean body weight, lower mean body weight gain and reduced bone growth) were observed at exposures (Cmax) approximately 2x the human clinical exposure. By the end of the recovery phase, bone parameters were similar across groups and body weights were also trending toward reversibility after a drug-free recovery period. The increased mortality has only been reported in pre-weaning rat pups (up to 21 days age) which is estimated to correspond to infants up to the age of 2 years old. The relevance of this finding to the paediatric population is unclear. A previous peri-postnatal study in rats at slightly lower doses found no adverse effects at 3 mg/kg compared with a low dose of 5 mg/kg in this study. Investigations revealed no evidence of impaired fertility or teratogenic effects. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of Pantoprazole in the foetus is increased shortly before birth.

Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. It is a substituted benzimidazole, a compound that inhibits gastric acid secretion. Its chemical name is sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy2-pyridinyOmethyl] sulfinyl] 1H-benzimidazole sesquihydrate. Its empirical formula is C16H14F2N3NaO4S. 1.5 H2O, with a molecular weight of 432.4 g/mol.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

PVC/PVDC-Alu blister strip of 15 tablets.

8.4 Storage and handing instructions

Store protected from moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

Do not take Pantoprazole

If you are allergic to Pantoprazole or to any of the other ingredients of this medicine.

If you are allergic to medicines containing other proton pump inhibitors.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Pantoprazole.

• If you have severe liver problems. Please tell your doctor if you have ever had problems with your liver in the past. Your doctor will check your liver enzymes more frequently, especially when you are taking Pantoprazole as a long-term treatment. In the case of a rise of liver enzymes the treatment should be stopped.

• If you have reduced body stores or risk factors for reduced Vitamin B12 and receive long-term treatment with Pantoprazole. As with all acid reducing agents, pantoprazole may lead to a reduced absorption of Vitamin B12.

• If you are taking HIV protease inhibitors such as Atazanavir (for the treatment of HIV-infection) at the same time as Pantoprazole, ask your doctor for specific advice.

• Taking a proton pump inhibitor like Pantoprazole, especially over a period of more than one year, may slightly increase your risk of fracture in the hip, wrist or spine. Tell your doctor if you have osteoporosis (reduced bone density) or if you have been told that you are at risk of getting osteoporosis (for example, if you are taking steroids).

• If you are on Pantoprazole for more than three months it is possible that the levels of Magnesium in your blood may fall. Low levels of magnesium can be seen as fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, increased heart rate. If you get any of these symptoms, please tell your doctor promptly. Low levels of magnesium can also lead to a reduction in Potassium or Calcium levels in the blood. Your doctor may decide to perform regular blood tests to monitor your levels of Magnesium.

• If you have ever had a skin reaction after treatment with a medicine similar to Pantoprazole that reduces stomach acid.

• If you get a rash on your skin, especially in areas exposed to the sun tell your doctor as soon as you can, as you may need to stop your treatment with Pantoprazole. Remember to also mention any other ill-effects like pain in your joints.

• If you are due to have a specific blood test (Chromogranin A).

Tell your doctor immediately, before or after taking this medicine, if you notice any of the following symptoms, which could be a sign of another, more serious, disease :

• An unintentional loss of weight.

• Vomiting, particularly if repeated.

• Vomiting blood; this may appear as dark coffee grounds in your vomit.

• You notice blood in your stools; which may be black or tarry in appearance.

• Difficulty in swallowing or pain when swallowing.

• You look pale and feel weak (anaemia)

• Chest pain

• Stomach pain

• Severe and/or persistent diarrhoea, because this medicine has been associated with a small increase in infectious diarrhoea

Your doctor may decide that you need some tests to rule out malignant disease because Pantoprazole also alleviates the symptoms of cancer and could cause delay in diagnosing it. If your symptoms continue in spite of your treatment, further investigations will be considered. If you take Pantoprazole on a long-term basis (longer than 1 year) your doctor will probably keep you under regular surveillance. You should report any new and exceptional symptoms and circumstances whenever you see your doctor.

Children and adolescents

Pantoprazole is not recommended for use in children as it has not been proven to work in children below 12 years of age.

Other medicines and Pantoprazole

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

This is because Pantoprazole may influence the effectiveness of other medicines, so tell your doctor if you are taking :

• Medicines such as Ketoconazole, Itraconazole and Posaconazole (used to treat fungal infections) or Erlotinib (used for certain types of cancer) because Pantoprazole may stop these and other medicines from working properly.

• Warfarin and Phenprocoumon, which affect the thickening, or thinning of the blood. You may need further checks.

• Medicines used to treat HIV-infection, such as Atazanavir.

• Methotrexate (used to treat rheumatoid arthritis, psoriasis, and cancer) - if you are taking Methotrexate your doctor may temporarily stop your Pantoprazole treatment because Pantoprazole can increase levels of Methotrexate in the blood.

• Fluvoxamine (used to treat depression and other psychiatric diseases) if you are taking Fluvoxamine your doctor may reduce the dose.

• Rifampicin (used to treat infections).

• St John’s wort (Hypericum perforatum) (used to treat mild depression).