Pantoprazole Mylan 20 mg Gastro-resistant Tablets

3. PHARMACEUTICAL FORM

Gastro-resistant tablet.

Dark yellow film coated, oval, approximately 4.3 mm x 8.4 mm, biconvex tablet that is blank on both sides.with ‘PS2’ imprinted in black ink on one side of the tablet.


6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Printing ink

Shellac (E904)

Iron oxide black (E172)

Ammonium hydroxide (E527)

10. DATE OF REVISION OF THE TEXT

May September 2017

4.2 Posology and method of administration

Special populations

Paediatric population below 12 years of age
Pantoprazole is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group (see section 5.2).

Renal Impairment
No dose adjustment is necessary in patients with impaired renal function (see section 5.2).

Older peopleElderly
No dose adjustment is necessary in elderly older patients (see section 5.2).

4.4 Special warnings and precautions for use

In presence of alarm symptomsGastric 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, as treatment with pantoprazole may alleviate symptoms and delay diagnosis.

Co-administration with atazanavir 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 with proton pump inhibitors is not recommended (see section 4.5). 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.

Influence on vitamin B12 absorption
Pantoprazole, as all as with all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.

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.

Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter and C.difficile.

4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products with pH-dependent absorption pharmacokinetics Effect of pantoprazole on the absorption of other medicinal products
Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce interfere with the absorption of drugs other medical products with a where gastric pH dependent is an important determination of oral bioavailability, e.g. some azole antifungals assuch as ketoconazole, itraconazole, posaconazole and other medicine as such as erlotinib.

HIV medications (atazanavir) protease inhibitors
Co-administration of atazanavir pantoprazole is not recommended with and other HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir due to significant reduction in their bioavailability 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 section 4.4).

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 Although no interaction during concomitant administration of phenprocoumon did not affect the or warfarin has been observed in clinical pharmacokinetic of warfarin, phenprocoumon or studies, a few isolated cases of changes in International Normalised Ratio (INR). However, there have been reported reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increase 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. during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of prothrombin time / INR is recommended after initiation, termination or during irregular use of pantoprazole.

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 may need to be considered.

Other interactions studies
Pantoprazole is extensively metabolized 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 drugs medicinal products also metabolized 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 effect 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 concomitantly 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 metabolized through these enzyme systems.

4.6 Fertility, pregnancy and lactation

Pregnancy
A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of pantoprazole.
There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of pantoprazole during pregnancy. The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.

Breast-feeding
Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on the Eexcretion of pantoprazole into in human milk but excretion into human milk has been reported has been reported. A risk to the newborns/infants cannot be excluded. Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue/abstain from pantoprazole therapy should take therapy with pantoprazole should be made taking into account the benefit of breastfeeding to for the child and the benefit of pantoprazole therapy to women for the woman.

4.7 Effects on ability to drive and use machines

Pantoprazole has no or negligible influence on the ability to drive and use machines

Frequency System Organ Class	Common	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders			Agranulocytosis Argranulocytosis	Thrombocytopenia; Leukopenia Pancytopenia
Immune system disorders			Hypersensitivity (including anaphylactic reactions and anaphylactic shock)
Metabolism and nutrition disorders			Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes		Hyponatraemia Hypomagnesaemia (see section 4.4); Hypocalcaemia in association with hypomagnesaemia; Hypokalaemia
Psychiatric disorders		Sleep disorders	Depression (and all aggravations)	Disorientation (and all aggravations)	hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)
Nervous system disorders		Headache; Dizziness	Taste disorders		Paraesthesia
Eye disorders			Disturbances in vision/ blurred vision
Gastrointestinal disorders	Fundic gland polyps (benign)	Diarrhoea; Nausea/ vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort
Hepatobiliary disorders		Liver enzymes increased (transaminases, γ-GT)	Bilirubin increased		Hepatocellular injury; Jaundice; Hepatocellular failure
Skin and sub-cutaneous tissue disorders		Rash/ exanthema/ eruption; Pruritus	Urticaria; Angioedema		Stevens-Johnson syndrome; Lyell syndrome; Erythema multi-forme; Subacute cutaneous lupus erythematosus (see section 4.4); photosensitivity
Musculoskeletal and connective tissue disorders		Fracture of the hip, wrist or spine (see section 4.4)	Arthralgia; Myalgia		Muscle spasm as a consequence of electrolyte disturbances
Renal and urinary disorders					Interstitial nephritis (with possible progression to renal failure)
Reproductive system and breast disorders			Gynaecomastia
General disorders and administration site conditions		Asthenia, fatigue and malaise	Body temperature increased; Oedema peripheral

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for acid related disorders, Proton pump inhibitors, ATC code: A02BC02


Characteristics in patients/special groups of subjectsSpecial populations

5.2 Pharmacokinetic properties

Poor metabolisers

Renal impairment

Hepatic impairment

Elderly

5.3 Preclinical safety data

Preclinical Non-clinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Gastro-resistant coating
Methacrylic acid-ethyl acrylate copolymer (1:1) dispersion
Sodium laurilsulfate
Polysorbate 80 (E433)
Triethyl citrate (E1505)

Film coating
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400
Iron oxide yellow Yellow iron oxide (E172)

Printing ink
(Shellac (E904)
Iron oxide black Black iron oxide (E172)
Ammonium hydroxide (E527)

4.4 Special warnings and precautions for use

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 (see section 4.2).

Co-administration with NSAIDs
The use of Pantoprazole 20 mg as a preventive of gastroduodenal ulcers induced by non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) should be restricted to patients who require continued NSAID treatment and have an increased risk to develop 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.

In presence of alarm symptoms
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, as treatment with pantoprazole may alleviate symptoms and delay diagnosis.

Further investigation is to be considered if symptoms persist despite adequate treatment.

Co-administration with atazanavir
Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). 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.

Influence on vitamin B12 absorption
Pantoprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.

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
Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter and C.difficile.

Hypomagnesaemia
Severe hypomagnesaemia has been reported in patients treated with 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. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or other medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare 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 presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fractures 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.

Subacute 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 (see section 5.1). 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.

5.1  Pharmacodynamic properties

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02

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.

Pharmacodynamic effects
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.

Clincal efficacy and safety
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 (see section 5.3) have not been observed in humans.

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.

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.

None provided