Peploc 20 Mg/40 Mg Tablets

PEPLOC 40 mg is indicated for the short-term treatment of duodenal ulcers, gastric ulcers and reflux oesophagitis. If the duodenal ulcer has been demonstrated to be associated with Helicobacter pylori infection, PEPLOC 40 mg used in combination with appropriate antibiotics may be useful. PEPLOC 40 mg is indicated for the treatment of Zollinger-Ellison Syndrome. PEPLOC 20 mg is indicated for the symptomatic improvement (e.g. heartburn, acid regurgitation, pain on swallowing) and healing of mild gastro-oesophageal reflux disease (GORD). In patients with healed reflux disease, recurring symptoms can be controlled using an on-demand regimen of PEPLOC 20 mg once daily when required. PEPLOC 20 mg is indicated for long-term management and prevention of relapse in gastro-oesophageal reflux disease (GORD). PEPLOC 20 mg is indicated for the prevention of gastroduodenal lesions and dyspeptic symptoms induced by non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at risk, and with a need for continuous NSAID treatment.

Duodenal ulcer
The recommended oral dose is 40 mg of PEPLOC once daily. The total treatment with intravenous and oral pantoprazole should be 2 to 4 weeks. If the duodenal ulcer has been demonstrated to be associated with Helicobacter pylori infection, 40 mg of PEPLOC used in combination with appropriate antibiotics may be useful.

Gastric ulcer
The recommended oral dose is 40 mg of PEPLOC once daily for 4 to 8 weeks. In the case of a suspected gastric ulcer, malignancy of the gastric ulcer should be excluded, as treatment could conceal the symptoms and may delay diagnosis.

Reflux oesophagitis
The recommended oral dose is 40 mg of PEPLOC once daily in the morning for 4 to 8 weeks.

Zollinger-Ellison Syndrome
For the management of Zollinger-Ellison Syndrome patients should start their treatment with a daily dose of 80 mg of PEPLOC. Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid secretion as a guide. With doses above 80 mg daily, the dose should be divided and given twice daily.

Mild Gastro-oesophageal reflux disease (GORD)
The recommended oral dose is 20 mg of PEPLOC per day. A 4-week period is usually required for healing of mild GORD. If this is not sufficient, healing will usually be achieved within a further 4 weeks. In patients with healed reflux disease, reoccurring symptoms can be controlled using an on-demand regimen of 20 mg once daily when required.

Long-term management and prevention of relapse in GORD
For long-term management a maintenance dose of one 20 mg PEPLOC tablet per day is recommended, increasing to 40 mg PEPLOC per day if a relapse occurs. After healing of the relapse, the dose can be reduced to 20 mg of PEPLOC. Experience with long-term administration is limited. For prevention of gastro-duodenal lesions and dyspeptic symptoms induced by non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at risk and with a need for continuous NSAID treatment, the recommended oral dose is 20 mg of PEPLOC per day.

Special populations

Elderly patients
No dosage adjustment is necessary in the elderly.

Impaired renal and liver function
No dosage adjustment is required in the presence of impaired renal function. A daily dose of 20 mg PEPLOC should not be exceeded in patients with mild to moderately severe liver impairment (see sections 4.4 and 5.2).

Paediatric population
Safety and efficacy in children has not been established (see section 4.3).

Method of administration
Oral use. The recommended once daily dose of PEPLOC should be taken in the morning. PEPLOC should be swallowed whole with a little water either before or during breakfast.

• hypersensitivity to pantoprazole or to any of the ingredients of PEPLOC (see section 6.1)
• safety and efficacy in children has not been established
• severely impaired liver function
• co-administration with atazanavir (see section 4.5).

The daily dose of PEPLOC 40 mg should not be exceeded in elderly patients or those with impaired renal function. Co-administration with anticoagulants The response to anticoagulants such as warfarin may be affected by any concomitant medication. It is therefore good practice to monitor the patient with additional PT (prothrombin time)/INR (international normalised ratio) determinations when PEPLOC is initiated, discontinued or taken irregularly. Changes in absorption should be observed when medicines whose absorption is pH-dependent, e.g. ketoconazole, are taken concomitantly.

Gastric malignancy
Prior to treatment, or in the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) the possibility of malignancy of a gastric ulcer or a malignant disease of the oesophagus should be excluded, as the treatment with PEPLOC may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.

Diagnosis of reflux oesophagitis
Diagnosis of reflux oesophagitis should be confirmed by endoscopy.

Clostridium difficile associated diarrhoea (CDAD)
PEPLOC may be associated with an increased risk of Clostridium difficile associated diarrhoea (CDAD). A diagnosis of CDAD should be considered for patients taking PEPLOC who develop diarrhoea that does not improve. Patients should use the lowest dose and shortest duration of PEPLOC therapy appropriate to the condition being treated.

Gastrointestinal infections caused by bacteria
PEPLOC might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract and may therefore lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.

Hypomagnesaemia
Severe hypomagnesaemia has been rarely reported in patients treated with proton pump inhibitors (PPIs) like PEPLOC 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 (see section 4.8). 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 medicines 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
The use of PEPLOC may be associated with an increased risk of bone fractures in the hip, wrist or spine. This effect has been reported mostly in people taking high doses, on long-term treatment, and in those who were 50 years and older. 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.

Hepatic impairment
In patients with severe liver impairment, the liver enzymes should be monitored regularly during treatment with PEPLOC. In the case of a rise of the liver enzymes, PEPLOC should be discontinued.

Mild gastro-intestinal complaints
PEPLOC should not be used for mild gastro-intestinal complaints such as nervous dyspepsia.

Vitamin B12 absorption
PEPLOC over a long period of time (e.g. longer than 3 years) in patients with Zollinger-Ellison syndrome and other pathological hyper secretory conditions may lead to malabsorption of vitamin B12 caused by hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption or if respective clinical symptoms are observed.

Co-administration with NSAIDs
Use of PEPLOC 20 mg as a preventative of gastroduodenal ulcers, induced by nonselective non-steroidal anti-inflammatory drugs (NSAIDs), should be restricted to patients who require continued NSAID treatment and have an increased risk to develop gastrointestinal complications.

Combination therapy
In the case of combination therapy, the summaries of product characteristics of the respective medicines should be observed.

Co-administration with HIV protease inhibitors
Co-administration of PEPLOC 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 (see section 4.5).

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

Subacute cutaneous lupus erythematosus (SCLE)
Proton pump inhibitors are associated with very infrequent cases of Subacute cutaneous lupus erythematosus (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 provider should consider stopping PEPLOC. 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, PEPLOC 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.

Acute Interstitial Nephritis:
Acute interstitial nephritis has been observed in patients taking proton pump inhibitors (PPIs) including PEPLOC. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction and is associated with damage to the tubulointerstitium, leading to acute kidney injury. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g. fever, rash or arthralgia). Interstitial nephritis may lead to renal failure. Discontinue PEPLOC if acute interstitial nephritis develops (see section 4.8).

Sodium
PEPLOC contains sodium. To be taken into consideration in patients on a sodium-controlled diet.

Concomitant intake of food has no influence on the bioavailability. Coumarin anticoagulants (phenprocoumon or warfarin) However, the response to anticoagulants such as warfarin, phenprocoumon and acenocoumarol may be affected by any concomitant medicine. It is therefore good practice to monitor the patient with additional PT (prothrombin time)/INR (international normalised ratio) determinations when PEPLOC is initiated, discontinued or taken irregularly. Medicines with pH-dependent absorption pharmacokinetics PEPLOC may reduce or increase the absorption of medicines whose bioavailability is pH-dependent, e.g. ketoconazole, itraconazole, posaconazole and other medicines like erlotinib.

HIV protease inhibitors
It has been shown that co-administration of atazanivir 300 mg/ritonavir 100 mg with proton pump inhibitors (PPI) such as PEPLOC resulted in a substantial reduction in the bioavailability of atazanivir. The absorption of atazanavir is pH-dependent. Therefore, PPIs, including PEPLOC, should not be co-administered with atazanavir. (see section 4.3). 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 PEPLOC dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitor may need to be adjusted.

Methotrexate
Concomitant use of PPIs, including PEPLOC, with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.

Inhibitors of 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 PEPLOC, or those with hepatic impairment.

Enzyme inducers affecting CYP2C19 and CYP3A4
Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St Johnu00b4s wort (Hypericum perforatum), may reduce the plasma concentrations of PPIs that are metabolized through these enzyme systems. Other interactions studies: The active ingredient of PEPLOC is metabolised in the liver via the cytochrome P450 enzyme system. An interaction of PEPLOC with other medicines or compounds which are metabolised using the same enzyme system cannot be excluded. However, no clinically significant interactions were observed when used concomitantly with caffeine, carbamazepine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline, warfarin and oral contraceptives. However, the response to anticoagulants such as warfarin, phenprocoumon and acenocoumarol may be affected by any concomitant medicine. It is therefore good practice to monitor the patient with additional PT (prothrombin time)/INR (international normalised ratio) determinations when PEPLOC is initiated, discontinued or taken irregularly. There were no interactions with concomitantly administered antacids.

Pregnancy
Safety in pregnancy and during lactation has not been established. Animal studies have shown reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of PEPLOC during pregnancy.

Breastfeeding
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, breastfeeding while on PEPLOC is not recommended.

Fertility
There was no evidence of impaired fertility following the administration of pantoprazole in animal studies. There is no data on fertility in humans with PEPLOC.

PEPLOC has no or negligible influence on the ability to drive and use machines. PEPLOC may affect the ability to drive in that adverse effects, such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines.

a. Summary of the safety profile
Approximately 5 % of patients can be expected to experience adverse drug reactions (ADRs). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

b. Tabulated list of adverse effects

System Organ Class Frequency Side effects

Infections and Infestations Frequency unknown Clostridium difficile -associated diarrhoea*

Blood and lymphatic system disorders Less frequent Leukopenia, thrombocytopenia, pancytopenia, agranulocytosis

Immune system disorders Less frequent Anaphylactic reactions including anaphylactic shock and angioedema

Metabolism and nutrition disorders Less frequent Increased bilirubin, elevated triglycerides and increased body temperature, lipid increases, hypocalcaemia**, hyperlipidaemia, weight changes

Psychiatric disorders Less frequent Frequency unknown Mental depression, sleep disorders, depression, disorientation Hallucination*, confusion*

Nervous system disorders Frequent Less frequent Frequency unknown Headache Dizziness, taste disorders Paraesthesia

Eye disorders Less frequent Disturbances in vision (blurred vision)

Gastrointestinal disorders Frequent Less frequent Frequency unknown Gastrointestinal complaints such as upper abdominal pain, diarrhoea, constipation or flatulence Nausea, vomiting, dry mouth, abdominal distension and bloating, abdominal pain and discomfort Microscopic colitis*

Hepatobiliary disorders Less frequent Frequency unknown Increased bilirubin Severe hepatocellular damage* leading to jaundice* with or without hepatic failure* and increased liver enzymes (transaminases, u03b3 -GT)

Skin and subcutaneous tissue disorders Less frequent Frequency unknown Allergic reactions such as pruritus and skin rash, urticaria Severe skin reactions such as Stevens-Johnson Syndrome*, erythema multiforme*, toxic epidermal necrolysis* (Lyell syndrome) and photosensitivity*, Drug reaction with eosinophilia and systemic symptoms (DRESS)*, subacute cutaneous lupus erythematosus*

Musculoskeletal, connective tissue and bone disorders Less frequent Frequency unknown Arthralgia, myalgia, fracture of the hip, wrist or spine Hyponatraemia, hypomagnesaemia, hypocalcaemia in association with hypomagnesaemia, muscle spasm as a consequence of electrolyte disturbance*

Renal and urinary disorders Frequency unknown Interstitial nephritis* (in some patients renal failure has been reported concomitantly) (see section 4.4)

Reproductive system and breast disorders Less frequent Gynaecomastia

General disorders and administrative site conditions Less frequent Asthenia, fatigue, malaise, and peripheral oedema, body temperature increased

*Post-marketing reports. **Hypocalcaemia in association with hypomagnesaemia.

Signs and symptoms: The described side effects may be exacerbated. There are no known symptoms of overdose in man. Systemic exposure with up to 240 mg administered intravenously over 2 minutes was well tolerated.

Management of overdose: As pantoprazole is extensively protein bound, it is not readily dialysable. No specific therapeutic recommendation can be made in cases of overdosage with clinical signs of intoxication. Treatment is symptomatic and supportive.