Ulcevan 20 mg Enteric coated tablets.

ULCEVAN is indicated for the temporary short term relief of heartburn and hyperacidity.

Posology

Adults

ULCEVAN is indicated for short term relief of heartburn and hyperacidity. The maximum dose is 20 mg per day and the treatment is for a maximum period of 14 days. If no symptom relief is obtained within 2 weeks of continuous treatment, the patient must be advised to consult a doctor.

Special populations

Elderly population

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 (mild to moderate). A daily dose of one ULCEVAN tablet should not be exceeded in patients with mild to moderately severe liver impairment (See Sections 4.4 and 5.2).

Method of administration

For oral administration. ULCEVAN should be swallowed whole with a little water either before or during breakfast.

ULCEVAN is contraindicated in:

• Patients with hypersensitivity to pantoprazole or to any excipients in ULCEVAN (see section 6.1).
• Safety in pregnancy and lactation (see section 4.6).
• Safety and efficacy in children have not been established.
• Severely impaired liver function (see sections 4.2 and 4.4)
• Co-administration with atazanavir and nelfinavir and other HIV medicines with pH dependent absorption (See Section 4.5).

Clostridium difficile associated diarrhoea (CDAD)

Treatment with proton pump inhibitors (PPIs), such as ULCEVAN, have been associated with an increased risk of CDAD, especially in hospitalised patients. If a patient develops persistent diarrhoea, this diagnosis should be excluded. Patients should use the lowest dose and shortest duration of ULCEVAN treatment appropriate to the condition being treated. Treatment with ULCEVAN may lead to slightly increased risk of gastrointestinal infections caused by bacteria (Salmonella and Campylobacter).

Bone fractures

ULCEVAN, 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. Patients should be advised to consult a medical practitioner if:

• They have unintentional weight loss, anaemia, gastrointestinal bleeding, dysphagia, persistent vomiting with blood, previously had gastric ulcer or gastrointestinal surgery. In these cases, malignancy must be excluded as treatment with ULCEVAN may alleviate symptoms and delay diagnosis.
• They have been taking an indigestion or heartburn remedy continuously for 4 or more weeks in order to control their symptoms.
• They have jaundice or hepatic impairment.

Gastrointestinal infections caused by bacteria

ULCEVAN, as a proton pump inhibitor (PPI), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract and may therefore lead to an increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.

Mild gastrointestinal complaints

ULCEVAN is not indicated for mild gastrointestinal complaints such as nervous dyspepsia. In the presence of 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. Prior to treatment, the possibility of malignancy of gastric ulcer or a malignant disease of the oesophagus should be excluded, as the treatment with ULCEVAN may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.

Hypomagnesaemia

Severe hypomagnesaemia has been rarely reported in patients treated with Proton pump inhibitors (PPIs) like ULCEVAN 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 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.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors, such as ULCEVAN, 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 provider should consider stopping ULCEVAN. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Liver impairment

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

Effect on cyanocobalamin (vitamin B12) absorption

Daily treatment with any acid-blocking medicines such as ULCEVAN, over a long period of time (e.g. longer than 3 years) may lead to malabsorption of cyanocobalamin due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption or if deficiency symptoms are observed.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, ULCEVAN 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.

Acute Tubulointerstitial Nephritis

Acute Tubulointerstitial Nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. TIN is characterised by an inflammatory reaction within the tubulointerstitial space of the kidney. Acute interstitial inflammatory reactions are associated with damage to the tubulointerstitium, leading to acute kidney injury. TIN may be drug-related, infectious, systemic, autoimmune, genetic, and idiopathic with the most common cause being related to a medication or drug exposure. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decrease renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extrarenal manifestations (e.g. fever rash or arthralgia). Discontinue ULCEVAN and evaluate patients with suspected acute TIN.

Concomitant intake of food has no influence on bioavailability. ULCEVAN may increase the availability of digoxin if administered for prolonged periods.

Decreased absorption of medicines that are gastric pH dependent

The bioavailability of the following medicines may be reduced when co-administered with ULCEVAN, thereby impacting on their efficacy e.g.

• some azole antifungals such as ketoconazole, itraconazole and posaconazole,
• other medicines such as erlotinib, atazanavir, nelfinavir and other HIV medicines with pH- dependent absorption (see section 4.3)

Coumarin anticoagulants (e.g. warfarin or phenprocoumon)

There have been reports of increased PT (Prothrombin Time)/INR (International Normalised Ratio) in patients receiving proton pump inhibitors, including ULCEVAN. Therefore, patients must be advised that additional PT/INR determinations may be required when taking ULCEVAN.

Other interactions studies

Pantoprazole, as in ULCEVAN, is extensively metabolised in the liver via the cytochrome P450 enzyme system (by CYP2C19 and other metabolic pathways including oxidation by CYP3A4) and may affect or be affected by other medicines, such as tacrolimis and fluvoxamine, metabolised by the same enzymes. Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St Johnu00b4s wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs, as in ULCEVAN, that are metabolised through these enzyme systems.

Voriconazole

Voriconazole inhibits the metabolism of proton-pump inhibitors: The exposure of both medicines is increased when ULCEVAN is co-administered with voriconazole.

Methotrexate

Concomitant use of high doses of methotrexate (e.g. 300 mg daily) and ULCEVAN is not recommended as proton-pump inhibitors have 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 ULCEVAN may need to be considered. There were no interactions with concomitantly administered antacids, and with antibiotics (clarithromycin, metronidazole, amoxicillin). The elimination of diazepam and phenytoin may be prolonged.

The safety of ULCEVAN in pregnancy and lactation has not been established. (see section 4.3)

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/ neonatal toxicity of ULCEVAN. Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of ULCEVAN during pregnancy.

Breastfeeding

Animal studies have shown excretion of pantoprazole, as in ULCEVAN, 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 newborns/infants cannot be excluded. Therefore, a decision should be taken by the medical practitioner on whether to discontinue breast-feeding or to discontinue/abstain from ULCEVAN therapy.

Fertility

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

ULCEVAN has moderate influence on the ability to drive or operate machinery. ULCEVAN can cause dizziness and blurred vision. Patients should be cautioned about operating hazardous machinery, including motor vehicles, while taking ULCEVAN.

a) Summary of the safety profile

Approximately 5 % of patients can be expected to experience adverse drug reactions (ADRs).

b) Tabulated list of adverse reactions

System organ class

Frequent

Less frequent

Frequency unknown

Infections and infestations

Clostridium difficile- associated diarrhoea and increased risk of gastrointestinal infections caused by Salmonella and Campylobacter

Blood and the lymphatic system disorders

Agranulocytosis, leukopenia, thrombocytopenia, pancytopenia

Immune system disorders

Hypersensitivity (incl. anaphylactic reactions and anaphylactic shock, allergic reactions such as pruritus, skin rash, urticaria and angioedema)

Metabolism and nutrition disorders

Hyperlipidaemias and lipid increases (triglycerides, cholesterol), weight changes

Hyponatraemia, hypomagnesaemia, hypocalcaemia1, hypokalaemia1

Nervous system disorders

Headache

Dizziness

Paraesthesia

Eye Disorders

Vision disturbances (blurred vision)

Psychiatric disorders

Sleep disorders, mental depression, disorientation/confusion

Hallucination

Vascular disorders

Peripheral oedema

Gastrointestinal disorders

Gastrointestinal complaints such as upper abdominal pain and discomfort, diarrhoea, constipation, abdominal distention and bloating.

Nausea, vomiting, dry mouth, taste disorders

Hepato-biliary disorders

Increased liver enzymes (transaminases, y-GT), Severe hepatocellular damage leading to jaundice with or without hepatic failure, increased bilirubin

Skin and subcutaneous tissue disorders

Severe skin reactions such as Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis (TEN) (Lyell syndrome) and photosensitivity, subacute cutaneous lupus erythematosus

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia, increased risk of hip, wrist and spine fractures, muscle spasm

Renal and urinary disorders

Interstitial nephritis

Reproductive system and breast disorders

Gynaecomastia

General disorders and administrative site conditions

Asthenia, fatigue, malaise, increased body temperature,

1. Hypocalcemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia (see section 4.4)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug reactions Reporting formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8 . Aspen Pharmacare: E-mail: [email protected] Tel: 0800 118 088

Symptoms

There are no known symptoms of overdose in man. No specific therapeutic recommendations can be made in the case of an overdose.

Treatment

Treatment is symptomatic and supportive.