Peptisec 10, 20 & 40 10 mg, 20 mg, 40 mg Capsules

PEPTISEC is indicated in:

Adults:

• Treatment of duodenal ulcer, including prevention of relapse, gastric ulcer and reflux oesophagitis.
• Long-term management of reflux oesophagitis and Zollinger-Ellison Syndrome.
• Symptomatic relief of heartburn in patients with gastro-oesophageal reflux disease (GORD) and the short-term relief of functional dyspepsia.
• Helicobacter pylori-positive duodenal ulcers as part of an eradication programme with appropriate antibiotics.
• Treatment of non-steroidal anti-inflammatory drugs (NSAID)-associated gastric and/or duodenal ulcer/erosions.
• Reduction of the risk to develop gastric and/or duodenal ulcer/erosions and reduction of the risk of relapse for previously healed gastric and/or duodenal ulcer/erosions in patients on NSAID treatment.

Children:

Short-term (up to 3 months) treatment of severe ulcerative reflux oesophagitis resistant to previous medical treatment.

Adults:

Duodenal ulcer

20 mg once daily for two to four weeks. In some duodenal ulcer patients refractory to other treatment regimens, 40 mg once daily may be effective.

Prevention of relapse in patients with duodenal ulcer

10 mg once daily. If necessary the dose can be increased to 20 u2013 40 mg once daily. The above recommended dosage regimens are inclusive of Helicobacter pylori-positive duodenal ulcers as part of the eradication programme with appropriate antibiotics.

Gastric ulcer and reflux oesophagitis

20 mg once daily for four to eight weeks. In some gastric ulcer and reflux oesophagitis patients refractory to other treatment regimens, 40 mg once daily may be effective.

For the long-term management of patients with reflux oesophagitis the recommended dose is 20 mg once daily. If necessary the dose can be increased to 20 u2013 40 mg once daily. In patients with severe or symptomatic recurrent reflux oesophagitis treatment can be continued with PEPTISEC at a dosage of 20 mg once daily.

NSAID-associated gastro-duodenal lesions with or without continued NSAID treatment

20 mg once daily. In most patients healing occurs within 4 weeks. For patients who may not be fully healed after the initial course healing usually occurs during a further 4 weeks of treatment.

Prevention of NSAID-associated gastro-duodenal lesions and dyspeptic symptoms

20 mg once daily.

Symptomatic gastro-oesophageal reflux disease

20 mg daily. Patients may respond adequately to 10 mg daily, therefore individual dose adjustments should be considered. If symptom control has not been achieved after 2 weeks of treatment with 20 mg daily further investigation is recommended.

Zollinger-Ellison Syndrome

60 mg once daily. The dosage should be adjusted individually and treatment continued as long as it is clinically indicated. With doses above 80 mg daily the dose should be divided and given twice daily.

There is very limited experience with the use of PEPTISEC in children (see section 4.4).

Severe ulcerative reflux oesophagitis in children from one year and older: Recommended dosages:

Weight Dosage

• 10 u2013 20 kg 10 mg once daily. If needed increase to 20 mg once daily
• >20 kg 20 mg once daily. If needed increase to 40 mg once daily

Special populations

Elderly: Dose reductions are not necessary in elderly patients.

Impaired renal function: Dose reductions are not necessary in renal impairment.

Impaired hepatic function: Bioavailability and plasma half-life of PEPTISEC are increased in patients with impaired hepatic function, therefore a daily dose of 10 u2013 20 mg is generally sufficient.

The long-term safety of PEPTISEC in patients with renal and hepatic impairment has not been established (see section 4.4).

Method of administration: PEPTISEC is recommended to be given in the morning and swallowed whole with a half glass of liquid. The capsules should not be chewed or crushed.

• Hypersensitivity to omeprazole or to any of the other ingredients of PEPTISEC (see section 6.1).
• Safety in pregnancy and lactation has not been established.
• PEPTISEC must not be used concomitantly with nelfinavir.
• Co-administration of atazanavir with PEPTISEC is not recommended.

In the presence of any alarming symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.

Hepatic impairment may require a reduction in dose (see section 4.2).

The long-term safety of PEPTISEC in patients with renal and/or hepatic impairment has not been established.

There is very limited experience with the use of PEPTISEC in children. Some children with chronic illnesses may require long-term treatment although it is not recommended.

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; omeprazole 20 mg should not be exceeded.

PEPTISEC, 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.

Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with medicines metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged.

Increased risk of bone fractures: PEPTISEC, 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 fracture by 10 to 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.

Increased risk of hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like PEPTISEC 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 dysrhythmia 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 PEPTISEC with digoxin or medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PEPTISEC treatment and periodically during treatment.

Subacute cutaneous lupus erythematosus (SCLE): Proton pump inhibitor (PPI) therapy like PEPTISEC is 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 health care professional should consider stopping PEPTISEC. SCLE after previous treatment with PEPTISEC 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, PEPTISEC 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 PEPTISEC treatment.

Effects related to acid inhibition: During long-term treatment gastric glandular cysts have been reported in increased frequency. These physiological changes result from pronounced inhibition of gastric acid secretion. Decreased gastric acidity increases gastric counts of bacteria normally present in the gastro-intestinal tract. Treatment with PEPTISEC may lead to an increased risk of gastro-intestinal infections such as Salmonella, Campylobacter or C. difficile.

Clostridium-difficile-associated diarrhoea: Proton pump inhibitor (PPI) therapy like PEPTISEC may be associated with an increased risk of Clostridium difficile associated diarrhoea (CDAD), especially in hospitalised patients. This diagnosis should be considered for diarrhoea that does not improve (see Section 4.8). Patients should use the lowest dose and shortest duration of PEPTISEC therapy appropriate to the condition being treated.

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 medicine-related, infectious, systemic, autoimmune, genetic, and idiopathic with the most common cause being related to medication exposure. 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 extrarenal manifestations (e.g., fever rash or arthralgia). Discontinue PEPTISEC and evaluate patients with suspected acute TIN.

As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia And systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP), which can be life threatening or fatal, have been reported very rarely in association with omeprazole treatment.

Excipient warning: PEPTISEC contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take PEPTISEC. PEPTISEC contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially u2018sodium-freeu2019.

Clopidogrel: Clopidogrel is metabolised to its active metabolite in part by CYP2C19. Co-administration of clopidogrel with omeprazole, an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel given concomitantly or 12 hours apart. Concomitant use of medicines that inhibit the activity of this enzyme may result in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Omeprazole is metabolised via the hepatic P450 cytochrome enzyme system, which may affect the metabolism of other medications metabolised by these enzymes, when given concomitantly. The elimination of diazepam, warfarin and phenytoin may be prolonged when omeprazole is given concomitantly. Monitoring of INR and phenytoin serum levels is recommended and dosage reductions may be necessary when omeprazole is given concomitantly.

There may be interactions with other medicines, which are also metabolised via the cytochrome P450 enzyme system.

Digoxin: Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10 %. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should then be reinforced (see Section 4.4).

Active substances with pH dependent absorption: The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption.

Nelfinavir and atazanavir: In case of co-administration with omeprazole, the plasma levels of nelfinavir and atazanavir are decreased. Concomitant administration of omeprazole with nelfinavir is contraindicated (see Section 4.3). Co-administration of omeprazole (40 mg once daily) reduced mean nelfinavir exposure by ca. 40 % and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75 to 90 %. The interaction may also involve CYP2C19 inhibition. Concomitant administration of omeprazole with atazanavir is not recommended. Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75 % decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30 % in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily.

Active substances metabolised by CYP2C19: Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such medicines are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.

Cilostazol: Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased C max and AUC for cilostazol by 18 % and 26 % respectively, and one of its active metabolites by 29 % and 69 % respectively.

Phenytoin: Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment.

Saquinavir: Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70 % for saquinavir associated with good tolerability in HIV-infected patients.

Tacrolimus: Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.

Methotrexate: When given together with omeprazole, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of omeprazole may need to be considered.

Other active substances: The absorption of posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced and thus clinical efficacy may be impaired. For posaconazole and erlotinib concomitant use should be avoided.

Inhibitors CYP2C19 and/or CYP3A4: Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazoleu2019s rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Inducers of CYP2C19 and/or CYP3A4: Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St Johnu2019s wort) may lead to decreased omeprazole serum levels by increasing omeprazoleu2019s rate of metabolism.

Safety in pregnancy and lactation has not been established (see section 4.3).

PEPTISEC may lead to drowsiness and impaired concentration that may be aggravated by the simultaneous intake of alcohol or other central nervous system depressants. Patients should be advised, particularly at the initiation of therapy, against taking charge of vehicles or machinery or performing potentially hazardous tasks where loss of concentration could lead to accidents.

Summary of the safety profile

The most common side effects are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.

System Organ Class Frequency Side effects

Infections and Infestations Frequency unknown Clostridium-difficile - associated diarrhoea

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

Immune system disorders Less frequent Hypersensitivity reactions (e.g. fever, angioedema, anaphylactic reaction/shock)

Endocrine disorders Less frequent Gynaecomastia

Metabolism and nutrition disorders Less frequent Frequency unknown Hyponatraemia, hypomagnesaemia Severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia

Psychiatric disorders Less frequent Reversible mental confusion, agitation, aggression, depression and hallucinations (predominantly in severely ill patients), insomnia

Nervous system disorders Frequent Less frequent Headache (severe enough to cause discontinuation in some patients) Dizziness, somnolence, insomnia, paraesthesia

Eye disorders Less frequent Blurred vision

Ear and labyrinth disorders Less frequent Vertigo

Vascular disorders Less frequent Peripheral oedema

Respiratory, thoracic and mediastinal disorders Less frequent Bronchospasm

Gastrointestinal disorders Frequent Diarrhoea (severe enough to require discontinuation of therapy in some patients), constipation, abdominal pain or colic, nausea, vomiting, flatulence, Less frequent Frequency unknown gastric glandular cysts, fundic gland polyps (benign) Dry mouth, stomatitis, oesophageal candidiasis, taste disturbances Microscopic colitis

Hepato-biliary disorders Less frequent Frequency unknown Raised liver enzymes, hepatitis with or without jaundice, hepatic encephalopathy (in patients with pre-existing liver disease), hepatic failure

Skin and subcutaneous tissue disorders Less frequent Frequency unknown Skin rash, urticaria, pruritus, photosensitivity, bullous eruption, toxic epidermal necrolysis, Stevens-Johnson syndrome, alopecia, erythema multiforme, toxic epidermal necrolysis (TEN), dermatitis acute generalised exanthematous pustulosis (AGEP) drug reaction with eosinophilia and systemic symptoms (DRESS) Subacute cutaneous lupus erythematosus (see section 4.4)

Musculoskeletal, and connective tissue disorders Less frequent Asthenia, arthralgia, myalgia, bone fracture (fracture of the hip, wrist or spine), muscular weakness

Renal and urinary disorders Less frequent Tubulointerstitial nephritis (with possible progression to renal failure)

General disorders and administration site conditions Less frequent Malaise, increased sweating

Reporting of suspected adverse reactions: Reporting of suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201cAdverse drug reaction and quality problem reporting formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/document/adverse-drug-reactions-and-quality-problem-reporting-form/

Blurred vision, confusion, diaphoresis, flushing, headache, malaise, nausea, vomiting, dizziness, abdominal pain, diarrhoea and tachycardia have been reported from over-dosage with omeprazole. Also apathy, depression and confusion have been described in single cases. There is no specific antidote for overdose with omeprazole. Treatment is symptomatic and supportive.

Due to extensive protein binding omeprazole is not readily dialysable. Patients in whom overdose is confirmed or suspected should be referred for medical practitioner/doctor consultation.