Lokit Od 20 mg, 40mg Hard gelatine capsules

LOKIT OD is indicated in:

• Treatment of duodenal ulcer, gastric ulcer, reflux oesophagitis and Zollinger - Ellison syndrome and for the symptomatic relief of heartburn in patients with gastro - oesophageal reflux disease.
• Helicobacter pylori - positive duodenal ulcers as part of an eradication programme with appropriate antibiotics.

Duodenal ulcer: The recommended dosage is 20 mg LOKIT OD 20 once daily for two to four weeks. In some duodenal ulcer patientu2019s refractory to other treatment regimens, 40 mg LOKIT OD 40 once daily may be effective. LOKIT OD 20 is indicated for H.pylori - positive duodenal ulcers, as part of the eradication programme with appropriate antibiotics.

Gastric ulcer and reflux oesophagitis: The recommended dosage is 20 mg once daily for 4 to 8 weeks. In some patients with gastric ulcer or reflux oesophagitis refractory to other treatment regimens, 40 mg LOKIT OD once daily may be effective. In patients with severe or symptomatic recurrent reflux oesophagitis treatment can be continued with LOKIT OD as dosage of 20 mg once daily.

Symptomatic gastro - oesophageal reflux disease: The recommended dosage is 20 mg LOKIT OD daily. If symptom control has not been achieved after four weeks treatment with 20 mg LOKIT OD daily, further investigation is recommended.

Zollinger - Ellison syndrome: The recommended initial dosage is 60 mg LOKIT OD once daily. The dosage should be adjusted individually and treatment continued as long as is indicated. Patients with severe disease have been effectively controlled on LOKIT OD 20 with more than 90 % maintained on doses of 20 mg to 120 mg daily. With doses above 80 mg daily, the dose should be divided and given twice daily.

Children: There is no experience with LOKIT OD in children.

Elderly: No dose adjustment is necessary in the elderly.

Impaired Renal Function: No dose adjustment is required in patients with impaired renal function.

Impaired Hepatic Function: As bioavailability and plasma half - life of omeprazole are increased in patients with impaired hepatic function a daily dose of 20 mg is generally sufficient. The long - term safety of LOKIT OD in patients with renal and hepatic impairment has not been established.

Method of administration: For oral administration.

LOKIT OD is contraindicated in patients with hypersensitivity to omeprazole or to any of the excipients listed in 6.1. LOKIT OD must not be used concomitantly with nelfinavir (see section 4.5). Safety in pregnancy and lactation has not been established.

In the presence of any alarm 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.

Co - administration of atazanavir with LOKIT OD is not recommended (see section 4.5). If the combination of atazanavir with LOKIT OD 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; LOKIT OD 20 mg should not be exceeded.

LOKIT OD 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.

LOKIT OD is a CYP2C19 inhibitor. When starting or ending treatment with LOKIT OD, the potential for interactions with medicines metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and LOKIT OD (see section 4.3). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of LOKIT OD and clopidogrel should be discouraged.

Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) such as LOKIT OD 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. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of LOKIT OD. For patients expected to be on prolonged treatment of LOKIT OD or who take PPIs with digoxin or medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting LOKIT OD treatment and periodically during treatment.

Proton pump inhibitors, such as LOKIT OD, 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.

Subacute cutaneous lupus erythematosus: Proton pump inhibitors such as LOKIT OD, 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 professional should consider stopping LOKIT OD. SCLE after previous treatment with LOKIT OD 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, LOKIT OD 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 LOKIT OD treatment.

Clostridium difficile - associated diarrhoea: Proton pump inhibitors including LOKIT OD, may be associated with an increased risk of Clostridium difficile - associated diarrhoea (CDAD). This diagnosis should be considered for diarrhoea that does not improve. Treatment with LOKIT OD may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. As in all long - term treatments, especially when exceeding a treatment period of 1 year, patients should be monitored.

Paediatric population: There is very limited experience with the use of LOKIT OD in children. LOKIT OD contains sucrose and therefore patients with rare hereditary problems of fructose intolerance, glucose - galactose malabsorption or sucrase - isomaltase insufficiency should not take LOKIT OD.

Effects of omeprazole on the pharmacokinetics of other active substances:

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

Nelfinavir, atazanavir: The plasma levels of nelfinavir and atazanavir are decreased in case of co - administration with LOKIT OD. Concomitant administration of omeprazole as in LOKIT OD with nelfinavir is contraindicated (see section 4.3). Co - administration of LOKIT OD (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 LOKIT OD with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole as in LOKIT OD (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 as in LOKIT OD on atazanavir exposure. The co - administration of omeprazole as in LOKIT OD (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.

Digoxin: Simultaneous treatment with omeprazole as in LOKIT OD and digoxin in healthy subjects lead to a 10 % increase in the bioavailability of digoxin as a consequence of the increased intragastric pH. Digoxin toxicity has been reported. However, caution should be exercised when LOKIT OD is given at high doses in elderly patients. Therapeutic medicine monitoring of digoxin should then be reinforced.

Clopidogrel: Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole as in LOKIT OD (80 mg p.o. daily) resulting in a decreased exposure to the active metabolite of clopidogrel by an average of 46 % and a decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16 %. Inconsistent data on the clinical implications of a PK/PD interaction of omeprazole as in LOKIT OD in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of LOKIT OD and clopidogrel should be discouraged (see section 4.4).

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.

Active substances metabolised by CYP2C19: LOKIT OD 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. Monitoring of patients receiving warfarin and phenytoin is recommended and a reduction of warfarin and phenytoin dose may be necessary.

Cilostazol: LOKIT OD, 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 LOKIT OD treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment.

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

Methotrexate: When given together with proton - pump inhibitors such as LOKIT OD, methotrexate levels have been reported to increase in some patients. In high - dose methotrexate administration a temporary withdrawal of LOKIT OD may need to be considered.

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.

Effects of other active substances on the pharmacokinetics of omeprazole: 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. 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.

Pregnancy: Safety in pregnancy has not been established (see section 4.3).

Breastfeeding: Safety in breastfeeding has not been established (see section 4.3). LOKIT OD is excreted in breast milk.

Fertility: Animal studies with the racemic mixture omeprazole, given by oral administration do not indicate effects with respect to fertility.

LOKIT OD may affect the ability to drive or use machines. Side effects such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machinery.

a. Summary of the safety profile: The most frequent side effects are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.

b. Tabulated list of adverse reactions:

Med DRA SOC / frequency Adverse reaction

Infections and infestations: Frequency unknown Clostridium difficile - associated diarrhoea

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

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

Metabolism and nutrition disorders: Less frequent Hyponatraemia.

Frequency unknown Hypomagnesaemia; severe hypomagnesaemia may result in hypocalcaemia, hypomagnesaemia may also be associated with hypokalaemia

Psychiatric disorders: Less frequent Confusion, agitation, aggression, depression and hallucinations, insomnia

Nervous system disorders: Frequent Headache Less frequent Dizziness, somnolence, paraesthesia, taste disturbance

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, constipation, abdominal pain or colic, nausea, vomiting, flatulence, fundic gland polyps (benign) Less frequent Dry mouth, stomatitis, oesophageal candidiasis, gastrointestinal candidiasis

Frequency unknown Microscopic colitis

Hepato - biliary disorders: Less frequent Increased 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 Dermatitis, rash, urticaria, pruritus, photosensitivity, bullous eruption, toxic epidermal necrolysis, Stevens - Johnson syndrome, alopecia, erythema multiforme

Frequency unknown Subacute cutaneous lupus erythematosus

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

Renal and urinary disorders: Less frequent Interstitial nephritis

Reproductive system and breast disorders: Less frequent Gynaecomastia

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

Reporting of suspected adverse reactions: Reporting 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 6.04 Adverse Drug Reaction Reporting Form, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Single oral doses of up to 400 mg of LOKIT OD have resulted in throbbing headache, drowsiness, tachycardia, flushing, blurred vision and dry mouth. Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Single cases of apathy, depression and confusion have been described. There is no antidote for overdose with LOKIT OD. Treatment is symptomatic and supportive.