AGIMEPZOL®20

Composition: Each hard capsule contains:
AGIMEPZOL 20
Omeprazole . . . . . . . . . . . . . . . . . . . . . . 20 mg
(as Omeprazole enteric coated pellet 8.5%).
Presentation:
AGIMEPZOL 20: Box of 10 blisters x 10 hard capsules; HD bottle contains 200 hard capsules.
Indications:
Agimepzole hard capsules are indicated for:
Adults:
Treatment of duodenal ulcers.
Prevention of relapse of duodenal ulcers.
Treatment of gastric ulcers.
Prevention of relapse of gastric ulcers.
Combination with appropriate antibiotics to eradicate H. pylori in peptic ulcer disease.
Treatment of NSAID-associated gastric and duodenal ulcers.
Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk.
Treatment of reflux esophagitis.
Long-term management of patients with healed reflux esophagitis.
Treatment of symptomatic gastro-esophageal reflux disease.
Treatment of Zollinger-Ellison syndrome.
Children:
Children aged over 1 year and ≥ 10kg:
Treatment of reflux esophagitis.
Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease.
Children and adolescents over 4 years of age:
Treatment of duodenal ulcer caused by H. pylori in combination with antibiotics.

Additional information

Dosage and administration

Dosage:
Adult:
Treatment of duodenal ulcers:
The recommended dose in patients with an active duodenal ulcer is omeprazol 20mg once daily. In most patients healing occurs within two weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further two weeks treatment period. In patients with poorly responsive duodenal ulcer Agimepzol 40mg once daily is recommended and healing is usually achieved within four weeks.
Prevention of relapse of duodenal ulcers:
For the prevention of relapse of duodenal ulcer in H. pylori negative patients or when H. pylori eradication is not possible the recommended dose is omeprazole 20mg once daily. In some patients a daily dose of 10mg may be sufficient. In case of therapy failure, the dose can be increased to 40mg.
Treatment of gastric ulcers:
The recommended dose is omeprazole 20mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. In patients with poorly responsive gastric ulcer omeprazole 40mg once daily is recommended and healing is usually achieved within eight weeks.
Prevention of relapse of gastric ulcers:
For the prevention of relapse in patients with poorly responsive gastric ulcer the recommended dose is 20mg once daily. If needed the dose can be increased to omeprazole 40mg once daily.
H. pylori eradication in peptic ulcer disease:
For the eradication of H. pylori, the selection of antibiotics should consider the individual patient's drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines.
Omeprazole 20mg + clarithromycin 500mg + amoxicillin 1, 000mg, each twice daily for one week, or.
Omeprazole 20mg + clarithromycin 250mg (alternatively 500mg) + metronidazole 400mg (or 500mg or tinidazole 500mg), each twice daily for one week or.
Omeprazole 40mg once daily with amoxicillin 500mg and metronidazole 400mg (or 500mg or tinidazole 500mg), both three times a day for one week.
In each regimen, if the patient is still H. pylori positive, therapy may be repeated.
Treatment of NSAID-associated gastric and duodenal ulcers:
For the treatment of NSAID-associated gastric and duodenal ulcers, the recommended dose is Agimepzol 20mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.
Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk:
For the prevention of NSAID-associated gastric ulcers or duodenal ulcers in patients at risk (age> 60, previous history of gastric and duodenal ulcers, previous history of upper GI bleeding) the recommended dose is 20mg once daily.
Treatment of reflux esophagitis:
The recommended dose is omeprazole 20mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.
In patients with severe esophagitis, omeprazole 40mg once daily is recommended and healing is usually achieved within eight weeks.
Long-term management of patients with healed reflux esophagitis:
For the long-term management of patients with healed reflux esophagitis the recommended dose is omeprazole 10mg once daily. If needed, the dose can be increased to omeprazole 20-40mg once daily.
Treatment of symptomatic gastro-esophageal reflux disease:
The recommended dose is omeprazole 20mg daily. Patients may respond adequately to 10mg daily, and therefore individual dose adjustment should be considered.
If symptom control has not been achieved after four weeks treatment with omeprazole 20mg daily, further investigation is recommended.
Treatment of Zollinger-Ellison syndrome:
In patients with Zollinger-Ellison syndrome the dose should be individualized and treatment continued as long as clinically indicated. The recommended initial dose is omeprazole 60mg daily. All patients with severe disease and inadequate response to other therapies have been effectively controlled and more than 90% of the patients maintained on doses of omeprazole 20-120mg daily. When dose exceed omeprazole 80mg daily, the dose should be divided and given twice daily.
The dosage for pediatric population
Children aged over 1 year and ≥ 10kg
Treatment of reflux esophagitis.
Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease.
The posology recommendations are as follows:
– ≥ 1 year of age & 10-20kg: 10mg once daily. The dose can be increased to 20mg once daily if needed
– ≥ 2 years of age & > 20kg: 20mg once daily. The dose can be increased to 40mg once daily if needed
Reflux esophagitis: The treatment time is 4-8 weeks.
Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease: The treatment time is 2–4 weeks. If symptom control has not been achieved after 2–4 weeks the patient should be investigated further.
Children aged over 4 years and adolescents:
Treatment of duodenal ulcer caused by H. pylori
When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents.
The treatment should be supervised by a specialist.
The posology recommendations are as follows:
– 15–30kg: Combination with two antibiotics: Omeprazole 10mg, amoxicillin 25mg/kg body weight and clarithromycin 7.5mg/kg body weight are all administered together two times daily for one week.
– 31–40kg Combination with two antibiotics: Omeprazole 20mg, amoxicillin 750mg and clarithromycin 7.5mg/kg body weight are all administered two times daily for one week.
– > 40kg: Combination with two antibiotics: Omeprazole 20mg, amoxicillin 1g and clarithromycin 500mg are all administered two times daily for one week.
Special population:
Patients with renal impairment: Dose adjustment is not needed in patients with impaired renal function.
Patients with hepatic impairment: In patients with impaired hepatic function a daily dose of 10–20mg may be sufficient.
Older people (> 65 years old): Dose adjustment is not needed in the elderly.
Administration:
Omeprazole capsule should be taken preferably in the morning before meal, swallowed whole with a glass of water. The capsules must not be chewed or crushed.
For patients with swallowing difficulties and for children who can drink or swallow semi-solid food.
Patients can open the capsule and swallow the contents with half a glass of water or after mixing the contents in a slightly acidic fluid e.g. fruit juice or applesauce, or in non-carbonated water. Patients should be advised that the dispersion should be taken immediately (or within 30 minutes) and always be stirred just before drinking and rinsed down with half a glass of water. Alternatively, patients can suck the capsule and swallow the pellets with half a glass of water. The enteric-coated pellets must not be chewed.

Contraindications

Hypersensitivity to omeprazole and any of the excipients of this medicine.
Like other proton pump inhibitors (PPIs), omeprazole must not be used concomitantly with nelfinavir.

Warnings and precautions for use

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 proton pump inhibitors is not recommended. 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 400mg with 100mg of ritonavir; omeprazole 20mg should not be exceeded.
Omeprazole, 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.
Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged.
Hypomagnesaemia:
Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like omeprazole 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 drugs that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
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 fracture 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.
Interference with laboratory tests:
Increased Chromogranin (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Agimepzol treatment should be stopped for at least five days before CgA measurements.
Some children with chronic illnesses may require long-term treatment although it is not recommended.
Treatment with proton pump inhibitors 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 kept under regular surveillance.
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 health care professional should consider stopping omeprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Recommendation for pregnancy and breastfeeding

Pregnancy:
In experimental studies show no evidence of teratogenic potential and fetal toxicity, however, monitoring time is not enough to eliminate any risk. Therefore, the use of omeprazole during pregnancy is only considered when it is necessary.
Breast-feeding:
Consideration should be made to discontinue the medicine or discontinue nursing because omeprazole is distributed in human breast milk.

Effects on ability to drive and use machines

Caution should be exercised when driving vehicles and operating machinery because this medicine may cause headache, drowsiness, dizziness.

Interactions, incompatibilities of medicine

Effects of omeprazole on the pharmacokinetics of other active substances:
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, atazanavir:
The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole. Concomitant administration of omeprazole with nelfinavir is contraindicated.
Co-administration of omeprazole (40mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75 –90%. The interaction may also involve CYP2C19 inhibition.
Concomitant administration of omeprazole with atazanavir is not recommended. Concomitant administration of omeprazole (40mg once daily) and atazanavir 300mg/ritonavir 100mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20mg once daily) with atazanavir 400mg/ritonavir 100mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300mg/ritonavir 100mg once daily.
Digoxin:
Concomitant treatment with omeprazole (20mg 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. Monitoring of treatment with digoxin should be then reinforced.
Clopidogrel:
Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300mg loading dose/75mg daily maintenance dose) and omeprazole (80mg 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 in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged.
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:
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 drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.
Cilostazol:
Omeprazole, given in doses of 40mg to healthy subjects in a cross-over study, increased Cmax 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.
Unknown mechanism:
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 proton-pump inhibitors, 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.
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 omeprazole's 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. John's wort) may lead to decreased omeprazole serum levels by increasing omeprazole's rate of metabolism.

Undesirable effects (ADRs)

The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.
The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to frequency and System Organ Class (SOC).
Frequency categories are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1, 000 to < 1/100); Rare (≥ 1/10, 000 to < 1/1, 000); Very rare (< 1/10, 000); Not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
– Rare: Leukopenia, thrombocytopenia
– Very rare: Agranulocytosis, pancytopenia
Immune system disorders
– Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock
Metabolism and nutrition disorders
– Rare: Hyponatraemia
– Not known: Hypomagnesaemia; Severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.
Psychiatric disorders
– Uncommon: Insomnia
– Rare: Agitation, confusion, depression
– Very rare: Aggression, hallucinations
Nervous system disorders
– Common: Headache
– Uncommon: Dizziness, paraesthesia, somnolence
– Rare: Taste disturbance
Eye disorders
– Rare: Blurred vision
Ear and labyrinth disorders
– Uncommon: Vertigo
Respiratory, thoracic and mediastinal disorders
– Rare: Bronchospasm
Gastrointestinal disorders
– Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting
– Rare: Dry mouth, stomatitis, gastrointestinal Candidiasis
– Not known: Microscopic colitis
Hepatobiliary disorders
– Uncommon: Increased liver enzymes
– Rare: Hepatitis with or without jaundice
– Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease
Skin and subcutaneous tissue disorders
– Uncommon: Dermatitis, pruritus, rash, urticaria
– Rare: Alopecia, photosensitivity
– Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)
– Not known: Subacute cutaneous lupus erythematosus.
Musculoskeletal and connective tissue disorders
– Uncommon: Fracture of the hip, wrist or spine
– Rare: Arthralgia, myalgia
– Very rare: Muscular weakness
Renal and urinary disorders
– Rare: Interstitial nephritis
Reproductive system and breast disorders
– Very rare: Gynaecomastia
General disorders and administration site conditions
– Uncommon: Malaise, peripheral oedema
– Rare: Increased sweating
Paediatric population:
The safety of omeprazole has been assessed in a total of 310 children aged 0 to 16 years with acid-related disease. There are limited long term safety data from 46 children who received maintenance therapy of omeprazole during a clinical study for severe erosive esophagitis for up to 749 days. The adverse event profile was generally the same as for adults in short- as well as in long-term treatment. There are no long-term data regarding the effects of omeprazole treatment on puberty and growth.

Overdose and management

Single doses up to 160 mg have been well tolerated.
When overdose occurs, primary clinical manifestations are drowsiness, headache and tachycardia .
There is no specific antidote for overdose with omeprazole. Omeprazole is strongly bound to plasma proteins, so omeprazole is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

Pharmacodynamic properties

Omeprazole is a substituted benzimidazole which has structures and effects similar to pantoprazole, lansoprazole, esomeprazole. Omeprazole inhibits gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system, also called proton pump, at the secretory surface of the gastric parietal cell. Maximum effects are achieved within 4 days of commencing treatment. In duodenal ulcer patients, a mean decrease of at least 80% in 24-hour intragastric acidity can be maintained.
Omeprazole may inhibit Helicobacter pylori in patients with duodenal ulcer and/or reflux esophagitis infected with H. pylori bacteria. The combination of omeprazole with some antibiotics (e.g. clarithromycin, amoxicillin) can eradicate H. pylori accompanied by healing of ulcer.

Pharmacokinetic properties

Absorption:
Omeprazole is destroyed in the acid environment. The drug is formulated as enteric-coated pellets packed in capsules or tablets to avoid the destruction at acid pH of the stomach. Absorption of omeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. Food has no influence on the bioavailability. The bioavailability from a single oral dose of omeprazole is approximately 40%. After repeated once-daily administration, the bioavailability increases to about 60%.
Distribution:
The apparent volume of distribution in healthy subjects is approximately 0.3l/kg body weight. Omeprazole is 97% plasma protein bound.
Biotransformation:
Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes.
Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole.
Elimination:
The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated oral once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Almost 80% of an oral dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion.
Linearity/non-linearity:
The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulphone). No metabolite has been found to have any effect on gastric acid secretion.
Special populations:
Hepatic impairment:
The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once daily dosing.
Renal impairment:
The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.
Older people:
The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age).
Paediatric:
During treatment with the recommended doses to children from the age of 1 year, similar plasma concentrations were obtained as compared to adults. In children younger than 6 months, clearance of omeprazole is low due to low capacity to metabolise omeprazole.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.