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Method of action:
Treatment option:
Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 26.06.2023
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Zoltenk VL is indicated in adults and children over 1 year of age and > 10kg.
Zoltenk VL gastro-resistant capsules are indicated in:
Adults:
- Treatment of duodenal ulcers
- Prevention of relapse of duodenal ulcers
- Treatment of gastric ulcers
- Prevention of relapse of gastric ulcers
- In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication 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
Paedriatric population:
Children over 1 year of age and >10 kg
- Treatment of reflux esophagitis,
- Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease
Children and adolescents over 4 years of age
- In combination with antibiotics in the treatment of duodenal ulcer caused by H. pylori
Zoltenk VL capsules are indicated in:
Adults
- Treatment of duodenal ulcers
- Prevention of relapse of duodenal ulcers
- Treatment of gastric ulcers
- Prevention of relapse of gastric ulcers
- In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication 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 oesophagitis
- Long-term management of patients with healed reflux oesophagitis
- Treatment of symptomatic gastro-oesophageal reflux disease
- Treatment of Zollinger-Ellison syndrome
Paediatric use
Children over 1 year of age and > 10 kg
- Treatment of reflux oesophagitis
- Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal reflux disease
Children and adolescents over 4 years of age
- In combination with antibiotics in treatment of duodenal ulcer caused by H. pylori
Posology in adults
Treatment of duodenal ulcers
The recommended dose in patients with an active duodenal ulcer is Zoltenk VL 20 mg 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 a poorly responsive duodenal ulcer Zoltenk VL 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 Zoltenk VL 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 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 a poorly responsive gastric ulcer Zoltenk VL 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 Zoltenk VL 20mg once daily. If needed the dose can be increased to Zoltenk VL 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.
- Zoltenk VL 20 mg + clarithromycin 500 mg + amoxicillin 1000 mg, each twice daily for 1 week
or
- Zoltenk VL 20 mg + clarithromycin 250 mg (alternatively 500mg) + metronidazole 400mg-(or 500 mg or tinidazole 500mg) each twice daily for one week
or
- Zoltenk VL 40 mg once daily with amoxicillin 500 mg + metronidazole 400mg (or 500 mg 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 Zoltenk VL 20 mg 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 and 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 Zoltenk VL once daily.
Treatment of reflux esophagitis
The recommended dose is Zoltenk VL 20mg once daily. In most patients healing occurs within 4 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 Zoltenk VL 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 Zoltenk VL 10mg once daily. If needed, the dose can be increased to Zoltenk VL 20-40mg once daily.
Treatment of symptomatic of gastro-esophageal reflux disease
The recommended dose is Zoltenk VL 20mg daily. Patients may respond adequately to 10mg daily, and therefore individual dose adjustments should be considered. If symptom control has not be achieved after four weeks treatment with Zoltenk VL 20mg daily, further investigation is recommended.
Treatment of Zollinger-Ellison syndrome
In patients with Zollinger-Ellison syndrome the dose should be individually adjusted and treatment continued as long as clinically indicated. The recommended initial dose is Zoltenk VL 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 Zoltenk VL 20-120mg daily. When the dose exceeds Zoltenk VL 80mg daily, the dose should be divided and given twice daily.
Paediatric population
The safety and efficacy of Zoltenk VL in children aged 0-12 months and < 10kg has not yet been established.
Children over 1 year of age and > 10 kg
Treatment of Reflux esophagitis
Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease
The posology recommendations are as follows:
| Age | Weight | Posology |
| > 1 year of age | 10 - 20 kg | 10 mg once daily. The dose can be increased to 20 mg once daily if needed |
| > 2 year of age | > 20 kg | 20 mg once daily. The dose can be increased to 40 mg once daily if needed |
Reflux esophatitis
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 and adolescents over 4 years of age
Treatment of duodenal ulcer caused by H pylori.
When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidelines 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:
| Weight | Posology |
| 15-30 kg | Combination with two antibiotics. Zoltenk VL 10 mg, amoxicillin 25 mg/kg body weight and clarithromycin 7.5 mg/kg body weight are all administered together 2 times daily for 1 week |
| 31-40 kg | Combination with two antibiotics. Zoltenk VL 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administered 2 times daily for 1 week |
| > 40 kg | Combination with two antibiotics. Zoltenk VL 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administered 2 times daily for 1 week |
Special Populations:
Renal impairment
Dose adjustment is not required in patients with impaired renal function.
Hepatic impairment
In patients with impaired hepatic function a daily dose of 10-20mg may be sufficient.
Elderly
Dose adjustment is not required in the elderly.
Method of administration:
It is recommended to take Zoltenk VL capsules in the morning, preferably without food, swallowed whole with half a glass of water.
The capsules must not be crushed or chewed.
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 apple sauce, 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.
Posology
Adults
Treatment of duodenal ulcers
The recommended dose in patients with an active duodenal ulcer is Zoltenk VL 20 mg 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 Zoltenk VL 40 mg 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 Zoltenk VL 20 mg once daily. In some patients a daily dose of 10 mg may be sufficient. In case of therapy failure, the dose can be increased to 40 mg.
Treatment of gastric ulcers
The recommended dose is Zoltenk VL 20 mg 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 Zoltenk VL 40 mg 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 Zoltenk VL 20 mg once daily. If needed the dose can be increased to Zoltenk VL 40 mg 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.
- Zoltenk VL 20 mg + clarithromycin 500 mg + amoxicillin 1,000 mg, each twice daily for one week, or
- Zoltenk VL 20 mg + clarithromycin 250 mg (alternatively 500 mg) + metronidazole 400 mg (or 500 mg or tinidazole 500 mg), each twice daily for one week or
- Zoltenk VL 40 mg once daily with amoxicillin 500 mg and metronidazole 400 mg (or 500 mg or tinidazole 500 mg), 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 Zoltenk VL 20 mg 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 Zoltenk VL 20 mg once daily.
Treatment of reflux oesophagitis
The recommended dose is Zoltenk VL 20 mg 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 oesophagitis Zoltenk VL 40 mg once daily is recommended and healing is usually achieved within eight weeks.
Long-term management of patients with healed reflux oesophagitis
For the long-term management of patients with healed reflux oesophagitis the recommended dose is Zoltenk VL 10 mg once daily. If needed, the dose can be increased to Zoltenk VL 20-40 mg once daily.
Treatment of symptomatic gastro-oesophageal reflux disease
The recommended dose is Zoltenk VL 20 mg daily. Patients may respond adequately to 10 mg daily, and therefore individual dose adjustment should be considered.
If symptom control has not been achieved after four weeks treatment with Zoltenk VL 20 mg daily, further investigation is recommended.
Treatment of Zollinger-Ellison syndrome
In patients with Zollinger-Ellison syndrome the dose should be individually adjusted and treatment continued as long as clinically indicated. The recommended initial dose is Zoltenk VL 60 mg 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 Zoltenk VL 20-120 mg daily. When dose exceed Zoltenk VL 80 mg daily, the dose should be divided and given twice daily.
Paediatric population
Children over 1 year of age and > 10 kg
Treatment of reflux oesophagitis
Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal reflux disease
The posology recommendations are as follows:
| Age | Weight | Posology |
| > 1 year of age | 10-20 kg | 10 mg once daily. The dose can be increased to 20 mg once daily if needed |
| > 2 years of age | > 20 kg | 20 mg once daily. The dose can be increased to 40 mg once daily if needed |
Reflux oesophagitis: The treatment time is 4-8 weeks.
Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal 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 and adolescents over 4 years of age
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:
| Weight | Posology |
| 15-30 kg | Combination with two antibiotics: Zoltenk VL 10 mg, amoxicillin 25 mg/kg body weight and clarithromycin 7.5 mg/kg body weight are all administered together two times daily for one week. |
| 31-40 kg | Combination with two antibiotics: Zoltenk VL 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administered two times daily for one week. |
| > 40 kg | Combination with two antibiotics: Zoltenk VL 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administered two times daily for one week. |
Special populations
Renal impairment
Dose adjustment is not needed in patients with impaired renal function.
Hepatic impairment
In patients with impaired hepatic function a daily dose of 10-20 mg may be sufficient.
Elderly
Dose adjustment is not needed in the elderly.
Method of administration
It is recommended to take Zoltenk VL capsules in the morning, swallowed whole with half 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.
Zoltenk VL like other proton pump inhibitors (PPIs) must not be used concommitantly with nelfinavir.
Omeprazole like other proton pump inhibitors (PPIs) must not be used concomitantly with nelfinavir.
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) 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; Zoltenk VL 20mg should not be exceeded.
Zoltenk VL as with 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.
Zoltenk VL is a CYP2C19 inhibitor. When starting or ending treatment with Zoltenk VL, the potential for interactions with drugs metabolized through CYP2C19 should be considered. An interaction is observed between clopidogrel and Zoltenk VL. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of Zoltenk VL and clopidogrel should be discouraged.
Hypomagnesaemia
Severe hypomagnesaemia has been reported in patients treated with PPIs like Zoltenk VL 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 other medicines 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 fractures 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.
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 healthcare professional should consider stopping Zoltenk VL. 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, Zoltenk VL treatment should be stopped for at least five 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.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and in hospitalised patients possibly also Clostridium difficile.
As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
Paediatric population:
Some children with chronic illnesses may require long-term treatment although it is not recommended.
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 400 mg with 100 mg of ritonavir; omeprazole 20 mg 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.
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.
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 Zoltenk VL. 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, omeprazole 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.
Some children with chronic illnesses may require long-term treatment although it is not recommended.
Zoltenk VL contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile.
As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
Zoltenk VL has no or negligible influence on the ability to drive or use machines. Adverse drug reactions such as dizziness and visual disturbance may occur. If affected, patients should not drive or operate machinery.
Zoltenk VL is not likely to affect the ability to drive or use machines. Adverse drug reactions such as dizziness and visual disturbances may occur. If affected, patients should not drive or operate machinery.
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 Zoltenk VL and post-marketing. None was found to be dose-related.
Adverse reactions listed below are classified according to the 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)
| SOC/ Frequency | Adverse reaction |
| Blood and lymphatic system disorders | |
| Rare: | Leukopenia, thrombocytopenia |
| Very rare: | Pancytopenia, agranulocytosis |
| Immune system disorders | |
| Rare: | Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/ shock |
| Metabolism and nutrition disorders | |
| Rare: | Hyponataemia |
| Not Known: | Hypomagneseamia; 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, paresthesia, 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 and vomiting fundic gland polyps (benign) |
| 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-Johnsonsyndrome, 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 Zoltenk VL 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 Zoltenk VL during a clinical study for severe erosive oesophagitis 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 Zoltenk VL treatment on puberty and growth.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Summary of the safety profile
The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.
Tabulated list of adverse reactions
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).
| SOC/frequency | Adverse reaction | |
| 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, fundic gland polyps (benign) | |
| 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 oesophagitis 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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.
There is limited information available on the effects of overdoses of Zoltenk VL in humans. In literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have been reached of up to 2,400 mg Zoltenk VL (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases.
The symptoms described in connection with Zoltenk VL overdose have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic.
There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases.
The symptoms described have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic.
Pharmacotherapeutic group: Proton pump inhibitors, ATC-code: A02BC01
Mechanism of Action:
Zoltenk VL, a racemic mixture of two enantiomers, reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing.
Zoltenk VL is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+, K+-ATPase - the acid pump. This effect on the final step of gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus.
Pharmacodynamic effects:
All pharmacodynamic effects observed can be explained by the effect of Zoltenk VL on acid secretion.
Clinical Efficacy and Safety:
Effect on gastric acid secretion:
Oral dosing with Zoltenk VL once daily provides for rapid and effective inhibition of daytime and night-time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With Zoltenk VL 20mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained on duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% 24 hours after dosing.
Oral dosing with Zoltenk VL 20mg maintains an intragastric pH of > 3 for a mean time of 17 hours of the 24-hour period in duodenal ulcer patients.
As a consequence of reduced acid secretion and intragastric acidity, Zoltenk VL dose-dependently reduces/normalizes acid exposure of the esophagus in patients with gastro-esophageal reflux disease. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of Zoltenk VL and not the actual plasma concentration at a given time.
No tachyphylaxis has been observed during treatment with Zoltenk VL.
Effect on H. pylori
H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer.
Eradication of H. pylori with Zoltenk VL and antimicrobials is associated with high rates of healing and long-term remission of peptic ulcers.
Dual therapies have been tested and have been found to be less effective than triple therapies. They could however be considered in cases where known hypersensitivity precludes the use of any triple combination.
Other effects related to acid inhibition
During long-term treatment gastric glandular cysts have been reported in somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric count of bacteria normally present in the gastrointestinal tract. Treatment with acid reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile..
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.
Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients (both children and adults) during long term treatment with Zoltenk VL. The findings are considered to be of no clinical significance.
Paediatric population
In a non-controlled study in children (1 to 16 years of age) with severe reflux esophagitis, Zoltenk VL at doses of 0.7 to 1.4 mg/kg improved esophagitis level in 90 % of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0-24 months with clinically diagnosed gastro-esophageal reflux disease were treated with 0.5, 1.0 or 1.5 mg Zoltenk VL/kg. The frequency of vomiting/regurgitation episodes decreased by 50 % after 8 weeks of treatment irrespective of the dose.
Eradication of Helicobacter pylori in children
A randomised, double-blind clinical study (Heliot study) concluded that Zoltenk VL in combination with two antibiotics (amoxicillin and clarithromycin) was safe and effective in the treatment of H. pylori infection in children of 4 years old and above with a gastritis: H. pylori eradication rate: 74 % (23/31 patients) with Zoltenk VL + amoxicillin + clarithromycin versus 9.4 % (3/32 patients) with amoxicillin + clarithromycin. However, there was no evidence of clinical benefit demonstrated regarding dyspeptic symptoms. This study does not support any information for children aged less than 4 years old.
Pharmacotherapeutic group: Drugs for acid-related disorders, proton pump inhibitors, ATC code: A02BC01
Mechanism of action
Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing.
Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+ K+-ATPase - the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus.
Pharmacodynamic effects
All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion.
Effect on gastric acid secretion
Oral dosing with omeprazole once daily provides for rapid and effective inhibition of daytime and night-time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With omeprazole 20 mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% 24 hours after dosing.
Oral dosing with omeprazole 20 mg maintains an intragastric pH of > 3 for a mean time of 17 hours of the 24-hour period in duodenal ulcer patients.
As a consequence of reduced acid secretion and intragastric acidity, omeprazole dose-dependently reduces/normalizes acid exposure of the oesophagus in patients with gastro-oesophageal reflux disease.
The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time.
No tachyphylaxis has been observed during treatment with omeprazole.
Effect on H. pylori
H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer.
Eradication of H. pylori with omeprazole and antimicrobials is associated with, high rates of healing and long-term remission of peptic ulcers.
Dual therapies have been tested and found to be less effective than triple therapies. They could, however, be considered in cases where known hypersensitivity precludes use of any triple combination.
Other effects related to acid inhibition
During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile.
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients (both children and adults) during long term treatment with omeprazole. The findings are considered to be of no clinical significance.
Paediatric population
In a non-controlled study in children (1 to 16 years of age) with severe reflux oesophagitis, omeprazole at doses of 0.7 to 1.4 mg/kg improved oesophagitis level in 90% of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0-24 months with clinically diagnosed gastro-oesophageal reflux disease were treated with 0.5, 1.0 or 1.5 mg omeprazole/kg. The frequency of vomiting/regurgitation episodes decreased by 50% after 8 weeks of treatment irrespective of the dose.
Eradication of H. pylori in children
A randomised, double blind clinical study (Héliot study) concluded that omeprazole in combination with two antibiotics (amoxicillin and clarithromycin), was safe and effective in the treatment of H. pylori infection in children age 4 years old and above with gastritis: H. pylori eradication rate: 74.2% (23/31 patients) with omeprazole + amoxicillin + clarithromycin versus 9.4% (3/32 patients) with amoxicillin + clarithromycin. However, there was no evidence of any clinical benefit with respect to dyspeptic symptoms. This study does not support any information for children aged less than 4 years.
Absorption
Zoltenk VL is acid labile and is therefore administered orally as enteric-coated granules in hard-gelatin capsules. Absorption of Zoltenk VL is rapid, with peak-plasma levels occurring 1-2 hours after the dose. Absorption of Zoltenk VL takes place in the small intestine and is usually completed within 3-6 hours. Concomitant intake of food has no influence on the bioavailability. The systemic availability (bioavailability) from a single oral dose of Zoltenk VL 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. Zoltenk VL is 97% protein bound.
Biotransformation
Zoltenk VL is completely metabolised, by the cytochrome P450 system (CYP). The major part of metabolism is dependent on the polymorphically expressed CYP 2C19 responsible for the formation of hydroxyZoltenk VL, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of Zoltenk VL Sulphone. As a consequence of high affinity of Zoltenk VL to CYP 2C19, there is the potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP 2C19. However due to low affinity to CYP3A4, Zoltenk VL has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition Zoltenk VL lacks an inhibitory effect on the main CYP enzymes.
Approximately 3% of the Caucasian population and 15-20% of the Asian population lack a functional CYP 2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of Zoltenk VL is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20mg Zoltenk VL 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 Zoltenk VL.
Elimination
The plasma elimination half life of Zoltenk VL is usually shorter than one hour both after single and repeated oral once daily dosing. Zoltenk VL is completely eliminated from plasma between doses with no tendency for accumulation during once daily administration. Almost 80% of an oral dose of Zoltenk VL is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion.
The AUC of Zoltenk VL 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 Zoltenk VL and /or it's metabolites (e.g. the sulphone).
No metabolite has been found to have any effect on gastric acid secretion.
Special Populations
Impaired hepatic function
The metabolism of Zoltenk VL in patients with liver dysfunction is impaired, resulting in an increased AUC. Zoltenk VL has not shown any tendency to accumulate with once-daily dosing.
Impaired renal function
The pharmacokinetics of Zoltenk VL, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.
Elderly
The metabolism rate of Zoltenk VL is somewhat reduced in elderly subjects (75-79 years of age).
Paediatric patients
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 Zoltenk VL is low due to low capacity to metabolise Zoltenk VL.
Absorption
Omeprazole and omeprazole magnesium are acid labile and are therefore administered orally as enteric-coated granules in capsules or tablets. 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. Concomitant intake of food has no influence on the bioavailability. The systemic availability (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 0.3 l/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 sulfone. 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 20 mg 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 sulfone).
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.
Elderly
The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age).
Paediatric population
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.
Gastric ECL-cell hyperplasia and carcinoids have been observed in life-long studies in rats treated with Zoltenk VL. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance.
Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance.
Not applicable.
Not applicable.
No special requirements for disposal.
No special requirements.
However, we will provide data for each active ingredient
