4.1. Therapeutic indications

- Treatment of duodenal and gastric ulcer.

- Treatment of reflux oesophagitis.

- Prophylaxis of reflux oesophagitis

- Eradication of Helicobacter pylori (H. pylori) concurrently given with appropriate antibiotic therapy for treatment of H.pylori-associated ulcers.

- Treatment of NSAID-associated benign gastric and duodenal ulcers in patients requiring continued NSAID treatment.

- Prophylaxis of NSAID-associated gastric ulcers and duodenal ulcers in patients at risk (see section 4.2) requiring continued therapy

- Symptomatic gastroesophageal reflux.disease.

- Zollinger-Ellison syndrome.

Lansoprazole is indicated in adults.

4.2. Posology and method of administration

Posology

Treatment of duodenal ulcer:

The recommended dose is 30 mg once daily for 2 weeks, in patients not fully healed within this period, the medication is continued at the same dose for another two weeks.

Treatment of gastric ulcer:

The recommended dose is 30 mg once daily for 4 weeks. The ulcer usually heals within 4 weeks, but in patients not fully healed within this time, the medication may be continued at the same dose for another 4 weeks.

Reflux oesophagitis:

The recommended dose is 30 mg once daily for 4 weeks. In patients not fully healed within this time, the treatment may be continued at the same dose for another 4 weeks.

Prophylaxis of reflux oesophagitis:

15 mg once daily. The dose may be increased up to 30 mg once daily as necessary.

Eradication of Helicobacter pylori:

When selecting appropriate combination therapy consideration should be given to official 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 recommended dose is 30 mg of Lansoprazole twice daily for 7 days in combination with one of the following:

clarithromycin 250-500 mg twice daily + amoxicillin 1 g twice daily

clarithromycin 250 mg twice daily + metronidazole 400-500 mg twice daily

The H. pylori eradication results obtained when clarithromycin is combined with either amoxicillin or metronidazole give rates of up to 90%, when used in combination with Lansoprazole.

Six months after successful eradication treatment, the risk of re infection is low and relapse is therefore unlikely.

Use of a regimen including lansoprazole 30 mg twice daily, amoxicillin 1 g twice daily and metronidazole 400-500 mg twice daily has also been examined. Lower eradication rates were seen using this combination than in regimens involving clarithromycin. It may be suitable for those who are unable to take clarithromycin as part of an eradication therapy, when local resistance rates to metronidazole are low.

Treatment of NSAID associated benign gastric and duodenal ulcers in patients requiring continued NSAID treatment:

30 mg once daily for four weeks. In patients not fully healed the treatment may be continued for another four weeks. For patients at risk or with ulcers that are difficult to heal, a longer course of treatment and/or a higher dose should probably be used.

Prophylaxis of NSAID associated gastric and duodenal ulcers in patients at risk (such as age > 65 or history of gastric or duodenal ulcer) requiring prolonged NSAID treatment:

15 mg once daily. If the treatment fails the dose 30 mg once daily should be used.

Symptomatic gastro-oesophageal reflux disease:

The recommended dose is 15 mg or 30 mg daily. Relief of symptoms is obtained rapidly. Individual adjustment of dosage should be considered. If the symptoms are not relieved within 4 weeks with a daily dose of 30 mg, further examinations are recommended.

Zollinger-Ellison syndrome:

The recommended initial dose is 60 mg once daily. The dose should be individually adjusted and the treatment should be continued for as long as necessary. Daily doses of up to 180 mg have been used. If the required daily dose exceeds 120 mg, it should be given in two divided doses.

Impaired renal function:

There is no need for a dose adjustment in patients with impaired renal function.

Impaired hepatic function:

Patients with moderate or severe liver disease should be kept under regular supervision and a 50% reduction of the daily dose is recommended (see section 4.4 and 5.2).

Elderly:

Due to reduced clearance of lansoprazole in the elderly an adjustment of dose may be necessary based on individual requirements. A daily dose of 30 mg should not be exceeded in the elderly unless there are compelling clinical indications.

Children:

The use of Lansoprazole is not recommended in children as clinical data are limited (see also section 5.2). Treatment of small children below one year of age should be avoided as available data have not shown beneficial effects in the treatment of gastro-oesophageal reflux disease.

Method of administration

For optimal effect, Lansoprazole should be given once daily in the morning, except when used for H. pylori eradication when treatment should be twice a day, once in the morning and once in the evening. Lansoprazole should be taken at least 30 minutes before food (see section 5.2). Lansoprazole should be placed on the tongue and gently sucked. The tablet rapidly disperses in the mouth, releasing gastroresistant microgranules which are swallowed with the help of a glass of water.

The orodispersible tablets may be dispersed in a small amount of water and administered via a nasogastric tube or oral syringe.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

In common with other anti-ulcer therapies, the possibility of malignant gastric tumour should be excluded when treating a gastric ulcer with lansoprazole because lansoprazole can mask the symptoms and delay the diagnosis.

Lansoprazole should not be co-administered with HIV protease inhibitors, such as atazanavir and nelfinavir, because there is a significant reduction in its bioavailability since the absorption of these depends on the intragastric acid pH (see section 4.5).

Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like lansoprazole 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), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Influence on the absorption of vitamin B12:

Lansoprazole, like all medicines that block acid secretion, can reduce the absorption of vitamin B12 (cyanocobalamin) due to hypochlorhydria or achlorhydria. This should be taken into account in long-term treatments in patients with vitamin B12 deficiency or with risk factors of reduced absorption of this vitamin, or in case clinical symptoms are observed.

Lansoprazole should be used with caution in patients with moderate and severe hepatic dysfunction (see sections 4.2 and 5.2).

Lansoprazole, like all proton pump inhibitors (PPIs), can increase gastric counts of bacteria normally present in the gastrointestinal tract. This can increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter and Clostridium difficile.

In patients suffering from gastro-duodenal ulcers, the possibility of H. pylori infection as an etiological factor should be considered.

If lansoprazole is used in combination with antibiotics for eradication therapy of H. pylori, then the instructions for the use of these antibiotics should also be followed.

Because of limited safety data for patients on maintenance treatment for longer than 1 year, regular review of the treatment and a thorough risk/benefit assessment should regularly be performed in these patients

Very rarely cases of colitis have been reported in patients taking lansoprazole. Therefore, in the case of severe and/or persistent diarrhoea, discontinuation of therapy should be considered.

The treatment for the prevention of peptic ulceration of patients in need of continuous NSAID treatment should be restricted to high risk patients (e.g. previous gastrointestinal bleeding, perforation or ulcer, advanced age, concomitant use of medication known to increase the likelihood of upper GI adverse events [e.g. corticosteroids or anticoagulants], the presence of a serious co-morbidity factor or the prolonged use of NSAID maximum recommended doses).

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.

Renal impairment

Acute tubulointersticial nephritis (TIN) has been observed in patients taking lansoprazole and may occur at any point during lansoprazole therapy (see section 4.8). Acute tubulointersticial nephritis can progress to renal failure.

Lansoprazole should be discontinued in case of suspected TIN, and appropriate treatment should be promptly initiated.

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 Lansoprazole. 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, Lansoprazole treatment should be stopped for at least 5 days before CgA measurements (see section 5.1). 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.

As Lansoprazole contains sucrose, patients with rare hereditary intolerance to fructose, problems with glucose or galactose absorption or sucrose-isomaltase deficiency should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of lansoprazole on other drugs

Medicinal products with pH-dependent absorption

Lansoprazole may interfere with the absorption of drugs where gastric pH is critical to bioavailability.

HIV Protease Inhibitors:

Co-administration of lansoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH, such as atazanavir and nelfinavir, due to significant reduction in their bioavailability (see section 4.4).

Ketoconazole and itraconazole:

The absorption of ketoconazole and itraconazole from the gastrointestinal tract is enhanced by the presence of gastric acid. Administration of lansoprazole may result in sub-therapeutic concentrations of ketoconazole and itraconazole and the combination should be avoided.

Digoxin:

Co-administration of lansoprazole and digoxin may lead to increased digoxin plasma levels. The plasma levels of digoxin should therefore be monitored and the dose of digoxin adjusted if necessary when initiating and ending lansoprazole treatment.

Methotrexate

Concomitant use with high-dose methotrexate may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. Therefore, in settings with high-dose of methotrexate is used a temporary withdrawal of lansoprazole may need to be considered.

Warfarin

Co-administration of lansoprazole 60 mg and warfarin did not affect the pharmacokinetics of warfarin or INR. There have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with lansoprazole and warfarin concomitantly may need to be monitored for increase in INR and prothrombin time.

Medicinal products metabolised by P450 enzymes

Lansoprazole may increase plasma concentrations of drugs that are metabolised by CYP3A4. Caution is advised when combining lansoprazole with drugs which are metabolised by this enzyme and have a narrow therapeutic window.

Theophylline:

Lansoprazole reduces the plasma concentration of theophylline, which may decrease the expected clinical effect at the dose. Patients treated with lansoprazole together with theophylline should be under medical supervision

Tacrolimus:

Co-administration of lansoprazole increases the plasma concentrations of tacrolimus (a CYP3A and P-gp substrate). Lansoprazole exposure increased the mean exposure of tacrolimus by up to 81%. Monitoring of tacrolimus plasma concentrations is advised when concomitant treatment with lansoprazole is initiated or ended.

Medicinal products carried by P-glycoprotein

Lansoprazole has been observed to inhibit the transport protein, P-glycoprotein (P-gp) in vitro. The clinical relevance of this is unknown.

Effects of other drugs on lansoprazole

Drugs which inhibit CYP2C19

Fluvoxamine:

A dose reduction may be considered when combining lansoprazole with the CYP2C19 inhibitor fluvoxamine. A study shows that the plasma concentrations of lansoprazole increase up to 4-fold.

Drugs which induce CYP2C19 and CYP3A4

Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin, and St John's Wort (Hypericum perforatum) can markedly reduce the plasma concentrations of lansoprazole.

Others

Sucralfate/antacids:

Sucralfate/Antacids may decrease the bioavailability of lansoprazole. Therefore lansoprazole should be taken at least 1 hour after taking these drugs.

No clinically significant interactions of lansoprazole with nonsteroidal anti-inflammatory drugs have been demonstrated, although no formal interactions studies have been performed.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is limited amount of data from the use of lansoprazole in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

As a precautionary measure, it is preferable to avoid the use of lansoprazole during pregnancy.

Lactation

It is not known whether lansoprazole is excreted in breast milk. Animal studies have shown excretion of lansoprazole in the milk.

A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with lansoprazole should be made taking into account the benefit of breastfeeding to the child and the benefit of lansoprazole therapy to the woman.

Fertility

No human data on the effect of lansoprazole on fertility are available. Reproductive studies in pregnant rats and rabbits revealed no lansoprazole-related impairment of fertility.

4.7. Effects on ability to drive and use machines

Adverse drug reactions such as dizziness, vertigo, visual disturbances and somnolence may occur (see section 4.8). Under these conditions the ability to react may be decreased.

4.8. Undesirable effects

Frequencies are defined as 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) or not known (cannot be estimated from the available data).

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

Thrombocytopenia, eosinophilia, leucopenia

Anaemia

Agranulocytosis, pancytopenia

Immune system disorders

Anaphylactic shock

Metabolism and nutritional disorders

Hypomagnesaemia (see section 4.4)

Psychiatric disorders

Depression

Insomnia, hallucinations, confusion

Visual hallucinations

Nervous system disorders

Headache, dizziness

Restlessness, vertigo, paraesthesia, somnolence, tremor

Eye disorders

Visual disturbances

Gastrointestinal disorders

Nausea, diarrhoea, stomach ache, constipation, vomiting, flatulence, dry mouth or throat, fundic gland polyps (benign)

Glossitis, candidiasis of the oesophagus, pancreatitis, taste disturbances

Colitis, stomatitis

Hepatobiliary disorders

Increase in liver enzyme levels

Hepatitis, jaundice

Skin and subcutaneous tissue disorders

Urticaria, itching, rash

Petechiae, purpura, hair loss, erythema multiforme, photosensitivity

Stevens-Johnson syndrome, toxic epidermal necrolysis

Subacute cutaneous lupus erythematosus (see section 4.4).

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia

Fracture of the hip, wrist or spine (see section 4.4)

Renal and urinary disorders

Tubulointerstitial nephritis (with possible progression to renal failure)

Reproductive system and breast disorders

Gynaecomastia

General disorders and administration site conditions

Fatigue

Oedema

Fever, hyperhydrosis, angioedema, anorexia, impotence

Investigations

Increase in cholesterol level and triglyceride levels, hypo-natraemia

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 or search for MHRA Yellow Card in the Google Play or Apple App store.

4.9. Overdose

The effects of overdose on lansoprazole in humans are not known (although the acute toxicity is likely to be low) and, consequently, instruction for treatment cannot be given. However, daily doses of up to 180 mg of lansoprazole orally and up to 90 mg of lansoprazole intravenously have been administered in trials without significant undesirable effects.

Please refer to section 4.8 for possible symptoms of lansoprazole overdose.

In the case of suspected overdose the patient should be monitored. Lansoprazole is not significantly eliminated by haemodialysis. If necessary, gastric emptying, charcoal and symptomatic therapy is recommended.