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 non-steroidal anti-inflammatory drug (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 gastro-oesophageal reflux disease

• Zollinger-Ellison syndrome.

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 time, 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 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.

Special populations

Renal impairment:

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

Hepatic impairment:

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.

Paediatric population:

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 oral use.

For optimal effect, lansoprazole should be taken 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.

The tablets are strawberry flavoured and should be placed on the tongue and gently sucked. The tablets rapidly disperse in the mouth, releasing gastro-resistant microgranules which are swallowed with the patient's saliva.

Alternatively, the tablets can be swallowed whole with a drink of water.

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

Lansoprazole orodispersible tablets should be taken at least 30 minutes before food (see section 5.2).

Administration by nasogastric tube:

- Remove the plunger of the syringe (use at least a 25 ml syringe for the 15 mg tablet).

- Put the tablet into the barrel.

- Put the plunger back onto the syringe.

- Draw 10 ml tap water into the syringe.

- Invert the syringe and draw an additional 5 ml of air into it.

- Shake the syringe gently for 10-20 seconds until the tablet is dispersed.

- Join the syringe to the tube and empty the syringe contents into the nasogastric tube.

- Refill the syringe with 10 ml of tap water and administer the contents into the tube.

It is important that the appropriateness of the selected syringe and tube is carefully tested. The recommended diameter of nasogastric tube to be used is 3.3 mm (size 10 French) or larger.

Oral administration by syringe:

- Remove the plunger of the syringe (at least 5 ml syringe for the 15 mg tablet).

- Put the tablet into the barrel.

- Put the plunger back onto the syringe.

- Draw 4 ml tap water into the syringe.

- Invert the syringe and draw an additional 1 ml of air into it.

- Shake the syringe gently for 10-20 seconds until the tablet is dispersed.

- The contents can be emptied directly into the mouth.

- Refill the syringe with 2-5 ml of tap water to flush the remnants out of the syringe into the mouth

- Repeat the precedent step if necessary.

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

Gastric malignancy

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.

Human immunodeficiency virus (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 4.5). If co-administration of lansoprazole with HIV protease inhibitors is unavoidable, close clinical monitoring is recommended.

Hypomagnesaemia

Severe hypomagnesaemia has been reported rarely 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. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see section 4.8). In most affected patients, hypomagnesaemia (and hypomagnesaemia associated hypocalcaemia and/or hypokalaemia) 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 medicinal products that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Lansoprazole Mylan 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.

Influence on vitamin B12 absorption

Daily treatment with any acid-suppressing medications over a prolonged period of time (several years) may lead to malabsorption of cyanocobalamin (vitamin B12) caused by hypo- or achlorhydria. Cyanocobalamin deficiency should be considered in patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring longterm treatment, individuals with reduced body stores or risk factors for reduced vitamin B12 absorption (such as the elderly) on long-term therapy or if relevant clinical symptoms are observed.

Hepatic impairment

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

Gastrointestinal infections caused by bacteria

Lansoprazole, like all proton pump inhibitors (PPIs), might increase the counts of bacteria normally present in the gastrointestinal tract. This may increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter and, especially in hospitalized patients, 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.

Long-term treatment

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.

Gastrointestinal disorders

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.

With the exception of patients treated for the eradication of H. pylori infection, if diarrhoea persists, administration of lansoprazole should be discontinued, due to the possibility of microscopic colitis with thickening of the collagen bundle or infiltration of inflammatory cells noted in the large intestine submucosa. In majority of cases, symptoms of microscopic colitis resolve on discontinuation of lansoprazole.

Co-administration with NSAIDs

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).

Bone fractures

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.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions, including Stevens‐Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life‐threatening or fatal, have been reported in association with the use of PPIs (see section 4.8). At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, lansoprazole should be withdrawn immediately

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 (see section 4.8).

Renal impairment

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

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

Excipients with known effects

This medicinal product contains 5.97 mg of aspartame per tablet.

Aspartame is a source of phenylalanine. Aspartame is hydrolysed in the gastrointestinal tract when orally ingested. One of the major hydrolysis products is phenylalanine. It may be harmful to patients with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

This medical product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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

Effects of lansoprazole on other medicinal products

Medicinal products with pH dependent absorption

Lansoprazole may interfere with the absorption of medicinal products where gastric pH is an important determinant of oral 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).

A study has shown that co-administration of lansoprazole (60 mg once daily) with atazanavir 400 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 90% decrease in AUC and Cmax).

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.

Medicinal products metabolised by P450 enzymes

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

Warfarin:

There have been reports of increased International Normalized Ratio (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.

Theophylline:

Lansoprazole reduces the plasma concentration of theophylline, which may decrease the expected clinical effect at the dose. Patient monitoring should be taken in co-administration of lansoprazole with theophylline.

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 lanzoprazole is initiated or ended.

Medicinal products transported 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 medicinal products on lansoprazole

Medicinal products which inhibit CYP2C19

Fluvoxamine:

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

Medicinal products 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

Methotrexate:

Concomitant use with high-dose methotrexate may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities.

Sucralfate/Antacids:

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

Non-steroidal anti-inflammatory medicinal products:

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

4.6. Fertility, pregnancy and lactation

Pregnancy

For lansoprazole no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Therefore, the use of lansoprazole during pregnancy is not recommended.

Breast-feeding

It is not known whether lansoprazole is excreted in human breast milk. Animal studies have shown excretion of lansoprazole in 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 breast-feeding for the child and the benefit of lansoprazole therapy for 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) and not known (cannot be estimated from the available data).

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

Thrombocytopenia*, eosinophilia, leukopenia*

Anaemia

Agranulocytosis*, pancytopenia*

Immune system disorders

Anaphylactic shock*

Metabolism and nutrition disorders

Hyponatraemia*

Hypomagnesaemia*

Hypocalcaemia*ϯ

Hypokalaemia*ϯ

Psychiatric disorders

Depression

Insomnia, hallucination, 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* ‡, drug reaction with eosinophilia and systemic symptoms (DRESS)* ‡

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia, fracture of the hip, wrist or spine‡

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, hyperhidrosis, angioedema, anorexia, impotence

Investigations

Increase in cholesterol and triglyceride levels

* Post-marketing events

Ϯ Hypocalcaemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia (see section 4.4)

‡ See section 4.4

Reporting of suspected adverse reactions

Reporting of 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 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.