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Lansoprazol Mylan

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Document: Lansoprazol Mylan gastro-resistant capsule, hard ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS


NAME OF THE MEDICINAL PRODUCT


Lansoprazol Mylan 15 mg hard gastro-resistant capsules

Lansoprazol Mylan 30 mg hard gastro-resistant capsules


2. QUALITATIVE AND QUANTITATIVE COMPOSITION


Each capsule contains 15 mg of lansoprazole

Each capsule contains 30 mg of lansoprazole


Excipients with known effect:

Each 15 mg capsule contains between 95 and 109 mg of sucrose (as in sugar spheres).

Each 30 mg capsule contains between 190 and 217 mg of sucrose (as in sugar spheres).


For the full list of excipients, see section 6.1.


3. PHARMACEUTICAL FORM


Hard gastro-resistant capsule


15 mg: Size 3 (approx. 16 mm), opaque, yellow hard gelatin capsule containing white or almost white spherical microgranules.


30 mg: Size 1 (approx. 19 mm), opaque, white hard gelatin capsule containing white or almost white spherical microgranules.


4. CLINICAL PARTICULARS


4.1 Therapeutic indications



4.2 Posology and method of administration


Posology


For optimal effect, Lansoprazol Mylan 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.


Treatment of duodenal ulcer:

The recommended dose is 30 mg once daily for 2 weeks. In patients not fully healed within this time, the treatment 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 treatment may be continued at the same dose for another 4 weeks.


Treatment of 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:

The recommended dose is 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


H. pylori eradication rates of up to 90%, are obtained when clarithromycin is combined with lansoprazole and amoxicillin or metronidazole.


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:

The recommended dose is 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:

The recommended dose is 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.


Hepatic or renal impairment:

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


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. Lansoprazol Mylan should be taken at least 30 minutes before food (see section 5.2). Capsules should be swallowed whole with liquid.


For patients with difficulty swallowing; studies and clinical practice suggest that the capsules may be opened and the granules mixed with a small amount of water, apple/tomato juice or sprinkled onto a small amount of soft food (e.g. yoghurt, apple puree) to ease administration. Capsules may also be opened and granules mixed with 40 ml of apple juice for administration through a nasogastric tube (see section 5.2). After preparing the suspension or mixture, the drug should be administered immediately.


4.3 Contraindications


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


Lansoprazole should not be administered with atazanavir (see section 4.5).


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


Decreased gastric acidity due to lansoprazole might be expected to increase gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with lansoprazole may lead to a slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.


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.


Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with proton-pump inhibitors (PPI) 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 other medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.


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 lansoprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.


Sucrose

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


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.


Atazanavir:

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). Lansoprazole should not be co-administered with atazanavir (see section 4.3).


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 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. Caution is advised when combining the two drugs.


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 drugs on lansoprazole


Drugs 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.


Drugs which induces 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 and 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

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 breastfeeding to the child and the benefit of lansoprazole therapy to the woman.


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 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).

Common

Uncommon

Rare

Very rare

Not known

Blood and

lymphatic

system disorders

Thrombocytopenia,

eosinophilia,

leucopenia

Anaemia

Agranulocytosis,

pancytopenia

Metabolism and nutrition disorders



Hypomagnesaemia (see section 4.4)

Psychiatric

disorders

Depression

Insomnia,

hallucination,

confusion

Nervous system

disorders

Headache,

dizziness

Restlessness, vertigo,

paresthesia,

somnolence, tremor

Eye disorders

Visual disturbances.

Gastrointestinal

disorders

Nausea, diarrhoea,

stomach ache,

constipation,

vomiting,

flatulence, dry

mouth or throat

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

Steven-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

Interstitial nephritis

Reproductive

system and

breast disorders

Gynaecomastia

General

disorders and

administration

site conditions

Fatigue

Oedema

Fever, hyperhidrosis,

angioedema,

anorexia, impotence

Anaphylactic shock

Investigations


Increase in

cholesterol and

triglyceride levels,

hyponatremia

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 [To be completed nationally].


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.


5. PHARMACOLOGICAL PROPERTIES


5.1 Pharmacodynamic properties


Pharmacotherapeutic group: Drugs for acid related disorders, proton pump inhibitors, ATC code: A02BC03


Mechanism of action

Lansoprazole is a gastric proton pump inhibitor. It inhibits the final stage of gastric acid formation by inhibiting the activity of H+/K+ATPase of the parietal cells in the stomach. The inhibition is dose-dependent and reversible, and the effect applies to both basal and stimulated secretion of gastric acid. Lansoprazole is concentrated in the parietal cells and becomes active in their acidic environment, whereupon it reacts with the sulphydryl group of H+/K+ATPase causing inhibition of the enzyme activity.


Pharmacodynamic effects


Effect on gastric acid secretion:

Lansoprazole is a specific inhibitor of the parietal cell proton pump. A single oral dose of lansoprazole inhibits pentagastrin-stimulated gastric acid secretion by about 80%. After repeated daily administration for seven days, about 90% inhibition of gastric acid secretion is achieved. It has a corresponding effect on the basal secretion of gastric acid. A single oral dose of 30 mg reduces basal secretion by about 70%, and the patients' symptoms are consequently relieved starting from the very first dose. After eight days of repeated administration the reduction is about 85%.

A rapid relief of symptoms is obtained by one capsule (30 mg) daily, and most patients with duodenal ulcer recover within 2 weeks, patients with gastric ulcer and reflux oesophagitis within 4 weeks. By reducing gastric acidity, lansoprazole creates an environment in which appropriate antibiotics can be effective against H. pylori.


5.2 Pharmacokinetic properties


Lansoprazole is a racemate of two active enantiomers that are biotransformed into the active form in the acidic environment of the parietal cells. As lansoprazole is rapidly inactivated by gastric acid, it is administered orally in enteric-coated form(s) for systemic absorption.


Absorption


Lansoprazole exhibits high (80-90%) bioavailability with a single dose. Peak plasma levels occur within 1.5 to 2.0 hours. Intake of food slows the absorption rate of lansoprazole and reduces the bioavailabilty by about 50%.


Studies have shown that granules from opened capsules give equivalent AUC as the intact capsule if the granules are suspended in a small amount of orange juice, apple juice, or tomato juice mixed with a tablespoon of apple or pear puree or sprinkled on a tablespoon of yoghurt, pudding or cottage cheese. Equivalent AUC has also been shown for granules suspended in apple juice administered through a naso-gastric tube.


Distribution

The plasma protein binding is 97%.


Biotransformation

Lansoprazole is extensively metabolised by the liver and the metabolites are excreted by both the renal and biliary route. The metabolism of lansoprazole is mainly catalysed by the enzyme CYP2C19. The enzyme CYP3A4 also contributes to the metabolism.


Elimination

The plasma elimination half-life ranges from 1 to 2 hours following single or multiple doses in healthy subjects. There is no evidence of accumulation following multiple doses in healthy subjects. Sulphone, sulphide and 5-hydroxyl derivatives of lansoprazole have been identified in plasma. These metabolites have very little or no antisecretory activity.


A study with 14C labelled lansoprazole indicated that approximately one-third of the administered

radiation was excreted in the urine and two-thirds was recovered in the faeces.


Special populations


Elderly

The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased

approximately 50% to 100%. Peak plasma levels were not increased in the elderly.


Paediatric population

The evaluation of the pharmacokinetics in children aged 1 –17 years of age showed a similar exposure as compared to adults with doses of 15 mg for those below 30 kg of weight and 30 mg for those above. The investigation of a dose of 17 mg/m2body surface or 1 mg/kg body weight also resulted in comparable exposure of lansoprazole in children aged 2-3 months up to one year of age compared to adults.


Higher exposure to lansoprazole in comparison to adults has been seen in infants below the age of 2-3 months with doses of both 1.0 mg/kg and 0.5 mg/kg body weight given as a single dose.


Hepatic impairment

The exposure of lansoprazole is doubled in patients with mild hepatic impairment and there is a greater increase in patients with moderate and severe hepatic impairment.


CYP2C19 poor metabolisers


CYP2C19 is subject to genetic polymorphism and 2-6 % of the population, called poor metabolisers (PMs), are homozygote for a mutant CYP2C19 allele and therefore lacks a functional CYP2C19 enzyme. The exposure of lansoprazole is several-fold higher in PMs than in extensive metabolisers (EMs).


5.3 Preclinical safety data


Preclinical data reveal no special hazards for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, toxicity to reproduction or genotoxicity.


In two rat carcinogenicity studies, lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids associated with hypergastrinaemia due to inhibition of acid secretion. Intestinal metaplasia was also observed, as were Leydig cell hyperplasia and benign Leydig cell tumours. After 18 months of treatment retinal atrophy was observed. This was not seen in monkeys, dogs or mice.


In mouse carcinogenicity studies dose-related gastric ECL cell hyperplasia developed as well as liver tumours and adenoma of rete testis.


The clinical relevance of these findings is unknown.


6. PHARMACEUTICAL PARTICULARS


6.1 List of excipients


Gastro-resistant granules

Sugar spheres (maize starch and sucrose)

Sodium laurilsulfate

Meglumine

Mannitol

Hypromellose

Macrogol

Talc

Polysorbate 80

Titanium dioxide (E171)

Methacrylic acid – ethyl acrylate copolymer 1:1,


Capsule shell

Gelatin

Titanium dioxide (E171)

Sodium laurilsulfate

[15 mg capsule]: Quinoline yellow (E104)


6.2 Incompatibilities


Not applicable.


6.3 Shelf life


3 years


6.4 Special precautions for storage


Do not store above 25°C.

Store in the original package in order to protect from moisture.


6.5 Nature and contents of container


Alu/OPA/PVC blister with Al/PVC/PVDC non-peelable foil or Al/PETP/PVC peelable foil packs containing 7, 14, 15, 28, 30, 35, 56, 60 and 98 capsules.


Alu/OPA/PVC/PET calendar pack (peelable or non-peelable).

28 and 98 capsules.


Not all pack sizes may be marketed.


6.6 Special precautions for disposal


No special requirements for disposal.


7. MARKETING AUTHORISATION HOLDER


[To be completed nationally]


8. MARKETING AUTHORISATION NUMBER(S)


[To be completed nationally]


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


[To be completed nationally]


10. DATE OF REVISION OF THE TEXT


2016-03-07