PATIENT INFORMATION LEAFLET
LANSOPRAL
TRADE NAME
Lansopral
INTERNATIONAL NONPROPRIETARY NAME
Lansoprazole
PHARMACEUTICAL FORM
Hard gelatin capsules.
Description: hard gelatin capsules, size No.0, white opa- que body and yellow opaque cap, containing white or off- white spherical pellets.
COMPOSITION
Capsule contains
Active ingredient: lansoprazole 30 mg.
Excipients: mannitol, sucrose, sodium laurilsulfate, disodium hydrogen phosphate, calcium carbonate, sodi- um carboxymethylcellulose, hydroxylpropylmethylcel- lulose Е5 and НР55, cetyl alcohol, titanium dioxide, sodi- um methylparaben, sodium propylparaben.
Capsule content: titanium dioxide, yellow iron oxide, ge- latin.
ATCCODE А02BC03
PHARMACOTHERAPEUTIC GROUP
Drugs for peptic ulcer and gastro-oesophageal reflux di- sease. Proton pump inhibitor.
PHARMACOLOGICAL PROPERTIES PHARMACODYNAMICS
Lansoprazole inhibits H+/K+-ATPase enzyme ("proton pump") in parietal stomach cells and therefore blocks final stage of hydrochloric acid production. It leads to re- duction of basal and stimulated secretion, irrespective of the stimulus nature. Lansoprazole is accumulated in pa- rietal cells and activates them in acidic medium, then re- acts with sulfhydryl groups of H+/K+-ATPase leading to inhibition of enzyme activity.
Effect on Hydrochloric acid secretion:
Single oral administration of lansoprazole 30 mg suppres- ses production of gastric hydrochloric acid enhanced by pengastrin by approximately 80%. Multiple daily admini- stration of lansoprazole for 7 days suppresses production of gastric hydrochloric acid enhanced by pengastrin by 90%. Single dose administration of lansoprazole 30 mg decreases basal secretion by 70%, which provides sym- ptom relief after the first administration. After daily admi- nistration of the drug for 8 days hydrochloric acid produc- tion is decreased by 85%. Rapid symptom relief is achie- ved by administration of 1 capsule (30 mg) once daily, ma- jority of patients with duodenal ulcer are recovered within 2 weeks and patients with duodenal ulcer and reflux eso- phagitis are recovered within 4 weeks. When gastric aci- dity is decreased, lansoprazole creates medium where the appropriate antibiotics are effective against Helico- bacter pylori.
PHARMACOKINETICS
Lansoprazole is a racemate of two active enantiomers that are biotransformed into the active form in the acidic medium of the parietal cells. Since lansoprazole is rapid- ly inactivated by the hydrochloric acid, it should be admi- nistered orally as an enterosoluble solid dosage forms. Absorption and distribution
Single dose of Lansopral has high bioavailability (80- 90%). Peak plasma concentration is 1.5 to 2 hours. Food intake reduces absorption of lansoprazole and its bio- availability by approximately 50%. Protein binding is 97%. Studies showed that if granules from open capsules or closed capsules were used, areas under concentration- time curve (AUC) were similar when such granules were dissolved in a small amount of orange, apple or tomato juice, or diluted with one spoon of apple or pear juice, or added to one spoon of yoghurt, pudding or yoghurt che- ese. Similar AUC values were observed when granules were weighed in apple juice or administered through a nasogastric tube.
Metabolism and elimination
Lansoprazole is metabolized in liver, metabolites are ex- creted by the liver and kidney. Lansoprazole is primarily metabolized by CYP2C19 major enzyme. CYP3A4 en- zyme also participates in the metabolism. Plasma elimi- nation half-life varies between 1 and 2 hours after single and multiple dose administration in healthy subjects. There are no evidences of drug accumulation after multi- ple dose administration in healthy subjects. The following lansoprazole derivatives are found in plasma: sulphone, sulphide and 5-hydroxy-lansoprazole.These metabolites are inactive or have no antisecretory activity. Study with 14С labelled lansoprazole showed that approximately
one third of lansoprazole is excreted in urine and two thirds are excreted in faeces.
Pharmacokinetics in elderly
Clearance of lansoprazole is decreased in elderly; elimi- nation half-life is increased by approximately 50-100%. Peak plasma concentrations are not increased.
Pharmacokinetics in patients with hepatic impairment Elimination half-life of lansoprazole in patients with hepa- tic impairment is increased by 3-4 times.
THERAPEUTIC INDICATIONS
DOSAGE AND ADMINISTRATION
To provide optimal effect, Lansopral should be taken on- ce daily in the morning; when used for Helicobacter pylori eradication Lansopral should be taken twice a day (in the morning and in the evening). Lansopral should be taken orally at least 30 minutes before food intake with small amount of liquid. Capsules shall be swallowed as a whole without chewing. If impossible, the capsules shall be opened and the granules shall be mixed with a small amount of apple/tomato juice (1 spoon) or added to a small amount of soft food (e.g. yoghurt, apple puree). Capsules may also be opened and granules may be mixed with 40 ml of apple juice and administered through a nasogastric tube. The drug should be administered immediately after preparation of the suspension or mix- ture.
Capsule content should not be divided into fractions. If lower doses should be administered, the other dosage form shall be considered.
Duodenal ulcer: the recommended dose is 30 mg (1 cap- sule) once daily for 2 weeks or 4 weeks if any drug resis- tance is observed.
Gastric ulcer and reflux oesophagitis: the recommended dose is 30 mg (1 capsule) once daily for 4 weeks or treat- ment period may be exceeded to 8 weeks, if necessary. Helicobacter Pylori eradication: the recommended dose is 30 mg (1 capsule) once daily for 7 days (if necessary- up to 14 days) in combination with antibacterial agents as follows: clarithromycin 250-500 mg twice a day + amoxi- cillin 1 g twice a day; clarithromycin 250 mg twice a day + metronidazole 400-500 mg twice a day.
NSAID-related erosive-ulcer of stomach and duodenum: the recommended dose is 30 mg (1 capsule) once daily for 4-8 weeks. The higher dose should be administered for the extended treatment period if any drug resistance is observed.
Symptomatic GRD treatment: 15-30 mg once daily for 4 weeks.
Zollinger-Ellison syndrome: the dose should be individu- ally adjusted. Generally, the initial dose is 60 mg (2 cap- sules) 1 once daily. If the required daily dose exceeds 120 mg, it should be divided into two daily doses. Daily dose up to 180 mg may be used.
No dose adjustment in patients with renal dysfunction is necessary.
Patients with moderate or severe liver dysfunction sho- uld be kept under supervision, 50% reduction of the daily dose is recommended.
The dosage in elderly patients should be individually ad- justed. Daily dose 30 mg shall not be exceeded without the appropriate clinical indications.
CONTRAINDICATIONS
SIDE EFFECTS
Parameters of adverse effects are defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to
< 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), unknown.
Blood and lymphatic system disorders: uncommon - thrombocytopenia, eosinophilia, leukopenia; rare - anaemia; very rare - agranulocytosis, pancytopenia.
Metabolism and nutritional disorders: unknown - hypo-
magnesemia.
Psychiatric disorders: uncommon - depression; rare - insomnia, hallucinations, mental confusion.
Nervous system disorders: common - headache, dizzi- ness; rare - restlessness, vertigo, paresthesia, somno- lence, tremor.
Eye disorders: rare - visual impairment.
Gastrointestinal disorders: common - nausea, diarrhoea, stomach ache, constipation, vomiting, meteorism, dry mo- uth or throat; rare - glossitis, oesophageal candidiasis, pancreatitis, hypogeusia.
Hepatobiliary disorders: common - increase in liver enzy- mes; rare - hepatitis, icterus.
Skin and subcutaneous tissue disorders: common - urti- caria, itchiness, rush; rare - petechia, purpura, loss of hair, erythema, photosensitivity; very rare - Stevens-John-son syndrome, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: uncom- mon - arthralgia, myalgia, hip, wrist or spine fractures.
Renal and urinary disorders: rare - interstitial nephritis. Reproductive system and breast disorders: rare - gyne- comastia.
General disorders: common - fatigue; uncommon- ede- ma; rare - fever, hyperhidrosis, angioedema, anorexia, impotency.
Laboratory findings: very rare - increase in cholesterol and triglyceride levels, hyponatremia.
PARTICULAR INDICATIONS
If lansoprazole is used to treat gastric ulcer or if any other antiulcer medications are used, the possibility of mali- gnant neoplasms in stomach and gullet should be exc- luded since lansoprazole may mask the symptoms and delay the diagnosis.
Lansopral should be administered with caution in pati- ents with moderate and severe renal impairment.
Decrease of intragastric acidity due to Lansopral admi- nistration may result in increase of bacterial count that normally present in the GI tract. Treatment with lanso- prazole may result in insignificantly increased risk of gas- trointestinal infections caused by Salmonella and Cam- pylobacter.
In patients with gastric or duodenum ulcer the possibility of Helicobacter pylori infection should be considered as the etiological factor.
When lansoprazole is used in Helicobacter pylori eradi- cation in combination with antibiotics, instructions for use of such antibiotics should be followed. Limited safety da- ta in patients administering the drug for more than 1 year as a supporting therapy require maintenance and thoro- ugh assessment of risk/benefit ratio in such patients.
Very rarely cases of colitis have been reported in patients taking lansoprazole. Therefore, in case of severe and/or persistent diarrhoea, discontinuation of therapy should be considered.
Administration of lansoprazole to prevent gastric ulcer in patients requiring continuous NSAID treatment shall be restricted to high risk patients, e.g.: history of gastrointes- tinal bleeding, perforation or ulcer, elderly age, concomi- tant administration of other drugs increasing possible ad- verse events in the upper gastrointestinal tract (e.g., cor- ticosteroids or anticoagulants), any severe concomitant diseases or long-term administration of the highest re- commended doses of NSAID. Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) including lansoprazole for a period of three months to one year. Serious manifestations of hy- pomagnesaemia such as fatigue, tetany, delirium, convul- sions, dizziness and ventricular arrhythmia may be harm- ful and overlooked. In most patients hypomagnesaemia was decreased after adminstration of magnesium and discontinuation of PPI treatment. If a long term concomi- tant treatment of a patient with PPI and digoxin or other drugs leading to hypomagnesemia (e.g., diuretics) is planned, a health care professional should estimate mag- nesium level in such patient before treatment and monitor it during the treatment.
When high doses of PPI are administered for a long period (> 1 year), a risk of hip, wrist or spine fracture may be increased predominantly in elderly patients or in pati- ents affected by other risk factors. Patients at risk of os- teoporosis should be treated according to current clinical recommendations and receive adequate amounts of vi- tamin D and calcium.
Lansopral contains sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not administer this drug.
INFLUENCE ON ABILITY TO DRIVE AND OPERATE MECHANISMS
Since dizziness, vertigo and visual disturbances may oc- cur, the ability to drive and use mechanisms requiring increased attention may be affected.
PREGNANCY AND LACTATION
There is not sufficient clinical data on effect of lansopra- zole during pregnancy. Animal studies showed no direct or indirect adverse effects of lansoprazole with respect to pregnancy, embryonal/pre-natal development, labour or post-natal development. Administration of lansoprazole during pregnancy is not recommended.
It is not known whether lansoprazole is excreted in hu-
man breast milk. But animal studies showed excretion of lansoprazole in milk. A decision on whether to continue/ discontinue breast-feeding or to continue/discontinue lansoprazole therapy should be made taking into acco- unt the benefit of breast-feeding to the child and the be- nefit of lansoprazole therapy to the woman.
PEDIATRIC USE
Administration of lansoprazole is not recommended in children or adolescent under 18 years old due to the limited clinical data. Treatment of small children under 1 year old should be avoided since available data have not shown beneficial effects of the drug in the treatment of gastro-oesophageal reflux disease.
DRUG INTERACTIONS
Lansoprazole may affect absorption of drugs with gastric pH critical to their bioavailability.
Atazanavir: studies showed that co-administrationof lan- soprazole (60 mg once daily) with atazanavir 400 mg by healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 90% decrease in AUC and Cmax). Lansopral should not be co-administered with atazanavir.
Ketoconazole and itraconazole: absorption of ketocona- zole and itraconazole from the gastrointestinal tract is enhanced in the presence of the hydrochloric acid. Admi- nistration of lansoprazole may result in subtherapeutic concentrations of ketoconazole and itraconazole and their co-administration should be avoided.
Digoxin: co-administration of lansoprazole and digoxin may lead to increase of digoxin plasma levels. Therefore, plasma levels of digoxin should be monitored and, if ne- cessary, the dose of digoxin should be adjusted when initiating and ending lansoprazole treatment.
Medicinal products metabolized by P450 cytochrome: lansoprazole may increase plasma concentrations of drugs metabolized by CYP3A4. Caution is recommen- ded when Lansopral is co-administered with such drugs with a narrow therapeutic window.
Theophylline: lansoprazole reduces theophylline plasma concentration, which may decrease the expected clinical effect of the drug. Caution is recommended when co- administering the two drugs.
Tacrolimus: co-administration of lansoprazole increases tacrolimus plasma concentrations. Lansoprazole increa- ses average exposure of tacrolimus by up to 81%. Moni- toring of tacrolimus plasma concentrations is recommen- ded when concomitant treatment with lansoprazole is ini- tiated or ended.
Fluvoxamine: dose reduction may be considered when lansoprazole is co-administered with CYP2C19 inhibitor fluvoxamine. Lansoprazole plasma concentrations are 4-fold increased.
CYP2C19 and CYP3A4 enzyme inducers such as rifa- mpicin, and St John´s wort (Hypericum perforatum) may significantlyreduce lansoprazoleplasma concentrations. Sucralfate/Antacids: sucralfate/antacids may decrease bioavailability of lansoprazole. Therefore, Lansopral should be administered at least 1 hour after taking such drugs.
OVERDOSE
Symptoms: No significant overdose was observed as a result of Lansopral administration.
Treatment: In the event of overdose, symptomatic and supporting therapy is recommended. Lansoprazole is not eliminated by haemodialysis.
PACKAGING
Hard gelatin capsules. 7 capsules in a blister.
STORAGE CONDITIONS
Store in a protected from moisture and light place at tem- perature not exceeding 25°С.
Keep out of reach of children!
SHELF LIFE
SALES TERMS
Sold under prescription.
MANUFACTURER
LANSOPRAL is a product and a trade mark of "Sanolife", Great Britain.
Manufactured by
"WORLD MEDICINE İLAÇ SAN. VE TİC. А.Ş.", TURKEY