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Home , H2 antagonist, Sucralfate

SUMMARY OF PRODUCT CHARACTERISTICS

RANITIDINA ABC 150 mg Film-coated Tablets RANITIDINA ABC 300 mg Film-coated Tablets

1. NAME OF THE MEDICINAL PRODUCT

RANITIDINA ABC 150 mg Film-coated Tablets RANITIDINA ABC 300 mg Film-coated Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION RANITIDINA ABC 150 mg film-coated tablets One film-coated tablet contains Active ingredient: 170 mg hydrochloride equivalent to 150 mg of ranitidine.

For a full list of excipients, see section 6.1.

RANITIDINE ABC 300 mg film-coated tablets One film-coated tablet contains Active ingredient: 340 mg ranitidine hydrochloride equivalent to 300 mg of ranitidine

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Film-coated tablets.

4. CLINICAL PARTICULARS 4.1 Therapeutic Indications Adults Duodenal ulcer and benign gastric ulcer, including that associated with non-steroidal anti- inflammatory agents, recurrent ulcer, post-operative ulcer, reflux oesophagitis, Zollinger- Ellison Syndrome, prophylaxis and treatment of upper gastrointestinal haemorrhages, premedication under anaesthesia, prevention and treatment of stress ulcers. Ranitidine is also indicated in conditions such as or duodenitis when associated with hypersecretion.

Children (3 to 18 years)  Short term treatment of peptic ulcer  Treatment of gastro-oesophageal reflux, including reflux oesophagitis and symptomatic relief of gastro-oesophageal reflux disease.

4.2. Posology and method of administration

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Adults (including the elderly) / Adolescent (12 years and older)

Usual dosage is 300 mg per day: 150 mg in the morning and 150 mg in the evening. In patients with gastric or duodenal ulcer, 300 mg may be administered as a single administration in the evening before bedtime (Ranitidina ABC 300 mg 1 tablet at bedtime). Moreover, in the following situations: patients with large ulcers and / or heavy smokers and severe peptic , it may be useful to increase the dosage up to 600 mg per day, returning as soon as possible to the standard dosing schedule and under direct medical supervision. In the prophylaxis of severe bleeding, recurrent haemorrhage in patients with bleeding peptic ulcer or patients in parenteral ranitidine still considered to be at risk, as soon as feeding is resumed by mouth, can be treated with Ranitidina ABC 150 mg twice a day. Duodenal ulcer, gastric ulcer, recurrent ulcer, post-operative ulcer The recommended daily dosage regimen is 300 mg. Healing usually occurs in 4 weeks. If necessary, treatment can be prolonged up to 6-8 weeks. In case of ulcers resulting from treatment with Non-steroidal Anti-inflammatory drugs (NSAID) and / or if continued treatment with such drugs is necessary, the recommended dose is 300 mg for 8 weeks. The treatment may need to be continued for up to 12 weeks. In the case of patients with large ulcers and / or heavy smokers, 300 mg twice daily may be more useful. In patients in whom, after the positive response to short-term , it is desirable to maintain the effect on gastric secretion, particularly in those with a tendency to relapse of ulcerative episodes, a maintenance therapy of 150 mg can be adopted in the evening. In patients already being treated with 600 mg a day it may be helpful to start maintenance therapy with a dosage of 300 mg in the evening for a period of 8-12 weeks, continuing successively with the standard dose. Smoking is associated with a higher incidence of ulcer recurrence. Therefore, smoking patients should be advised to abandon this habit; if this does not happen, the maintenance dose of 300 mg in the evening offers additional protection compared to the standard dose of 150 mg. Maintenance therapy (150 mg and 300 mg orally in the evening) should be prescribed by the doctor and performed under his supervision. Reflux esophagitis The recommended daily dose in oesophageal reflux disease is 300 mg / day, divided into two 150 mg doses, over a period of 8 weeks. In moderate-to-severe peptic esophagitis, the dosage can be increased to 600 mg / day, divided into 2-4 administrations, up to 12 weeks, under the direct supervision of the physician, returning as soon as possible to the standard posology. In long-term treatment, for the prevention of relapse, the recommended dose is 150 mg twice a day. Zollinger-Ellison syndrome The daily dose is 450 mg (150 mg three times a day) which can be increased if necessary at 600-900 mg (Ranitidina ABC 300 mg, 2-3 tablets a day). Hemorrhages of the upper gastro-intestinal tract In the prophylaxis and treatment of haemorrhages of the upper gastro-intestinal tract the oral dose is 300 mg per day.

2 If oral therapy is not immediately possible, treatment can be started with ranitidine solution for injection and continued with oral therapy (300 mg per day for as long as necessary). Premedication under anaesthesia Those patients who run the risk of developing an acidic aspiration syndrome (Mendelson's syndrome) may be given an oral dose of 150 mg 2 hours before the induction of general anesthesia and, preferably, also a dose of 150 the previous evening. The parenteral route of administration can also be used. Stress ulcer In the prevention and treatment of stress ulcers in severe patients the recommended daily dose is 300 mg. If the patient's condition does not allow oral administration, treatment can be started with injectable ranitidine and then continued with oral therapy. Patients with renal impairment In patients with severe renal impairment (creatinine clearance less than 50 ml / min), ranitidine accumulation occurs, resulting in increased plasma concentrations. It is recommended that the daily dose in such patients is 150 mg to be taken in the evening.

Children from 3 to 11 year and over 30 kg of weight See section 5.2 Pharmacokinetic properties (other special populations)

Peptic ulcer acute treatment The recommended oral dose for the treatment of peptic ulcer in children is 4 mg/kg/day to 8 mg/kg/day administered as two divided doses to a maximum of 300 mg ranitidine per day for a duration of 4 weeks. For those patients with incomplete healing, another 4 weeks of therapy is indicated, as healing usually occurs after 8 weeks of treatment.

Gastro-Oesophageal reflux The recommended oral dose for treatment of gastro-oesophageal reflux in children is 5 mg/kg/day to 10 mg/kg/day administered as two divided doses to a maximum of 600 mg (the maximum dose is likely to apply to heavier children or adolescents with severe symptoms).

Neonates Safety and efficacy in new-born patients has not been established.

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 carcinoma Before to initiating ranitidine therapy in patients with gastric ulcer or in middle-aged or older patients who have recently or recently-changed dyspeptic symptoms, its possible malignancy must be excluded since treatment with ranitidine may mask the symptoms of gastric carcinoma. Renal disease

3 Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment. The dosage should be adjusted as detailed in section 4.2 Patients with renal impairment. Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks. Ranitidine should therefore be avoided in patients with a history of acute porphyria. In patients such as the elderly, persons with chronic lung disease, diabetes or the immunocompromised, there may be an increased risk of developing community acquired . A large epidemiological study showed an increased risk of developing community acquired pneumonia in current users of ranitidine alone H2 antagonists (monotherapy with ranitidine) versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.82 (95% CI 1.26-2.64). Regular supervision of patients who are taking non-steroidal anti-inflammatory drugs concomitantly with ranitidine is recommended, especially in the elderly and in those with a history of peptic ulcer. Recurrences of objective and subjective symptomatology may occur either after the suspension of drug intake, or during long-term maintenance treatment at a lower than full dose. Dosage and duration of administration should always be established by the physician, bearing in mind that the symptoms usually disappear before the ulcer has scarred. Ranitidine administration, like all H2-receptor antagonists, favours intragastric bacterial development due to decreased gastric acidity. Caution should be used in patients with hepatic impairment.

4.5 Interaction with other medicinal products and other forms of interactions

Ranitidine has the potential to affect the absorption, or renal of other drugs. The altered may necessitate dosage adjustment of the affected drug or discontinuation of treatment. Interactions occur by several mechanisms including: 1) Inhibition of -linked mixed function oxygenase system: Ranitidine at usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this system such as diazepam, , , and . There have been reports of altered prothrombin time with coumarin (e.g. ). Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine. 2) Competition for renal tubular secretion: Since ranitidine is partially eliminated by the cationic system, it may affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g. such as those used in the treatment of Zollinger-Ellison syndrome) may reduce the excretion of procainamide and N- acetylprocainamide resulting in increased plasma levels of these drugs. 3) Alteration of gastric pH: The of certain drugs may be affected. This can result in either an increase in absorption (e.g. triazolam, midazolam, glipizide) or a decrease in absorption (e.g. , atazanavir, delaviridine, gefitnib). There is no evidence of an interaction between ranitidine and amoxicillin and . If high doses (2 g) of are co-administered with ranitidine the absorption of the latter may be reduced. This effect is not seen if sucralfate is taken after an interval of 2 h.

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4.6 Fertility, and lactation

Fertility There are no data on the effects of ranitidine on human fertility. There were no effects on male and female fertility in animal studies (see section 5.3).

Pregnancy Ranitidine crosses the placenta. Like other drugs ranitidine should only be used during pregnancy if considered essential. Lactation Ranitidine is excreted in human breast milk. Like other drugs ranitidine should only be used during nursing if considered essential. .

4.7 Effects on ability to drive and use machines

If, during therapy, any dizziness, drowsiness or dizziness are noticed, avoid driving or using machines or performing activities that require prompt supervision. Administration of Ranitidina ABC may potentiate the effect of small amounts of alcohol. 4.8 Undesirable effects

The following convention has been used for the classification of undesirable effects: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data)

Adverse event frequencies have been estimated from spontaneous reports from post- marketing data.

Blood & Lymphatic System Disorders Very Rare: count changes (leucopenia, thrombocytopenia). These are usually reversible. or pancytopenia, sometimes with marrow hypoplasia or marrow aplasia.

Immune System Disorders Rare: Hypersensitivity reactions (urticaria, dermatitis bullous, eczema, angioneurotic oedema, fever, bronchospasm, ,chest pain and eosinophilia). Very Rare: Anaphylactic shock. Not known: dyspnea.

These events have been reported after a single dose.

Psychiatric Disorders Very Rare: Reversible mental confusion, depression, hallucinations and agitation. These have been reported predominantly in severely ill patients, in elderly and in nephropathic patients. In such cases the administration should be stopped.

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Nervous System Disorders Very Rare: (sometimes severe), dizziness, drowsiness, insomnia and reversible involuntary movement disorders.

Eye Disorders Very Rare: Reversible blurred vision. There have been reports of blurred vision, which is suggestive of a change in accommodation.

Cardiac Disorders Very Rare: As with other H2 receptor antagonists bradycardia, , tachycardia, Asystole (solution for injection only), palpitations, extrasystole, atrioventricular block and shock state..

Vascular Disorders Very Rare: Vasculitis.

Gastrointestinal Disorders Very Rare: Acute pancreatitis, diarrhoea, vomit Uncommon: abdominal pain, , , nausea (these symptoms mostly improved during continued treatment)

Hepatobiliary Disorders Rare: Transient and reversible changes in function tests. Very Rare: Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, these were usually reversible on discontinuation of treatment with ranitidine.

Skin and Subcutaneous Tissue Disorders Rare: Skin rash. Very Rare: Erythema multiforme, alopecia

Musculoskeletal and connective tissue disorders Very rare: Musculoskeletal symptoms such as arthralgia and myalgia.

Renal and Urinary Disorders Very rare: Acute interstitial nephritis Rare: elevation of plasma creatinine (usually slight; normalised during continued treatment)

Reproductive System and Breast Disorders Very Rare: Reversible impotence, libido altered, breast symptoms and breast conditions (such as gynaecomastia and galactorrhoea)

Paediatric population The safety of ranitidine has been assessed in children aged 0 to 16 years with acid-related disease and was generally well tolerated with an adverse event profile resembling that in

6 adults. There are limited long term safety data available, in particular regarding growth and development.

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 national reporting system listed in Appendix V.

4.9 Overdosage Symptoms and Signs Ranitidine is very specific in action and no particular problems are expected following overdosage with ranitidine formulations.

Treatment Symptomatic and supportive therapy should be given as appropriate.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic Group: drug for the treatment of peptic ulcer and gastroesophageal reflux disease; H2 – receptor antagonists ATC Code: A02B A02

Ranitidine is a specific rapidly acting H2-antagonist. It inhibits basal and stimulated secretion of , reducing both the volume and the acid and content of the secretion. Ranitidine has a relatively long duration of action and so a single 150 mg dose effectively suppresses gastric acid secretion for twelve hours.

5.2 Pharmacokinetic properties Absorption Following oral administration of 150 mg od ranitidine, maximum plasma concentrations (300 to 550 ng/mL) occurred after 1-3 hours. Two distinct peaks or plateau in the absorption phase result from reabsorption of drug excreted into the intestine. The absolute bioavailability of ranitidine is 50-60% and plasma concentrations increase proportionally with increasing dose up to 300 mg. Distribution Ranitidine is not extensively bound to plasma (15%), but exhibits a large volume of distribution ranging from 96 to 142 L. Metabolism Ranitidine is not extensively metabolised. The fraction of the dose recovered as metabolites is similar after both oral and i.v. dosing; and includes 6% of the dose in urine as the N-oxide, 2% as S-oxide, 2% as dermethylranitidine and 1 to 2% as the furoic acid analogue. Elimination

7 Plasma concentrations decline bi-exponentially, with a terminal half-life of 2-3 hours. The major route of elimination is renal. After IV administration of 150 mg 3H-ranitidine, 98% of the dose was recovered, including 5% in faeces and 93% in urine, of which 70% was unchanged parent drug. After oral administration of 150 mg 3H-ranitidine, 96% of the dose was recovered, 26% in faeces and 70% in urine of which 35% was unchanged parent drug. Less than 3% of the dose is excreted in . Renal clearance is approximately 500 ml/min, which exceeds glomerular filtration indicating net renal tubular secretion. Other special populations

Children (3 years and above) Limited pharmacokinetic data show that there are no significant differences in half-life (range for children 3 years and above: 1.7 – 2.2 h) and plasma clearance (range for children 3 years and above 9 – 22 ml/min/kg) between children and healthy adults receiving oral ranitidine when correction is made for body weight.

Patients over 50 years of age In patients over 50 years of age, half-life is prolonged (3-4 h) and clearance is reduced, consistent with the age-related decline of renal function. However, systemic exposures and accumulation are 50% higher. This difference exceeds the effect of declining renal function, and indicates increased bioavailability in older patients.

5.3 Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety , repeated dose , genotoxicity, carcinogenic potential and reproduction toxicity.

6.0 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline Cellulose Croscarmellose Sodium Magnesium stearate Polymethacrylat Macrogol 6000 Hypromellose Talc Titanium dioxide (E171)

6.2 Incompatibilities None

6.3 Shelf life 3 years

6.4 Special precautions for storage Do not store above 25oC

8 6.5 Nature and contents of container Al / Al Blisters 150 mg Film-coated Tablets: Box containing 20 tablets 300 mg Film-coated Tablets: Box containing 10 tablets

6.6 Instructions for use/handling and disposal

No special requirements

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally] 8. MARKETING AUTHORIZATION NUMBER

[To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

[To be completed nationally] 10. DATE OF REVISION OF THE TEXT

[To be completed nationally]

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