SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS

2 1. NAME OF THE MEDICINAL PRODUCT Ranitidin Actavis 150 mg film-coated tablets Ranitidin Actavis 300 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 150 mg or 300 mg ranitidine (as ranitidine hydrochloride). For the full list of excipients, see section PHARMACEUTICAL FORM Film-coated tablets 150 mg: Circular, convex, white to yellowish, film-coated tablets, scored on one side. Diameter: 10 mm. 300 mg: Oblong, convex, white to yellowish, film-coated tablets, scored on one side. Tablet size: 8.2 x 17 mm. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adults Duodenal ulcer, benign gastric ulcer, reflux oesophagitis, Zollinger-Ellison's syndrome. Symptomatic gastro-oesophageal reflux disease. Prophylactic treatment of chronic recurrent duodenal ulcer. 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 Posology Adults/adolescents (12 years and older) Duodenal ulcer, benign gastric ulcer 300 mg/24 hours, either 300 mg at night or 150 mg in the morning and evening. The duration of treatment is generally 4 weeks. In those patients whose ulcer has not completely healed after 4 weeks of treatment, the treatment should be continued for a further 4 weeks. If required, the dose may be increased to 300 mg in the morning and evening for 4 weeks. Prophylactic treatment of chronic recurrent duodenal ulcer 150 mg in the evening. Reflux oesophagitis 150 mg in the morning and evening, alternatively 300 mg at night, for 4-8 weeks, but the dose and duration of treatment should be individualised in accordance with the severity of the condition. In

3 severe cases, the 24-hour dose may be increased to 600 mg in divided doses for up to 12 weeks. For maintenance treatment the recommended dose is 150 mg in the morning and evening. Symptomatic gastro-oesophageal reflux disease 150 mg in the morning and evening for 2-4 weeks. Zollinger-Ellison's syndrome 150 mg 3 times a day, but the dose may be increased, if necessary. Doses up to 6 g of ranitidine have been prescribed. The dose should be reduced in the presence of impaired renal and/or liver function and in elderly patients. Paediatric population Children 12 years and over For children 12 years and over the adult dosage is given. Children from 3 to 11 years and over 30 kg of weight See section 5.2 Pharmacokinetic properties Special patient 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 eight weeks of treatment. Gastro-oesophageal reflux The recommended oral dose for the treatment of gastro-oesophageal reflux in children is 5 mg/kg/day to 10 mg/kg/day administered as two divided doses in a maximum dose 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. Patients with impaired renal function The plasma half-life is prolonged and the plasma concentrations are increased in the presence of impaired renal function. Therefore, in the case of markedly impaired renal function, the dose should be halved at least, in accordance with the following table. An appropriate dose for oral therapy would thus be 150 mg at night. Creatinine clearance Serum creatinine 24-hour dose of ranitidine ml/min micromol/l Oral dosage > 50 < mg x mg x 1 Ranitidine is eliminated from the body by haemodialysis. Patients on dialysis should therefore take ranitidine after each dialysis. Method of administration As the absorption of ranitidine is not affected by food, the tablets can be taken during or between meals. The tablets can be swallowed whole, divided or crushed.

4 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section Special warnings and precautions for use Suspected ulcer disease must be objectively verified at an early stage by x-ray or endoscopy in order to avoid inadequate treatment. In the treatment of gastric ulcer, malignancy must be excluded as treatment may mask symtoms of stomach carcinoma. 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 in renal impairment as detailed in section 4.2. A lower dose is recommended for patients with impaired liver function and for elderly patients. 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 pneumonia. A large epidemiological study showed an increased risk of developing community acquired pneumonia in current users of ranitidine alone versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.82 (95% CI, ). 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. 4.5 Interaction with other medicinal products and other forms of interaction Ranitidine has the potential to affect the absorption, metabolism or renal excretion of other drugs. The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment. Interactions occur by several mechanisms including: 1) Alteration of gastric ph The bioavailability 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. ketoconazole, atazanavir, delaviridine, gefitnib). There is no evidence of an interaction between ranitidine and amoxicillin. If antacids or high doses (2 g) of sucralfate are co-administered with ranitidine the absorption of the latter may be reduced. Ranitidine should be taken about two hours before these medicinal products. 2) Inhibition of cytochrome P450-linked mixed function oxygenase system Ranitidine at usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme system such as diazepam (CYP2C19), lidocaine, and propranolol. There have been reports of altered prothrombin time with coumarin anticoagulants (e.g. warfarin) when treatment with ranitidine was initiated. Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine. There are several case reports of increased plasma concentrations of theophylline. Although, the interaction has not been observed in a number of clinical studies, available information cannot preclude that an interaction may occur in some individuals. There have also been reports of increased plasma concentrations of phenytoin.

5 3) Competition for renal tubular secretion Since ranitidine is partially eliminated by active secretion via the cationic transporter system (OCT) in the kidney, 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. The effect of alcohol may increase by taking ranitidine. 4.6 Fertility, pregnancy and lactation Pregnancy Ranitidine crosses the placenta. Like other drugs ranitidine should only be used during pregnancy if considered essential. Breastfeeding Ranitidine is excreted in human breast milk in such amounts that there is a risk of effects in the infant, even with therapeutic doses. Like other drugs ranitidine should only be used during nursing if considered essential. 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). 4.7 Effects on ability to drive and use machines Taking ranitidine may increase the effect of alcohol, furthermore side-effects as e.g. headache, dizziness, tiredness, confusion and hallucinations may possibly occur. Under these circumstances the ability to react as well as the power of judgement may be reduced, thus impairing the ability to drive and the ability to operate machinery. 4.8 Undesirable effects Frequencies are defined as follows: 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). Adverse event frequencies have been estimated from spontaneous reports from post-marketing data. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Blood and lymphatic system Immune system Common Uncommon Rare Very rare Unknown Haemolytic anemia. Hypersensitivity reactions (urticaria, Blood count changes (leucopenia, thrombocytopenia). These are usually reversible. Agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or marrow aplasia. Anaphylactic shock (reported after a single dose) Dyspnoea

6 Psychiatric Nervous system Eye Cardiac Vascular Gastrointestinal Common Uncommon Rare Very rare Unknown Abdominal pain, diarrhoea, constipation, nausea (these symptoms mostly improved during continued treatment). angioneurotic oedema, fever, dyspnoea, throat tightness, bronchospasm, hypotension and chest pain). These events have been reported after a single dose. Drug hypersensitivity hepatitis. Reversible mental confusion, depression and hallucinations. These adverse reactions have been reported predominantly in severely ill patients, in the elderly and in nephropathic patients. Headache (sometimes severe), dizziness and reversible involuntary movement. Reversible blurred vision, suggestive of accommodation disturbances. As with other H2 receptor antagonists bradycardia, A-V block, tachycardia Vasculitis Acute pancreatitis.

7 Hepatobiliary Skin and subcutaneous tissue Musculoskeletal and connective tissue Renal and urinary disorder Reproductive system and breast General and administration site conditions Common Uncommon Rare Very rare Unknown Non-specific skin reactions Tiredness. Liver failure, sometimes fatal, transient and reversible changes in liver function tests. Skin rash Elevation of plasma creatinine (usually slight; normalised during continued treatment) Erectile dysfunction. Fever. Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, these were usually reversible. Erythema multiforme, alopecia Arthralgia, myalgia. Acute interstitial nephritis. Reversible impotence, 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 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 Overdose Symptoms of overdose Bradycardia and dyspnoea have been described. Uncoordinated muscle activity, seizure. Treatment of overdose Symptomatic and supportive therapy should be given. Ranitidine may be removed from the plasma by haemodialysis. Toxicity

8 7.5 g to an adult caused no or mild intoxication; 2.5 mg 4 times/24 hours to a 3-month-old infant caused opisthotonus; mg to a 3-year-old produced no symptoms after charcoal had been administered. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: H2-receptor antagonists, ATC code: A02BA02. Ranitidine, a chemically substituted amino alkyl furane, is an H 2 -receptor antagonist, which competitively blocks the action of histamine on the H 2 -receptor. It thereby inhibits the basal and stimulated secretion of gastric juice, both in volume and in percentage of hydrochloric acid. Through the reduction in the volume of gastric juice, the secretion of total pepsinogen is also reduced. 5.2 Pharmacokinetic properties After oral administration, ranitidine has a bioavailability of about 50%. The maximum plasma concentration ( ng/ml) is reached 2-3 hours after an oral dose of 150 mg. Large individual variations occur. Binding to plasma protein is about 15%. The volume of distribution constitutes L/kg in adults and 2.5 L/kg in children. Measurement of the total clearance showed an average of ml/min in adults. In children and adolescents, a total clearance of almost 800 ml/min/1.73 m 2 occurred, with large interindividual variations. Ranitidine is metabolised in the liver to ranitidine-n-oxide, N-desmethyl ranitidine, ranitidine-soxide, and the analogue, furanic acid. After oral administration, ranitidine is eliminated within 24 hours via the kidneys as about 30% unconverted ranitidine, 6% N-oxide, a small amount in desmethylated and S-oxidated form, and as the analogue, furanic acid. In patients with healthy kidneys, the renal excretion is effected for the most part through tubular secretion with a renal clearance of about ml/min. Ranitidine is also excreted via the bile. After oral ingestion, the average half-life in patients with healthy kidneys is hours. In patients with renal insufficiency, the half-life is doubled or trebled. Ranitidine crosses into the cerebrospinal fluid to a very low extent. Ranitidine may cross the placental barrier. After an intravenous injection or an oral dose of ranitidine during pregnancy, the concentration of ranitidine in the umbilical chord corresponds to the maternal serum concentration. Twelve hours after delivery, the blood concentration of ranitidine was very low in the infant. Ranitidine crosses into breast milk. Two hours after ingestion, the proportion between the milk and plasma concentration is 1.9 (range ). Special patient populations Children (3 years and above) Limited pharmacokinetic data have shown that there are no significant differences in half-life (range for children 3 years and above: 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.

9 5.3 Preclinical safety data Animal studies do not indicate any special risks for humans in terms of acute toxicity, general toxic effects, reproduction effects, genotoxicity, or carcinogenicity. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Croscarmellose sodium Magnesium stearate Microcrystalline cellulose Coating: Polymethacrylate (Eudragit E 100) Hypromellose Macrogol 6000 Talc Titanium dioxide (E 171) 6.2 Incompatibilities Not applicable. 6.3 Shelf-life 3 years. 6.4 Special precautions for storage Do not store above 25 C. 6.5 Nature and content of container Blister packs (opa-al-pvc/al). Pack sizes: 150 mg: 10, 20, 30, 60, mg: 10, 14, 20, 30, 60, 90. Not all pack sizes may be marketed. 6.6 Special precaution for disposal and other handling No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Actavis Group PTC ehf. Reykjavikurvegi 76-78

10 IS-220 Hafnarfjordur Island 8. MARKETING AUTHORISATION NUMBER(S) <[To be completed nationally]> <Sweden: > 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION <Sweden: / > <Date of first authorisation: {DD month YYYY}> <Date of latest renewal: {DD month YYYY}> <[To be completed nationally]> 10. DATE OF REVISION OF THE TEXT <{DD/MM/YYYY}> <{DD month YYYY}> <[To be completed nationally]>