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Document: spc-doc_PL 21880-0023 change

• spc-doc_PL 14894-0005
• spc-doc_PL 17907-0029
• spc-doc_PL 20075-0063
• spc-doc_PL 21880-0023

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ranitidine 150 mg film-coated tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains ranitidine 150mg (as the hydrochloride).

For excipients, see 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablets.

White coloured, round, biconvex film-coated tablets with k logo on one face and 150 on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Duodenal ulcer and benign gastric ulcer, including that associated with non-steroidal anti-inflammatory agents.

Prevention of non-steroidal anti-inflammatory drug associated duodenal ulcers. Treatment of duodenal ulcers associated with Helicobacter pylori infection. Post-operative ulcer.

Oesophageal reflux disease including long term management of healed oesophagitis. Symptomatic relief in gasto-oesophageal reflux disease.

Zollinger-Ellison syndrome.

Chronic episodic dyspepsia, characterised by pain (epigastric or retrosternal) which is related to meals or disturbs sleep but not associated with the above conditions.

Prophylaxis of gastrointestinal haemorrhage from stress ulceration in seriously ill patients.

Prophylaxis of recurrent haemorrhage with bleeding peptic ulcers.

Before general anaesthesia in patients at risk of acid aspiration (Mendelson’s syndrome), particularly obstetric patients during labour.

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

The tablets should be swallowed whole.

Adults:

Usual dosage is 150 mg twice daily, taken in the morning and evening.

Duodenal ulcer, gastric ulcer:

The standard dosage regimen is 150 mg twice daily or 300 mg at night. It is not necessary to time the dose in relation to meals. In most cases of duodenal ulcer, benign gastric ulcer and postoperative ulcer, healing occurs within 4 weeks. Healing usually occurs after a further 4 weeks of treatment in those not fully healed after the initial course of therapy.

Ulcers following NSAID therapy or associated with continued NSAID’s:

8 weeks treatment may be necessary.

Prevention of NSAID associated duodenal ulcers:

150 mg twice daily may be given concomitantly with NSAID therapy.

In duodenal ulcer, 300 mg twice daily for 4 weeks results in healing rates which are higher than those at 4 weeks with ranitidine 150 mg twice daily or 300 mg at night. The increased dose has not been associated with an increased incidence of unwanted effects.

Duodenal ulcers associated with Helicobacter pylori infection:

For duodenal ulcers associated with Helicobacter pylori infection, ranitidine 300 mg at bedtime or 150 mg twice daily may be given with oral amoxycillin 750 mg three times daily and metronidazole 500 mg three times daily for two weeks. Therapy with ranitidine should continue for a further two weeks. This dose regimen significantly reduces the frequency of duodenal ulcer recurrence. Maintenance treatment at a reduced dosage of 150 mg at bedtime is recommended for patients who have responded to short-term therapy, particularly those with a history of recurrent ulcer.

Gastro-oesophageal reflux disease:

Symptom relief in gastro-oesophageal reflux disease. In patients with gastro-oesophageal reflux disease, a dose regimen of 150 mg twice daily for 2 weeks is recommended and this can be repeated in patients in whom the initial symptomatic response is inadequate.

Oesophageal reflux disease:

In the management of oesophageal reflux disease, the recommended course of treatment is either 150 mg twice daily or 300 mg at bedtime for up to 8 weeks or 12 weeks if necessary.

In patients with moderate to severe oesophagitis, the dosage of ranitidine may be increased to 150 mg 4 times daily for up to 12 weeks. The increased dose has not been associated with an increased incidence of unwanted effects.

Healed oesophagitis:

For long-term treatment, recommended adult dose is 150 mg twice daily. Long-term treatment is not indicated in management of patients with unhealed oesophagitis with or without Barrett’s epithelium.

Zollinger-Ellison syndrome:

The starting dose for Zollinger-Ellison syndrome is 150 mg three times daily, and this may be increased as necessary. Doses up to 6 grams per day have been well tolerated.

Chronic episodic dyspepsia:

The standard dosage regimen for patients with chronic episodic dyspepsia is 150 mg twice daily for up to 6 weeks. Anyone not responding or relapsing shortly afterwards should be investigated.

Prophylaxis of haemorrhage from stress ulceration in seriously ill patients or prophylaxis of recurrent haemorrhage in patients bleeding from peptic ulceration:

150 mg twice daily may be substituted for the injection once oral feeding commences.

Prophylaxis of acid aspiration (Mendelson’s) syndrome:

150 mg oral dose can be given 2 hours before anaesthesia, and preferably also 150 mg the previous evening. Alternatively, the injection is also available. In obstetric patients in labour 150 mg every 6 hours, but if general anaesthesia is required it is recommended that a non-particulate antacid (e.g. sodium citrate) be given in addition. The usual precautions to avoid acid aspiration should also be taken.

Children:

The recommended dose for treating active peptic ulcer is 2-4 mg/kg, twice daily, up to a maximum daily dose of 300 mg ranitidine, given in divided doses.

Children 12years and over

For children 12years 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.

Renal impairment:

Accumulation of ranitidine with resulting elevated plasma concentrations will occur in patients with severe renal impairment.

Accordingly, it is recommended that the daily dose of ranitidine in such patients should be 150 mg at night for 4-8 weeks. The same dose should be used for maintenance treatment, if necessary. If an ulcer has not healed after treatment, 150 mg twice daily dosage should be instituted followed, if need be, by maintenance treatment of 150 mg at night

4.3 Contraindications

Ranitidine is contra-indicated in patients known to have hypersensitivity to any component of the preparation.

4.4 Special warnings and precautions for use

Malignancy: The possibility of malignancy should be excluded before commencement of therapy in patients with gastric ulcer (and if indications include dyspepsia, patients of middle age and over with new or recently changed dyspeptic symptoms) as treatment with ranitidine may mask symptoms of gastric carcinoma.

Renal disease: 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 above under dosage in Renal Impairment.

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.

Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks. Ranitidine should therefore be avoided in patients with a history of acute porphyria.

Use in elderly patients: Rates of healing of ulcers in clinical trial patients aged 65 and over have not been found to differ from those in younger patients. Additionally there was no difference in the incidence of adverse effects.

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 H2 receptor

antagonists versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.63 (95% CI, 1.07-2.48).

4.5 Interaction with other medicaments 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)    Inhibition of cytochrome P450-linked mixed function oxygenase system:

Ranitidine at usual therapeutics doses does not potentiate the actions of drugs which are inactivated by this enzyme systems such as diazepam, lidocaine, phenytoin, propranol and theophylline.

There have been reports of altered prothrombin time with coumarin anticoagulants (e.g. warfarin). 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 secrection:

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 level of these drugs.

3)    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 amoxycillin or metronidazole. If high doses (2 g) of sucralfate 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 hr.

4.6 Pregnancy and lactation

Ranitidine crosses the placenta but therapeutic doses administered to obstetric patients in labour or undergoing caesarean section have been without any adverse effect on labour, delivery or subsequent neonatal progress. It is excreted in human breast milk.

Like other drugs it should only be used during pregnancy and nursing if considered essential.

4.7 Effects on ability to drive and use machines

Not applicable

4.8 Undesirable Effects

The following have been reported as events in clinical trials or in the routine management of patients treated with ranitidine. The relationship to ranitidine therapy has not been established in many cases.

Transient and reversible changes in liver function tests can occur. There have been occasional reports of hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice. These were usually reversible.

Acute pancreatitis has been rarely reported.

Leucopenia and thrombocytopenia have occurred rarely in patients. hese are usually reversible.

Rare cases of agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or aplasia have been reported.

Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension, anaphylactic shock) have been seen rarely following the parenteral and oral administration of ranitidine. These reactions have occasionally occurred after a single dose.

As with other H2 receptor antagonists there have been rare reports of bradycardia and A-V block.

Headache, sometimes severe, and dizziness have been reported in a very small proportion of patients. Rare cases of reversible mental confusion, depression and hallucinations have been reported, predominantly in severely ill and elderly patients.

Skin rash has been reported, including rare cases of erythema multiforme. Musculoskeletal symptoms such as arthralgia and myalgia have been reported rarely.

No clinically significant interference with endocrine or gonadalfunction has been reported. There have been a few reports of breast symptoms (swelling and/or discomfort) in men taking ranitidine; some cases have resolved on continued ranitidine treatment.

Discontinuation of therapy may be necessary in order to establish the underlying cause.

Antibiotic associated diarrhoea may occur when amoxycillin and metronidazole are taken with ranitidine.

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.

4.9 Overdose

Ranitidine is very specific in action and accordingly no particular problems are expected following overdosage. Symptomatic and supportive therapy should be given as appropriate. If need be, the drug may be removed from the plasma by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

5.2 Pharmacokinetic properties

Absorption of ranitidine after oral administration is rapid and peak plasma concentrations are usually achieved within two hours of administration. Absorption is not significantly impaired by food or antacids. The elimination half-life of ranitidine is approximately 2 hours. Ranitidine is excreted via the kidneys mainly as the free drug and in minor amounts as metabolites It’s major metabolite is an Noxide and there are smaller quantities of S-oxide and desmethyl ranitidine. The 24-hour urinary recovery of free ranitidine and its metabolites is about 40% with orally administered drug.

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: 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.

Preclinical safety data

No additional data of relevance.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose, Magnesium stearate, Hypromellose, Titanium dioxide

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

30 and 60 tablets; 10 tablets packed individually in a foil/blister strip; 3 or 6 blister strips are inserted into a pre-printed carton.

-    Aluminium foil soft, mat side primered and lacquer laminated against Polyamide 0,025 mm (Nylon 6), bright side lacquer laminated against PCV 0,060 mm.

-    Aluminium-foil hard, mat side lacquered with clear heat resistant print primer, bright side heat seal lacquered to seal to PVC and PvDC.