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Ranitidine 300mg Effervescent Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ranitidine 300mg Effervescent Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 300 mg ranitidine (as hydrochloride).

3    PHARMACEUTICAL FORM

Effervescent Tablets.

Yellow white to light yellow cylindircal, biplanar tablets with bevel-edges on both sides.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ranitidine Effervescent Tablets are indicated for:

Treatment of duodenal ulcer including that associated with non-steroidal antiinflammatory drugs (NSAIDs)

Prevention of NSAID associated duodenal ulcers

Treatment of duodenal ulcers associated with Helicobacter pylori infection

Treatment of post-operative ulcer

Oesophageal reflux disease including the long term management of healed oesophagitis as well as the symptomatic relief of gastro-oesophageal reflux disease.

Patients with chronic episodic dyspepsia, characterised by pain (epigastric or retrosternal) which is related to meals or disturbs sleep but is not associated with the preceding conditions may benefit from ranitidine treatment.

Ranitidine Effervescent tablets are also indicated for the following conditions where reduction of gastric secretion and acid output is desirable:

The prophylaxis of gastrointestinal haemorrhage from stress ulceration in seriously ill patients; the prophylaxis of recurrent haemorrhage in patients with bleeding peptic ulcers and before general anaesthesia in patients considered to be 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 Adults

The usual dosage is 150mg twice daily, taken in the morning and evening. Alternatively, patients with duodenal ulceration, gastric ulceration or oesophageal reflux disease may be treated with a single bedtime dose of 300mg. In most cases of duodenal ulcer, benign gastric ulcer and postoperative ulcer, healing occurs in four weeks. Healing usually occurs after a further four weeks of treatment in those patients whose ulcers have not fully healed after the initial course of therapy.

In ulcers following non-steroidal anti-inflammatory drug (NSAID) therapy or associated with continued NSAID therapy, eight weeks treatment may be necessary.

For the prevention of NSAID-associated duodenal ulcers, ranitidine 150mg twice daily may be given concomitantly with NSAID therapy. In duodenal ulcer, 300mg twice daily for 4 weeks results in healing rates which are higher than those at 4 weeks with ranitidine 150mg twice daily or 300mg nocte.

The increased dose has not been associated with increased incidence of unwanted effects.

For duodenal ulcers associated with Helicobacter pylori infection ranitidine 300mg at bedtime or 150mg twice daily may be given with oral amoxicillin 750mg three times daily and metronidazole 500mg three times daily for two weeks. Therapy with ranitidine should continue for a further 2 weeks. The dose regimen significantly reduces the frequency of duodenal ulcer recurrence.

Maintenance treatment at a reduced dosage of 150mg at bedtime is recommended for patients who have responded to short term therapy, particularly those with a history of recent ulcer.

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

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

In patients with moderate to severe oesophagitis the dose of ranitidine may be increased to 150mg four times daily for up to 12 weeks. The increased dose has not been associated with an increased incidence of unwanted effects. Long term treatment is not indicated in the management of patients with unhealed oesophagitis, with or without barret’s epithelium.

In patients with Zollinger-Ellison syndrome, the starting dose is 150mg three times daily and this may be increased as necessary. Patients with this syndrome have been given increasing doses up to 6g per day and these doses have been well-tolerated.

For patients with chronic episodic dyspepsia the recommended course of treatment is 150mg twice daily for up to six weeks. Anyone not responding or relapsing shortly afterwards should be investigated.

In the prophylaxis of haemorrhage from stress ulceration in seriously ill patients or the prophylaxis of recurrent haemorrhage in patients bleeding from peptic ulceration, treatment with Ranitidine Effervescent tablets 150mg twice daily may be substituted for Zantac injection once oral feeding commences in patients considered to be still at risk from these conditions.

In patients thought to be at risk of acid aspiration syndrome an oral dose of 150mg can be given 2 hours before induction of general anaesthesia, preferably also 150mg the previous evening.

In obstetric patients at commencement of labour, an oral dose of 150mg may be given followed by 150mg at six-hourly intervals. It is recommended that since gastric emptying and drug absorption are delayed during labour, any patient requiring emergency general anaesthesia should be given, in addition, a

non-particulate antacid (e.g. sodium citrate) prior to induction of anaesthesia. The usual precautions to avoid acid aspiration should also be taken.

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.

Method of Administration

Dissolve the tablet completely in half a glass of water (minimum 75ml) before swallowing.

4.3. Contra-indications

Hypersensitivity to ranitidine or any of the other ingredients.

4.4 Special warnings and precautions for use

Treatment with a histamine H2-antagonist may mask symptoms associated with carcinoma of the stomach and may therefore delay diagnosis of the condition. Accordingly, where

gastric ulceration has been diagnosed or in patients of middle age and over with new or recently changed dyspeptic symptoms the possibility of malignancy should be excluded before therapy with ranitidine tablets is instituted.

Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment. Accordingly, it is recommended that the therapeutic regimen for ranitidine tablets in such patients be 150mg at night for 4 to 8 weeks. The same dose should be used for maintenance treatment should this be deemed necessary. If the ulcer has not healed after treatment the standard dosage regimen of 150mg twice daily should be instituted, followed, if need be, by maintenance treatment of 150mg at night.

Regular supervision of patients who are taking non-steroidal anti-inflammatory drugs (NSAIDs) concomitantly with ranitidine is recommended, especially, in the elderly. Current evidence shows that ranitidine protects against NSAID-associated ulceration in the duodenum and not in the stomach.

Although clinical reports of acute intermittent porphyria associated with ranitidine administration have been rare and inconclusive, ranitidine should be avoided in patients with a history of this condition.

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 of 1.82 (95% CI 1.26-2.64).

Ranitidine effervescent tablets contain sodium. Care should therefore be taken in treating patients in whom sodium restriction is indicated.

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)    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, lidocaine, phenytoin, propranolol 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 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 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, gefitinib).

There is no evidence of an interaction between ranitidine and amoxicillin 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 h.

4.6 Fertility, pregnancy and lactation

Reproductive studies in animals have revealed no evidence of impaired fertility or harm to the foetus. There are however, no well-controlled studies in pregnant women and ranitidine should be used in pregnancy only when it is clearly needed.

Ranitidine crosses the placenta and like other drugs should only be used in pregnancy if considered essential. 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.

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

None stated.

4.8 Undesirable effects

The following convention has been utilised for the classification of undesirable effects:

very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000).

Adverse event frequencies have been estimated from spontaneous reports from postmarketing data.

Blood & Lymphatic System Disorders

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

Immune System Disorders

Very Rare: Anaphylactic shock

Rare: Hypersensitivity reactions (urticaria, angioedema, fever, bronchospasm, hypotension and chest pain).

These events have been reported after a single dose.

Psychiatric Disorders

Very Rare: Reversible mental confusion, depression and hallucinations.

These have been reported predominantly in severely ill and elderly patients.

Nervous System Disorders

Very Rare: Headache (sometimes severe), dizziness 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, A-V block and asystole (injection only).

Vascular Disorders

Very Rare: Vasculitis.

Gastrointestinal Disorders

Very Rare: Acute pancreatitis

Uncommon: abdominal pain, diarrhoea, constipation, nausea (these symptoms mostly improved during continued treatment).

Hepatobiliary Disorders

Rare: Transient and reversible changes in liver function tests.

Very Rare: Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, which is usually reversible.

Skin and Subcutaneous Tissue Disorders

Very Rare: Erythema multiforme, alopecia.

Rare: Skin rash.

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, 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.

4.9. Overdose

No specific features of overdose have been reported and oral overdosage of 18g has been reported to be safe. Studies in animals suggest that vomiting, muscular tremors and hyperventilation may occur. In the case of massive overdose, activated charcoal may be given and the usual supportive care. If necessary haemodialysis would be expected to partially clear ranitidine but it is very unlikely to be required. Clinicians should be aware of the sodium content in cases of acute overdosage with effervescent formulations.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Ranitidine is a competitive inhibitor of histamine at histamine H2-receptor sites. In vitro and in vivo it is more active than cimetidine on a molar basis. In humans ranitidine inhibits basal gastric acid secretion and that stimulated by pentagastrin, histamine and normal meals, being about four to five times more active than cimetidine in healthy subjects and in patients with duodenal ulcer.

5.2. Pharmacokinetic Properties

After oral administration, absorption of ranitidine is rapid with a mean lag time of 15 minutes and peak plasma concentrations are attained within 1 to 3 hours. Following a single oral dose of ranitidine 150mg, the mean plasma concentration and the mean area under the curve (AUC) are about 0.37 mg/L and 1.9 mg/L.h , respectively, in otherwise healthy duodenal ulcer patients. Considerable variation in ranitidine plasma concentrations between individuals administered the same total dose has been noted. Nonetheless, linearity between the dose and the mean peak plasma concentration has been demonstrated between 50 and 200mg and 100 and 400mg.

The apparent volume of distribution of ranitidine (approximately 1.4L/kg) is larger than the actual body water, indicative of some binding to tissues. Plasma binding of ranitidine in normal subjects is around 15%.

The forms of ranitidine which are excreted in the urine are unchanged drug, ranitidine -N-oxide, demethylranitidine and ranitidine-S-oxide. Following oral administration, the percentage of ranitidine recovered unchanged in urine over 24 to 48 hours is about 30% of the dosage, with the main metabolite, the N-oxide, accounting for 1.9 to 6%. When given intravenously, the urinary recovery of unchanged ranitidine accounts for about 70% of the dosage and the N-oxide metabolite for 3 to 6%. A relatively longer half-life of elimination has been found in both normal subjects and duodenal ulcer patients given oral ranitidine (3h) compared with intravenous drug (2h).The tablets, syrup, effervescent and dispersible preparations are bioequivalent. About 50% of the drug is bioavailable after oral dosing and there is significant presystemic metabolism (first-pass effect).

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.

5.3. Preclinical Safety Data

There are no additional preclinical data of relevance to the prescriber which are additional to those stated in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Tartaric acid a-Lactose monohydrate Povidone K25

Riboflavin 5’-phosphate sodium Sodium cyclamate Saccharin sodium

Lemon flavour (contains: citral, citronella oil, coriander oil, gum arabic, lime oil).

Macrogol 6000 Sodium bicarbonate

Simethicone emulsion (methylcellulose + sorbic acid)

Magnesium stearate

6.2. Incompatibilities

None known.

6.3. Shelf Life

36 months.

6.4.


Special Precautions for Storage

Do Not Store Above 25°C. Keep the container tightly closed. Store in the original package.

6.5.    Nature and Contents of Container

Polypropylene tube with a low density polyethylene cap containing desiccant. Each tube contains 2x15 tablets (30 tablets per pack).

6.6.    Instruction for Use/Handling

Dissolve the tablet in half a glass of water (minimum 75 ml) before swallowing. Replace cap firmly after use.

7    MARKETING AUTHORISATION HOLDER

Waymade plc

t/a Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex, SS14 3FR

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 06464/0582

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 3 May 2002

10 DATE OF REVISION OF THE TEXT

23/10/2013