Zantac Syrup

Ranitidine Hydrochloride 168.0 mg (Equivalent to Ranitidine 150.0 mg)

Syrup

Adults

Zantac syrup is indicated for the treatment of duodenal ulcer and benign gastric ulcer, including that associated with non-steroidal anti-inflammatory agents. In addition, Zantac syrup is indicated for the prevention of NSAID associated duodenal ulcers. Zantac syrup is also indicated for the treatment of post-operative ulcer, Zollinger-Ellison Syndrome and oesophageal reflux disease including long term management of healed oesophagitis. Other 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. Zantac syrup is indicated for the following conditions where reduction of gastric secretion and acid output is desirable; the prophylaxis of gastro-intestinal 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. For appropriate cases Zantac injection is also available (see separate SPC).

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.

See section 4.4 Special warnings and precautions for use.

Route of administration: Oral

Adults (including the elderly) / Adolescents (12 years and over)

The usual dosage is 150 mg 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 300 mg. It is not necessary to time the dose in relation to meals.

Duodenal ulcer, benign gastric ulcer and post-operative ulcer:

In most cases of duodenal ulcer, benign gastric ulcer and post operative ulcer, healing occurs in four weeks. Healing usually occurs after a further 4 weeks of treatment in those patients whose ulcers have not fully healed after the initial course of therapy.

NSAID associated peptic ulceration, including prophylaxis of duodenal ulcers:

In ulcers following non-steroidal anti-inflammatory drug therapy or associated with continued non-steroidal anti-inflammatory drugs, 8 weeks treatment may be necessary.

For the prevention of non-steroidal anti-inflammatory drug associated duodenal ulcers ranitidine 150 mg twice daily may be given concomitantly with non-steroidal anti-inflammatory drug 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 nocte. The increased dose has not been associated with an increased incidence of unwanted effects.

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:

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 if necessary 12 weeks.

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

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

Zollinger-Ellison syndrome:

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

Chronic episodic dyspepsia:

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

Prophylaxis of haemorrhage from stress ulceration or recurrent haemorrhage:

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

Prophylaxis of Mendelson's syndrome:

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

In obstetric patients at commencement of labour, an oral dose of 150 mg may be given followed by 150 mg 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 (eg sodium citrate) prior to induction of anaesthesia. The usual precautions to avoid acid aspiration should also be taken.

Children (3 to 11 years):

See Section 5.2 Pharmacokinetic Properties (Special Patient Population)

Zantac syrup contains approximately 7.5%w/v ethanol. Therefore an alternative formulation of ranitidine may be considered necessary for at-risk groups, including children (see section 4.4 Special warnings and precautions for use).

Patients over 50 years of age

See Section 5.2 Pharmacokinetic Properties (Special Patient Populations, Patients over 50 years of age)

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 to a maximum of 600 mg (the maximum dose is likely to apply to heavier children or adolescents with severe symptoms).

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 renal impairment (creatinine clearance less than 50 ml/min). Accordingly, it is recommended that the daily dose of ranitidine in such patients be 150 mg at night for 4 to 8 weeks. The same dose should be used for maintenance treatment if necessary. If an ulcer has not healed after treatment, the standard dosage regimen of 150 mg twice daily should be instituted, followed, if need be, by maintenance treatment at 150 mg at night.

Ranitidine is contraindicated for patients known to have hypersensitivity to any component of the preparation.

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 ulcer 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 Zantac is instituted.

Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with renal impairment. The dosage should be adjusted as detailed in section 4.2 in Renal Impairment.

Regular supervision of patients who are taking non-steroidal anti-inflammatory drugs 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.

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.

Zantac syrup contains approximately 7.5% w/v ethanol (alcohol), i.e. up to 405 mg per 5 ml spoonful which is equivalent to about 11 ml of beer or 5 ml of wine. It is harmful for those suffering from alcoholism. It should be taken into account in pregnant or lactating women, high-risk groups (those suffering from alcoholism, liver disease, epilepsy, brain injury or disease) and children (see section 4.2). It may modify or increase the effects of other medicines.

Alternative formulation of Zantac may be considered preferential in these populations.

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 1.26-2.64). Postmarketing data indicate reversible mental confusion, depression, and hallucinations have been reported most frequently in severely ill and elderly patients (see section 4.8).

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, propanolol 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)..

Zantac 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. Zantac is also excreted in human breast milk. Like other drugs, Zantac should only be used during pregnancy and nursing if considered essential.

Not applicable

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 post-marketing data.

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 available, in particular regarding growth and development.

Zantac is very specific in action and accordingly no particular problems are expected following overdosage with the drug. Symptomatic and supportive therapy should be given as appropriate.

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

Following oral administration of 150 mg 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 proteins (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 the S-oxide, 2% as desmethylranitidine and 1 to 2% as the furoic acid analogue.

Elimination

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 bile. Renal clearance is approximately 500 mL/min, which exceeds glomerular filtration indicating net renal tubular secretion.

Special Patient 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 exposure and accumulation are 50% higher. This difference exceeds the effect of declining renal function, and indicates increased bioavailability in older patients.

No clinically relevant findings were observed in preclinical studies.

Hydroxypropyl methylcellulose USP

2906 or 2910

Ethanol (96%) BP

Propyl hydroxybenzoate BP

Butyl hydroxybenzoate BP

Potassium dihydrogen

Orthophosphate AR

Disodium hydrogen orthophosphat

Anhydrous AR

Sodium chloride BP

Saccharin sodium BP

Sorbitol solution 1973 BPC

Mint flavour IFF 17: 42: 3632

Purified water BP

Not applicable.

24 months.

Zantac syrup should be stored at a temperature not exceeding 25ºC.

Amber glass bottles with polypropylene child resistant caps, or plastic child resistant closures, or plastic child resistant tamper evident closures with either pet faced/al foil/epe wads, or pet faced/al foil/folding box board

Pack sizes: 300 ml, 2 x 150 ml.

None.

Glaxo Wellcome UK Ltd., trading as GlaxoSmithKline UK

Stockley Park West,

Uxbridge,

Middlesex, UB11 1BT

PL 10949/0108

17 April 2003

13^th December 2010

POM