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Zantac - Information Sheet for Doctors

ZANTAC Tablets.

Ranitidine hydrochloride Tablets

Qualitative and Quantitative Composition

Zantac 150mg Tablets: white film-coated, circular, biconvex tablets, engraved Zantac 150 on one face and GLAXO on the other. Each tablet contains ranitidine 150mg (as the hydrochloride).

Zantac 300mg Tablets: white, capsule shaped film coated tablet, 17mm long, 7.5mm wide and 4.4mm deep, engraved Zantac 300 on one face and GLAXO on the other. Each tablet contains ranitidine 300mg (as the hydrochloride).

Pharmaceutical Form

Tablet.

Clinical Particulars

Therapeutic Indications

Zantac Tablets are indicated for the treatment of duodenal ulcer and benign gastric ulcer.

The pathogenesis of duodenal ulcer disease is multifactorial and infection with Helicobacter pylori appears to be one important factor in the process. The United States National Institute of Health has recommended that regimens to eradicate Helicobacter pylori in patients with peptic ulcer disease, whether on first presentation with the illness or on recurrence, should contain both anti-secretory agents (including H2 antagonists) and anti-microbial agents (to which Helicobacter pylori has been demonstrated to be sensitive in vivo ). A recent trial by Hentschel et al 1.in patients with recurrent duodenal ulcer disease has demonstrated that ranitidine in combination with amoxycillin (750mg three times daily) and metronidazole (500mg three times daily) for 12 days is effective in eradicating Helicobacter pylori in 89% of cases. Following this combination therapy the relapse rate for duodenal ulcer disease was only 2% at 12 months suggesting a causal role for Helicobacter pylori in recurrent duodenal ulcer. Therefore Zantac Tablets, when used in a treatment regimen with amoxycillin and metronidazole, are indicated for the treatment of duodenal ulcers associated with Helicobacter pylori infection.

Zantac Tablets are also indicated for:

the treatment of duodenal ulcer and benign gastric ulcer associated with non-steroidal anti-inflammatory agents.
the prevention of non-steroidal anti-inflammatory agent (including aspirin) associated duodenal ulcers in patients with a history of duodenal ulceration proven by endoscopy.
the treatment of post-operative ulcer
the treatment of chronic episodic dyspepsia, characterised by pain (epigastric or retrosternal) which is related to meals or disturbs sleep but not associated with the above conditions
symptom relief in gastro-oesophageal reflux disease
the treatment of oesophageal reflux disease
the treatment of Zollinger-Ellison syndrome

Zantac Tablets are also indicated for the following conditions where reduction of gastric secretion and acid output is desirable:

the prophylaxis of upper gastrointestinal haemorrhage from stress ulceration in seriously ill patients
the prophylaxis of recurrent haemorrhage in patients with bleeding peptic ulcers
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 Zantac Injection Data Sheet).

1Hentschel E, Brandstätter G, Dragosics B et al. Effect of ranitidine and amoxycillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med 1993; 328: 308-312.

Posology and method of administration

Adults

Duodenal Ulcer and Benign Gastric Ulcer - Eradication of Helicobacter pylori: For duodenal ulcers associated with Helicobacter pylori infection Zantac 300mg at bedtime or 150mg twice daily may be given with oral amoxycillin 750mg three times daily and metronidazole 400mg-600mg three times daily for two weeks. Therapy with Zantac only should continue for a further two weeks. This dose regimen eradicates Helicobacter pylori and significantly reduces the frequency of duodenal ulcer recurrence.

Duodenal Ulcer and Benign Gastric Ulcer - Acute Treatment: The usual dosage is one 150mg tablet twice daily, taken in the morning and evening. Alternatively, patients with duodenal ulceration or gastric ulceration may be treated with a single bedtime dose of 300mg. It is not necessary to time the dose in relation to meals.

In most cases of duodenal ulcer or benign gastric 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.

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 an increased incidence of unwanted effects.

Duodenal Ulcer and Benign Gastric Ulcer - Long Term Management: For the long term management of duodenal ulcer or benign gastric ulcer, not associated with Helicobacter pylori, the usual dosage regimen is 150mg nocte.

Smoking is associated with a higher rate of duodenal ulcer relapse, and such patients should be advised to stop smoking. In those who fail to comply with such advice a dose of 300mg nocte provides additional therapeutic benefit in these patients over the 150mg dosage regimen.

NSAID Associated Peptic Ulceration - Acute Treatment: In ulcers following non-steroidal anti-inflammatory medicine therapy or associated with continued non-steroidal anti-inflammatory medicines, 8 weeks treatment may be necessary with 150mg twice daily or 300mg nocte.

NSAID Associated Peptic Ulceration - Prophylaxis: For the prevention of non-steroidal anti-inflammatory agent associated duodenal ulcers, Zantac 150mg twice daily may be given concomitantly with non-steroidal anti-inflammatory therapy.

Postoperative Ulcer: The standard dosage regimen for postoperative ulcer is 150mg twice daily. Most cases heal within 4 weeks. Those not fully healed after the initial 4 weeks usually do so after a further 4 weeks.

Chronic Episodic Dyspepsia: 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.

Gastro-Oesophageal Reflux Disease: Symptom relief in gastro-oesophageal reflux disease

For the relief of symptoms associated with oesophageal acid reflux, the recommended regimen is 150mg twice daily for two weeks. This regimen may be continued for a further two weeks in those patients in whom the initial response is inadequate.

Acute reflux oesophagitis: In the management of oesophageal reflux disease, the recommended course of treatment is either one 150mg tablet twice daily or one 300mg tablet at bedtime for up to 8 weeks.

In patients with moderate to severe oesophageal reflux disease, the dosage of ranitidine may be increased to 150mg four times daily for up to twelve weeks.

Long-term management of reflux oesophagitis: For the long-term management of reflux oesophagitis the recommended adult oral dose is 150mg twice daily.

Zollinger-Ellison Syndrome: 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.

Prophylaxis of Haemorrhage from Stress Ulceration in Seriously Ill Patients or the Prophylaxis of Recurrent Haemorrhage in Patients Bleeding from Peptic Ulceration: Treatment with Zantac Tablets 150mg twice daily may be substituted for Zantac Injection (see Zantac Injection Data Sheet) 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 150mg can be given two hours before induction of general anaesthesia, and preferably also a 150mg tablet the previous evening. Alternatively Zantac Injection for intravenous and intramuscular use is also available (see Zantac Injection Data Sheet).

In obstetric patients at commencement of labour, an oral dose of 150mg can be given followed by 150mg at six hourly intervals. It is recommended that since gastric emptying and medicine 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

Experience with Zantac Tablets in children is limited and such use has not been fully evaluated in clinical studies. It has however been used successfully in children aged 8 to 18 years in doses up to 150mg twice daily.

Renal Impairment

Accumulation of ranitidine with resulting elevated plasma concentrations will occur in patients with severe renal impairment (creatinine clearance less than 50 mL/min). It is recommended that the daily dose of ranitidine in such patients should be 150mg. In patients undergoing chronic ambulatory peritoneal dialysis or chronic haemodialysis, ranitidine (150mg) should be taken immediately after dialysis.

Contraindications

Zantac is contraindicated in patients known to have hypersensitivity to any component of the preparation.

Special warnings and special 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.

Interaction with other medicaments and other forms of interaction

Ranitidine, at blood levels produced by standard recommended doses, does not inhibit the hepatic cytochrome P450-linked mixed function oxygenase system. Accordingly, ranitidine in usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme; these include diazepam, lignocaine, phenytoin, propranolol, theophylline and warfarin. There is no evidence of an interaction between ranitidine and amoxycillin and metronidazole.

If high doses (2g) 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 hours.

Pregnancy and lactation

Ranitidine crosses the placenta and is excreted in human breast milk.

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

Effects on the ability to drive and operate machinery

None reported.

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.

Blood & Lymphatic

Blood count changes (leucopenia, thrombocytopenia) have occurred in a few patients. These are usually reversible. Rare cases of agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or aplasia have been reported.

Cardiovascular

As with other H2 receptor antagonists, rare reports of bradycardia and A-V Block. Rare cases of vasculitis have been reported.

Eye

There have been a few reports of reversible blurred vision suggestive of a change in accommodation.

Gastrointestinal

Very rare cases of diarrhoea have been reported.

Hepatobiliary tract and Pancreas

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.

Musculoskeletal

Musculoskeletal symptoms such as arthralgia and myalgia have been reported rarely.

Neurology/Psychiatry

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. In addition, reversible involuntary movement disorders have been reported rarely.

Non-site specific/Skin

Skin rash has been reported, including rare cases of erythema multiforme. Rare cases of vasculitis and alopecia have been reported.

Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension, anaphylactic shock, chest pain) have been seen rarely after a single dose.

Renal

Very rare cases of acute interstitial nephritis have been reported.

Reprodcution

Reversible impotence has been reported rarely. There have been a few reports of breast symptoms in men taking ranitidine.

Overdose

Ranitidine is very specific in action and no particular problems are expected following overdosage with Zantac Tablets.

Symptomatic and supportive therapy should be given as appropriate. If need be, the drug may be removed from the plasma by haemodialysis.

Pharmacological Properties

Pharmacodynamic properties

Zantac 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. Zantac has a relatively long duration of action and so a single 150mg dose effectively suppresses gastric acid secretion for twelve hours. Clinical evidence has shown that ranitidine combined with amoxycillin and metronidazole eradicates Helicobacter pylori in approximately 90% of patients. This combination therapy has been shown to significantly reduce duodenal ulcer recurrence.

Helicobacter pylori infects about 95% of patients with duodenal ulcer and 80% of patients with gastric ulcer.

Pharmacokinetic properties

The bioavailability of ranitidine is consistently about 50%. Peak concentrations in plasma, normally in the range 300-550ng/mL, occur 2-3 hours after oral administration of a 150mg dose. Concentrations of ranitidine in plasma are proportional to dose up to and including 300mg.

Ranitidine is not extensively metabolised. Elimination of the drug is primarily by tubular secretion. The elimination half-life is 2-3 hours.

In balance studies with 150mg 3H-ranitidine 93% of an intravenous dose was excreted in urine and 5% in faeces; 60-70% of an oral dose was excreted in urine and 26% in faeces. Analysis of urine excreted in the first 24 hours after dosing showed that 70% of the intravenous dose and 35% of the oral dose were eliminated unchanged. The metabolism of ranitidine is similar after both oral and intravenous dosing; about 6% of the dose being excreted in urine as the N-oxide, 2% as the S-oxide, 2% as desmethylranitidine and 1-2% as the furoic acid analogue.