section 4.2 - addition of standard dose regimen, administrative updates,
section 4.4 - addition to information about excipients; sodium warnings
section 4.5 - addition of interactions with erlotinib

section 5.1 - administrative update

section 9 - correction to renewal date
section 10 - update to revision date
 

section 2 - correction to typo error to include 'lung', addition of drug interactions with erlotinib , addition of sodium warning
section 6 - update to revision date
 

Store below 25^oC. Store in the original package in order to protect from moisture.

4.2       Posology and Method of Administration

Renal Insufficiency:

In patients with a creatinine clearance < 50ml/min the usual dose is 150mg nightly.  In patients on dialysis, dosage should be given on completion of dialysis.

Accumulation of ranitidine with resulting elevated plasma concentrations will occur in patients with renal impairment (creatinine clearance less than 50 ml/min). It is recommended that the daily dose of ranitidine in such patients should be 150 mg.

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4.4  Special warnings and precautions for use

Before initiation of ranitidine treatment for any gastric ulceration, malignancy should be excluded by endoscopy and biopsy if possible.  Treatment may mask the symptoms of malignancy, delaying diagnosis.

Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment, adjust dosage detailed under section 4.2 above.

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.

In patients such as the elderly, persons with chronic lung disease, diabetes orf 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 antagonistsranitidine alone versus those who had stopped treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07-2.48)increase of 1.82 (95% CI 1.26 – 2.64).

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4.6  Fertility, Ppregnancy and lactation

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4.8  Undesirable effects

Gastrointestinal Disorders

Very Rare:       Acute pancreatitis. Diarrhoea.

Uncommon:     Abdominal pain, constipation, nausea (these symptoms mostly improved during continued treatment)

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 in men, breast symptoms and breast conditions (such as gynaecomastia and galactorrhoea)

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5.  PHARMACOLOGICAL PROPERTIES

5.2  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.

Absorption:

Following oral administration of 150 mg ranitidine, maximum plasma concentrations (300 to 550 ng/mL) occurred after 1-3 hours. Two distinct peaks or a 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 include 6% of the dose in urine as 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.

4.1  Therapeutic indications

In the treatment of duodenal ulcer and benign gastric ulcer including that associated with non-steroidal anti-inflammatory agents.  Prevention of non-steroidal anti-inflammatory drug (including aspirin) associated duodenal ulcers, especially in patients with a history of peptic ulcer disease.  Zantac Tablets are also indicated for treatment of post-operative ulcer, reflux oesophagitis, Zollinger-Ellison syndrome and other conditions where reduction of gastric acid secretion is likely to be beneficial.

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

New Date of last Renewal: 1^st December 2007

5.1  (Pharmacodynamic properties). The following section has been added: In patients such as the elderly, persons with chronic lung disease, diabetes of 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 of 4.63 (95% CI, 1.07-2.48)

6.6 (Instructions for use/handling) “none” has been deleted and “No special requirements” has been added.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alimentary tract and metabolism.

ATC code: A02 BA02.

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.

Although no clear casual link has been established, a large epidemiological study showed 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).  Therefore, in patients with conditions predisposing to the development of pneumonia, such as chronic lung disease, diabetes, or the immunocompromised, there may be an increased risk of developing community acquired pneumonia.