Change to address of the Irish MA Holder

Section 4.4: H2 receptor antagonists changed to ranitidine alone.
Section 4.5: Amended to include information on interaction between ranitidine and amoxicillin and metronidazole.
Section 4.8: Dyspnoea included as unknown adverse event under Immune System Disorders. Tachycardia added as very rare adverse event under Cardiac Disorders. Nephropatic patients referenced under Psychiatric Disorders. Paediatric subheading and adverse event reporting details included

2	Update to excipient information
4.2	Update re treatment for patients with reflux oesophagitis
4.3	Update to statement for hypersensitivity
4.4	Update to the warnings
4.5	Change to the information regarding one of the medicines that interacts
4.6	Rewording of this section
4.9	Rewording of this section

Change to:

Change to in use shelf life

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)

 

The usual initial dosage is 150mg bd or 300mg nocte.  This may be increased to ranitidine 300mg twice daily without an increased incidence of unwanted effects.  Subsequently a maintenance dose of 150mg nocte may be used.  Smoking is associated with a higher rate of ulcer relapse, and such patients should be advised to stop smoking.  In those who fail to comply with such advice, a dose of 300mg at night provides additional therapeutic benefit over the standard dose.

 

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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).

 

Safety and efficacy in new-born patients has not been established

 

The recommended oral dose for the treatment of peptic ulcer in children is 2mg/kg to 4mg/kg twice daily to a maximum of 300mg ranitidine per day.

 

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 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) or a decrease in absorption (e.g. ketoconazole, atazanavir, glipizide, delaviridine, gefitnib).

 

Ranitidine, at blood levels produced by standard recommended doses, does not inhibit the hepatic cytochrome P₄₅₀-linked mixed function oxygenase system.  Accordingly, ranitidine in the usual therapeutic dose does not potentiate the actions of drugs which are inactivated by this enzyme; these include diazepam, lignocaine, phenytoin, propranolol, theophylline and warfarin.

 

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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).

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Reproductive System and Breast Disorders

Very Rare:      Reversible impotence. Breast symptoms in men

 

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.

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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.

 

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.

 

10.  DATE OF (PARTIAL) REVISION OF THE TEXT

 

April 2010

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each 10ml of Syrup contains ranitidine hydrochloride equivalent to 150mg of ranitidine.

Excipients: Each 10ml Zantac Syrup also contains:

800mg Ethanol (96%) equivalent to 750mg of pure ethanol:

1.5mg Propyl parahydroxybenzoate (E216)

0.75mg Butyl parahydroxybenzoate

1g of Sorbitol

 

For a full list of excipients, see Section 6.1

 

3. PHARMACEUTICAL FORM

 

Syrup. Oral solution.

 

A clear, colourless to pale yellow liquid with an odour of mint.

 

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6. PHARMACEUTICAL PARTICULARS

 

6.1 List of excipients

 

Ethanol

Sodium Chloride

Potassium Dihydrogen Othophosphate

Disodium Hydrogen Orthophosphate Anhydrous

Hypromellose

Propyl parahydroxybenzoate

Butyl parahydroxybenzoate

Saccharin sodium

Sorbitol 70% non-crystallsing

Mint flavour

Purified Water

 

6.2 Incompatibilities

 

Dilution of Zantac Syrup with syrup BP or sorbitol solution is not recommended as this may result in precipitation.

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

 

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6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medical product and other handling of the product

 

Dilution of Zantac Syrup with syrup BP or sorbitol solution is not recommended as this may result in precipitation.

 

No special requirements

 

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10. DATE OF (PARTIAL) REVISION OF THE TEXT

 

March 2010

 

Improved electronic version

 

The following Text has been added to section 4.4:

 

Although no clear casual link has been established, 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). 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.

 

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 in current users of H2 receptor antagonists versus those who had stopped treatment, with an observed adjusted relative risk increase of 4.63 (95% CI, 1.07 2.48).

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.