Section 2 - Changes quantity of sodium from 328mg to 327mg
Section 4.4:
Addition of sodium warning: This medicinal product contains 327 mg sodium per dose, equivalent to 16% of the WHO recommended maximum daily intake for sodium.
The maximum daily dose of this product is equivalent to 65% of the WHO recommended maximum daily intake for sodium.
Zantac Effervescent Tablets is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

 

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

4.3	QRD 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
6.1	Update to the excipients
6.3	Shelf life is 2 years – previously approved in another variation
6.4	Storage conditions do not store above 25 degrees – previously approved in another variation

Change to:

 

 

Section 6.3 - Shelf life

 

 

 

6.4 Special precautions for storage

 

Do not store above 2530°C

Tubes: Keep container tightly closed in order to protect from light and moisture.

 

10.  DATE OF (PARTIAL) REVISION OF THE TEXT

 

July 2011July 2012

3.  PHARMACEUTICAL FORM

 

Effervescent tablet.

 

A white to pale yellow, round bevelled tablet marked “GS LHK” on one side and flat on the other which effervesces on dissolution in water to give a clear orange/grapefruit flavoured solution.

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.

 

 

 

 

SUMMARY OF PRODUCT CHARACTERISTICS

 

 

1. NAME OF THE MEDICINAL PRODUCT

 

Zantac 150mg Effervescent Tablets

 

2.  QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each effervescent tablet contains 150mg ranitidine (as hydrochloride)

Excipients – contains Aspartame (E951) 30.0mg, Sorbitol (E420) approximately 1.14mg and Sodium 328mg

For a full list of excipients, see section 6.1

 

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4.  CLINICAL PARTICULARS

 

 

4.4  Special warnings and special 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 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 1.63 (95% CI, 1.07-2.48)

 

Zantac Effervescent Tablets contain 14.3mEq (328mg) of sodium.  Care should therefore be taken in treating patients in whom sodium restriction is indicated.

 

As Zantac Effervescent Tablets contain aspartame they should be used with caution in patients with phenylketonuria.

 

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

 

Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks.  Ranitidine should therefore be avoided in patients with a history of acute porphyria.

 

In keeping with the recommended clinical practice it is advisable that patients on long-term maintenance therapy receive regular routine assessment by practitioners.

 

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6.  PHARMACEUTICAL PARTICULARS

 

 

6.4 Special precautions for storage

 

Do not store above 30°C

Tubes: Keep container tightly closed in order to protect from light and moisture.

 

Blisters: Store in the original package

 

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6.5  Nature and contents of containers

 

Zantac Effervescent Tablets 150mg are packed in white polypropylene tubes fitted with white polyethylene caps filled with silica gel.  The Two tubes are packed into a cardboard carton which has a tamper evident closure.  Each tube contains 15 tablets. Alternatively one tube of 10 tablets is packed into a cardboard carton which has a tamper evident closure.

 

Not all pack sizes may be marketed.

 

Alternatively, Zantac effervescent tablets 150mg are packed in heat-sealable aluminium foil strips. Each aluminium foil strip contains six tablets and five of these strips are packed into a cardboard carton, which has a tamper evident closure.

 

A sample pack of 6 tablets in a foil strip is also available

 

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

 

One or two Zantac Effervescent Tablets should be dissolved in half a tumbler of water (at least 75ml) and stirred thoroughly until completely dissolved before swallowing.

 

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9.  DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

 

Date of first authorisation: 27 June 1990

Date of last renewal: 27 June 2010

 

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10.  DATE OF (PARTIAL) REVISION OF THE TEXT

 

November 2010

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.

 

In most cases of duodenal ulcer, benign gastric ulcer and post operative ulcer, healing occurs within 4 weeks.  Healing usually occurs after a further 4 weeks in those not fully healed after the initial 4 weeks.  In ulcers following non-steroidal anti-inflammatory drug therapy, 8 - 12 weeks treatment may be necessary.  For the prevention of non-steroidal anti-inflammatory drug associated duodenal ulcers ranitidine 150mg bd may be given concomitantly with non-steroidal anti-inflammatory drug therapy.

 

In the management of reflux oesophagitis the usual course of treatment is either 150mg twice daily or 300mg at night administered for up to a period of 8, or if necessary 12 weeks.  In patients with moderate to severe oesophagitis the dosage may be increased to 150mg four times daily, alternatively 300mg twice a day, if necessary.

 

For the long-term management of reflux oesophagitis, the recommended adult oral dose is 150mg twice daily for the prevention of relapse in patients with reflux oesophagitis.  Zantac 150mg effervescent tablets are not indicated in patients with complications of reflux oesophagitis e.g. severe oesophegeal stricture or Barratt’s oesophagus.

 

In keeping with the recommended clinical practice it is advisable that patients on long-term maintenance therapy receive regular routine assessment by practitioners.

 

In patients with Zollinger-Ellison syndrome the starting dose is 150mg thrice daily, increased as necessary up to a maximum of 6 grams daily.

 

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 Zantac 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 obstetric patients an oral dose of 150mg may be given at commencement of labour, followed by 150mg at 6 hourly intervals.  It is recommended that in addition, a non-particulate antacid (eg sodium citrate) should be given prior to induction of anaesthesia in any patient requiring emergency general anaesthesia.

 

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.

 

……………………………..

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).

……………………………..

 

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.

……………………………..

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

 

March 2010

Immproved electronical 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.

6.3 Shelf life

        3 years

6.5 nature & contents of the container

Zantac Effervescent Tablets 150mg are packed in white polypropylene tubes fitted with white polyethylene caps filled with silica gel. The tubes are packed into a cardboard carton which has a tamper evident closure. Each tube contains 15 tablets.

Alternatively, Zantac effervescent tablets 150mg are packed in heat-sealable aluminium foil strips. Each aluminium foil strip contains six tablets and five of these strips are packed into a cardboard carton, which has a tamper evident closure.

A sample pack of 6 tablets in a foil strip is also available