Zantac Effervescent Tablets 150mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zantac Effervescent Tablets 150 mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains ranitidine 150 mg (as the hydrochloride).
Excipients with known effect:
Contains 14.2 mEq (328 mg) of sodium.
Contains aspartame (E951)
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Effervescent Tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults
Duodenal ulcer and benign gastric ulcer, including that associated with nonsteroidal 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.
Treatment of duodenal ulcers associated with Helicobacter pylori infection. Post-operative ulcer.
Oesophageal reflux disease.
Symptom relief in gastro-oesophageal reflux disease.
Zollinger-Ellison Syndrome.
Chronic episodic dyspepsia, characterised by pain (epigastric or retrosternal) which is related to meals or disturbs sleep but not associated with the above conditions.
Prophylaxis of stress ulceration in seriously ill patients.
Prophylaxis of recurrent haemorrhage from peptic ulcer.
Prophylaxis of Mendelson's syndrome.
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
Posology
Adults (including the elderly)
Duodenal ulcer and benign gastric ulcer:
Acute treatment:
The standard dosage regimen for duodenal or benign gastric ulcer is 150 mg twice daily or 300 mg nocte. In most cases of duodenal ulcer or benign gastric ulcer healing occurs within 4 weeks. Healing usually occurs after a further 4 weeks in those not fully healed after the initial 4 weeks.
Long-term management:
For the long-term management of duodenal or benign gastric ulcer the usual dosage regimen is 150 mg nocte.
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.
NSAID associated peptic ulceration:
Acute treatment:
In ulcers following non-steroidal anti-inflammatory drug therapy, or associated with continued non-steroidal anti-inflammatory drugs, 8-12 weeks treatment may be necessary with 150 mg twice daily or 300 mg nocte. Prophylaxis:
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.
For duodenal ulcers associated with Helicobacter pylori infection, ranitidine 300 mg at bedtime or 150 mg twice daily may be given with oral amoxicillin 750 mg three times daily and metronidazole 500 mg three times daily for two weeks. Therapy with ranitidine should continue for a further two weeks. This dose regimen significantly reduces the frequency of duodenal ulcer recurrence.
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.
Gastro-oesophageal reflux disease:
Symptom relief in gastro-oesophageal reflux disease.
In patients with gastro-oesophageal reflux disease, a dose regimen of 150 mg twice daily for 2 weeks is recommended and this can be repeated in patients in whom the initial symptomatic response is inadequate.
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 12 weeks if necessary.
In patients with moderate to severe oesophagitis, the dosage of ranitidine may be increased to 150 mg 4 times daily for up to 12 weeks. The increased dose has not been associated with an increased incidence of unwanted effects.
Zollinger-Ellison syndrome:
The initial dosage regimen for Zollinger-Ellison syndrome is 150 mg three times daily, but this may be increased as necessary. Doses up to 6 grams per day have been well tolerated.
Chronic episodic dyspepsia:
The standard dosage regimen for patients with chronic episodic dyspepsia is 150 mg twice daily for up to 6 weeks. Anyone not responding or relapsing shortly afterwards should be investigated.
Prophylaxis of haemorrhage from stress ulceration in seriously ill patients or prophylaxis of recurrent haemorrhage in patients bleeding from peptic ulceration:
150 mg twice daily may be substituted for the injection once oral feeding commences.
Prophylaxis of Mendelson's syndrome:
150 mg 2 hours before anaesthesia, and preferably 150 mg the previous evening. Alternatively, the injection is also available. In obstetric patients in labour 150 mg every 6 hours, but if general anaesthesia is required it is recommended that a non-particulate antacid (e.g. sodium citrate) be given in addition.
Children 12 years and over
For children 12 years and over the adult dosage is given.
Children from 3 to 11 years and over 30 kg of weight
See section 5.2 Pharmacokinetic properties (Other special populations)
Patients over 50 years of age
See Section 5.2 Pharmacokinetic Properties (Other special 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).
Neonates
Safety and efficacy in new-born patients has not been established.
Patients with renal impairment
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.
Method of administration
For oral administration. See section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Malignancy
The possibility of malignancy should be excluded before commencement of therapy in patients with gastric ulcer and in 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 renal impairment.
The dosage should be adjusted as detailed in section 4.2 Patients with renal impairment.
Regular supervision of patients who are taking non-steroidal antiinflammatory 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.
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). Post-marketing data indicate reversible mental confusion, depression, and hallucinations have been reported most frequently in severely ill and elderly patients (see section 4.8).
Zantac Effervescent Tablets contain sodium (see section 2 and 6.1). Care should therefore be taken in treating patients in whom sodium restriction is indicated.
Zantac Effervescent Tablets contain aspartame. They should be used with caution in patients with phenylketonuria.
4.5 Interaction with other medicinal products 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, 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 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 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).
There is no evidence of an interaction between ranitidine and amoxicillin or metronidazole.
If high doses (2 g) 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.
4.6 Fertility, pregnancy and lactation
Pregnancy
Ranitidine crosses the placenta.
Like other drugs, ranitidine should only be used during pregnancy if considered essential.
Breast-feeding
Ranitidine is excreted in human breast milk. Like other drugs, ranitidine should only be used during breast-feeding if considered essential.
Fertility
There are no data on the effects of ranitidine on human fertility. There were no effects on male and female fertility in animal studies (see section 5.3).
4.7 Effects on ability to drive and use machines
None reported.
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). Adverse event frequencies have been estimated from spontaneous reports from post-marketing data.
Blood & Lymphatic System Disorders
Very Rare:
Blood count changes (leucopenia, thrombocytopenia). These are usually reversible. Agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or marrow aplasia.
Immune System Disorders
Rare:
Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension and chest pain).
Very Rare:
Anaphylactic shock.
Not known:
Dyspnoea.
These events have been reported after a single dose.
Psychiatric Disorders
Very Rare:
Reversible mental confusion, depression and hallucinations.
These have been reported predominantly in severely ill patients, in elderly and in nephropatic patients.
Nervous System Disorders
Very Rare:
Headache (sometimes severe), dizziness and reversible involuntary movement disorders.
Eye Disorders
Very Rare:
Reversible blurred vision.
There have been reports of blurred vision, which is suggestive of a change in accommodation.
Cardiac Disorders
Very Rare:
As with other H2 receptor antagonists bradycardia, A-V block and tachycardia.
Vascular Disorders
Very Rare:
Vasculitis.
Gastrointestinal Disorders
Uncommon:
Abdominal pain, constipation, nausea (these symptoms mostly improved during continued treatment).
Very Rare:
Acute pancreatitis, diarrhoea
Hepatobiliary Disorders
Rare:
Transient and reversible changes in liver function tests.
Very Rare:
Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, these were usually reversible.
Skin and Subcutaneous Tissue Disorders
Rare:
Skin Rash.
Very Rare:
Erythema multiforme, alopecia.
Musculoskeletal and Connective Tissue Disorders
Very Rare:
Musculoskeletal symptoms such as arthralgia and myalgia.
Renal and Urinary Disorders
Rare:
Elevation of plasma creatinine (usually slight; normalised during continued treatment)
Very Rare:
Acute interstitial nephritis.
Reproductive System and Breast Disorders
Very Rare:
Reversible impotence, breast symptoms and breast conditions (such as gynaecomastia and galactorrhoea).
Paediatric population
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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose
Symptoms and signs
Ranitidine is very specific in action and accordingly no particular problems are expected following overdosage with the drug. Clinicians should be aware of the sodium content (see section 4.4 Special warnings and precautions for use).
Treatment
Symptomatic and supportive therapy should be given as appropriate.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: H2-receptor antagonists ATC code: A02BA02
Mechanism of action
Ranitidine 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. Ranitidine has a relatively long duration of action and so a single 150 mg dose effectively suppresses gastric acid secretion for twelve hours.
5.2 Pharmacokinetic properties
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.
Other special populations Children (3 years and above)
Limited pharmacokinetic data have shown that there is 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.
5.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Monosodium Citrate Anhydrous
Sodium Bicarbonate
Aspartame
Povidone
Sodium Benzoate
Orange Flavour (IFF No. 6)
Grapefruit Flavour (IFF 18C 222)
Pharmaceutical Industrial Alcohol or Ethanol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store below 30°C in a dry place.
6.5 Nature and contents of container
Polypropylene tubes with polyethylene tamper evident cap, each tube contains 15 tablets packed in cartons of 15 or 60 tablets.
Aluminium foil strips of six tablets packed in cartons of 6 or 30 tablets.
6.6 Special precautions for disposal
No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Place the tablets in half a glass of water (minimum 75 ml) and allow to dissolve completely before swallowing.
7 MARKETING AUTHORISATION HOLDER
Glaxo Wellcome UK Limited
trading as GlaxoSmithKline UK
Stockley Park West
Uxbridge
Middlesex
UB11 1BT
8 MARKETING AUTHORISATION NUMBER(S)
PL 10949/0137
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28 April 2002
10 DATE OF REVISION OF THE TEXT
13/10/2015