Ranitidine Tablets 300mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ranitidine Tablets 300mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Ranitidine hydrochloride equivalent to Ranitidine 300mg.
3 PHARMACEUTICAL FORM
Film coated tablets:
Oblong, biconvex, white to yellowish film coated tablets with R2 debossed on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Ranitidine tablets are used for the treatment of conditions where reduction of gastric secretions and acid output are required. Ranitidine tablets may be used for treating:
Duodenal ulcers including duodenal ulcers associated with Helicobacter pylori infection.
Benign gastric ulcers.
Ulcers associated with non-steroidal anti-inflammatory drug (NSAID) therapy and the prophylaxis of duodenal ulcers associated with NSAIDS.
Oesophageal reflux disease and its long-term management.
Zollinger-Ellison syndrome.
Ranitidine tablets may also be useful in management of patients with:
Chronic dyspepsia, characterised by retrosternal or epigastric pain not associated with conditions above, but which is related to meals and disturbed sleep.
Serious illness who are liable to suffer from stress ulceration.
Bleeding peptic ulcers to prevent haemorrhage.
Ranitidine may also be of value before general anaesthesia in patients thought to be at risk of acid aspiration (Mendelson’s syndrome) particularly in obstetric patients.
Children (3 to18 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
For oral administration only.
Adults:
The normal dose is 150mg twice daily. As an alternative, 300mg can be given as a single dose at bedtime. In patients with duodenal ulcers, 300mg ranitidine given twice daily achieves a more rapid rate of healing without increasing the frequency of side effects. Healing of ulcers is usually achieved after four weeks’ treatment but a further four weeks may be required in some patients. In patients with ulcers resulting from NSAIDs, treatment may need to continue for eight weeks.
Prevention of duodenal ulcers associated with NS AID treatment: 150mg ranitidine twice daily during NSAID therapy.
Duodenal ulcers associated with Helicobacter pylori: The normal dose of ranitidine (150mg twice daily or 300mg at night) should be given together with amoxycillin 750mg three times daily and metronidazole 500mg three times daily for a period of two weeks. Ranitidine therapy should be continued for another two weeks.
Maintenance treatment: 150mg at bedtime in patients who have responded to short-term therapy, especially those with a history of recurrent ulcer.
Oesophageal reflux disease: The usual dose is 150mg twice daily or 300mg at bedtime continued for 8 to 12 weeks. The dose can be increased to 150mg four times daily in patients with moderate to severe oesophagitis and the dose continued for up to 12 weeks. Long-term maintenance in patients with healed oesophagitis is 150mg twice daily. Ranitidine is not recommended for longterm treatment of patients with unhealed oesophagitis or Barrett’s epithelium.
Zollinger-Ellison syndrome: The initial dose is 150mg three times daily and this can be increased if required: up to 6g daily has been tolerated.
Chronic episodic dyspepsia: 150mg twice daily for up to six weeks. Patients who do not respond or who relapse soon after such a course should be investigated.
Prevention of Mendelson’s Syndrome: 150mg two hours before induction of anaesthesia can be given to patients considered to be at risk from acid aspiration. An additional dose of 150mg given the night before anaesthesia is desirable. In obstetric patients during labour, 150mg given at six-hourly intervals is recommended. Because gastric emptying may be delayed during labour, it is also recommended that patients needing emergency anaesthesia be given a non-particulate antacid and the standard precautions to prevent inhalation of gastric contents must also be taken.
In the prevention of stress ulceration in seriously ill patients and recurrent haemorrhage in patients with bleeding ulcers: When oral administration is appropriate 150mg twice daily may be given.
Patients with severe renal impairment: 150mg at bedtime for four to eight weeks. This dosage should be used for maintenance treatment if necessary. If an ulcer has not healed after treatment the standard dosage regimen of 150mg twice daily should be used, followed if necessary by maintenance treatment of 150mg at night.
Elderly:
It is reported that the healing rates of ulcers in patients ages 65 and over have not been found to differ from those of younger patients. In addition there was no difference in the incidence of adverse effects.
Children 12 years and over
For children 12 years and over the adult dosage is given.
Peptic ulcer: 2mg/kg to 4mg/kg twice daily to maximise of 300mg daily.
Children from 3 to 11 years and over 30kg 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 4mg/kg/day to 8mg/kg/day administered as two divided doses to a maximum of 300mg 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 5mg/kg/day to 10mg/kg/day administered as two divided doses in a maximum dose of 600mg (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.
4.3 Contraindications
Ranitidine is contra-indicated in patients known to have hypersensitivity to ranitidine and any of the other excipients present in the tablet.
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 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 renal impairment. The dosage should be adjusted as detailed in section 4.2 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.
Use in elderly patients:
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). Postmarketing data indicate reversible mental confusion, depression, and hallucinations have been reported most frequently in severely ill and elderly patients (see section 4.8).
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, 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 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.
4.6 Pregnancy and lactation
It is known that ranitidine crosses the placenta. Therapeutic doses of ranitidine administered to obstetric patients in labour or undergoing caesarean section have not led to adverse effects on labour, delivery or subsequent neonatal progress. Ranitidine is also excreted in human breast milk.
Like other drugs it should only be used during pregnancy and nursing if considered essential.
4.7 Effects on ability to drive and use machines
Patients should be warned to avoid driving or operating machinery if they experience dizziness when taking ranitidine.
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 (i 1/1000, < 1/100), rare (^ 1/10,000, ^ 1/1000), very rare (i 1/10,000), unknown (cannot be estimated from the available 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.
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 and elderly patients. Nervous System Disorders
Very rare: Headache (sometimes severe), dizziness 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 and A-V Block. Vascular Disorders
Very rare: Vasculitis.
Gastrointestinal Disorders
Very rare: Acute pancreatitis, diarrhoea.
Uncommon: abdominal pain, constipation, nausea (these symptoms mostly improved during continued treatment).
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 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 and breast conditions (such as gynaecomastia and galactorrhoea).
The exact relationship between side effects reported to occur and ranitidine treatment has not been established in many cases.
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 even 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.
Overdose
4.9
Ranitidine is very specific in action and accordingly no particular problems are expected following overdosage. Symptomatic and supportive therapy should be given as appropriate.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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 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 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.
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 - 22ml/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
There are no reports of tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to 2,000mg/kg per day. Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for mutagenicity at concentrations up to the maximum recommended for these assays.
In a dominant lethal assay, a single oral dose of 1,000mg/kg to male rats was without effect on the outcome of two matings per week for the next nine weeks.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Croscarmellose sodium, magnesium stearate, microcrystalline cellulose, hypromellose, titanium dioxide, talc, macrogol 6000, polymethylacrylate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package.
6.5 Nature and contents of container
The tablets are packed in Aluminium/Aluminium blisters.
Pack sizes: 7, 14, 15, 20, 21, 28, 30, 56, 60, 84, 90, 100, 112, 120, 168 and 240.
The blister strips are packed in cartons.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Ennogen Pharma Limited Unit G4,
Riverside Industrial Estate,
Riverside Way,
Dartford DA1 5BS UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 40147/0077
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
11 July 2001
10 DATE OF REVISION OF THE TEXT
23/01/2013