Ranitidine 300mg Tablets
1 NAME OF THE MEDICINAL PRODUCT
Ranitidine 300mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 300mg of ranitidine (as hydrochloride)
Excipients with known effect: Each tablet contains 3.00mg of lactose (as lactose monohydrate).
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Film coated tablet
White, oblong film coated tablet with an approximate diameter of 17mm x 7mm x 5mm with score notch on both side
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults
- Treatment of duodenal and benign gastric ulcer, including those associated with nonsteroidal anti-inflammatory agents
- Prevention of non- steroidal anti-inflammatory drug (NSAID) (including aspirin)-associated duodenal ulcers especially in patients with a history of peptic ulcer disease.
- Treatment of duodenal ulcers associated with Helicobacter pylori infection
- Treatment of post-operative ulcers
- Treatment of Zollinger-Ellison syndrome
- Treatment of oesophageal reflux disease including the long-term management of healed oesophagitis
- Treatment of chronic episodic dyspepsia, characterised by pain (epigastric or retrosternal) which is related to meals or disturbs sleep, but is not associated with the preceding conditions
- For symptomatic relief in gastro-oesophageal reflux disease.
- For reduction of gastric secretion and acid output in the following cases:
- prophylaxis of gastrointestinal haemorrhage from stress ulceration in seriously ill patients
- prophylaxis of recurrent haemorrhage in patients with bleeding peptic ulcers and before general anaesthesia in patients considered to be at risk of acid aspiration (Mendelson’s syndrome), particularly in obstetric patients during labour
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 older people)
The usual dosage is 150mg twice daily, taken in the morning and evening.
Duodenal ulcer, gastric ulcer:
The standard dosage regimen is 150mg twice daily or 300mg at night. It is not necessary to time the dose in relation to meals.
In most cases of duodenal ulcer, benign gastric ulcer and post-operative ulcer, healing occurs within four weeks. Healing usually occurs after a further four weeks of treatment in those patients whose ulcers have not fully healed after the initial course of therapy.
Ulcer following NSAID therapy or associated with continued NSAIDs:
In ulcers following NSAIDs therapy or associated with continued NSAIDs, eight weeks treatment may be necessary.
Prevention of NSAID-associated duodenal ulcers:
For the prevention of NSAID-associated duodenal ulcers one Ranitidine 150mg Tablet twice daily may be given concomitantly with NSAID therapy.
In duodenal ulcer 300mg twice daily for 4 weeks results in healing rates which are higher than those at 4 weeks with ranitidine 150mg twice daily or 300mg at bedtime. The increased dose has not been associated with an increased incidence of unwanted effects.
Duodenal ulcer associated with Helicobacter pylori infection:
For duodenal ulcers associated with Helicobacter pylori infection one Ranitidine 150mg Tablet twice daily or one Ranitidine 300mg Tablet at bedtime may be given with oral amoxicillin 750mg three times daily and metronidazole 500mg 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.
Maintenance treatment at a reduced dosage of 150mg at bedtime is recommended for patients who have responded to short-term therapy, particularly those with a history of recurrent ulcer.
Gastro-oesophageal reflux disease:
In the management of oesophageal reflux disease, the recommended course of treatment is either 150mg twice daily or 300mg at bedtime for up to 8 weeks or, if necessary, 12 weeks.
In patients with moderate to severe oesophagitis, the dosage of ranitidine may be increased to 150mg four times daily for up to 12 weeks. The increased dose has not been associated with an increased incidence of unwanted effects.
Healed oesophagitis:
For the long-term treatment of healed oesophagitis, the recommended adult oral dose is 150mg twice daily. Long-term treatment is not indicated in the management of patients with unhealed oesophagitis, with or without Barrett’s epithelium.
Zollinger-Ellison syndrome:
In patients with Zollinger-Ellison syndrome, the starting dose is 150mg three times daily, and this may be increased as necessary. Patients with this syndrome have been given increasing doses up to 6g of ranitidine per day and these doses have been well tolerated.
Chronic episodic dyspepsia:
For patients with chronic episodic dyspepsia, the recommended course of treatment is 150mg twice daily for up to six 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:
In the prophylaxis of haemorrhage from stress ulceration in seriously ill patients, or prophylaxis of recurrent haemorrhage in patients bleeding from peptic ulceration, 150mg ranitidine twice daily may be substituted for ranitidine injection, once oral feeding commences in patients considered to be still at risk from these conditions.
Prophylaxis of acid aspiration (Mendelson ’s syndrome):
In patients thought to be at risk of acid aspiration syndrome, an oral dose of 150mg can be given two hours before induction of general anaesthesia, and preferably also 150mg the previous evening. Alternatively, the injection is also available.
In obstetric patients at commencement of labour, an oral dose of 150mg ranitidine may be given followed by 150mg at six-hourly intervals. It is recommended that since gastric emptying and drug absorption are delayed during labour, any patient requiring emergency general anaesthesia should be given, in addition, a non-particulate antacid (e.g. sodium citrate) prior to induction anaesthesia. The usual precautions to avoid acid aspiration should also be taken.
Paediatric population Children 12 years and over
For children 12 years and over the adult dosage is given.
Children (3 to 11 years) and over 30kg of weight See section 5.2 (Special Patient Population).
Patients over 50 years of age
See section 5.2 (Special Patient Population, Patients over 50 years of age).
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 to a maximum 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.
Renal Impairment:
Ranitidine is excreted via the kidney. Accumulation of ranitidine with resulting elevated plasma concentrations will occur in patients with renal impairment (creatinine clearance less than 50ml/min). Accordingly, it is recommended that the therapeutic regimen for ranitidine in such patients should be 150mg at night for 4 to 8 weeks. The same dose 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 instituted, followed, if need be, by maintenance treatment of 150mg at night.
Ranitidine has been used in patients with renal transplants.
Method of administration
The tablets are taken orally.
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 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 (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. Current evidence shows that ranitidine protects against NSAID-associated ulceration in the duodenum and not in the stomach.
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 older people:
Rates of healing of ulcers in clinical trial patients aged 65 and over have not been found to differ from those in younger patients. Additionally there was no difference in the incidence of adverse effects.
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 (H2 receptor antagonists) alone versus those who had stopped treatment, with an observed adjusted relative risk increase of 1. 82 (95% CI, 1. 26-2.648). 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).
Note: This preparation contains lactose as one of the excipients, so patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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, delavirdine, gefitinib).
There is no evidence of an interaction between ranitidine and amoxicillin or metronidazole If high doses (2g) 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, but therapeutic doses administered to obstetric patients in labour or undergoing caesarean section have been without any adverse effect on labour, delivery or subsequent neonatal progress. Like other drugs ranitidine should only be used during pregnancy if considered essential.
Breastfeeding
Ranitidine is also excreted in human breast milk. Like other drugs ranitidine should only be used during breastfeeding 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 the animal studies.
4.7 Effects on ability to drive and use machines
None known
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), not known (cannot be estimated from the available data). Adverse event frequencies have been estimated from spontaneous reports from postmarketing 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 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.
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.
Musculoskeletal and Connective Tissue Disorders
Very Rare: Musculoskeletal symptoms such as arthralgia, 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) in men.
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 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
Ranitidine is very specific in action and accordingly no particular problems are expected following overdosage , however a doctor should be consulted immediately.
Treatment
Symptomatic and supportive therapy should be given as appropriate.
The therapy is orientated to treating the symptoms of the overdose and to the clinical picture. In order to remove any tablet remains from the stomach the usual measures can be performed. If necessary, the patient can be connected to an artificial kidney (haemodialysis) in order to remove any absorbed active ingredient from the blood.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacodynamic group: H2-receptor antagonist
ATC code: A02BA
Ranitidine is a specific, rapidly acting histamine H2-receptor antagonist. It inhibits basal and stimulated secretion of gastric acid, reducing both the volume as well as the acid and pepsin content of the secretion.
Ranitidine has a relatively long duration of action and so a single 150mg dose effectively suppresses gastric acid secretion for twelve hours.
Clinical evidence has shown that ranitidine combined with amoxicillin and metronidazole eradicates Helicobacter pylori in approximately 90% of patients. This combination therapy has been shown to significantly reduce duodenal ulcer recurrence.
Helicobacter pylori infects about 95% of patients with duodenal ulcer and 80% of patients with gastric ulcer.
5.2 Pharmacokinetic properties Absorption
Absorption of 150mg ranitidine after oral administration is rapid and peak plasma concentrations (300-550ng/mL) are usually achieved within two hours of administration. Absorption is not significantly impaired by food or antacids. 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 concentration increases proportionally with increasing dose to 300mg.
Distribution
Ranitidine is not extensively bound to plasma proteins (15%), but exhibits a large volume of distribution ranging from 96 to 142L.
Metabolism
Ranitidine is not extensively metabolised. Its major metabolite is an N-oxide and there are smaller quantities of S-oxide and desmethyl ranitidine. 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 concentration decline bi-exponentially, with the elimination half-life of approximately 2-3 hours. Ranitidine is excreted via the kidneys mainly as the free drug and in minor amounts as metabolites. After IV administration of 150mg 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 500mL/ min, which exceeds glomerular filtration indicating net renal tubular secretion.
Children (3 years and above)
Limited pharmacokinetic data show that there are no significant differences in half-life (range for children 3 years and above: 1.7-2.2 hours) 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 hours) and clearance is reduced, consistent with age-related decline of renal function. However, systemic exposure and accumulation are 50% higher. The difference exceeds the effect of declining renal function, and indicates bioavailability in older patients.
5.3 Preclinical safety data
Toxicological studies have been performed with ranitidine in a number of species for which single and multiple doses were tested.
Long-term carcinogenicity studies in the rat and mouse gave no evidence for a tumorigenic potential.
There were no foetotoxic effects to rabbit or rat foetuses..
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.
However as with all medicines ranitidine should only be used during pregnancy or lactation if considered essential.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose
Calcium hydrogen phosphate dihydrate
Maize starch
Sodium starch glycollate (Type A)
Magnesium stearate Colloidal anhydrous silica Titanium dioxide E171 Lactose monohydrate Hypromellose Macrogol 4000
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25°C Store in the original container
6.5 Nature and contents of container
Aluminium/aluminium blisters Pack sizes 20, 30, 50, 100 tablets Not all packs sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd
3 Howard Road
Eaton Socon
St. Neots
Cambs
PE19 3ET
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0139
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 11/07/2000 Date of latest renewal: 08/09/2005
10 DATE OF REVISION OF THE TEXT
20/05/2016