Ranitidine 300mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ranitidine 300mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Ranitidine hydrochloride equivalent to Ranitidine 300 mg.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Oblong, biconvex, white to yellowish film-coated biconvex tablet. Tablet size:
8.2 x 17mm.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Adults
Ranitidine tablets are indicated in the treatment of ulcers of the duodenum and of benign gastric ulcers, including those associated with use of non-steroidal anti-inflammatory agents (NSAID’s) and/or prevention of NS AID induced duodenal ulcers.
Ranitidine tablets may also be used in conditions where reduction of gastric secretion and acid output may be beneficial, such as: prophylaxis of gastrointestinal haemorrhage arising from stress ulceration in seriously ill patients; prophylaxis of recurring haemorrhage associated with bleeding peptic ulcers; before general anaesthesia in patients considered to be at risk of acid aspiration (Mendelson’s syndrome) for example in obstetric patients during labour.
Other indications include the treatment of Zollinger-Ellison syndrome, gastro-oesophageal reflux disease (including the long-term management of healed oesophagitis) and post-operative ulcer. Patients with chronic episodic dyspepsia, characterised by pain (epigastric or retrosternal) which disturbs sleep or is related to meals but is not associated with the preceding conditions may also benefit from treatment with Ranitidine.
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 and older people Treatment of ulcers
The normal starting dose for Ranitidine is 150 mg twice daily, morning and evening. Absorption is not affected by the presence of food.
Patients with duodenal ulceration, gastric ulceration or gastro-oesophageal reflux disease may be treated with a single dose of 300 mg at bedtime. In duodenal ulcer it has been reported that use of 300 mg twice daily for 4 weeks results in healing rates which are higher than those at 4 weeks with ranitidine 150mg twice daily or 300 mg nocte without an associated increase in the incidence of adverse reactions.
In most cases of duodenal ulcer, benign gastric ulcer and post-operative ulcer, healing occurs in four weeks. A further four week course of treatment may be necessary in those patients whose ulcers have not fully healed after the initial course of therapy; healing normally takes place following the second course of treatment.
NSAID associated ulcers
In ulcers following NSAID therapy or associated with continued NSAID’s, eight weeks’ treatment may be necessary to induce healing.
For the prevention of NSAID associated duodenal ulcers, Ranitidine 150mg twice daily may be given with NSAID therapy.
Maintenance treatment of ulcers
Maintenance treatment at a reduced dosage of 150 mg at bedtime is recommended for patients who have responded to short-term therapy, particularly those with a history of recurrent ulcer.
Oesophageal Reflux Disease
In the management of oesophageal reflux disease, the recommended course of treatment is either 150 mg twice daily or 300mg at bedtime for up to 8 or 12 weeks.
In patients with moderate to severe gastro-oesophagitis, the dosage of ranitidine may be increased to 150 mg four times daily for up to twelve weeks. The increased dose has not been associated with an increased incidence of adverse reactions.
The recommended adult oral dose is 150 mg twice daily for the long-term treatment of healed oesophagitis. Long-term treatment is not indicated in the management of patients with unhealed oesophagitis.
Mendelson’s Syndrome
Ranitidine tablets 150 mg can be given orally 2 hours before induction of general anaesthesia, and if possible, an additional dose of 150 mg the previous evening, in patients regarded to be at risk of acid aspiration syndrome.
At onset of labour, an oral dose of 150 mg of ranitidine may be given to obstetric patients followed by a further 150 mg every six hours. Since gastric emptying and drug absorption are delayed during labour, it is recommended that any patient requiring emergency general anaesthesia should also be given a non-particulate antacid (e.g. sodium citrate) prior to induction of anaesthesia. The usual precautions to avoid acid aspiration should also be taken.
Zollinger-Ellison syndrome
In patients with Zollinger-Ellison syndrome, the recommended starting dose is 150 mg three times daily, which may be increased as necessary. Doses increasing to 6 g per day have been used in patients with this syndrome and it has been reported that these doses have been well tolerated.
Chronic episodic dyspepsia
The recommended course of treatment in such cases is 150 mg twice daily for up to six weeks. Further investigations should be carried out in nonresponding patients.
Paediatric population
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.
Method of administration
Oral
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
Treatment with a histamine H2-antagonist may mask the symptoms associated with carcinoma of the stomach and may therefore delay diagnosis of the condition. Where gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with ranitidine is started.
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 Posology and Method of Administration.
Although clinical reports of acute intermittent porphyria associated with ranitidine administration have been rare and inconclusive, ranitidine should be avoided in patients with a history of this condition.
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 H2 receptor antagonists 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 Undesirable effects).
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 blood levels produced by standard doses, does not inhibit or interact significantly with the hepatic cytochrome P450-linked mixed function oxygenase system.
Accordingly, ranitidine in usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme system. These include 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).
Oral Formulations
There is no evidence of an interaction between ranitidine and metronidazole and amoxycillin. 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 h.
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.
Breast-feeding
Like other drugs ranitidine should only be used during pregnancy or lactation if considered essential by a physician.
Ranitidine is also excreted in human breast milk.
Fertility
There is no data on the effects of ranitidine on human fertility. There were no effects on male and female fertility in animal studies.
4.7 Effects on ability to drive and use machines
Ranitidine may cause dizziness and the patient should be warned not to drive or to operate machinery if affected.
4.8 Undesirable effects
The following convention has been utilised for the classification of undesirable effects: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <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 post-marketing data.
Blood and 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 and asystole.
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 galactorrhea).
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 Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
Symptoms
Ranitidine is very specific in action and accordingly, no particular problems are expected following overdosage with the drug.
Management
Symptomatic and supportive therapy should be given as appropriate.
Ranitidine may be removed by haemodialysis.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: H2 receptor antagonists,
ATC code: A02B A02
Mechanism of action
Ranitidine is a specific, rapidly acting histamine H2 -antagonist. It inhibits basal and stimulated secretion of gastric acid, thereby reducing both the volume and the acid and pepsin content of the gastric secretions.
The clinical data available mentions the use of ranitidine in children to prevent stress ulcers. No direct evidence for prevention of stress ulcers is available. Treatment for these patients is based on the observation that pH is above 4 after administration of ranitidine. The value of this surrogate parameter in children with stress ulcers remains to be established.
5.2. Pharmacokinetic properties
Absorption
Absorption of ranitidine after oral administration is rapid and peak plasma concentrations are usually achieved 2-3 hours after administration. Absorption is not significantly impaired by food or antacids. Oral bioavailability is approximately 50%.
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 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 - 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. Pre-clinical 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
Croscarmellose sodium Magnesium stearate Microcrystalline cellulose Hydroxypropylmethylcellulose Titanium dioxide Talc
Polyethylene glycol 6000
Polymethylmethacrylic acid copolymer (Eudragit E)
6.2. Incompatibilities
None known.
6.3. Shelf Life
2 years (unopened).
6.4. Special precautions for storage
Store below 25°C in a dry place.
6.5. Nature and Contents of Container
Carton of 30 tablets, packed in A1/A1 blisters.
6.6. Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd
No. 1 Croydon,
12-16 Addiscombe Road,
Croydon CR0 0XT, UK
8. MARKETING AUTHORISATION NUMBER(S)
PL 12762/0012
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
27 October 1997
10 DATE OF REVISION OF THE TEXT
27/05/2015