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 300mg.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated Tablet
Creamish-yellow, round, biconvex, film-coated tablets marked with “MR 300” on one side.
4.1. Therapeutic Indications
Adults
Ranitidine tablets are indicated for the treatment of benign gastric ulcers and
duodenal ulcers, including that associated with non-steroidal 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. Post-operative ulcer.
Oesophageal reflux disease including long term management of healed oesophagitis. Symptomatic 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 gastrointestinal haemorrhage from stress ulceration in seriously ill patients
Prophylaxis of recurrent haemorrhage with bleeding peptic ulcers.
Before general anaesthesia in patients at risk of acid aspiration (Mendelson's syndrome), particularly obstetric patients during labour.
Ranitidine tablets are indicated for the long-term treatment of duodenal and benign gastric ulcers to prevent their recurrence. Long-term treatment is indicated in patients with a history of recurrent ulcers.
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 and adolescents (12 years and older)
The usual dose is 150 mg twice daily, taken in the morning and evening.
Duodenal ulcer, gastric ulcer:
The standard dosage regimen is 150 mg twice daily or 300 mg 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 4 weeks. Healing usually occurs after a further 4 weeks of treatment in those not fully healed after the initial course of therapy.
Ulcers following NSAID therapy or associated with continued NSAIDs:
8 weeks treatment may be necessary
Prevention of NSAID associated duodenal ulcers:
150 mg twice daily may be given concomitantly with NSAID therapy.
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 at night. The increased dose has not been associated with an increased incidence of unwanted effects.
Duodenal ulcers associated with Helicobacter pylori infection:
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.
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.
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
Oesophageal reflux disease:
For the management of reflux oesophagitis, the recommended dose is 150 mg twice daily or 300 mg at bedtime, usually for up to 8 weeks, this may be extended to a maximum of 12 weeks if necessary.
Moderate to severe Oesophagitis:
The dosage of ranitidine may be increased to 150 mg, four times a day for up to a maximum of 12 weeks. This raised level of dosing has not been associated with a raised level of side effects.
Healed oesophagitis:
For long term treatment, recommended adult dose is 150 mg twice daily. Long-term treatment in patients with unhealed oesophagitis is not indicated, either in the presence of Barrett’s epithelium or its absence.
Zollinger-Ellison Syndrome:
An initial dose of 150 mg, three times a day, may be increased up to 300 mg three times a day. Daily divided doses of up to 6g have been used and found to be 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 acid aspiration (Mendelson's) syndrome:
150 mg oral dose can be given 2 hours before anaesthesia, and preferably also 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. The usual precautions to avoid acid aspiration should also be taken.
Children 12 years and over
For children 12 years and over the adult dosage is given.
Patients over 50 years of age
See Section 5.2 Pharmacokinetic Properties (Special Patient Populations, Patients over 50 years of age)
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).
Neonates
Safety and efficacy in new-born patients has not been established.
Renal Impairment:
In patients with severe renal impairment, plasma levels of the drug are increased. The dose in such patients is 150 mg at night for 4-8 weeks. The same dose is used for maintenance. If healing has not occurred, 150 mg twice daily should be used, followed by 150 mg at night for maintenance.
|
Creatinine clearance mL/min. |
Dose of ranitidine |
|
<50 |
150 mg |
|
>50 |
300 mg |
Ranitidine is removed by hemodialysis. Dialysis patients should therefore take Ranitidine after each dialysis occasion.
Method of Administration
The tablet should be swallowed whole with a sufficient amount of fluid. In children the tablets may be dissolved in water or crushed. The application of a more convenient dosage form may be considered.
4.3. Contraindications
Hypersensitivity to ranitidine or any component of Ranitidine Tablets.
4.4. Special Warnings and Precautions for Use
Malignancy:
Treatment with histamine H2receptor antagonists may mask symptoms of stomach carcinoma and therefore delay its diagnosis of the condition. Accordingly, where gastric ulcer has been diagnosed , or in patients of middle age and over with new or recently changed dyspeptic symptoms the possibility of malignancy should be excluded before therapy with ranitidine Tablets is instituted
Renal disease:
Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment. The dose should be adjusted as detailed above under Dosage in Renal Impairment.
Regular supervision of patients who are taking non-steroidal anti-inflammatory drugs concomitantly with ranitidine is recommended, especially in the elderly. Current evidence shows that ranitidine protects against NSAID associated ulceration in the duodenum and not in the stomach.
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.
Use in elderly patients:
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 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). 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, 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 secrection:
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 Fertility, pregnancy and lactation
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. It is excreted in human breast milk.
Like other drugs it should only be used during pregnancy and nursing if considered essential.
There are no data on the effect 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
Not applicable.
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 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 and 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.
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 in men (such as gynaecomastia and galactorrhoea).
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
Ranitidine is very specific in action and accordingly no particular problems are expected following overdosage. Symptomatic and supportive therapy should be given as appropriate.
5.1. Pharmacodynamic Properties
Pharmacotherapeutic Group: H2-Receptor Antagonists-ATC Code: A02BA02
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 secretionRanitidine has a relatively long duration of action an so single 150mg dose effectively suppressing gastric acid secretion for 12 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 demthylranitidine 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 - 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.
PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
Microcrystalline cellulose; hypromellose; croscarmellose sodium; castor oil; colloidal anhydrous silica; purified talc; magnesium stearate; ferric oxide yellow (E172) ; titanium dioxide (E171).
6.2 Incompatibilities
None reported
6.3 Shelf Life
3 years
6.4 Special Precautions for Storage
Store in the original container
6.5 Nature and Contents of Container
Ranitidine Tablets are packed in cold-form blister sheets (structure from outer to inner side: oriented polyamide/aluminium foil/hard PVC film with a backing of aluminium foil coated with heat seal lacquer) in the following pack sizes:-
Blister sheets of five tablets each, in boxes of 5 tablets per carton.
Blister sheets of seven tablets each, in boxes of 7, 14, 28, 56, 98 and 112 tablets per carton.
Blister sheets of eight tablets each, in boxes of 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88 and 96 tablets per carton.
Blister sheets of ten tablets each, in boxes of 10, 20, 30, 50, 60, 80, 100 and 120 tablets per carton.
Blister sheets of fifteen tablets each, in boxes of 15, 30, 45, 60, 75, 90, 105 and 120 tablets per carton.
Blister sheets of thirty tablets each, in boxes of 30, 60, 90, 120 and 150 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
None.
7 MARKETING AUTHORISATION HOLDER
Milpharm Limited,
Ares,
Odyssey Business Park,
West End Road,
South Ruislip HA4 6QD,
United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 16363/0070
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
08/01/2009
07/04/2015