Ranitidine 150mg/10ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ranitidine 150mg/10ml Oral Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 10ml contains 150mg Ranitidine as ranitidine hydrochloride.
The product also contains:
Sorbitol, liquid (non crystallising): 3000mg per 10ml Sodium: 19.28mg per 10ml Ethanol (96%): 800mg per 10ml For a full list of excipients, see 6.1.
3 PHARMACEUTICAL FORM
Oral Solution
Clear pale yellow liquid with an odour of peppermint.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
In adults Ranitidine 150mg/10ml Oral Solution is indicated for:
• the treatment of duodenal ulcer and benign gastric ulcer, including that associated with non-steroidal anti-inflammatory agents.
• the prevention of NSAID associated duodenal ulcers.
• the treatment of post-operative ulcer, Zollinger-Ellison Syndrome and oesophageal reflux disease including long term management of healed oesophagitis.
• Other patients with 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 may benefit from ranitidine treatment.
• the following conditions where reduction of gastric secretion and acid output is desirable; the prophylaxis of gastro-intestinal haemorrhage from stress ulceration in seriously ill patients, the 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 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.
See section 4.4. Special warnings and precautions for use.
4.2 Posology and method of administration
Adults
The usual dosage is 150mg twice daily, taken in the morning and evening. Alternatively, patients with duodenal ulceration, gastric ulceration or oesophageal reflux disease may be treated with a single bedtime dose of 300mg. It is not necessary to time the dose in relation to meals.
Duodenal ulcer, benign gastric ulcer and post-operative ulcer:
In most cases of duodenal ulcer, benign gastric ulcer and post operative ulcer, healing occurs in four weeks. Healing usually occurs after a further 4 weeks of treatment in those patients whose ulcers have not fully healed after the initial course of therapy.
NSAID associated peptic ulceration, including prophylaxis of duodenal ulcers:
In ulcers following non-steroidal anti-inflammatory drug therapy or associated with continued non-steroidal anti-inflammatory drugs, 8 weeks treatment may be necessary.
For the prevention of non-steroidal anti-inflammatory drug associated duodenal ulcers ranitidine 150mg twice daily may be given concomitantly with non-steroidal antiinflammatory drug 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 nocte. The increased dose has not been associated with an increased incidence of unwanted effects.
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 twelve weeks. The increased dose has not been associated with an incidence of unwanted effects.
For the long-term management of 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 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 or recurrent haemorrhage:
In the prophylaxis of haemorrhage from stress ulceration in seriously ill patients or in the prophylaxis of recurrent haemorrhage in patients bleeding from peptic ulceration, treatment with an oral dose of 150mg twice daily may be substituted for injections of ranitidine once oral feeding commences in patients considered to be still at risk from these conditions.
Prophylaxis of Mendelson ’s syndrome:
In patients thought to be at risk of acid aspiration syndrome an oral dose of 150mg can be given 2 hours before induction of general anaesthesia, and preferably also 150mg the previous evening.
In obstetric patients at commencement of labour, an oral dose of 150mg 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 of anaesthesia. The usual precautions to avoid acid aspiration should also be taken.
Patients over 50 years of age
See Section 5.2 Pharmacokinetic Properties (Special Patient Populations, Patients over 50 years of age)
Children 12 years and over
For children 12 years and over the adult dosage is given.
Children (3 to 11 years)
See section 5.2 Pharmacokinetic Properties - Special Patient Populations.
Ranitidine 150mg/10ml Oral Solution contains approximately 8% w/v ethanol. Therefore an alternative formulation of ranitidine may be considered necessary for at-risk groups, including children (see section 4.4 Special warnings and precautions for use).
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.
Renal Impairment
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 daily dose of ranitidine in such patients 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 at 150mg at night.
Method of administration
For oral administration.
4.3 Contraindications
Hypersensitivity to ranitidine hydrochloride 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 symptoms associated with carcinoma of the stomach and may therefore delay 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 Oral Solution is instituted.
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 antiinflammatory 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 acute porphyria.
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.
Ranitidine 150mg/10ml Oral Solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Ranitidine 150mg/10ml Oral Solution contains sodium. A dose of up to 150mg ranitidine contains less than 1mmol, essentially sodium free. A dose of 300mg ranitidine contains 39mg or 1.68mmol of sodium. Care should be taken with patients on a controlled sodium diet.
Ranitidine 150mg/10ml Oral Solution contains approximately 8% w/v ethanol (alcohol). Each 5ml of solution contains approximately 400mg of ethanol (96%), equivalent to 8ml of beer or 3ml of wine. High doses of Ranitidine Oral Solution, greater than 35ml (1,050mg ranitidine), contain more than 3g of alcohol. It is harmful for those suffering from alcoholism. It should be taken into account in pregnant or lactating women, high risk groups (those suffering from alcoholism, liver disease, epilepsy, brain injury or disease) and children (see section 4.2). Alternative formulations of ranitidine may be considered preferential in some populations. The amount of alcohol may modify or increase the effect of other medicines. The amount of alcohol in Ranitidine Oral Solution may impair the patient’s ability to drive or operate machinery (see section 4.7).
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).
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).
4.6 Fertility, pregnancy and lactation
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.
Pregnancy
Ranitidine crosses the placenta but therapeutic doses administered to obstetric patients in labour or undergoing caesarean section have been without any adverse effects on labour, delivery or subsequent neonatal progress. Like other drugs ranitidine should only be used during pregnancy if considered essential.
Lactation
Ranitidine is also excreted in human breast milk. Like other drugs ranitidine should only be used during nursing if considered essential.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
This medicinal product contains alcohol. Refer to section 4.4 for full details of its effects.
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 (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), 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
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 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 Oral Liquid is very specific in action and no particular problems are expected following overdosage with ranitidine.
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 H2-antagonist. It inhibits basal and stimulated secretion of gastric acid, reducing both the volume of the acid and pepsin content of the secretion. Ranitidine has a relatively long duration of action and a single 150mg dose effectively suppresses gastric acid secretion for twelve hours.
5.2 Pharmacokinetic properties
Following oral administration of 150mg ranitidine, maximum plasma concentrations (300 to 550ng/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 300mg.
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 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 150mg 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.
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 - 2.2h) 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
Sorbitol, liquid (non crystalising)
Ethanol (96%)
Disodium hydrogen phosphate dihydrate Sodium dihydrogen phosphate dihydrate Hydroxyethyl cellulose Peppermint flavour Saccharin sodium Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months
Use within 3 months of opening.
6.4 Special precautions for storage
Do not store above 25oC.
Store in original carton/bottle in order to protect from light.
6.5 Nature and contents of container
Amber Ph Eur type 3 glass bottle containing 300ml with child resistant, tamper-evident, polypropylene lid.
6.6 Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Focus Pharmaceuticals Ltd Capital House, 1st Floor,
85 King William Street,
London EC4N 7BL,
United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 20046/0046
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19/06/2012
10 DATE OF REVISION OF THE TEXT
01/10/2015