Ranitidine 50mg/2ml Solution for Injection and Infusion

Each one ml of solution contains 25mg ranitidine as ranitidine hydrochloride. Each 2ml ampoule contains 50mg ranitidine.

For a full list of excipients, see section 6.1.

Solution for Injection and Infusion

Clear, colourless solution.

Ranitidine Solution for Injection is indicated for the treatment of duodenal ulcer, benign gastric ulcer, post - operative ulcer, and of Zollinger - Ellison Syndrome.

In the management of conditions where reduction of gastric secretion and acid output is desirable, such as reflux oesphagitis.

As prophylaxis against:

• gastrointestinal haemorrhage from stress ulceration in seriously ill patients

• recurrent haemorrhage in patients with bleeding peptic ulcers

• acid aspiration (Mendelson's Syndrome) before anaesthesia in patients at risk, particularly obstetric patients during labour.

Children (6 months 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.

For intravenous or intramuscular injection or, after dilution, for intravenous infusion. Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.

Adults (including elderly) and adolescents (12 years and older)

Ranitidine Solution for Injection may be given as:

• a slow intravenous injection (over at least two minutes) of 50 mg, after dilution to a volume of 20 ml per 50 mg dose. This dose may be repeated every six to eight hours

• an intermittent intravenous infusion at a rate of 25 mg per hour for two hours. The infusion may be repeated at six to eight hour intervals

• an intramuscular injection of 50 mg (2ml) every six to eight hours.

In the prophylaxis of haemorrhage from stress ulceration in seriously ill patients or the prophylaxis of recurrent haemorrhage in patients bleeding from peptic ulceration, parenteral administration may be continued until oral feeding commences. Patients considered to be still at risk may then be treated orally with tablets 150 mg twice daily.

In the prophylaxis of upper gastro-intestinal haemorrhage from stress ulceration in seriously ill patients a priming dose of 50 mg as a slow intravenous injection followed by a continuous intravenous infusion of 0.125 - 0.250 mg/kg/hr may be preferred.

In patients considered at risk of developing acid aspiration (Mendelson's) syndrome, Ranitidine Solution for Injection 50 mg may be given intramuscularly or by slow intravenous injection (over 2 minutes), 45 to 60 minutes before induction of general anaesthesia.

Children (6 months to 11 years)

See section 5.2 Pharmacokinetic Properties – Special Patient Populations

Ranitidine Injection may be given as a slow (over 2 minutes) i.v. injection up to a maximum of 50mg every 6 to 8 hours.

Peptic Ulcer Acute Treatment and Gastro-Oesophageal Reflux

Intravenous therapy in children with peptic ulcer disease is indicated only when oral therapy is not possible.

For acute treatment of peptic ulcer disease and gastro-oesophageal reflux in paediatric patients, Ranitidine injection may be administered at doses that have been shown to be effective for these diseases in adults and effective for acid suppression in critically ill children. The initial dose (2.0 mg/kg or 2.5 mg/kg, maximum 50 mg) may be administered as a slow intravenous infusion over 10 minutes, either with a syringe pump followed by a 3 ml flush with normal saline over 5 min, or following dilution with normal saline to 20 ml. Maintenance of pH> 4.0 can be achieved by intermittent infusion of 1.5 mg/kg every 6 h to 8 h. Alternatively treatment can be continuous, administering a loading dose of 0.45 mg/kg followed by a continuous infusion of 0.15 mg/kg/hr.

Prophylaxis of stress ulceration in seriously ill patients

The recommended dose for prophylaxis of stress ulceration is 1mg/kg (maximum 50 mg) every 6h to 8h.

Alternatively treatment can be continuous, administering 125 - 250 micrograms/kg/hr as continuous infusion.

Neonates (under 1 month)

See Section 5.2 Pharmacokinetic Properties – Special Patient Populations.

Renal Impairment

Accumulation of ranitidine with resulting elevated plasma concentrations will occur in patients with severe renal impairment (creatinine clearance less than 50ml/min). It is recommended in such patients that Ranitidine Solution for Injection be administered in doses of 25mg.

Hypersensitivity to the active substance(s) or to any of the excipients.

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 severe renal impairment. The dosage should be adjusted as detailed in Section 4.2 Posology and Method of Administration.

Asystole and bradycardia in association with rapid administration of ranitidine has been reported rarely, usually in patients with factors predisposing to cardiac rhythm disturbances. Recommended rates of administration should not be exceeded.

It has been reported that the use of higher than recommended doses of intravenous H₂-antagonists has been associated with rises in liver enzymes when treatment has been extended beyond five days.

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 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).

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; these include 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).

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. Ranitidine is also excreted in human breast milk. Like other drugs, ranitidine should only be used during pregnancy or lactation if considered essential by a physician.

None known.

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), unknown (cannot be estimated from the available data).

Blood & Lymphatic System Disorders

Unknown: Blood count changes (leucopenia, thrombocytopenia). These are usually reversible. Agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or marrow aplasia.

Immune System Disorders

Uncommon: Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension and chest pain).

Unknown: Anaphylactic shock

These events have been reported after a single dose.

Psychiatric Disorders

Very Rare: Depression.

Unknown: Reversible mental confusion and hallucinations.

These have been reported predominantly in severely ill and elderly patients.

Nervous System Disorders

Common: Headache (sometimes severe) and dizziness..

Unknown: Reversible involuntary movement disorders

Eye Disorders

Uncommon: Reversible blurred vision.

There have been reports of blurred vision, which is suggestive of a change in accommodation.

Cardiac Disorders

Unknown: As with other H₂ receptor antagonists bradycardia and A-V Block.

Vascular Disorders

Unknown: Vasculitis.

Gastrointestinal Disorders

Common: Diarrhoea.

Unknown: Acute pancreatitis.

Hepatobiliary Disorders

Very Rare: Transient and reversible changes in liver function tests.

Unknown: Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, these were usually reversible.

Skin and Subcutaneous Tissue Disorders

Uncommon: Skin Rash.

Unknown: Erythema multiforme, alopecia.

Musculoskeletal and Connective Tissue Disorders

Unknown: Musculoskeletal symptoms such as arthralgia and myalgia.

Renal and Urinary Disorders

Unknown: Acute interstitial nephritis.

Reproductive System and Breast Disorders

Unknown: Reversible impotence. Breast symptoms and breast conditions (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.

Ranitidine is very specific in action and accordingly, no particular problems are expected following overdosage with the drug. Symptomatic and supportive therapy should be given as appropriate. Ranitidine may be removed by haemodialysis.

Pharmacotherapeutic group: drugs for peptic ulcer and gastro-oesophageal reflux disease. H₂– receptor antagonist.

ATC code: A02B A02

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.

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 below 4 after administration of ranitidine. The value of this surrogate parameter in children with stress ulcers remains to be established.

Absorption of ranitidine after intramuscular injection is rapid and peak plasma concentrations are usually achieved within 15 minutes of administration. Ranitidine is not extensively metabolised. The elimination of the drug is primarily by tubular secretion. The elimination half-life of ranitidine is 2-3 hours. In studies with 150mg 3H-ranitidine, 93% of an intravenous dose was excreted in urine and 5% in faeces. Analysis of urine excreted in the first 24 hours after dosing showed that 70% of the intravenous dose was eliminated unchanged. About 6% of the dose is excreted in the urine as the N-oxide, 2% as desmethyl ranitidine and 1-2% as the furoic acid analogue.

Special Patient Populations

Children/infants (6 months and above)

Limited pharmacokinetic data show that there were 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 intravenous ranitidine when correction is made for body weight. Pharmacokinetic data in infants is extremely limited but appears to be in line with that for older children.

Neonates (under 1 month)

Limited pharmacokinetic data from term babies undergoing treatment with Extracorporeal Membrane Oxygenation (EMCO) suggests that plasma clearance following iv administration may be reduced (1.5-8.2 ml/min/kg) and the half-life increased in the new-born. Clearance of ranitidine appeared to be related to the estimated glomerular filtration rate in the neonates.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Potassium dihydrogen phosphate

Disodium hydrogen phosphate dihydrate

Sodium chloride

Water for Injections

None

2 years

Do not store above 25°C. Keep ampoules in the outer carton in order to protect from light.

2 ml solution in amber, type 1 glass ampoules.

Pack size: 5 ampoules

Ranitidine Injection has been shown to be compatible with the following intravenous infusion fluids:

Sodium Chloride 0.9% w/v

Dextrose 5% w/v

Sodium Chloride 0.18% w/v and Dextrose 4% w/v

Sodium Bicarbonate 4.2% w/v

Hartmann's solution

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless preparation of solutions has taken place in controlled and validated aseptic conditions.

All solutions of Ranitidine Solution for Injection should be discarded after use.

Beacon Pharmaceuticals Ltd

85 High Street

Tunbridge Wells

Kent TN1 1YG

UK

PL 18157/0019

21 October 2008

01 September 2010