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2.      QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient(s) with known effect:

Disodium hydrogen phosphate dihydrate

Sodium chloride

.Each ampoule contains 0.55mg (0.014mmol) of Potassium and 2.23mg (0.097mmol) of Sodium.

4.      Clinical particulars

4.1    Therapeutic indications

Adults

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

4.2    Posology and method of administration

See section 5.2 Pharmacokinetic Properties – Special Patient Populations

Posology

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

Patients with Renal Impairment

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

MethodRoute of Administration

Intravenous or intramuscular injection

For instructions on dilution of the medicinal product before administration, see section 6.6

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.

Malignancy

The possibility of malignancy should be excluded before commencement of therapy in patients with gastric ulcer 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 Patients with Renal Impairment.Posology and Method of Administration.

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. Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks.  Ranitidine should therefore be avoided in patients with a history of acute porphyria

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 aloneof 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).

4.5        Interaction with other medicinal products and other forms of interaction

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 at usual therapeutic doses, does not potentiate the actions of drugs which are inactivated by this enzyme systems such as; 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.

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. 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. 

Breast-feeding

Ranitidine is also excreted in human breast milk.  Like other drugs, ranitidine should only be used during breast-feeding if considered essential.

Fertility

There are not data on the effects of ranitidine on human fertility. There were no effects on male and female fertility in animal studies (see section 5.3).

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), 

Aadverse event frequencies have been estimated from spontaneous reports from post-marketing data).

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.

4.9    Overdose

Treatment

Symptomatic and supportive therapy should be given as appropriate.  Ranitidine may be removed by haemodialysis.

5.      PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Mechanism of action

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.

Paediatric population

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        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

Potassium dihydrogen phosphate

Disodium hydrogen phosphate dihydrate

Sodium chloride

Water for Injections

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.None

10.    DATE OF REVISION OF THE TEXT

February 20156

4.2     Posology and method of administration

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.

See section 5.2 Pharmacokinetic Properties – Special Patient Populations

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) up to a maximum of 50 mg, after dilution to a volume of 20 ml per 50 mg dose.  This dose may be repeated every six 6 to eight 8 hours or 

·         As an intermittent intravenous infusion at a rate of 25 mg per hour for two hours.  The infusion may be repeated at six 6 to eight 8 hour intervals

·         As an intramuscular injection of 50 mg (2ml) every six 6 to eight 8 hours.

Prophylaxis of haemorrhage from stress ulceration or recurrent haemorrhage:

Patients considered to be still at risk may then be treated orally with Ranitidine tablets 150 mg twice daily.

Prophylaxis of Mendleson’s syndrome:

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.

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 ranitidine Solution for Injection be administered in doses of 25mg.

Route of Administration

Intravenous or intramuscular injection

4.3     Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4      Special warnings and precautions for use

Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment. 

Asystole and bradycardia Bradycardia in association with rapid administration of ranitidine injection has been reported rarely, usually in patients with factors predisposing to cardiac rhythm disturbances.

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 1.82 (95% CI, 1.26–2.64).1.63 (95% CI, 1.07–2.48). 

4.8      Undesirable effects

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2;  Tel: +353 1 6764971; Fax +353 1 6762517.  Website: www.hpra.ie, E-mail: medsafety@hpra.ie.

5.1     Pharmacodynamic properties

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

Treatment for these patients is based on the observation that pH is below above 4 after administration of ranitidine.

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipient(s) with known effect:

Disodium hydrogen phosphate dihydrate

Sodium chloride.

4.2     Posology and method of administration

Children / Infant (6 months to 11 years)

Patients over 50 years of age

See Section 5.2 Pharmacokinetic properties  (Special Patient Populations, Patients over 50   years of age).

4.4      Special warnings and precautions for use