SPC 4.1 - amendment to name inline with EU QRD

SPC 4.2 -amendment to name inline with EU QRD

SPC 4.3 - deletion of text in reference to prophylaxis of stress ultceration in serioulsy ill patients

SPC 4.4 - addition of sodium free and potassium free statements

SPC 5.1 - admins change

SPC 6.5 - addition of pack size

SPC 9 -alignment to QRD

SPC 10 - addition of approval date

Change to address of the Irish MA Holder

Section 4.4: H2 receptor antagonists changed to ranitidine alone.
Section 4.5: Amended to include information on interaction between ranitidine and amoxicillin and metronidazole.
Section 4.8: Dyspnoea included as unknown adverse event under Immune System Disorders. Tachycardia added as very rare adverse event under Cardiac Disorders. Nephropatic patients referenced under Psychiatric Disorders. Paediatric subheading and adverse event reporting details included

4.3	Update to statement for hypersensitivity
4.4	Update to the warnings
4.5	Change to the information regarding one of the medicines that interacts
4.6	Rewording of this section

 

1. TRADE NAME OF THE MEDICINAL PRODUCT

 

Zantac Solution for Injection or Infusion 25mg/ml

 

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4.4 Special warnings and precautions for use

 

Asystole and Bradycardia in association with rapid administration of Zantac Injection has been reported rarely, usually in patients with factors predisposing to cardiac rhythm disturbances. Recommended rates of administration should not be exceeded.  The use of higher than recommended doses of intravenous H₂-antagonist has been associated with rises in liver enzymes when treatment has been extended beyond five days.

 

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.

 

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

 

 

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

 

Although no clear casual link has been established, 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). Therefore, in patients with conditions predisposing to the development of pneumonia, such as chronic lung disease, diabetes, or the immunocompromised, there may be an increased risk of developing community acquired pneumonia.

 

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 antagonistsranitidine alone versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.63 (95% CI, 1.07 – 2.48).1.82 (95% CI 1.26 – 2.64).

 

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4.6 Fertility, Ppregnancy and lactation

 

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4.8 Undesirable effects

 

 

Gastrointestinal Disorders

Very Rare:       Acute pancreatitis. Diarrhoea.

Uncommon:     Abdominal pain, constipation, nausea (these symptoms mostly improved during continued treatment).

 

 

Renal and Urinary Disorders

Very rare:        Acute interstitial nephritis.

Rare:                Elevation of plasma creatinine (usually slight; normalised during continued treatment).

 

Reproductive System and Breast Disorders

Very Rare:       Reversible impotence. Breast symptoms in men., breast symptoms and breast conditions (such as gynaecomastia and galactorrhoea).

 

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5.2 Pharmacokinetic properties

 

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.  Elimination of the drug is primarily by tubular secretion.  The elimination half-life is 2-3 hours. 

 

In balance studies with 150mg ³H-ranitidine 93% of an intravenous dose was excreted in urine and 5% in faeces: 60-70% of an oral dose was excreted in urine and 26% in faeces.  Analysis of urine excreted in the first 24 hours after dosing showed that 70% of the intravenous dose and 35% of the oral dose were eliminated unchanged. The metabolism of ranitidine is similar after both oral and intravenous dosing; about 6% of the dose being excreted in urine as the N-oxide, 2% as S-oxide, 2% as desmethylranitidine and 1-2% as the furoic acid analogue.

 

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 a 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 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 i.v. 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 tubular secretion.

 

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4. CLINICAL PARTICULARS

 

4.1 Therapeutic indications

 

Zantac is used in the treatment of benign ulceration of the oesophagus, stomach, upper intestinal tract (including post-operative stomal area), and of the Zollinger-Ellison syndrome.

 

In the management of conditions benefiting from reduced gastric acid secretion, such as reflux oesophagitis.

 

As prophylaxis against:

(i)         acid aspiration (Mendelson’s) syndrome

(ii)        stress lesions of the upper gastrointestinal tract.

(iii)       recurrent haemorrhage from the upper gastrointestinal tract.

 

Children (6 months to 18 years)

o   Short term treatment of peptic ulcer

o   Treatment of gastro-oesophageal reflux, including reflux oesophagitis and symptomatic relief of gastro-oesophageal reflux disease.

 

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4.2 Posology and method of administration

 

Adults: Adults (including the elderly) / Adolescents (12 years and over)

 

Zantac Injection may be given either as a slow (over two minutes) intravenous injection of 50 mg, diluted to a volume of 20 ml, every six to eight hours as required until oral therapy can be introduced; or as an intermittent intravenous infusion at 25 mg per hour for two hours, repeated at six to eight hour intervals; or as an intramuscular injection of 50 mg every six to eight hours.

 

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

 

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 with Zantac Tablets 150 mg twice daily.

 

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

 

Children

Use in children has not been evaluated

 

Children / Infants (6 months to 11 years)

 

See section 5.2 Pharmacokinetic properties – Special Patient Populations.

 

Zantac injection may be given as a slow (over 2 minutes) i.v. injection up to a maximum of 50 mg 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, Zantac 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 1 mg/kg (maximum 50 mg) every 6 h to 8 h.

 

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.

 

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4.5 Interaction with other medicaments and other forms of interaction

Ranitidine, at blood levels produced by standard doses, does not inhibit or interact significantly with the hepatic cytochrome P450-linked mixed function oxygenase enzyme system.

 

Accordingly, ranitidine in usual therapeutic doses does not potentiate the action of drugs which are inactivated by this enzyme; these include diazepam, lignocaine, phenytoin, propranolol, theophylline and warfarin.

 

To date interactions of ranitidine have not been shown with warfarin, barbiturates or diazepam.

 

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, 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 levels 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) or a decrease in absorption (e.g. ketoconazole, atazanavir, glipizide, delaviridine, gefitnib).

 

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4.8 Undesirable effects

 

Reproductive System and Breast Disorders

Very Rare:       Reversible impotence. Breast symptoms in men.

 

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.

 

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5.1 Pharmacodynamic properties

 

Pharmacotherapeutic group: Alimentary tract and metabolism.

ATC code: A02 BA02.

 

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

 

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5.2 Pharmacokinetic properties

 

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.  Elimination of the drug is primarily by tubular secretion.  The elimination half-life is 2-3 hours. 

 

In balance studies with 150mg ³H-ranitidine 93% of an intravenous dose was excreted in urine and 5% in faeces: 60-70% of an oral dose was excreted in urine and 26% in faeces.  Analysis of urine excreted in the first 24 hours after dosing showed that 70% of the intravenous dose and 35% of the oral dose were eliminated unchanged. The metabolism of ranitidine is similar after both oral and intravenous dosing; about 6% of the dose being excreted in urine as the N-oxide, 2% as S-oxide, 2% as desmethylranitidine 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.

 

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6.4 Special precautions for storage

 

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

 

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6.5 Nature and contents of container

 

Zantac injection is stored in clear Type I 2ml glass ampoules.

 

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10. DATE OF (PARTIAL) REVISION OF THE TEXT

 

May July 2010

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each ampoule contains ranitidine hydrochloride equivalent to 50 mg ranitidine in 2 ml i.e. 25mg/ml.

 

Each ampoule also contains 1.3mg (0.06mmol) of sodium and 0.6mg (0.015mmol) of potassium

 

For a full list of excipients see section 6.1.

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6.2 Incompatibilities

 

See instructions for Use and Handling

 

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

 

6.3 Shelf life

 

3 years.

 

All admixtures of Zantac Injection with compatible infusion fluids (as listed in Section 6.6) should be stored below 25°C and discarded 24 hours after preparation.

From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions are the responsibility of the user. Dilution should take place in controlled and validated aseptic conditions.

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6.6 Instructions for Use and Handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal products and other handling of the product

 

Zantac Injection is compatible with the following intravenous infusion fluids:

0.9% Sodium Chloride BP

5% Dextrose BP

0.18% Sodium Chloride and 4% Dextrose BP

4.2% Sodium Bicarbonate BP

Hartmann's Solution.

 

Although compatibility studies have only been undertaken in polyvinyl chloride infusion bags (in glass for Sodium Bicarbonate BP) and polyvinyl chloride administration sets, it is considered that adequate stability would be conferred by use of a polyethylene infusion bag.

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

 

For single use only. Discards any unused contents

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9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

23^rd November 1983/23^rd November 20038

 

 

10. DATE OF (PARTIAL) REVISION OF THE TEXT

 

July 2007

 

May 2010

Improved electronic version

 

The following Text has been added to section 4.4:

 

Although no clear casual link has been established, 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). Therefore, in patients with conditions predisposing to the development of pneumonia, such as chronic lung disease, diabetes, or the immunocompromised, there may be an increased risk of developing community acquired pneumonia.

 

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 in current users of H2 receptor antagonists versus those who had stopped treatment, with an observed adjusted relative risk increase of 4.63 (95% CI, 1.07 2.48).

5.1 Pharmacodynamic properties

 

Pharmacotherapeutic group: Alimentary tract and metabolism.

ATC code: A02 BA02.

 

Zantac 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.

 

Although no clear casual link has been established, a large epidemiological study showed 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).  Therefore, in patients with conditions predisposing to the development of pneumonia, such as chronic lung disease, diabetes, or the immunocompromised, there may be an increased risk of developing community acquired pneumonia.