ranitidine 25mg/ml solution for injection or infusion

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Public Assessment Report

Decentralised Procedure RANITIDINE 25MG/ML SOLUTION FOR INJECTION OR

INFUSION

UK/H/1894/001/DC UK Licence No: PL 20568/0022

CLARIS LIFESCIENCES UK LIMITED

PAR Ranitidine 25mg/ml Solution for Injection or Infusion UK/H/1894/001/DC

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LAY SUMMARY

On 11th Janury 2011, the UK granted Claris Lifesciences UK Limited a Marketing Authorisation (licence) for the medicine Ranitidine 25mg/ml Solution for Injection or Infusion. Ranitidine 25mg/ml Solution for Injection or Infusion contains ranitidine hydrochloride which belongs to a group of medicines called H2 receptor antagonists. Ranitidine lowers the amount of acid in your stomach. Ranitidine 25mg/ml Solution for Injection may be used for the treatment of:

• stomach ulcers and ulcers in the duodenum (where the stomach empties into), • reflux oesophagitis (acid in the food pipe) often called heartburn • Zollinger-Ellison-Syndrome (a condition where too much acid is produced in the

stomach) Ranitidine 25mg/ml Solution for Injection may be used for the prevention of:

• bleeding in the gut in seriously ill patients • bleeding in the gut in patients with bleeding stomach ulcers • acid coming up from the stomach while under anaesthesia during an operation

No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Ranitidine 25mg/ml Solution for Injection outweigh the risks; hence a Marketing Authorisation has been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 11 Module 4: Labelling Page 15 Module 5: Scientific Discussion Page 18 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6: Steps taken after initial procedure Not applicable


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Module 1

Product Name

Ranitidine 25mg/ml Solution for Injection or Infusion

Type of Application

Generic, Article 10.1

Active Substance

Ranitidine hydrochloride

Form

25mg/ml Solution for Injection or Infusion

MA Holder

Claris Lifesciences UK Limited

Reference Member State (RMS)

UK

Concerned Mmeber States (CMS)

Austria (AT), Germany (DE), France (FR), Ireland (IE), Denmark (DK), Portugal (PT), Romania (RO)

Procedure Number

UK/H/1894/001/DC

End of Procedure

Day 210 – 25th November 2010


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Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Ranitidine 25mg/ml Solution for Injection or Infusion 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1ml of Solution for Injection contains 25 mg Ranitidine Each 2 ml ampoule contains 50 mg Ranitidine (as Ranitidine Hydrochloride) Sodium and Potassium is present as less than 1mmol per ml. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for Injection or Infusion A clear, colourless to pale yellow solution, free from visible particles. pH between 6.70 and 7.30 Osmolarity of the drug product solution: 310.17 mOsmol/L.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Adults: Ranitidine is indicated for the following conditions where a reduction of gastric acid secretion is desirable: - Short term treatment of duodenal ulcer and benign gastric ulcer - Short term treatment of reflux oesophagitis - Zollinger-Ellison-Syndrome - Prophylaxis of gastrointestinal haemorrhage from stress ulceration in seriously ill patients - Prophylaxis of recurrent haemorrhage in patients with bleeding peptic ulcers - Prophylaxis of acid aspiration (Mendelson’s Syndrome) before general anaesthesia in patients

considered to be at risk of acid aspiration. 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’. 4.2 Posology and method of administration

(See Section 5.2 Pharmacokinetic Properties – Special patient Populations) Adults (including elderly) Ranitidine Injection may be given either as a slow (over 2 minutes) intravenous injection up to a maximum of 50 mg, after dilution to a volume of 20 ml per 50 mg dose, which may be repeated every 6 to 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 6 to 8 hour intervals. Peptic Ulcer Acute Treatment, Gastro-Oesophageal Reflux and Zollinger-Ellison-Syndrome I.v. therapy for peptic ulcer disease and reflux oesophagitis, and Zollinger-Ellison-Syndrome is only indicated as long as oral therapy is not possible. Prophylaxis of haemorrhage from stress ulceration or recurrent haemorrhage: 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 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 Ranitidine tablets 150 mg twice daily. 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.


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Alternatively treatment can be continuous, administering 125 - 250 micrograms/kg/hr as continuous infusion. Prophylaxis of Mendleson's syndrome: In patients considered to be at risk of developing acid aspiration syndrome, Ranitidine Injection 50 mg may be given by slow intravenous injection 45 to 60 minutes before induction of general anaesthesia. Children / Infants and Adolescents: (6 months to 18 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 50 mg every 6 to 8 hours. Peptic Ulcer Acute Treatment, Gastro-Oesophageal Reflux 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. 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 50 ml/min). Accordingly, it is recommended in such patients that ranitidine be administered in doses of 25 mg. Route of Administration Intravenous injection

4.3 Contraindications

Ranitidine is contraindicated for patients known to have hypersensitivity to any component of the preparation.

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. Accordingly, where gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with Ranitidine is instituted. Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with renal impairment. Accordingly, it is recommended in such patients that Ranitidine be administered in doses of 25 mg. Bradycardia in association with rapid administration of Ranitidine Injection 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. This medicinal product contains less than 1 mmol (0.8745 mmol) sodium per 100 ml, i.e. essentially “sodium-free” and less than 1 mmol (0.718 mmol) potassium per 100ml, i.e. essentially “potassium free”.

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


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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 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/plasma concentration (e.g. triazolam, midazolam, glipizide) or a decrease in absorption/plasma concentration (e.g. ketoconazole, itraconazole, posaconazole, atazanavir, delaviridine, gefitnib, erlotinib). 4) Interaction with cyanocobalamine : Interaction to take into account due to the potential cyanocobalamine deficiency after prolonged treatment (many years) related the potential absorption decrease of vitamin B12 by means of a reduced acidity.

4.6 Fertility, pregnancy and lactation

Pregnancy Data on a large number (> 1000) of exposed pregnancies indicate no adverse effects of ranitidine on pregnancy or the health of the fetus/newborn. To date, no other relevant epidemiological data are available. Ranitidine should not be administered during pregnancy or lactation unless considered essential by the physician. Caution should be exercised when prescribing to pregnant woman. Lactation The active ingredient is excreted in breast milk. As nothing is known of the effect of ingestion of ranitidine in the infant and the possibility of disturbances of gastric acid secretion cannot be excluded, breast-feeding should be avoided during treatment. Fertility Ranitidine had no effect on male or female fertility in animals (see section 5.3).

4.7 Effects on ability to drive and use machines

In the case of symptoms of hallucinations, dizziness, confusion or headache following the administration of Ranitidine, patients should not drive or use machinery until the symptoms have ceased.

4.8 Undesirable effects

The following convention has been utilised for the classification of undesirable effects

Very common (>1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000), Unknown Cannot be estimated from the available data

Adverse event frequencies have been estimated from spontaneous reports from post-marketing 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.


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Immune System Disorders Uncommon: Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension and chest pain). Unknown: Anaphylactic shock, Laryngeal spasm These events have been reported after a single dose. Psychiatric Disorders Very Rare: depression Unknown: Reversible mental confusion hallucinations, Agitation. These have been reported predominantly in severely ill and elderly patients or suffering from renal impairment. Nervous System Disorders Common: Headache (sometimes severe) and dizziness Very Rare: reversible involuntary movement disorders (tremors, myoclonus, and involuntary ocular movements). 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 with sinusal break and asystole. Vascular Disorders Unknown: Vasculitis. Gastrointestinal Disorders Common: Diarrhoea. Unknown: Acute pancreatitis, nausea and constipation. 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, Pruritus. Musculoskeletal and Connective Tissue Disorders Unknown: Musculoskeletal symptoms such as arthralgia and myalgia. Renal and Urinary Disorders Unknown: Acute interstitial nephritis, Increased plasma creatinine. Reproductive System and Breast Disorders Unknown: Reversible impotence. Breast symptoms in men. General disorders and administration site conditions Asthenia The safety of ranitidine has been assessed in children aged 0 to 16 years with acid-related disease and shows an adverse event profile resembling that in adults. There are limited long term safety data available, in particular regarding growth and development. With increased pH in ventilated and seriously ill patients (increased bacterial counts in the GI tract and possibly the bronchial system, increased rate of nosocomial pneumonia).

4.9 Overdose

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.


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5 PHARMACOLOGICAL PROPERTIES Group: H2- receptor antagonist ATC Code: A02BA02

5.1 Pharmacodynamic properties

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

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. The elimination of the drug is primarily by tubular secretion. The elimination half-life of ranitidine is 2-3 hours. In balance, 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.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. Ranitidine did not affect overall fertility in male and female rats.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Sodium Chloride (for tonicity adjustment) Potassium Dihydrogen Phosphate Anhydrous Disodium Hydrogen Phosphate Water for Injections Ranitidine Injection contains less than 1 mmol sodium (0.08475 per mL) and is essentially ‘sodium-free’.

6.2 Incompatibilities

See 6.6 Instructions for Use/Handling. Please cross-refer to section 6.6 for stability following dilution. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

12 months After first opening: Single dose container. Use immediately after first opening. 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 dilution has taken place in controlled and validated conditions.


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6.4 Special precautions for storage

Do not store above 25ºC, store in original carton in order to protect from light. Do not refrigerate or freeze. Ranitidine Injection should not be autoclaved.

6.5 Nature and contents of container

2 ml colourless Type I glass ampoules. Pack size: Each of these 2ml ampoules are placed in blisters and supplied in cartons of 5, 10 and 25 ampoules.

6.6 Special precautions for disposal and other handling

Ranitidine Injection has been shown to be compatible with the following intravenous infusion fluids in polyvinyl chloride bags and administrative set:- 0.9% Sodium Chloride BP 5% Dextrose BP 0.18% Sodium Chloride and 4% Dextrose BP 4.2% Sodium Bicarbonate BP Hartmann's Solution Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

7 MARKETING AUTHORISATION HOLDER

Claris Lifesciences UK Limited Crewe Hall Crewe Cheshire CW1 6UL United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20568/0022 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 11/01/2011 10 DATE OF REVISION OF THE TEXT

11/01/2011


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Module 3 Product Information Leaflet


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Module 4 Labelling

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Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, Austria, Germany, France, Ireland, Denmark, Portugal, Romania and the UK considered that the application for Ranitidine 25mg/ml Solution for Injection could be approved. The product is a prescription only medicine (POM) and is indicated in adults for the following conditions where a reduction of gastric acid secretion is desirable:

• Short term treatment of duodenal ulcer and benign gastric ulcer • Short term treatment of reflux oesophagitis • Zollinger-Ellison-Syndrome • Prophylaxis of gastrointestinal haemorrhage from stress ulceration in seriously ill

patients • Prophylaxis of recurrent haemorrhage in patients with bleeding peptic ulcers • Prophylaxis of acid aspiration (Mendelson’s Syndrome) before general anaesthesia in

patients considered to be at risk of acid aspiration. It is indicated in children ages between 6 months to 18 years for:

• Short term treatment of peptic ulcer • Treatment of gastro-oesophageal reflux, including reflux oesophagitis and

symptomatic relief of gastro-oesophageal reflux disease. This application for Ranitidine 25mg/ml Solution for Injection is submitted as an abridged application according to Article 10.1 of Directive 2001/83/EC, claiming to be a generic medicinal product of Zantac Injection 50mg/2ml, first authorised in the UK to Glaxo Operation UK Limited in 1993. This then underwent a Change of Ownership to Glaxo Wellcome UK Limited on 2nd August 1993. No new non-clinical studies were conducted, which is acceptable given that the product contains a widely-used, well-known active substance. No clinical studies have been performed and none are required for this application as the pharmacology of ranitidine hydrochloride is well-established. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the community, the RMS has accepted copies of current GMP Certificates or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.

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The RMS considers that the pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. The Marketing Authorisation Holder has provided adequate justification for not submitting a Risk Management Plan.

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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Ranitidine 25mg/ml Solution for Injection or Infusion

Name(s) of the active substance(s) (INN) Ranitidine hydrochloride Pharmacotherapeutic classification (ATC code)

H2- receptor antagonist (A02 BA02)

Pharmaceutical form and strength(s) 25mg/ml Solution for Injection or Infusion Reference numbers for the Decentralised Procedure UK/H/1894/001/DC Reference Member State (RMS) United Kingdom Member States concerned (CMS) Austria (AT), Germany (DE), France (FR),

Ireland (IE), Denmark (DK), Portugal (PT), Romania (RO)

Marketing Authorisation Number(s) PL 20568/0022 Name and address of the authorisation holder Claris Lifesciences UK Limited

Crewe Hall Crewe Cheshire CW1 6UL

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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance Ranitidine Hydrochloride INN/Ph.Eur name: Ranitidine hydrochloride Chemical name: N-[2-[[[5-[(Dimethyl-amino)methyl]furan-2-

yl]methyl]sulphinyl]ethyl]-N΄-methyl-2-nitroethene-1,1-diamine hydrochloride

Structural formula:

Molecular formula: C13H23ClN4O3S Appearance: White to pale yellow, crystalline powder Solubility: Freely soluble in water, sparingly soluble or slightly soluble in

anhydrous ethanol, very slightly soluble in methylene chloride. Molecular weight: 350.9 Ranitidine hydrochloride complies with the European Pharmacopoeia monograph. All aspects of the manufacture of the active substance from its starting materials are controlled by a Certificate of Suitability. Appropriate proof of structure data has been supplied for the active pharmaceutical ingredient. All potential known impurities have been identified and characterised. An appropriate specification is provided for the active substance ranitidine hydrochloride, with suitable test methods and limits. The methods of testing and limits for residual solvents are in compliance with current guidelines. Suitable Certificates of Analysis have been provided for all reference standards used. Batch analysis data are provided and comply with the proposed specification. Appropriate stability data have been generated showing the active substance to be a physically and chemically stable drug, and supporting an appropriate retest period. P. Medicinal Product Other Ingredients Other ingredients are pharmaceutical excipients sodium chloride (for tonicity adjustment), potassium dihydrogen phosphate, anhydrous disodium hydrogen phosphate, water for injections. All excipients comply with their European Pharmacopoeia monographs.

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None of the excipients used contain material of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the development programme was to produce a product that could be considered a generic medicinal product of Zantac Injection 50mg/2ml. The applicant has provided suitable product development sections. Justifications for the use and amounts of each excipient have been provided and are valid. Manufacturing Process A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results. Process validation data on pilot-scale batches have been provided. The applicant has committed to perform process validation with future production batches of the drug product. Finished Product Specification The finished product specification proposed for the product is acceptable. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used. Container-Closure System This product is packaged in 2ml ampoules composed of colourless Type I glass. Each of these ampoules are placed in blisters and packed into cartons. Pack sizes are 5, 10 and 25 ampoules. Satisfactory specifications and certificates of analysis have been provided for all packaging components. All primary packaging complies with the European Pharmacopoeia Type III and relevant regulations regarding use of materials in contact with food. Stability of the product Stability studies were performed on batches of the finished products in the packaging proposed for marketing and in accordance with current guidelines. These data support a shelf-life of 12 months with storage instructions, ‘Do not store above 25 °C, store in original carton in order to protect from light’ and ‘do not refrigerate or freeze’. There is also the warning, ‘Ranitidine injection should not be autoclaved’. The product is in a single dose container, from a microbiological point of view, the product should be used immediately after first opening. 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 dilution has taken place in controlled and validated conditions. Summary of Product Characteristics (SPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labelling are pharmaceutically acceptable.

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User testing results have been submitted for a typical PIL for this product. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. MAA forms The MAA form is pharmaceutically satisfactory. Expert report The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion It is recommended that Marketing Authorisations are granted for this application.

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III.2 NON-CLINICAL ASPECTS The pharmacodynamics, pharmacokinetics and toxicological properties of ranitidine hydrochloride are well-known. As these are widely used, well-known active substances, the applicant has not provided any additional studies and none are required. The non-clinical expert report has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment.

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III.3 CLINICAL ASPECTS This assessment report represents an evaluation of the key elements of the information provided by the company in the dossier. CLINICAL PHARMACOLOGY No new pharmacokinetic or pharmacodynamic data were submitted with this application and none were required, as per the Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98, as the applicant’s product is similar to the reference product in terms of qualitative and quantitative composition and is expected to perform identically in vivo. A human bioavailability study is not relevant to this application as the compound is intended for intravenous infusion. EFFICACY No new efficacy data were submitted with this application and none were required. SAFETY No new safety data were submitted with this application and none were required. SUMMARY OF PRODUCT CHARACTERISTICS (SPC), PATIENT INFORMATION LEAFLET (PIL) AND LABELLING The SmPC, PIL and labelling are medically satisfactory and consistent with those for the reference product, where appropriate. CLINICAL EXPERT REPORT The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. MAA FORM The MAA Form is medically satisfactory. CONCLUSIONS It is recommended that a Marketing Authorisation is granted for this application.

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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Ranitidine 25mg/ml Solution for Injection or Infusion are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type. EFFICACY No bioequivalence studies have been performed and none are required for this application, given the composition of the product and its intended route of administration. No new or unexpected safety concerns arise from this application. The SmPCs, PILs and labelling are satisfactory and consistent with that for the reference product. RISK-BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with ranitidine hydrochloride is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.

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Module 5

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

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ranitidine 25mg/ml solution for injection or infusion

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