Orbifen Cold Flu Oral Suspension PL 17862 0004 … · ORBIFEN COLD & FLU ORAL SUSPENSION PL 17862/0004 ... including in-process control steps have been provided ... UKPAR Orbifen

ORBIFEN COLD & FLU ORAL SUSPENSION PL 17862/0004

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 13

Steps taken after authorisation – summary

Page 14

Summary of Product Characteristics

Page 15

Patient Information Leaflet

Page 24

Labelling Page 26

UKPAR Orbifen Cold & Flu Oral Suspension PL 17862/0004

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LAY SUMMARY The MHRA granted Orbis Consumer Products Ltd a Marketing Authorisation (licence) for the medicinal product Orbifen Cold & Flu Oral Suspension (PL 17862/0004). This product is a Pharmacy only medicine (P) for the treatment of cold and flu symptoms. Orbifen Cold & Flu Oral Suspension contains the active ingredients ibuprofen and pseudoephedrine hydrochloride. No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking Orbifen Cold & Flu Oral Suspension outweigh the risks, hence a Marketing Authorisation has been granted.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment (including statistical assessment)

Page 9

Overall conclusion and risk benefit assessment Page 12


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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the UK granted a Marketing Authorisation for the medicinal product Orbifen Cold & Flu Oral Suspension (PL 17862/0004) to Orbis Consumer Products Ltd on 10 August 2007. This application was submitted as an abridged application according to Article 10a of Directive 2001/83/EC. The product contains the active ingredients ibuprofen and pseudoephedrine and is indicated for the relief of feverishness and symptoms of colds and influenza with associated congestion, including aches and pains, headache, sore throat, blocked nose and sinuses. Ibuprofen is a phenylpropionic acid derivative classified as an NSAID which has analgesic and antipyretic properties. Pseudoephedrine is a decongestant. The application for Orbifen Cold & Flu Oral Suspension has provided bibliographic published literature on the availability, efficacy and safety of this product. A bioequivalence study was also submitted to support the efficacy in the proposed indications.


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PHARMACEUTICAL ASSESSMENT COMPOSITION The proposed formulation is identical to that of Orbifen for Children (Orbis Consumer Products Ltd) except for the inclusion of pseudoephedrine and the use of an alternate flavour. The product is formulated as an oral suspension containing the active pharmaceutical ingredients ibuprofen and pseudoephedrine hydrochloride at strengths of 100mg/5ml and 15mg/5ml respectively. The excipients present are glycerine, xanthan gum, maltitol syrup, polysorbate, sodium saccharin, citric acid monohydrate, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, cherry flavour and purified water. The oral suspension is presented in a 100ml amber type III glass bottle with a child resistant, tamper evident, polypropylene cap.

DRUG SUBSTANCE

Ibuprofen Synthesis of the drug substance from the designated starting material has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents and these are supported by relevant certificates of analysis. An appropriate specification based on the European Pharmacopoeia has been provided. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Ibuprofen is stored in appropriate packaging. Batch analysis data are provided and comply with the proposed specification. Appropriate stability data have been generated that support the retest period for the drug substance when stored in the proposed packaging. Pseudoephedrine Synthesis of the drug substance from the designated starting material has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents and these are supported by relevant certificates of analysis. An appropriate specification based on the European Pharmacopoeia has been provided.


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Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Pseudoephedrine is stored in appropriate packaging. Batch analysis data are provided and comply with the proposed specification. Appropriate stability data have been generated that support the retest period for the drug substance when stored in the proposed packaging.

DRUG PRODUCT Orbifen Cold & Flu Oral Suspension is developed on the basis of Orbifen for Children (an Ibuprofen 100mg/5ml oral suspension). Data have been provided which demonstrate that the introduction of pseudophedrine did not produce any significant changes in physio-chemical properties. The flavour was changed to more satisfactorily mask the bitter taste of pseudoephedrine. Other ingredients All excipients used in the manufacture of the suspension are routinely tested for compliance with their respective European Pharmacopoeial monograph, with the exception of cherry flavour which complies with a satisfactory in-house specification. Satisfactory certificates of analysis have been provided for all excipients. None of the excipients used contain material of animal or human origin. Dissolution profile The dissolution profile of ibuprofen was found to be similar to that of the reference product, Orbifen for Children. Manufacture A Good Manufacturing Practice (GMP) certificate has been provided for the manufacturing site. A full description and a detailed flow-chart of the manufacturing method, including in-process control steps have been provided. Satisfactory batch formulae have been provided for the manufacture of the product along with an appropriate account of the manufacturing process. The manufacturing process has been validated and appropriate in-process controls are applied. Additionally, a commitment has been provided that the next three full-scale commercial production batches will be validation batches. Finished product specification The proposed finished product specification is acceptable and the analytical methods used have been suitably validated. Certificates of analysis have been provided for all reference standards used. Batch analysis data have demonstrated compliance with the proposed release specification.


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Container Closure System Satisfactory specifications and certificates of analysis have been provided for the packaging components. Stability Finished product stability data support the proposed shelf-life of 24 months with storage conditions of ‘Do not store above 25°C’, including data to show that the product is satisfactorily re-suspended, on shaking the container. SPC, PIL, Labels The SPC, PIL and labels are pharmaceutically acceptable. CONCLUSION It is recommended that a Marketing Authorisation is granted for this application.


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PRECLINICAL ASSESSMENT

No new preclinical data have been supplied with this application and none are required for an application of this type.


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CLINICAL ASSESSMENT INTRODUCTION AND BACKGROUND This is a standard abridged bibliographic application for an oral suspension containing 100mg/5ml ibuprofen and 15mg/5ml pseudoephedrine hydrochloride. The application is submitted under the provisions of Directive 2001/83/EC Article 10a, which requires that detailed references to published scientific literature are presented to show that the constituents of the proposed medicinal product have a well-established medicinal use, with recognised efficacy and an acceptable level of safety. INDICATIONS For the relief of feverishness and symptoms of colds and influenza with associated congestion, including aches and pains, headache, sore throat, blocked nose and sinuses. DOSE AND DOSE SCHEDULE The proposed dose and dose schedule for this product to be used for the above indications ranges is: Adults and Children over 12 years: 10ml-20ml every 4-6 hours up to four times a day. Leave at least four hours between doses and do not take more than 60ml in 24 hours. Not to be given to children under 12 years. Elderly: no special dosage modifications are required, unless renal or hepatic function is impaired, in which case dosage should be assessed individually. These are considered satisfactory. CLINICAL PHARMACOLOGY Bioavailability/bioequivalence In addition to a bioequivalence study for Orbifen for Children which supported the similarity of the formulations with respect to ibuprofen only, another bioequivalence study has been submitted which was conducted to principles of Good Clinical Practice (GCP). This was an open label, balanced, randomised, three treatment, three period, six sequence, single dose, cross-over, comparative bioavailability study in healthy adult males, under fasting conditions. Study design Eighteen subjects were enrolled in the bioequivalence study. Three subjects withdrew for satisfactory reasons prior to completion.


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The three treatments were as follows:

• (A) Reference Product – Orbifen for Children, an ibuprophen 100mg/5ml oral suspension (Orbis Consumer Products Ltd)

• (B) Reference Product – Pseudoephedrine hydrochloride 15mg/5ml (a Certificate of Analysis has been provided for this product which was prepared by Orbis Consumer Products Ltd, but is not marketed)

• (C) Test Product – Orbifen Cold & Flu Oral Suspension After randomisation, a single 10ml dose of the relevant medication was administered. Blood samples were obtained prior to dosing as well as 12 hours after dosing for product A and 36 hours after dosing for products B and C. This is accepted given the known half-lives of the active substances and is supported by the AUC data provided. Plasma ibuprofen and pseudoephedrine levels were determined via HPLC and LC-MS/MS respectively. Satisfactory validation data have been provided. PK parameters and the 90% CI of ln-transformed data were determined using appropriate pharmacokinetic computer software. Results The results are summarised in the following tables: Ibuprofen

Untransformed data (SD) Parameters Test (Treatment C) Reference (Treatment A)

AUC(0-t) (mcg. h/mL) 58.037 (11.0408) 60.544 (8.6760) AUC(0-∞) (mcg. h/mL) 60.762 (10.9719) 63.711 (9.2920) Cmax (mcg/mL) 17.679 (4.9248) 18,595 (4.0696) tmax(h)* 1.423 (1.0532) 1.277 (0.7118)

90% CI of Treatment Comparisons

transformed data AUC(0-∞) Ratio 91.57 – 97.85 Cmax Ratio 81/03 – 108.10

Pseudoephedrine

Untransformed data (SD) Parameters Test (Treatment C) Reference (Treatment B)

AUC(0-t) (ng. h/mL) 909.099 (242.6263) 891.113 (307.0542) AUC(0-∞) (ng. h/mL) 937.493 (243.0388) 916.655 (313.0922) Cmax (ng/mL) 99.306 (21.2827) 100.602 (21.2337) tmax(h)* 1.951 (0.6183) 1.893 (0.8837)

90% CI of Treatment Comparisons

transformed data AUC(0-∞) Ratio 97.94 – 111.28 Cmax Ratio 92.41 – 106.87


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Discussion With respect to both ibuprofen and pseudoephedrine the test product is bioequivalent to the single component reference products. The data show that there are no pharmacokinetic interactions between the two active substances. CLINICAL EFFICACY The bibliographic data alone were not sufficient to support the efficacy in the proposed indications, so a bioequivalence study was requested which adequately upholds the approved indications. CLINICAL SAFETY No formal safety data are presented in this application and none are required. CLINICAL EXPERT REPORT The clinical expert report has been written by an appropriately qualified medical doctor. It is an adequate summary of the clinical data provided in the dossier. SPC, PIL and LABELS The SPC, PIL and labels are acceptable. CONCLUSIONS Overall, there is no clinical objection to grant a Marketing Authorisation for this application. No new or unexpected safety concerns arose from the application.


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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Orbifen Cold & Flu Oral Suspension 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. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY No new or unexpected safety concerns arise from this application. The SPC, PIL and labelling are satisfactory. RISK BENEFIT ASSESSMENT Extensive clinical experience with ibuprofen and pseudoephedrine is considered to have demonstrated the therapeutic value of the compounds. The risk benefit is, therefore, considered to be positive.


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STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 10 May 2002.

2 Following standard checks and communication with the applicant the MHRA

considered the application valid on 02 August 2002.

3 Following assessment of the application the MHRA requested further information relating to the clinical dossier on 08 October 2002, and further information relating to the quality dossier on 13 December 2002, 13 July 2006 and 20 June 2007.

4 The applicant responded to the MHRA’s requests, providing further information on 21 July 2004 and 12 August 2004 for the clinical section and again on 26 July 2004, 30 May 2006, 06 November 2006 and 06 August 2007 for the quality section.

5 The application was determined on 10 August 2007.


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STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date submitted

Application type

Scope Outcome


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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Orbifen Cold & Flu Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Active ingredients in 5ml Quantity Ibuprofen 100mg Pseudoephedrine Hydrochloride 15mg

For excipients- see section 6.1

3 PHARMACEUTICAL FORM Oral Suspension

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Orbifen Cold & Flu is effective in the relief of feverishness and symptoms of colds and influenza with associated congestion, including aches and pains, headache, sore throat, blocked nose and sinuses.

4.2 Posology and method of administration For oral administration and for short term use only. The minimum effective dose should be used for the shortest time necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen or if the product os required for more than 10 days. Adults and Children over 12 years: 10ml-20ml every 4-6 hours up to four times a day. Leave at least four hours between doses and do not take more than 60ml in 24 hours. Not to be given to children under 12 years. Elderly: no special dosage modifications are required, unless renal or hepatic function is impaired, in which case dosage should be assessed individually.


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4.3 Contraindications Hypersensitivity to Ibuprofen, Pseudoephedrine or any of the constituents in the product. Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs. Active or previous peptic ulcer History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see section 4.5 Interactions). Severe hepatic failure, renal failure or heart failure (see section 4.4, Special warnings and precautions for use) Patients with severe cardiovascular disease, tachycardia, hypertension, angina pectoris, hepatic failure, renal failure, hyperthyroidism, diabetes, phaeochromocytoma, closed-angle glaucoma, prostatic enlargement. Pregnancy

4.4 Special warnings and precautions for use Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease. Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration. The elderly are at increased risk of the serious consequences of adverse reactions. Systemic lupus erythematosus and mixed connective tissue disease - increased risk of aseptic meningitis (see section 4.8 Undesirable effects) Chronic inflammatory intestinal disease (ulcerative colitis, Crohn’s disease) – as these conditions may be exacerbated (See section 4.8 Undesirable effects). Hypertension and/or cardiac impairment as renal function may deteriorate and/or fluid retention occur. Renal impairment as renal function may further deteriorate (See section 4.3 Contraindications and Section 4.8 Undesirable effects)


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Hepatic dysfunction (See section 4.3 Contraindications and Section 4.8 Undesirable effects) There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment. GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5 Interactions). When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn. The label will include: Read the enclosed leaflet before taking this product. Do not take if you

• have or have ever had a stomach ulcer, perforation or bleeding • are allergic to ibuprofen or any other ingredient of the product,

aspirin or other related painkillers • are taking other NSAID painkillers, or aspirin with a daily dose

above 75mg • are pregnant

Speak to a pharmacist or your doctor before taking this product if you

• have asthma , liver, heart, kidney or bowel problems

If symptoms persist or worsen, consult your doctor.

4.5 Interaction with other medicinal products and other forms of interaction Ibuprofen should not be used in combination with: Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.3 Contraindications). Other NSAIDS: As these may increase the risk of adverse effects (see section 4.3 Contraindications). Pseudoephedrine should not be used in combination with:


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Cardiac glycosides: pseudoephedrine may increase the possibility of arrhythmias. Sympathomimetics and MAOI/other antidepressants: Co-administration of pseudoephedrine with drugs which interfere with the catabolism of sympathomimetic agents may cause a rise in blood pressure. Such drugs include tricyclic antidepressants and sympathomimetic agents (such as decongestants, appetite suppressants and amphetamine-likepsychostimulants), and monoamine oxidase inhibitors(MAOIS). Pseudoephedrine should not be given to patients receiving MAOI therapy or within 14 days of discontinuing such therapy as it may cause a hypertensive crisis. Pseudoephedrine may partially reverse the hypotensive action of drugs which interfere with sympathetic activity including alpha- and beta-adrenergic blocking drugs and methyldopa. Ibuprofen should be used with caution in combination with: Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs.

Corticosteroids: May increase the risk of adverse reactions in the gastrointestinal tract (see Section 4.4 Special warnings). Lithium: There is evidence for potential increases in plasma levels of lithium. Methotrexate: There is a potential for an increase in plasma methotrexate. Zidovudine: There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

4.6 Pregnancy and lactation Whilst no teratogenic effects have been demonstrated with ibuprofen in animal experiments, there is a possible association between the development of foetal abnormalities and exposure to pseudoephedrine in the first trimester. The use of Orbifen Cold and Flu during pregnancy should, therefore, be avoided. During the 3rd trimester, ibuprofen is contraindicated as there is there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. (See section 4.3 Contraindications). Although ibuprofen appears in breast milk in very low concentrations, significant amounts of pseudoephedrine are secreted into breast milk. The use of Orbifen Cold and Flu during lactation should, therefore, be avoided.


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See section 4.4 regarding female fertility.

4.7 Effects on ability to drive and use machines None expected at recommended doses and duration of therapy.

4.8 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), including isolated reports Side effects of Ibuprofen are as follows: Hypersensitivity reactions have been reported and these may consist of:

(a) Non-specific allergic reactions and anaphylaxis (b) Respiratory tract reactivity, eg asthma, aggravated asthma, bronchospasm, dyspnoea (c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Hypersensitivity reactions: Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock). Exacerbation of asthma and bronchospasm.

Gastrointestinal: Uncommon: abdominal pain, nausea and dyspepsia. Rare: diarrhoea, flatulence, constipation and vomiting. Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, particularly in the elderly. Exacerbation of ulcerative colitis and Crohn’s disease (See section 4.4).

Nervous System: Uncommon: Headache

Renal: Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.


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Hepatic: Very rare: liver disorders. Haematological: Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Skin: Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as erythema multiforme and epidermal necrolysis can occur.

Immune System: In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (See section 4.4) Side effects of Pseudoephedrine include: Dyspepsia, gastro-intestinal intolerance and bleeding, skin rashes, nausea, vomiting, sweating, giddiness, dry mouth, tachycardia, precordial pain, palpitations, restlessness and insomnia. Less frequently Orbifen Cold & Flu may cause difficulty in micturition (particularly when there is prostatic enlargement), muscle weakness, tremors, anxiety, hallucinations and thrombocytopenia.

4.9 Overdose Symptoms of overdosage include headache, nausea, vomiting, thirst, anxiety, restlessness, irritability, fever, sinus tachycardia, sweating, insomnia, dilated pupil, blurred vision, delusions and hallucinations, muscular weakness, difficulty in micturition, tremors, convulsions, coma, respiratory depression, hypertension, supraventricular and ventricular arrhythmias. Treatment consists of gastric lavage and if necessary correction of serum electrolytes. Symptomatic and supportive treatment should be undertaken, particularly with regard to the cardiovascular and respiratory systems. Convulsions should be controlled with intravenous diazepam. Chlorpromazine may used to control marked excitement and hallucinations. Severe hypertension may need to be treated with and alpha-receptor blocking drug such as phentolamine. A beta-receptor blocking drug may be required to control cardiac arrhythmias.


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5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Ibuprofen is a propionic acid derivative, having analgesic, anti-inflammatory and antipyretic activity. The drug’s therapeutic effects as a non-steroidal anti-inflammatory drug are thought to result from inhibitory activity on prostaglandin synthesis. Furthermore, ibuprofen reversibly inhibits platelet aggregation Pseudoephedrine is a sympathomimetic agent with direct and indirect effects on adrenergic receptors. It has alpha and beta stimulant adrenergic activity and some stimulant effect on the central nervous system. The sympathomimetic effect of Pseudoephedrine produces vasoconstriction, which in turn relieves nasal congestion.

5.2 Pharmacokinetic properties Ibuprofen is rapidly absorbed from the gastrointestinal tract, and is rapidly distributed throughout the whole body. Peak serum concentrations occur 1-2 hours after administration. The elimination half-life is approximately two hours.

Ibuprofen is metabolised in the liver to two major inactive metabolites and the kidney excretes these together with unchanged ibuprofen either as such or as conjugated. Excretion by the kidney is both rapid and complete.

Ibuprofen is extensively bound to plasma proteins.

Pseudoephedrine is absorbed from the gastrointestinal tract and is largely excreted in the urine unchanged, together with small amounts of a hepatic metabolite. It has an elimination half-life of several hours, which may be reduced by acidifying the urine.

5.3 Preclinical safety data No relevant information additional to that contained elsewhere in the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Glycerol xanthan gum maltitol liquid polysorbate 80 saccharin sodium citric acid monohydrate


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cherry flavour sodium methyl parahydroxybenzoate sodium propyl parahydroxybenzoate purified water.

6.2 Incompatibilities Not Applicable

6.3 Shelf life 24 months.

6.4 Special precautions for storage Do not store above 25ºC.

6.5 Nature and contents of container Amber type III glass bottle Child Resistant Tamper Evident Cap - High density polypropylene cap with a polyethylene lining 2.5ml/ 5ml Polypropylene double ended spoon Pack size available100ml

6.6 Special precautions for disposal Not Applicable

7 MARKETING AUTHORISATION HOLDER Orbis Consumer Products Limited Cunard Road Park Royal London NW10 6PN

8 MARKETING AUTHORISATION NUMBER(S) PL 17862 / 0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 10/08/2007


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10 DATE OF REVISION OF THE TEXT

10/08/2007

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)


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PATIENT INFORMATION LEAFLET


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LABELLING


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Documents

Orbifen Cold Flu Oral Suspension PL 17862 0004 … · ORBIFEN COLD & FLU ORAL SUSPENSION PL 17862/0004 ... including in-process control steps have been provided ... UKPAR Orbifen