Public Assessment Report. Decentralised Procedure

Transcription

1 Public Assessment Report Decentralised Procedure Nurofen 400 mg Capsule, soft UK/H/3809/001/DC UK licence number: PL 00063/0615 Reckitt Benckiser Healthcare (UK) Ltd 1

2 LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted Reckitt Benckiser Healthcare (UK) Ltd a Marketing Authorisation (licence) for the medicinal product Nurofen 400 mg Capsule, soft (PL 00063/0615) on 01 February This is a P licensed medicine, available only from pharmacies, under the supervision of a pharmacist. The active ingredient, ibuprofen, belongs to a group of medicines called non-steroidal antiinflammatory drugs (NSAIDs). Nurofen 400 mg Capsule, soft is used in adults and adolescents (12 years of age and above), weighing 40 kg and above, for the symptomatic treatment of: mild to moderate pain such as headache, period pain and dental pain. fever and pain associated with the common cold. No new or unexpected safety concerns arose from this application. It was judged that the benefits of Nurofen 400 mg Capsule, soft outweigh the risk, hence a Marketing Authorisation has been granted. 2

3 TABLE OF CONTENTS Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 15 Module 4: Labelling Page 24 Module 5: Scientific Discussion Page 27 1 Introduction Page 27 2 About the product Page 29 3 Quality aspects Page 30 4 Non-clinical aspects Page 33 5 Clinical aspects Page 33 6 Overall conclusions Page 38 Module 6 Steps taken after initial procedure Page 39 3

4 Module 1 Information about Initial Procedure Product Name Nurofen 400 mg Capsule, soft Type of Application Line extension (known active substance), Article 8.3 Active Substance Form Strength MA Holder Reference Member State (RMS) Concerned Member States (CMS) Procedure Number Ibuprofen Soft capsule 400 mg Reckitt Benckiser Healthcare (UK) Ltd Slough SL1 4AQ UK UK Austria, Bulgaria, Cyprus, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Romania, Spain. UK/H/3809/001/DC Timetable End of Procedure: Day December

5 Module 2 Summary of Product Characteristics The UK Summary of Product Characteristics (SmPC) for Nurofen 400 mg Capsule, soft (PL 00063/0615) is as follows: 1 NAME OF THE MEDICINAL PRODUCT Nurofen 400 mg Capsule, soft 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains Ibuprofen 400 mg Excipient(s): Sorbitol (E420) mg/capsule Ponceau 4R (E124) 0.79 mg/capsule For a full list of excipients, see section PHARMACEUTICAL FORM Capsule, soft A red, oval-shaped transparent soft gelatin capsule with a nurofen logo printed in white. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications This medical product is indicated in adults and adolescents weighing from 40 kg (12 years of age and above) for the symptomatic treatment of mild to moderate pain such as headache, period pain, dental pain and fever and pain associated with the common cold. 4.2 Posology and method of administration For oral use and short-term use only. Capsules should not be chewed. Undesirable effects may be minimized by using the lowest effective dose for the shortest possible duration necessary to control symptoms (see section 4.4) Adults and adolescents weighing from 40 kg (12 years of age and above). Initial dose, one capsule with water. Then, if necessary, one capsule every six hours. Do not exceed three capsules (1200 mg) in any 24-hour period. If the product is required for more than 3 days in the case of fever and 4 days for treatment of pain, or if the symptoms worsen the patient is advised to consult a doctor. It is recommended that patients with a sensitive stomach take Nurofen with food. If taken shortly after eating, the onset of action of Nurofen may be delayed. If this happens do not take more Nurofen than recommended within section 4.2 (posology) or until the correct re-dosing interval has passed. Special patient groups Elderly: No special dose adjustment is required. Because of the possible undesirable-effect profile (see section 4.4), the elderly should be monitored particularly carefully. Renal insufficiency: No dose reduction is required in patients with mild to moderate impairment to renal function (patients with severe renal insufficiency, see section 4.3). 5

6 Hepatic insufficiency (see section 5.2): No dose reduction is required in patients with mild to moderate impairment to hepatic function (patients with severe hepatic dysfunction, see section 4.3). Children and adolescents: For use in children and adolescents, see section Contraindications Hypersensitivity to the active substance, ponceau 4R (E124) or to any of the other excipients listed in section 6.1. In patients with a history of hypersensitivity reactions (e.g. bronchospasm, asthma, rhinitis, angioedema or urticaria) associated with the intake of acetylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs (NSAIDs). History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding). Patients with severe hepatic failure, severe renal failure, or severe heart failure. See also section 4.4. In patients with cerebrovascular or other active bleeding. In patients with bleeding diathesis or coagulation disorders. In patients with unclarified blood-formation disturbances. In patients with severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake). During the last trimester of pregnancy (see Section 4.6). Adolescents weighing less than 40 kg or children under 12 years of age. 4.4 Special warnings and precautions for use Undesirable effects may be minimised by using the lowest effective dose for the shortest possible duration necessary to control symptoms (see gastrointestinal (GI) and cardiovascular risks below). Caution is required in patients with certain conditions, which may be made worse: systemic lupus erythematosus and mixed connective tissue disease increased risk of aseptic meningitis (see section 4.8). congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria). gastrointestinal disorders and chronic inflammatory intestinal disease (ulcerative colitis, Crohn s disease) (see section 4.8). hypertension and/or cardiac impairment (see section 4.3 and 4.8). renal impairment as renal function may deteriorate (see sections 4.3 and 4.8). hepatic dysfunction (see sections 4.3 and 4.8). directly after major surgery. in patients who show allergic reactions to other substances, as they are also at a higher risk of hypersensitivity reactions when using Nurofen in patients who suffer from hayfever, nasal poyps,chronic obstructive respiratory disorders, or have a history of allergic disease, as an increased risk exists for them of allergic reactions occurring. These may present as asthma attacks (so-called analgesics asthma). Quincke s oedema or urticaria. Gastrointestinal (GI) safety The use with concomitant NSAID s, including cyclo-oxygenase-2 specific inhibitors, increases risk of adverse reactions (see section 4.5) and should be avoided. 6

7 Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal (GI) bleeding and perforation which may be fatal. (see section 4.2) Gastrointestinal (GI) bleeding, ulceration or perforation: Gastrointestinal (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 GI events. When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses and patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3) and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and section 4.5). Patients with a history of GI toxicity, particularly the 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 ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRI s) or anti-platelet agents such as aspirin (See section 4.5). NSAID s should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn s disease) as these conditions may be exacerbated (see section 4.8). Skin reactions Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Nurofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Exceptionally, varicella can be at the origin of serious cutaneous and soft tissues infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of Nurofen in case of varicella. Cardiovascular and cerebrovascular effects Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that the use of ibuprofen, particularly at high doses (2400 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g mg daily) is associated with an increased risk of myocardial infarction. Other notes Severe acute hypersensitivity reactions (for example anaphylactic shock) are observed very rarely. At the first signs of a hypersensitivity reaction after taking/administering Nurofen therapy must be stopped. Medically required measures, in line with the symptoms, must be initiated by specialist personnel. Ibuprofen, the active substance of Nurofen may temporarily inhibit the blood-platelet function (thrombocyte aggregation). Therefore, it is recommended to monitor patients with coagulation disturbances carefully. 7

8 In prolonged administration of Nurofen regular checking of the liver values, the kidney function, as well as of the blood count, is required. Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache (MOH) should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications. The habitual intake of painkillers, particularly the combination of several painkillers, may lead to permanent renal damage with the risk of renal failure (analgesic nephropathy). This risk may be increased by salt loss and dehydration. Through concomitant consumption of alcohol, active substance-related undesirable effects, particularly those that concern the gastrointestinal tract or the central nervous system, may be increased on use of NSAID s. There is some evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment (see section 4.6). The medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. This medicinal product contains Ponceau 4R(E124). It may cause allergic reactions. 4.5 Interaction with other medicinal products and other forms of interaction Acetylsalicylic acid (low dose): Ibuprofen should be avoided in combination with acetylsalicylic acid unless low dose acetylsalicylic acid (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.4). Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. However, the limitation of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusion can be made for regular ibuprofen use and no clinical relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1). Other NSAIDs, including cyclooxygenase-2 selective inhibitors: The concomitant administration of several NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to a synergistic effect. The concomitant use of ibuprofen with other NSAIDs should therefore be avoided (see section 4.4). Digoxin, phenytoin, lithium: The concomitant use of Nurofen with digoxin, phenytoin or lithium preparations may increase serum levels of these medicinal products. A check of serum-lithium, serum-digoxin and serum-phenytoin levels is not as a rule required on correct use (maximum over 4 days). Corticosteroids: Corticosteriods as these may increase the risk of adverse reactions, especially of the gastrointestinal tract (gastrointestinal ulceration or bleeding). (see Section 4.3) Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding. (See section 4.4). Anticoagulants: NSAIDs may enhance the effect of anti-coagulants, such as warfarin (see section 4.4). Probenecid and sulfinpyrazone: Medicinal products that contain probenecid or sulfinpyrazone may delay the excretion of ibuprofen. Diuretics, ACE inhibitors, betareceptor-blocker and angiotensin-ii antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor, betareceptor-blocker or angiotensin-ii antagonist 8

9 and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter. Potassium sparing diuretics: The concomitant administration of Nurofen and potassium-sparing diuretics may lead to hyperkalaemia (check of serum potassium is recommended). Methotrexate: The administration of Nurofen within 24 hours before or after administration of methotrexate may lead to elevated concentrations of methotrexate and an increase in its toxic effect. Ciclosporin: The risk of a kidney-damaging effect due to ciclosporin is increased through the concomitant administration of certain nonsteroidal antiinflammatory drugs. This effect also cannot be ruled out for a combination of ciclosporin with ibuprofen. Tacrolimus: The risk of nephrotoxicity is increased if the two medicinal products are administered concomitantly Zidovudine: There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen. Increased risk of haematological toxicity when NSAIDs are given with zidovudine. Sulfonylureas: Clinical investigations have shown interactions between nonsteroidal anti-inflammatory drugs and antidiabetics (sulphonylureas). Although interactions between ibuprofen and sulphonylureas have not been described to date, a check of blood-glucose values is recommended as a precaution on concomitant intake. Quinolone antibiotics: Animal data indicate that NSAID s can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAID s and quinolones may have an increased risk of developing convulsions. Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone. 4.6 Fertility, Pregnancy and lactation Pregnancy: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, ibuprofen should not be given unless clearly necessary. If ibuprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to: 9

10 - cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); - renal dysfunction, which may progress to renal failure with oligo-hydroamniosis; the mother and the neonate, at the end of pregnancy, to: - possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; - inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, ibuprofen is contraindicated during the third trimester of pregnancy. Lactation: Ibuprofen and its metabolites can pass in low concentrations into the breast milk. No harmful effects to infants are known to date, so for short-term treatment with the recommended dose for pain and fever interruption of breast-feeding would generally not be necessary. Fertility: The use of ibuprofen may affect female fertility. This effect is reversible on withdrawal of treatment. Therefore use of ibuprofen is not recommended in women having difficulties becoming pregnant (see section 4.4.). 4.7 Effects on ability to drive and use machines Patients who experience dizziness, drowsiness, vertigo or visual disturbances while they are taking ibuprofen, should avoid driving or using machinery. Single administration or short term use of ibuprofen does not usually warrant the adoption of any special precautions. This applies to a greater extent in combination with alcohol. 4.8 Undesirable effects The list of the following undesirable effects comprises all undesirable effects that have become known under treatment with ibuprofen, also those under high-dose long-term therapy in rheumatism patients. The stated frequencies, which extend beyond very rare reports, refer to the short-term use of daily doses up to a maximum of 1200 mg ibuprofen for oral dosage forms and a maximum of 1800 mg for suppositories. With the following adverse drug reactions, it must be accounted for that they are predominantly dosedependent and vary interindividually. The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Particularly the risk of gastrointestinal bleeding occurring is dependent on the dose range and the duration of use. Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high dose (2400 mg daily), and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4). 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 patient is to be instructed to inform a doctor at once and to stop taking Nurofen Express if they experience any of the above. 10

11 Please note that within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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) Not known (cannot be estimated from the available data) Infections and infestations: Very rare: Exacerbation of infection-related inflammations (e.g. development of necrotising fasciitis) coinciding with the use of nonsteroidal anti-inflammatory drugs has been described. This is possibly associated with the mechanism of action of the nonsteroidal anti-inflammatory drugs. If signs of an infection occur or get worse during use of Nurofen, the patient is therefore recommended to go to a doctor without delay. It is to be investigated whether there is an indication for an antiinfective/antibiotic therapy. The symptoms of aseptic meningitis with neck stiffness, headache, nausea, vomiting, fever or consciousness clouding have been observed under ibuprofen. Patients with autoimmune disorders (SLE, mixed connective-tissue disease) appear to be predisposed. Blood and Lymphatic System Disorders: Very rare: Disturbances to blood formation (anaemia, leukopenia, thrombocytopenia, pancytopenia, agranuloctosis). The first signs may be fever, sore throat, superficial wounds in the mouth, influenzalike complaints, severe lassitude, nosebleeds and skin bleeding. In such cases the patient should be advised to discontinue the medicine immediately, to avoid any self-medication with analgesics or antipyretics and to consult a physician. The blood count should be checked regularly in long-term therapy Immune system disorders (Hypersensitivity): Uncommon: Hypersensitivity reactions with urticaria and pruritus, as well as asthma attacks (possibly with drop in blood pressure). Very rare: severe general hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock). Exacerbation of asthma and bronchospasm. Psychiatric disorders: Very rare: Psychotic reactions, depression Nervous System Disorders: Uncommon: Central nervous disturbances such as headache, dizziness, sleeplessness, agitation, irritability or tiredness Eye disorders: Uncommon: Visual disturbances Ear and labyrinth disorders: Rare: Tinnitus Cardiac Disorders: Very rare: palpitations, heart failure, myocardial infarction Vascular disorders: Very rare: Arterial hypertension 11

12 Gastrointestinal Disorders: Common: Gastro-intestinal complaints such as dyspepsia, pyrosis, abdominal pain, nausea, vomiting, flatulence, diarrhoea, constipation and slight gastro-intestinal blood losses that may cause anaemia in exceptional cases Uncommon: Gastrointestinal ulcers, potentially with bleeding and perforation. Ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4), gastritis Very rare: Oesophagitis, pancreatitis, formation of intestinal diaphragm-like strictures. The patient is to be instructed to withdraw the medicinal product and to go to a doctor immediately if severe pain in the upper abdomen or melaena or haematemesis occurs. Hepatobiliary Disorders: Very rare: Hepatic dysfunction, hepatic damage, particularly in long-term therapy, hepatic failure, acute hepatitis Skin and Subcutaneous Tissue Disorders: Very rare: Bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia. In exceptional cases, severe skin infections and soft-tissue complications may occur during a varicella infection (see also "Infections and infestations"). Renal and Urinary Disorders : Rare: Kidney-tissue damage (papillary necrosis) and elevated uric acid concentrations in the blood may also occur rarely Very rare: Formation of oedemas, particularly in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis that may be accompanied by acute renal insufficiency. Renal function should therefore be checked regularly. 4.9 Overdose In adolescents and adults the dose response effect is not clear cut. The half-life in overdose is hours Symptoms Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as dizziness, drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics. Management Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids; propionic acid derivative ATC Code: M01A E01 Nurofen is a nonsteroidal anti-inflammatory drug (NSAID) that in the conventional animal-experiment inflammation models has proven to be effective via prostaglandin-synthesis inhibition. In humans, ibuprofen reduces inflammatory-related pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits ADP and collagen induced platelet aggregation 12

13 Experimental data suggests that ibuprofen may inhibit the effect of low dose ASA on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 h before or within 30 min after immediate release ASA dosing (81 mg), a decreased effect of ASA on the formation of thromboxane of platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusion can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use. 5.2 Pharmacokinetic properties On oral administration, ibuprofen is partly absorbed in the stomach and then completely in the small intestine. Following hepatic metabolism (hydroxylation, carboxylation, conjugation), the pharmacologically inactive metabolites are completely eliminated, mainly renally (90 %), but also with the bile. The elimination half-life in healthy individuals and those with liver and kidney diseases is hours. Plasma-protein binding is about 99 %. Peak plasma levels following oral administration of a normal-release pharmaceutical form (tablet) are reached after 1-2 hours. Ibuprofen is absorbed rapidly from the gastrointestinal tract following oral administration. In a pharmacokinetic study (R ), the time to peak plasma levels (median Tmax) in fasted state, for normal-release pharmaceutical form ibuprofen acid tablets (Nurofen tablets) was 90 min compared with 40 min for Nurofen Capsules, soft. Ibuprofen is detected in the plasma for more than 8 hours after administration of Nurofen. 5.3 Preclinical safety data The subchronic and chronic toxicity of ibuprofen in animal experiments was observed principally as lesions and ulcerations in the gastro-intestinal tract. In vitro and in vivo studies gave no clinically relevant evidence of a mutagenic potential of ibuprofen. In studies in rats and mice no evidence of carcinogenic effects of ibuprofen was found. Ibuprofen led to inhibition of ovulation in rabbits as well as disturbance of implantation in various animal species (rabbit, rat, mouse). Experimental studies have demonstrated that ibuprofen crosses the placenta, for maternally toxic doses, an increased incidence of malformations (e.g. ventricular septal defects) was observed. In animal studies it has been observed that the use of NSAIDs, known to inhibit prostaglandin synthesis, may increase the incidence of dystocia and delayed parturition. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Fill Macrogol 600 Potassium hydroxide Purified water Capsule Shell: Gelatin Sorbitol Liquid (E420) Ponceau 4R (E124) Ink: Titanium Dioxide (E171), Propylene Glycol, Hypromellose (E464). Processing Aids: Triglycerides (medium chain) Lecithin (E322) 6.2 Incompatibilities Not applicable. 13

14 6.3 Shelf life 2 years 6.4 Special precautions for storage Do not store above 25 C. Store in the original package to protect from moisture. Do not refrigerate or freeze. 6.5 Nature and contents of container Blister, white opaque PVC/ PVDC aluminium. Each blister tray contains 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 40 or 50 capsules, soft. The blisters are packed in a cardboard carton. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7 MARKETING AUTHORISATION HOLDER Reckitt Benckiser Healthcare (UK) Ltd Slough SL1 4AQ UK 8 MARKETING AUTHORISATION NUMBER(S) PL 00063/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 01/02/ DATE OF REVISION OF THE TEXT 01/02/

15 Module 3 Product Information Leaflet text version The MAH has submitted a text version only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. 15

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24 Module 4 Labelling text version The MAH has submitted a text version only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. 24

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27 Module 5 Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Reckitt Benckiser Healthcare (UK) Ltd a Marketing Authorisation for the medicinal product, Nurofen 400 mg Capsule, soft (PL 00063/0615, UK/H/3809/001/DC), on 01 February The product is a P licensed medicine. This application concerns a line extension application, submitted in accordance with Article 8(3) of Directive 2001/83/EC (as amended) for a known active substance, to the marketing authorisation granted to Reckitt Benckiser Healthcare (UK) Ltd for Nurofen 200 mg tablets (PL 00065/0385, licensed on 29 th January 2011). The line extension application concerns a change of pharmacokinetics, strength and pharmaceutical form. Nurofen 200 mg tablets (PL 00065/0385) was initially authorised to Crookes Healthcare Limited (PL 00327/0146) on 15 th July 2003 as a line-extension to the original Marketing Authorisation for Nurofen 200 mg Tablets (PL 00327/0004, Crookes Healthcare Limited), granted on 6 th May PL 00327/0146 underwent a Change of Ownership (CoA) procedure to the current Reckitt Benckiser Healthcare (UK) Ltd licence on 29 th January The originator UK reference product has been authorised in the EU for more than 10 years, thus the period of data exclusivity has expired. With the UK as the Reference Member State (RMS) in this Decentralised Procedure, Reckitt Benckiser Healthcare (UK) Ltd applied for a Marketing Authorisation for Nurofen 400 mg Capsule, soft in Austria, Bulgaria, Cyprus, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Romania and Spain. Nurofen 400 mg soft capsules are indicated in adults and adolescents weighing from 40 kg (12 years of age and above) for the symptomatic treatment of mild to moderate pain such as headache, period pain, dental pain and fever and pain associated with the common cold. Ibuprofen (ATC classification: M01AE01) is a non-steroidal anti-inflammatory drug (NSAID) that, in the conventional animal-experiment inflammation models, has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits ADP- and collagen-inducted platelet aggregation. No new non-clinical or clinical efficacy studies were conducted for this application, which is acceptable given that the application was a line extension application for a known active substance. The application is supported by a bioequivalence study comparing the pharmacokinetic profile of the test product, Nurofen 400 mg soft capsules, to that of two clinical reference products, 2 x Nurofen 200 mg Tablets (Crookes Healthcare Ltd. Reference product B) and a commercially available form of Ibuprofen 400 mg liquid capsules (Reference product C). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of 27

28 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. The RMS considers that the pharmacovigilance system as described by the Marketing Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified Person (QP) 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 an adequate Risk Management Plan (RMP). The safety profile of the active is well-established. The MAH has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). There is no reason to conclude that marketing of this product will change the overall use pattern of the existing market. There are no environmental concerns associated with the method of manufacture or formulation of the product. 28

29 II. ABOUT THE PRODUCT Name of the product in the Reference Member State Name(s) of the active substance(s) (INN) Pharmacotherapeutic classification (ATC code) Pharmaceutical form and strength(s) Reference numbers for the Decentralised Procedure Reference Member State Member States concerned Nurofen 400 mg Capsule, soft Ibuprofen Anti-inflammatory and antirheumatic products, non steroids; propionic acid derivatives (M01AE01) Soft capsules 400 mg UK/H/3809/001/DC United Kingdom AT, BG, CY, DE, ES, FR, HU, IT, NL, PO, PT, RO. Marketing Authorisation Number(s) PL 00063/0615 Name and address of the authorisation holder Reckitt Benckiser Healthcare (UK) Ltd Slough SL1 4AQ UK 29

30 III III.1 SCIENTIFIC OVERVIEW AND DISCUSSION QUALITY ASPECTS ACTIVE SUBSTANCE Ibuprofen Nomenclature: INN: Ibuprofen Chemical names: i) (2RS)-2-[4-(2-methylpropyl)phenyl]propanoic acid ii) 2-(4-Isobutylphenyl)-propionic acid Structure: Molecular formula: C 13 H 18 O 2 Molecular weight: g/mol CAS No: Physical form: A white or almost white, crystalline powder or colourless crystals Solubility: Practically insoluble in water, freely soluble in acetone, in methanol and in methylene chloride The active substance, ibuprofen, is the subject of a European Pharmacopeia (Ph. Eur.) monograph. All aspects of the manufacture and control of ibuprofen are supported by European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability (CEP). The certificates are accepted as confirmation of the suitability of ibuprofen for inclusion in this medicinal product. The applied retest periods are supported by satisfactory information. 30

31 MEDICINAL PRODUCT Description and Composition Nurofen 400 mg soft capsules are red, oval-shaped transparent soft gelatin capsules with a Nurofen logo printed in white. Each capsule contains ibuprofen 400 mg. Other ingredients consist of pharmaceutical excipients, namely gelatin, sorbitol liquid (E420) and Ponceau 4R making up the capsule shells; macrogol 600, potassium hydroxide and purified water making up the capsule contents; titanium dioxide (E171), propylene glycol and hypromellose (E464) making up the printing ink (Opacode NS white); and medium chain triglycerides and lecithin (E322) acting as processing aids. Appropriate justification for the inclusion of each excipient has been provided. All excipients used comply with their respective Ph. Eur monographs, with the exceptions of Ponceau 4R and Opacode NS white, which are controlled to satisfactory in-house specifications. The constituents of Opacode NS white comply with their respective Ph. Eur monographs. Satisfactory Certificates of Analysis have been provided for all excipients. The only excipient used that contains material of animal or human origin is gelatin. Satisfactory documentation has been provided by the gelatin suppliers stating that the gelatin they provide complies with the criteria described in the current version of the monograph Products with risk of transmitting agents of animal spongiform encephalopathies. None of the excipients are sourced from genetically modified organisms. There were no novel excipients used. Pharmaceutical development Details of the pharmaceutical development of the medicinal product have been supplied and are satisfactory. The proposed ibuprofen capsule was developed to be an oral soft capsule formulation containing ibuprofen 400 mg in a liquid based medium. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies were conducted and the results were satisfactory. The validation data demonstrated consistency of the manufacturing process. Finished product specifications Finished product specifications are provided for both release and shelf-life and are satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used. 31

32 Container Closure System Nurofen 400 mg soft capsules are licensed for marketing in polyvinylchloride (PVC)- polyvinylidene chloride (PVdC)-aluminium foil blister strips, which are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 40 or 50 soft capsules. The MAH has stated that not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability Finished product stability studies have been conducted in accordance with current guidelines, using product stored in the packaging proposed for marketing. These data support the applied shelf-life of 2 years, with the storage instructions Do not store above 25 C. Store in the original package to protect from moisture. Do not refrigerate or freeze. Quality Overall Summary A satisfactory quality overview is provided, and has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Product Information The approved Summary of Product Characteristics (SmPC), and Patient Information Leaflet (PIL) and labelling texts are satisfactory. The MAH has submitted text versions of the PIL and labelling only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. The labelling texts fulfil the statutory requirements for Braille. The PIL text is in line with the SmPC and is satisfactory. The user-testing of the PIL text has been accepted based on a bridging report provided by the applicant making reference to the successful user-testing of the parent PIL for Nurofen Actilast 200 mg Capsule, soft. The text, content and layout of the proposed PIL are considered to be sufficiently similar to the approved PIL for the parent product. The bridging is accepted. Conclusion All pharmaceutical issues have been resolved and the quality grounds for this application are considered adequate. There are no objections to approval of Nurofen 400 mg Capsule, soft from a pharmaceutical point of view. 32

33 III.2 NON-CLINICAL ASPECTS Specific non-clinical studies have not been performed, which is acceptable considering that this is a line extension application for a known active substance. The non-clinical overview provides a satisfactory review of the pharmacodynamic, pharmacokinetic, and toxicological properties of ibuprofen, a widely used and well-known active substance. The overview, dated November 2008, cites 86 references from the published literature dated up to year The CV of the non-clinical expert has been supplied. For applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the originator product, Nurofen 200 mg Tablets (Reckitt Benckiser Healthcare (UK) Ltd). The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). There are no objections to approval of Nurofen 400 mg Capsule, soft from a non-clinical point of view. III.3 CLINICAL ASPECTS CLINICAL BACKGROUND Ibuprofen was originally introduced in the late 1960s as a prescription only medicine and became available over the counter in 1983 in the UK. Ibuprofen inhibits prostaglandin synthesis by competitive inhibition of the two isomers of cyclooxygenase, COX-1 and COX- 2. It is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory and antipyretic properties. INDICATIONS Nurofen 400 mg soft capsules are indicated in adults and adolescents weighing from 40 kg (12 years of age and above) for the symptomatic treatment of mild to moderate pain such as headache, period pain, dental pain and fever and pain associated with the common cold. The indications are satisfactory. POSOLOGY AND METHOD OF ADMINISTRATION Full details concerning the posology are provided in the SmPC. The posology is satisfactory. The MAH has discussed whether the shorter T max of the proposed product, compared to standard Nurofen tablets, would be affected if the product were taken after food. It was agreed that GI toxicity is dose-dependent, and that there is no evidence that the risk is reduced by ingestion in the fed state. Pharmacokinetic data were presented regarding the effect of food on absorption parameters. As expected, C max is reduced and T max is increased in the fed state, compared to the fasted state, for ibuprofen acid and ibuprofen lysine formulations. The expert report concluded that the bioavailability of ibuprofen formulations, including lysinate (a faster acting formulation), is not affected by food. However, C max is reduced. There is no published evidence to support recommendations to take ibuprofen in the fed state, or with milk. 33

34 CLINICAL PHARMACOLOGY The clinical pharmacology of ibuprofen is well-known. With the exception of the bioequivalence study, no new pharmacodynamic or pharmacokinetic data are supplied and none are required for this application. The proposed formulation contains ibuprofen in a solubilised form. The MAH claims that absorption will be faster when compared to standard Nurofen tablets, but extent of absorption (AUC) will be equivalent. Data from a single bioequivalence study (detailed below) is submitted to support this claim. The clinical overview also discusses the slowing of absorption when ibuprofen is taken after food, with no significant reduction in bioavailability. Pharmacokinetics bioequivalence study The application is supported by a bioequivalence study comparing the pharmacokinetic profile of the test product, Nurofen 400 mg soft capsules, to that of two clinical reference products, 2 x Nurofen 200 mg Tablets (Crookes Healthcare Ltd. Reference product B) and a commercially available form of Ibuprofen 400 mg liquid capsules (Reference product C). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). Certificates of Analysis were provided for the test and reference products. This was a randomised, single-dose open-label, four-way crossover bioequivalence study conducted in healthy, adult human male and female subjects under fasting conditions. Following an overnight fast of at least 10 hours, a single dose of the investigational products was administered orally according to the randomisation schedule, with water, to each subject in each period. A satisfactory washout period of 7 days was maintained between the dosing days in each group. Blood samples were taken pre-dose and at specified time points up to 12.0 hours after administration of test or reference product. Plasma levels of ibuprofen were quantified by a validated HPLC-MS/MS bioanalytical method. The primary pharmacokinetic parameters for the study were C max, AUC 0-t and AUC 0-. Bioequivalence of the test product versus the reference products was concluded if the 90% Confidence Intervals (CI) of the ratio of the test and reference products fell within the acceptance range, (80%-125%), for log-transformed C max, AUC 0-t and AUC 0- for ibuprofen. Results: Safety 8 subjects experienced a total of 14 adverse events (AEs) over the course of the study. Adverse events were mild to moderate in intensity. There were no deaths or serious or significant adverse events. The summary of the results of the bioequivalence study are tabulated below: 34

35 Summary pharmacokinetic data for ibuprofen for a randomised, 4-way, single-dose crossover study; healthy subjects, dosed fasted; t=12 hours. Wash-out period: 7 days. Nurofen 400 mg soft capsules vs. 2 x Nurofen 200 mg Tablets (Reference product B) C max AUC 0-t AUC 0- maximum plasma concentration area under the plasma concentration-time curve from time zero to t hours area under the plasma concentration-time curve from time zero to infinity Summary pharmacokinetic data for ibuprofen for a randomised, 4-way, single-dose crossover study; healthy subjects, dosed fasted; t=12 hours. Wash-out period: 7 days. Nurofen 400 mg soft capsules vs. Ibuprofen 400 mg liquid capsules (Reference product C) C max AUC 0-t AUC 0- maximum plasma concentration area under the plasma concentration-time curve from time zero to t hours area under the plasma concentration-time curve from time zero to infinity Based on the submitted bioequivalence study, Nurofen 400 mg soft capsules are considered bioequivalent with Nurofen 2 x 200 mg tablets for AUC, but not C max. Nurofen 400 mg soft capsules are considered bioequivalent with Ibuprofen 400 mg liquid capsules for AUC and C max. Clinical efficacy No new data have been submitted and none are required. Efficacy is reviewed in the clinical overview. The efficacy of ibuprofen is well-established from its extensive use in clinical practice. The MAH has adequately reviewed the literature in support of the claimed indications of mild to moderate pain such as headache, period pain, dental pain and fever and pain associated with the common cold. Efficacy data was presented from the literature regarding a range of formulations of ibuprofen, including solubilised (liquigel) formulations. 35

36 The MAH discusses the potential advantage to the patient of a faster onset of analgesia and has summarised a number of studies from the literature that support the hypothesis that faster absorption of ibuprofen results in faster onset of analgesia. Clinical studies from the literature showing a faster onset of analgesia, compared to standard ibuprofen tablets, were presented for arginine, sodium and lysine salts. The T max and C max values from the submitted bioequivalence study appear comparable to other fast-acting ibuprofen formulations, as presented by the MAH. Clinical safety The MAH refers to the well-established safety profile of the active substance, ibuprofen. A summary of tolerability data for ibuprofen preparations associated with a higher C max than standard ibuprofen tablets is presented. There is no evidence from this data that adverse events differ according to formulation. The MAH has provided an adequate review of drug interactions, and use in special groups, to support the proposed SmPC. The clinical overview on the clinical pharmacology, efficacy and safety is adequate. In the submitted bioequivalence study, values for C max of Nurofen 400 mg soft capsules exceeded the predefined bioequivalence range when compared with the reference product, Nurofen 200 mg Tablets and T max -values were significantly shorter. Therefore, the applicant was asked to provide specific evidence that the higher Cmax and the shorter Tmax do not adversely affect the benefit/risk-balance of Nurofen 400 mg soft capsules when compared with the reference product Nurofen 200 mg Tablets. The MAH provided a discussion of Study X, an endoscopy safety study comparing two salt formulations of ibuprofen (lysinate and sodium dihydrate) with standard ibuprofen and placebo after repeat dosing. In general, ibuprofen salts show a faster absorption which is characterised by a higher C max and a shorter T max. In Study X, evidence of higher Lanza scores was provided with ibuprofen salts compared to standard ibuprofen. The ibuprofen salts displayed a significantly more unfavourable gastrointestinal safety profile in comparison to standard ibuprofen, although when this study was conducted a modified Lanza scoring system was used. In Study X the maximum daily dose and the maximum treatment duration for OTC were exceeded by 400 mg ibuprofen and 3 days respectively. Nevertheless the findings of Study X are considered to be of value with regard to the safety evaluation of rapidly absorbed ibuprofen formulations. The increased endoscopy lesion and bleeding score associated with the lysinate and sodium dihydrate formulations are considered relevant to the liquid formulation of potassium ibuprofen present in the Nurofen 400 mg soft capsule formulation. The MAH also cited a smaller endoscopic study, performed by Gisbert (Gisbert et al., 2005). In this study, endoscopic lesions were lower in a group treated with ibuprofen arginate than in the group receiving standard ibuprofen but the differences did not reach statistical significance. Endoscopic studies No endoscopic studies were conducted as part of the clinical programme for this product so there are no GI tolerability data available to present or discuss. However, since the pharmacovigilance data indicate that the incidence of all adverse events for the soft gel capsules is similar to that for standard Nurofen tablets and to that for ibuprofen salt formulations, there is no reason to suspect that there will be a significant difference in GI adverse events reported with soft gel capsules. 36

37 Incidence of Dental wound infections and of dry socket The MAH clarifies that Nurofen 400 mg soft capsules are not designed to dissolve in the mouth and patients are advised not to chew the capsules but to swallow them whole. Once the capsule has dissolved and the ibuprofen has dissociated in the GI tract, the released ibuprofen is chemically identical to ibuprofen from other preparations and, therefore, a higher incidence of dental wound infections and dry socket is not expected with this product. Conclusion The MAH has provided discussion of the safety of ibuprofen formulations with higher C max values than standard ibuprofen acid, with reference to the literature. There is no conclusive evidence of a difference between formulations with respect to Lanza scores and adverse events. Post-marketing data is also supportive of the conclusion of comparable safety. The results of the submitted bioequivalence study demonstrated that Nurofen 400 mg soft capsules were bioequivalent to Ibuprofen 400 mg liquid capsules (Reference product C) for AUC and C max. The demonstration of bioequivalence of C max, in addition to T max, with this European marketed product provides additional reassurance concerning the efficacy and safety of the proposed formulation. The proposed formulation has a similar PK profile to a number of marketed ibuprofen formulations in Europe. There is insufficient evidence to conclude that the application for Nurofen 400 mg soft capsules is non-approvable, based on an inferior safety profile to Nurofen 200 mg tablets. Commitment - the MAH has provided a post-approval commitment to conduct an appropriately designed gastrointestinal safety study to compare mucosal damage following short-term treatment with Nurofen 400 mg soft capsules, compared to Nurofen 200 mg tablets, both dosed at 1200 mg daily, and placebo. The results will be provided within 18 months of approval of this procedure, and will be submitted as a Type II variation. PRODUCT INFORMATION: Summary of Product Characteristics (SmPC) The approved SmPC is acceptable. Product Information Leaflet (PIL) The final PIL text is in line with the approved SmPC and is satisfactory. Labelling The labelling text is satisfactory. Clinical overview A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified expert. The overview, dated July 2009, cites 95 references from the published literature dated up to year The CV of the clinical expert has been supplied. CONCLUSIONS Sufficient clinical information has been submitted to support this application. The riskbenefit of the product is considered favourable from a clinical perspective. The grant of a Marketing Authorisation was, therefore, recommended. 37

38 IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Nurofen 400 mg Capsule, soft 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 applications of this type. CLINICAL Based on the submitted bioequivalence study, Nurofen 400 mg soft capsules are considered bioequivalent with Nurofen 2 x 200 mg tablets for AUC, but not C max. Nurofen 400 mg soft capsules are considered bioequivalent with a commercially available form of Ibuprofen 400 mg liquid capsules for AUC and C max. The MAH has provided discussion of the safety of ibuprofen formulations with higher C max values than standard ibuprofen acid, with reference to the literature. There is no conclusive evidence of a difference between formulations with respect to adverse events. Post-marketing data is supportive of the conclusion of comparable safety. The MAH has provided a post-approval commitment to conduct an appropriately designed gastrointestinal safety study to compare mucosal damage following short-term treatment with Nurofen 400 mg soft capsules, compared to Nurofen 200 mg tablets, both dosed at 1200 mg daily, and placebo. The results will be provided within 18 months of approval of this procedure, and will be submitted as a Type II variation. PRODUCT LITERATURE The approved SmPC is satisfactory. The final PIL text is in line with the SmPC and is satisfactory. User-testing of the PIL text has been accepted based on bridging to the successful user-testing of the PIL for Nurofen Actilast 200 mg Capsule, soft. The results show that the leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. The approved labelling texts are satisfactory and fulfil the statutory requirements for Braille. The MAH has submitted text versions only for the PIL and labelling and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. This application is a line extension of Nurofen 200 mg Tablets Extensive clinical experience with ibuprofen is considered to have demonstrated the therapeutic value of the active substance. The benefit: risk ratio is considered to be positive. 38

39 Module 6 STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted Application type Scope Outcome 39