SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ketocid 200mg Capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each modified release capsule contains 200 mg ketoprofen.

For excipients see section 6.1

3. PHARMACEUTICAL FORM

Modified release capsule

Each size 1 hard gelatin capsule contains white to whitish pellets. The capsule shell has an opaque, pink cap and transparent body. “KET 200 CR” is axially printed on the cap.

4. CLINICAL PARTICULARS

4.1. Therapeutic Indications

Ketoprofen is an analgesic, anti-inflammatory and antipyretic; and is recommended for the treatment of:

-    rheumatoid arthritis, osteoarthritis, ankylosing spondylitis

-    other musculoskeletal conditions including bursitis, capsulitis, synovitis, tendinitis, fibrositis and low back pain.

-    the relief of pain from sciatica, acute gout and dysmenorrhoea.

4.2 Posology and method of administration

Route of Administration

For oral administration

Dosage Recommendations

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

The maximum daily dose is 200mg. The balance of risks and benefits should be carefully considered before commencing treatment with 200mg daily, and higher doses are not recommended (see also section 4.4)

Adults

One 200 mg capsule to be taken orally once daily, preferably with or after food.

The Elderly

As for adult dosage as there is no evidence that the pharmacokinetics of ketoprofen are altered in the elderly.

The elderly are at risk of increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for gastrointestinal bleeding during NSAID therapy.

Children

There are no recommendations for the use of this product in children.

4.3 Contraindications

Hypersensitivity to ketoprofen or to any of the excipients.

Active peptic ulcer, or any history of gastrointestinal bleeding, ulceration or perforation.

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, urticaria), in response to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.

Severe heart failure, hepatic failure and renal failure (see section 4.4)

During the last trimester of pregnancy (see section 4.6).

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

The use of Ketocid with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

As with other drugs in the same therapeutic category, patients should be advised to take ketoprofen with food, to minimise gastric intolerance.

Elderly

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which can be fatal (see section 4.2).

Respiratory disorders

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, renal and Hepatic Impairment

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formulation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3).

NSAIDs have been reported to cause nephrotoxicity in various forms: interstitial nephritis, nephrotic syndrome and renal failure

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for ketoprofen.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ketoprofen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

Some epidemiological evidence suggests that ketoprofen may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially at high doses (see also section 4.2 and 4.3).

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in 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 patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

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 ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ketoprofen, the treatment should be withdrawn.

NSAIDs 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).

SLE and mixed connective tissue disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).

Dermatological

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. Ketocid should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Impaired female fertility

The use of Ketocid may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Ketocid should be considered.

4.5 Interaction with other medicinal products and other forms of interaction

Care should be taken in patients treated with any of the drugs mentioned below because, as with other NSAIDs, ketoprofen has the potential to induce the following interactions.

Other analgesics including cyclooxygenase-2 selective inhibitors

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may

increase the risk of adverse effects (see section 4.4).

Anti-hypertensives

Reduced anti-hypertensive effect.

Diuretics

Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. These properties should be kept in mind when treating patients with compromised cardiac function or hypertension, to avoid a possible worsening of these conditions.

Cardiac Glycosides

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycosides levels.

Anticoagulants, Sulphonamides and Hydantoins

Ketoprofen, is highly protein bound, and therefore, it might be expected to displace other protein bound drugs e.g. anticoagulants, sulphonamides and hydantoins such as phenytoin. Patients must be monitored closely for change in dosage requirements when giving ketoprofen to patients already receiving other highly protein bound drugs.

NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Quinolone Antibiotics

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Mifepristone

NSAIDs should not be used for 8 to 12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Methotrexate

Decreased elimination of methotrexate.

Ciclosporin

Increased risk of nephrotoxicity.

Corticosteroids

Increased risk of gastrointestinal ulceration and bleeding (see section 4.4).

Aminoglycosides

Reduction in renal function in susceptible individuals, decreased elimination of aminoglycosides and increased plasma concentrations have been reported.

Probenecid

Reduction in metabolism and elimination of NSAID and metabolites occurs with probenecid.

Lithium

Decreased elimination of lithium.

Oral Hypoglycaemic Agents

Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia is known to occur with oral hypoglycaemic agents.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section 4.4).

Tacrolimus

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine

Increased risk of haematological toxicity when NSAIDs are given with 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

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester or pregnancy is contraindicated. 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). NSAIDs should also not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

See section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue, nausea, confusion, visual disturbances and headaches are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Gastrointestinal

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, heartburn, 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. Pancreatitis has been reported very rarely.

Hypersensitivity Reactions

Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of:

non-specific allergic reactions and anaphylaxis

respiratory tract reactivity comprising of asthma, aggravated asthma, bronchospasm or dyspnoea

assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and less commonly, bullous dermatoses (including epidermal necrolysis, erythema multiforme and exfoliative dermatitis)

Cardiovascular

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Other less common adverse events include:

Renal

Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.

Hepatic

Abnormal liver function, hepatitis and jaundice Neurological and Special Senses

Visual disturbances, optic neuritis, headaches, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4), paraesthesia, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue, drowsiness, mood changes and insomnia.

Haematological Reactions

Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia

Dermatological Reaction

Bullous skin reactions. Photosensitivity

Should any severe adverse event occur, treatment should be stopped immediately.

4.9 Overdose

Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions, hypotension and bronchospasm. In cases of significant poisoning acute renal failure and liver damage are possible.

Management

Patients should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

Other measures may be indicated by the patient’s clinical condition.

The correction of severe electrolyte abnormalities may need to be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Ketoprofen is a propionic acid derivative which has analgesic, anti-pyretic and anti-inflammatory properties. It is a strong inhibitor of prostaglandin synthetase.

5.2. Pharmacokinetic Properties

This controlled release (modified release) ketoprofen formulation is designed to release ketoprofen over a period of time. Following a pharmacokinetic study in volunteers it was found that the average time to achieve maximum plasma concentration was 6.9 hours. The average half-life was found to be 7.4 hours, with a range of 5.5 to 8.0 hours. The average mean residence time was about 14 hours with an average clearance of 2.4 litres per hour. The study carried out over a five day period at the proposed dosage of once daily indicates that there is no accumulation on continued daily dosing. Ketoprofen is very highly bound to plasma protein.

5.3. Pre-clinical Safety Data

None provided.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

For modified-release _pellets:

Corn Starch Sucrose Macrogol 4000

For _pellet coating: Eudragit ‘RS’

Ethylcellulose Stearic Acid (purified) Talc

For capsule shell:

Erythrosine (E127) Titanium dioxide (E171) Gelatin

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf-Life

48 months.

6.4.    Special Precautions for Storage

Do not store above 25°C. Keep container in the outer carton.

6.5.    Nature and Content of Container

The modified-release capsules are enclosed in blister packs composed of 250pm PVC coated with 40g m" PVdC and 25pm aluminium coated with 20g m^-2 PVdC.

The blister packs are boxed in cardboard cartons containing 28, 30, 56, 60 or 100 modified-release capsules and a user leaflet.

6.6.    Instruction for Use, Handling and Disposal

Not applicable.

7. MARKETING AUTHORISATION HOLDER

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK8 3GY

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

PL 08829/0041

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

24/06/2008

10 DATE OF REVISION OF THE TEXT

22/12/2008