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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Larafen* CR Capsules 200mg.

Ketoprofen Controlled Release Capsules 200mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains Ketoprofen BP 200mg.

3 PHARMACEUTICAL FORM

Hard gelatine capsule with an opaque pink cap and transparent body containing white to whitish pellets. Each capsule is embossed with “KET 200 CR” on the body

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Larafen* CR is an analgesic, anti-inflammatory and antipyretic; recommended for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and other musculoskeletal conditions including bursitis, capsulitis, synovitis, tendinitis, fibrositis and low back pain. It is also useful to relieve the pain of sciatica, acute gout and dysmenorrhoea.

4.2 Posology and method of administration

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

Adults:

One 200mg Larafen CR Capsule to be taken orally once daily with a little food.

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).

Patients with impaired renal function and the elderly:

It is advisable to reduce the initial dosage and maintain such patients on the minimal effective dose. Individual adjustment may be considered, only after good individual tolerance has been ascertained (see section 5).

Elderly:

The elderly are at increased risk of serious adverse reactions from NSAIDs. If a NSAID is considered necessary, it is generally advisable in the elderly to begin ketoprofen therapy at the lower end of the dose range and to maintain such patients on the lowest effective dosage. The patient should be monitored for GI bleeding during NSAID therapy.

Patients with impaired hepatic function:

These patients should be carefully monitored and kept at the minimal effective daily dosage (see section 4.3 and 5).

Children:

The safety and effectiveness of ketoprofen capsules have not been established.

There are no recommendations for the use of Larafen CR in children.

Method of administration:

Oral. Larafen CR capsules should always be prescribed "To be taken with or after food" to minimise gastric intolerance

4.3 Contraindications

Larafen CR is contra-indicated in patients who have a history of hypersensitivity reactions such as bronchospasm, asthma attacks, rhinitis, angioedema, urticaria or other allergic-type reactions to ketoprofen, any other ingredients in the product, ASA or other NSAIDs. Severe, rarely fatal, anaphylactic reactions have been reported in such patients (see section 4.8). Larafen CR is also contra-indicated in the following cases:-

•    Severe heart failure,

•    an active, or a history of, peptic ulcer/haemorrhage, ulceration or perforation,

•    a history of gastrointestinal bleeding or perforation related to NSAIDs therapy,

•    haemorrhagic diathesis

•    severe hepatic insufficiency,

•    severe renal insufficiency

•    in the third trimester of pregnancy.

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 Larafen CR with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Elderly:

The elderly have an increased risk of adverse reactions to NSAIDs, especially

gastro- intestinal bleeding and perforation which may be fatal (see section 4.2).

Respiratory disorders:

Some patients with a history of bronchial asthma or allergic disease may suffer bronchospasm, particularly those with a history of allergy to ketoprofen and related compounds.

Cardiovascular, Renal and Hepatic impairment:

At the start of treatment, renal function must be carefully monitored in patients with heart impairment, heart failure, liver dysfunction, cirrhosis and nephrosis, in patients receiving diuretic therapy, in patients with chronic renal impairment, particularly if the patient is elderly. In these patients, administration of ketoprofen may induce a reduction in renal blood flow caused by prostaglandin inhibition and lead to renal decomposition. (see also Section 4.3).

NSAIDs have also been reported to cause nephrotoxicity in various forms and this can lead to interstitial nephritis, nephrotic syndrome and renal failure.

In patients with abnormal liver function tests or with a history of liver disease, transaminase levels should be evaluated periodically, particularly during long term therapy. Rare cases of jaundice and hepatitis have been described with ketoprofen.

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).

Gastro-intestinal 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 sections 4.2 and 4.3).

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

NSAIDs should only be given with care to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8). 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 corticosteroids, or anti-coagulants 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 Ketovail, the

treatment should be withdrawn.

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).

Female fertility:

The use of ketoprofen, as with other NSAIDs, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or who are undergoing investigation of infertility, withdrawal of ketoprofen should be considered.

Skin reactions:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, StevensJohnson syndrome and toxic epidermal necrolysis have been reported very rarely in association with the use of NSAIDs. 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. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Infectious disease:

As with other NSAIDs, in the presence of an infectious disease, it should be noted that the anti-inflammatory, analgesic and the antipyretic properties of ketoprofen may mask the usual signs of infection progression such as fever.

Visual disturbances:

If visual disturbances such a blurred vision occur treatment should be discontinued. This medicine contains sucrose.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Anticoagulants (heparin and warfarin) and platelet aggregation inhibitors (i.e.ticlopidine, clopidogrel):

Increased risk of bleeding.

If co-administration is unavoidable, patient should be closely monitored (see section 4.4)

Lithium: Ketoprofen can increase lithium blood levels to possibly toxic levels due to decreased elimination of lithium. If administered together, plasma concentrations of lithium should be monitored in order to adjust the lithium dose.

Other analgesics/NSAIDs    (including cyclooxygenase-2 selective

inhibitors)and high dose salicylates:

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects, particularly gastrointestinal ulceration and bleeding (see section 4.4).

Methotrexate:

Serious interactions have been recorded after the use of high dose methotrexate with NSAIDs, including ketoprofen, due to decreased elimination of methotrexate.

At doses greater than 15mg/week:

Increased risk of haematologic toxicity of methotrexate, particularly if administered at high doses (>15 mg/week), possibly related to displacement of

protein-bound methotrexate and to its decreased renal clearance. At doses lower than 15mg/week:

During the first weeks of combination treatment, full blood count should be monitored weekly. If there is any alteration of the renal function or if the patient is elderly, monitoring should be done more frequently.

Mifepristone:

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

Pentoxifylline:

There is an increased risk of bleeding. More frequent clinical monitoring and monitoring of bleeding time is required.

Antihypertensives (beta-blockers, angiotensin converting enzyme inhibitors, diuretics: Reduced anti hypertensive effect. Risk of decreased antihypertensive potency (inhibition of vasodilator prostaglandins by NSAIDs).

Diuretics: Risk of reduced diuretic effect. Patients and particularly dehydrated patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition. Such patients should be rehydrated before initiating coadministration therapy and renal function monitored when the treatment is started (see section 4.4).

Cardiac glycosides:

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

Ciclosporin: Increased risk of nephrotoxicity, particularly in elderly subjects.

Corticosteroids: Increased risk of GI ulceration or bleeding (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.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus, particularly in elderly subjects.

Thrombolytics: Increased risk of bleeding.

Probenecid: Concomitant administration of probenecid may markedly reduce the plasma clearance of ketoprofen.

Anti-platelet agents and Selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).

ACE inhibitors and Angiotensin II Antagonists:

In patients with compromised renal function (e.g. dehydrated patients or elderly patients the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure.

Zidovudine: increased risk of haematological toxicity when NSAlDs 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 Fertility, pregnancy and lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest 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, ketoprofen should not be given unless clearly necessary. If ketoprofen 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:

-    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 the 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, ketoprofen is contraindicated during the third trimester of pregnancy.

Lactation

Small amounts of ketoprofen are excreted in breast milk so use in nursing mothers should be avoided.

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

4.7 Effects on ability to drive and use machines

Ketoprofen can cause nausea, dizziness, confusion and drowsiness, visual disturbances or headaches, therefore patients should be warned of these effects and if affected, patients should not drive or operate machinery.

4.8 Undesirable effects

The following CIOMS frequency rating is used, when applicable:

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).

The following adverse reactions have been reported with Ketoprofen in adults:

Blood and the lymphatic system disorders:

Rare: haemorrhagic anaemia, anaemia due to bleeding

Not known: thrombocytopenia, neutropenia, agranulocytosis, bone marrow

aplasia and haemolytic anaemia

Immune    system

disorders:

Rare: - anaphylactic reactions (including shock)

Psychiatric disorders:

Not known: mood disorders, insomnia

Nervous    system

disorders:

Uncommon: headache, dizziness, somnolence

Not known: convulsions, dysgeusia, depression, confusion, hallucinations, vertigo, malaise, and drowsiness, reports of aseptic meningitis (especially in patients with existing auto- immune disorders such as systemic lupus erythematosis, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4 Warnings and precautions for use).

Rare: paraesthesia

Eye

disorders:

Rare: visual disturbances such as blurred vision (see section 4.4 Warnings and precautions)

Not known: optic neuritis

Ear and labyrinth disorders:

Rare: tinnitus

Cardiac

disorders:

Not known: oedema, cardiac failure

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).

Vascular disorders

Not known: hypertension, vasodilatation

Gastrointestinal

disorders:

Common: dyspepsia, abdominal pain, nausea, vomiting, indigestion, heartburn

Uncommon: diarrhoea, constipation, flatulence, gastritis

Rare: stomatitis, peptic ulcer, pancreatitis;

Very rare reports of pancreatitis have been noted with NSAIDs Not known: exacerbation of colitis and Crohn's disease, gastrointestinal bleeding and perforation, gastralgia, melaena, haematemesis

Gastro-intestinal bleeding may sometimes be fatal, particularly in the

elderly

(see section 4.4 Special warnings and precautions for

use).

Hepato-biliary

disorders:

Rare: elevation of transaminase levels, elevated serum bilirubin due to

hepatitis disorders, and rare cases of hepatitis

Not known: abnormal liver function, hepatic damage, jaundice

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus

Not known: Photosensitivity reactions, alopecia, urticaria, angioedema, bullous eruption (including, Stevens Johnson Syndrome and Toxic Epidermal Necrolysis), exfoliative and bullous dermatoses (including epidermal necrolysis, erythema multiforme) purpura.

Not known: abnormal renal function tests, acute renal failure, tubulointerstitial nephritis, nephritic syndrome, renal damage

General disorders and administration site conditions:

Uncommon: oedema, fatigue,

Not known: headache, taste perversion

Respiratory, thoracic and mediastinal disorders

Rare: aggravated asthma, asthmatic attack,

Not known: bronchospasm (particularly in patients with known hypersensitivity to ASA and other NSAIDs), rhinitis, non-specific allergic reactions, dyspnoea

Investigations Rare: weight increased

Should any severe adverse events occur, treatment with Larafen CR should be stopped immediately.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

Cases of overdose have been reported with doses up to 2.5g of ketoprofen. In most instances, the symptoms have been benign and limited to lethargy, drowsiness, nausea, vomiting and epigastric pain. Headache, rarely diarrhoea, disorientation, excitation, coma, dizziness, tinnitus, fainting, occasionally convulsions may also occur. Adverse effects seen after overdose with propionic acid derivatives such as hypotension, bronchospasm and gastro-intestinal haemorrhage may occur because Larafen CR is a controlled release preparation, continued absorption from capsules in the gastrointestinal tract may be expected.

In cases of significant poisoning, acute renal failure and liver damage are possible.

If renal failure is present, haemodialysis may be useful to remove circulating medicinal product.

As with other propionic acid derivatives, ketoprofen demonstrates less toxicity than asprin or paracetamol.

Owing to the slow release characteristics of Larafen CR, it should be expected that ketoprofen will continue to be absorbed for up to 16 hours after ingestion.

Therapeutic measures:

Gastric lavage, aimed at recovering pellets that may still be in the stomach should be performed if the patient is seen soon after ingestion. It should be possible to identify the pellets in the gastric contents. Treatment is otherwise supportive and symptomatic.

Within one hour of ingestion of a potentially toxic amount, administration of activated charcoal in an attempt to reduce absorption of slowly-released ketoprofen should be considered. It should be possible to identify the pellets in the gastric contents. Correction of severe electrolyte abnormalities may need to be considered.

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.

The benefit of gastric decontamination is uncertain.

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

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.

Anti-inflammatory

It inhibits the development of carageenan-induced abscesses in rats at 1mg/kg, UV-radiation induced erythema in guinea pigs at 6mg/kg. It is also a potent inhibitor of PGE2 and PFG2 synthesis in guinea pig and human chopped lung preparations.

Ketoprofen effectively reduced visceral pain in mice caused by phenyl benzoquinone or by bradykinin following p.o. Administration at about 6mg/kg.

Antipyretic

Ketoprofen (2 and 6mg/kg) inhibited hyperthermia caused by s.c injection of brewer's yeast in rats and, at 1mg/kg hyperthermia caused by i.v. administration of anticoagulant vaccine to rabbits.

Ketoprofen at 10mg/kg i.v. did not affect the cardiovascular, respiratory, central nervous system or autonomic nervous systems.

5.2 Pharmacokinetic properties

Larafen CR Capsule is a controlled release formulation which 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 Preclinical safety data

Not applicable.

No Data Held

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Polyethylene glycol, ethylcellulose, purified stearic acid, talc, polymers of methacrylic acid, acrylic esters and methacrylic acid esters, sucrose, corn starch, gelatin, erythrosine (E127) and titanium dioxide (E171).

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 15 September 1993.

DATE OF REVISION OF THE TEXT

13/08/2014