Tiloket

Valket 200 Retard

Each capsule contains ketoprofen 200.0 mg

Excipient with known effect: Each tablet contains 37.87mg of sucrose.

For the full list of excipients, see section 6.1.

Capsules with pH sensitive controlled release.

Hard gelatin size 1 capsules with an opaque pink cap and transparent body.

The capsules are either unmarked or marked 'KZ 200 AB' and contain white to whitish controlled release pellets.

Valket 200 Retard 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, tendonitis, fibrositis and low back pain. It is also useful to relieve the pain of sciatica, acute gout and dysmenorrhoea.

Posology

Adults: One 200 mg capsule to be taken orally once daily with a little food.

Older people:

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest dose should be used and the patient should be monitored for GI bleeding for 4 weeks following initiation of NSAID therapy.

Paediatric population:

The safety and efficacy of Ketoprofen in children has not yet been established.

No data are available.

There are no recommendations for the use of ketoprofen in children.

Method of Administration

For oral administration.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Valket 200 Retard should not be given to patients with chronic dyspepsia; known history of hypersensitivity reactions (e.g. bronchospasm, asthma/ asthmatic attacks, rhinitis or urticaria or other allergic-type reactions) to ketoprofen, aspirin or other non-steroidal anti-inflammatory agents.

Severe, rarely fatal, anaphylactic reactions have been reported in such patients (see section 4.8).

Ketoprofen is also contraindicated in the third trimester of pregnancy.

Ketoprofen is contraindicated in the following cases:

• severe heart failure

• or with severe renal dysfunction/ insufficiency

• Active peptic ulcer, or any history of gastrointestinal bleeding, ulceration or perforation haemorrhagic diathesis

• severe hepatic insufficiency

Warnings

The use of Valket with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 for 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 gastrointestinal toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal 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 Valket, the treatment should be withdrawn.

NSAIDs have been reported to cause nephrotoxicity in various forms; interstitial nephritis, nephrotic syndrome and renal failure. In patients with renal, cardiac or hepatic impairment caution is required since the use of NSAIDs may result in deterioration of renal function: the dose should be kept as low as possible and renal function should be monitored.

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

Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

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

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). There are insufficient data to exclude such a risk for ketoprofen.

Precautions

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).

At the start of treatment, renal function must be carefully monitored in patients with heart failure, 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 decompensation.

Caution is required in 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.

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.

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.

The use of NSAIDs 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 the NSAID should be considered.

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to aspirin and/or NSAIDs than the rest of the population. Administration of this medicinal product can cause asthma attacks or bronchospasm, particularly in subjects allergic to aspirin or NSAIDs (see section 4.3).

As with all NSAIDs, careful consideration should be given when treating patients with existing uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease, as well as, before initiating long term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

If visual disturbances, such a blurred vision, occur treatment should be discontinued.

Not recommended medicinal product associations

Other NSAIDs (including cyclooxygenase-2 selective inhibitors) and high dose salicylates:

Increased risk of gastrointestinal ulceration and bleeding. A concomitant use of two or more NSAIDs should be avoided.

Anticoagulants:

NSAIDs may enhance the effects of anticoagulants (such as heparin and warfarin) and platelet aggregation inhibitors (i.e. ticlopidine, clopidogrel):

Increased risk of bleeding (see section 4.4).

If co-administration is unavoidable, patient should be closely monitored.

Lithium:

Risk of elevation of lithium plasma levels, sometimes reaching toxic levels due to decreased lithium renal excretion. Where necessary, plasma lithium levels should be closely monitored and the lithium dosage levels adjusted during and after NSAID therapy.

Methotrexate at doses greater than 15 mg/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.

Medicinal product associations requiring precautions for use

Diuretics:

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).

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.

Methotrexate at doses lower than 15 mg/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.

Corticosteroids:

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

Pentoxifylline:

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

Medicinal product associations to be taken into account

Antihypertensive agents (beta-blockers, angiotensin converting enzyme inhibitors, diuretics):

Risk of decreased antihypertensive potency (inhibition of vasodilator prostaglandins by NSAIDs).

Thrombolytics:

Increased risk of bleeding.

Anti-platelet agents and Selective serotonin reuptake inhibitors (SSRIs):

Increased risk of gastrointestinal bleeding (see section 4.4).

Probenecid:

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

The active ingredient of Valket 200 Retard, ketoprofen, is highly protein bound, therefore, alteration of the dosage of other protein bound drugs such as anticoagulant, sulphonamides and hydantoins such as phenytoin may be necessary when taken together. Serious interactions have been reported with digoxin.

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels. NSAID's should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

An increased risk of nephrotoxicity with ciclosporin may occur when NSAIDs are taken contemporaneously.

Tacrolimus:

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

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.

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 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.

Breast-feeding

No data are available on excretion of ketoprofen in human milk. Ketoprofen is not recommended in nursing mothers.

Ketoprofen can cause nausea, dizziness, confusion, somnolence/ drowsiness, visual disturbances, headaches or convulsions as undesirable effects; therefore, patients should be warned of these effects and advised not to drive or operate machinery.

Classification of expected frequencies

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 lymphatic system disorders

Rare: haemorrhagic anaemia

Not known: agranulocytosis, thrombocytopenia, bone marrow failure, neutropenia, aplastic anaemia and haemolytic anaemia

Infections and infestations

Poor resistance to infection

Immune system disorders

Not known: anaphylactic reactions (including shock)

Psychiatric disorders

Not known: mood altered, depression, confusion, hallucinations, insomnia

Nervous system disorders

Uncommon: headache, dizziness, somnolence

Rare: paraesthesia − not known: convulsions, dysgeusia

Not known: drowsiness, convulsions, dysgeusia

Eye disorders

Rare: vision blurred (see section 4.4)

Not known: visual disturbances, optic neuritis

Ear and labyrinth disorders

Rare: tinnitus

Not known: vertigo

Cardiac disorders

Not known: heart failure

Vascular disorders

Not known: hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders

Rare: asthma

Not known: bronchospasm (particularly in patients with known hypersensitivity to ASA and other NSAIDs), rhinitis, dyspnoea

Gastrointestinal disorders:

Common: dyspepsia (applies only to solids and syrup), nausea, abdominal pain (abdominal pain applies only to solids and syrup), vomiting

Uncommon: constipation, diarrhoea, flatulence (flatulence applies only to solids and syrup), gastritis

Rare: stomatitis, peptic ulcer

Not known: exacerbation of colitis and Crohn's disease (applies only to solids and syrup), gastrointestinal haemorrhage and perforation

Hepatobiliary disorders

Rare: hepatitis, (Abnormal liver function) transaminases increased, elevated serum bilirubin due to hepatitis disorders

Not known: enlargement of the liver

Skin and subcutaneous disorders

Uncommon: rash, pruritis

Not known: photosensitivity reaction, alopecia, urticaria, angioedema, bullous eruption including Stevens-Johnson syndrome and toxic epidermal necrolysis, erythema multiforme and exfoliative dermatitis

Renal and urinary disorders

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

General disorders and administration site conditions

Uncommon: oedema

Not known: malaise, fatigue

Investigations

Rare: weight increased

Injury, poisoning and procedural complications

Not known: tendency to bruise or bleed easily

Reproductive system and breast disorders

Not known: impotence

Musculoskeletal and connective tissue disorders

Not known: muscle problems in patients with kidney disease or underactive thyroid gland.

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).

General disorders and administration site conditions

Uncommon: fatigue

Should any severe adverse event occur, treatment with Valket 200 Retard should be stopped immediately. Patients should be warned of the potential side effects.

As with other propionic acid derivatives, ketoprofen demonstrates less toxicity than aspirin or paracetamol. Cases of overdose have been reported with doses up to 2.5 g of ketoprofen. In most instances, the symptoms observed have been benign and limited to lethargy, drowsiness, nausea, dizziness, abdominal/ epigastric pain and vomiting but hypotension, bronchospasm and gastro-intestinal haemorrhage may occur. Because Valket 200 Retard is a controlled release preparation, continued absorption from capsules in the gastro-intestinal tract may be expected. There are no specific antidotes to ketoprofen overdosages. In cases of suspected massive overdosages, a gastric lavage is recommended, the use of activated charcoal and correction of severe electrolyte abnormalities and symptomatic and supportive treatment should be instituted to compensate for dehydration, to monitor urinary excretion and to correct acidosis, if present.

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

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

ATC Code: M01AE

The Ketoprofen 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.

None stated.

Macrogol 4000

Ethylcellulose

Stearic acid (Purified)

Talc

Eudragit 'RS'

Neutral Pellets

Sucrose

Corn starch

Ingredients removed during the manufacturing process

Ethanol 96%

Acetone

Purified water

Capsule shell

Erythrosine E127

Titanium dioxide E171

Gelatin

None reported.

4 years, unopened.

Store in a dry place below 25°C. Protect from light.

Blister packaging composed of PVC-PVdC aluminium.

28, 30, 56, 60 or 100 capsules

Not all pack sizes may be marketed.

Composition

PVC transparent foil 0.25 mm ± 8%

PVdC 40 g/sq.m. ± 10%

Crude Aluminium foil 0.025 mm ± 8%

PVdC 20 g/sq.m. ± 10%

No special requirements for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

Tillomed Laboratories Ltd

220 Butterfield

Great Marlings

Luton

LU2 8DL

UK

PL 11311/0460

12/03/2001

17/04/2018