Tiloket Capsules 50mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Tiloket 50mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains ketoprofen 50mg
Excipient with known effect: Each tablet contains 107.600mg of lactose. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsule, hard.
Opaque, white, size 4, gelatin capsules containing white powder.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
These have their origin in the anti-inflammatory effect of ketoprofen, in the extent of the drug's side effects in the place that it occupies in the range of currently available anti-inflammatory drugs.
They are limited to:
• long-term-symptomatic treatment of:
o chronic inflammatory rheumatic states, particularly rheumatoid arthritis, ankylosing spondylitis or related syndromes such as Fiessinger-Leroy-Reiter's syndrome and psoriatic rheumatism. o certain painful and incapacitating osteoarthritic conditions.
• short-term, symptomatic treatment of acute attacks of:
o abarticular rheumatism (acute painful shoulder, tendinitis etc.) o microcrystalline arthritis
o osteoarthritis
o lumbar region pain, severe radiculalgia
4.2 Posology and method of administration
Posology
50 - 100mg twice daily depending on patient weight and on severity of symptoms.
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)
In the event of minor gastrointestinal side effects (heartburn, pains), the prescribing of gastro-duodenal topical preparations may help.
Medication should be taken early in the morning and late at night.
Best results are obtained by titrating dosage to suit each patient: start with a low dosage for a mild chronic disease and a high dosage for acute or severe disease.
Some patients derive greater benefit from treatment with a higher dosage at night-time rather than early morning.
Where patients require a maximum oral dosage initially an attempt should be made to reduce this dosage of maintenance use since a lower dosage might be better tolerated for purposes of long-term treatment.
No reduction was seen in the absorption of ketoprofen when co-administered with aluminium oxide gels.
Adults:
100 - 200 mg daily depending on patient weight and on severity of symptoms, to be taken preferably with food.
Older people:
The elderly are at 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.
In the elderly it is advisable to begin therapy at the lower end of the dose range and to maintain such patients on the lowest effective dosage.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
Paediatric population:
The safety and efficacy of Tiloket Capsules in children under 15 years has not yet been established.
No data are available.
Method of administration
For oral administration
The capsules are to be taken with a glass of water at mealtimes.
4.3 Contraindications
Ketoprofen is contraindicated in the following cases:
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Known allergy to aspirin, and to substances with a similar effect (nonsteroidal anti-inflammatory agents): who have a history of hypersensitivity reactions such as bronchospasm, asthmatic attacks, rhinitis, urticaria or other allergic-type reactions to ketoprofen. Severe, rarely fatal, anaphylactic reactions have been reported in such patients (see section 4.8).
• Active peptic ulcer, or any history of gastrointestinal bleeding, ulceration or perforation
• Severe hepatocellular insufficiency
• Severe renal insufficiency
• Children aged less than 15 years
• Severe heart failure
• Haemorrhagic diathesis
• Ketoprofen is also contraindicated in the third trimester of pregnancy.
4.4 Special warnings and precautions for use
Warnings
The use of Tiloket 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 (see section 4.2, and GI and cardiovascular risks below).
Ketoprofen should be used with caution:
at the start of treatment, close supervision is necessary of the volume of urine passed and of renal function in patients with cardiac insufficiency, cirrhosis and nephrosis, in patients on diuretics, in patients with chronic renal
insufficiency and, in particular, in elderly patients
intrauterine device: a possible reduction of the device’s effectiveness.
Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.
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 Tiloket, the treatment should be withdrawn.
Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).
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 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.
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.
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.
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 as fluid retention and oedema have been reported in association with NSAID therapy. 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).
If visual disturbances, such a blurred vision, occur treatment should be discontinued.
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 longterm 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).
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).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine because it contains lactose
4.5 Interaction with other medicinal products and other forms of interaction
Not recommended medicinal product associations
Ketoprofen may alter the action of certain other medicaments by exerting a potentiating or inhibiting effect on them.
Co-administration of ketoprofen with the following drug product necessitates stringent supervision of the clinical and biochemical state of the patient:
Other NSAIDs (including cyclooxygenase-2 selective inhibitors) and high dose salicylates:
Increased risk of gastrointestinal ulcers and haemorrhages)
Anticoagulants (heparin and warfarin) and platelet aggregation inhibitors (i.e. ticlopidine, clopidogrel):
Ketoprofen may heighten the effects of oral anticoagulants (heparin and warfarin) and platelet aggregation inhibitors (i.e. ticlopidine, clopidogrel): increased risk of haemorrhage through inhibition of platelet function and irritation of digestive system mucosa. (see section 4.4).
If coadministration is unavoidable, patient should be closely monitored.
Where concomitance with K antivitamins is necessary, supervise the prothrombin time on account of the possible risk of potentiation.
Ketoprofen may result in an increase in the hypoglycaemic effect of sulphonamides (displacement of their bonds to plasma proteins)
Lithium:
Ketoprofen is a lithaemia-elevating factor, possibly up to the threshold of toxicity due to decreased lithium renal excretion. Where necessary, plasma lithium levels should be closely monitored and adjust lithium dosage during co-administration and after it has been discontinued.
Methotrexate at doses greater than 15 mg/week:
Ketoprofen increases the risk of haematological toxicity of methotrexate (potentiation), 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 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.
Antihypertensive agents (beta-blockers, angiotensin converting enzyme inhibitors, diuretics, 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. Ketoprofen may decrease the action of antihypertensive potency antihypertensive effects (inhibition of vasodilator prostaglandins by NSAIDs).
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).
-potential NSAID drug interactions: cyclosporin, corticosteroids. mifepristone. cardiac glycosides, quinolone antibiotics
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.
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.
Combinations to be taken into consideration:
Cyclosporin, tacrolimus:
Risk of additive nephrotoxic effects, particularly in elderly subjects.
4.6 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.
Ketoprofen is not recommended:
- during the first 3 months of pregnancy on account of a possible teratogenic effect. In rodents ketoprofen was neither embryotoxic nor teratogenic. In rabbits there remains a doubt: in one study there was a marked dose-dependence in the percentage of resorption, a fall in the number of live foetuses and a higher number of abnormal foetuses. In the monkey ketoprofen was not embryotoxic nor teratogenic. These facts can be explained as mainly due to the ketoprofen mechanism of action, and are standard for the NSAID class.
- during the last three months, all prostaglandin synthesis inhibitors may expose the foetus which may result in possible delay to the birth, cardiopulmonary toxicity (premature closing of the arterial canal (ductus arteriosus)) and pulmonary hypertension and possible haemorrhagic symptoms in the neonate.
- 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
In the absence of a pharmacological data on excretion of ketoprofen in human
milk, ketoprofen is not recommended in nursing mothers.
4.7 Effects on ability to drive and use machines
Patients should be warned about the potential for somnolence, dizziness or convulsions and be advised not to drive or operate machinery if these symptoms occur.
4.8 Undesirable effects
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 a moderate fall in red blood cells have been reported
Immune system disorders
Not known: anaphylactic reactions (including shock)
Psychiatric disorders
Not known: mood altered, insomnia
Nervous system disorders
Uncommon: headache, dizziness, somnolence Rare: paraesthesia
Not known: convulsions, dysgeusia, 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), depression, confusion, hallucinations, vertigo, malaise, drowsiness
Eye disorders
Rare: vision blurred (see section 4.4)
Not known: visual disturbances, optic neuritis
Ear and labyrinth disorders
Rare: tinnitus
Cardiac disorders
Not known: heart failure
Vascular disorders
Not known: hypertension, vasodilatation
Respiratory, thoracic and mediastinal disorders
Rare: asthma
Not known: bronchospasm (possibility of asthma attacks, particularly in patients with known hypersensitivity to ASA and other NSAIDs), rhinitis
Gastrointestinal disorders
Common: dyspepsia, nausea, abdominal pain, vomiting
Uncommon: constipation, diarrhoea, flatulence , gastritis
Rare stomatitis, peptic ulcer
Not known: exacerbation of colitis and Crohn’s disease, gastrointestinal
haemorrhage and perforation
Hepatobiliary disorders
Rare: hepatitis, transaminases increased, elevated serum bilirubin due to hepatitis disorders
Skin and subcutaneous disorders
Uncommon: rash, pruritis
Not known: photosensitivity reaction, alopecia, urticaria, angioedema, bullous
eruption including Stevens-Johnson syndrome and toxic epidermal necrolysis
Renal and urinary disorders
Not known: renal failure acute, tubulointerstitial nephritis, nephritic syndrome,
renal function tests abnormal
possible aggravation of an existing renal condition (see 4.4 Special Warnings and Precautions for Use)
General disorders and administration site conditions
Uncommon: oedema Not known: fatigue
Investigations
Rare: weight increased
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).
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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard
4.9. Overdose
Cases of overdose have been reported with doses up to 2.5 g of ketoprofen.
Like other propionic acid derivatives, ketoprofen is of low toxicity in overdosage. Symptoms after acute ketoprofen intoxication are benign and largely limited to drowsiness, lethargy, nausea, epigastric pain and vomiting, but adverse effects seen after overdosage with propionic acid derivatives such as hypotension, bronchospasm and gastrointestinal haemorrhage should be anticipated.
There are no specific antidotes to ketoprofen overdosages.In cases of suspected massive overdosages, a gastric lavage is recommended 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ketoprofen is a non-steroidal antiinflammatory of the propionic groups, a derivative of aryl carboxylic acid. It has anti-inflammatory, analgesic and antipyretic effects; it inhibits prostaglandin synthesis and has an inhibitory effect on platelet aggregation.
ATC Code: M01AE
5.2 Pharmacokinetic properties
Absorption
Successive measurements of serum concentrations following administration of a therapeutic dose show that ketoprofen is very rapidly absorbed. Time-to-peak serum concentration is 60-90 minutes after oral dose.
Distribution
Mean plasma half-life for the oral route is 1.5 to 2 hours. 99% of ketoprofen binds to plasma proteins. Ketoprofen passes into synovial fluid where it persists at concentrations higher than those found in serum after Hour 4 following an oral dose. It crosses the placental barrier.
Metabolism
Biotransformation of ketoprofen is performed via 2 processes: one very minor (hydroxylation) and the other largely predominant (conjugation with glucuronic acid).
Less than 1% of the administered dose of ketoprofen is recovered from urine as parent
drug, while glucuronoconjugates represent between approximately 65 and 75%.
Excretion
In the 5 days following oral dosing, 75-90% of the dose is excreted through the
kidneys and 1-8% in faeces. Excretion, which is essentially via urine, is very rapid:
50% of the administered dose is eliminated in the 6 hours following dosing. Elderly Patients
Ketoprofen absorption is not affected: the lengthening of the elimination halflife and the reduction in total clearance would seem to reflect a slowing of metabolic transformation.
Renal Insufficiency
Plasma clearance is reduced and elimination half-life lengthened.
5.3 Preclinical safety data
Not applicable.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose
Anhydrous colloidal silica Magnesium stearate
Capsule shell consisting of:
Gelatin
Sulfur dioxide (E220)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25 °C.
6.5 Nature and contents of container
Boxes of 28, 56, 84 and 112 capsules in PVC/aluminium blister strips. Not all pack sizes may be marketed.
Special precautions for disposal and other handling
6.6
No special requirements for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd 3 Howard Road Eaton Socon St. Neots
Cambs. PE19 8ET United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
PL 11311/0155
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/03/2009
10 DATE OF REVISION OF THE TEXT
12/05/2015