Valket 200 Retard
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Valket 200 Retard
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Ketoprofen BP 200.0 mg
3 PHARMACEUTICAL FORM
Capsules with pH sensitive controlled release.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
ADULTS: One 200 mg capsule to be taken orally once daily with a little food.
ELDERLY: 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.
CHILDREN: There are no recommendations for the use of ketoprofen in children.
4.3 Contraindications
Hypersensitivity to any of the constituents.
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 .history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy
• Active peptic ulcer, or any history of gastrointestinal bleeding, ulceration or perforation haemorrhagic diathesis
• severe hepatic insufficiency
4.4 Special warnings and precautions for use
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 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 antiplatelet agents such as aspirin (see section 4.5).
When GI bleeding or ulceration occurs in patients receiving Valket, 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).
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
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).
Precautions
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 discontinue
4.5 Interaction with other medicinal products and other forms of interaction
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 coadministration is unavoidable, patient should be closely monitored.
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.
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).
Medicinal product associations requiring precautions for use
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
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.
Lithium and Methotrexate:
A decreased elimination of lithium and methotrexate can occur if lithium and methotrexate are taken with NSAIDs respectively. 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.
NSAIDs 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 cyclosporin may occur when NSAIDs are taken contemporaneously.
Corticosteroids: The simultaneous administration of NSAIDs with corticosteroids may increase risk of GI bleeding/ulceration and may enhance anticoagulant effect with anticoagulants. (See section 4.4)
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.
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.
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.
Lactation
No data are available on excretion of ketoprofen in human milk. Ketoprofen is not recommended in nursing mothers.
4.7 Effects on ability to drive and use machines
Ketoprofen can cause nausea, dizziness, confusion, somnolence/ drowsiness, visual disturbances, headaches or convulsions as undesiderable effects; therefore patients should be warned of these effects and advised not to drive or operate machinery.
4.8 Undesirable effects
Classification of expected frequencies (frequencies are only applicable to the oral formulations):
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
Immune system disorders
- not known: anaphylactic reactions (including shock) , poor resistance to infection 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
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: 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.
- rare stomatitis
Less frequently, gastritis has been observed.
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
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.
4.9 Overdose
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Ketoprofen is a propionic acid derivative which has analgesic, anti-pyretic and antiinflammatory properties. It is a strong inhibitor of prostaglandin synthetase.
5.2 Pharmacokinetic properties
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.
5.3 Preclinical safety data
None stated.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
|
Macrogol 4000 |
16.30 |
mg | |
|
Ethylcellulose |
35.25 |
mg | |
|
Stearic acid (Purified) |
3.52 |
mg | |
|
Talc |
1.25 |
mg | |
|
Eudragit ‘RS’ |
3.16 |
mg | |
|
Neutral Pellets | |||
|
Sucrose |
37.87 |
mg | |
|
Corn starch |
12.63 |
mg | |
|
Ingredients removed during the manufacturing process | |||
|
Ethanol 96% |
ND | ||
|
Acetone |
ND | ||
|
Purified water |
ND | ||
|
Capsule shell | |||
|
Erythrosine E127 |
0.0431 |
mg | |
|
Titanium dioxide E171 |
1.6160 |
mg | |
|
Gelatin |
q.s. up to |
77.0 |
mg |
6.2 Incompatibilities
None reported
Shelf life
6.3
48 months, unopened
6.4 Special precautions for storage
Store in a dry place below 25°C. Protect from light.
6.5 Nature and contents of container
Blister packaging composed of PVC-PVdC aluminium.
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%
6.6 Special precautions for disposal
None stated.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd.,
3 Howard Road, Eaton Socon, St Neots,
Cambridgeshire PE19 8ET
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0460
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12/03/2001
10
DATE OF REVISION OF THE TEXT
30/05/2012