There is insufficient data available on the consequences of Urodulox in humans.
a) Symptoms
Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal irritation, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, hypotension, respiratory depression, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.
b) Therapeutic measure:
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.
Given the route of administration and the pharmaceutical form, an overdose with injectable Urodulox is unlikely.
Specific therapies such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism. 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. In case of frequent or prolonged convulsions, patients should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.
Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures.
Hypersensitivity to Urodulox or to any of the excipients.
Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
History of active bleedings or bleeding disorders
NSAIDS are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. Asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.
Patients with established congestive heart failure (NYHA class II-IV), ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
Severe heart failure, hepatic failure and renal failure.
History of gastrointestinal bleeding or perforation, related to previous NSAIDS therapy.
Urodulox should not be prescribed during pregnancy, especially during the last trimester of pregnancy, unless there are compelling reasons for doing so. The lowest effective dosage should be used.
Not applicable
Exceptionally, occurrence of serious cutaneous and soft tissues infections complications during varicella has been reported in association with NSAID treatment.
Urodulox is both structurally related and metabolised to diclofenac for which a greater amount of clinical and epidemiological data consistently point towards an increased risk of general arterial thrombotic events (myocardial infarction or stroke, particularly at high doses and in long treatment).4 for contraindication and Special warnings and special precautions for use).
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. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Hypersensitivity:
Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).
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).
Other adverse reactions reported less commonly include:
Renal:
Nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome and renal failure.
Hepatic:
abnormal liver function, hepatitis and jaundice.
Neurological and special senses:
Visual disturbances, optic neuritis, headaches, paraesthesia, 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 , depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.
Haematological:
Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
Dermatological:
Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity.
Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| System organ class | Common (>1/100 to <1/10) | Uncommon (>1/1,000 to <1/100) | Rare (>1/10,000 to <1/1,000) | Very rare/ isolated reports (<1/10,000) |
| Blood and lymphatic system disorders | Anaemia | Bone Marrow depression, Granulocytopenia Thrombocytopenia Neutropenia Haemolytic anaemia | ||
| Immune system disorders | Anaphylactic reaction (including shock) Hypersensitivity | |||
| Metabolism and nutrition disorders | Hyperkalemia | |||
| Psychiatric disorders | Depression Abnormal dreams Insomnia | |||
| Nervous system disorders | Dizziness | Paraesthesia Tremor Somnolence Headache Dysgeusia (abnormal taste) | ||
| Eye disorders | Visual disturbance | |||
| Ear and labyrinth disorders | Vertigo Tinnitus | |||
| Cardiac disorders | Cardiac failure | Palpitations | ||
| Vascular disorders | Hypertension | Flushing Hot flush vasculitis | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Bronchospasm Stridor | ||
| Gastrointestinal disorders | Dyspepsia Abdominal pain Nausea Diarrhoea | Flatulence Gastritis Constipation Vomiting Mouth ulceration | Melaena Gastrointestinal haemorrhage Gastrointestinal ulceration | Stomatitis Intestinal perforation Exacerbation of Crohn's disease and colitis Ulcerative Haematemesis Gastrointestinal haemorrhage Gastric ulcer Pancreatitis |
| Skin and subcutaneous tissue disorders | Pruritus Rash Dermatitis Urticaria | Face oedema Angioedema | Purpura Severe mucocutaneous skin reaction (including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis) Dermatitis bullous | |
| Musculoskeletal and connective tissue disorders | Cramps in the leg | |||
| Renal and urinary disorders | Blood urea increased Blood creatinine increased | Renal insufficiency Nephrotic syndrome Renal failure | ||
| Hepatobiliar disorders | Hepatic enzyme increased | Hepatitis Jaundice Hepatic injury (including hepatitis) Blood alkaline phosphatase increased | ||
| General disorders and administration site conditions | Oedema Fatigue Cramps in legs | |||
| Investigations | Weight increase |
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.
The results from preclinical studies conducted with Urodulox are consistent with those expected for NSAIDs. The principal target organ was the gastro-intestinal tract.
No unexpected findings were recorded.
Urodulox was not considered to have any mutagenic activity in three in vitro studies and an in vivo study in the mouse.
Urodulox was not found to be carcinogenic in either the mouse or rat.
Urodulox film-coated tablets are indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
Urodulox is a non-steroidal agent with marked anti-inflammatory and analgesic properties.
ATC code: M01A B16
The mode of action of Urodulox is largely based on the inhibition to prostaglandin synthesis. Urodulox is a potent inhibitor of the enzyme cyclo-oxygenase, which is involved in the production of prostaglandins.
After oral administration, Urodulox is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3.00 hours following ingestion. Urodulox penetrates into the synovial fluid, where the concentrations reach approximately 57% of those in plasma. The volume of distribution is approximately 25 L.
The mean plasma elimination half-life is around 4 hours. Urodulox is highly protein- bound (>99%). Urodulox circulates mainly as unchanged drug. 4'- hydroxyUrodulox is the main metabolite detected in plasma. Approximately two- thirds of the administered dose is excreted via the urine, mainly as hydroxymetabolites.
No changes in the pharmacokinetics of Urodulox have been detected in the elderly.
The use of Urodulox with concomitant NSAIDs including cyclooxygenase- 2 selective inhibitors should be avoided.
Elderly:
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
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 formation and precipitate renal failure.).
Renal:
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, liver dysfunction, those being treated with diuretics or recovering from major surgery. Effects on renal function are usually reversible on withdrawal of Urodulox Tablets.
Patients with mild to moderate renal impairment should be kept under surveillance, since the use of NSAIDs may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored regularly. Effects on renal function are usually reversible on withdrawal of Urodulox.
Hepatic:
If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Urodulox Tablets should be discontinued. Close medical surveillance is necessary in patients suffering from mild to moderate impairment of hepatic function. Hepatitis may occur without prodromal symptoms.
Use of NSAIDs in patients with hepatic porphyria may trigger an attack.
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. As the cardiovascular risks of Urodulox may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re- evaluated periodically.
Urodulox should also be administered with caution and under close medical surveillance to patients with congestive heart failure, significant risk factors for cardiovascular events and history of cerebrovascular bleeding.
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 Urodulox.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Urodulox 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.
Close medical surveillance is imperative in patients with:
- symptoms indicative of gastro-intestinal disorders involving either the upper or lower gastrointestinal tract
- with a history suggestive of gastro-intestinal ulceration, bleeding or perforation
- with ulcerative colitis or with Crohn's disease
- bleeding diathesis or haematological abnormalities.
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 , and in the elderly.).
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 antiplatelet agents such as aspirin.
When GI bleeding or ulceration occurs in patients receiving Urodulox, 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.
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.
Dermatological:
Impaired female fertility:
The use of Urodulox Tablets 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 Urodulox Tablets should be considered.
Hypersensitivity/Dermatological reactions:
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Jonson syndrome, and toxic epidermal necrolysis, have been reporting 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. Urodulox should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Exceptionally, varicella can trigger serious cutaneous and soft tissues infections complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of Urodulox in case of varicella.
Haematological:
Urodulox Tablets may reversibly inhibit platelet aggregation (see anticoagulants under 'Interactions').
Long-term treatment:
All patients who are receiving NSAIDs should be monitored as a precautionary measure e.g. renal failure, hepatic function (elevation of liver enzymes may occur) and blood counts.
Undesirable effects such as dizziness, vertigo, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
Urodulox film-coated tablets are supplied for oral administration and should be swallowed whole with a sufficient quantity of liquid.
To be taken preferably with or after food. When Urodulox was administered to fasting and fed healthy volunteers only the rate and not the extent of Urodulox absorption was affected.
Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.
Adults
The recommended dose is 200 mg daily, taken as two separate 100 mg doses, one tablet in the morning and one in the evening.
Paediatric population
There are no clinical data on the use of Urodulox in children and therefore it is not recommended for use in children under 18 years of age.
Elderly
The elderly, who are more likely to be suffering from impaired renal, cardiovascular or hepatic function and receiving concomitant medication, are at increased risk of 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 GI bleeding during NSAID therapy.
The pharmacokinetics of Urodulox are not altered in elderly patients, therefore it is not considered necessary to modify the dose or dose frequency.
Renal insufficiency
There is no evidence that the dosage of Urodulox needs to be modified in patients with mild renal impairment, but as with other NSAIDs caution should be exercised.
Hepatic insufficiency
There is some evidence that the dose of Urodulox should be reduced in patients with hepatic impairment and it is suggested that an initial daily dose of 100 mg be used.
Method of administration
Swallow the tablet whole with a glass of water. Do not crush or chew the tablets. Never change the dose of your medicine without talking to your doctor first. Continue to take your tablets for as long as your doctor recommends.
Any unused product or waste material should be disposed of in accordance with local requirements.
