Tenoxicam 20mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20mg Tenoxicam.

Also contains lactose.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Round, yellowish film-coated tablet.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Tenoxicam tablets are for the treatment of pain and inflammation in osteoarthritis and rheumatoid arthritis. It is also indicated for short term treatment of acute musculoskeletal disorders including strains, sprains and other soft-tissue injuries.

4.2 Posology and method of administration

The tablets are for oral use and should be taken with water or other fluid, preferably with or after food.

Adults: The recommended dosage is a single daily dose of 20mg taken at the same time each day.

As there is no significantly greater therapeutic effect at higher doses, and higher doses may result in an increase of adverse events, oral doses greater than recommended should be avoided.

Tenoxicam 20 mg Tablets should only be used for up to a maximum of 2 weeks in cases of severe acute musculoskeletal disorders. Usually treatment of up to 7 days is sufficient.

Elderly: The elderly are at increased risk of the serious consequences of adverse reactions. They are also more likely to be receiving concomitant medication or to have impaired hepatic, renal or cardiovascular function. 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 for 4 weeks following initiation of NSAID therapy.

Children: Tenoxicam 20mg Tablets should not be used in children until sufficient data become available.

Use in renal and hepatic insufficiency:

Creatinine clearance	Dosage regimen
Greater than 25ml/min	Usual dosage but monitor patients carefully (see section 4.4)
Less than 25ml/min	Insufficient data to make dosage recommendations

Because of the high plasma protein-binding of tenoxicam, caution is required when plasma albumin concentrations are markedly reduced (e.g. in nephrotic syndrome) or when bilirubin concentrations are high.

There are insufficient data to make dosage recommendations for Tenoxicam in patients with pre-existing hepatic impairment. (see 4.4 Special warnings and special precautions for use).

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

4.3 Contraindications

Tenoxicam 20 mg Tablets is contra-indicated in:-

• Severe heart failure, hepatic failure and renal failure (see section 4.4).

• Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

• History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

• Patients with a known hypersensitivity to ibuprofen, aspirin or other nonsteroidal anti-inflammatory drugs (symptoms of asthma, rhinitis, angioedema or urticaria).

• Previous known hypersensitivity to tenoxicam or any of the excipients

contained in Tenoxicam 20 mg Tablets

• The last trimester of pregnancy (see section 4.6).

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 Tenoxicam with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see sections 4,5).

Care should be taken to regularly monitor the patients to detect possible interactions with concomitant therapy and to review renal, hepatic and cardiovascular function which may be potentially influenced by NSAIDs.

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). Particular care should be taken to regularly monitor elderly patients to detect possible interactions with concomitant therapy and to review renal, hepatic and cardiovascular function which may be potentially influenced by non-steroidal anti-inflammatory drugs.

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 cause bronchospasm in such patients.

Cardiovascular, Renal and Hepatic Impairment:

In rare cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, papillary necrosis and the nephrotic syndrome. Such agents inhibit the synthesis of renal prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased. Administration of a NSAID in these patients may precipitate overt renal decompensation, which returns to the pre-treatment state upon withdrawal of the drug. Patients at greatest risk of such a reaction are those with pre-existing renal disease (including diabetics with impaired renal function), nephrotic syndrome, volume depletion, hepatic disease, congestive cardiac failure and those patients receiving concomitant therapy with diuretics or potentially nephrotoxic drugs. Such patients should have their renal, hepatic and cardiac functions carefully monitored, and the dose should be kept as low as possible in patients with renal, hepatic or cardiac impairment. NSAIDs should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with NSAID administration.

Occasional elevations of serum transaminases or other indicators of liver function have been reported. The reports in most cases have been small and transient increases above the normal range. If the abnormality is significant or persistent, Tenoxicam should be stopped and follow-up tests carried out. Particular care is required in patients with pre-existing hepatic disease.

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 Tenoxicam.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with tenoxicam 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.

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. misoprotol 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 histoy of GI toxicity, particularly whne 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 anti-platelet agents such as aspirin (see section 4.5)

When GI bleeding or ulceration occurs in patients receiving Tenoxicam, the treatment should be withdrawn.

NSAIDs should only be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these condition may be exacerbated (see section 4.8).

SLE and mixed connective tissue disease:

In patients with systemic lupus erthematosus (SLE) and mixed connective tissue disorders there may be increased risk of aseptic meningitis (see section 4.8).

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epiderma; necroylsis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for 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. Tenoxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensititivy.

Impaired female fertility:

The use of Tenoxicam 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 Tenoxicam should be considered.

Platelet aggregation:

Tenoxicam reduces platelet aggregation and may prolong bleeding time. Care is therefore required in patients undergoing major surgery and in patients whose bleeding time needs to be determined.

Ophthalmological Impairment:

Minor and serious ocular effects have been reported rarely in patients taking NSAIDs; ophthalmic evaluation is recommended for patients who develop visual disturbances during treatment with Tenoxicam.

• Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) have been reported with the use of tenoxicam.

• Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

• If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, tenoxicam treatment should be discontinued.

• The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

• If the patient has developed SJS or TEN with the use of tenoxicam, tenoxicam must not be re-started in this patient at any time.

Tenoxicam 20mg Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids may reduce the rate, but not the extent, of absorption of tenoxicam. The differences are not likely to be of clinical significance. No interaction has been found with concomitantly administered cimetidine.

No interaction has been found with concomitantly administered cimetidine.

No clinically relevant interaction between tenoxicam and low molecular weight heparin has been observed in healthy subjects.

Care should be taken in patients treated with any of the following drugs as interactions have been reported in some patients.

Anti-hypertensives: reduces anti-hypertensive effect.

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

Diuretics: NSAIDs may cause sodium, potassium and fluid retention and may interfere with the natriuretic action of diuretic agents, which can increase the risk of nephrotoxicity of NSAIDs. This should be kept in mind when treating patients with compromised cardiac function or hypertension since they may be responsible for a worsening of those conditions.

Lithium: More frequent monitoring is recommended and the patient warned to maintain fluid intake and to be aware of symptoms of lithium intoxication. Lithium toxicity may result due to decreased elimination of lithium.

Methotrexate: Methotrexate toxicity due to decreased elimination of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

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

Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) due to increased risk of adverse effects (see section 4.4).

Salicylates: Salicylates can displace tenoxicam from protein-binding sites and so increase the clearance and volume of distribution of tenoxicam. Concomitant treatment should therefore be avoided because of the increased risk of adverse reactions (particularly gastro-intestinal).

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

Anti-coagulants: As tenoxicam is highly bound to serum albumin it can enhance the anticoagulant effect of warfarin and other anticoagulants. Close monitoring of the effects of anticoagulants and oral hypoglycaemic agents is advised, especially during the initial stages of treatment with tenoxicam. No interaction with digoxin has been observed. In healthy subjects no clinically relevant interaction between tenoxicam and low molecular weight heparin has been observed.

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.

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

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDS are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine.

Gold/penicillamine: No clinically relevant interaction was found in small numbers of patients receiving treatment with penicillamine or parenteral gold.

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 sysnthesis 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, tenoxicam should not be given unless clearly necessary. If tenoxicam 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-hydramniosis;

• 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 low doses.

• inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, tenoxicam is contraindicated during the third trimester of

pregnancy.

Lactation:

In the limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

See section 4.4 Special warning and precautions for use, regarding female fertility.

4.7. Effects on Ability to Drive and Use Machines

Dizziness, drowsiness, visual disturbances or headaches are possible undesirable effects after taking NSAIDs, if affected, patients should not drive or operate machinery.

4.8 Undesirable effects

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, constipation, indigestion, flatulence, dyspepsia, abdominal pain and discomfort, melaena, epigastric distress, haematemesis, stomatitis, ulcerative stomatitis, anorexia, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely. Should any of these be reported during treatment, Tenoxicam should be stopped immediately and appropriate treatment instituted.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of non-specific allergic reactions and anaphylaxis, respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or assorted skin disorders, including rashes of various types, pruritis have been reported. Nail disorders, alopecia, erythema, urticaria, purpura and more rarely exfoliative, angioedema and, less commonly, bullous dermatoses (including epidermal necrolysis and erythema multiforme). Photosensitivity reactions have also been reported rarely. Reversible elevations of blood urea nitrogen and creatinine have been reported (see section 4.4).

Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported very rarely (see section 4.4).

Cardiovascular: Oedema has been reported in association with NSAID treatment. Caution is advised in elderly patients with compromised cardiac function as an increase in oedema may result in congestive cardiac failure. Palpitations and dyspnoea have been reported rarely.

Central nervous system reactions of headache and dizziness have been reported in a small number of patients. Somnolence, insomnia, depression, nervousness, dream abnormalities, mental confusion, paraesthesias and vertigo have been reported rarely.

Other adverse events reported less commonly include:

Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.

Hepatic: As with most other non-steroidal anti-inflammatory drugs, changes in various liver function parameters have been observed. Some patients may develop raised serum transaminase levels during treatment. Although such reactions are rare, if abnormal liver function tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations occur (e.g. eosinophilia, rash), tenoxicam should be discontinued. Hepatitis and jaundice have also been reported.

Neurological and special senses: Visual disturbances (such as visual impairment and vision blurred, 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 (see section 4.4), depression, nervousness, confusional state, hallucinations, dream abnormalities, insomnia, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Haematological: Decreases in haemoglobin, unrelated to gastro-intestinal bleeding, have occurred. Anaemia, aplastic anaemia, haemolytic anaemia, thrombocytopenia and non-thrombocytopenic purpura, neutropenia, leucopenia and eosinophilia have been reported. Epistaxis has been reported infrequently. Rare cases of agranulocytosis have been reported.

Metabolic effects: There have been rare occurrences of hyperglycaemia or weight increase or decrease.

Ophthalmological effects: Swollen eyes, blurred vision and eye irritation have been reported. No evidence of ocular changes has been revealed by ophthalmoscopy and slit-lamp examination.

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) (see section 4.4).

4.9 Overdose

a) Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, 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.

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. Other measnures may be indicated by patient’s clinical condition.

5.1 Pharmacodynamic properties

Tenoxicam is a non-steroidal anti-inflammatory drug. It has antiinflammatory, analgesics, and antipyretic effects. Its primary mode of action is the inhibition of the cyclooxygenases which are involved in the biosynthesis of prostaglandins and thromboxanes from arachidonic acid.

5.2 Pharmacokinetic properties

Tenoxicam is long-acting; a single daily dose is effective.

Following oral administration, tenoxicam is rapidly and completely absorbed as unchanged drug from the gastrointestinal tract. Concurrent administration of food reduces the rate but not the extent of absorption of tenoxicam. Tenoxicam does not undergo any pre-systemic metabolism. The bioavailability of the drug is essentially 100%.

Tenoxicam is distributed rapidly throughout the body. It is highly bound to plasma proteins, primarily to albumin. Peak concentrations of tenoxicam in synovial fluid are approximately half those in plasma.

Tenoxicam is eliminated slowly from the plasma, the mean plasma elimination halflife in healthy volunteers is approximately 67 hours and 40-52 hours in rheumatic patients. Elimination is almost entirely by metabolism in the liver. The majority of an oral dose (67%) is excreted in the urine mainly as the pharmacologically inactive metabolite, 5-hydroxytenoxicam, and the remainder in the bile much of it as glucuronide conjugates of hydroxy-metabolites.

The absorption, distribution, and elimination kinetics of tenoxicam are independent of dose. Steady state therapeutic plasma concentrations are achieved after 10-15 days of daily administration of 20 mg tenoxicam.

No age-specific changes in the pharmacokinetics of Tenoxicam have been found although inter-individual variation tends to be higher in elderly persons.

5.3. Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6.1 List of excipients

Lactose Maize starch Pregelatinised starch Magnesium stearate Talc

Colloidal silicon dioxide Hypromellose Titanium dioxide (E171) Iron oxide yellow (E172)

6.2. Incompatibilities

Not applicable.

6.3 Shelf life

60 months

6.4. Special Precautions for Storage

Do not store above 25 °C.

6.5. Nature and Contents of Container

PVC/PVdC / Al/PVdC blisters in carton boxes of 28.

6.6. Instruction for Use/Handling and Disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR,

United Kingdom.

8. MARKETING AUTHORISATION NUMBER(S)

PL: 04416/0397

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

20^th August 2001

10 DATE OF REVISION OF THE TEXT

19/02/2016