This information is intended for use by health professionals

1. Name of the medicinal product

Mobiflex Tablets 20mg.

2. Qualitative and quantitative composition

Each tablet contains 20mg tenoxicam.

For a full list of excipients, see 6.1.

3. Pharmaceutical form

Film-coated tablet.

A greyish yellow, film-coated oval tablet imprinted “20” on one face with a break line on the other.

4. Clinical particulars
4.1 Therapeutic indications

Mobiflex is indicated for the relief of pain and inflammation in osteoarthritis and rheumatoid arthritis. It is also indicated for the short term management of acute musculoskeletal disorders including strains, sprains and other soft-tissue injuries. IV, IM tenoxicam is also available for these indications in those patients considered unable to take oral tenoxicam.

4.2 Posology and method of administration

For oral administration.

To be taken preferably with or after food.

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

Adults

A single daily dose of 20mg Mobiflex should be taken at the same time each day. Mobiflex Tablets are for oral administration with water or other fluid.

Higher doses should be avoided as they do not usually achieve significantly greater therapeutic effect but may be associated with a higher risk of adverse events.

In acute musculoskeletal disorders treatment should not normally be required for more than 7 days, but in severe cases it may be continued up to a maximum of 14 days.

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 during NSAID therapy.

Children

There are insufficient data to make a recommendation for administration of Mobiflex to children.

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 is insufficient information to make dosage recommendations for Mobiflex in patients with pre-existing hepatic impairment.

4.3 Contraindications

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

History of gastro-intestinal bleeding (melaena, haematemesis), perforation related to previous NSAID therapy or severe gastritis.

Hypersensitivity to tenoxicam or to any of the excipients.

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (induce symptoms of asthma, rhinitis, angio-oedema or urticaria) in response to salicylates, ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS).

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

Mobiflex is contraindicated during 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 Mobiflex with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors or 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 should be avoided (see section 4.5).

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.

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 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 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 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).

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).

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN), have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients should be advised of the signs and symptoms and monitored closely for skin reactions. 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. Mobiflex should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. 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.

Cardiovascular, renal and hepatic impairment

In rare cases, non-steroidal anti-inflammatory drugs 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. In these patients, administration of a non-steroidal anti-inflammatory drug 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, patients receiving concomitant therapy with diuretics or potentially nephrotoxic drugs and the elderly. Such patients should have their renal, hepatic and cardiac functions carefully monitored (see also section 4.3), and the dose should be kept as low as possible in patients with renal, hepatic or cardiac impairment.

Respiratory disorders

Caution is required if administered to patients suffering from, or with a previous history of bronchial asthma since ibuprofen has been reported to cause bronchospasm in such patients.

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

Mobiflex reduces platelet aggregation and may prolong bleeding time. This should be borne in mind for patients who undergo major surgery (e.g. joint replacement) and when bleeding time needs to be determined.

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). Debilitated patients seem to tolerate ulceration or bleeding less well than others. Most of the fatal gastrointestinal events associated with non-steroidal anti-inflammatory drugs occurred in the elderly and/or debilitated patients.

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.

Ocular effects

Adverse eye findings have been reported with non-steroidal anti-inflammatory drugs, therefore it is recommended that patients who develop visual disturbances during treatment with Mobiflex have ophthalmic evaluation.

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).

Antipyretic effects

As known for other anti-inflammatory drugs, Mobiflex may mask the usual signs of infection.

Laboratory Tests

NSAIDs inhibit renal prostaglandin synthesis and consequently may have an undesirable effect on renal haemodynamics and on salt and water balance. It is necessary to adequately monitor the patient with a special emphasis on cardiac and renal function (BUN, creatinine, development of edema, weight gain, etc.) when giving Mobiflex to patients with conditions that could increase their risk of developing renal failure, such as pre-existing renal disease, impaired renal function in diabetics, hepatic cirrhosis, congestive heart failure, volume depletion or concomitant treatment with potentially nephrotoxic drugs, diuretics and corticosteroids. This group of patients is at special risk in peri- and post-operative phases of major surgery due to possibility of serious blood loss. They therefore require close monitoring in the post-operative and recovery periods.

Because of the high plasma protein binding of tenoxicam, caution is required when plasma albumin levels are markedly reduced

Mobiflex Film-coated tablets contains lactose

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

Impaired female fertility

The use of Mobiflex may impair 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 Mobiflex should be considered.

4.5 Interaction with other medicinal products and other forms of interaction

Other analgesics including cyclooxygenase-2 selective inhibitors

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4).

Acetylsalicylate and salicylates

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

Antacids and H2-receptor antagonists

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

Anticoagulants

Tenoxicam is highly bound to serum albumin, and can, as with all NSAIDs, enhance the effects of anticoagulants such as warfarin (see section 4.4). Close monitoring of the effects of anticoagulants and oral glycaemic agents is advised, especially during the initial stages of treatment with Mobiflex. No interaction with digoxin has been observed. In healthy subjects no clinically relevant interaction between Mobiflex and low molecular weight heparin has been observed.

Cardiac glycosides

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels when co-administered with cardiac glycosides.

Ciclosporin

As with all NSAIDs caution is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.

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.

Lithium

Non-steroidal anti-inflammatory drugs have been reported to decrease elimination of lithium. If tenoxicam is prescribed for a patient receiving lithium therapy, the frequency of lithium monitoring should be increased, the patient warned to maintain fluid intake and to be aware of symptoms of lithium intoxication.

Diuretics and Antihypertensives

Non-steroidal anti-inflammatory drugs 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. These properties 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.

No clinically significant interaction between Mobiflex and furosemide was noted, but Tilcotil attenuates the blood pressure lowering effect of hydrochlorothiazide. As known from other NSAIDs, Mobiflex might attenuate the antihypertensive effects of alpha-adrenergic blockers and ACE-inhibitors.

No interactions have been reported between Mobiflex and centrally acting alpha agonists or calcium channel blockers.

There was no clinically relevant interaction when Mobiflex was administered together with atenolol. During clinical trials no interaction was reported for patients treated concomitantly with digitalis products. Thus concurrent dosing of Mobiflex and digoxin appears to be without major risk.

Methotrexate

Caution is advised where methotrexate is given concurrently because of possible enhancement of its toxicity, since NSAIDs have been reported to decrease elimination of methotrexate.

Oral Antidiabetics

The clinical effect of the oral antidiabetic drugs glibornuride, glibenclamide, tolbutamide, was likewise not modified by Mobiflex. Nevertheless, as for other NSAIDs, careful monitoring is recommended when patients concomitantly receive oral antidiabetic drugs.

Colestyramine

Colestyramine may increase the clearance and reduce the half-life of tenoxicam.

Dextromethorphan

The concomitant administration of tenoxicam and dextromethorphan may increase the analgesic effect compared to monotherapy.

Food

The extent of absorption of tenoxicam is not influenced by food, but the rate of absorption (Cmax) may be slower than in fasting state.

Others

Co-administration of probenecid and tenoxicam treatment may increase plasma concentration of tenoxicam. The clinical significance of this observation has not been established.

Mifepristone

NSAIDs should not be used for 8 – 12 days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.

Corticosteroids

As with all NSAIDs, caution should be taken when co-administering cortico-steroids because of the increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

There is an increased risk of gastrointestinal bleeding (see section 4.4) when anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.

Tacrolimus

There is a possible risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine

There is an 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 and ibuprofen.

Gold/penicillamine

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

4.6 Fertility, pregnancy and lactation

Fertility

The use of tenoxicam, as with any drug known to inhibit cyclooxygenase/ prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of tenoxicam should be considered. (See section 4.4).

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

Based on findings from single dose administration, a very small amount (mean value less than 0.3% of the dose) of tenoxicam passes into breast milk (see section 5.2 Pharmacokinetic properties). There is no evidence of adverse reactions in breast-fed infants of mothers taking Mobiflex. Nevertheless, infants should be weaned or the drug discontinued.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Usually the undesirable effects reported were mild and transient. In a small proportion of patients the interruption of treatment due to undesirable effects was necessary.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), 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)

Blood and lymphatic disorders

Frequency not known: agranulocytosis, anemia, aplastic anemia, haemolytic anemia, leucopenia, thrombocytopenia, non-thrombocytopenic purpura, eosinophilia

Immune system disorders

Frequency not known: hypersensitivity reactions such as asthma, anaphylactic reactions, angioedema

Metabolism and nutrition disorders

Common: anorexia

Rare: Metabolic abnormalities (like: hyperglycaemia, weight increased/decreased)

Psychiatric disorders

Rare: sleep disorder (e.g. insomnia), depression, nervousness, dream abnormalities, Frequency not known: confusional state, hallucinations

Nervous system disorders

Common: dizziness, headache

Frequency not known: Somnolence, paraesthesia

Eye disorders

Frequency not known: visual disturbances (such as visual impairment and vision blurred), swollen eyes, eye irritation

Ear and labyrinth disorders

Rare: vertigo

Frequency not known: tinnitus

Cardiac disorders

Rare: palpitations

Frequency not known: cardiac failure

The possibility of precipitating congestive cardiac failure in elderly patients or those with compromised cardiac function should therefore be borne in mind.

Vascular disorders

Rare: Thrombotic events (e.g. myocardial infarction or stroke)

Frequency not known: vasculitis, hypertension

Clinical trial and epidemiological data suggest that use of selective Cyclooxygenase 2 inhibitors (COX2 inhibitors) and 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) (see section 4.4). Also tenoxicam has not shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude such a risk with tenoxicam.

Respiratory, thoracic and mediastinal disorders

Rare: bronchospasm, aggravated asthma, dyspnoea

Frequency not known: epistaxis

Bronchospasm and aggravated asthma have been reported following treatment with NSAIDs.

Gastrointestinal disorders

Very Common: gastric, epigastric and abdominal pain and discomfort, dyspepsia, nausea, vomiting, flatulence, constipation, diarrhea, indigestion, epigastric distress, stomatitis

Common: gastrointestinal haemorrhage, gastrointestinal perforation, gastrointestinal ulcers, peptic ulcer, sometimes fatal, particularly in the elderly, haematemesis, melena, constipation, diarrhoea, mouth ulceration, gastritis, dry mouth, exacerbation of colitis and Crohn's disease (see section 4.4 Special warning and precautions for use).

Very rare: pancreatitis

Hepatobiliary disorders

Uncommon: increased hepatic enzymes

Frequency not known: hepatitis, jaundice

Skin and subcutaneous tissue disorders

Uncommon: pruritus, erythema, exanthema, rash, urticaria

Rare: vesiculo-bullous reactions.

Very rare: Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome, toxic epidermal necrolysis (see section 4.4)

Frequency not known: photosensitivity reaction.

Nail disorders and, photosensitivity reaction and alopecia have been reported rarely following treatment with NSAIDs.

Renal and urinary disorders

Uncommon: increased blood urea or creatinine

Frequency not known: nephrotoxicity (e.g. renal failure, interstitial nephritis, nephrotic syndrome, increased blood urea or creatinine).

Reproductive system and breast disorders

Isolated cases of female infertility have been reported with drugs known to inhibit cyclooxygenase/prostaglandin synthesis including tenoxicam.

General disorders and administration site conditions

Uncommon: fatigue, oedema -

Frequency not known: Malaise

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

Symptoms

In general, symptoms of NSAID overdosage usually include nausea, vomiting, epigastric pain, rarely diarrhoea, gastrointestinal bleeding, tinnitus, headache, blurred vision and dizziness. There have been isolated reports of more serious toxicity after ingestion of substantial quantities; they include seizures, excitation, drowsiness hypotension, apnoea, coma electrolyte imbalance and renal failure. Exacerbation of asthma is a possible effect.

Management:

Patients should be treated symptomatically as required. In case of overdosage, discontinuation of the drug, and the administration of activated charcoal, gastric lavage, antacids and proton-pump inhibitors may be indicated. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. There are no specific antidotes. The benefit of gastric decontamination is uncertain. Dialysis does not significantly clear NSAIDs from the blood stream. Good urine output should be ensured – maintain adequate hydration. 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 measures may be indicated by the patient's clinical condition.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Antirheumatic, anti-inflammatory and analgesic agent

ATC code: M01AC02

Mechanism of action

Mobiflex is a non-steroidal anti-inflammatory drug (NSAID) which has anti-inflammatory, analgesic, antipyretic properties and it also inhibits platelet aggregation. Tenoxicam reduces prostaglandin biosynthesis by inhibition of cyclooxygenase 1 (COX1) and 2 (COX2), both in vitro (sheep seminal vesicles) and in vivo (protection of arachidonic acid-induced toxicity in mice).

In-vitro investigation on cyclo-oxygenase isoenzymes prepared from human COS-7 cells have shown that tenoxicam inhibits COX-1 and COX-2 isoenzymes approximately to the same extent, i.e. COX-2/COX-1 ratio equals to 1.34.

In-vitro tests of leukocyte peroxidase suggest that tenoxicam may act as a scavenger for active oxygen at the site of inflammation.

Mobiflex is a potent in-vitro inhibitor of human metalloproteinases (stromelysin and collagenase) which induce cartilage breakdown.

A further possible mechanism of action is the reduction of nitrite levels indicating an alteration of NO pathways.

These pharmacological effects explain, at least in part, the therapeutic benefit of Mobiflex in the treatment of painful inflammatory and degenerative disorders of the musculoskeletal system.

Clinical / Efficacy Studies

The clinical efficacy of tenoxicam is proven in clinical studies for:

Rheumatoid arthritis: It was shown that a dose of 20 or 40 mg once daily was effective and the effect was maintained for up to two years.

Osteoarthritis: Tenoxicam is effective in the treatment of osteoarthritis. Anti-inflammatory and analgesic effects have been maintained for up to three years.

Extra-articular disorders: Tenoxicam (20 mg once daily) was at least as effective as piroxicam (20 mg daily) and diclofenac (75 mg daily). Tenoxicam was better tolerated than diclofenac.

5.2 Pharmacokinetic properties

Absorption

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

After oral administration, Mobiflex is rapidly and completely absorbed as unchanged drug. Concomitant food reduces the rate, but not the extent, of absorption of Mobiflex. Tenoxicam penetrates well into synovial fluid to give concentrations approximately half those in plasma. The mean plasma elimination half-life is approximately 72 hours.

With the recommended dosage regimen of 20mg once daily, steady-state plasma concentrations are reached within 10 - 15 days, with no unexpected accumulation. The average concentration at steady state is 11 mg/L when tenoxicam is given at oral doses of 20 mg once daily and this does not change even on treatment for up to four years.

Mobiflex is strongly bound to plasma proteins. As predictable from single dose kinetic, plasma concentrations at steady state are 6-fold higher than those reached after a single dose.

The pharmacokinetics of tenoxicam are linear in the investigated dose range of 10 to 100 mg

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

Distribution

During the first two hours following intravenous administration of tenoxicam, plasma levels of the drug decline rapidly.

After this short period, no differences in plasma concentrations between intravenous and oral dosing are seen. The mean volume of distribution at steady state is 10 to 12 L.

In the blood over 99% of the drug is bound to albumin. Tenoxicam penetrates well into the synovial fluid. Peak concentrations are reached later than in plasma.

Metabolism and elimination

Mobiflex is cleared from the body almost exclusively by metabolism. Approximately two-thirds of the administered dose is excreted in the urine, mainly as the pharmacologically inactive 5-hydroxypyridyl metabolite, and the remainder in the bile, much of it as glucuronide conjugates of hydroxy-metabolites. Less than 1% of the administered dose is recovered in the urine in form of the parent drug. The mean elimination half-life of tenoxicam is 72 hours (range 59 to 74 hours). The total plasma clearance is 2 mL/min.

Special Populations

Studies in the elderly and in patients with renal insufficiency or liver cirrhosis suggest that no dose adjustment is necessary to achieve plasma concentrations similar to those seen in healthy subjects.

Patients with rheumatic diseases and the elderly show the same kinetics profile as healthy volunteers.

Because of the high plasma protein binding of tenoxicam, caution is required when plasma albumin levels are markedly reduced (see section 4.4 Special warnings and precautions for use, Laboratory Tests).

5.3 Preclinical safety data

Carcinogenicity

Tenoxicam showed no carcinogenic effects in animals.

Mutagenicity

Tenoxicam showed no mutagenic effects in animals.

Impairment of fertility

See section 4.6

Teratogenicity

Tenoxicam showed no teratogenic effects in rats.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose

Maize starch

Magnesium stearate

Talc

Hypromellose

Titanium dioxide E171

Yellow iron oxide E172.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

PVC/Aluminium foil blister pack containing 30 tablets.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Mylan Products Ltd,

Station Close,

Potters Bar,

Hertfordshire,

EN6 1TL,

United Kingdom

8. Marketing authorisation number(s)

PL 46302/0134

9. Date of first authorisation/renewal of the authorisation

10th August 1988/11th November 2009

10. Date of revision of the text

February 2018

LEGAL STATUS

POM