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Pharmacodynamic properties Pharmacotherapeutic group: Antiinflammatory antirheumatic products; antiinflammatory and antirheumatic products, non-steroids, ATC Code: M01AC02 Mechanism of action Arthrinal is a non-steroidal anti-inflammatory drug (NSAID) which has antiinflammatory, 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. Arthrinal 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 Arthrinal 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. Antiinflammatory 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.  Pharmacokinetic properties Absorption Arthrinal is long-acting; a single daily dose is effective. After oral administration, Arthrinal is rapidly and completely absorbed as unchanged drug. Concomitant food reduces the rate, but not the extent, of absorption of Arthrinal. 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 20 mg 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.  Arthrinal 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 Arthrinal 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 Arthrinal 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).

Each film-coated tablet contains 20 mg tenoxicam. Excipient(s) with known effect: Each tablet contains 119.3 mg lactose.

Arthrinal 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 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. 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).

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.

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. Acetylsalicylate and salicylates: Salicylates can displace tenoxicam from protein-binding sites and so increase the clearance and volume of distribution of Arthrinal. 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 Arthrinal. 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 Arthrinal. No interaction with digoxin has been observed. In healthy subjects no clinically relevant interaction between Arthrinal and low molecular 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 Arthrinal and furosemide was noted, but Arthrinal attenuates the blood pressure lowering effect of hydrochlorothiazide. As known from other NSAIDs, Arthrinal might attenuate the antihypertensive effects of alpha-adrenergic blockers and ACE-inhibitors. No interactions have been reported between Arthrinal and centrally acting alpha agonists or calcium channel blockers. There was no clinically relevant interaction when Arthrinal was administered together with atenolol. During clinical trials no interaction was reported for patients treated concomitantly with digitalis products. Thus concurrent dosing of Arthrinal and digoxin appears to be without major risk.  Methotrexate: Caution is advised where methotrexate is given concurrently because of possibl 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 Arthrinal. 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 corticosteroids 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 antiplatelet 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.

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.

Posology Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. Adults A single daily dose of 20 mg Arthrinal should be taken at the same time each day. Arthrinal 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 Arthrinal to children. Use in renal and hepatic insufficiency             Creatinine clearance                                                      Dosage regimen      Greater than 25 ml/min                                          Usual dosage but monitor patients carefully           Less than 25 ml/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 Arthrinal in patients with pre-existing hepatic impairment. Method of administration For oral administration. To be taken preferably with or after food.

Store below 25 °C. Protect from light and moisture.