lactose, maize starch, talc, magnesium stearate, hypromellose, titanium dioxide and iron oxide yellow (CI77492).

Greyish yellow, oval, cylindrical, biconvex film-coated tablets with the imprint "20" on one side and a break-score on the other side.

Clinical Particulars

Dosage and Administration

Standard dosage

Undesirable effects may be minimised by using the lowest effective dose for the shortest possible duration necessary to control symptoms. For all indications except primary dysmenorrhoea, post-operative pain and acute gout, a daily dosage of 20 mg should be given at the same time of day. The recommended dose for primary dysmenorrhoea is 20 to 40 mg once daily. For post-operative pain the recommended dose is 40 mg once daily up to five days and for acute attacks of gout the recommended dose is 40 mg once daily for two days followed by 20 mg once daily for a further five days. In treatment of chronic disorders the therapeutic effect of tenoxicam is evident early in treatment and there is a progressive increase in response over time. In chronic disorders, daily doses higher than 20 mg are not recommended since this would increase the frequency and intensity of unwanted reactions without significantly increasing efficacy. For patients needing long-term treatment a reduction to a daily oral dose of 10 mg may be tried for maintenance. The tablets should be taken with a glass of water. It is preferable to take this medicine during or immediately after a meal.

Special dosage instructions

In principle, the above dosage recommendations also apply to elderly patients and to patients suffering from kidney or liver disease. Dosage should be minimised in the elderly and in patients with renal impairment. Because of lack of clinical experience, no dosage recommendations have been established for children and adolescents.

Contraindications

Tilcotil is contraindicated in patients with: known hypersensitivity to tenoxicam, to any component of the product or to other non-steroidal anti-inflammatory drugs (NSAIDs);

asthma, or in whom salicylates or other NSAIDs induce symptoms of asthma, rhinitis or urticaria; active or a history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding) haemorrhagic diathesis, as with other NSAIDs severe heart failure, as with other NSAIDs.

Warnings and Precautions

Tilcotil is relatively contraindicated in patients with liver dysfunction. The use of tenoxicam with concomitant NSAIDs, including cyclo-oxygenase-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 (see Dosage and Administration; Gastrointestinal bleeding, ulceration and perforation and cardiovascular/cerebrovascular effects below).

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 selective cyclo oxygenase 2 inhibitors (COX2 inhibitors) and some NSAIDs (particularly at high doses and long term treatment) may be associated with an increased risk of serious cardiovascular events, including myocardial infarction and stroke, which may increase with dose or duration of use. Patients with cardiovascular disease or cardiovascular risk factors may also be at greater risk. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Tilcotil 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). To minimise the potential risk of an adverse cardiovascular event in patients taking an NSAID, especially in those with cardiovascular risk factors, the lowest effective dose should be used for the shortest possible duration (see Dosage and Administration). NSAIDs may lead to the onset of new hypertension or worsening of pre- existing hypertension and patients taking anti-hypertensives with NSAIDs may have an impaired anti-hypertensive response.

Caution is advised when prescribing NSAIDs to patients with hypertension. Blood pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter. Fluid retention and oedema have been observed in some patients taking NSAIDs; therefore, caution is advised in patients with fluid retention or heart failure. There is no consistent evidence to suggest that concurrent use of aspirin mitigates the possible increased risk of serious cardiovascular thrombotic events associated with NSAID use.

GI bleeding, ulceration and perforation, which can be fatal, has been reported with all all NSAIDs, including Tilcotil therapy, These effects can occur at any time during treatment, with or without warning symptoms, or a previous history of serious GI events. Studies have not identified any subset of patients not at risk of developing peptic ulcer and bleeding. Upper gastrointestinal ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 - 6 months and in about 2 - 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious gastrointestinal event at some time during the course of therapy. However, even short term therapy is not without risk. Caution is advised in patients with risk factors for gastrointestinal events who may be at greater risk of developing serious gastrointestinal events e.g. the elderly, those with a history of serious gastrointestinal events, smoking and alcoholism. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. Debilitated patients do not seem to tolerate ulceration or bleeding as well as others. Most of the fatal gastrointestinal events associated with NSAIDs occurred in the elderly and/or debilitated patients. 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 Contraindications) and in the elderly. Patients with risk factors should commence treatment on the lowest dose possible. Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant low dose aspirin or other drugs likely to increase gastrointestinal toxicity (see Interactions). NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis; Crohn's disease) as their condition may be exacerbated. 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. If peptic ulceration or gastrointestinal bleeding occurs, Tilcotil should be withdrawn immediately. Physicians should warn patients about the signs and symptoms of serious gastrointestinal toxicity. Caution is advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g. warfarin), selective serotonin-reuptake inhibitors or anti- platelet agents (e.g. aspirin). The concurrent use of aspirin and NSAIDs also increases the risk of serious gastrointestinal adverse events (see Interactions).

Life-threatening cutaneous reactions such as exfoliative dermatitis, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), which can be fatal and occur without warning, have been reported with tenoxicam. These serious adverse effects are idiosyncratic and are independent of dose or duration of use. Patients should be advised of the signs and symptoms of serious skin reactions and monitored closely for skin reactions. The highest risk of 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 of mucosal lesions) are present, Tilcotil should be discontinued. The best results for managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspected 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 inhibits platelet aggregation and may affect haemostasis. Tilcotil has no significant influence on blood coagulation factors, coagulation time, prothrombin time or activated thromboplastin time. Patients having coagulation disorders or receiving therapy that interferes with haemostasis should, however, be carefully observed when Tilcotil is administered.

Adverse eye findings have been reported with NSAIDs including Tilcotil. Thus ophthalmic evaluation is recommended for patients who develop visual disturbances.

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

As Tilcotil contains lactose, patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients experiencing adverse events that might affect driving or using machines, such as vertigo, dizziness or visual disturbances should refrain from driving a car or using machines.

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 oedema, weight gain, etc.) when giving Tilcotil 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 medicines, diuretics and corticosteroids. This group of patients is at special risk in peri- and post-operative phases of major surgery due to the 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.

Interactions

Salicylates increase the clearance and volume of distribution of NSAIDs including tenoxicam and decrease the mean minimum steady-state plasma concentrations of tenoxicam by displacing them from protein binding sites. Concurrent treatment with salicylate or other NSAIDs is not recommended because of increased risk of undesirable reactions.

There is an increased risk of gastrointestinal bleeding when anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs) are combined with NSAIDs (see Warnings and Precautions: Gastrointestinal bleeding, ulceration and perforation).

The co-administration of some NSAIDs and methotrexate has been associated with reduced renal tubular secretion of methotrexate, higher plasma concentrations of methotrexate, and severe methotrexate toxicity. Therefore, caution should be exercised when Tilcotil is administered concurrently with methotrexate.

As Tilcotil may decrease the renal clearance of lithium, their concomitant administration may lead to increased plasma levels and toxicity of lithium. The plasma levels of lithium should be closely monitored.

As with NSAIDs in general, Tilcotil should not be administered concurrently with potassium sparing diuretics. There is a known interaction between these two classes of compounds, which may cause hyperkalaemia and renal failure. No clinically significant interaction between Tilcotil and furosemide was noted, but Tilcotil attenuates the blood pressure lowering effect of hydrochlorothiazide. As known from other NSAIDs, Tilcotil might attenuate the antihypertensive effects of alpha-adrenergic blockers and ACE-inhibitors. No interactions have been reported between Tilcotil and centrally acting alpha agonists or calcium channel blockers. There was no clinically relevant interaction when Tilcotil was administered together with atenolol. During clinical trials no interaction was reported for patients treated concomitantly with digitalis products. Thus concurrent dosing of Tilcotil and digoxin appears to be without major risk.

Antacids and H2-receptor antagonists No clinically relevant interaction has been found with concomitantly administered antacids and cimetidine at the recommended dosages.

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

No clinically relevant interaction has been found with concomitantly administered warfarin and phenprocoumon, and low molecular weight heparin at the recommended dosages. Nevertheless, as for other NSAIDs, careful monitoring is recommended when patients concomitantly receive anticoagulants.

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

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

There is no significant pharmacodynamic interaction between Tilcotil and alcohol.

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

Use in Special Populations

The use of tenoxicam, as with any agent known to inhibit cyclo- oxygenase/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. The safety of Tilcotil in pregnancy has not been established. Tilcotil should only be given in pregnancy if the benefit for the mother outweighs a possible embryo-foetal risk. NSAIDs have an inhibitory effect on prostaglandin synthesis and when given during late pregnancy may cause closure of the foetal ductus arteriosus, prolong labour and delay parturition. Treatment during the third trimester of pregnancy should be avoided.

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 Pharmacokinetic Properties). There is no evidence of adverse reactions in breast-fed infants of mothers taking Tilcotil. Nevertheless, infants should be weaned or the medicine discontinued.

Adverse Effects

Based on clinical trials including large numbers of patients, Tilcotil proved to be well tolerated in the recommended dose. 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. The safety profile from post-marketing experience is consistent with the experience from clinical trials. Adverse effects are listed below in CIOMS frequency categories:

Common:>1%; Uncommon:>0.1% and <1%; Rare:>0.01% and <0.1%; Very rare:

<0.01%, Not known:cannot be estimated from the available data

Blood and lymphatic system disorders

Frequency not known:anaemia, agranulocytosis, leukopenia, thrombocytopenia.

Immune system disorders

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

Metabolism and nutrition disorders

Common:appetite loss

Tilcotil-DS-NZ-17Oct13A.doc 9

Psychiatric disorders Rare:sleep disturbances Nervous system disorders Common:dizziness, headache

Eye disorders

Frequency not known:visual disturbances

Ear and labyrinth disorders

Rare:vertigo Cardiac disorders Rare:palpitations Frequency not known:cardiac failure

Vascular disorders

Frequency not known:hypertension, vasculitis Clinical trial and epidemiological data suggest that use of selective cyclo- oxygenase-2 (COX-2) 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). Although tenoxicam has not shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude such a risk with tenoxicam.

Gastrointestinal disorders

Very common:gastric, epigastric and abdominal discomfort, dyspepsia, nausea, vomiting Common:gastrointestinal bleeding, gastrointestinal perforation, gastrointestinal ulcers, peptic ulcer, sometimes fatal, particularly in the elderly, haematemesis, melena, constipation, diarrhoea, stomatitis, gastritis, dry mouth, exacerbation of colitis and Crohn's disease (see Warnings and Precautions).

Hepatobiliary disorders

Uncommon:increased hepatic enzymes Frequency not known:hepatitis

Skin and subcutaneous tissue disorders

Tilcotil-DS-NZ-17Oct13A.doc 10

Uncommon:itching, erythema, exanthema, rash, urticaria Very rare:Severe cutaneous adverse reactions (SCARs): Stevens-Johnson Syndrome, toxic epidermal necrolysis have been reported Frequency not known:photosensitivity reaction

Renal and urinary disorders

Uncommon:increased blood urea or creatinine

Reproductive system and breast disorders

Isolated cases of female infertility have been reported with agents known to inhibit cyclo-oxygenase/prostaglandin synthesis including tenoxicam.

General disorders and administration site conditions

Uncommon:fatigue, oedema

Overdose

In general, symptoms of NSAID overdosage usually include nausea and vomiting, headache, drowsiness, blurred vision and dizziness. There have been isolated reports of more serious toxicity after ingestion of substantial quantities; they include seizures, hypotension, apnoea, coma and renal failure

Patients should be managed by symptomatic and supportive care following NSAIDs overdose. Discontinuation of the medicine, gastric lavage, and the administration of activated charcoal, antacids and proton-pump inhibitors may be indicated. There are no specific antidotes. Dialysis does not significantly clear NSAIDs from the blood stream.

Pharmacological Properties

Mechanism of action

The active ingredient of Tilcotil, tenoxicam, is a NSAID with anti-inflammatory, analgesic, antipyretic properties and it also inhibits platelet aggregation. Tenoxicam inhibits prostaglandin biosynthesis, both in vitro (sheep seminal vesicles) and in vivo (protection of arachidonic acid-induced toxicity in mice).

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.

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

Tilcotil is a potent in vitro inhibitor of human metalloproteinases (stromelysin and collagenase) which induce cartilage breakdown. These pharmacological effects explain, at least in part, the therapeutic benefit of Tilcotil in the treatment of painful inflammatory and degenerative disorders of the musculoskeletal system.

Absorption

Oral absorption of tenoxicam is rapid and complete (absolute bioavailability 100%), whereas absorption after rectal administration is approximately 80%. Peak plasma concentrations following an oral or rectal administration are reached within two hours in fasting subjects. When taken with a meal, tenoxicam is absorbed to the same extent but the time to reach peak concentration is delayed. With the recommended dosage regimen of 20 mg once daily, steady-state conditions are reached within ten to fifteen days without 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. As predicted 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 100mg.

Distribution

During the first two hours following intravenous administration of tenoxicam, plasma levels of the medicine decline rapidly. After this short period, no difference 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 medicine is bound to albumin. Tenoxicam penetrates well into the synovial fluid. Peak concentrations are reached later than in plasma.

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 Warnings and Precautions: Nursing mothers).

Metabolism and Elimination

Tenoxicam is excreted after virtually complete biotransformation to pharmacologically inactive metabolites. Up to two thirds of an oral dose is excreted in the urine (mainly as the inactive 5'-hydroxy-tenoxicam) and the rest via the bile (a significant portion in the form of glucuronidated compounds). Less than 1% of the administered dose is recovered in the urine in form of the parent compound. The mean elimination half-life of tenoxicam is 72 hours (range 59 to 74 hours). The total plasma clearance is 2 mL/min.

Pharmacokinetics in 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; Warnings and Precautions: Laboratory Tests ).

Preclinical safety

Pharmaceutical Particulars

Storage

Tilcotil is sensitive to moisture. Store in the original package. Store below 30 degC.

Package Quantities

Medicine Classification

Name and Address

Valeant Pharmaceuticals New Zealand Ltd c/o Supply Chain Solutions 74 Westney Road Airport Oaks AUCKLAND Telephone: 09-257-0521

rheumatoid arthritis;
osteoarthritis; arthrosis; ankylosing spondylitis; extra-articular disorders, e.g.	tendinitis, bursitis,	periarthritis of

Data Sheet

Pharmaceutical Form

Qualitative and Quantitative Composition