Oramellox

Short-Term Symptomatic Treatment of Exacerbations of Osteoarthritis. Long Term Symptomatic Treatment of Rheumatoid Arthritis or Ankylosing Spondylitis.

Oral Use

- Exacerbations of Osteoarthritis: 7.5 mg/day (half a 15 mg tablet); if necessary, in the absence of improvement, the dose may be increased to 15 mg/day.

- Rheumatoid arthritis, Ankylosing Spondylitis: 15 mg/day (one 15 mg tablets).

(See also 'Special Populations')

According to the therapeutic response, the dose may be reduced to 7.5 mg/day (half a 15mg tablet).

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis.

DO NOT EXCEED THE DOSE OF 15 MG/DAY.

Oramellox Orodispersible Tablets should be placed in the mouth on the tongue and allowed to dissolve slowly for five minutes (the tablet should not be chewed and should not be swallowed undissolved), before swallowing with a drink of 240 ml of water.

Water may be used to moisten the buccal mucosa in patients with a dry mouth.

Special Populations

Elderly patients and patients with increased risks for adverse reaction :

The recommended dose for long term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg (half a 15 mg tablet) per day. Patients with increased risks for adverse reactions should start treatment with 7.5 mg per day.

Renal impairment :

In dialysis patients with severe renal failure, the dose should not exceed 7.5 mg (half a 15 mg tablet) per day.

No dose reduction is required in patients with mild to moderate renal impairment (i.e. patients with a creatinine clearance of greater than 25 ml/min)..

Hepatic Impairment :

No dose reduction is required in patients with mild to moderate hepatic impairment.

Children and adolescents:

Oramellox Orodispersible Tablets is contraindicated in children and adolescents aged under 16 years.

This medicinal product is contra-indicated in the following situations:

- 'Pregnancy and lactation');

- Children and adolescents aged under 16 years;

- Hypersensitivity to Oramellox or to one of the excipients or hypersensitivity to substances with a similar action, e.g. NSAIDs, aspirin. Oramellox should not be given to patients who have developed signs of asthma, nasal polyps, angioneurotic oedema or urticaria following the administration of aspirin or other NSAIDs;

- 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);

- Active intestinal inflammatory disease (Crohn´s disease, ulcerative colitis);

- Severely impaired liver function;

- Non-dialysed severe renal failure;

- Gastrointestinal bleeding, cerebrovascular bleeding or other bleeding disorders;

- Severe heart failure;

- Oramellox is contraindicated in treatment of perioperative pain after coronary artery bypass surgery (CABG).

The recommended maximum daily dose should not be exceeded in case of insufficient therapeutic effect, nor should an additional NSAID be added to the therapy because this may increase the toxicity while therapeutic advantage has not been proven. The use of Oramellox Orodispersible Tablets with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Oramellox Orodispersible Tablets is not appropriate for the treatment of patients requiring relief from acute pain.In the absence of improvement after several days, the clinical benefit of the treatment should be reassessed.

Any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment with Oramellox. Attention should routinely be paid to the possible onset of a recurrence in patients treated with Oramellox and with a past history of this type.

Gastrointestinal effects

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 , 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 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 is advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as heparin as curative treatment or given in geriatrics, anticoagulants such as warfarin, or other non steroidal anti-inflammatory drugs, including acetylsalicylic acid given at anti-inflammatory doses (> 1g as single intake or > 3g as total daily amount).

When GI bleeding or ulceration occurs in patients receiving Oramellox orodispersible tablets the treatment should be withdrawn.

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 monitoring of blood pressure for patients at risk is recommended at baseline and especially during treatment initiation with Oramellox Orodispersible Tablets.

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 Oramellox.

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

Skin reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDSs (see 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. Oramellox should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Parameters of liver and renal function

As with most NSAIDs, occasional increases in serum transaminase levels, increases in serum bilirubin or other liver function parameters, as well as increases in serum creatinine and blood urea nitrogen as well as other laboratory disturbances, have been reported. The majority of these instances involved transitory and slight abnormalities. Should any such abnormality prove significant or persistent, the administration of Oramellox should be stopped and appropriate investigations undertaken.

Functional renal failure

NSAIDs, by inhibiting the vasodilating effect of renal prostaglandins, may induce a functional renal failure by reduction of glomerular filtration. This adverse event is dose-dependant. At the beginning of the treatment, or after dose increase, careful monitoring of diuresis and renal function is recommended in patients with the following risk factors:

- Elderly

- Interaction with other medicinal products and other forms of interaction)

- Hypovolemia (whatever the cause)

- Congestive heart failure

- Renal failure

- Nephrotic syndrome

- Lupus nephropathy

- Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score 10)'

In rare instance NSAIDs may be the cause of interstitial nephritis, glomerulonephritis, renal medullary necrosis or nephrotic syndrome.

The dose of Oramellox in patients with end-stage renal failure on haemodialysis should not be higher than 7.5 mg (half a 15 mg tablet). No dose reduction is required in patients with mild or moderate renal impairment (i.e. patients with a creatinine clearance of greater than 25 ml/min).

Sodium, potassium and water retention

Induction of sodium, potassium and water retention and interference with the natriuretic effects of diuretics may occur with NSAIDs. Furthermore, a decrease of the antyhypertensive effect of antyhypertensive drugs can occur. Consequently, oedema, cardiac failure or hypertension may be precipitated or exacerbated in susceptible patients as a result. Clinical monitoring is therefore necessary for patients at risk.

Hyperkalaemia

Hyperkalaemia can be favoured by diabetes or concomitant treatment known to increase kalaemia. Regular monitoring of potassium values should be performed in such cases.

Adverse reactions are often less well tolerated in elderly, fragile or weakened individuals, who therefore require careful monitoring. As with other NSAIDs, particular caution is required in the elderly, in whom renal, hepatic and cardiac functions are frequently impaired. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Oramellox orodispersible tablet, as any other NSAID may mask symptoms of an underlying infectious disease.

The use of Oramellox orodispersible tablet, 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 difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of Oramellox should be considered.

Oramellox orodispersible tablet contains a source of phenylalanine:

Aspartame (E951) and may be harmful for people with phenylketonuria.

Oramellox orodispersible tablet contains Sorbitol (E420): Patients with rare hereditary problems of fructose intolerance should not take this medicine.

There are no specific studies on the ability to drive and use machinery. However, on the basis of the pharmacodynamic profile and reported adverse drug reactions, Oramellox is likely to have no or negligible influence on these abilities. However, when visual disturbances or drowsiness, vertigo or other central nervous system disturbances occur, it is advisable to refrain from driving and operating machinery.

a) General Description

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).

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

The most commonly-observed adverse events are gastrointestinal in nature.- Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed.

The frequencies of adverse drug reactions given below are based on corresponding occurrences of reported adverse events in 27 clinical trials with a treatment duration of at least 14 days. The information is based on clinical trials involving 15197 patients who have been treated with daily oral doses of 7.5 or 15 mg Oramellox tablets or capsules over a period of up to one year.

Adverse drug reactions that have come to light as a result of reports received in relation to administration of the marketed product are included.

Adverse reactions have been ranked under headings of frequency using the following convention:

Very common ( > 1/10); common ( > 1/100, < 1/10); uncommon ( > 1/1000, < 1/100); rare ( > 1/10000, < 1/1000); very rare ( < 1/10000)

b) Table of adverse reactions

Blood and lymphatic system disorders

Very rare cases of agranulocytosis have been reported (see section c).

Immune system disorders

Psychiatric disorders

Eye disorders

Ear and labyrinth disorders

Cardiac disorders

Cardiac failure has been reported in association with NSAID treatment.

Vascular disorders

Respiratory, thoracic and mediastinal disorders

Gastrointestinal disorders

Gastrointestinal haemorrhage, ulceration or perforation may sometimes be severe and potentially fatal, especially in elderly.

Hepatobiliary disorders

Skin and subcutaneous tissue disorders

Renal and urinary disorders

General disorders and administration site conditions

c) Information Characterising Individual Serious and/or Frequently Occurring Adverse Reactions

Very rare cases of agranulocytosis have been reported in patients treated with Oramellox and other potentially myelotoxic drugs.

d) Adverse reactions which have not been observed yet in relation to the product, but which are generally accepted as being attributable to other compounds in the class

Organic renal injury probably resulting in acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported .

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAID and may occur following an overdose.

Patients should be managed with symptomatic and supportive care following an NSAID overdose. Accelerated removal of Oramellox by 4 g oral doses of cholestyramine given three times a day was demonstrated in a clinical trial.

Pharmacotherapeutic group: Non steroidal anti-inflammatory agents, oxicams

ATC code: M01 AC06

Oramellox is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam family, with anti-inflammatory, analgesic and antipyretic properties.

The anti-inflammatory activity of Oramellox has been proven in classical models of inflammation. As with other NSAID, its precise mechanism of action remains unknown. However, there is at least one common mode of action shared by all NSAID (including Oramellox): inhibition of the biosynthesis of prostaglandins, known inflammation mediators.

Absorption

Oramellox is well absorbed from the gastrointestinal tract, which is reflected by a high absolute bioavailability of 89% following oral administration (capsule). Tablets, oral suspension and capsules were shown to be bioequivalent.

Following single dose administration of Oramellox, mean maximum plasma concentrations achieved within 2 hours for the suspension and within 5-6 hours with solid oral dosage forms (capsules and tablets).

With multiple dosing, steady state conditions were reached within 3 to 5 days. Once daily dosing leads to drug plasma concentrations with a relatively small peak-trough fluctuation in the range of 0.4 - 1.0 µg/ml for 7.5 mg doses and 0.8 - 2.0 µg/ml for 15 mg doses, respectively (cmin and cmax at steady state, respectively). Maximum plasma concentrations of Oramellox at steady state, are achieved within five to six hours for the tablet, capsule and the oral suspension, respectively. Extent of absorption for Oramellox following oral administration is not altered by concomitant food intake.

Distribution

Oramellox is very strongly bound to plasma proteins, essentially albumin (99%). Oramellox penetrates into synovial fluid to give concentrations approximately half of those in plasma.

Volume of distribution is low, on average 11 L. Inter-individual variation is the order of 30-40%.

Biotransformation

Oramellox undergoes extensive hepatic biotransformation. Four different metabolites of Oramellox were identified in urine, which are all pharmacodynamically inactive. The major metabolite, 5'-carboxyOramellox (60% of dose), is formed by oxidation of an intermediate metabolite 5'- hydroxymethylOramellox, which is also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP 2C9 plays an important role in this metabolic pathway, with a minor contribution from the CYP 3A4 isoenzyme. The patient's peroxidase activity is probably responsible for the other two metabolites, which account for 16% and 4% of the administered dose respectively. Elimination

Oramellox is excreted predominantly in the form of metabolites and occurs to equal extents in urine and faeces. Less than 5% of the daily dose is excreted unchanged in faeces, while only traces of the parent compound are excreted in urine.

The mean elimination half-life is about 20 hours. Total plasma clearance amounts on average 8 mL/min. Linearity/non-linearity

Oramellox demonstrates linear pharmacokinetics in the therapeutic dose range of 7.5 mg 15 mg following per oral or intramuscular administration.

Special populations

Hepatic/renal insufficiency:

Neither hepatic, nor mild nor moderate renal insufficiency has a substantial effect on Oramellox pharmacokinetics. In terminal renal failure, the increase in the volume of distribution may result in higher free Oramellox concentrations, and a daily dose of 7.5 mg must not be exceeded.

Elderly:

Mean plasma clearance at steady state in elderly subjects was slightly lower than that reported for younger subjects.

The toxicological profile of Oramellox has been found in preclinical studies to be identical to that of NSAID: Gastrointestinal ulcers and erosions, renal papillary necrosis at high doses during chronic administration in two animal species.

Oral reproductive studies in the rat have shown a decrease of ovulations and inhibition of implantations and embryotoxic effects (increase of resorptions) at maternotoxic dose levels at 1 mg/kg and higher. Studies of toxicity on reproduction in rats and rabbits did not reveal teratogenicity up to oral doses of 4 mg/kg in rats and 80 mg/kg in rabbits.

The affected dose levels exceeded the clinical dose (7.5-15 mg) by a factor of 10 to 5-fold on a mg/kg dose basis (75 kg person). Foetotoxic effects at the end of gestation, shared by all prostaglandin synthesis inhibitors, have been described.

No evidence has been found of any mutagenic effect, either in vitro or in vivo. No carcinogenic risk has been found in the rat and mouse at doses far higher than those used clinically.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.