FELDENE™ 10mg CAPSULES.

FELDENE™ 20mg CAPSULES.

FELDENE™ 20mg/ml INTRAMUSCULAR INJECTION.

Feldene™ Melt 20mg.

Active Ingredient: piroxicam.

Capsules: piroxicam 10mg or 20mg (anhydrous).

I.M.: the intramuscular injection contains 1ml of piroxicam solution (20mg/ml) in ampoules of 1ml.

Melt tablets: piroxicam 20mg.

For a full list of excipients, see section 6.1.

Capsules (10mg and 20mg): Capsules for oral administration.

I.M.: Solution for intramuscular injection.

Melt tablets: Fast Dissolving Dosage Form (Tablet).

Capsules, Melt tablets, IM: Feldene is indicated for symptomatic relief of osteo-arthritis, rheumatoid arthritis or ankylosing spondylitis.

Due to its safety profile (see sections 4.2, 4.3 and 4.4), Feldene is not a first line option should an NSAID be indicated. The decision to prescribe Feldene should be based on an assessment of the individual patient's overall risks (see sections 4.3 and 4.4).

IM only: Feldene I.M. is for intramuscular administration only.

The prescription of Feldene should be initiated by physicians with experience in the diagnostic evaluation and treatment of patients with inflammatory or degenerative rheumatic diseases.

The maximum recommended daily dose is 20 mg.

Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms. The benefit and tolerability of treatment should be reviewed within 14 days. If continued treatment is considered necessary, this should be accompanied by frequent review.

Given that piroxicam has been shown to be associated with an increased risk of gastrointestinal complications, the need for possible combination therapy with gastro-protective agents (e.g. misoprostol or proton pump inhibitors) should be carefully considered, in particular for elderly patients.

Use in the elderly

Elderly, frail or debilitated patients may tolerate side-effects less well and such patients should be carefully supervised. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function.

I.M. only:

The dosage of Feldene I.M. intramuscular injection is identical to the dosage of oral Feldene. For continuation of treatment, oral (capsules or FDDF tablets) dose forms should be used. Feldene I.M. intramuscular injection should be administered by deep intramuscular injection into the upper, outer quadrant of the buttock. Feldene I.M. intramuscular injection should not be administered intravenously.

Melt tablets and capsules only:

For oral administration. To be taken preferably with or after food.

Melt tablets only:

The fast dissolving dosage form may be swallowed with water, or placed on the tongue to disperse and then swallowed with the saliva. The fast dissolving dosage form dissolves almost instantly in the mouth in the presence of water or saliva.

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

History of gastro-intestinal ulceration, bleeding or perforation.

Patient history of gastrointestinal disorders that predispose to bleeding disorders such as ulcerative colitis, Crohn's disease, gastrointestinal cancers or diverticulitis.

Patients with active peptic ulcer, inflammatory gastrointestinal disorder or gastrointestinal bleeding.

Concomitant use with other NSAIDs, including COX-2 selective NSAIDs and acetylsalicylic acid at analgesic doses.

Concomitant use with anticoagulants.

History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Hypersensitivity to the active substance or excipients, previous skin reaction (regardless of severity) to piroxicam, other NSAIDs and other medications.

Patients in whom aspirin and other non-steroidal anti-inflammatory drugs induce the symptoms of asthma, nasal polyps, angioedema or urticaria.

Severe heart failure.

During the last trimester of pregnancy.

Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

The clinical benefit and tolerability should be re-evaluated periodically and treatment should be immediately discontinued at the first appearance of cutaneous reactions or relevant gastrointestinal events.

Gastrointestinal (GI) Effects, Risk of GI Ulceration, Bleeding, and Perforation

NSAIDs, including piroxicam, can cause serious gastrointestinal events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

NSAID exposures of both short and long duration have an increased risk of serious GI event. Evidence from observational studies suggests that piroxicam may be associated with a high risk of serious gastrointestinal toxicity, relative to other NSAIDs.

Patients with significant risk factors for serious GI events should be treated with piroxicam only after careful consideration (see sections 4.3 and below).

The possible need for combination therapy with gastro-protective agents (e.g. misoprostol or proton pump inhibitors) should be carefully considered (see section 4.2).

Serious GI Complications

Identification of at-risk subjects

The risk for developing serious GI complications increases with age. Age over 70 years is associated with high risk of complications. The administration to patients over 80 years should be avoided.

Patients taking concomitant oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or anti-platelet agents such as low-dose acetylsalicylic acid are at increased risk of serious GI complications (see below and section 4.5). As with other NSAIDs, the use of piroxicam in combination with protective agents (e.g. misoprostol or proton pump inhibitors) must be considered for these at-risk patients.

Patients and physicians should remain alerted for signs and symptoms of GI ulceration and/or bleeding during piroxicam treatment. Patients should be asked to report any new or unusual abdominal symptom during treatment. If a gastrointestinal complication is suspected during treatment, piroxicam should be discontinued immediately and additional clinical evaluation and treatment should be considered.

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.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with piroxicam after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

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 Feldene.

Feldene should be used with caution in patients with a history of bronchial asthma (see also section 4.3).

Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance (see section 5.2).

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 NSAIDs (see section 4.8). Evidence from observational studies suggests that piroxicam may be associated with a higher risk of serious skin reaction than other non-oxicam NSAIDs. Patients appear to be at highest risk of 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. Piroxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Feldene should be used with caution in patients with renal, hepatic and cardiac impairment. In rare cases, non-steroidal anti-inflammatory drugs may cause interstitial nephritis, glomerulitis, papillary necrosis and the nephrotic syndrome. Such agents inhibit the synthesis of the 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 is typically followed by recovery to pretreatment state upon discontinuation of non-steroidal anti-inflammatory therapy. Patients at greatest risk of such a reaction are those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease, such patients should be carefully monitored whilst receiving NSAID therapy. Because of reports of adverse eye findings with non-steroidal anti-inflammatory drugs, it is recommended that patients who develop visual complaints during treatment with Feldene have ophthalmic evaluation.

Impaired female fertility

The use of Feldene 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 Feldene should be considered.

Melt tablets only:

Patients with phenylketonuria: Due to aspartame content of Feldene Melt, each 20mg tablet contains 0.14mg phenylalanine.

Antacids: Concomitant administration of antacids had no effect on piroxicam plasma levels.

Anticoagulants: NSAIDs, including piroxicam, may enhance the effects of anticoagulants, such as warfarin. Therefore the use of piroxicam with concomitant anticoagulant such as warfarin should be avoided (see section 4.3).

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

Aspirin and other Non-Steroidal Anti-Inflammatory Drugs: Feldene, like other non-steroidal anti-inflammatory drugs decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.

As with other NSAIDs, the use of piroxicam together with acetylsalicylic acid or concomitant use with other NSAIDs, including other piroxicam formulations, must be avoided, since data are inadequate to show that combinations produce greater improvement that that achieved with piroxicam alone; moreover, the potential for adverse reactions is enhanced (see section 4.4). Human studies have shown that concomitant use of piroxicam and acetylsalicylic acid reduces the plasma piroxicam concentration to about 80% of the usual value.

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

Ciclosporin, Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with ciclosporin or tacrolimus.

Cimetidine: Results of two separate studies indicate a slight but significant increase in absorption of piroxicam following cimetidine administration but no significant changes in elimination rate constants or half-life. The small increase in absorption is unlikely to be clinically significant.

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

Digoxin, Digitoxin: Concurrent therapy with Feldene and digoxin, or Feldene and digitoxin, did not affect the plasma levels of either drug.

Diuretics: Non-steroidal anti-inflammatory drugs may cause sodium, potassium and fluid retention and may interfere with the natriuretic action of diuretic agents. These properties should be kept in mind when treating patients with compromised cardiac function or hypertension since they may be responsible for the worsening of those conditions.

Highly protein-bound drugs: Feldene is highly protein-bound and therefore might be expected to displace other protein-bound drugs. The physician should closely monitor patients for change when administering Feldene to patients on highly protein-bound drugs.

Lithium: Non-steroidal anti-inflammatory drugs, including Feldene, have been reported to increase steady state plasma lithium levels. It is recommended that these levels are monitored when initiating, adjusting and discontinuing Feldene.

Feldene, like other non-steroidal anti-inflammatory drugs, may interact with the following drugs / classes of therapeutic agents:

Antihypertensives - antagonism of the hypotensive effect

Methotrexate - reduced excretion of methotrexate, possibly leading to acute toxicity

Quinolone antibiotics - possible increased risk of convulsions

Mifepristone - NSAIDs could interfere with mifepristone-mediated termination of pregnancy

Use in pregnancy: Although no teratogenic effects were seen in animal testing, the safety of Feldene during pregnancy or during lactation has not yet been established. Feldene inhibits prostaglandin synthesis and release through a reversible inhibition of the cyclo-oxygenase enzyme. This effect, as with other non-steroidal anti-inflammatory drugs, has been associated with an increased incidence of dystocia and delayed parturition in pregnant animals when drug administration was continued in late pregnancy. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Nursing mothers: A study indicates that piroxicam appears in the breast milk at about 1% to 3% of the maternal plasma concentrations. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment for up to 52 days. Feldene is not recommended for use in nursing mothers as clinical safety has not been established.

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

Gastro-intestinal: These are the most commonly encountered side-effects but in most instances do not interfere with the course of therapy. They include stomatitis, anorexia, epigastric distress, gastritis, nausea, vomiting, constipation, abdominal discomfort, flatulance, diarrhoea, abdominal pain and indigestion, rare cases of pancreatitis have been reported.

Objective evaluations of gastric mucosa appearances and intestinal blood loss show that 20mg/day of Feldene administered either in single or divided doses is significantly less irritating to the gastro-intestinal tract than aspirin. Peptic ulceration, perforation and gastro-intestinal bleeding (including haematemesis and melaena) in rare cases fatal, have been reported with Feldene.

Some epidemiological studies have suggested that piroxicam is associated with higher risk of gastro-intestinal adverse reactions compared with some NSAIDs, but this has not been confirmed in all studies. Administration of doses exceeding 20mg daily (of more than several days duration) carries an increased risk of gastro-intestinal side-effects, but they may also occur with lower doses. See section 4.2 Posology and method of administration.

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment. The possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should therefore be borne in mind.

CNS: Dizziness, headache, somnolence, insomnia, depression, nervousness, hallucinations, mood alterations, dream abnormalities, mental confusion, paraesthesiae and vertigo have been reported rarely.

Dermal hypersensitivity: Rash and pruritis. Onycholysis and analopoecia have rarely been reported. Photosensitivity reactions occur infrequently. As with other non-steroidal anti-inflammatory drugs, toxic epidermal necrolysis (Lyell's disease) and Stevens-Johnson syndrome may develop in rare cases. Vesiculo bullous reactions have been reported rarely.

Hypersensitivity reactions: Hypersensitivity reactions such as anaphylaxis, bronchospasm, urticaria/angioneurotic oedema, vasculitis and serum sickness have been reported rarely.

Renal function: Interstitial nephritis, nephrotic syndrome, renal failure and renal papillary necrosis have been reported rarely.

Haematological: Decreases in haemaglobin and haematocrit, unassociated with obvious gastro-intestinal bleeding have occurred. Anaemia, thrombocytopenia and non-thrombocytopenia purpura (Henoch-Schoenlein), leucopenia and eosinophilia have been reported. Cases of aplastic anaemia, haemolytic anaemia and epistaxis have rarely been reported.

Liver function: Changes in various liver function parameters have been observed. As with most other non-steroidal anti-inflammatory drugs, some patients may develop increased serum transaminase levels during treatment with Feldene. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with Feldene. Although such reactions are rare, if abnormal liver function tests persist or worsen, if clinical symptoms consistent with liver disease develop, or if systemic manifestations occur e.g. eosinophilia, rash etc., Feldene should be discontinued.

Other: The following have been reported rarely, palpitations and dyspnoea, anecdotal cases of positive ANA, anecdotal cases of hearing abnormalities, metabolic abnormalities such as hypoglycaemia, hyperglycaemia, weight increase or decrease. Swollen eyes, blurred vision and eye irritations have been reported. Routine ophthalmoscopy and slit-lamp examination have revealed no evidence of ocular changes. Malaise and tinnitus may occur.

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) (see section 4.4).

I.M. only:

Intramuscular: Transient pain upon injection has occasionally been reported. Local adverse reactions (burning sensations) or tissue damage (sterile abscess formation, fatty tissue necrosis) may occasionally occur at the site of injection.

In the event of overdosage with Feldene, supportive and symptomatic therapy is indicated. Studies indicate that administration of activated charcoal may result in reduced re-absorption of piroxicam, thus reducing the total amount of active drug available.

Although there are no studies to date, haemodialysis is probably not useful in enhancing elimination of piroxicam since the drug is highly protein bound.

Capsules and Melt tablets:

Piroxicam is a non-steroidal anti-inflammatory agent which also possesses analgesic and antipyretic properties. Oedema, erythema, tissue proliferation, fever and pain can all be inhibited in laboratory animals by the administration of piroxicam. It is effective regardless of the aetiology of the inflammation. While its mode of action is not fully understood, independent studies in vitro as well as in vivo have shown that piroxicam interacts at several steps in the immune and inflammation responses through:

Inhibition of prostanoid synthesis, including prostaglandins, through a reversible inhibition of the cyclo-oxygenase enzyme.

Inhibition of neutrophil aggregation.

Inhibition of polymorphonuclear cell and monocyte migration to the area of inflammation.

Inhibition of lyosomal enzyme release from stimulated leucocytes.

Reduction of both systemic and synovial fluid rheumatoid factor production in patients with seropositive rheumatoid arthritis.

It is established that piroxicam does not act by pituitary-adrenal axis stimulation. In-vitro studies have not revealed any negative effects on cartilage metabolism.

I.M. only:

Feldene is a non-steroidal anti-inflammatory agent useful in the treatment of inflammatory conditions. Although the mode of action for this agent is not precisely understood, Feldene inhibits prostaglandin synthesis and release through a reversible inhibition of the cyclo-oxygenase enzyme.

Transient pain upon injection has occasionally been reported. Local adverse reactions (burning sensations) or tissue damage (sterile abscess formation, fatty tissue necrosis) may occasionally occur at the site of injection.

Capsules and Melt tablets:

Piroxicam is well absorbed following oral administration. With food there is a slight delay in the rate but not the extent of absorption following administration. The plasma half-life is approximately 50 hours in man and stable plasma concentrations are maintained throughout the day on once-daily dosage. Continuous treatment with 20mg/day for periods of 1 year produces similar blood levels to those seen once steady state is first achieved.

Drug plasma concentrations are proportional for 10 and 20mg doses and generally peak within 3 to 5 hours after medication. A single 20mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 microgram/ml while maximum plasma concentrations, after repeated daily ingestion of 20mg piroxicam, usually stabilise at 3 to 8 microgram/ml. Most patients approximate steady state plasma levels within 7 to 12 days.

Treatment with a loading dose regimen of 40mg daily for the first 2 days followed by 20mg daily thereafter allows a high percentage (approximately 76%) of steady state levels to be achieved immediately following the second dose. Steady state levels, area under the curves and elimination half-life are similar to that following a 20mg daily dose regimen.

A multiple dose comparative study of the bioavailability of the injectable forms with the oral capsule has shown that after intramuscular administration of piroxicam, plasma levels are significantly higher than those obtained after ingestion of capsules during the 45 minutes following administration the first day, during 30 minutes the second day and 15 minutes the seventh day. Bioequivalence exists between the two dosage forms.

A multiple dose comparative study of the pharmacokinetics and the bioavailability of Feldene FDDF with the oral capsule has shown that after once daily administration for 14 days, the mean plasma piroxicam concentration time profiles for capsules and Feldene FDDF were nearly superimposable. There were no significant differences between the mean steady state C_max values, C_min values, T½, or T_max values. This study concluded that Feldene FDDF (Fast Dissolving Dosage Form) is bioequivalent to the capsule after once daily dosing. Single dose studies have demonstrated bioequivalence as well when the tablet is taken with or without water.

Piroxicam is extensively metabolised and less than 5% of the daily dose is excreted unchanged in urine and faeces. Piroxicam metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. One important metabolic pathway is hydroxylation of the pyridyl ring of the piroxicam side-chain, followed by conjugation with glucuronic acid and urinary elimination.

Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

I.M. only:

Feldene I.M. and Feldene capsules are bioequivalent. However, Feldene I.M. provides significantly higher plasma levels of piroxicam during the first 45 minutes on the first day and 30 minutes on the second day.

The plasma half-life is approximately 50 hours in man and stable plasma concentrations are maintained throughout the day on once-daily dosage.

Feldene is extensively metabolised and less than 5% of the daily dose is excreted unchanged in urine and faeces. One important metabolic pathway is hydroxyiation of the pyridyl ring of the piroxicam side chain followed by conjugation with glucuronic acid and urinary elimination.

None stated

Capsules 10mg and 20mg:

Lactose

Corn starch

Vegetable magnesium stearate

Sodium lauryl sulphate

10mg capsule shell cap (red) contains:

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

The body of the capsule shell (blue) contains:

Gelatin

Titanium dioxide (E171)

Indigotin (E132)

20mg capsule shell (white opaque) and body (white opaque) contain gelatin and titanium dioxide (E171).

I.M. Intramuscular Injection:

Sodium dihydrogen phosphate

Nicotinamide

Propylene glycol

Ethanol

Benzyl alcohol

Sodium hydroxide

Hydrochloric acid

Water for injection

Melt tablets:

Gelatin USNF

Mannitol Ph.Eur

Aspartame USNF

Citric acid Ph.Eur

Purified water Ph.Eur

None stated.

Capsules:

Store below 30ºC.

I.M., Melt tablets:

Store below 25ºC.

Capsules 10mg: original pack of 30 capsules contained in a white HDPE bottle with a blue round ribbed cap.

Capsules 20mg: original pack of 30 capsules contained in a white HDPE bottle with a blue round ribbed cap.

I.M.: Type I, 2ml amber glass ampoules containing 1ml.

Melt tablets 20mg: blister strip PVC/PVdC and paper foil laminate containing 10 units. Each pack contains 30 units (3 x strips of 10 tablets).

No special requirements.

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

Capsules: 08/12/2009

IM: 08/12/2009

Melt tablets: 08/12/2009

POM

Ref: FE 10_0