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Feldene Melt 20mg Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Feldene Melt 20 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Piroxicam 20 mg

3 PHARMACEUTICAL FORM

Fast Dissolving Dosage Form (Tablet)

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Feldene is a non-steroidal anti-inflammatory drug indicated for a variety of conditions requiring anti-inflammatory and/or analgesic activity, such as rheumatoid arthritis, osteoarthritis (arthrosis, degenerative joint disease), ankylosing spondylitis, acute musculo-skeletal disorders and acute gout. Pain following orthopaedic, dental and other minor surgery

4.2 Posology and Method of Administration

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

Therapy should be initiated at the lowest recommended dose, especially in elderly patients.

Adults:

Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis: The recommended starting dose is 20 mg given as a single dose. The majority of patients will be maintained on 20 mg daily. A relatively small group of patients may require up to 30 mg daily given in single or divided doses. Administration of doses exceeding 20 mg daily (or more than several days duration) carries an increased risk of gastrointestinal side effects.

Acute gout: Therapy should be initiated by a single dose of 40 mg followed by the next 4 to 6 days with 40 mg daily, given in a single or divided daily dosage. Feldene is not indicated for the long-term management of gout.

Acute musculo-skeletal disorders: Therapy should be initiated with 40 mg for the first 2 days, given in single or divided doses. For the remainder of the 7 to 14 day treatment period, the dose should be reduced to 20 mg daily.

Post-operative pain:

Dental and other minor surgery: The recommended starting and maintenance dose is 20mg once daily. Doses of 40mg daily, in single or divided doses, for the first two days of treatment may provide faster onset of action.

Orthopaedic surgery: Therapy should be initiated with 40mg daily for the first two days, given in single or divided doses. For the remainder of the treatment period, the dose should be reduced to 20mg daily.

Children:

Dosage recommendations and indications for use in children other than in juvenile chronic arthritis using Feldene Dispersible Tablets have not been established.

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.

Combined Administration:

The total daily dosage of Feldene administered as capsules, dispersible tablets, melt tablets, suppositories and intramuscular injection, should not exceed the maximum recommended daily dosage as indicated above.

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.

4.3 Contra-Indications

1. Active peptic ulceration or history of recurrent ulceration.

Feldene should not be used in those patients who have previously shown a hypersensitivity to the drug. The potential exists for cross-sensitivity to aspirin and other non-steroidal anti-inflammatory drugs.

3. Feldene should not be given to patients in whom aspirin and other non-steroidal anti-inflammatory drugs induce the symptoms of asthma, nasal polyps, angioedema or urticaria.

4. Severe heart failure.

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 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 older than 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 or a history of bronchial asthma (see also 'Contra-indications').

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

Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) have been reported with the use of piroxicam.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for 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 or mucosal lesions) are present, piroxicam treatment should be discontinued.

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 piroxicam, piroxicam must not be re-started in this patient at any time.

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 reactions 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 antiinflammatory drug may precipitate overt renal decompensation, which is typically followed by recovery to pretreatment state upon discontinuation of non-steroidal antiinflammatory therapy. Patients at greatest risk of such a reaction are 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.

The use of Feldene with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

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.

Patients with phenylketonuria:

Due to aspartame content of Feldene Melt, each 10mg tablet contains 0.07mg phenylalanine. Each 20mg tablet contains 0.14mg phenylalanine.

4.5 Interactions with other Medicinal Products and other Forms of Interaction

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

Anticoagulants: As with other non-steroidal anti-inflammatory drugs, bleeding has been reported rarely when Feldene has been administered to patients on coumarin-type anticoagulants. Patients should be monitored closely if Feldene and oral anticoagulants are administered together.

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 non-steroidal anti-inflammatory drugs, the use of Feldene with aspirin or the concomitant use of two non-steroidal anti-inflammatory drugs is not recommended because data are inadequate to demonstrate that the combination produces greater improvement than that with the drug alone and the potential for adverse reactions is increased.

Studies in man have shown that the concomitant administration of Feldene and aspirin resulted in a reduction of plasma levels of piroxicam to about 80% of the normal values.

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.

Digoxin, Digitoxin: Concurrent therapy with Feldene and digoxin, or Feldene and digitoxin, 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

Cyclosporin - possible increased risk of nephrotoxicity

Corticosteroids - increased risk of gastro-intestinal bleeding and ulceration

Quinolone antibiotics - possible increased risk of convulsions

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

4.6 Fertility, pregnancy and lactation

Fertility: Based on the mechanism of action, the use of NSAIDs, including Feldene, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including Feldene, should be considered.

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).

Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and postimplantation loss. 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.

Lactation: 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.

4.7 Effects on Ability to Drive and Use Machines

None known.

4.8 Undesirable effects

System Organ Class

Very

Common

>1/10

Common >1/100 to <1/10

Uncommon >1/1000 to <1/100

Rare >1/10 000 to <1 000

Very

Rare

<1/10000

Not Known (cannot be estimated from available data)

Blood and lymphatic system disorders

Anaemia

Eosinophilia

Leucopenia

Thrombocytopenia

Aplastic anaemia

Haemolytic

anaemia

Immune system disorders

Anaphylaxis Serum sickness

System Organ Class	Very Common >1/10	Common >1/100 to <1/10	Uncommon >1/1000 to <1/100	Rare >1/10 000 to <1 000	Very Rare <1/10000	Not Known (cannot be estimated from available data)
Metabolism and nutrition disorders		Anorexia Hyperglycaemia	Hypoglycaemia			Fluid retention
Psychiatric disorders						Depression Dream abnormalities Hallucinations Insomnia Mental confusion Mood alterations Nervousness
Nervous system disorders		Dizziness Headache Somnolence Vertigo				Paresthesia
Eye disorders			Blurred vision			Eye irritations Swollen eyes
Ear and labyrinth disorders		Tinnitus				Hearing impairment
Cardiac disorders			Palpitations			Cardiac failure Arterial thrombotic events
Vascular disorders						Vasculitis Hypertension
Respiratory, thoracic and mediastinal disorders						Bronchospasm Dyspnoea Epistaxis
Gastrointestinal disorders		Abdominal discomfort Abdominal pain Constipation Diarrhoea Epigastric distress Flatulence Nausea Vomiting Indigestion	Stomatitis			Gastritis Gastrointestinal bleeding (including hematemesis and melena) Pancreatitis Perforation Ulceration
Hepatobiliary disorders						Fatal hepatitis Jaundice

System Organ Class	Very Common >1/10	Common >1/100 to <1/10	Uncommon >1/1000 to <1/100	Rare >1/10 000 to <1 000	Very Rare <1/10000	Not Known (cannot be estimated from available data)
Renal and urinary disorders				Interstitial nephritis Nephrotic syndrome Renal failure Renal papillary necrosis
Skin and subcutaneous tissue disorders		Pruritis Skin rash			Severe cutaneous adverse reactions (SCARs): Stevens- Johnson syndrome (SJS)and toxic epidermal necrolysis (TEN) (see section 4.4)	Alopecia Angioedema Dermatitis exfoliative Erythema multiforme Nonthrombocytopenic purpura (Henoch-Schoenlein) Onycholysis Photoallergic reactions Urticaria Vesiculo bullous reactions
Reproductive system and breast disorders						Female fertility decreased
General disorders and administration site conditions		Oedema (mainly of the ankle)				Malaise
Investigations		Increased serum transaminase levels Weight increase				Positive ANA Weight decrease Decreases in hemoglobin and hematocrit unassociated with obvious gastrointestinal bleeding

Gastrointestinal: These are the most commonly encountered side-effects but in most instances do not interfere with the course of therapy. 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 gastrointestinal tract than aspirin. Some epidemiological studies have suggested that piroxicam is associated with higher risk of gastrointestinal 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 gastrointestinal side effects, but they may also occur with lower doses (see Section 4.2).

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.

Liver function: Changes in various liver function parameters have been observed. 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: Routine ophthalmoscopy and slit-lamp examination have revealed no evidence of ocular changes.

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

Piroxicam is well absorbed following oral or rectal 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 mcg/ml while maximum plasma concentrations, after repeated daily ingestion of 20mg piroxicam, usually stabilise at 3 to 8 mcg/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, T'A, 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.

Pharmacogenetics:

CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels, respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following administration of an oral single dose. The mean elimination half life values of piroxicam for subjects with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3 genotype is 0% to 5.7% in various ethnic groups.

5.3 Preclinical Safety Data

None Stated.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Feldene Melt: Gelatin USNF; Mannitol Ph.Eur.; Aspartame USNF; Citric Acid Ph.Eur. Purified Water Ph.Eur.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

60 months.

6.4 Special Precautions for Storage

Below 25°C.

6.5 Nature and contents of container

Blister strip PVC/PVdC and paper foil laminate containing 10 units. Each pack contains 30 units (3 x strips of 10 tablets).

6.6 Instruction for Use and Handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent CT13 9NJ

8. MARKETING AUTHORISATION NUMBER(S)

Feldene Melt 20 mg PL 00057/0352

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

14 September 1992

DATE OF REVISION OF THE TEXT

20/01/2014