Piroxicam Capsules 20 Mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Piroxicam Capsules 20 mg or
Piroflex 20 or Piroflam 20 or
Kentene (Kent Pharmaceuticals).
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 20 mg of Piroxicam PhEur.
3 PHARMACEUTICAL FORM
Capsules for oral use.
Appearance:
Hard gelatin, maroon coloured capsule printed with the company logo and ‘C31’, or printed with ‘PIROFLEX 20’, or printed with ‘P20’, or printed with ‘PIROXICAM 20’.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Piroxicam is a non-steroidal anti-inflammatory agent indicated for symptomatic relief of osteoarthritis, rheumatoid arthritis or ankylosing spondylitis.
Due to its safety profile (see sections 4.2, 4.3 and 4.4) piroxicam is not a first line option should use of NSAIDs be indicated. The decision to prescribe piroxicam should be based on an assessment of the individual patient’s overall risk (see sections 4.3 and 4.4).
4.2 Posology and method of administration
Treatment with piroxicam should only 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 lowest 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.
Piroxicam has been shown to be associated with increased risk of gastrointestinal complications. Careful consideration should be given to the need for combination therapy with gastrointestinal protective agents (eg, misoprostol or proton pump inhibitors), particularly in the elderly.
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.
Administration: Oral: The capsules should be swallowed with a drink of water, preferably with or after food.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
4.3 Contraindications
1. History of gastrointestinal ulceration, bleeding or perforation.
2. Patient history of gastrointestinal disorders that predispose to bleeding disorders such as ulcerative colitis, Crohn’s disease, gastrointestinal cancers or diverticulitis.
3. Active peptic ulceration, inflammatory gastrointestinal disorder or gastrointestinal bleeding.
4. Concomitant use with other NSAIDs, including COX-2 selective NSAIDs and acetylsalicylic at analgesic doses.
5. Concomitant use with anticoagulants.
6. Concomitant use with ritonavir (increased risk of piroxicam toxicity).
7. History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as erythema multiforme, Stevens Johnson syndrome or toxic epidermal necrolysis.
8. Piroxicam should not be used in those patients who have previously shown a hypersensitivity to the drug or to any of the excipients; previous skin reaction (regardless of severity) to piroxicam other NSAIDs and other medications.
9. Piroxicam should not be given to patients in whom aspirin and other nonsteroidal anti-inflammatory drugs induce the symptoms of asthma, nasal polyps, angioedema or urticaria.
10. Severe heart failure.
11. During the last trimester of pregnancy.
12. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 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 piroxicam.
Piroxicam should be used with caution in patients with a history of bronchial asthma (see also section 4.3).
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.
Piroxicam 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 pre-treatment 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 piroxicam have ophthalmic evaluation.
Impaired female fertility
The use of piroxicam 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 piroxicam should be considered.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine also contains colour amaranth (E123). This colour may cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
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 anticoagulants such as warfarin should be avoided (see section 4.3).
Anti-platelet agents and selective serotonin re-uptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).
Antivirals: Plasma concentration of piroxicam is increased by ritonavir (risk of toxicity). Avoid concomitant use.
Aspirin and other Non-Steroidal Anti-Inflammatory Drugs: Piroxicam, 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 Piroxicam with aspirin or the concomitant use of two non-steroidal anti-inflammatory drugs, including other piroxicam formulations, must be avoided because data are inadequate to show that the combinations produce greater improvement than that achieved with piroxicam alone; moreover, the potential for adverse reactions is enhanced (see section 4.4).
Human studies have shown that the concomitant administration of Piroxicam and aspirin resulted in a reduction of plasma levels of Piroxicam to about 80% of the normal values.
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).
Diuretics: Non-steroidal anti-inflammatory drugs may cause sodium, potassium and fluid retention and may interfere with the natriuretic action of diuretic agents. There 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: Piroxicam 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 Piroxicam to patients on highly protein-bound drugs.
Lithium: Non-steroidal anti-inflammatory drugs, including Piroxicam, have been reported to increase steady state plasma lithium levels. It is recommended that these levels are monitored when initiating, adjusting and discontinuing Piroxicam
Piroxicam, 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
Quinoline antibiotics - possible increased risk of convulsions Mifepristone - NSAIDs could interfere with mifepristone-mediated termination of pregnancy
4.6 Fertility, Pregnancy and lactation
Use in Pregnancy
Although no teratogenic effects were seen in animal testing, the safety of piroxicam used during pregnancy or during lactation, has not yet been established. Piroxicam 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 into late pregnancy. Non-steroidal antiinflammatory drugs are known to have effects on the foetal cardiovascular system(risk of closure of the ductus arteriosus). Therefore 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 unless the potential benefit to the mother outweighs the potential risk to the foetus.
Use in 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.
Piroxicam is not recommended for use in nursing mothers as the clinical safety has not been established.
4.7 Effects on ability to drive and use machines
Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected patients should not drive or operate machinery.
4.8 Undesirable Effects
Gastro-intestinal: Gastro-intestinal symptoms are the most commonly encountered side effects but in most instances do not interfere with the course of therapy. These adverse reactions include stomatitis, anorexia, epigastric distress, gastritis, nausea, vomiting, constipation, abdominal discomfort, flatulence, diarrhoea, abdominal pain and indigestion. Rare cases of pancreatitis have been reported. Objective evaluations of gastric mucosal appearances and intestinal blood loss show that 20 mg per day of piroxicam administered either in single or divided daily 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 piroxicam.
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 20 mg 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 Posology and method of administration.
Oedema, hypertension, and cardiac failure: have been reported in association with NSAID treatment. The possibility of precipitating congestive cardiac 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 pruritus, onycholysis and alopecia have rarely been reported. Photo-allergic reactions occur infrequently. As with other non-steroidal antiinflammatory 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 haemoglobin and haematocrit, unassociated with obvious gastro-intestinal bleeding have occurred. Anaemia has been reported. Thrombocytopenia and non-thrombocytopenic purpura (Henoch-Schoenlein), leucopenia and eosinophilia have been
reported. Cases of aplastic anaemia, haemolytic anaemia andepistaxis 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 piroxicam. Severe hepatic reactions, including jaundice and cases of fatal hepatitis have been reported. Although such reactions are rare, if abnormal liver function tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash), piroxicam 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).
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 the yellow card scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
In the event of overdosage with piroxicam, 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
Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products ATC code: M01AC01
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 lysosomal enzyme release from stimulated leucocytes.
Reduction of both systemic and synovial fluid rheumatoid factor production in patients and 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 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.
Piroxicam is extensively metabolised and less than 5% of the daily dose is excreted unchanged in urine and faeces. One important metabolic pathway is hydroxylation of the pyridyl ring of the piroxicam side chain followed by conjugation with glucuronic acid and urinary elimination.
5.3 Preclinical safety data
Not available.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose BP, Maize Starch BP, Sodium Lauryl Sulphate BP, Crospovidone NF (Kollidon CL), Magnesium Stearate BP, amaranth (E123), Titanium Dioxide BP (E171), and Gelatin PhEur.
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store below 30°C.
6.5 Nature and contents of container
1. Polypropylene tubes with low density polyethylene caps.
2. Blister packs consisting of clear PVC and hard temper aluminium foil contained in a
carton.
3. Tracer Packs: Child resistant containers consisting of polypropylene tubes with high
density polyethylene caps
Pack sizes: 28, 30, 56, 60, 100, 250 and 500 capsules.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Relonchem Limited,
Cheshire House,
Gorsey Lane,
Widnes,
Cheshire,
WA8 0RP,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 20395/0115
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25/02/2009
10 DATE OF REVISION OF THE TEXT
19/08/2015