Piroxicam Capsules 10mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Piroxicam Capsules 10mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains Piroxicam Ph.Eur 10 mg
3 PHARMACEUTICAL FORM
Capsule, hard.
Hard gelatin capsule with a dark blue opaque cap and a scarlet opaque body, printed in white ink with PRX 10 and Crescent moon logo containing a whitish to slightly yellowish, odourless, homogenous powder.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Piroxicam is 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 an NSAID be indicated. The decision to prescribe piroxicam should be based on an assessment of the individual patient’s overall risks (see sections 4.3 and 4.4).
4.2 Posology and method of administration
For oral administration
To be taken preferably with or after food.
The prescription of piroxicam 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 possible need for combination therapy with gastro-protective agents (e.g. misoprostol or proton pump inhibitors) should be carefully considered, in particular for elderly patients.
Elderly
The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.
Children
The use of piroxicam in children is not recommended.
4.3 Contra-indications
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.
Hypersensitivity to the active substance or to any of the excipients, previous skin reaction (regardless of severity) to piroxicam, other NSAIDs and other medications.
Piroxicam should not be given to patients in whom ibuprofen, aspirin and other nonsteroidal anti-inflammatory drugs induce the symptoms of asthma, rhinitis, nasal polyps, angioedema or urticaria.
History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Concomitant use with other NSAIDs, including COX-2 selective NSAIDs and acetyl-salicylic acid at analgesic doses.
Concomitant use with anticoagulants.
Severe heart failure, hepatic failure and renal failure (see section 4.4).
During the last trimester of pregnancy (see section 4.6)
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 reevaluated periodically and treatment should be immediately discontinued at the first appearance of cutaneous reactions or relevant gastrointestinal events.
Piroxicam, like other non-steroidal anti-inflammatory agents, decreases platelet aggregration and prolongs bleeding time, a factor to be kept in mind when interpreting this measurement.
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.
Respiratory disorders:
Caution is also required if administered to patients suffering from or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.
Cardiovascular, Renal and Hepatic impairment:
The administration of an NS AID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. 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 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 nonsteroidal 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 this reaction are those with impaired renal function, nephrotic syndrome and overt renal disease, hepatic dysfunction, liver cirrhosis, cardiac impairment, hypertension or congestive heart failure, those taking diuretics and the elderly, such patients should be carefully monitored whilst receiving NSAID therapy.
Ophthalmic effects: Because of reports of adverse eye findings with nonsteroidal anti-inflammatory drugs, it is recommended that patients who develop visual complaints during treatment with Piroxicam have ophthalmic evaluation.
Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).
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 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.
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 disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).
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
SLE and mixed connective tissue disease:
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).
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 month 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.
Other serious skin reactions including exfoliative dermatitis 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.
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.
Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine as it contains lactose.
4.5 Interaction with other medicinal products and other forms of interactions
Antacids: Concomitant administration of antacids had no effect on piroxicam plasma levels.
Highly protein-bound drugs: Piroxicam is highly protein-bound, and therefore might be expected to displace other protein-bound drugs. Patients should be closely monitored for change in dosage requirements when administering piroxicam to patients on highly protein-bound drugs.
Lithium: Non-steroidal anti-inflammatory agents including piroxicam have been reported to increase steady state plasma lithium levels. Monitoring is recommended when initiating, adjusting and discontinuing piroxicam.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside 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).
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 considered when treating patients with compromised cardiac function or hypertension, since they may be responsible for a worsening of those conditions. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
Cimetidine: It is reported that the results of 2 separate studies indicate a slight, but significant, increase in absorption of piroxicam following cimetidine administration, but not significant changes in elimination rate constants or half-life. It is unlikely that the small increase in absorption is clinically significant.
Anti-hypertensives: The effects of antihypertensive drugs can be decreased or abolished by non-steroidal anti-inflammatory drugs such as piroxicam.
Methotrexate: As with other non-steroidal anti-inflammatory drugs the use of piroxicam in conjunction with methotrexate causes excretion of methotrexate to be reduced therefore increasing toxicity, in some cases this has been life threatening. The toxicity may be related to the methotrexate dosage. This risk is reduced in patients taking low dose methotrexate.
Ciclosporin: It is reported that concomitant use of piroxicam and ciclosporin can lead to an increased risk of nephrotoxicity (increased serum creatinine levels have been reported).
Mifepristone: The use of non-steroidal anti-inflammatory drugs should be avoided for at least 8-12 days after administration of mifepristone. This avoidance is essential because of a theoretical risk to the efficacy of the mifepristone.
Corticosteroids: It is reported that the use of corticosteroids in conjunction with nonsteroidal anti-inflammatory drugs increases the risk of gastrointestinal bleeding and ulceration (see section 4.4). Concurrent use should be well monitored.
Digoxin, Digitoxin: Concurrent therapy with Piroxicam and digoxin, or Piroxicam and digitoxin, did not affect the plasma levels of either drug.
Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
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: Piroxicam like other nonsteroidal 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 agents, the use of piroxicam together with acetyl-salicylic acid or concomitant use with other non-steroidal antiinflammatory agents, including other piroxicam formulations, must be avoided, since data are inadequate to show that such 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 concomitant use of piroxicam and acetyl-salicylic acid reduces the plasma piroxicam concentration to about 80% of the usual values.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
4.6 Fertility, pregnancy and lactation
Fertility:
Based on the mechanism of action, the use of NSAIDs, including piroxicam, 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 piroxicam, should be considered.
Pregnancy:
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development . Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesisinhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, piroxicam should not be given unless clearly necessary. If piroxicam is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
- -cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;
the mother and the neonate, at the end of pregnancy, to:
- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
- Inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, piroxicam is contraindicated during the third trimester of pregnancy.
Lactation:
It is reported that piroxicam appears in breast milk at about 1% to 3% of the maternal plasma concentrations. There was no accumulation of piroxicam in the milk relative to that in plasma during treatment for up to 52 days. Piroxicam is not recommended for use in nursing mothers as clinical safety in neonates 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
|
System Organ Class |
Very common >1/10 |
Common >1/100 to <1/10 |
Uncommon >1/1000 to <1/100 |
Rare >1/10000 to <1/1000 |
Very Rare <1/100 00 |
Not Known (cannot be estimated from available data) |
|
Infections and infestations |
aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4) | |||||
|
Blood and lymphatic system disorders |
anaemia eosinophilia leucopenia thrombocytopenia |
neutropenia agranulocytosis aplastic anaemia haemolytic anaemia | ||||
|
Immune system disorders |
serum sickness photoallergic reactions | |||||
|
Metabolism and nutrition disorders |
anorexia hyperglycaemia |
hypoglycaemia |
metabolic abnormalities fluid retention | |||
|
Psychiatric disorders |
depression mental confusion hallucinations drowsiness insomnia nervousness mood alterations dream abnormalities | |||||
|
Nervous system disorders |
dizziness headache somnolence vertigo |
paraesthesia | ||||
|
Eye disorders |
visual disturbances optic neuritis blurred vision |
swollen eyes eye irritations | ||||
|
Ear and labyrinth disorders |
tinnitus |
hearing impairment | ||||
|
Cardiac disorders |
palpitations |
cardiac failure arterial thrombotic events | ||||
|
Vascular disorders |
hypertension vasculitis | |||||
|
Respiratory, |
epitaxis |
|
thoracic and mediastinal disorders | ||||||
|
Gastrointestin al disorders |
nausea vomiting diarrhoea flatulence constipation dyspepsia abdominal pain or discomfort epigastric distress |
ulcerative stomatitis |
peptic ulcers, perforation or GI bleeding (including haematemesis and melaena) sometimes fatal, particularly in the elderly, may occur (see section 4.4). exacerbation of colitis and Crohn’s disease (see section 4.4) gastritis pancreatitis | |||
|
Hepatobiliary disorders |
fatal hepatitis jaundice | |||||
|
Skin and subcutaneous tissue disorders |
nonthrombocytopenic purpura (Schoenlein-Henoch), onycholysis, alopecia, vesiculo-bullous reactions, photosensitivity | |||||
|
Renal and urinary disorders |
interstitial nephritis, glomerulone phritis, renal papillary necrosis, nephrotic syndrome, renal failure | |||||
|
Reproductive system and breast disorders |
female fertility decreased | |||||
|
General disorders and administration site conditions |
oedema (mainly of the ankle) |
malaise fatigue | ||||
|
Investigations |
increased serum transaminase levels weight increase |
weight decrease decreases in haemoglobin and haemocrit unassociated with obvious gastrointestinal bleeding reversible elevations of blood urea nitrogen and creatinine positive ANA |
Gastrointestinal: The most commonly observed adverse events are gastrointestinal in nature 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 Piroxicam administered either in single or divided doses is significantly less irritating to the gastro-intestinal 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 gastro-intestinal side-effects, but they may also occur with lower doses. See section 4.2 Posology and method of administration.
Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses including erythema multiforme and severe cutaneous adverse reactions (SCARs): Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN/Lyell’s disease) (see section 4.4).
Cardiovascular and cerebrovascular: 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.
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).
Hepatic: Changes in different liver function parameters have been observed. If abnormal liver function tests persist or get worse, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg: eosinophilia, rash), piroxicam should be discontinued.
Other: Routine opthalmoscopy and slit-lamp examination have revealed no evidence of ocular changes.
Use in Elderly: Elderly, frail or debilitated patients may tolerate side effects less well and such patients should be carefully supervised. As with other nonsteroidal anti-inflammatory agents, caution should be exercised in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function.
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 symptoms, emergency procedures, antidotes
a) Symptoms:
Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.
b) Therapeutic measures:
Patients should be treated symptomatically as required.
Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Studies indicate that administration of activated charcoal may result in reduced re-absorption of piroxicam, thus reducing thetotal 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
Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.
Good urine output should be ensured.
Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts.
Frequent or prolonged convulsions should be treated with intravenous diazepam.
Other measures may be indicated by the patient’s clinical condition.
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
The following mean values were obtained with Piroxicam Capsules 20mg in 12 healthy volunteers:-
Elimination (T'A)
Time to peak Peak
Area under fitted curve Area by trapezoid rule Curve fitting
27.08 hours 5.23 hours 2.07 pg ml-1 92.47 hours pg ml-1 94.22 hours pg ml-1 0.989
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 piroxicam 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 piroxicam FDDF were nearly superimposable. There were no significant differences between the mean steady state Cmax values, Cmin values, T'A, or Tmax values. This study concluded the piroxicam 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 metabolisers 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 4.4).
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
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 Pharmaceutical particulars
6.1 List of Excipients
Sodium laurilsulfate Maize starch Lactose monohydrate Magnesium stearate.
Capsule shells:
Gelatin
Titanium dioxide (E171) Erythrosine (E127) Indigo carmine (E132) Iron oxide black (E172)
TekPrint SW-0012 White Ink (containing shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, purified water, potassium hydroxide, titanium dioxide E171)
6.2. Incompatibilities
None known.
6.3. Shelf Life
36 months, as packaged for sale.
6.4. Special Precautions for Storage
Store in a cool, dry place below 30°C and protect from light.
6.5. Nature and Contents of Container
Securitainers.
Pack sizes 28, 30, 56 and 60.
6.6. Instruction for Use/Handling Not applicable.
7. MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited Units 3 and 4
Quidhampton Business Units Polhampton Lane Overton
Hants RG25 3ED United Kingdom
8.
MARKETING AUTHORISATION NUMBER
PL 20416/0137
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
05/03/2009
10 DATE OF REVISION OF THE TEXT
02/04/2015