INFORMATION FOR HEALTH PROFESSIONALS
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CANDYL-D 10mg dispersible tablets: A white, flat, bevel-edged, round tablet of 10mm diameter embossed with 10 on one side.
CANDYL-D 20mg dispersible tablets: A white drapsule shaped tablet 14mm x 6mm with a breakline on one face and embossed 20 on the other.
CANDYL 10mg capsules: A size 2, hard gelatine capsule with an opaque maroon cap and a light blue body, filled with an off-white powder.
CANDYL 20mg capsules: A size 2, hard gelatine capsule with an opaque maroon cap and an opaque maroon body, filled with an off-white powder.
Piroxicam is a non-steroidal, anti-inflammatory agent possessing both analgesic and antipyretic properties. The mode of action of piroxicam is not fully established at this time, however, as a result
of piroxicam's inhibition of prostaglandin synthetase, prostaglandin biosynthesis is decreased. This may explain, in part, its anti-inflammatory action. It is known that pituitary-adrenal stimulation is not a mechanism of action of piroxicam.
A 20mg dose of piroxicam daily has similar efficacy to 4.5g of ASA daily in the treatment of rheumatoid arthritis. The anti-inflammatory activity of oral doses of piroxicam has been shown in rats, guinea pigs and dogs. A 4.0mg/kg dose administered to rats induced a 50% inhibition of carogeenan-induced foot oedema. Adjuvant-induced arthritis in rats was inhibited by piroxicam in doses of 0.3-3.3mg/kg. Inhibition of cotton string-induced granuloma formation in rats was observed after doses of 10 and 18mg/kg. Guinea pigs given a 0.3mg/kg dose of piroxicam showed a 50% inhibition of ultraviolet light induced erythema. Piroxicam given intravenously to dogs in a dose of 5mg/kg inhibited the inflammatory response to urate-induced synovitis in knee joints.
Analgesic activity of piroxicam has been demonstrated in mice given 1.85mg/kg orally, using the phenylquinone-induced writhing test. Oral doses of 1-2mg/kg of piroxicam were effective in elevating the threshold to pressure in edematous rat paws. Doses up to 100mg/kg orally were inactive in hot-plate and tail-flick tests.
Antipyretic activity of piroxicam given orally to rats at 10mg/kg has been demonstrated in a model of hyperpyrexia induced by intramuscular injections of E. coli lipopolysaccharide.
Prostaglandin biosynthesis is reduced by piroxicam due to inhibition of prostaglandin synthetase. Collagen-induced aggregation of platelets is also inhibited. Anti-inflammatory activity in adrenalectomised rats demonstrated the independence of piroxicam's anti-inflammatory activity from adrenal stimulation. Piroxicam does not have significant cardiovascular or central nervous system activity in animals.
Piroxicam is well absorbed when given orally. Neither food nor antacids effect the rate or extent of absorption. Peak plasma concentrations of piroxicam are achieved in about 4 hours following a single 20mg dose. In man, the plasma half-life is approximately 38 hours. When administered daily, plasma concentrations of piroxicam increase for five to eight days to reach a steady state level.
A single dose (20mg) bioavailability study was performed by Richardson et al in order to evaluate age and sex-related differences in the pharmacokinetics of piroxicam. It was found that elderly women (62 to 75 years) had 33% lower piroxicam clearance than young women (20 to 31 years), a difference that was reflected in the significantly different half-life of 61.7 and 44.9 hours, respectively. No significant difference of the clearance rate was found between young men and elderly men.
The predicted steady state plasma concentrations were found to be 5.7, 5.4 and 5.7mcg/ml in young women, young men and elderly men, compared with 9.3mcg/ml in elderly women. These results are at variance with the findings of Hobbs et al and Woolf et al, who concluded that age had no or negligible effect on piroxicam clearance and steady state plasma levels.
Piroxicam undergoes extensive hepatic metabolism with less than 5% excreted unchanged in the urine or faeces. Hydroxylation of the pyridyl ring constitutes the major pathway of metabolism after which the metabolite that is inactive is conjugated with glucuronic acid and excreted as such in the urine and faeces.
Studies have shown that subjects had significantly lower average daily faecal blood loss over a 4 day period when given piroxicam
20mg daily (in single or divided doses) than when given aspirin 3.9g daily.
Piroxicam is indicated for the treatment of symptoms related to rheumatoid arthritis, osteoarthritis (degenerative joint disease) and ankylosing spondylitis.
In the symptomatic treatment of rheumatoid arthritis and ankylosing spondylitis, the recommended starting dose of piroxicam is a single daily dose of 20mg, or if desired, 10mg twice daily. The majority of patients will require a maintenance dose of 20mg daily although some may be maintained on 10mg daily. The recommended dosage of piroxicam for the initiation of treatment of osteoarthritis is 20mg once daily or, if desired, 10mg twice daily. Usual maintenance therapy is 10-20mg daily.
Because of increased risk of toxicity for elderly, debilitated and frail patients or patients with impaired renal function, a starting dose of 10mg/day is recommended. The dose may be increased to 20mg/day, if necessary (see Warnings and Precautions ). Because of the length of time required to attain steady-state plasma concentrations on once per day dosing (5-8 days), the full effect of treatment should not be assessed for two weeks.
Piroxicam should not be administered to patients with, or with a recent or recurrent history of, peptic ulcer disease or active gastrointestinal inflammatory disease.
Piroxicam is contraindicated in patients that have shown hypersensitivity to piroxicam. It should not be administered to patients in whom ASA or other non-steroidal, anti-inflammatory agents have precipitated bronchoconstriction, nasal polyps or urticaria because of the possibility of cross-sensitivity.
Gastrointestinal bleeding, peptic ulceration and perforation have been observed during therapy with piroxicam. These side effects were sometimes severe, and in some instances, fatal. If piroxicam must be used in patients with a history of gastrointestinal tract disease, this should be done with great caution and under close supervision. The use of doses higher than the recommended dose, 20mg daily, is associated with an increase in the incidence of gastrointestinal irritation and ulcers.
There is no evidence that the concurrent administration of H2 antagonists or antacids will either prevent the occurrence of gastrointestinal adverse reactions, or allow continuation of piroxicam therapy in the presence of these adverse reactions.
Use in the Elderly, Frail or Debilitated Patients: Since gastrointestinal side effects and ulceration from piroxicam are dose related, persons with a decreased ability to eliminate piroxicam may be more susceptible to adverse effects. Treatment in elderly, frail or debilitated patients, especially those aged 65 and over should be started with 10mg a day and increased to 20mg a day if necessary. Careful monitoring of these patients is essential.
Use in Pregnant or Lactating Women: The safety of piroxicam has not been established in these conditions and therefore the use of piroxicam is not recommended during pregnancy or lactation. It has not been determined whether piroxicam crosses the placenta. Piroxicam was present in human milk in a concentration of approximately 1% of that reached in plasma.
Animal reproductive studies have not demonstrated any teratogenic effects. Pregnant rats and rabbits receiving piroxicam have shown an increased frequency of dystocia and delayed parturition. Suppression of lactation has been observed in rats receiving piroxicam.
Gastrointestinal tract toxicity was increased in pregnant females or females in earlier trimesters of pregnancy.
Use in Children: Piroxicam is not recommended for use in children under 16 years of age. Dose and indications for paediatric patients have not been established.
Piroxicam should be used cautiously in patients with decreased renal function. Because of the extensive renal excretion of piroxicam and its biotransformation products (less than 5% of the daily dose excreted unchanged), lower doses of piroxicam should be anticipated in patients with impaired renal function and they should be carefully monitored. Acute renal failure and hyperkalaemia as well as reversible elevations of BUN and serum creatinine have been reported with piroxicam.
In addition to reversible changes in renal function, interstitial nephritis, glomerulitis, papillary necrosis and the nephrotic syndrome have been reported with piroxicam. Patients with impaired renal function, congestive heart failure, cirrhosis with ascites or those on diuretics, as well as elderly patients are more at risk. Patients on long term therapy with piroxicam, especially those in the high risk categories should have blood chemistry and kidney function tests monitored periodically. If renal function deterioration commences, piroxicam administration should be stopped.
Piroxicam should be used cautiously in patients with decreased hepatic function. Borderline elevations of one or more liver function tests may occur in patients taking piroxicam. These abnormalities may progress, remain essentially unchanged or may be transient with continued therapy. Any patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while receiving piroxicam therapy.
Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with piroxicam. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc), piroxicam should be discontinued (see also Adverse Reactions ). All patients on long term piroxicam therapy should have periodic liver function tests.
Piroxicam, like other non-steroidal, anti-inflammatory agents, inhibits prostaglandin biosynthesis and therefore interferes with platelet function, partly due to a decrease in platelet aggregation. Therefore, patients who may be adversely affected by such an action should be carefully observed during piroxicam administration.
Patients who develop visual complaints during treatment with piroxicam should have ophthalmic evaluation since there have been reports of adverse eye findings with non-steroidal, anti-inflamatory agents.
Approximately 2% of patients treated with piroxicam experience peripheral oedema. Therefore, piroxicam should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention, since its usage may be associated with a worsening of these conditions. Congestive heart failure may be precipitated in the elderly and in patients with compromised cardiac function.
Patients should be monitored for a combination of dermatological and/or allergic signs and symptoms of serum sickness which have occasionally occurred in conjunction with the use of piroxicam. These include arthralgias, pruritus, fever, fatigue and rash including vesiculo bullous reactions and exfoliative dermatitis.
Because of the drug's anti-inflammatory activity, piroxicam may mask the usual signs of infection.
Although at the recommended dose of 20mg/day of piroxicam increased faecal blood loss due to gastrointestinal irritation did not occur, in about 4% of the patients treated with piroxicam alone or concomitantly with ASA, reductions in haemoglobin and haematocrit values were observed. Therefore, these values should be checked periodically.
Mutagenicity: None of the studies demonstrated any mutagenic activity of piroxicam.
Carcinogenicity: In a 24-month rat study, piroxicam administered in the diet to provide doses of 0.3 and 1.0mg/kg, induced non-neoplastic lesions. The principal drug induced pathologic changes consisted of renal papillary necrosis, suppurative pyelonephritis and pyloric ulceration. Except for suppurative pyelonephritis, females were more often effected than males.
Approximately 30% of all patients receiving daily doses of 20mg of piroxicam experienced side effects. The most frequent side effects occurring in patients receiving piroxicam (20% of patients) have been gastrointestinal in origin. Approximately 4% of patients have been required to discontinue piroxicam treatment due to gastrointestinal complaints. The most severe adverse reactions are peptic ulceration and gastrointestinal bleeding.
The following adverse reactions, with approximate incidences have been reported:
Gastrointestinal:
Abdominal discomfort 5.7% Flatulence 5.2% Nausea 4.8% Abdominal pain 4.7% Epigastric distress 4.1% Constipation 3.8% Diarrhoea 3.2% Peptic ulceration 1.8% Stomatitis 1-3% Anorexia 2.0% Vomiting 1.0% Indigestion 0.7% Gastrointestinal bleeding 0.1%
Liver function abnormalities, jaundice, hepatitis, haematemesis, melena and dry mouth were seen in less than 1% of patients.
Central Nervous System:
Dizziness 4.1% Headache 4.1% Drowsiness/Sedation 2.1%
Amnesia, anxiety, depression, hallucinations, insomnia, nervousness, paresthesia, personality change, tremors and vertigo were seen in less than 1% of patients.
Dermatologic:
Rash 2.4% Pruritus 1.1%
Alopecia, sweating, erythema, bruising, desquamation, exfoliative dermatitis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, vesiculobullous reaction, and photoallergic reactions were seen in less than 1% of patients.
Genito-Urinary:
Oedema 2.7% BUN elevation 1-3% Creatinine elevation 1-3%
ENT: Blurred vision, eye irritation/swelling, deafness, tinnitus, epistaxis and glossitis were seen in less than 1% of patients.
Haematological:
Decreases in haemoglobin and haematocrit 3-9% Anaemia 1-3% Leukopenia 1-3% Eosinophilia 1-3%
Thrombocytopenia, petechial rash, ecchymosis, bone marrow depression including aplastic anaemia, and epistaxis were seen in less than 1% of patients.
Cardiovascular/Repiratory: Hypertension, worsening of congestive heart failure, exacerbation of angina, palpitations, tachycardia, and breathlessness were seen in less than 1% of patients.
Metabolic: Hypoglycaemia, hyperglycaemia, weight increase, and weight decrease were seen in less than 1% of patients.
Hypersensitivity: Bronchospasm, anaphylaxis, angioedema, vasculitis, and serum sickness were seen in less than 1% of patients.
Miscellaneous: Pain (colic), fever, flu-like syndrome, thirst, chills, flushing, and increased appetite were seen in less than 1% of patients.
The propensity of piroxicam to interact with other medicines may influence the treatment of other conditions. Piroxicam is highly bound to plasma proteins and may displace other protein-bound agents. Patients being treated with coumarin anticoagulants or other highly protein-bound drugs should have their dosage requirements monitored closely during concomitant piroxicam administration.
Concomitant administration of antacids has no effect on piroxicam plasma levels; however, plasma levels are depressed to approximately 80% of their normal values when piroxicam is administered in conjunction with acetyl-salicylic acid (3.9g/day).
The use of piroxicam in conjunction with acetylsalicylic acid or another non-steroidal, anti-inflammatory agent is not recommended since data are not available demonstrating that the combination produces greater improvement than that achieved with either drug alone, and the potential for adverse reactions is increased.
Non-steroidal, anti-inflammatory agents, including piroxicam, have been reported to increase steady state plasma lithium levels. When initiating, adjusting and discontinuing piroxicam, it is recommended that plasma lithium levels be monitored.
A few cases of overdose (up to 1800mg) have been reported. Recovery was complete. Symptoms and signs included nausea, abdominal pain, multiple superficial gastric and duodenal ulcers, and gastrointestinal tract bleeding.
No specific antidote is known to piroxicam. The usual supportive and symptomatic treatment is recommended. In animals, the use of activated charcoal has been shown to reduce the absorption of piroxicam.
Protect from light and moisture. Store below 30°C. Keep out of reach of children.
Prescription Medicine.
100 tablets packed in HDPE bottles
30 tablets packed in blister trays
100 capsules packed in HDPE bottles
30 capsules packed in blister trays
Piroxicam belongs to the chemical class of N-heterocyclic carboxamides of 1,2-benzo-thiazine-1,1-dioxide (oxicams).
An amphoteric compound, piroxicam has a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.5) as determined by ultra-violet absorption spectrophotometry in methanol-water (2.5/97.5, v/v) solvent medium.
Chemical Name: N-1(pyridyl)-4-hydroxy-2-methyl-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide. It has a molecular formula and weight of C15H13N3O4S and 331.35 respectively.
Description: Piroxicam is a white, crystalline, hygroscopic solid. Melting point is 196-200°C. It is poorly soluble in water, dilute acid and most organic solvents and slightly soluble in alcohols and aqueous alkaline solution.
Acute Toxicity:
Oral LD50 mg/kg (95% Confidence Limits)
Mice: 395 (255-612)
Rats: 320 (244-419)
Toxic effects observed in mice and rats included apathy, decreased motor activity, depression, dyspnea, ataxia, ptosis and prostration.
Necropsy of these animals revealed internal haemorrhage of the stomach wall, adjacent small intestine and adrenals, congested adrenal glands, livers and lungs, and partial thickening of the stomach wall.
The oral LD50 in dogs has been reported to be greater than 500mg/kg.
Subacute and Chronic Toxicity: Studies in beagle dogs, rhesus monkeys and rats illustrate that the major toxic effects are manifested in the GI tract and kidneys.
Other ingredients of the tablets/capsules are: Lactose, Microcrystalline cellulose, Hydroxypropyl cellulose and Sodium stearyl fumarate.
Douglas Pharmaceuticals Ltd
PO Box 45-027
Auckland 8
Ph: (09) 835-0660
Fax: (09) 835-0665
8 March 1999