In the event of overdosage with Brexin, 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.
Overdose is unlikely to occur with this topical preparation.
None stated.
The metabolism of Brexin is inhibited by cimetidine and it itself can inhibit antipyrine metabolism.
| 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 Thrombo-cytopenia | Aplastic anaemia Haemolytic anaemia | ||||
| Immune system disorders | Anaphylaxis Serum sickness | |||||
| 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 | |||||
| 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) | Alopecia Angioedema Dermatitis exfoliative Erythema multiforme Non-thrombocytopenic 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 gastro-intestinal 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 Brexin 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.
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 a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
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.), Brexin should be discontinued.
Other: Routine ophthalmoscopy and slit-lamp examination have revealed no evidence of ocular changes.
The systemic absorption of Brexin 0.5% Gel is very low. In common with other topical NSAIDs, systemic reactions occur infrequently. Mild to moderate local irritation, erythema, pruritus, and dermatitis may occur at the application site.
Gastrointestinal: nausea, dyspepsia, abdominal pain and gastritis have been reported.
Respiratory, thoracic and mediastinal disorders: There have been isolated reports of bronchospasm and dyspnoea.
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported very rarely.
Contact dermatitis, eczema and photosensitivity skin reaction have also been observed from post-marketing experience.
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 (Website: www.mhra.gov.uk/yellowcard).
None stated.
There are no preclinical data of relevance to the prescriber which are additional to those included elsewhere in the SPC.
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.
Pharmacotherapeutic group: Anti-inflammatory preparations, non-steroids for topical use (ATC code M02AA07).
Brexin inhibits the enzyme cyclo-oxygenase. This is a basic characteristic of non-steroidal anti-inflammatory drugs, which allows them to influence many physiological processes.
Depending on the site of action, NSAID may;
- reduce the vascular phase of inflammation,
- decrease sensitisation of nociceptors to stimulation,
- act as an antipyretic,
- inhibit the secondary phase of platelet aggregation,
- affect the motility of bronchi and of the uterus,
- cause a dose dependent decrease in renal blood flow particularly in patients with renal impairment,
- lead to the activation of free radicals by neutrophils,
- affect the permeability of the foetal umbilical arterial canal,
- interfere with the renal resorption of uric acid,
- affect the gastric mucosa leading to ulceration of the muscularis mucosa.
Brexin's pharmacological profile is based on the inhibition of prostaglandin synthesis from arachidonic acid in vitro, of collagen-induced aggregation of human and animal platelets in vitro, of the release of lysosomal enzymes, of the generation of the reactive superoxide anion, of chemostaxis/migration of neurophils, macrophages, monocytes, platelets, of the carrageenin-induced foot oedema in rats, of the benzoquinone-induced writhing in mice, of E.coli-induced fever in rats and of urate crystal-induced synovitis.
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 Brexin 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 Brexin FDDF were nearly superimposable. There were no significant differences between the mean steady state Cmax values, Cmin values, T½, or Tmax values. This study concluded that Brexin FDDF (Fast Dissolving Dosage Form) is bioequivalent to the capsule after once daily dosing. Single dose studies have demonstrated bioequivalence as well when the tablet is taken with or without water.
Piroxicam is extensively metabolised and less than 5% of the daily dose is excreted unchanged in urine and faeces. Piroxicam metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. One important metabolic pathway is hydroxylation of the pyridyl ring of the piroxicam side-chain, followed by conjugation with glucuronic acid and urinary elimination.
Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.
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.
A study in man examining skin biopsies following Brexin gel administration concluded that Brexin rapidly permeates through the stratum corneum into the epidermis/dermis after application of the gel with plasma levels being low.
A separate study in man demonstrated mean plasma concentrations of Brexin gel to be approximately 5% of those observed after equivalent doses of oral or intramuscular Brexin. In healthy subjects or patients following the administration of a single oral dose, the pharmacokinetics of Brexin are linear, with maximum plasma concentration usually being obtained in about 2 h, but this can vary from 1-6 h in different subjects. It has a low clearance rate of approximately 45 h, but the half-life can vary from 30-60 h. After repeated doses of 20 mg daily, steady - state concentrations are generally achieved in 7-12 days; with a peak plasma concentration ranging from 4.5-2.2 mg/l.
In humans it penetrates into the synovial fluid of patients with rheumatoid arthritis, osteoarthritis, and reactive synovitis where mean concentrations are approximately 40% of those in plasma; it is also demonstrable in synovial tissues. Concentrations of Brexin in breast milk are about 1% of those in the maternal plasma at the same time. Overall, Brexin is 99% bound to plasma protein. Pharmacokinetics of the drug do not appear to be age related, and renal function has only a limited influence on its elimination, but plasma concentrations are increased in patients with severe liver dysfunction.
Brexin is eliminated by biotransformation in the liver. The major route is by hydroxylation, with the resultant products being excreted alone or as a glucuronide in urine and faeces. The metabolites of Brexin have little or no anti-inflammatory activity in animal models. Approximately 10% of an oral dose is excreted as unchanged drug in 10 days.
Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
None known.
No special requirements.
Pierce the tube by reversing the cap and screwing down to break the seal on the tube. Apply 3cm (1¼†approximately) of the gel on the affected area. Rub the gel into the skin until the gel disappears. Do this three or four times a day. For muscle sprains and strains, you should start to feel better within one week. If the pain has not got any less after a week, tell your pharmacist or doctor. Replace the cap after use.
Wash hands after each application unless it is the hand that is being treated.
