Instructions for Brexin tablets 20 mg blister No. 10
Composition
active ingredient: piroxicam;
1 tablet contains piroxicam-betadex 191.2 mg, which is equivalent to 20 mg of piroxicam;
Excipients: lactose monohydrate; pregelatinized starch; sodium starch glycolate (type A); magnesium stearate; colloidal silicon dioxide; crospovidone.
Dosage form
Pills.
Main physicochemical properties: pale yellow, hexagonal tablets with a deep break line in the middle.
Pharmacotherapeutic group
Drugs affecting the musculoskeletal system. Nonsteroidal anti-inflammatory and antirheumatic drugs. Oxycam. Piroxicam.
ATX code M01A C01.
Pharmacological properties
Pharmacodynamics
Piroxicam belongs to the oxicam group of NSAIDs, the effective action of which is based primarily on the inhibition of prostaglandin synthesis. Piroxicam has anti-inflammatory, analgesic and antipyretic effects. β-cyclodextrin is a cyclic, unreduced, water-soluble oligosaccharide produced by enzymatic hydrolysis of starch. Due to its chemical structure, betadex (β-cyclodextrin) can form inclusion complexes “molecular encapsulation” with various drugs, thereby improving some of their properties, such as solubility, stability and bioavailability.
Brexin® is piroxicam in the form of a complex with β-cyclodextrin (piroxicam-β-cyclodextrin) in a molar ratio of 1:2.5.
Brexin® is very easily soluble in water, fully and more rapidly absorbed than pure piroxicam after oral administration, and therefore has a faster onset of effective action and greater tolerance from the gastrointestinal tract.
Pharmacokinetics
Absorption and distribution: Piroxicam-β-cyclodextrin disintegrates presystemically, and only free piroxicam, not the complex or β-cyclodextrin, is absorbed. The enhanced bioavailability results in a rapid rise in plasma levels of piroxicam, with peak values being reached earlier (approximately 30–60 minutes).
Metabolism and elimination: The elimination half-life is 50 (30-60) hours. Urinary excretion of the main metabolite (5-hydroxy-piroxicam) is more than 72 hours, corresponding to approximately 10% of the administered dose.
In case of hepatic insufficiency, increased plasma levels of piroxicam should be expected. After the maximum recommended daily dose for adults was reduced from 40 mg to 20 mg based on existing data, use in children under 15 years of age is no longer recommended due to the lack of new pharmacokinetic data. The contraindication for use in children allows us to draw an additional conclusion: the dose of the drug cannot be calculated based on body weight.
Indication
Symptomatic treatment:
osteoarthritis;
rheumatoid arthritis;
Bechterew's disease (ankylosing spondylitis).
Due to its safety profile, piroxicam is not the first choice when other NSAIDs are indicated. The decision to prescribe piroxicam should be based on an assessment of the individual patient's overall risk.
Since a constant effective concentration of piroxicam is achieved only 5–10 days after the start of the usual daily dose, this drug is not used as a starting therapy for diseases requiring a rapid onset of action.
Contraindication
Hypersensitivity to acetylsalicylic acid and to other non-steroidal and antirheumatic drugs (cross-sensitivity), with simultaneous use of which there have been cases of asthma, urticaria, rhinitis or angioedema.
Hypersensitivity to the active substance or to any of the excipients, previous skin reactions (regardless of severity) in response to the use of piroxicam and other antirheumatic drugs and non-steroidal anti-inflammatory drugs (NSAIDs), other medicinal products.
History of gastrointestinal ulcers, bleeding, and perforations.
Gastrointestinal disorders that lead to bleeding, such as ulcerative colitis, Crohn's disease, gastrointestinal cancer, or a history of diverticulitis.
Ulcer in the acute stage, inflammatory diseases of the gastrointestinal tract or gastrointestinal bleeding.
Concomitant use with other NSAIDs, including selective COX-2 inhibitors and acetylsalicylic acid in analgesic doses.
Concomitant use with anticoagulants.
Previous serious allergic reactions of any type to drugs, especially skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Hematopoiesis disorders.
Hemorrhagic diathesis.
Cerebrovascular or other types of active bleeding.
Severe renal and hepatic insufficiency.
Severe heart failure.
Interaction with other medicinal products and other types of interactions
Acetylsalicylic acid and other NSAIDs: As with other NSAIDs, the concomitant use of piroxicam with acetylsalicylic acid or other NSAIDs, including other formulations of piroxicam, should be avoided, as the available data are insufficient to demonstrate that such combinations lead to a greater improvement than that achieved with piroxicam alone; in addition, the likelihood of adverse reactions is increased (see section 4.4).
Studies have shown that concomitant use of piroxicam and acetylsalicylic acid in humans reduces the plasma concentration of piroxicam by approximately 80% of the value obtained with piroxicam monotherapy (see section "Contraindications").
Piroxicam interacts with acetylsalicylic acid, other nonsteroidal anti-inflammatory drugs and platelet aggregation inhibitors (see sections "Contraindications" and "Special Instructions").
Corticosteroids: Increased risk of gastrointestinal ulcers or bleeding (see section "Special warnings and precautions for use").
Anticoagulants: NSAIDs, including piroxicam, may enhance the effects of anticoagulants such as warfarin. Therefore, concomitant use of piroxicam with anticoagulants such as warfarin is contraindicated (see Contraindications).
Antithrombotic agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section "Special warnings and precautions for use").
Diuretics, ACE inhibitors and angiotensin II receptor antagonists. NSAIDs may reduce the therapeutic effect of diuretics and other antihypertensive drugs, possibly by blocking prostaglandin synthesis. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function), the concomitant use of ACE inhibitors or angiotensin II receptor antagonists, as well as cyclooxygenase inhibitors, may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. These interactions should be considered in patients taking piroxicam together with ACE inhibitors or angiotensin II receptor antagonists.
Therefore, this combination should be used with caution, especially in elderly patients.
Patients should be adequately hydrated; renal function should be considered after initiation of concomitant therapy.
In case of concomitant use of potassium-containing drugs or potassium-sparing diuretics, there is an additional risk of increased serum potassium concentration (hyperkalemia).
Lithium. Concomitant administration of lithium and NSAIDs increases plasma lithium concentrations; therefore, lithium concentrations should be monitored at the beginning, during and after treatment with piroxicam. Piroxicam is highly bound to blood proteins, so displacement of other drugs with high protein binding is possible. Patients receiving piroxicam concomitantly with other drugs with high protein binding should be carefully monitored for possible dose adjustment. Piroxicam absorption is slightly increased after administration of cimetidine. However, this increase was not clinically significant.
Alcohol consumption should be avoided, as it impairs the tolerability of the medication.
Piroxicam may reduce the effectiveness of intrauterine and emergency contraceptives.
Concomitant use with nonsteroidal anti-inflammatory drugs and quinolone drugs is contraindicated.
Cyclosporine and tacrolimus: There is a potential for an increased risk of nephrotoxicity when NSAIDs are used concomitantly with cyclosporine or tacrolimus.
Cardiac glycosides (digoxin): Increased blood concentrations of these drugs are associated with concomitant administration of NSAIDs, but this interaction was not observed in a study of piroxicam.
Oral antidiabetic agents: Blood sugar levels may fluctuate, so more frequent monitoring is recommended.
Phenytoin: Increased phenytoin blood levels are possible, therefore appropriate monitoring and dose adjustment is recommended if piroxicam therapy is initiated, and if necessary, adjustment and discontinuation of use.
Probenecid, sulfinpyrazone. Slowing down the elimination of piroxicam.
Methotrexate: Taking piroxicam before or after treatment with methotrexate may lead to increased levels of methotrexate in the blood and, as a result, increased adverse reactions to methotrexate (the combination should be avoided).
Cyclophosphamide, vinca alkaloids. Taking piroxicam before or after treatment with these drugs may increase the adverse reactions associated with these substances (the combination should be avoided).
Cholestyramine accelerates the elimination of piroxicam.
Application features
Adverse reactions can be minimized by using the lowest effective dose for the shortest period of time necessary to control symptoms.
Clinical benefit and tolerability should be reviewed periodically, and treatment should be discontinued immediately at the first appearance of skin reactions or clinically significant gastrointestinal reactions.
NSAIDs, including piroxicam, can cause serious gastrointestinal disorders, such as bleeding, ulcers and perforation of the stomach, small intestine and colon, which can be fatal. These serious adverse reactions can occur at any time with or without warning symptoms in patients treated with NSAIDs.
Both short- and long-term exposure to NSAIDs increases the risk of serious gastrointestinal reactions. Research data suggest that piroxicam is associated with a higher risk of serious gastrointestinal toxicity compared with other NSAIDs.
Patients with significant risk factors for gastrointestinal disorders should be prescribed piroxicam only after a careful risk/benefit assessment (see section "Contraindications").
The need for combination therapy with gastroprotective agents (e.g. misoprostol or proton pump inhibitors) should be carefully considered (see section 4.2).
Serious gastrointestinal complications
Identification of risk subjects
The risk of developing serious gastrointestinal complications increases with patient age. Patients over 70 years of age are at high risk of complications. The drug should be avoided in patients over 80 years of age.
Patients taking concomitant oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs), anticoagulants (e.g. warfarin) or antiplatelet agents (e.g. low-dose acetylsalicylic acid) are at increased risk of serious gastrointestinal complications (see section 4.5).
As with other NSAIDs, piroxicam may be used in combination with gastroprotective agents (such as misoprostol or proton pump inhibitors) for patients at risk.
During treatment with piroxicam, patients and physicians should closely monitor for symptoms of gastrointestinal ulceration and/or bleeding. Patients should report any new or unusual abdominal symptoms during treatment. If a gastrointestinal complication is suspected during treatment, piroxicam should be discontinued immediately and further clinical evaluation and alternative treatment should be considered.
Cardiovascular and cerebrovascular effects.
Appropriate monitoring and caution should be exercised in patients with a history of hypertension and/or heart failure, as fluid retention and edema have been reported in association with NSAID treatment.
Clinical trials and epidemiological data suggest that the use of some non-steroidal anti-inflammatory drugs (especially at high doses and over long periods) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). There is no evidence to exclude such a risk with piroxicam. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be given piroxicam only after a careful benefit/risk assessment. Such an assessment is necessary before initiating long-term treatment in patients with possible cardiovascular risk factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).
Piroxicam, like other NSAIDs, reduces platelet aggregation, prolonging coagulation time; these effects should be taken into account when performing blood tests and when patients are taking other platelet aggregation inhibitors at the same time.
Patients with impaired renal function should be monitored, as in such patients, inhibition of prostaglandin synthesis by piroxicam may cause a severe decrease in renal blood flow and ultimately lead to acute renal failure. Elderly patients and patients receiving diuretic therapy are at risk in this regard.
Dehydrated patients are at risk of worsening renal function.
Caution should also be exercised when treating patients with reduced liver function. Periodic monitoring of clinical and laboratory parameters is recommended, especially in the case of long-term treatment.
Due to the drug's effect on arachidonic acid metabolism, bronchospasm and possible shock and other allergic phenomena may occur in asthmatic patients and patients prone to asthma.
Since some changes in the visual system have been identified during NSAID therapy, periodic ophthalmological examinations are recommended during long-term treatment.
In addition, it is recommended to frequently check blood glucose levels in diabetic patients and prothrombin time in patients receiving concomitant anticoagulant treatment with dicumarol derivatives.
Skin reactions: Observational data suggest that the use of piroxicam may be associated with a higher risk of serious skin reactions than other non-oxicam NSAIDs.
Patients should be warned about the symptoms associated with these adverse reactions and monitored closely for the occurrence of such skin reactions. The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis is highest in the first weeks of treatment.
If symptoms or signs of SCD or TEN appear (e.g. progressive skin rash, often with blisters or mucosal lesions), treatment with Brexin® should be discontinued.
The best results in the treatment of SSRIs and TEN are observed with early diagnosis and prompt discontinuation of the drug associated with these adverse reactions. Early discontinuation is associated with better prognosis.
If a patient develops a SCD or TEN while taking Brexin®, this drug should not be prescribed again to such a patient regardless of the time after use.
Women planning to become pregnant are not recommended to use piroxicam, as well as any drugs with known inhibition of prostaglandin/cyclooxygenase synthesis.
Piroxicam should be discontinued in women with fertility problems or undergoing fertility studies.
Cases of fixed toxicoderma have been reported with the use of piroxicam.
Piroxicam should not be re-administered to patients with a history of fixed toxicoderma associated with piroxicam. Potential cross-reactivity with other oxicams may occur.
Adaptive porphyria: Piroxicam should be used in patients with adaptive porphyria only after careful risk/benefit assessment, as exacerbation of the disease is possible.
Renal disorders caused by NSAIDs. Rarely, nonsteroidal anti-rheumatic drugs can cause interstitial nephritis, glomerulonephritis, papillary necrosis and nephrotic syndrome. NSAIDs inhibit the synthesis of renal prostaglandins, which contribute to renal perfusion in patients with limited renal blood flow and reduced renal blood volume. Such patients may develop renal failure associated with NSAID treatment, which usually disappears when treatment is discontinued. Patients at high risk for this type of reaction include patients with chronic heart failure, cirrhosis of the liver, nephrotic syndrome and patients in the immediate post-major surgery period. For this reason, such patients should be closely monitored during treatment with NSAIDs.
During prolonged use of analgesics, headache may develop, the treatment of which cannot be resolved by increasing the dose of the drug. The patient should be informed of this.
Abrupt discontinuation of analgesics after prolonged use in high doses may cause complaints (headache, fatigue, nervousness), which usually disappear within a few days. Analgesics may only be resumed with the permission of a doctor and in the absence of complaints of these side effects.
Lactose. One tablet of Brexin® contains 102.8 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Brexin®.
Sodium: This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially ‘sodium-free’.
Use during pregnancy or breastfeeding
Piroxicam is contraindicated in pregnant women, women planning pregnancy, and women who are breastfeeding.
Pregnancy.
Inhibition of prostaglandin synthesis may adversely affect the course of pregnancy and/or the intrauterine development of the fetus. Epidemiological data suggest an increased risk of miscarriage, as well as cardiac malformations and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac complications increases from less than 1% to approximately 1.5%. The risk is expected to increase with dose and duration of treatment.
Reproductive toxicity has been observed in animal studies. In animals, the use of prostaglandin synthesis inhibitors has been shown to increase pre-implantation and post-implantation loss and intrauterine fetal death. In addition, an increased incidence of birth defects, including cardiovascular anomalies, has been observed in animal studies treated with prostaglandin synthesis inhibitors during the organogenesis phase.
From the 20th week of pregnancy, the use of NSAIDs may cause oligohydramnios due to fetal renal dysfunction. This condition may occur shortly after initiation of treatment and is usually reversible upon discontinuation of treatment. In addition, narrowing of the ductus arteriosus has been reported following treatment during the second trimester, which in most cases resolved after discontinuation of treatment.
During the third trimester of pregnancy, prostaglandin synthesis inhibitors may cause the fetus to:
- cardiopulmonary defects (premature narrowing/closure of the ductus arteriosus and pulmonary hypertension);
- renal functional disorders (see above).
Prostaglandin synthesis inhibitors may also cause the following risks to the mother and fetus before delivery:
- inhibition of uterine contractions, which will lead to delayed or prolonged labor.
Breast-feeding.
Available data indicate that the amount of piroxicam excreted in breast milk is approximately 1% to 3% of its concentration in maternal plasma. Piroxicam is contraindicated during breastfeeding as its safety in newborns has not been established.
Fertility.
Piroxicam impairs female fertility and is therefore not recommended for women attempting to conceive. For women who have difficulty conceiving or who are undergoing fertility evaluation, discontinuation of piroxicam should be considered.
Ability to influence reaction speed when driving vehicles or other mechanisms
Piroxicam may impair concentration, which may adversely affect the ability to drive vehicles and perform activities requiring rapid motor reactions.
Method of administration and doses
Brexin® should be taken once daily. The tablet is for oral use. The score line on the tablet is intended only for ease of swallowing and not for dividing into equal doses. To divide the tablet, place it on a flat surface with the score line facing up and press lightly with your thumb.
Piroxicam should be prescribed by a physician experienced in the diagnostic evaluation and treatment of patients with inflammatory or degenerative rheumatic diseases.
For adults, the maximum recommended daily dose is 20 mg. Adverse reactions can be minimized by using the lowest effective dose for the shortest period of time necessary to control symptoms.
The benefit of treatment and tolerability of the drug should be determined within 14 days. If the need for continued treatment is determined, such reassessment should be carried out more frequently. When prescribing piroxicam, it should be taken into account that its use carries a risk of gastrointestinal complications, therefore, the possible need for combination therapy with gastroprotective drugs (such as misoprostol or proton pump inhibitors) should be considered, especially in elderly patients.
Elderly patients.
The physician should carefully determine the dosage for the treatment of elderly patients, as a reduction in the above doses may be necessary.
Children
The drug should not be used in children, as dosage and indications for children have not been established.
Overdose
Symptoms of overdose.
The most common symptoms of overdose are headache, vomiting, drowsiness, dizziness, and loss of consciousness.
In case of overdose, supportive and symptomatic treatment is prescribed.
Although no specific studies have been conducted to date, hemodialysis is ineffective in promoting the elimination of piroxicam, as the drug is highly bound to plasma proteins.
Side effects
Edema, hypertension, and heart failure have been reported with NSAID treatment.
Clinical trials and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a modest increased risk of arterial thromboembolic events (e.g. myocardial infarction or stroke).
As with other substances with similar effects, some patients have experienced an increase in blood urea levels, which, with continued administration, do not rise above a certain level; after discontinuation of therapy, the level returns to normal values. The following adverse reactions are listed below, classified by organ system and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).
From the blood and lymphatic system.
Common: anemia.
Rare: aplastic and hemolytic anemia, leukopenia, eosinophilia, thrombocytopenia, pancytopenia.
From the side of the cardiac system.
Uncommon: rapid heartbeat.
Not known: heart failure, arterial thrombotic events.
On the part of the hearing organs and disorders of the labyrinth system.
Common: tinnitus, vertigo.
Not known: hearing disorders.
From the organs of vision.
Uncommon: blurred vision.
Rare: visual disturbances, eye irritation, eye swelling.
From the gastrointestinal tract.
Common: abdominal discomfort, abdominal pain, constipation, diarrhea, epigastric pain or discomfort, flatulence, nausea, vomiting, dyspepsia.
Uncommon: ulcerative stomatitis.
Not known: gastritis, gastrointestinal bleeding, gastrointestinal perforation, hematemesis, peptic ulcer, pancreatitis, dry mouth, esophagitis, glossitis, heartburn, taste disturbance, indigestion.
General disorders.
Rare: edema.
Not known: general malaise, asthenia, sweating.
On the part of the hepatobiliary system.
Rare: jaundice (rare cases of fatal hepatitis).
Not known: hepatitis, hepatic failure.
From the immune system.
Rare: serum sickness, anaphylaxis, allergic edema (face and hands).
Not known: hypersensitivity reactions.
Laboratory studies.
Not known: increased transaminases, weight increased, weight decreased, positive antinuclear antibodies, abnormal blood counts, decreased hemoglobin, decreased hematocrit.
From the side of metabolism and nutrition.
Not known: fluid retention, hypoglycemia, hyperglycemia, abnormal weight gain, decreased appetite, anorexia.
From the nervous system.
Common: headache.
Uncommon: paresthesia, dizziness, drowsiness.
Not known: abnormal dreams, tremor, convulsions, coma, meningitis, memory impairment, agitation.
Mental disorders.
Not known: anxiety, insomnia, depression, mood changes, nervousness, hallucinations, psychotic reactions, confusion, akathisia.
On the part of the kidneys and urinary system.
Rare: renal failure, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
Very rare: bladder dysfunction.
Not known: hematuria, dysuria, proteinuria.
From the reproductive system and mammary glands.
Not known: decreased female fertility.
On the part of the respiratory system, chest organs and mediastinum.
Not known: bronchospasm, epistaxis, pneumonia, dyspnea.
On the skin and subcutaneous tissue.
Common: skin rash, itching.
Rare: photosensitivity reactions, urticaria, angioedema, nonthrombocytopenic purpura, Henoch-Schönlein disease.
Very rare: serious skin adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) (see section "Special warnings and precautions for use").
Not known: alopecia, skin peeling, erythema multiforme, eschymosis, abnormal nail growth, bullous eruptions, redness, eczema, onycholysis, exfoliative dermatitis, fixed toxicoderma (see section "Special instructions").
From the side of the vessels.
Not known: vasculitis, shock (warning symptoms), hypertension.
The most frequently reported adverse reactions are gastrointestinal. Peptic ulceration and gastrointestinal perforation or bleeding, sometimes fatal, may occur, especially in elderly patients.
There is information about colitis and exacerbation of Crohn's disease when taking piroxicam.
There is reason to believe that the piroxicam-ß-cyclodextrin complex is better tolerated by the gastrointestinal tract than conventional piroxicams; the short residence time of the active substance in the gastrointestinal cavity does reduce the level of contact irritation.
Treatment with piroxicam should be discontinued if clinical signs and symptoms of liver disorders appear. Some cases of acute renal failure, fluid retention, which may manifest as peripheral edema and mainly affects the lower extremities, or disorders of the cardiocirculatory system (arterial hypertension, decompensation) have been reported.
Reporting of suspected adverse reactions
It is important to report suspected adverse reactions after the registration of a medicinal product. This allows for continuous monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the link: https://aisf.dec.gov.ua.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C, out of the reach of children.
Packaging
10 tablets in a blister. 1, 2 or 3 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
Chiesi Farmaceutici SpA, Italy.
Location of the manufacturer and address of its place of business.
Via San Leonardo 96, 43122, Parma, Italy/Via San Leonardo 96 – 43122, Parma, Italy.
Applicant
Chiesi Pharmaceuticals GmbH, Austria.
Applicant's location
Gonzagagasse 16/16, 1010 Vienna, Austria/Gonzagagasse 16/16, 1010 Wien, Ausrtia.
