INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Piroxicam Sopharma (PIROXICAM SOPHARMA)

Composition:

Active substance: piroxicam;

1 capsule contains 10 or 20 mg of piroxicam;

Excipients: wheat starch, microcrystalline cellulose, glycine, anhydrous colloidal silicon dioxide, magnesium stearate, talc, hard gelatin capsule (for 10 mg: gelatin, titanium dioxide (E 171), indigo carmine (E 132); for 20 mg: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), yellow sunset FCF (E 110)).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard cylindrical gelatin capsules containing a powder mixture from white to pale yellow, odorless.

Capsule color:

for 10 mg – blue opaque/white opaque;

for 20 mg – orange opaque/light beige opaque.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and anti-rheumatic drugs. Oxicams. Piroxicam.

ATC code M01A C01.

Pharmacological properties.

Pharmacodynamics.

Piroxicam belongs to the group of nonsteroidal anti-inflammatory drugs (NSAIDs). It has pronounced anti-inflammatory, analgesic, and antipyretic activity. The mechanism of action is due to a pronounced and prolonged, but reversible, inhibition of prostaglandin synthesis through suppression of cyclooxygenase. It also exerts an inhibitory effect on platelet aggregation.

Pharmacokinetics.

Absorption. When administered orally, piroxicam is rapidly and completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 3–5 hours. A stable plasma concentration is achieved within 7–12 days.

Distribution. Distributed in all tissues and organs. Binds to plasma proteins by 90–98%. When used concomitantly with other medicinal products, it may displace them from protein binding sites, thereby potentially enhancing their therapeutic effects. Penetrates through the placental and blood-brain barriers.

Does not accumulate.

Metabolism. Metabolized in the liver via oxidation and conjugation. Its main metabolites—5-hydroxypiroxicam, N-methylbenzylsulfonamide, and others—are pharmacologically inactive.

Excretion. The elimination half-life of piroxicam varies and is approximately 50 hours. It is prolonged in patients with liver disease. Piroxicam is primarily excreted via the kidneys and feces (twice as much is found in urine than in feces), mainly as glucuronides (5% is excreted unchanged). It is excreted in breast milk.

Clinical characteristics.

Indications.

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis.

Due to its safety profile, piroxicam is not a first-line agent when other nonsteroidal anti-inflammatory and antirheumatic drugs are indicated. The decision to prescribe piroxicam should be based on an assessment of the individual patient's overall risk.

Contraindications.

Use is contraindicated in:

Hypersensitivity to the active substance or to excipients, transient skin reactions (regardless of severity) in response to piroxicam, other nonsteroidal anti-inflammatory and antirheumatic drugs, or other medicinal products;
Concomitant use of other nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors and acetylsalicylic acid at analgesic doses;
History of gastrointestinal ulcers, active peptic ulcer, inflammatory gastrointestinal diseases, or gastrointestinal bleeding, perforation, gastrointestinal cancer, or diverticulitis;
History of gastrointestinal disorders predisposing to bleeding, such as ulcerative colitis or Crohn’s disease;
Concomitant use of anticoagulants;
Hemorrhagic diathesis, blood picture changes of unknown origin (including in history);
History of severe allergic reactions of any type, particularly skin reactions such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis;
Severe heart failure;
Severe renal or hepatic impairment.

Contraindicated in patients in whom previous administration of acetylsalicylic acid or other NSAIDs induced bronchial asthma, rhinitis, nasal polyps, angioneurotic edema, and/or urticaria.

Interaction with other medicinal products and other forms of interaction.

Caution is advised in patients taking any of the following medicinal products.

As with other NSAIDs, concomitant use of piroxicam with acetylsalicylic acid or simultaneous use with other NSAIDs, including other formulations of piroxicam, should be avoided, as there is insufficient evidence that such combinations provide greater benefit than monotherapy with piroxicam. Furthermore, the potential for adverse effects increases. Studies in volunteers show that concomitant administration of piroxicam and acetylsalicylic acid results in an 80% reduction in plasma concentrations of piroxicam compared to normal levels.

Aspirin and other NSAIDs: Like other NSAIDs, piroxicam reduces platelet aggregation and prolongs bleeding time. This effect should be considered when determining bleeding time.

Corticosteroids: Increased risk of gastrointestinal ulceration (formation of ulcers) or bleeding.

Anticoagulants: NSAIDs, including piroxicam, may enhance the effect of anticoagulants such as warfarin. Therefore, concomitant use of piroxicam with anticoagulants such as warfarin should be avoided.

Concomitant use of piroxicam and immunosuppressants leads to increased toxicity.

Methotrexate: Decreases methotrexate excretion, potentially leading to acute toxicity.

Cyclosporine, tacrolimus: Possible increased risk of nephrotoxicity.

Cyclosporine: Increased risk of gastrointestinal injury, kidney and/or liver damage (avoid combination with low-dose piroxicam; monitoring of kidney and liver function is recommended).

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

Lithium: Piroxicam may increase plasma levels of lithium salts, prolonging and enhancing their effects.

Diuretics: NSAIDs, including piroxicam, may reduce the therapeutic efficacy of diuretics when used concomitantly. Diuretics may increase the nephrotoxic potential of NSAIDs.

Concomitant use of piroxicam with potassium-sparing diuretics or other medicinal products containing potassium poses a risk of hyperkalemia.

Antihypertensive agents: Piroxicam may reduce the antihypertensive effect of ACE inhibitors and beta-blockers when used concomitantly.

Cardiac glycosides: NSAIDs may cause exacerbation of heart failure, decreased glomerular filtration, and increased plasma levels of cardiac glycosides.

Digoxin, digitoxin: Concomitant use with digoxin or digitoxin does not affect plasma levels of these drugs.

Quinolones: Concomitant use of quinolones and piroxicam increases the risk of seizures in patients with epilepsy or a history of seizures.

Aminoglycosides: Concomitant use with aminoglycosides in patients with impaired renal function leads to reduced excretion and increased plasma concentration of the latter.

Probenecid: Reduces metabolism and elimination of NSAIDs and their metabolites when used concomitantly.

Oral antidiabetic agents: NSAIDs inhibit the metabolism of sulfonylurea drugs and increase the risk of hypoglycemia.

Antacids: Concomitant use of antacids does not affect plasma levels of piroxicam.

Cimetidine: Study results indicate increased absorption of piroxicam after cimetidine administration; however, there are no significant changes in elimination constant or half-life. The increased absorption is not considered clinically significant.

Mifepristone: NSAIDs may interfere with mifepristone-mediated termination of pregnancy.

Phenytoin: Possible increase in blood levels of phenytoin – appropriate monitoring and dose adjustment are recommended when piroxicam therapy is initiated, adjusted, or discontinued as necessary.

Cyclophosphamide, vinca alkaloids: Administration of piroxicam before or after treatment with these drugs may potentiate their adverse reactions (such combinations should be avoided).

Alcohol: Worsens tolerability of the drug (should be avoided).

MEDICINAL PRODUCTS THAT ARE HIGHLY PROTEIN-BOUND: Piroxicam is highly bound to plasma proteins and may therefore displace other protein-bound medicinal products. When piroxicam is administered to patients taking other highly protein-bound medicinal products, physicians should closely monitor patients and adjust dosage as necessary.

Special precautions for use.

Due to its safety profile, piroxicam is not a first-line agent when other nonsteroidal anti-inflammatory and antirheumatic drugs are indicated.

The decision to prescribe piroxicam should be based on an assessment of the individual patient's overall risk. Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Clinical benefit and tolerability should be reviewed periodically, and treatment should be discontinued immediately upon the first signs of skin reactions or clinically significant gastrointestinal adverse events.

In elderly patients, the frequency of adverse reactions associated with NSAIDs is increased, particularly gastrointestinal bleeding and perforation, which may be fatal.

Gastrointestinal effects, risk of gastrointestinal ulceration, bleeding, and perforation.

NSAIDs, including piroxicam, can cause serious gastrointestinal adverse events, including bleeding, ulceration, and perforation of the stomach, small intestine, and large intestine, which may be fatal. These serious adverse effects may occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory and antirheumatic drugs.

Both short- and long-term use of NSAIDs increases the risk of serious gastrointestinal events. Observational study data suggest that piroxicam use, similar to other NSAIDs, may be associated with a high risk of serious gastrointestinal toxicity.

Consideration should be given to the possible need for concomitant treatment with gastroprotective agents (e.g., misoprostol or proton pump inhibitors). Patients with significant risk factors for serious gastrointestinal reactions should be prescribed piroxicam only after careful risk/benefit assessment.

Individuals at risk of serious gastrointestinal complications.

The risk of developing serious gastrointestinal complications increases with age. Age over 70 years is associated with a high risk of complications, and gastrointestinal bleeding or perforation in this age group may be fatal. Avoid using the drug in patients aged 80 years and older.

Patients who are concurrently taking oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs), or platelet antiaggregants such as low-dose acetylsalicylic acid have an increased risk of serious gastrointestinal complications (see below, and section «Interaction with other medicinal products and other forms of interaction»).

As with other NSAIDs, in these patients, it may be appropriate to use piroxicam in combination with gastroprotective agents (e.g., misoprostol or proton pump inhibitors).

During piroxicam treatment, both patients and physicians should closely monitor for signs and symptoms of gastrointestinal ulceration and/or bleeding. Patients should be instructed to report any new or unusual abdominal symptoms during treatment. If gastrointestinal complications are suspected during treatment, piroxicam should be discontinued immediately, and further clinical evaluation and management should be initiated.

Cardiovascular and cerebrovascular effects.

Appropriate monitoring and patient counseling are required for patients with a history of hypertension and/or mild to moderate congestive heart failure, as there have been reports of edema and fluid retention associated with NSAID therapy.

Clinical trials and epidemiological data indicate that NSAID use (particularly at high doses and for prolonged periods) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). There is insufficient data to exclude such a risk with piroxicam.

The drug should be prescribed with caution to patients with a history of coagulation disorders, especially those with intracranial hemorrhage or hemorrhagic diathesis, since piroxicam inhibits prostaglandin biosynthesis and affects platelet function.

Piroxicam should be prescribed to patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful risk/benefit assessment. Such an assessment is required before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., hypertension, hyperlipidemia, diabetes, smoking).

Skin reactions.

Serious skin reactions, some of which are fatal, have been very rarely reported, including cases of exfoliative dermatitis (see section «Adverse reactions»). Observational data suggest that piroxicam use may be associated with a higher risk of serious skin reactions compared to other NSAIDs not belonging to the oxicam class. Cases of life-threatening skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported during treatment with this medicinal product. Patients should be warned about the symptoms, and close monitoring for such skin reactions is necessary. The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis is highest during the first weeks of treatment. If signs of toxic epidermal necrolysis or Stevens-Johnson syndrome appear (e.g., progressive skin rash, possibly with blisters or mucosal involvement), piroxicam treatment should be discontinued immediately. Optimal outcomes are observed with early diagnosis and immediate discontinuation of any suspected medicinal product. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis during piroxicam use, this drug must not be re-administered to that patient.

Fixed drug eruptions have been reported with piroxicam use.

Piroxicam should not be re-administered to patients with a history of fixed drug eruption associated with piroxicam. Cross-reactivity with other oxicams may occur.

Piroxicam should be used with caution in patients with renal impairment due to the potential for kidney damage. In rare cases, the drug may cause interstitial nephritis, glomerulonephritis, renal papillary necrosis, or nephrotic syndrome. Like other NSAIDs, piroxicam inhibits renal prostaglandin synthesis, which supports renal perfusion in patients with reduced renal blood flow and overall blood volume. In such patients, NSAID use may lead to marked renal decompensation, requiring discontinuation of treatment. The highest risk of such complications exists in patients with congestive heart failure, liver cirrhosis, nephrotic syndrome, or kidney disease, who should be under close monitoring during NSAID therapy.

Prolonged treatment with piroxicam, as with other NSAIDs, may lead to changes in liver function, necessitating periodic monitoring of liver enzymes.

Due to its anti-inflammatory properties, the drug may mask signs of acute infection; therefore, bacterial infection should be ruled out before initiating treatment.

Use of NSAIDs carries a risk of hyperkalemia, particularly in patients aged 65 years and older, those with renal impairment, and those receiving beta-blockers, ACE inhibitors, or potassium-sparing diuretics. Serum potassium levels should be monitored in these patients.

Reversible inhibition of fertility in women of reproductive age should be considered when attempting pregnancy.

The drug is contraindicated for the treatment of postoperative pain following coronary artery bypass graft (CABG) surgery.

Piroxicam may be used in patients with porphyria only after careful risk/benefit assessment, as it may provoke an acute attack.

Before prescribing to patients with bronchial asthma, allergic rhinitis, nasal mucosal polyps, or chronic obstructive pulmonary diseases, the appropriateness of treatment should be carefully considered.

Alcohol consumption is not recommended during treatment.

Due to reports of adverse ocular effects associated with NSAID use, ophthalmological examination is recommended for patients who develop visual disturbances during piroxicam treatment.

Prolonged use of analgesics may lead to medication-overuse headache, which cannot be resolved by increasing the drug dose. Patients should be informed about this possibility.

Abrupt discontinuation of analgesics after prolonged high-dose use may cause symptoms (headache, fatigue, nervousness), which usually resolve within a few days. Resumption of analgesic use should only occur with a physician's approval and in the absence of symptoms.

The medicinal product contains wheat starch as an excipient. It may be used in patients with celiac disease. Patients with wheat allergy (distinct from celiac disease) should not use this medicinal product.

Capsules of 20 mg contain the colorant E 110, which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy. Piroxicam should not be used during pregnancy due to insufficient safety data. Teratogenic effects were not observed in animal studies. Piroxicam reduces prostaglandin synthesis and release by reversible inhibition of the cyclooxygenase enzyme. This effect, as with other NSAIDs, is associated with prolonged and difficult labor in experimental animals when administered during late pregnancy. NSAIDs are known to have the potential to induce premature closure of the ductus arteriosus in newborns.

There is a risk of oligohydramnios and constriction of the ductus arteriosus in the fetus with accidental or potential use during pregnancy.

Breastfeeding. Experimental studies show that the amount of piroxicam passing into breast milk is approximately 1% to 3% of its plasma concentration in the mother. No accumulation in breast milk has been observed.

The use of the drug during breastfeeding is contraindicated due to insufficient safety data or requires discontinuation of breastfeeding during treatment.

Ability to influence reaction speed when driving or operating machinery.

Piroxicam may cause adverse reactions such as tinnitus, dizziness, somnolence, and auditory and visual disturbances, which may impair attention and reflexes. Drivers and machine operators should be aware of these adverse effects, especially at the beginning of treatment.

Method of Administration and Dosage

The initial prescription of piroxicam should be made by a physician experienced in diagnosing and treating patients with inflammatory or degenerative rheumatic diseases.

The maximum recommended daily dose is 20 mg.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The benefit of treatment and drug tolerability should be reviewed every 14 days. If long-term treatment is considered necessary, this reassessment should be performed more frequently.

Given the established fact that piroxicam use is associated with an increased risk of gastrointestinal complications, careful consideration should be given to the need for concomitant gastroprotective therapy (e.g., misoprostol or proton pump inhibitors), especially in elderly patients.

Adults.

Administer orally, 2 capsules of 10 mg or 1 capsule of 20 mg once daily, preferably during or immediately after a meal, with water.

The duration of treatment depends on the course of the disease and is determined by the physician.

When combining different dosage forms of the drug (capsules, tablets, solutions, suspensions, suppositories), the total daily dose must not exceed 20 mg.

Elderly patients (over 65 years of age).

Particular caution is required when treating patients over 65 years of age with piroxicam, especially those with impaired renal, hepatic, or cardiac function.

Children.

There is insufficient clinical experience regarding the safe use of piroxicam in children.

Overdose.

Symptoms: visual disturbances, drowsiness, nausea, vomiting, epigastric pain, possible gastrointestinal bleeding; rarely coma, arterial hypertension, acute renal failure, respiratory depression; with larger doses – loss of consciousness.

Treatment: symptomatic. The prolonged half-life of piroxicam must be taken into account. Elimination of piroxicam may be accelerated by administration of antacids and activated charcoal.

Initial elimination (careful gastric lavage);
monitoring of acid-base balance;
correction of electrolyte levels and blood glucose;
intensive medical support;
acceleration of elimination (alkaline forced diuresis);
administration of diazepam in case of seizures.

Administration of activated charcoal (only in patients who are conscious!) affects the resorption and absorption of piroxicam, thereby reducing the total amount of active substance in blood plasma.

Piroxicam cannot be removed from the body by hemodialysis.

Adverse Reactions

Adverse effects are classified by organ systems.

Gastrointestinal disorders: ulcerative stomatitis, esophagitis, gastritis, glossitis, hematemesis, rectal bleeding, melena, anorexia, epigastric pain, constipation, diarrhea, dyspepsia, flatulence, belching, heartburn, nausea, vomiting, severe gastrointestinal bleeding/perforation and ulcers (gastric, duodenal) – asymptomatic perforation may occur, exacerbation of colitis or Crohn’s disease (see section «Special precautions for use»), pancreatitis, stomach pain/discomfort, digestive disturbances.

Nervous system disorders: dizziness, headache, vertigo, sensation of disorientation, anxiety, weakness, difficulty concentrating, depression, somnolence, insomnia, hallucinations, increased fatigue, irritability, psychotic reactions, mood changes, sensory disturbances including paresthesia; memory disorders, confusion, nervousness, pathological dreams, convulsions.

Cardiovascular system disorders: palpitations, angina pectoris, tachycardia, heart failure, edema, arterial hypertension, arrhythmia, increased risk of thrombotic complications (myocardial infarction or stroke) (see section «Special precautions for use»).

Blood and lymphatic system disorders: eosinophilia, leukopenia, non-thrombocytopenic purpura of Henoch-Schönlein, epistaxis, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, appearance of antinuclear antibodies.

Skin and subcutaneous tissue disorders: pruritus with or without rash, rash, photosensitivity, severe skin reactions (SCARs): Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome) (see section «Special precautions for use»), exfoliative dermatitis, bullous eruptions, erythema, eczema, allergic-type purpura, fixed drug eruption (see section «Special precautions for use»).

Renal and urinary disorders: edema, fluid retention, polyuria, hematuria, dysuria, interstitial nephritis, nephrotic syndrome, proteinuria, acute renal failure, papillary necrosis, reversible increase in plasma levels of urea and creatinine.

Eye disorders: diplopia, blurred vision, eye irritation, eye swelling.

Ear and labyrinth disorders: hearing disturbances, tinnitus.

Hepatobiliary disorders: increased serum transaminase levels (ALAT, ASAT), transient increase in bilirubin levels, toxic hepatitis including jaundice, fulminant hepatitis, hepatic failure.

Immune system disorders: hypersensitivity reactions, including bronchospasm, anaphylactic or anaphylactoid reactions in patients with allergies, serum sickness, urticaria/angioedema, vasculitis, erythema multiforme.

Respiratory system disorders: respiratory depression, pneumonia.

Metabolism and nutrition disorders: hypoglycemia, hyperglycemia, weight gain or weight loss.

General disorders: taste disturbances, malaise, influenza-like symptoms, general discomfort, increased sweating, onycholysis, nail growth disorders, alopecia.

Shelf life.

3 years.

Storage conditions.

Keep out of reach and sight of children.

Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

10 capsules per blister pack made of PVC film and aluminum foil. 2 blisters per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Sofarmina JSC.

Manufacturer’s name and address.

16 Iliensko Shose Str., Sofia, 1220, Bulgaria.

Piroxicam sofarma