Artosan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AROTOXAN (ARTOXAN)

Composition:

Active substance: tenoxicam;

One vial of lyophilisate for injection solution contains 20 mg of tenoxicam;

Excipients: mannite (E 421), disodium edetate, ascorbic acid, tromethamine, sodium hydroxide, sodium hydroxide or diluted hydrochloric acid.

One ampoule of solvent contains 2 ml of water for injections.

Dosage form. Lyophilisate for solution for injection.

Main physicochemical characteristics: yellow lyophilized powder.

Solvent (water for injections): clear, colorless solution.

Injection solution: clear yellow solution.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Oxicams. ATC code M01A C02.

Pharmacological properties.

Pharmacodynamics.

Tenoxicam is a non-steroidal anti-inflammatory drug (NSAID). It exerts analgesic, anti-inflammatory, and antipyretic effects.

The mechanism of action is based on non-selective inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzyme activity, leading to impaired synthesis of prostaglandins and thromboxanes. It inhibits platelet aggregation.

In vitro studies also indicate that tenoxicam may act as an acceptor of active oxygen at the site of inflammation and has the ability to inhibit metalloproteinases (stromelysin and collagenase) responsible for cartilage destruction.

Pharmacokinetics.

The bioavailability of tenoxicam following intramuscular and oral administration is similar. After intravenous administration of a 20 mg dose, plasma levels rapidly decline over 2 hours, which is related to the distribution process. After this short period, there is no difference in plasma concentrations of tenoxicam following intravenous and oral administration. Tenoxicam is highly bound (99%) to plasma proteins and penetrates well into synovial fluid.

The mean volume of distribution at steady state is 10–12 L. At the recommended dosage regimen of 20 mg daily, steady-state plasma concentration is achieved within 10–15 days. Accumulation is not observed.

Tenoxicam is completely metabolized in the body. Approximately two-thirds of the administered dose is excreted mainly in urine as the pharmacologically inactive metabolite 5-hydroxypyridyl, and the remainder is excreted in bile, primarily as glucuronide conjugates of hydroxymetabolites. The elimination half-life is 72 hours. Total plasma clearance is 2 mL/min.

The pharmacokinetics of tenoxicam are linear within the studied dose range of 10 to 100 mg.

No age-related changes in tenoxicam pharmacokinetics have been identified, although individual variability is generally greater in elderly patients.

Clinical characteristics.

Indications.

• Relief of pain and inflammation in osteoarthritis and rheumatoid arthritis.
• Short-term treatment of acute musculoskeletal disorders, including sprains, dislocations, and other soft tissue injuries.

The medicinal product should be used in the above indications when it is not possible to use tenoxicam in tablet form.

Contraindications.

• Hypersensitivity to the active substance or to other excipients of the medicinal product.
• History of hypersensitivity reactions (including asthma, rhinitis, angioedema, urticaria) to acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).
• Active or recurrent peptic ulcer/hemorrhage (2 or more distinct episodes of peptic ulcer or bleeding), ulcerative colitis, Crohn's disease, severe gastritis.
• History of gastrointestinal bleeding (melena, hematemesis) or perforation associated with previous NSAID therapy.
• History of cerebrovascular hemorrhage or other coagulation disorders.
• Severe heart, liver, or kidney failure.
• Third trimester of pregnancy.
• Breastfeeding period.
• Pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interactions.

With other NSAIDs (including COX-2 inhibitors) – possible increased risk of adverse reactions. Concomitant use of two or more NSAIDs should be avoided.

With acetylsalicylic acid and other salicylates – possible increased clearance and altered distribution of tenoxicam due to competition for plasma protein binding sites. Concomitant use of these agents should be avoided due to increased risk of adverse reactions (especially gastrointestinal).

With anticoagulants (warfarin) – possible potentiation of their effects. When used concomitantly, anticoagulant effects should be monitored, especially during initial stages of tenoxicam therapy. No clinically significant interactions between tenoxicam and low-molecular-weight heparin have been reported.

With cardiac glycosides – possible exacerbation of heart failure, decreased glomerular filtration rate, and increased plasma levels of cardiac glycosides. No clinically significant interactions between tenoxicam and digoxin or digitalis preparations have been reported.

With cyclosporine – possible increased risk of nephrotoxicity. Caution should be exercised when these agents are used concomitantly.

With quinolones – preclinical data indicate that NSAID use increases the risk of quinolone-induced seizures. Concomitant use of these agents may increase the risk of seizures.

With lithium – possible decreased elimination of lithium. When used concomitantly, plasma lithium levels should be monitored regularly, patients should be advised to maintain adequate fluid intake, and informed about symptoms of lithium toxicity.

With diuretics – possible reduction in natriuretic activity of diuretics and increased risk of nephrotoxicity due to the ability of NSAIDs to retain potassium, sodium, and fluid. In patients with hypertension or heart failure, tenoxicam may worsen the course of these conditions. No clinically significant interactions between tenoxicam and furosemide have been reported; however, reduced antihypertensive effect of hydrochlorothiazide has been reported when used concomitantly with tenoxicam.

With antihypertensive agents – possible attenuation of effects of alpha-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors. No clinically significant interactions between tenoxicam and calcium channel blockers, atenolol, or central alpha-adrenergic agonists have been reported.

With methotrexate – possible increased toxicity of methotrexate due to reduced elimination. Caution should be exercised when these agents are used concomitantly.

With oral hypoglycemic agents – although there are no reports of effects on clinical outcomes of glipizide, glyburide, or tolbutamide, careful monitoring of patients is recommended when oral hypoglycemic agents are used concomitantly with tenoxicam.

With dextromethorphan – possible potentiation of the analgesic effect of tenoxicam.

With cholestyramine – possible increased clearance and reduced half-life of tenoxicam.

With probenecid – possible increased plasma levels of tenoxicam. The clinical significance of this phenomenon has not been established.

With mifepristone – possible reduced efficacy of mifepristone. NSAIDs should be administered 8–12 days after completion of mifepristone treatment.

With corticosteroids – possible increased risk of gastrointestinal bleeding and perforation. Caution should be exercised when these agents are used concomitantly.

With antiplatelet agents, selective serotonin reuptake inhibitors (SSRIs) – possible increased risk of gastrointestinal bleeding.

With tacrolimus – possible increased risk of nephrotoxicity.

With zidovudine – possible increased risk of hematological toxicity. Evidence suggests increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen.

With penicillamine, parenteral gold preparations – no clinically significant interactions have been observed in a small number of patients receiving these agents concomitantly.

Special precautions for use.

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

Concomitant use of tenoxicam with NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and agents that increase the risk of ulcers or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), and selective serotonin reuptake inhibitors (SSRIs), should be avoided.

Gastrointestinal bleeding, ulcers, and perforations.

Gastrointestinal bleeding, ulcers, and perforations, including fatal cases, have been reported with the use of all NSAIDs. These events may occur at any time during treatment with tenoxicam, with or without warning symptoms, and both in patients with and without a history of gastrointestinal disorders.

The risk of such events increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should be initiated on the lowest possible effective dose. For these patients, as well as for those taking low-dose acetylsalicylic acid or other agents increasing gastrointestinal complications, consideration should be given to concomitant therapy with agents such as misoprostol or proton pump inhibitors.

Patients, particularly elderly individuals, with a history of gastrointestinal toxicity should be informed about any unusual gastrointestinal symptoms, especially bleeding. This is particularly important during the initial stages of treatment.

Tenoxicam should be used with caution in patients receiving medications that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents (e.g., acetylsalicylic acid).

If gastrointestinal bleeding or ulceration occurs, tenoxicam should be discontinued.

Tenoxicam should be used with caution in patients with a history of gastrointestinal diseases (e.g., ulcerative colitis, Crohn’s disease), as it may exacerbate these conditions.

Use in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.

The use of NSAIDs in such patients increases the risk of aseptic meningitis.

Cutaneous effects.

Rarely, NSAIDs may cause severe skin reactions, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, including fatal cases. The risk of such reactions is highest at the beginning of treatment, with most cases occurring within the first month of therapy.

Patients should be informed about symptoms and closely monitored for such skin reactions.

At the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity, tenoxicam should be discontinued immediately. Optimal outcomes in Stevens–Johnson syndrome and toxic epidermal necrolysis are achieved with early diagnosis and discontinuation of any suspected drug.

Tenoxicam must not be re-administered to patients who previously experienced Stevens–Johnson syndrome or toxic epidermal necrolysis during its use.

Cardiovascular, renal, and hepatic disorders.

Rarely, NSAIDs may cause interstitial nephritis, glomerulonephritis, papillary necrosis, or nephrotic syndrome due to inhibition of renal prostaglandin synthesis, which supports renal perfusion in patients with reduced renal blood flow and hypovolemia. In such patients, NSAID use may lead to marked renal decompensation, which typically reverses after discontinuation of the drug. The highest risk of such complications occurs in patients with pre-existing renal disease (including diabetic nephropathy), nephrotic syndrome, hypovolemia, hepatic dysfunction, congestive heart failure, those receiving diuretics or nephrotoxic agents, and elderly patients. In these patients, renal, hepatic, and cardiac functions should be monitored closely during treatment. Tenoxicam should be administered at the lowest possible dose in patients with renal, hepatic, or cardiac impairment.

Respiratory effects.

Tenoxicam should be used with caution in patients with bronchial asthma or a history of bronchial asthma, as NSAID use may provoke bronchospasm.

Elevated plasma transaminase levels or other liver function abnormalities may occur during NSAID use. In most cases, these changes are transient. If significant and persistent abnormalities develop, tenoxicam should be discontinued and liver function assessed. Tenoxicam should be used with caution in patients with hepatic impairment.

Tenoxicam reduces platelet aggregation and prolongs bleeding time, which should be considered prior to surgical procedures and when measuring bleeding time.

Use in elderly patients.

The frequency of adverse reactions, particularly gastrointestinal bleeding and perforation (including fatal cases), increases in elderly patients receiving NSAIDs. Ulcers and bleeding are poorly tolerated in debilitated patients. Most fatal gastrointestinal events associated with NSAID use have occurred in elderly and debilitated patients. Particular caution and regular monitoring of renal, hepatic, and cardiovascular function, as well as overall patient status, are required in such patients to detect potential interactions with concomitantly administered drugs.

Ophthalmological effects.

Ocular adverse events have been reported with NSAID use. If such events occur during treatment, an ophthalmological examination should be performed.

Cardiovascular and cerebrovascular effects.

Patients with hypertension and/or a history of mild to moderate heart failure should be closely monitored during treatment, as NSAIDs have been associated with edema and fluid retention.

Long-term use of some NSAIDs, particularly at high doses (150 mg/day), may increase the risk of arterial thrombosis, myocardial infarction, or stroke. Currently, there is insufficient data to exclude such risk with tenoxicam.

Tenoxicam should be used only after careful assessment in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Such assessment is particularly important before initiating long-term treatment in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking).

Antipyretic effects.

Like other NSAIDs, tenoxicam may mask symptoms of infection.

Laboratory tests.

NSAIDs inhibit renal prostaglandin synthesis and may adversely affect renal hemodynamics and fluid-electrolyte balance.

Careful monitoring, especially of cardiac and renal function (plasma urea, creatinine, development of edema, weight gain), is required in patients with conditions that may increase the risk of renal failure, such as pre-existing renal disease, renal dysfunction in diabetic patients, hepatic cirrhosis, congestive heart failure, hypovolemia, concomitant use of potentially nephrotoxic agents, diuretics, or corticosteroids. These patients are at particular risk during the peri- and postoperative periods following major surgical procedures due to potential severe blood loss.

Due to tenoxicam’s high plasma protein binding, the drug should be used with caution in patients with markedly reduced plasma albumin levels.

Effect on fertility.

Tenoxicam is not recommended for women attempting to conceive. Consideration should be given to discontinuing the drug in women experiencing infertility or undergoing fertility investigations.

Warnings regarding excipients.

The medicinal product contains less than 1 mmol of sodium (23 mg) per dose, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis following exposure to prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk may increase with higher doses and longer duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryonic/fetal mortality. In addition, increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed in animals exposed to prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of gestation, tenoxicam use may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction following second-trimester treatment, most of which resolved after stopping the drug.

During the first and second trimesters of pregnancy, tenoxicam should not be used except in cases of extreme necessity.

If used in women attempting to conceive or during the first or second trimester of pregnancy, the drug should be administered at the lowest effective dose for the shortest possible duration.

Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to tenoxicam for several days starting from the 20th gestational week. Treatment should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors may have the following effects:

on the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios (see above);

on the mother and neonate, and at the end of pregnancy:

• possible prolonged bleeding time; antiplatelet effect, which may occur even with very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

The drug is contraindicated during the third trimester of pregnancy.

Breastfeeding.

Tenoxicam passes into breast milk in very small amounts. If treatment is necessary, breastfeeding should be discontinued.

Fertility.

Tenoxicam may impair female fertility; therefore, it is not recommended for women attempting to conceive.

Consideration should be given to discontinuing the drug in women experiencing infertility or undergoing fertility investigations.

Ability to influence reaction speed when driving or operating machinery.

Dizziness, drowsiness, fatigue, and visual disturbances may occur during NSAID use. If such reactions occur, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

The medicinal product is intended for intravenous and intramuscular administration.

Before use, the contents of the vial must be dissolved in 2 mL of water for injections, which is included in the medicinal product's package. After complete dissolution of the lyophilizate, the solution should be used immediately.

Adults.

The recommended dose of the medicinal product is 20 mg per day for the first 1–2 days of treatment; thereafter, transition to tablet administration is required, with tablets taken daily at the same time.

Recommended doses should not be exceeded, as higher doses do not necessarily produce a more pronounced therapeutic effect and increase the risk of adverse reactions.

The duration of treatment with tenoxicam for acute musculoskeletal disorders usually does not exceed 7 days. In exceptional cases, therapy may be extended up to 14 days.

Elderly patients.

The medicinal product, like other NSAIDs, should be used with particular caution in elderly patients. They have an increased risk of adverse reactions and more frequently receive concomitant medications or have impaired renal, hepatic, or cardiovascular function. If necessary, the medicinal product should be administered to elderly patients at the lowest effective dose of 20 mg for the shortest duration required to control disease symptoms. Such patients should be carefully monitored for gastrointestinal bleeding during the 4 weeks following initiation of therapy.

Patients with impaired renal and/or hepatic function.

In patients with creatinine clearance greater than 25 mL/min, dosage adjustment is not required. The condition of such patients should be closely monitored.

There is insufficient data to provide dosage recommendations for tenoxicam in patients with creatine clearance less than 25 mL/min.

There is insufficient data to provide dosage recommendations for tenoxicam in patients with hepatic insufficiency.

The medicinal product should be used with caution in patients with low albumin concentrations (e.g., in nephrotic syndrome) or high plasma bilirubin levels, as tenoxicam is highly protein-bound.

Children.

Safety data on the use of tenoxicam in children are lacking; therefore, the medicinal product should not be administered to this patient group.

Overdose.

General symptoms of NSAID overdose include nausea, vomiting, epigastric pain, gastrointestinal bleeding, tinnitus, headache, visual disturbances, dizziness, and rarely diarrhea. In isolated cases, more severe disturbances have been reported, such as seizures, agitation, somnolence, hypotension, apnea, coma, electrolyte imbalance, and renal failure. Exacerbation of bronchial asthma is also possible.

Treatment. Administration of the medicinal product should be discontinued immediately. Adequate hydration should be maintained, and liver and kidney functions should be monitored. The patient should remain under medical supervision for at least 4 hours after overdose. Symptomatic therapy should be administered if necessary. Hemodialysis is ineffective. There is no specific antidote.

Adverse Reactions

Criteria for assessing the frequency of adverse drug reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

The most commonly observed adverse reactions are gastrointestinal – erosive and ulcerative lesions of the gastrointestinal tract, including ulcerogenic effects.

Blood and lymphatic system disorders:

Frequency not known – agranulocytosis, anemia, aplastic anemia, hemolytic anemia, leukopenia, thrombocytopenia, non-thrombocytopenic purpura, eosinophilia.

Immune system disorders:

Frequency not known – hypersensitivity reactions, including asthma, anaphylactic shock, angioneurotic edema.

Metabolism and nutrition disorders:

Common – anorexia; rare – metabolic disturbances (hyperglycemia, weight gain/weight loss).

Psychiatric disorders:

Rare – sleep disturbances, insomnia, depression, nervousness, restlessness, abnormal dreams; frequency not known – confusion, hallucinations.

Nervous system disorders:

Common – dizziness, headache; frequency not known – somnolence, paresthesia, optic neuritis.

Eye disorders:

Frequency not known – visual disturbances (blurred vision, visual impairment), eye irritation and swelling.

Ear and labyrinth disorders:

Rare – vertigo; frequency not known – tinnitus.

Cardiac disorders:

Rare – palpitations; frequency not known – heart failure.

Congestive heart failure should be considered as a possible adverse effect in elderly patients and in patients with pre-existing cardiac dysfunction.

Vascular disorders:

Rare – arterial thrombosis (myocardial infarction, stroke); frequency not known – vasculitis, hypertension.

Long-term use of some NSAIDs, especially at high doses (150 mg/day), may increase the risk of arterial thrombosis, myocardial infarction, or stroke. Currently, there is insufficient data to exclude such risk for tenoxicam.

Respiratory, thoracic and mediastinal disorders:

Rare – bronchospasm, asthma exacerbation, dyspnea; frequency not known – epistaxis.

Bronchospasm and asthma exacerbation have been reported during NSAID use.

Gastrointestinal disorders:

Very common – gastritis, epigastric pain, abdominal pain and discomfort, dyspepsia, nausea, vomiting, flatulence, constipation, diarrhea, distress syndrome, stomatitis; common – gastrointestinal ulcers, bleeding and perforations, peptic ulcers, hematemesis, melena, oral ulcers, gastritis, dry mouth, exacerbation of colitis and Crohn’s disease; very rare – pancreatitis.

Hepatobiliary disorders:

Uncommon – increased liver enzyme levels; frequency not known – hepatitis, jaundice.

Skin and subcutaneous tissue disorders:

Uncommon – pruritus, erythema, exanthema, rash, urticaria; rare – vesiculobullous reactions; very rare – Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency not known – photosensitivity reactions.

Skin reactions such as nail damage and alopecia have also been reported with NSAID use.

Renal and urinary disorders:

Uncommon – increased creatinine and urea levels; frequency not known – nephrotoxicity (renal failure, interstitial nephritis, nephrotic syndrome).

Reproductive system and breast disorders:

Cases of reversible female infertility have been reported with the use of drugs that inhibit COX and prostaglandin synthesis.

General disorders and administration site conditions:

Uncommon – fatigue, edema; frequency not known – malaise.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging and out of reach of children.

Packaging.

Lyophilisate for injection solution, 20 mg per vial, pack of 3 vials with solvent (water for injections) 2 ml in 3 ampoules, in a blister pack; 1 blister pack in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

WORLD MEDICINE ILAC SAN. VE TIC. A.S. / WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business.

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey / COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine / WORLD MEDICINE, LLC, Ukraine.