Artosan

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

Composition:

Active substance: tenoxicam;

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

Excipients: mannitol (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.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: yellow lyophilized powder.

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

Reconstituted solution: clear yellow-green 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, its plasma concentration rapidly decreases over 2 hours, which is related to the distribution process. After this short period, there is no difference in plasma concentrations of tenoxicam between intravenous and oral administration. Tenoxicam is highly bound (99%) to plasma proteins and penetrates well into synovial fluid.

The mean volume of distribution at equilibrium is 10–12 L. At the recommended dosage regimen of 20 mg daily, steady-state plasma concentrations are achieved within 10–15 days. No accumulation occurs.

Tenoxicam is completely metabolized in the body. Approximately two-thirds of the administered dose is excreted in the urine mainly as the pharmacologically inactive metabolite 5-hydroxypyridyl, and the remainder via 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 the pharmacokinetics of tenoxicam have been observed, 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 when administration of tenoxicam in tablet form is not feasible.

Contraindications.

• Hypersensitivity to the active substance or to any of the 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 recurrent peptic ulceration/bleeding or history of recurrent episodes (two or more distinct episodes of peptic ulcer or bleeding), ulcerative colitis, Crohn's disease, severe gastritis.
• History of gastrointestinal bleeding (melena, hematochezia) or perforation associated with previous NSAID therapy.
• History of cerebrovascular bleeding or other coagulation disorders.
• Severe heart, liver, or kidney failure.
• Third trimester of pregnancy.
• Breastfeeding period.
• Pediatric population (under 18 years of age).

Interaction with other medicinal products and other forms of interaction.

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

With acetylsalicylic acid and other salicylates – possible enhancement of clearance and 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 (particularly gastrointestinal).

With anticoagulants (warfarin) – possible potentiation of their effects. When used concomitantly, anticoagulant effects should be monitored, especially during initial stages of tenoxicam treatment. Clinically significant interactions between tenoxicam and low-molecular-weight heparin have not been reported.

With cardiac glycosides – possible exacerbation of heart failure, reduction in glomerular filtration rate, and increased plasma levels of cardiac glycosides. Clinically significant interactions between tenoxicam and digoxin or digitalis preparations have not 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 NSAIDs may enhance the seizure risk associated with quinolones. Concomitant use of these agents may increase the risk of seizures.

With lithium – possible decreased elimination of lithium. When these agents are 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. Clinically significant interactions between tenoxicam and furosemide have not 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-blockers and angiotensin-converting enzyme (ACE) inhibitors. Clinically significant interactions between tenoxicam and calcium channel blockers, atenolol, or central alpha-adrenergic agonists have not 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 glyburide, glybenclamide, or tolbutamide, patients should be closely monitored when oral hypoglycemic agents are used concomitantly with tenoxicam.

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

With cholestyramine – possible increased clearance and reduced elimination 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 attenuation of its effects. 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 hematomas in HIV-infected patients with hemophilia when zidovudine and ibuprofen are used concomitantly.

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

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 this medicinal product with NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and other 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 disease, especially 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 concurrently that increase gastrointestinal complications risk, consideration should be given to concomitant therapy with agents such as misoprostol or proton pump inhibitors.

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

The medicinal product 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 platelet agents (e.g., acetylsalicylic acid).

If gastrointestinal bleeding or ulceration occurs, the medicinal product should be discontinued.

The medicinal product should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn’s disease), as tenoxicam may exacerbate their symptoms.

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

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

Cutaneous effects.

NSAIDs may rarely cause severe skin reactions, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, including fatal cases. The risk of such reactions is highest during the initial stages of treatment: in most cases, the first signs occurred within the first month of therapy.

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

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

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, NSAID use may lead to interstitial nephritis, glomerulonephritis, papillary necrosis, or nephrotic syndrome due to inhibition of renal prostaglandin synthesis, which maintains renal perfusion in patients with reduced renal blood flow and overall blood volume. In such patients, NSAID use may cause pronounced renal decompensation, which typically reverts to the pre-treatment state after discontinuation. The highest risk of such complications exists in patients with pre-existing renal disease (including diabetes with impaired renal function), nephrotic syndrome, reduced total blood volume, hepatic dysfunction, congestive heart failure, those concurrently using diuretics or nephrotoxic agents, and elderly patients. During treatment of such patients, renal, hepatic, and cardiac functions should be continuously monitored. The medicinal product should be administered at the lowest possible dose in patients with impaired renal, hepatic, or cardiac function.

Respiratory effects.

The medicinal product 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 indicators of hepatic function may occur during NSAID use. In most cases, these changes are transient. If significant and persistent abnormalities develop, the medicinal product should be discontinued and liver function assessed. The medicinal product should be used with caution in patients with hepatic dysfunction.

Tenoxicam reduces platelet aggregation and prolongs bleeding time, which should be considered in upcoming 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 when NSAIDs are used in elderly patients. Ulcers and bleeding are poorly tolerated in debilitated patients. Most fatal gastrointestinal events associated with NSAID use have been observed in elderly and debilitated patients. Special caution should be exercised during treatment of such patients, with regular monitoring of renal, hepatic, and cardiovascular functions, as well as the patient’s general condition, to detect possible interactions with concomitantly administered medicinal products.

Ophthalmological effects.

Adverse effects on the visual organs have been reported with NSAID use. If such disturbances 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 edema and fluid retention have been reported during NSAID therapy.

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

The medicinal product 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. This assessment should be performed prior to 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 thus adversely affect renal hemodynamics and fluid-electrolyte balance.

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

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

Effects on fertility.

The medicinal product is not recommended for women who are trying to conceive. Consideration should be given to discontinuing the medicinal product in women experiencing difficulties with conception or undergoing infertility investigations.

Precautions regarding excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformations increased 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. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

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

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

If used in women who are trying to conceive or during the first and second trimesters of pregnancy, the medicinal product 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 several days of tenoxicam exposure, starting from the 20th gestational week. The medicinal product should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, 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 newborn, particularly near term:

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

The medicinal product 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 use may impair female fertility; therefore, the medicinal product is not recommended for women who are trying to conceive.

Consideration should be given to discontinuing the medicinal product in women experiencing difficulties with conception or undergoing infertility investigations.

Ability to affect 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 lyophilisate, the solution should be used immediately.

Adults.

The recommended dose of the medicinal product is 20 mg per day during the first 1–2 days of treatment; thereafter, transition to tablet administration is recommended, with tablets to be 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 may 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 are at 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. These patients should be carefully monitored for gastrointestinal bleeding during the 4 weeks following initiation of therapy.

Patients with Renal and/or Hepatic Impairment.

Dose adjustment is not required for patients with creatinine clearance greater than 25 mL/min. However, such patients should be closely monitored.

There are insufficient data to recommend dosage adjustments of tenoxicam for patients with creatinine clearance less than 25 mL/min.

There are insufficient data to recommend dosage adjustments of tenoxicam for patients with hepatic impairment.

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 bound to plasma proteins.

Children.

There are no data on the safety of tenoxicam use in children; therefore, the medicinal product should not be used in this patient population.

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 events 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 (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from 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, angioedema.

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 may occur in elderly patients and in patients with pre-existing cardiac dysfunction and should be considered.

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 levels of liver enzymes; 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 including nail damage and alopecia have also been reported with NSAID use.

Renal and urinary disorders:

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

Reproductive system and breast disorders:

Cases of reversible female infertility have been reported with 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 continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

Medicinal product ready for use – 3 years.

Solvent – 5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Incompatibilities.

Not known.

Packaging.

20 mg lyophilisate for injection solution in a vial;

2 ml solvent (water for injection) in an ampoule;

3 vials of lyophilisate for injection solution with 3 ampoules of solvent in a blister pack; 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Mefar Ilac San. A.S.

Manufacturer's address and location of business operations.

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.