Oxiliten

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OXILITEN (OXILITEN)

Composition:

Active substance: tenoxicam;

One vial contains 20 mg of tenoxicam;

Excipients: mannitol (E 421), sodium hydroxide, tromethamine, sodium metabisulfite, disodium edetate;

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

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: yellow or yellowish-green compacted powder.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and anti-rheumatic agents. Oxicams. Tenoxicam.

ATC code M01A C02.

Pharmacological properties.

Pharmacodynamics.

Tenoxicam is a non-steroidal anti-inflammatory drug. It exerts pronounced analgesic, anti-inflammatory, and some antipyretic effects.

As with other non-steroidal anti-inflammatory agents (NSAIDs), the exact mechanism of action is unknown, although it is likely to be multifactorial, including inhibition of prostaglandin biosynthesis and reduction of leukocyte accumulation at the site of inflammation.

Pharmacokinetics.

Tenoxicam in lyophilisate form is a long-acting preparation; administration once daily is effective.

Tenoxicam penetrates well into synovial fluid, where its concentration is approximately half of its plasma concentration.

After intravenous administration of tenoxicam at a dose of 20 mg, its plasma level rapidly decreases during the first 2 hours, which is related to the distribution process. After intramuscular injection, a level of at least 90% or more of the maximum concentration is achieved within 15 minutes.

With the recommended dosing regimen of 20 mg daily, steady-state plasma concentration is reached within 10–15 days. Accumulation is not expected.

The drug is highly bound to plasma proteins.

Tenoxicam is almost completely metabolized in the body. Approximately two-thirds of the administered dose is excreted in urine as the pharmacologically inactive metabolite 5-hydroxypyridyl, and the remainder is excreted in bile, mainly as glucuronide conjugates of hydroxymetabolites.

No age-related changes in tenoxicam pharmacokinetics have been identified, although individual variations are 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.

In the above indications, the drug should be administered intravenously or intramuscularly when oral administration of tenoxicam is not feasible.

Contraindications.

• Hypersensitivity to tenoxicam or to any excipients of the drug. History of hypersensitivity reactions (including asthma, rhinitis, angioedema, or urticaria) to other NSAIDs, including ibuprofen and acetylsalicylic acid, due to possible cross-sensitivity to tenoxicam.
• Active or history of recurrent peptic ulcer/bleeding of the gastrointestinal tract (two or more distinct episodes of peptic ulcer or bleeding), ulcerative colitis, Crohn's disease, severe gastritis, or gastrointestinal bleeding or perforation associated with prior use of NSAIDs.
• Severe cardiac, hepatic, or renal insufficiency.
• Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Anticoagulants: In healthy volunteers, no clinically significant interaction was observed between tenoxicam in lyophilisate form and low molecular weight heparin. Tenoxicam is highly bound to serum albumin and, similar to other NSAIDs, may enhance the anticoagulant effect of warfarin and other anticoagulants (see section "Special precautions for use"). Particular caution is required to monitor the effects of anticoagulants and oral hypoglycemic agents at the beginning of tenoxicam therapy.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section "Special precautions for use").

Antihypertensive agents: Tenoxicam and other NSAIDs may attenuate the effect of antihypertensive drugs.

Cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when used concomitantly.

Cyclosporine: As with all NSAIDs, concomitant use with cyclosporine requires caution due to increased risk of nephrotoxicity.

Cimetidine: No interaction was observed when used concomitantly with cimetidine.

Corticosteroids: As with all NSAIDs, concomitant use with corticosteroids requires caution due to increased risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

Diuretics: Reduced diuretic effect. NSAIDs can cause potassium and sodium retention, fluid retention, and interfere with the natriuretic effect of diuretics, thereby increasing the risk of NSAID-induced nephrotoxicity. These properties should be considered when treating patients with arterial hypertension or heart failure, as tenoxicam may worsen the course of these conditions.

Lithium: Reduced lithium elimination has been reported with NSAID use. If tenoxicam is prescribed to a patient receiving lithium therapy, increased frequency of lithium level monitoring is recommended, and the patient should be advised to maintain adequate fluid intake and to watch for symptoms of lithium toxicity.

Methotrexate: Caution is recommended when used concomitantly with methotrexate due to possible methotrexate intoxication, as NSAIDs have been reported to reduce its elimination.

Mifepristone: NSAIDs should not be used within 8–12 days after mifepristone administration, as these agents may reduce the efficacy of mifepristone.

NSAIDs, selective cyclooxygenase-2 (COX-2) inhibitors, salicylates: Concomitant use of two or more NSAIDs (including acetylsalicylic acid) should be avoided due to possible increased risk of adverse reactions (see section "Special precautions for use"). Salicylates may displace tenoxicam from plasma protein binding sites, increasing its clearance and distribution. Concomitant treatment with salicylates or other NSAIDs should be avoided due to the risk of increased adverse reactions (particularly gastrointestinal).

Penicillamine, parenteral gold preparations: In a small number of patients receiving these agents concomitantly, no clinically significant interaction was observed.

Quinolone antibiotics: Preclinical data indicate that NSAID use enhances the risk of quinolone-induced seizures. Concomitant use of these agents may increase the risk of seizures in patients.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are used with tacrolimus.

Zidovudine: Possible increased risk of hematologic toxicity when NSAIDs are used with zidovudine. Evidence suggests an increased risk of hemarthrosis and hematomas in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen.

Special precautions for use.

Concomitant use of the drug with NSAIDs, including selective COX-2 inhibitors, should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Adverse reactions of tenoxicam can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks below).

Cardiovascular and cerebrovascular effects

Patients with arterial hypertension and/or a history of mild or moderate heart failure should be closely monitored during treatment, as edema and fluid retention have been reported during NSAID therapy.

Clinical studies and epidemiological data indicate that the use of certain NSAIDs, especially at high doses and for prolonged periods, may slightly increase the risk of thrombotic events (e.g., myocardial infarction or stroke). Currently, there is insufficient information to exclude such a risk for tenoxicam.

The drug should be administered only after careful assessment to patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. A similar assessment should be performed prior to initiating long-term treatment in patients with risk factors for cardiovascular diseases (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Cardiovascular, renal, and hepatic disorders

NSAID use may cause dose-dependent reduction in prostaglandin formation and acute renal failure. The risk of such reactions is higher in patients taking diuretics and in elderly patients. Renal function should be monitored in these patients (see section "Contraindications").

Rare cases of increased serum transaminase levels or other signs of hepatic dysfunction have been reported. In most cases, these elevations were mild and transient, exceeding the normal range. If significant or persistent elevation occurs, tenoxicam should be discontinued and appropriate tests performed. Particular caution is required when administering the drug to patients with pre-existing liver disease.

In rare cases, 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 blood volume. In such patients, NSAID use may cause marked deterioration in renal function, which usually reverts to the pre-treatment state upon discontinuation of the drug. The highest risk of such complications exists in patients with pre-existing renal disease (including diabetes with impaired renal function), nephrotic syndrome, reduced blood volume, hepatic or cardiac dysfunction, and in patients receiving concomitant diuretics or potentially nephrotoxic agents. Renal, hepatic, and cardiac functions should be monitored regularly in such patients during treatment. The drug should be administered at the lowest possible dose in patients with impaired renal, hepatic, or cardiac function. NSAIDs should be used with caution in patients with a history of heart failure or arterial hypertension, as edema has been reported with ibuprofen use.

Dermatological effects

Rarely, NSAID use may cause severe skin reactions, sometimes fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see section "Adverse reactions"). The risk of such reactions is highest at the beginning of treatment: in most cases, initial symptoms occurred within the first month of therapy. At the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity, the drug should be discontinued immediately.

Use in elderly patients

When NSAIDs are used in elderly patients, the frequency of adverse reactions increases, particularly gastrointestinal bleeding and perforations, including fatal outcomes (see section "Dosage and administration"). Special caution should be exercised and regular monitoring performed in elderly patients during treatment to detect possible interactions with concomitantly administered drugs, and regular checks of renal, hepatic, and cardiovascular functions, which may be affected by NSAIDs.

Effect on female fertility

The drug may affect female fertility and therefore is not recommended for women wishing to become pregnant. Consideration should be given to discontinuing the drug in women experiencing difficulties in conception or undergoing infertility investigations.

Gastrointestinal bleeding, ulcers, and perforations

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders.

Gastrointestinal bleeding, ulcers, and perforations, including fatal cases, have been reported during treatment with all NSAIDs, which may occur at any time during therapy, with or without warning symptoms, both in patients with and without a history of gastrointestinal disease.

The risk of such events increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Treatment in such patients should be initiated at the lowest possible 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, especially elderly ones, with a history of gastrointestinal toxicity should be advised to report any unusual gastrointestinal symptoms, particularly bleeding. This is especially important at the beginning of treatment.

The drug should be used with caution in patients receiving concomitant 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) (see section "Interaction with other medicinal products and other forms of interaction").

Patients with gastrointestinal symptoms receiving tenoxicam treatment should be closely monitored. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued immediately.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as tenoxicam may exacerbate their symptoms (see section "Adverse reactions").

Hematological effects

Tenoxicam reduces platelet aggregation and may prolong bleeding time, which should be considered in planned major surgical procedures (e.g., joint replacement) and when bleeding time needs to be determined.

Ophthalmological effects

Visual disturbances have been reported during NSAID use. If such disturbances occur during treatment, an ophthalmological examination should be performed.

Respiratory effects

The drug should be used with caution in patients with bronchial asthma or a history of bronchial asthma, as NSAID intake may provoke bronchospasm in such patients.

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 (see section "Adverse reactions").

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically 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 congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of treatment. In animal studies, administration of a prostaglandin synthesis inhibitor has been shown to increase pre- and post-implantation losses and embryonic/fetal mortality. Furthermore, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

From the 20th week of pregnancy, the use of tenoxicam may cause oligohydramnios due to fetal renal dysfunction. Renal impairment may occur shortly after the start of treatment and is usually reversible upon discontinuation of tenoxicam. Additionally, there have been reports of arterial duct constriction after treatment in the second trimester, which resolved after discontinuation of therapy. Therefore, tenoxicam should not be prescribed during the first and second trimesters of pregnancy, except in cases of extreme necessity.

If a woman attempting to become pregnant or in the first or second trimester of pregnancy takes tenoxicam, the lowest possible dose for the shortest duration should be used. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after tenoxicam use for several days starting from the 20th week of pregnancy. The drug should be discontinued if signs of oligohydramnios or arterial duct constriction are 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);
• impaired renal function, which may progress to renal failure with oligohydramnios (see above);

on the mother and newborn, near the end of pregnancy:

• possible prolongation of bleeding time; anti-aggregatory effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, tenoxicam is contraindicated during the third trimester of pregnancy.

Breastfeeding period

In limited available studies, NSAIDs may be present in breast milk in very low concentrations. NSAID use during breastfeeding should be avoided if possible. According to data from single-dose administration, a very small amount (mean less than 0.3% of the dose) of tenoxicam passes into breast milk. There is no evidence of adverse reactions in infants breastfed by mothers taking tenoxicam.

Nevertheless, breastfeeding should be discontinued if use of the medicinal product is necessary.

Fertility

Use of tenoxicam may impair fertility due to inhibition of cyclooxygenase/prostaglandin synthesis; therefore, the drug is not recommended for women wishing to become pregnant. In women experiencing difficulties with conception or undergoing infertility investigations, discontinuation of tenoxicam should be considered (see section "Special precautions for use").

Ability to influence reaction speed when driving or operating machinery.

Patients who experience adverse reactions that may affect their ability to drive or operate machinery, such as vertigo, dizziness, somnolence, fatigue, or visual disturbances, should refrain from driving or operating machinery.

Method of Administration and Dosage.

Adverse reactions to tenoxicam can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Adults

The medicinal product is intended for intravenous and intramuscular administration.

The recommended dose is 20 mg once daily during the first 1–2 days of treatment. Thereafter, a switch to tablet administration should be made, with tablets taken daily at the same time each day. Prior to administration, the contents of the vial must be dissolved in 2 mL of water for injections provided in the product package. After complete reconstitution of the lyophilisate, the solution should be used immediately.

Recommended doses should not be exceeded, since higher doses do not necessarily provide greater therapeutic effect but increase the risk of adverse reactions.

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

Elderly Patients

Oxilithen, 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 drug should be administered to elderly patients at the lowest effective dose for the shortest possible duration. Such patients should be carefully monitored during NSAID therapy for gastrointestinal bleeding.

Patients with Renal and/or Hepatic Impairment

Creatinine clearance	Dosing
Greater than 25 mL/min	Under medical supervision without dosage adjustment (see section "Special precautions for use")
Less than 25 mL/min	Insufficient data to recommend dosing

The drug should be used with caution in patients with low albumin concentrations (e.g., in nephrotic syndrome) or with high plasma bilirubin concentrations, since tenoxicam is highly bound to plasma proteins.

There are insufficient data to recommend dosage adjustments of tenoxicam in patients with hepatic insufficiency.

Children.

There are insufficient data to recommend the use of tenoxicam in children.

Overdose.

Symptoms. There have been no reports of severe cases of tenoxicam overdose. Symptoms of NSAID overdose include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, occasionally diarrhea, disorientation, excitement, coma, drowsiness, dizziness, tinnitus, weakness, and occasionally seizures. Severe intoxication may lead to significant renal or hepatic insufficiency.

Treatment. If necessary, symptomatic therapy should be administered. 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. In case of frequent or prolonged seizures, diazepam should be administered intravenously. Administration of H₂-antagonists may be beneficial. Other measures should be carried out as clinically indicated, depending on the patient's condition.

Adverse Reactions

In most patients, adverse reactions are temporary and do not require discontinuation of treatment. Gastrointestinal effects are the most commonly reported.

Cardiovascular system: Edema, hypertension, and heart failure associated with NSAID therapy have been reported. Dyspnea and palpitations have been reported rarely.

Clinical trials and epidemiological data indicate that the use of NSAIDs (particularly at high doses and with prolonged use) may increase the risk of arterial thrombosis (e.g., myocardial infarction, stroke) (see section "Special Warnings and Precautions for Use").

Skin and subcutaneous tissue: Photosensitivity and bullous reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis (very rare), have been reported.

Eye disorders: Visual disturbances (such as blurred vision) have been reported with unknown frequency.

Gastrointestinal tract: The most common adverse reactions are gastrointestinal. These include dyspepsia, nausea, vomiting, abdominal pain and discomfort, constipation, diarrhea, flatulence, dyspeptic disorders, epigastric distress, melena, hematemesis, ulcerative stomatitis, anorexia, and exacerbations of colitis and Crohn’s disease (see section "Special Warnings and Precautions for Use").

As with other NSAIDs, there is a risk of peptic ulceration, perforation, or gastrointestinal bleeding, which may be fatal, especially in elderly patients (see section "Special Warnings and Precautions for Use").

Gastritis has been observed less frequently.

Pancreatitis has been reported very rarely.

Blood and lymphatic system: Decreased hemoglobin levels not related to gastrointestinal bleeding have been observed. Anemia, aplastic anemia, hemolytic anemia, thrombocytopenia, non-thrombocytopenic purpura, leukopenia, neutropenia, and eosinophilia have been reported. Epistaxis has been reported uncommonly. Agranulocytosis has been reported rarely.

Hepatobiliary system: Liver function abnormalities. As with most NSAIDs, various changes in liver function parameters have been observed. During treatment, serum transaminase levels may increase in some patients. Although such reactions are rare, if persistent abnormalities or worsening of liver function tests occur, or if clinical signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) are present, the drug should be discontinued. Hepatitis and jaundice have also been reported.

Hypersensitivity reactions: Hypersensitivity reactions have been reported with NSAID use, including non-specific allergic reactions and anaphylactic reactions; respiratory tract reactivity, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea; skin disorders such as rashes of various types, alopecia, angioneurotic edema, pruritus, and purpura. Disorders of nails, erythema, urticaria, and photosensitivity have been reported rarely. As with other NSAIDs, exfoliative and bullous dermatitis, including epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, vesiculobullous reactions, and vasculitis have been reported rarely.

Metabolism and nutrition: Metabolic disturbances such as hyperglycemia, and increased or decreased body weight have been observed rarely.

Nervous system: Malaise and tinnitus may occur.

Less frequent reports include aseptic meningitis (particularly in patients with pre-existing autoimmune disorders such as systemic lupus erythematosus or mixed connective tissue disease), with symptoms such as neck stiffness, headache, nausea, vomiting, fever, or disorientation, dizziness, malaise, fatigue, and somnolence.

Headache, insomnia, depression, nervousness, sleep disturbances, and dizziness have been reported rarely. Somnolence and paresthesia have been reported with unknown frequency.

Psychiatric disorders: Confusion and hallucinations have been reported with unknown frequency.

Renal and urinary system: Various forms of nephrotoxicity have been reported, including interstitial nephritis, nephrotic syndrome, and renal failure.

Reversible increases in blood urea nitrogen and serum creatinine have been reported (see section "Special Warnings and Precautions for Use").

Reporting of Adverse Reactions

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

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

1 vial of lyophilisate and solvent (water for injection) 2 ml in ampoule No. 1 in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Anfarm Ellas S.A.

Manufacturer's address and place of business.

61st km National Road Athens-Lamia, Schimatari Viotias, 32009, Greece.