Tenoliof

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TENOLIOF

Composition:

Active substance: tenoxicam;

1 vial contains 20 mg of tenoxicam;

Excipients: mannitol, disodium edetate, sodium metabisulfite (E 223), tromethamine, 1 M solution of sodium hydroxide.

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

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical characteristics: lyophilized powder or compacted mass of yellow to greenish-yellow color.

Pharmacotherapeutic group.
Non-steroidal anti-inflammatory and antirheumatic agents. Enolic acids (oxicams). Tenoxicam.

ATC code M01A C02.

Pharmacological Properties

Pharmacodynamics

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

As with other NSAIDs, the precise mechanism of action is unknown, although it is likely multifactorial, including inhibition of prostaglandin biosynthesis and reduction of leukocyte accumulation at the site of inflammation.

Pharmacokinetics

Tenoxicam in the form of a lyophilisate is a long-acting formulation; administration once daily is effective.

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

After intravenous administration of tenoxicam at a dose of 20 mg, plasma levels decline rapidly during the first 2 hours, which is related to the distribution process. After intramuscular injection, plasma levels reach at least 90% of the maximum concentration within 15 minutes.

With the recommended dosage regimen of 20 mg daily, steady-state plasma concentrations are achieved 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 the pharmacokinetics of tenoxicam have been observed, 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.

The drug should be administered intravenously or intramuscularly in cases where 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 ulceration/gastrointestinal bleeding (two or more distinct episodes of peptic ulcer or bleeding), ulcerative colitis, Crohn’s disease, severe gastritis, or gastrointestinal perforation or hemorrhage associated with previous use of NSAIDs.
• Severe heart, liver, or renal failure.
• History of cerebrovascular hemorrhage or other coagulation disorders.
• Breastfeeding period.
• Third trimester of pregnancy.
• Age under 18 years.

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"). Close monitoring of anticoagulant and oral hypoglycemic agents is particularly recommended 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 reduce the efficacy 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, caution is recommended when used concomitantly with cyclosporine due to increased risk of nephrotoxicity.

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

Corticosteroids. As with all NSAIDs, caution is recommended when used concomitantly with corticosteroids due to increased risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

Diuretics. Reduced diuretic effect. NSAIDs may 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 during NSAID use. If tenoxicam is prescribed to patients receiving lithium therapy, more frequent monitoring of lithium levels is recommended, and patients should be advised to maintain adequate fluid intake and be aware of 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. The drug should not be used within 8–12 days after mifepristone intake, as NSAIDs may reduce the effect 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 the potential for increased risk of adverse reactions (see section "Special precautions for use"). Salicylates may displace tenoxicam from 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 drugs concomitantly, no clinically significant interaction was observed.

Quinolone antibiotics. Preclinical data indicate that NSAID use increases the risk of quinolone-induced seizures. Concomitant use of these drugs 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 hematological toxicity when NSAIDs are used with zidovudine. Evidence suggests an increased risk of hemarthrosis and hematoma 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 fluid retention and edema have been reported with NSAID therapy.

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

Patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated after careful consideration of risks versus benefits. A similar risk-benefit assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Cardiovascular, renal, and hepatic disorders

NSAID use may cause dose-dependent reduction in prostaglandin synthesis and acute renal failure. Patients taking diuretics and elderly patients are at higher risk of such reactions. 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. If significant or persistent increases occur, tenoxicam should be discontinued and appropriate tests performed. Extreme caution is required when administering the drug to patients with pre-existing liver disease.

In rare cases, NSAIDs may cause 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 lead to marked deterioration of renal function, which typically reverses after discontinuation of the drug. The highest risk of such complications occurs in patients with pre-existing renal disease (including diabetes with renal impairment), 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 closely monitored during treatment in such patients. The drug should be administered at the lowest possible dose in patients with renal, hepatic, or cardiac impairment. 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, NSAIDs may cause severe, sometimes fatal, skin reactions, 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, with most cases occurring 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

The frequency of adverse reactions, particularly gastrointestinal bleeding and perforation, including fatal outcomes, increases when NSAIDs are used in elderly patients (see section "Dosage and administration"). Particular caution should be exercised when administering the drug to elderly patients, with regular monitoring for potential interactions with concomitant medications and periodic assessment of renal, hepatic, and cardiovascular function, which may be affected by NSAIDs.

Effect on female fertility

The drug may affect female fertility and is therefore not recommended for women attempting to conceive. Consideration should be given to discontinuing the drug in women experiencing difficulty in conceiving or undergoing infertility investigations.

Gastrointestinal bleeding, ulcers, and perforations

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

Gastrointestinal bleeding, ulcers, and perforations, including fatal outcomes, have been reported during treatment with all NSAIDs, and may occur at any time during therapy, with or without warning symptoms, and with or without prior gastrointestinal disease.

The risk of such events increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Treatment in these patients should be initiated at the lowest possible dose. For these patients, as well as for those receiving concomitant low-dose acetylsalicylic acid or other drugs increasing gastrointestinal 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 advised to report any unusual gastrointestinal symptoms, particularly bleeding. This is particularly important at the beginning of treatment.

The drug should be used with caution in patients receiving concomitant medications that increase the risk of ulcers or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, 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 therapy should be closely monitored. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued immediately.

The drug should be used with caution in patients with a history of gastrointestinal disorders (e.g., ulcerative colitis, Crohn’s disease), as tenoxicam may exacerbate these conditions (see section "Adverse reactions").

Hematological effects

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

Ophthalmological effects

Ocular adverse events have been reported with NSAID use. If such events occur during treatment, ophthalmological evaluation 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 use may provoke bronchospasm in such patients.

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

The use of NSAIDs in these 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., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological studies indicate that use of drugs inhibiting prostaglandin synthesis during early pregnancy increases the risk of miscarriage and fetal malformations, including cardiac defects and abdominal wall defects. The absolute risk of cardiovascular malformations increases from <1% to approximately 1.5%. The risk is considered to increase with higher drug doses and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors have been shown to increase pre- and post-implantation loss and embryofetal mortality. Furthermore, administration of prostaglandin synthesis inhibitors during organogenesis in animals has been associated with increased incidence of fetal malformations, including cardiovascular abnormalities.

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 fetal ductus arteriosus constriction following treatment in the second trimester, most of which resolved after stopping the drug. Therefore, tenoxicam should not be prescribed during the first and second trimesters unless clearly necessary. If tenoxicam is used by a woman attempting to conceive or during the first or second trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after several days of tenoxicam exposure starting from the 20th gestational week. Tenoxicam should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors may pose the following risks:

Risks to the fetus:

• Cardio-pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• Renal dysfunction (see above);

Risks to the mother at the end of pregnancy and to the newborn:

• 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 (see section "Contraindications").

Breastfeeding

Tenoxicam may pass into breast milk in small amounts. Administration of the drug during breastfeeding should be avoided if possible.

Fertility

See section "Special precautions for use" for information on effects on female fertility.

Ability to influence the speed of reactions when driving vehicles or operating machinery

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

Dosage and Administration.

The adverse reactions of 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, after which a switch to tablet administration should be made, taken daily at the same time. Prior to administration, the contents of the vial must be dissolved in 2 mL of water for injections, which is included in the product package. After complete dissolution of the lyophilisate, the solution should be used immediately.

The recommended doses must not be exceeded, as higher doses do not necessarily provide greater 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

Tenolif, like other NSAIDs, should be used with particular caution in elderly patients, as these patients have an increased risk of adverse reactions and more frequently have concomitant medication use or impaired renal, hepatic, or cardiovascular function. If necessary, the medicinal product should be administered to elderly patients at the lowest effective dose for the shortest possible duration. Careful monitoring of these patients is required during NSAID therapy to detect gastrointestinal bleeding.

Patients with Renal and/or Hepatic Impairment

The drug should be used with caution in patients with low albumin concentrations (e.g., in nephrotic syndrome) or with high plasma bilirubin levels, 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 sometimes 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. For frequent or prolonged seizures, diazepam should be administered intravenously. Administration of H2-receptor antagonists may be beneficial. Other measures should be applied as indicated, depending on the patient's clinical condition.

Adverse Reactions

In most patients, adverse reactions are temporary and do not require discontinuation of treatment. The most commonly observed adverse reactions are gastrointestinal.

Cardiovascular system: development of edema, arterial hypertension, and heart failure associated with NSAID therapy; rarely – dyspnea and palpitations.

Clinical studies 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).

Eye disorders: frequency unknown – visual disturbances (visual impairment and blurred vision).

Gastrointestinal tract: gastrointestinal adverse reactions are the most common. These include dyspepsia, nausea, vomiting, abdominal pain and discomfort, constipation, diarrhea, flatulence, indigestion, epigastric distress, melena, hematemesis, ulcerative stomatitis, anorexia, and exacerbation 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, particularly in elderly patients (see section "Special Warnings and Precautions for Use); rarely – gastritis; very rarely – pancreatitis.

Blood and lymphatic system: decreased hemoglobin levels unrelated to gastrointestinal bleeding; anemia, aplastic anemia, hemolytic anemia, thrombocytopenia and non-thrombocytopenic purpura, leukopenia, neutropenia, and eosinophilia; uncommon – epistaxis; rarely – agranulocytosis.

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

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

Metabolism and nutrition: rarely – metabolic disturbances such as hyperglycemia, weight gain or weight loss.

Nervous system: malaise and tinnitus may occur;

uncommon – aseptic meningitis (particularly in patients with pre-existing autoimmune disorders such as SLE or mixed connective tissue disease), with symptoms such as neck stiffness, headache, nausea, vomiting, fever, or disorientation, dizziness, malaise, fatigue, and somnolence; rarely – headache, insomnia, depression, nervousness, sleep disturbances, and dizziness; frequency unknown – somnolence and paraesthesia.

Psychiatric disorders: frequency unknown – confusion and hallucinations.

Renal and urinary system: various forms of nephrotoxicity, including interstitial nephritis, nephrotic syndrome, and renal failure;

reversible increase in blood urea nitrogen and creatinine (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any 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 in the original packaging to protect from light at a temperature not exceeding 25°C.

Keep out of reach of children.

Incompatibilities.

Not known.

Packaging.

1 vial of lyophilisate and 1 ampoule of solvent in a blister pack, 3 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

K.T. Rompharm Company S.R.L./S.C. ROMPHARM COMPANY S.R.L

Manufacturer's address and location of operations.

Str. Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania / Eroilor str. No 1 A, Otopeni city, 075100, county Ilfov, Romania.

Marketing Authorization Holder.

LLC Rompharm Company Georgia.

Address of Marketing Authorization Holder.

Georgia, Tbilisi, Saakadze Downhill, 8, office 7a / Georgia, Tbilisi, Saakadze Downhill, 8, office 7a.