BIKALUTAMID-VISTA AS

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TENIKAM (TENIKAM)

Composition

active substance: (tenoxicam) tenoxicam; 1 vial contains tenoxicam 20 mg; excipients: mannitol, disodium edetate, sodium metabisulfite (E 223), tromethamine, sodium hydroxide.

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

Pharmaceutical form.

Lyophilisate for solution for injection.

Main physical and chemical properties:

Compact mass from yellow to greenish-yellow color.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and anti-rheumatic products. Oxicams. Tenoxicam. ATC code M01A C02.

Pharmacological properties.

Pharmacodynamics.

Tenoxicam is a non-steroidal anti-inflammatory drug. It has 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 the inhibition of prostaglandin biosynthesis and the reduction of leukocyte accumulation at the site of inflammation.

Pharmacokinetics.

Tenoxicam in the form of lyophilisate is a long-acting drug, and once-daily administration is effective.

Tenoxicam penetrates well into the synovial fluid, where its concentration is approximately half of its concentration in plasma. The mean half-life from plasma is approximately 72 hours.

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

With the recommended regimen of 20 mg per day, the equilibrium concentration in plasma is achieved within 10-15 days. Accumulation is not expected. Tenoxicam is strongly bound to plasma proteins.

Tenoxicam is almost completely metabolized in the body. Approximately 2/3 of the applied dose is excreted in the urine in the form of a pharmacologically inactive metabolite, 5-hydroxypyridyl, and the rest with bile, mainly in the form of glucuronide conjugates of hydroxymetabolites.

No changes in the pharmacokinetics of tenoxicam depending on the patient's age were found, although individual differences are usually greater in elderly patients.

Clinical characteristics.

Indications.

For the relief of pain and inflammation in osteoarthritis and rheumatoid arthritis.

For short-term treatment of acute musculoskeletal disorders, including sprains, strains, and other soft tissue injuries.

The drug should be used intravenously or intramuscularly when oral administration of tenoxicam is not possible.

Contraindications.

Hypersensitivity to tenoxicam or any of the excipients of the medicinal product. History of symptoms of hypersensitivity (including symptoms of asthma, rhinitis, angioedema, or urticaria) when using other NSAIDs, including ibuprofen and acetylsalicylic acid, due to possible cross-sensitivity to tenoxicam.

Recurrent peptic ulcer disease / gastrointestinal bleeding in active form or in history (2 or more pronounced episodes of peptic ulcer disease or bleeding), ulcerative colitis, Crohn's disease, severe gastritis, or gastrointestinal bleeding, or perforation associated with previous use of NSAIDs.

Severe heart, liver, or kidney failure.

Cerebrovascular bleeding in history or other coagulation disorders.

Breastfeeding period.

Third trimester of pregnancy.

Childhood (up to 18 years).

Interactions with other medicinal products and other types of interactions.

Anticoagulants: in healthy volunteers, no clinically significant interaction was observed between tenoxicam in the form of lyophilisate and low molecular weight heparin. Tenoxicam is strongly bound to serum albumin and, like other NSAIDs, may enhance the anticoagulant effect of warfarin and other anticoagulants (see "Special instructions"). Particular attention should be paid to controlling the effect of anticoagulants and oral hypoglycemic agents at the initial stages of tenoxicam treatment.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): the risk of gastrointestinal bleeding is increased (see "Special instructions").

Antihypertensive agents: tenoxicam and other NSAIDs may weaken the effect of antihypertensive agents.

Cardiac glycosides: NSAIDs may enhance cardiac failure, reduce glomerular filtration rate, and increase the level of cardiac glycosides in the blood when used concomitantly.

Cyclosporine: as with the use of all other NSAIDs, when using tenoxicam with cyclosporine, caution is recommended, as the risk of nephrotoxicity increases.

Cimetidine: no interaction was found when used concomitantly with cimetidine.

Corticosteroids: as with the use of all other NSAIDs, when using tenoxicam with corticosteroids, caution should be exercised, as the risk of gastrointestinal ulcers or bleeding is increased (see "Special instructions").

Diuretics: reduction of diuretic effect. NSAIDs are able to retain ions of potassium, sodium, as well as fluid, and affect the natriuretic effect of diuretics, increasing the risk of nephrotoxicity of NSAIDs. These properties should be taken into account when treating patients with arterial hypertension or heart failure, as tenoxicam may worsen the course of these diseases.

Lithium: when using NSAIDs, a decrease in lithium elimination has been reported. If tenoxicam is prescribed to a patient receiving lithium therapy, it is recommended to monitor the lithium level more frequently, and the patient should be warned about the need to consume sufficient fluids and about the symptoms of lithium intoxication.

Methotrexate: when used concomitantly with methotrexate, caution is recommended due to the possibility of methotrexate intoxication, as it has been reported that NSAIDs reduce its elimination.

Mifepristone: NSAIDs should not be used within 8-12 days after taking mifepristone, as these agents can reduce the effect of mifepristone.

NSAIDs, selective cyclooxygenase-2 (COX-2) inhibitors, salicylates: it is recommended to avoid concomitant use of two or more NSAIDs (including acetylsalicylic acid) due to the increased risk of adverse reactions (see "Special instructions"). Salicylates may displace tenoxicam from its binding site with proteins, increasing its clearance and distribution. Concomitant treatment with salicylates or other NSAIDs should be avoided due to the risk of increased adverse reactions (especially gastrointestinal).

Penicillamine, gold preparations for parenteral use: in a small number of patients who took these agents simultaneously, no clinically significant interaction was observed.

Quinolone antibiotics: preclinical data indicate that the use of NSAIDs increases the risk of quinolone-induced seizures. When these agents are used concomitantly, the risk of seizures increases in patients.

Tacrolimus: the risk of nephrotoxicity increases when NSAIDs are used with tacrolimus.

Zidovudine: the risk of hematological toxicity increases when NSAIDs are used with zidovudine. There is evidence of an increased risk of developing hemarthrosis and hematomas in HIV-infected patients with hemophilia when zidovudine and ibuprofen are used concomitantly.

Special instructions.

Concomitant use of tenoxicam with NSAIDs, including selective COX-2 inhibitors, should be avoided (see "Interactions with other medicinal products and other types of interactions").

Tenoxicam's adverse reactions can be minimized by using the lowest effective dose for the shortest time necessary to control symptoms (see "Method of administration and doses" and information on gastrointestinal and cardiovascular risks below).

Cardiovascular and cerebrovascular effects

Patients with arterial hypertension and/or mild or moderate heart failure in history should be carefully monitored while taking the drug, as NSAID treatment has been reported to cause edema and fluid retention.

Clinical trials and epidemiological data suggest that the use of some NSAIDs, especially at high doses and for a long time, slightly increases the risk of thrombotic events (such as myocardial infarction or stroke). Currently, there is insufficient data to exclude such a risk when using tenoxicam.

Patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease should use the drug only after careful analysis of their condition. A similar analysis should be performed before starting long-term treatment in patients with risk factors for cardiovascular disease (such as arterial hypertension, hyperlipidemia, diabetes, smoking).

Cardiovascular, renal, and hepatic disorders

The use of NSAIDs may cause dose-dependent reduction of prostaglandin formation and rapid renal failure. The risk of such reactions is higher in patients taking diuretics and in the elderly. In such patients, kidney function should be monitored (see "Contraindications").

There have been reports of rare cases of elevated serum transaminase levels or other signs of liver dysfunction. These were mostly minor and temporary elevations above the normal range. In case of significant or persistent elevation, tenoxicam should be discontinued, and appropriate tests should be performed. Particular caution is necessary when treating patients with existing liver diseases.

Use in elderly patients

When using NSAIDs in elderly patients, the frequency of adverse reactions increases, especially gastrointestinal bleeding and perforation, including fatal ones (see "Method of administration and doses"). When using the drug in elderly patients, particular caution should be exercised, and their condition should be regularly monitored to detect possible interactions with concomitantly used medicinal products, as well as regular monitoring of kidney, liver, and cardiovascular function, which may be affected by NSAIDs.

Effect on female fertility

The drug may affect female fertility, and therefore, it is not recommended for women who wish to become pregnant. The need to stop using the drug should be considered in women who have difficulty conceiving or are undergoing infertility examination.

Gastrointestinal bleeding, ulcers, and perforation

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

When using all NSAIDs, gastrointestinal bleeding, ulcers, and perforation have been reported, which can occur at any time during treatment, with or without warning symptoms, regardless of the presence or absence of gastrointestinal diseases in history.

The risk of such events increases with the dose of NSAIDs in patients with a history of peptic ulcer disease, especially complicated by bleeding or perforation (see "Contraindications"), as well as in elderly patients. Such patients should start treatment with the lowest possible dose. For these patients, as well as those taking low doses of acetylsalicylic acid or other agents that increase the risk of gastrointestinal complications, the possibility of combined therapy with such agents as misoprostol or proton pump inhibitors should be considered.

Elderly patients, especially those with a history of toxic gastrointestinal damage, should be informed about any unusual gastrointestinal symptoms, especially bleeding. This is especially important at the beginning of treatment.

The drug should be used with caution in patients who are taking concomitantly medicinal products that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (such as warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (such as acetylsalicylic acid) (see "Interactions with other medicinal products and other types of interactions").

The condition of patients with symptoms of gastrointestinal diseases who are being treated with tenoxicam should be carefully monitored. If gastrointestinal bleeding or ulcers occur, the use of the drug should be discontinued immediately.

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

Hematological effects

Tenoxicam reduces platelet aggregation and may increase bleeding time, which should be taken into account when planning major surgical interventions (e.g., joint replacement) and when determining bleeding time.

Ophthalmological effects

When using NSAIDs, visual disturbances have been reported. If such disturbances occur during tenoxicam 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 the development of bronchospasm in such patients.

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

When using NSAIDs in such patients, the risk of developing aseptic meningitis increases (see "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 period

Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or fetal development. According to the results of epidemiological studies, the use of prostaglandin synthesis inhibitors in early pregnancy increases the risk of miscarriage, fetal heart defects, and non-closure of the anterior abdominal wall. The absolute risk of developing cardiovascular system anomalies increases from <1% to approximately 1.5%. It is believed that the risk of such events increases with the dose of the drug and the duration of therapy. The use of prostaglandin synthesis inhibitors in animals has caused increased pre- and post-implantation losses and embryofetal mortality. In addition, in animals that received prostaglandin synthesis inhibitors during organogenesis, the frequency of fetal developmental anomalies increased, including cardiovascular system anomalies.

Tenoxicam should not be prescribed during the first and second trimesters of pregnancy, except in cases of absolute necessity. If tenoxicam is used in women who are trying to become pregnant or during the first and second trimesters of pregnancy, the dose should be as low as possible, and the duration of treatment should be as short as possible.

During the third trimester, all prostaglandin synthesis inhibitors cause:

• risks for the fetus:
• cardiopulmonary toxic syndrome (premature closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which can progress to renal failure with the development of oligohydramnios;
• risks at the end of pregnancy for the mother and child:
• prolongation of bleeding time (effect of platelet aggregation inhibition), which is possible even with low doses;
• delayed uterine contraction with corresponding delayed labor and prolonged labor.

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

Breastfeeding period

Limited data on the use of NSAIDs indicate that these agents may penetrate into breast milk in very small amounts. The use of NSAIDs during breastfeeding should be avoided.

There is no information on the penetration of tenoxicam into human breast milk. Animal studies indicate the possibility of achieving significant levels of the drug.

Fertility

See "Special instructions" for information on the effect on female fertility.

Ability to affect reaction rate when driving vehicles or using other mechanisms

Patients who develop adverse reactions that may affect their ability to drive a car or use other mechanisms, such as vertigo, dizziness, drowsiness, fatigue, or visual disturbances, should refrain from driving a car or using other mechanisms.

Method of administration and doses

Adverse reactions to tenoxicam can be minimized by using the lowest effective dose for the shortest time necessary to control symptoms (see "Special instructions").

Adults

The drug is intended for intravenous and intramuscular use.

The recommended dose of the drug is 20 mg once a day for the first 1-2 days of treatment, then the patient should be switched to oral tablets, which should be taken daily at the same time. Before use, the contents of the vial must be dissolved in 2 ml of water for injections, which is included in the package of the medicinal product. After complete dissolution of the lyophilisate, the solution should be used immediately.

The recommended doses of the drug should not be exceeded, as the use of higher doses does not always lead to a more pronounced therapeutic effect, and the risk of adverse reactions increases.

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

Elderly patients

Tenoxicam, like other NSAIDs, should be used with caution in elderly patients. They have an increased risk of developing adverse reactions and more often receive concomitant medications or have impaired kidney, liver, or cardiovascular function. If necessary, the drug should be used in elderly patients at the lowest effective dose for the shortest time. The condition of such patients should be carefully monitored to detect gastrointestinal bleeding during NSAID therapy.

Patients with impaired renal and/or hepatic function

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

There is insufficient data to recommend dosing of tenoxicam in patients with liver failure.

Children

There is 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, abdominal pain, gastrointestinal bleeding, diarrhea, loss of orientation, agitation, coma, drowsiness, dizziness, tinnitus, weakness, and sometimes seizures. Possible severe kidney or liver failure in severe poisonings.

Treatment. Symptomatic therapy should be performed if necessary. Adequate hydration should be maintained, and liver and kidney function should be monitored. The patient should be under medical supervision for at least 4 hours after overdose. In case of frequent or prolonged seizures, diazepam should be administered intravenously. The introduction of H2 antagonists may be useful. Other measures should be taken according to the patient's clinical condition.

Adverse reactions

In most patients, adverse reactions are temporary and do not require discontinuation of treatment. Adverse effects from the gastrointestinal tract are most commonly observed.

From the cardiovascular system:

there have been reports of the development of edema, arterial hypertension, and heart failure associated with NSAID treatment. Dyspnea and palpitations have been reported rarely.

Clinical trials and epidemiological data indicate that the use of NSAIDs (especially at high doses and for a long time) increases the risk of thrombotic events (such as myocardial infarction or stroke) (see "Special instructions").

From the skin and subcutaneous tissue:

there have been reports of photosensitization and bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).

From the organs of vision:

there have been reports of visual disturbances (such as visual impairment and blurred vision) - frequency unknown.

From the gastrointestinal tract:

the most common adverse reactions are related to the gastrointestinal tract. They include dyspepsia, nausea, vomiting, abdominal pain, and discomfort, constipation, diarrhea, flatulence, digestive disorders, epigastric distress, melena, hematemesis, peptic stomatitis, anorexia, exacerbation of colitis and Crohn's disease (see "Special instructions").

As with the use of other NSAIDs, there is a risk of peptic ulcers, perforation, or gastrointestinal bleeding, which can be life-threatening, especially in elderly patients (see "Special instructions").

Gastritis has been observed less frequently.

Pancreatitis has been reported very rarely.

From the blood and lymphatic system:

there have been reports of a decrease in hemoglobin levels not associated with gastrointestinal bleeding. Anemia, aplastic anemia, hemolytic anemia, thrombocytopenia, and non-thrombocytopenic purpura, leukopenia, neutropenia, and eosinophilia have been observed. Nosebleeds have been reported occasionally. Agranulocytosis has been reported rarely.

From the hepatobiliary system:

liver dysfunction. As with the use of most NSAIDs, various changes in liver function parameters have been observed. In some patients, during treatment, the levels of transaminases in the blood may increase. Although such reactions are rare, if there are persistent deviations in liver tests or their deterioration, as well as clinical signs of liver disease or systemic manifestations (e.g., eosinophilia, rash), the drug should be discontinued. Hepatitis and jaundice have also been reported.

Hypersensitivity reactions:

when using NSAIDs, hypersensitivity reactions, including non-specific allergic reactions and anaphylactic reactions, have been reported; respiratory tract reactivity, including bronchial asthma, exacerbation of asthma, bronchospasm, or dyspnea; skin disorders: rashes of various types, alopecia, angioedema, pruritus, and purpura. Rarely, disorders of the nails, erythema, and photosensitization have been reported. As with the use of other NSAIDs, rare reports of exfoliative and bullous dermatitis, including epidermal necrolysis, multiform erythema, and Stevens-Johnson syndrome, vesiculobullous reactions, and vasculitis have been reported.

From metabolism:

rarely, metabolic disorders, such as hyperglycemia, weight gain, or weight loss, have been observed.

From the nervous system:

there may be malaise and tinnitus.

Rarely, aseptic meningitis (especially in patients with 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 drowsiness has been reported.

Headache, insomnia, depression, nervousness, sleep disturbances, and dizziness have been reported rarely. Drowsiness and paresthesia have also been reported - frequency unknown.

From the psyche:

there have been reports of confusion and hallucinations - frequency unknown.

From the urinary system:

various forms of nephrotoxicity, including interstitial nephritis, nephrotic syndrome, and kidney failure, have been observed.

Reversible increases in blood urea and creatinine levels have been reported (see "Special instructions").

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after the registration of a medicinal product is of great importance. This allows for the monitoring of the benefit/risk ratio of the use of this medicinal product. Medical and pharmaceutical workers, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product through the automated information system for pharmacovigilance at: https://aisf.dec.gov.ua/.

Shelf life

3 years.

Storage conditions

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

Store in a place inaccessible to children.

Incompatibility

Unknown.

Packaging

1 vial with lyophilisate and 1 ampoule with solvent in a cardboard box.

Release category

By prescription.

Manufacturer

ANFARM HELLAS S.A.

Location of the manufacturer and address of the place of its activity

61st km Nat. Rd. Athens - Lamia, Shimatari Viotias, 32009, Greece.