Etova-500

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETOVA-400 (ETOVA-400) ETOVA-500 (ETOVA-500)

Composition:

Active substance: etodolac;

One tablet contains etodolac 400 or 500 mg;

Excipients: lactose monohydrate, crospovidone, sodium lauryl sulfate, povidone, talc, colloidal silicon dioxide, magnesium stearate, Opadry brown coloring agent (ETOVA-400), Opadry yellow coloring agent (ETOVA-500).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

ETOVA-400: pinkish-brown film-coated tablets, oval-shaped, smooth on both sides;

ETOVA-500: yellow film-coated tablets, oval-shaped, smooth on both sides.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related compounds. ATC code M01AB08.

Pharmacological properties.

Pharmacodynamics.

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID), an indoleacetic acid derivative, differing from other nonsteroidal anti-inflammatory drugs (NSAIDs) by the presence of a tetrahydropyranoindole nucleus. Etodolac possesses anti-inflammatory, analgesic, and antipyretic properties. The drug reduces the synthesis of prostaglandins (PGs) from arachidonic acid by inhibiting the enzyme cyclooxygenase (COX), thereby decreasing the sensitivity of receptors to pain mediators (histamine, bradykinin), reducing exudation and leukocyte migration, as well as reducing the sensitivity of hypothalamic thermoregulatory centers to the action of endogenous pyrogens (interleukin-1). Etodolac has moderate selectivity for COX-2; therefore, it acts predominantly at the site of inflammation.

Pharmacokinetics.

After oral administration, etodolac is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 1 hour and amounts to 18 mcg/mL. Plasma protein binding is 95%, with the free fraction ranging from 1.2 to 4.7%.

The elimination half-life from plasma is approximately 7 hours. Etodolac is metabolized in the liver and is primarily excreted by the kidneys (up to 60% as metabolites). The volume of distribution is 0.4 L/kg; plasma clearance is 41 mL/h/kg. The bioavailability of etodolac is not less than 80%. Food intake and antacids do not affect bioavailability.

Clinical characteristics.

Indications.

For emergency or long-term treatment of osteoarthritis, rheumatoid arthritis.

Treatment of pain syndrome of various origins.

Contraindications.

Hypersensitivity to any component of the drug; history of hypersensitivity reactions (e.g. bronchial asthma attacks, urticaria, rhinitis, angioneurotic edema) due to intake of acetylsalicylic acid, ibuprofen, or other NSAIDs; active or recurrent peptic ulcer/bleeding in history (two or more separate confirmed episodes of ulcer or bleeding); gastrointestinal bleeding or perforation related to previous NSAID therapy in history; cytopenia, severe hepatic, renal, or cardiac insufficiency. Pregnancy and breastfeeding period. Pediatric age.

Contraindicated for pain treatment in coronary artery bypass grafting.

Interaction with other medicinal products and other types of interactions.

Since etodolac binds to blood proteins, dosage adjustment of other medicinal products that also bind well to blood proteins may be required.

Other analgesics, including selective cyclooxygenase-2 inhibitors. Avoid concomitant use of two or more NSAIDs (including acetylsalicylic acid), as the risk of adverse effects increases (see section "Special precautions for use").

Antihypertensive medicinal products. Decreases hypotensive effect.

Diuretics. Decreases diuretic effect. Diuretics increase the risk of nephrotoxicity of NSAIDs. Cardiac glycosides. NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase blood levels of glycosides.

Lithium. Lithium excretion is reduced.

Methotrexate. Methotrexate excretion is reduced.

Cyclosporine. May increase cyclosporine-related nephrotoxicity. Mifepristone. NSAIDs should not be used within 8–12 days after mifepristone administration, as NSAIDs may reduce the efficacy of mifepristone.

Corticosteroids. Increases the risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

Anticoagulants. NSAIDs may enhance the effect of anticoagulants such as warfarin (see section "Special precautions for use"). Prothrombin time may be prolonged when etodolac is used with other NSAIDs; therefore, when used with warfarin, the risk of bleeding increases.

Quinolone antibiotics. Animal studies show that NSAIDs increase the risk of seizures associated with quinolone antibiotics. In patients taking NSAIDs and quinolone antibiotics, the risk of developing seizures is increased.

Antiplatelet medicinal products and selective serotonin reuptake inhibitors. Increases the risk of gastrointestinal bleeding (see section "Special precautions for use").

Tacrolimus. When NSAIDs are used concomitantly with tacrolimus, the risk of nephrotoxicity increases.

Zidovudine. The risk of hematotoxicity increases when NSAIDs are used concomitantly with zidovudine. Evidence exists of an increased risk of hemarthrosis and hematoma in HIV-positive patients with hemophilia who are concurrently taking zidovudine and ibuprofen.

Phenylbutazone. Concomitant use of phenylbutazone and etodolac is not recommended, as phenylbutazone increases (by approximately 80%) the free fraction of etodolac. In vivo studies have not been conducted.

Antacids. Concomitant use of antacids does not affect the overall absorption of etodolac. Antacids may reduce the peak concentration of etodolac by 15–20%, but do not have a significant impact on peak concentration.

Laboratory data. When etodolac is used, a false positive result in bilirubin testing may occur due to the presence of phenolic metabolites of etodolac in urine.

Special precautions for use.

Adverse reactions 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).

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

Respiratory disorders.

Caution should be exercised when administering etodolac to patients with bronchial asthma, including those with a history of asthma, as NSAIDs may provoke bronchospasm in such patients.

Cardiovascular, renal, and hepatic impairment.

In patients receiving NSAIDs, dose-dependent reduction in prostaglandin formation and subsequent renal decompensation may occur. Patients at high risk of these reactions include those with impaired renal or hepatic function, heart failure, patients taking diuretics and ACE inhibitors, and elderly patients. Dose reduction and monitoring of renal function are required in these patients (see section "Contraindications").

Etodolac should be used with caution in patients with fluid retention, arterial hypertension, or heart failure.

During prolonged treatment with etodolac, regular monitoring of liver and kidney function, as well as peripheral blood counts, is necessary.

Platelets.

Although NSAIDs do not have a direct effect on platelets, as does aspirin, all these drugs may inhibit prostaglandin biosynthesis, which can affect platelet function. Patients in whom a negative effect on platelet function is possible should be monitored.

Elderly.

In general, dose adjustment is not required in elderly patients. However, caution should be exercised when selecting the dose, especially when increasing the dose. The frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, is increased in elderly patients (see section "Dosage and administration").

Cardiovascular and cerebrovascular disorders.

Careful monitoring is recommended in patients with arterial hypertension and/or mild to moderate congestive heart failure in their medical history, as fluid retention and edema have been observed during NSAID therapy.

Clinical trial data and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and during long-term treatment) is associated with an increased risk of vascular thrombotic events (e.g., myocardial infarction or stroke). There is insufficient data to exclude such a risk with etodolac.

Therapy with etodolac should be initiated only after careful assessment in patients with uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

A similar assessment is required before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Gastrointestinal disorders.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, regardless of prior symptoms or history of serious gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increased NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risks, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered (see information below and section "Interaction with other medicinal products and other forms of interaction").

Patients with a history of gastrointestinal toxicity, especially elderly patients, should be informed about any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially during the initial stages of treatment.

Caution should be exercised in patients who are concurrently using drugs that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in patients taking etodolac, treatment should be discontinued.

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

Systemic lupus erythematosus and connective tissue diseases.

Patients with systemic lupus erythematosus and connective tissue diseases have an increased risk of developing aseptic meningitis (see section "Adverse reactions").

Skin disorders.

Serious skin reactions, some of which have been fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have very rarely been observed with NSAIDs (see section "Adverse reactions"). The highest risk of such reactions occurs early in treatment, with most cases appearing within the first month of therapy. If skin rashes, mucosal lesions, or other signs of hypersensitivity occur, etodolac should be discontinued immediately.

Fertility.

Etodolac may affect reproductive function. The drug is not recommended for women wishing to become pregnant. For women planning pregnancy or undergoing infertility evaluation, discontinuation of etodolac should be considered.

The product contains lactose; therefore, it should not be used in patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy and breastfeeding.

Ability to influence reaction speed when driving vehicles or operating machinery.

Etodolac may cause dizziness, drowsiness, weakness, and visual disturbances (impaired vision). Patients should be aware of this when driving vehicles or operating machinery. If such reactions occur, patients should avoid driving or operating machinery.

Method of Administration and Dosage.

Adults: The recommended single dose is 400 or 500 mg, administered
twice daily: 1 tablet in the morning and 1 tablet in the evening, after meals.

Maximum daily dose – 1000 mg.

For rheumatic diseases, the duration of treatment depends on the therapeutic response and the nature of the disease. During prolonged therapy, the dose should be adjusted every 2–3 weeks of treatment.

For the treatment of pain due to acute inflammatory conditions (such as dental pain, myositis, tendinitis), as well as postoperative pain syndromes, the treatment course lasts 5 days. For headache and menstrual pain, the drug should be taken at a dose of 1–2 tablets per day, as needed, for no more than 3 days.

Children.

The safety and efficacy of etodolac have not been established in children; therefore, it is not used in pediatric practice.

Overdose.

Symptoms.

Symptoms of overdose include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhea, disorientation, excitement, coma, drowsiness, dizziness, tinnitus, fainting, and occasionally seizures. In cases of significant overdose, acute renal failure and liver damage are possible.

Treatment.

Symptomatic treatment. Within 1 hour after ingestion of a potentially toxic amount of the drug, activated charcoal should be administered. In adults, gastric lavage should be performed within 1 hour after ingestion of a life-threatening amount of the drug. Adequate diuresis should be maintained, and renal and hepatic functions should be monitored. Patients should be observed for at least 4 hours after ingestion of a potentially toxic amount of the drug. In case of frequent and prolonged seizures, intravenous diazepam should be administered. Depending on the patient's clinical condition, other interventions may be required.

Adverse reactions.

The most common adverse reactions were gastrointestinal disorders.

Blood and lymphatic system disorders: thrombocytopenia, neutropenia, leukopenia, pancytopenia, agranulocytosis, anemia, aplastic anemia, hemolytic anemia, prolonged bleeding time, lymphadenopathy.

Immune system disorders: hypersensitivity reactions have been observed during the use of NSAIDs: non-specific allergic reactions and anaphylaxis; anaphylactoid reactions; respiratory tract reactivity, including bronchial asthma, exacerbation of bronchial asthma, bronchospasm, and dyspnea; various skin disorders, including different types of rashes, pruritus, urticaria, purpura, angioedema, and less frequently exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Nervous system disorders: depression, headache, dizziness, insomnia, confusion, impaired consciousness, hallucinations, disorientation (see section "Special precautions"), paresthesia, tremor, weakness, nervousness, excitement, convulsions, coma, somnolence, taste disturbances, aseptic meningitis (particularly in patients with autoimmune diseases such as systemic lupus erythematosus or connective tissue disorders), with symptoms such as nuchal rigidity, headache, nausea, vomiting.

Eye disorders: eye disorders (visual disturbances), optic neuritis, blurred vision, photophobia, conjunctivitis.

Ear and labyrinth disorders: tinnitus, vertigo, deafness.

Cardiovascular system disorders: edema, arterial hypertension, arrhythmia, palpitations, heart failure, vasculitis, facial flushing.

Data from clinical trials and epidemiological studies suggest that the use of certain NSAIDs (particularly at high doses and during long-term treatment) may be associated with an increased risk of vascular thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions").

Gastrointestinal disorders: peptic ulcer, gastrointestinal perforation or gastrointestinal bleeding, sometimes fatal, especially in elderly patients (see section "Special precautions"), nausea, vomiting, diarrhea, dyspepsia, epigastric pain, abdominal pain, ulcerative stomatitis, constipation, flatulence, vomiting of blood, melena, gastrointestinal ulcers, digestive disturbances, heartburn, rectal bleeding, exacerbation of colitis and Crohn’s disease (see section "Special precautions"), gastritis, pancreatitis, glossitis, thirst, dry mouth, anorexia, belching, duodenitis, esophagitis with or without strictures or cardiospasm.

Hepatobiliary disorders: liver function abnormalities (bilirubinuria), increased liver enzyme activity, hepatitis, cholestatic hepatitis, jaundice, cholestatic jaundice, liver failure, liver necrosis.

Skin and subcutaneous tissue disorders: bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, photosensitivity, increased sweating, hyperpigmentation, alopecia, skin desquamation, ecchymoses.

Renal and urinary disorders: dysuria, increased frequency of urination, various forms of nephrotoxicity, including interstitial nephritis, nephrotic syndrome, renal failure, elevated blood urea levels, elevated creatinine levels, renal papillary necrosis, oliguria/polyuria, proteinuria, hematuria, cystitis, kidney stones.

Respiratory system disorders: pulmonary infiltration with eosinophilia, bronchitis, pharyngitis, rhinitis, sinusitis, respiratory depression, pneumonia, nosebleeds.

General disorders: increased fatigue, weakness, asthenia, chills, elevated body temperature, disturbances in water-electrolyte balance, hypernatremia, hyperkalemia.

Other: leukorrhea; irregular uterine bleeding; hyperglycemia in patients with controlled blood sugar levels suffering from diabetes; changes in body weight; infections; sepsis; fatal cases.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister pack. 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Ipca Laboratories Ltd.

Manufacturer's address and place of business.

P.O. Sajawta, District Ratlam – 457002 (M.P.), India.