Indometacin sofarma

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INDOMETACIN SOPHARMA (INDOMETACIN SOPHARMA)

Composition:

Active substance: indometacin;

One enteric-coated tablet contains 25 mg of indometacin;

Excipients: lactose monohydrate, wheat starch, povidone K 25, microcrystalline cellulose, magnesium stearate, talc, colloidal anhydrous silicon dioxide;

Enteric coating: copolymer of methacrylic acid : ethyl acrylate (1:1) 30% dispersion (Eudragit L 30 D-55), copolymer of methyl acrylate : methyl methacrylate : methacrylic acid 30% dispersion (Eudragit FS 30 D), sodium hydroxide, triethyl citrate, polysorbate 80, pigment suspension – brown W.A.S. FS (talc, triethyl citrate, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), propylene glycol alginates, potassium sorbate).

Pharmaceutical form. Enteric-coated tablets.

Main physico-chemical properties: round, biconvex, enteric-coated tablets, 7 mm in diameter, orange-brown in color.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and anti-rheumatic drugs. Acetic acid derivatives and related substances.

ATC code M01AB01.

Pharmacological Properties.

Pharmacodynamics.

Indomethacin is a derivative of indole acetic acid and belongs to the group of nonsteroidal anti-inflammatory drugs (NSAIDs). It has pronounced anti-inflammatory activity, which significantly exceeds that of phenylbutazone and acetylsalicylic acid. Its analgesic activity is comparable to that of metamizole. It possesses antipyretic properties. Indomethacin strongly inhibits prostaglandin synthesis by suppressing cyclooxygenase. Additionally, it reduces platelet aggregation and lipoxygenase activity at the site of inflammation, thereby reducing leukotriene activity; it also decreases the release of endogenous pyrogens, inactivates lysosomal enzymes, and inhibits the activity of neutral proteases. Other effects may also be significant, such as uncoupling of oxidative phosphorylation, inhibition of catecholamine reuptake, enhanced metabolism of norepinephrine, and known ganglion-blocking action.

Pharmacokinetics.

Absorption: When administered orally, 80–90% of the administered dose is absorbed through the mucous membrane in the small intestine and to a lesser extent in the stomach. Maximum plasma concentration is reached within 1–2 hours.

Distribution: It distributes into all tissues and organs. It penetrates through the placental and blood-brain barriers. It passes through the synovial membrane into joints, where its concentration in synovial fluid is higher than in blood plasma. It is bound to plasma proteins by 90–98%, and therefore is capable of displacing other drugs from protein binding sites and enhancing their therapeutic effects when used concomitantly.

Metabolism: It is metabolized in the liver via oxidation and conjugation.

Excretion: The half-life of indomethacin ranges between 2.6 and 11.2 hours, averaging 5.8 hours. Up to 60–75% is excreted by the kidneys, of which 10–20% is excreted unchanged, while the remainder is excreted via bile and feces. It penetrates into breast milk.

Clinical characteristics.

Indications.

The efficacy of short-term symptomatic treatment with indometacin has been established for the following conditions:

• Acute and chronic pain associated with inflammatory and degenerative disorders of the musculoskeletal system: rheumatoid arthritis; acute and chronic ankylosing spondylitis (Bechterew's disease) in flare-up phase; gout attack and gouty arthritis; moderate to severe osteoarthritis;
• Disorders of periarticular tissues: tendinitis, bursitis (acute painful shoulder), tendobursitis, tenosynovitis, pain and inflammation following trauma (including in athletes) and surgical procedures;
• Discopathy, plexitis, radiculoneuritis;
• Dysmenorrhea.

The potential benefits and risks of using indometacin, as well as alternative treatment options, should be carefully evaluated before deciding to prescribe indometacin. The lowest effective dose should be used for the shortest duration necessary to achieve the individual patient's treatment goals (see section "Special precautions for use").

Contraindications.

• Hypersensitivity to the components of the drug;
• Hypersensitivity to acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) with clinical manifestations such as asthma attack, angioedema, urticaria, or rhinitis;
• Active peptic ulcer of the stomach or duodenum or recurrent episodes (two or more documented cases of ulcers or bleeding), ulcerative colitis and/or enterocolitis;
• History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs;
• Concomitant use of other nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors, due to increased risk of adverse effects;
• Severe heart failure;
• Severe hepatic or renal insufficiency;
• Pre- and postoperative pain associated with coronary artery bypass graft (CABG) surgery.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of zalcitabine and indometacin causes changes in their pharmacodynamics.

Concomitant use of zidovudine and indometacin increases the risk of hematological toxicity.

The risk of indometacin toxicity is increased when used concomitantly with ritonavir.

Concomitant use with antiepileptic drugs should be done with caution due to enhanced effects of phenytoin.

Concomitant use with haloperidol enhances drowsiness.

Concomitant use with benzodiazepines increases the risk of dizziness.

Indometacin increases the bioavailability of diphosphonates when used concomitantly with tiludronic acid.

Concomitant use with desmopressin enhances its effect.

NSAIDs should be avoided for 8–12 days after administration of mifepristone.

Indometacin can reduce the elimination rate of baclofen, thereby increasing its toxic effects.

Indometacin may interfere with laboratory test results:

• May cause elevated levels of one or more liver enzymes;
• May lead to false-negative results in the dexamethasone suppression test.

Concomitant use of NSAIDs and COX-2 inhibitors increases the risk of developing "analgesic" nephropathy and renal papillary necrosis. Therefore, their combined use should be avoided.

Concomitant use with vasodilators increases the risk of bleeding.

Other NSAIDs, alcohol: concomitant use of indometacin with other NSAIDs and alcohol increases the risk of gastrointestinal adverse effects.

Diflunisal: increases plasma levels and reduces renal clearance of indometacin. There is a risk of fatal gastrointestinal hemorrhage. This combination is not recommended.

Digoxin: indometacin may increase digoxin plasma concentration (by reducing its renal excretion), requiring dose adjustment and monitoring of digoxin levels.

Lithium salts: indometacin prolongs and potentiates the effects of lithium salts and increases lithium toxicity, necessitating monitoring of lithium levels.

Immunosuppressants: concomitant use of indometacin with immunosuppressants such as methotrexate and cyclosporine leads to increased toxicity.

Concomitant use with tacrolimus increases the risk of nephrotoxicity; concomitant use with muromonab-CD3 increases the risk of psychosis and encephalopathy. Caution is advised when using concomitantly with cyclophosphamide due to the risk of water intoxication.

Diuretics: NSAIDs reduce the therapeutic efficacy of diuretics (due to decreased tubular secretion). There may be an increased risk of hyperkalemia when used concomitantly with potassium-sparing diuretics, and reduced kidney function with an increased risk of acute renal failure when combined with thiazide diuretics (triamterene). Concomitant use with triamterene should be avoided due to the risk of reversible renal insufficiency. Diuretics may enhance the nephrotoxicity of indometacin.

Antihypertensive agents: indometacin may attenuate the antihypertensive effects of ACE inhibitors and beta-blockers when used concomitantly.

Corticosteroids: increased risk of gastrointestinal ulceration and hemorrhage (see section "Special precautions for use").

Anticoagulants: increased risk of ulceration and hemorrhage due to inhibition of platelet function and aggressive effects on the gastrointestinal mucosa.

Bleeding time and prothrombin time should be monitored. Indometacin competitively interacts with coumarin anticoagulants at plasma protein binding sites, resulting in increased plasma concentrations of the latter. When used concomitantly, indometacin should be prescribed at the lowest possible dose, and the use of protective agents should be considered (see section "Special precautions for use").

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

Concomitant use with antidepressants (SSRIs) should be done with caution due to increased risk of bleeding.

Concomitant use with antibacterial agents may increase the risk of seizures; combined use of quinolones and indometacin may increase the risk of seizures in patients with or without a history of epilepsy or seizures; with ciprofloxacin – increased risk of skin reactions and neurotoxicity.

Probenecid: slows excretion and increases the toxicity of indometacin.

Antidiabetic agents: indometacin does not alter the therapeutic efficacy of oral antidiabetic agents or insulin, despite some observations of hypoglycemic or hyperglycemic effects during concomitant use. The effect of sulfonylurea derivatives may be enhanced by NSAIDs. In isolated cases, concomitant use with metformin may cause metabolic acidosis.

Special precautions for use.

General

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms (see section «Dosage and administration» and the gastrointestinal and cardiovascular risk factors outlined below).

In patients with systemic lupus erythematosus and connective tissue diseases, there is a possible increased risk of developing viral meningitis.

Caution should be exercised when administering the drug to patients after surgical procedures, as bleeding time may be prolonged.

In patients with reduced blood flow, in whom renal prostaglandins play an important role in maintaining renal perfusion, NSAIDs may provoke marked renal decompensation. Patients at risk of such a reaction include those with renal or hepatic dysfunction, patients with diabetes mellitus, elderly patients, patients with reduced extracellular fluid volume, congestive heart failure, sepsis, and those concurrently taking nephrotoxic agents. Renal function should be monitored in these patients during treatment.

The drug should be used with caution in patients with impaired renal, hepatic, or cardiac function, or conditions leading to fluid retention, as indometacin may cause decreased renal function and fluid retention.

Use of NSAIDs carries a risk of hyperkalemia, particularly in patients aged 65 years and older, patients with renal insufficiency, and those being treated with beta-blockers, ACE inhibitors, or potassium-sparing diuretics. Serum potassium levels should be monitored in such patients.

Patients undergoing long-term treatment with the drug should have periodic blood tests, liver function tests, and gastrointestinal assessments to detect any adverse effects as early as possible.

Use with particular caution in patients with hypersensitivity to food or drugs, and in patients with allergic conditions such as hay fever, bronchial asthma, or nasal polyps. Caution is advised when administering the drug to patients with bronchial asthma due to the possibility of bronchospasm.

Elderly patients (over 65 years of age)

Use of NSAIDs in patients aged 65 years and older is associated with a higher frequency of adverse reactions, predominantly gastrointestinal bleeding or perforation, sometimes fatal (see section «Dosage and administration»).

Gastrointestinal bleeding, ulcers, and perforations

Gastrointestinal bleeding, ulcers, and perforations (sometimes fatal) have been observed with all NSAIDs at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events.

The risk of gastrointestinal adverse reactions is higher when high doses of NSAIDs are used, in patients with a history of peptic ulcer, especially if complicated by hemorrhage or perforation, and in elderly patients. For such patients, treatment should be initiated at the lowest possible dose, with consideration given to the need for concomitant gastroprotective agents (e.g., misoprostol or proton pump inhibitors). This approach is also recommended when low-dose acetylsalicylic acid or other drugs increasing the risk of gastrointestinal complications (corticosteroids, anticoagulants, antiplatelet agents, selective serotonin reuptake inhibitors) are used concomitantly.

Particular caution is required when treating patients with other gastrointestinal disorders (ulcerative colitis, Crohn’s disease), which may be exacerbated by NSAIDs, and in patients with abnormalities of the sigmoid colon.

Increased risk of gastrointestinal complications exists in patients who abuse alcohol or are smokers; therefore, treatment of these patients should be conducted with particular caution.

Patients with a history of gastrointestinal disorders (especially elderly patients) should be informed about unusual abdominal symptoms (particularly gastrointestinal bleeding), especially at the beginning of treatment.

Special caution is required when treating patients with concomitant medications that may increase the risk of ulceration or bleeding (oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid) (see section «Interaction with other medicinal products and other forms of interaction»).

Treatment with the drug should be discontinued if gastrointestinal lesions or bleeding occur.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and medical advice should be provided to patients with a history of hypertension and/or mild to moderate congestive heart failure, as there have been reports of edema and fluid retention associated with NSAID therapy.

Clinical studies and epidemiological data indicate that the use of certain NSAIDs (particularly at high doses and with long-term use) may be associated with a slight increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). There is insufficient data to exclude such a risk for indometacin.

Indometacin should be used in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease, as well as in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking) only after careful assessment of the benefit-risk ratio.

Such assessment is also required prior to initiating long-term treatment in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking).

Skin effects

Serious skin reactions, including fatal cases, are very rare with NSAIDs and include exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk of these reactions occurs early in treatment (within the first month). The drug should be discontinued at the first signs of skin rash or other symptoms of hypersensitivity.

Renal effects

Indometacin should be used with caution in patients with renal disease (creatinine clearance < 30 ml/min) due to the potential for renal damage.

Hematological effects

The drug should be prescribed with caution in patients with a history of coagulation disorders, as it inhibits prostaglandin biosynthesis and affects platelet function.

Hepatic effects

Treatment with indometacin, as with other NSAIDs, may cause changes in liver function during long-term use, necessitating periodic monitoring of liver enzymes.

Infections and vaccinations

Due to the anti-inflammatory action of the drug, symptoms of acute inflammation may be masked in isolated cases; therefore, bacterial infection must be ruled out before initiating treatment. Caution should also be exercised when administering live vaccines.

Effect on fertility

In women of reproductive age, there is a risk of reversible suppression of fertility with use of the drug.

There is a risk of oligohydramnios and constriction of the fetal arterial duct in case of accidental or potential use during pregnancy or breastfeeding.

Psychiatric effects

Use with caution in patients with psychiatric disorders, depression, epilepsy, or Parkinsonism, as this may worsen the underlying condition.

Excipients

Lactose is included as an excipient in the tablet formulation. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Wheat starch is included as an excipient in the tablet formulation. It can be used in patients with celiac disease. Patients with wheat allergy (distinct from celiac disease) should not use this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

The drug is contraindicated during pregnancy.

Breastfeeding

Breastfeeding should be discontinued during treatment, as indometacin passes into breast milk in small amounts.

Ability to affect reaction speed when driving or operating machinery.

Indometacin Sopharma may cause adverse reactions (tinnitus, dizziness, somnolence, hearing and vision disturbances) that may impair attention and reflexes and affect the ability to drive vehicles or operate machinery.

Administration and Dosage

Administration method

The medication should be taken orally after meals. The tablet should be swallowed whole with sufficient amount of liquid.

Dosage

Adults and children aged 14 years and older

Initial dose – 25–50 mg (1–2 tablets) 2–4 times daily.

If the therapeutic effect is insufficient, the dose may be increased up to 150 mg (6 tablets) per day, divided into 3 doses. The maximum daily dose is 200 mg (8 tablets). During prolonged treatment, the daily dose should not exceed 75 mg (3 tablets).

Gout

To manage acute gout attacks, initiate treatment with an initial dose of 100 mg (4 tablets), followed by 50 mg (2 tablets) 3 times daily until pain subsides.

Elderly patients (aged 65 years and older)

There is an increased risk of adverse reactions. The lowest effective dose for the shortest possible duration is recommended. Patients should be monitored for possible gastrointestinal bleeding.

Treatment duration

Treatment should be conducted for the shortest duration and with the lowest effective dose possible to minimize the risk of adverse effects (see section «Special precautions for use»).

Children

Indomethacin is contraindicated in children under 14 years of age.

Overdose

Symptoms: nausea, vomiting, abdominal pain, severe headache, dizziness, memory impairment, confusion, disorientation, or lethargy. There have been reports of paresthesia, stiffness, and convulsions.

Treatment: symptomatic and supportive care.

Gastric lavage should be performed as soon as possible if the drug was recently ingested. If spontaneous vomiting does not occur, vomiting should be induced using ipecac preparations. After gastric emptying, 25 g or 50 g of activated charcoal may be administered. Depending on the patient's condition, continuous medical monitoring and nursing care may be required. The patient should remain under observation for several days, as gastrointestinal ulceration and bleeding are reported side effects of indomethacin. Administration of antacids may be beneficial. Indomethacin cannot be removed from the body by hemodialysis.

Side effects.

The most common adverse reactions are gastrointestinal disorders. Peptic ulcer, gastrointestinal perforation or bleeding (sometimes fatal) may occur, predominantly in elderly patients (see section «Special instructions»).

Blood and lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia, agranulocytosis, anemia (including hemolytic and aplastic), disseminated intravascular coagulation.

Immune system disorders: very rarely – bronchospasm, asthmatic attacks, anaphylactic or anaphylactoid reactions in allergic patients, fever, vasculitis, anaphylaxis, pulmonary edema, cerebral edema.

Metabolism and nutrition disorders: increased urea levels, weight gain, elevated liver enzymes, increased sweating, accelerated cartilage degeneration, fluid retention, hyperglycemia, glucosuria, hyperkalemia.

Nervous system disorders: excitation, convulsions, muscle weakness, involuntary muscle movements, psychiatric disorders, exacerbation of epilepsy and Parkinsonism, impaired consciousness, coma, dysarthria, aseptic meningitis, hallucinations, fear, dizziness, headache, somnolence, depression, fatigue, anxiety, weakness, difficulty concentrating; sensory disturbances including paresthesia; disorientation, insomnia, irritability, peripheral neuropathy, memory disorders, psychotic reactions.

Respiratory system disorders: nosebleeds, pulmonary subacute eosinophilia, dyspnea, acute respiratory distress.

Eye disorders: optic neuritis, corneal deposits and retinal damage, conjunctivitis, periorbital pain, diplopia, blurred vision.

Ear and labyrinth disorders: deafness, very rarely – hearing impairment, tinnitus.

Cardiac disorders: tachycardia, angina pectoris, palpitations, arrhythmias, edema, very rarely – worsening of heart failure associated with NSAID use.

Clinical studies and epidemiological data suggest that the use of certain NSAIDs (especially at high doses and during long-term treatment) may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section «Special instructions»).

Vascular disorders: arterial hypertension, hypotension, thrombotic microangiopathy.

Gastrointestinal disorders: anorexia, taste disturbances, gastroenteritis, erosive and ulcerative lesions, gastrointestinal bleeding and perforation, proctitis, intestinal strictures, gastritis, bleeding from the sigmoid colon or diverticulum, regional ileitis, cholestasis, nausea, vomiting, diarrhea, dyspepsia, constipation, abdominal pain, flatulence, melena, hematemesis, ulcerative stomatitis, exacerbation of ulcerative colitis, Crohn’s disease, exacerbation of pre-existing ulcers.

Hepatobiliary disorders: toxic hepatitis with or without jaundice, very rarely – fulminant hepatitis.

Skin and subcutaneous tissue disorders: hair loss, exacerbation of psoriasis, eczema, pruritus with or without rash, urticaria, petechiae, ecchymoses, very rarely – angioneurotic edema, exfoliative dermatitis, purpura, nodular erythema, multiform erythema, bullous rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Renal and urinary system disorders: impaired kidney function, edema, vaginal bleeding, breast enlargement and tenderness, gynecomastia, proteinuria, hematuria, nephrotic syndrome, interstitial nephritis, acute renal failure, papillary necrosis.

Laboratory and instrumental test abnormalities: elevated serum aminotransferase levels (ALT, AST), transient increase in bilirubin.

Shelf life. 5 years.

Storage conditions.

Keep out of reach of children.

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

Packaging.

30 tablets in a blister pack made of PVC film and aluminum foil. One blister pack per cardboard box.

Prescription status. Prescription only.

Manufacturers.

JSC "Sofarma".

JSC "VITAMINS".

Manufacturers' addresses and locations of their business activities.

JSC "Sofarma"

16 Iliensko Shose Str., Sofia, 1220, Bulgaria.

JSC "VITAMINS"

31 Uspenska Str., Uman, Cherkasy region, 20300, Ukraine.