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

Composition:

Active ingredient: ibuprofen;

One tablet contains 200 mg of ibuprofen calculated as 100% dry substance;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: hypromellose, copovidone, polyethylene glycols, caprylocaproyl polyoxiglycerides, dextrin-containing excipients, titanium dioxide (E 171), ponceau 4R (E 129).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round-shaped film-coated tablets of pink color, with a biconvex surface. A cross-section reveals a core surrounded by a layer of the film coating.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. ATC Code M01AE01.

Pharmacological Properties.

Pharmacodynamics.

Ibuprofen is a derivative of phenylpropionic acid that exerts anti-inflammatory, analgesic, and antipyretic effects. Its mechanism of action is associated with non-selective inhibition of cyclooxygenase (COX-1 and COX-2) activity—the key enzyme in arachidonic acid metabolism, which is a precursor of prostaglandins playing a central role in the pathogenesis of inflammation, pain, and fever. The analgesic effect is due to both peripheral (indirectly, via inhibition of prostaglandin synthesis) and central mechanisms, the latter being mediated by suppression of prostaglandin synthesis in the central nervous system (CNS). Ibuprofen reduces platelet aggregation.

Pharmacokinetics.

After oral administration, ibuprofen is almost completely absorbed from the gastrointestinal tract. Maximum blood concentration is reached within 1–2 hours. Concomitant food intake slows the rate of absorption in the gastrointestinal tract. The drug is highly bound to plasma proteins—90–95%. It slowly penetrates into the joint cavity but is retained in the synovial fluid, achieving higher concentrations there than in blood plasma. Metabolism of ibuprofen occurs in the liver. The elimination half-life is 2–3 hours. Approximately 80% of the administered dose is excreted in urine, primarily as metabolites (10% unchanged); the remaining 20% is excreted via the intestine, also in the form of metabolites.

Clinical characteristics.

Indications.

Symptomatic treatment of headache, toothache, dysmenorrhea, neuralgia, back pain, joint and muscle pain, rheumatic pain, as well as symptoms of cold and flu.

Contraindications.

Hypersensitivity to ibuprofen (or to any other component of the drug) and to other nonsteroidal anti-inflammatory drugs (NSAIDs).
Hypersensitivity reactions (e.g., bronchial asthma, rhinitis, angioedema, or urticaria) previously observed after administration of ibuprofen, acetylsalicylic acid (aspirin), or other NSAIDs.
History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.
Active or recurrent peptic ulcer/gastrointestinal bleeding (two or more distinct episodes of peptic ulcer or bleeding in the past).
Severe impairment of kidney and/or liver function, severe heart failure (NYHA class IV).
Cerebrovascular or other bleeding conditions.
Coagulation disorders or blood clotting abnormalities.
Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).
Active inflammatory bowel disease.
Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Caution should be exercised when using NSAIDs in combination with other medicinal products that may increase the risk of gastrointestinal ulcers, gastrointestinal bleeding, or worsening of kidney function.

Ibuprofen, like other NSAIDs, should not be used in combination with:

acetylsalicylic acid: because this may increase the risk of adverse reactions, except in cases where acetylsalicylic acid (dose not exceeding 75 mg per day) has been prescribed by a physician.

Experimental data indicate that concomitant use of ibuprofen may competitively inhibit the effect of low-dose aspirin on platelet aggregation. Although there is uncertainty regarding the extrapolation of these data to clinical practice, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose aspirin. With occasional, non-regular use of ibuprofen, such a clinically significant effect is considered unlikely;

other NSAIDs, including selective COX-2 inhibitors: due to the increased risk of adverse reactions.

Ibuprofen should be used with caution in combination with:

corticosteroids: increased risk of gastrointestinal ulceration or gastrointestinal bleeding;

antihypertensive agents (ACE inhibitors and angiotensin II antagonists) and diuretics: NSAIDs may attenuate the effect of diuretics and other antihypertensive drugs. In some patients with impaired kidney function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II antagonist and drugs that inhibit cyclooxygenase may lead to further deterioration of kidney function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed with caution, especially in elderly patients. If long-term treatment is necessary, adequate hydration of the patient should be ensured, and monitoring of kidney function should be considered at the start of combination therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs;

anticoagulants (e.g., warfarin): NSAIDs may enhance their effects;

antiplatelet agents and serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding;

cardiac glycosides (digoxin): possible worsening of heart failure, reduced glomerular filtration rate, and increased plasma levels of cardiac glycosides;

lithium preparations: reduced elimination of lithium occurs;

methotrexate: potential increase in methotrexate plasma levels;

cyclosporine, tacrolimus: increased risk of nephrotoxicity;

mifepristone: NSAIDs should not be used earlier than 8–12 days after mifepristone administration, as they reduce its efficacy;

zidovudine: increased risk of hematological toxicity is known. There is information about increased risk of hemarthrosis and hematoma in HIV-infected individuals with hemophilia receiving concomitant treatment with zidovudine and ibuprofen;

quinolone antibiotics: in patients receiving NSAIDs and quinolone antibiotics simultaneously, an increased risk of seizures may occur;

aminoglycosides: possible reduction in their excretion;

probenecid, sulfinpyrazone: concomitant use with ibuprofen may cause delayed elimination of the latter from the body;

cholestyramine: simultaneous administration may reduce the gastrointestinal absorption of ibuprofen. Clinical significance is unknown;

antidepressants, clopidogrel, prasugrel, heparin, pentoxifylline, herbal extracts (e.g., Ginkgo biloba): possible increased risk of bleeding when used with NSAIDs, including ibuprofen;

CYP2C9 inhibitors: possible pharmacokinetic interaction: increased exposure (prolonged effect) of ibuprofen (a CYP2C9 substrate). A reduction in the dose of ibuprofen should be considered when used concomitantly with potent CYP2C9 inhibitors (such as voriconazole, fluconazole), especially at high doses of ibuprofen;

aliskiren, α-adrenergic blockers, β-adrenergic blockers, calcium channel blockers, clonidine, methyldopa, nitrates: NSAIDs may counteract their hypotensive effects;

sulfonylurea derivatives and phenytoin: possible potentiation of effects.

Special precautions for use.

Adverse effects associated with the use of ibuprofen and nonsteroidal anti-inflammatory drugs (NSAIDs) in general can be minimized by using the lowest effective dose required to control symptoms, for the shortest possible duration.

Elderly patients have an increased risk of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

Respiratory effects

Patients suffering from bronchial asthma, allergic rhinitis, or chronic bronchitis may experience particularly severe reactions to the drug (asthma attacks, swelling of the nasal mucosa).

Other NSAIDs

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Systemic lupus erythematosus and mixed connective tissue disease

Ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue disease due to an increased risk of aseptic meningitis. Aseptic meningitis has also been reported in patients without these chronic conditions. Cases of aseptic meningitis have been reported during ibuprofen therapy. Although this effect is more likely in patients with systemic lupus erythematosus or mixed connective tissue disorders, such cases have also been reported in some patients without chronic diseases; therefore, this should be considered when using this medicinal product.

Cardiovascular and cerebrovascular effects

Ibuprofen should be used with caution in patients with a history of arterial hypertension, or moderate to severe heart failure with fluid retention or edema associated with NSAID use.

Epidemiological data suggest that the use of ibuprofen, particularly at high doses (2400 mg/day) and over prolonged periods, may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke.

Overall, results from epidemiological studies do not indicate that low-dose ibuprofen (e.g., ≤1200 mg daily) is associated with an increased risk of arterial thrombotic events, including myocardial infarction. Long-term treatment with NSAIDs should be prescribed to patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful assessment of the benefit-risk ratio.

Patients with uncontrolled arterial hypertension, congestive heart failure (NYHA class II–III), established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful clinical evaluation. High doses (2400 mg/day) should be avoided.

Careful clinical assessment is also required before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2400 mg/day) are required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen therapy. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Effects on kidneys/liver

Ibuprofen should be used with caution in patients with kidney or liver disease, particularly when used concomitantly with diuretics, as prostaglandin inhibition may lead to fluid retention and further deterioration of renal function. These patients should receive the lowest possible dose of ibuprofen, and renal function should be monitored regularly. Adequate fluid intake should be ensured in cases of dehydration. There is a risk of renal impairment in dehydrated children (aged 6 years and older) and adolescents.

Prolonged use of analgesics, especially combinations of different painkillers, may lead to chronic kidney damage with a risk of renal failure (analgesic nephropathy). The highest risk of this reaction occurs in elderly patients, patients with renal, cardiac, or hepatic impairment, and those receiving diuretics or angiotensin-converting enzyme (ACE) inhibitors. After discontinuation of NSAID therapy, renal function typically returns to the pre-treatment state.

Like other NSAIDs, ibuprofen may cause a slight, temporary increase in certain liver function parameters, as well as a significant increase in AST and ALT levels. Treatment should be discontinued if substantial increases in these parameters occur.

During prolonged ibuprofen therapy, regular monitoring of liver function, kidney function, and hematological parameters/blood count is necessary.

Surgical procedures

Caution should be exercised immediately after major surgical procedures.

Effect on female fertility

Limited data suggest that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Gastrointestinal (GI) effects

Nonsteroidal anti-inflammatory drugs should be prescribed with caution to patients with a history of ulcerative colitis or Crohn’s disease.

Cases of gastrointestinal bleeding, ulcers, or perforation, which may be fatal, have been reported during treatment with all NSAIDs, occurring at any stage of therapy, regardless of prior warning symptoms or gastrointestinal disorders in the patient's history.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should start treatment with the lowest dose. These patients, as well as those requiring concomitant use of low-dose aspirin or other drugs that may increase gastrointestinal risk, should be considered for combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors).

Patients with a history of gastrointestinal toxicity, especially elderly patients, should be advised to report any unusual gastrointestinal symptoms (particularly gastrointestinal bleeding), especially at the beginning of treatment.

Ibuprofen should be prescribed cautiously to patients taking medications that may increase the risk of gastrointestinal ulcers or bleeding, such as oral corticosteroids, anticoagulants (warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents like aspirin.

The development of gastrointestinal ulcers or gastrointestinal bleeding in patients receiving ibuprofen requires immediate discontinuation of treatment with this drug.

Serious skin adverse reactions (SSARs)

Serious skin adverse reactions (SSARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported during ibuprofen use (see section "Adverse reactions"). Most of these reactions occur within the first month of treatment.

If signs or symptoms suggestive of these reactions appear, ibuprofen should be discontinued immediately, and alternative treatment should be considered (if necessary).

Prolonged use of analgesics may lead to worsening of headaches, which should not be treated with higher doses of this drug. In such cases, patients should consult a physician and discontinue treatment. Medication-overuse headache should be considered in patients suffering from frequent or daily headaches despite (or due to) regular use of headache medications.

Masking symptoms of underlying infections

Ibuprofen may mask symptoms of infectious disease, potentially delaying the initiation of appropriate treatment and thereby complicating the course of the illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When ibuprofen is used for fever or pain relief during infection, monitoring of the infectious condition is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

In some cases, varicella may lead to severe skin and soft tissue infections. At present, the potential negative impact of NSAIDs on these infections cannot be excluded; therefore, the use of ibuprofen is not recommended in cases of varicella.

Ibuprofen, like other NSAIDs, may affect platelet aggregation and may be indicated for the prevention of thrombosis.

Ibuprofen may mask signs of infection.

Porphyrin metabolism

Caution should be exercised in patients with inherited disorders of porphyrin metabolism (e.g., acute intermittent porphyria).

Each tablet contains approximately 0.81 mg of sodium from croscarmellose sodium, which should be considered when prescribing the drug to patients on a low-sodium diet.

Use during pregnancy or breastfeeding

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following the use of prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryonic/fetal mortality. In addition, increased frequencies of various developmental abnormalities, including cardiovascular malformations, have been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of pregnancy, the use of ibuprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of ductus arteriosus constriction have been reported after treatment during the second trimester, most of which resolved after stopping treatment. Therefore, ibuprofen should not be used during the first two trimesters of pregnancy, except when absolutely necessary.

If ibuprofen is used by a woman trying to conceive or during the first or second trimester of pregnancy, the lowest possible dose should be used for the shortest possible duration. Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ibuprofen for several days starting from the 20th gestational week. Ibuprofen use should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

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

to the fetus:
- cardiopulmonary toxicity (characterized by premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
- impaired renal function, which may progress to renal failure associated with oligohydramnios;
to the mother at the end of pregnancy and the newborn:
- possible prolongation of bleeding time, antiplatelet effect, which may occur even at very low doses;
- inhibition of uterine contractions, leading to delayed or prolonged labor.

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

In limited studies, ibuprofen has been detected in breast milk at very low concentrations; therefore, it is unlikely to have a negative effect on the breastfed infant.

Ability to influence reaction speed when driving or operating machinery

When used according to recommended doses and treatment duration, the drug does not affect reaction speed when driving or operating machinery. Patients who experience dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving or operating machinery.

Dosage and Administration

For short-term oral use only. Tablets should be swallowed with water, not chewed. During short-term use, if symptoms persist or worsen, the patient should consult a physician.

The minimum effective dose should be used for the shortest duration necessary to treat pain symptoms – no more than 5 days, and no more than 3 days for cold symptoms (see section "Special Precautions"). If treatment longer than 5 days is required (if symptoms do not resolve or worsen), the patient should consult a physician.

The drug is indicated for adults and children with body weight over 20 kg (aged 6 years and older). The usual dosage is 20 to 30 mg/kg of body weight per day. The maximum daily dose should not exceed 30 mg/kg of body weight.

For children with body weight between 20 and 30 kg (aged 6 to 11 years): 200 mg (1 tablet), with repeat doses as needed every 6 hours, but not exceeding 600 mg (3 tablets) per day.

For adults and children with body weight over 30 kg: 200–400 mg (1–2 tablets) every 4–6 hours as needed. Do not exceed 6 tablets within 24 hours.

Elderly patients do not require special dosage adjustments.

Patients with mild to moderate renal or hepatic impairment do not require dose adjustment.

Children

Do not use in children under 6 years of age or with body weight less than 20 kg.

Overdose

Most reported cases of overdose were asymptomatic. Symptoms may occur with ibuprofen doses exceeding 80–100 mg/kg. Administration of ibuprofen to children in doses exceeding 400 mg/kg may cause symptoms of intoxication. In adults, dose effects are less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms
Symptoms of overdose typically appear within 4 hours after ingestion. Possible manifestations of ibuprofen overdose include: headache, dizziness, lethargy, loss of consciousness, disorientation, agitation, tinnitus, weakness, epigastric pain, gastrointestinal bleeding, diarrhea, nausea, and vomiting. In more severe poisoning, toxic CNS effects may occur, such as drowsiness, nystagmus, visual disturbances, agitation, disorientation, or coma, and seizures. Severe intoxication may lead to hyperkalemia and metabolic acidosis, acute renal failure, liver damage, arterial hypotension, respiratory depression, and cyanosis. In patients with bronchial asthma, an asthma exacerbation may occur.

Treatment
Treatment is symptomatic and should include maintaining airway patency and monitoring vital signs until stabilization. After ingestion of a small amount of the drug (less than 50 mg/kg of ibuprofen), drinking water is recommended to minimize gastrointestinal disturbances. Gastric lavage is indicated within 1 hour after ingestion of a potentially toxic dose of ibuprofen; activated charcoal should be administered. Electrolyte imbalances should be corrected as needed. Intravenous diazepam is indicated for frequent or prolonged seizures. Bronchodilators should be used in patients with bronchial asthma. Immediate medical attention is required. There is no specific antidote.

Patients should be monitored for at least 4 hours. Renal and hepatic function should be monitored. Hemodialysis is ineffective.

Adverse reactions.

The following list of adverse reactions refers to those observed with the use of ibuprofen at over-the-counter doses during short-term treatment. Additional adverse effects may occur during treatment of chronic conditions or with long-term therapy.

The most commonly observed adverse reactions are those affecting the gastrointestinal tract. Adverse reactions are mostly dose-dependent; in particular, the risk of gastrointestinal bleeding depends on the dose and duration of treatment.

Blood and lymphatic system disorders: blood dyscrasias (thrombocytopenia, agranulocytosis, neutropenia, aplastic anemia, hemolytic anemia, decreased hemoglobin and hematocrit, leukopenia, pancytopenia, eosinophilia), which may occur during prolonged treatment. Initial symptoms include: fever, sore throat, oral mucosal ulceration, flu-like symptoms, severe fatigue, unexplained bleeding, and bruising.

Immune system disorders: hypersensitivity reactions¹, such as anaphylaxis, bronchial asthma, bronchospasm, dyspnea, pruritus, including urticaria, purpura, Quincke's edema, facial, tongue, or laryngeal swelling, serum sickness, lupus-like syndrome, Henoch-Schönlein purpura.

Nervous system disorders: dizziness, sleep disturbances, somnolence, disturbances in visual and auditory perception, optic neuritis, headache, irritability, nervousness, convulsions, paresthesia; aseptic meningitis².

Cardiovascular system disorders: edema, arterial hypotension, tachycardia, arrhythmias (sinus tachycardia, sinus bradycardia), arterial hypertension, heart failure. The use of ibuprofen, particularly at high doses (2400 mg/day) and over prolonged periods, may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke, and Kounis syndrome (frequency unknown).

Gastrointestinal disorders: nausea, anorexia, vomiting, epigastric discomfort, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, exacerbation of ulcerative colitis and Crohn's disease, melena, hematemesis; possible development of erosive-ulcerative gastrointestinal lesions (ulcerative stomatitis, gastric ulcer, perforation, gastrointestinal bleeding, which may be fatal), gastritis, pancreatitis.

Hepatobiliary system disorders: liver function abnormalities, elevated serum transaminases, hepatic failure, hepatitis, hepatonecrosis, hepatorenal syndrome, jaundice.

Skin and subcutaneous tissue disorders: serious skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) (very rare), skin rashes; drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP) (frequency unknown).

Renal and urinary system disorders: possible renal function impairment leading to hyperkalemia, hyperuricemia, azotemia, toxic nephropathy in various forms, including interstitial nephritis, cystitis, hematuria, nephrotic syndrome, papillary necrosis, tubular necrosis, glomerulonephritis, acute renal failure, decreased creatinine clearance, reduced urine output (oliguria), polyuria, edema.

Sensory organs disorders: tinnitus, hearing loss, blurred vision, amblyopia, color vision disturbances, conjunctivitis, diplopia, cataract.

Psychiatric disorders: depression, anxiety, psychomotor agitation, emotional lability, confusion, hallucinations.

Other: malaise, fatigue, dry eyes and oral mucosa, gingival ulcers, rhinitis, decreased appetite, gynecomastia, alveolitis, acidosis, alopecia, photosensitivity reactions.

Description of selected adverse reactions

1 There have been reports of hypersensitivity reactions following ibuprofen treatment. These include: non-specific allergic reactions and anaphylaxis, respiratory tract reactions such as bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea, various skin disorders including rashes of different types, pruritus, urticaria, purpura, angioneurotic edema, and less frequently, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

2 The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, available data on aseptic meningitis associated with NSAID use suggest a hypersensitivity reaction (based on temporal relationship to drug intake and resolution of symptoms after drug discontinuation). In particular, during ibuprofen treatment, isolated cases of aseptic meningitis symptoms (such as nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) have been observed in patients with pre-existing autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).

Shelf life. 3 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, 5 blisters per carton.

Availability. Over-the-counter.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of business activity.

17 Myru Street, Kyiv, 03134, Ukraine.