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

Composition:

Active ingredient: ibuprofen;

1 tablet contains 200 mg of ibuprofen;

Excipients: potato starch, magnesium stearate, povidone, Opadry II Pink 85F34660 (a mixture of substances: polyvinyl alcohol, titanium dioxide E 171, polyethylene glycol 3350, talc, carmoisine E 122, sunset yellow FCF E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: round, film-coated tablets with a biconvex surface, light pink to dark pink in color. When examined under a magnifying glass, the cross-section reveals a core surrounded by a single continuous layer.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and anti-rheumatic drugs. Propionic acid derivatives. ATC code M01AE01.

Pharmacological Properties

Pharmacodynamics

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a derivative of propionic acid, which has demonstrated efficacy by inhibiting the synthesis of prostaglandins. In humans, ibuprofen reduces pain associated with inflammation, swelling, and fever. It exerts pronounced analgesic, antipyretic, and anti-inflammatory effects. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose aspirin (acetylsalicylic acid) on platelet aggregation when these drugs are used concomitantly. Some pharmacodynamic studies have shown that administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release aspirin (acetylsalicylic acid) (81 mg) was associated with reduced effect of aspirin (acetylsalicylic acid) on thromboxane formation or platelet aggregation. Although there is uncertainty regarding extrapolation of these data to clinical settings, the possibility cannot be excluded that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. With occasional (non-regular) use of ibuprofen, such a clinically significant effect is considered unlikely.

Pharmacokinetics

After administration, ibuprofen is rapidly absorbed from the gastrointestinal tract and binds to plasma proteins.

Maximum plasma concentration of the active substance is achieved within 45 minutes after administration on an empty stomach, and in synovial fluid – within 3 hours after administration. When the drug is taken with food, peak levels are observed within 1–2 hours after administration. Ibuprofen is metabolized in the liver and excreted by the kidneys either unchanged or as metabolites. The elimination half-life is approximately 2 hours.

In elderly patients, no significant differences in pharmacokinetic profile have been observed.

Clinical characteristics.

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

Contraindications.

Hypersensitivity to ibuprofen or to any of the other components of the medicinal product.
Allergic reactions (e.g. bronchial asthma, rhinitis, Quincke's edema or urticaria) following the administration of ibuprofen, acetylsalicylic acid (aspirin), or other nonsteroidal anti-inflammatory drugs (NSAIDs) in medical history.
Active peptic ulcer or gastrointestinal bleeding, or history of recurrent episodes (two or more episodes of confirmed peptic ulcer or bleeding).
History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.
Severe heart failure (NYHA class IV), severe hepatic impairment, or severe renal impairment.
Third trimester of pregnancy.
Active inflammatory bowel disease.
Hemorrhagic diathesis or other disorders of blood coagulation.

Interaction with other medicinal products and other forms of interaction.

In general, 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 renal function.

Ibuprofen, like other nonsteroidal anti-inflammatory drugs (NSAIDs), should not be used in combination with:

acetylsalicylic acid (aspirin), as this increases the risk of adverse reactions, except when aspirin (dose not exceeding 75 mg per day) has been prescribed by a physician.

Experimental data indicate that concomitant administration of ibuprofen may competitively inhibit the effect of low-dose aspirin (acetylsalicylic acid) on platelet aggregation. Although uncertainty exists regarding extrapolation of these data to clinical settings, the possibility that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. Such a clinically significant effect is considered unlikely with occasional, non-systematic use of ibuprofen.

other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors. Concomitant use of two or more NSAIDs should be avoided, as this increases the frequency of adverse effects.

Ibuprofen should be used with caution in combination with the following medicinal products:

Anticoagulants: nonsteroidal anti-inflammatory drugs may enhance the effect of anticoagulants such as warfarin.

Antihypertensive agents (ACE inhibitors and angiotensin II antagonists) and diuretics: NSAIDs may reduce the therapeutic effect of these drugs. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II antagonist with drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients receiving coxibs concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, such combinations should be used with caution, particularly in elderly patients. If treatment is necessary, adequate hydration of the patient should be ensured, and monitoring of renal function should be considered at the start of combined therapy and periodically thereafter. Diuretics increase the risk of nephrotoxic effects of NSAIDs.

Corticosteroids: increase the risk of gastrointestinal ulceration and bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increase the risk of gastrointestinal bleeding.

Cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of glycosides.

Lithium and methotrexate: evidence suggests a potential increase in plasma levels of lithium and methotrexate.

Cyclosporine: increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be taken within 8–12 days after administration of mifepristone, as this may reduce the efficacy of mifepristone.

Tacrolimus: increased risk of nephrotoxicity when NSAIDs are used concomitantly with tacrolimus.

Zidovudine: increased risk of hematological toxicity when zidovudine is used concomitantly with NSAIDs. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

Quinolone antibiotics: concomitant use of ibuprofen and quinolone antibiotics increases the risk of seizures.

Special precautions for use.

Adverse effects associated with ibuprofen can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

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

Respiratory system effects.

Bronchospasm may occur in patients with bronchial asthma, patients with allergic disorders, and patients with a history of bronchospasm.

Other NSAIDs.

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided, as this increases the risk of adverse reactions.

Systemic lupus erythematosus and mixed connective tissue disease.

Ibuprofen should be used with caution in patients with systemic lupus erythematosus and mixed connective tissue disease due to an increased risk of aseptic meningitis.

Cases of aseptic meningitis have been reported during ibuprofen therapy. Although this effect is more likely in patients with systemic lupus erythematosus and other connective tissue disorders, 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.

Caution should be exercised when initiating treatment in patients with a history of hypertension and/or heart failure (medical consultation is required), as fluid retention, hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs.

The use of ibuprofen, particularly at high doses (2400 mg daily) and with long-term treatment, slightly increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). However, there is no evidence of an association between low-dose ibuprofen (e.g., less than 1200 mg daily) and increased risk of myocardial infarction.

Patients with uncontrolled hypertension, congestive heart failure (NYHA class II-III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful assessment of the clinical condition. High doses (2400 mg per day) should be avoided.

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

Cases of Kounis syndrome have been reported in patients receiving ibuprofen therapy. Kounis syndrome is characterized by cardiovascular symptoms due to coronary artery spasm resulting from an allergic or hypersensitivity reaction, which may lead to myocardial infarction.

Effects on kidneys/liver.

Caution is advised in patients with renal impairment due to the possibility of worsening renal function. 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 failure in dehydrated children (from 6 years of age) and adolescents.

In general, chronic 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, heart, or liver failure, and in those receiving diuretics or ACE inhibitors. After discontinuation of NSAID therapy, renal function usually returns to the pre-treatment state.

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

During prolonged ibuprofen use, liver function, kidney function, and hematological parameters/blood counts should be monitored regularly.

Effect on female fertility.

There is insufficient evidence that medicinal products which inhibit cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Gastrointestinal tract effects.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as their condition may worsen.

Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported during NSAID therapy at any stage of treatment, regardless of prior warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, or ulcers increases with higher NSAID doses, particularly in patients with a history of peptic ulcer disease, especially complicated by bleeding or perforation, and in elderly patients. Elderly patients have an increased risk of serious adverse effects. These patients should start treatment with the lowest doses. For such patients, and for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) is recommended.

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

Headache may occur with long-term, high-dose use of analgesics and cannot be treated by increasing the dose of the drug. Prolonged use of any analgesic for headache treatment may worsen the condition. 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 because of) regular use of headache medications.

The drug should be used with caution in patients receiving concomitant therapy with drugs that increase the risk of ulcers or bleeding, particularly oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid).

In case of gastrointestinal bleeding or ulceration in patients receiving ibuprofen, treatment should be discontinued immediately.

Skin and subcutaneous tissue reactions.

Very rarely, severe skin adverse reactions have occurred with ibuprofen use, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis, which may be life-threatening or fatal (see section "Adverse reactions"). These reactions usually occur within the first month of treatment.

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

In rare cases, chickenpox may lead to severe skin and soft tissue infections. At present, a negative influence of NSAIDs on the course of these infections cannot be ruled out; therefore, the use of ibuprofen is not recommended in cases of chickenpox.

Masking symptoms of underlying infections.

Ibuprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thus complicating the disease course. This has been observed in bacterial community-acquired pneumonia and bacterial complications of chickenpox. 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.

The medicinal product contains the dyes carmoisine E 122 and sunset yellow FCF E 110, which may cause allergic reactions.

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 after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

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

From the 20th week of pregnancy, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of fetal ductus arteriosus constriction have been reported after ibuprofen use in the second trimester, which in most cases resolved after treatment cessation.

Use of the drug should be avoided during the first and second trimesters of pregnancy. NSAIDs should not be used during the first and second trimesters unless the potential benefit to the patient outweighs the potential risk to the fetus. Women attempting to conceive, as well as during the first and second trimesters of pregnancy, should use the lowest possible dose for the shortest possible duration. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be advisable if ibuprofen exposure occurred over several days starting from the 20th gestational week. Ibuprofen treatment should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

All prostaglandin synthesis inhibitors used during the third trimester of pregnancy pose risks:

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

The drug is contraindicated during the third trimester of pregnancy (see section "Contraindications").

In limited studies, ibuprofen was detected in breast milk at very low concentrations; therefore, it is unlikely to adversely affect 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.

Method of Administration and Dosage

For short-term oral use only. Tablets should be taken with water, without chewing.

The lowest effective dose for the shortest duration necessary to relieve symptoms should be used (see section "Special Precautions"). If treatment longer than 5 days is required (if symptoms persist or worsen), medical advice should be sought.

The drug is indicated for adults and children with body weight above 20 kg (aged 6 years and older). The recommended daily dose is 20–30 mg/kg body weight. Do not exceed 30 mg/kg body weight per day.

Children with body weight from 20 to 30 kg (aged 6 to 11 years): 200 mg (1 tablet) per dose. Repeat the dose every 6 hours if needed, but do not exceed 600 mg (3 tablets) per day.

Adults and children with body weight above 30 kg: 200–400 mg (1–2 tablets) per dose. Repeat the dose every 4–6 hours if needed. Do not exceed 1200 mg (6 tablets) within 24 hours.

Elderly patients do not require special dosage adjustment.

Children. Do not use in children with body weight below 20 kg or aged under 6 years.

Overdose.

Most reported cases of overdose were asymptomatic. Risk of symptoms occurs at ibuprofen doses exceeding 80–100 mg/kg.

Administration of ibuprofen to children at doses above 400 mg/kg may cause symptoms of intoxication. In adults, the dose effect is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms. Symptoms of overdose typically appear within 4 hours after ingestion.
In most patients, ingestion of clinically significant amounts of nonsteroidal anti-inflammatory drugs causes only nausea, vomiting, epigastric pain, or very rarely diarrhea. Other possible symptoms include tinnitus, headache, and gastrointestinal bleeding. In more severe poisoning, toxic effects on the central nervous system may occur, such as vertigo, dizziness, lethargy, drowsiness, occasionally nervous agitation, ataxia, disorientation, or coma. Seizures may occasionally occur. In more severe cases, hyperkalemia, metabolic acidosis, and prolonged prothrombin time/INR (International Normalized Ratio) may develop, likely due to interaction with circulating blood coagulation factors. Rarely, moderate to severe symptoms have been observed, such as acute renal failure, liver damage, hypotension, hypothermia, cyanosis, dyspnea/acute respiratory distress syndrome, and transient episodes of apnea (in children after ingestion of large amounts of the drug). In patients with bronchial asthma, asthma exacerbation may occur. Nystagmus, visual disturbances, and loss of consciousness are also possible.

Treatment. There is no specific antidote. Treatment is symptomatic and supportive, including maintaining airway patency and monitoring cardiac function and vital signs until the patient's condition normalizes. After ingestion of small amounts of the drug (less than 50 mg/kg of ibuprofen), drinking water is recommended to minimize gastrointestinal disturbances. Oral administration of activated charcoal or gastric lavage is recommended within 1 hour after ingestion of a potentially toxic dose. If ibuprofen has already been absorbed, alkalinizing agents may be used to enhance urinary excretion of acidic ibuprofen. The benefit of measures such as forced diuresis, hemodialysis, and hemoperfusion has not been proven, as ibuprofen is highly protein-bound. In case of frequent or prolonged muscle spasms, diazepam or lorazepam should be administered intravenously. In cases of bronchial asthma, bronchodilators should be used. Seek immediate medical attention.

Adverse Reactions

The adverse reactions listed below were observed during short-term use of ibuprofen at over-the-counter doses. Other adverse reactions may occur during treatment of chronic conditions or with prolonged use. The most commonly observed adverse reactions were gastrointestinal in nature. Adverse reactions are generally dose-dependent; in particular, the risk of gastrointestinal bleeding depends on both dose and duration of treatment.

Adverse reactions associated with the use of ibuprofen are classified by organ systems and frequency. Frequency is defined as follows: very common – (≥1/10); common – (≥1/100 to <1/10); uncommon – (≥1/1000 to <1/100); rare – (≥1/10,000 to <1/1000); very rare – (<1/10,000); frequency not known (cannot be estimated from available data). Within each frequency group, reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders:

Very rare: blood disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms may include fever, sore throat, oral ulcers, flu-like symptoms, severe fatigue, unexplained bleeding, and unexplained bruising.

Immune system disorders:

Hypersensitivity reactions^1; uncommon: urticaria and pruritus; very rare: severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal edema, dyspnea, tachycardia, hypotension (anaphylactic reaction, angioneurotic edema, or severe shock); frequency not known: respiratory tract reactivity, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea.

Nervous system disorders:

Uncommon: headache; very rare: aseptic meningitis^2.

Cardiac disorders:

Frequency not known: heart failure, edema, Coxsackie syndrome.

Clinical trial data and epidemiological evidence suggest that the use of ibuprofen, especially at high doses (2400 mg daily) and during long-term treatment, may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Vascular disorders:

Frequency not known: arterial hypertension.

Gastrointestinal disorders:

Uncommon: abdominal pain, nausea, dyspepsia; rare: diarrhea, flatulence, constipation, and vomiting; very rare: peptic ulceration of the stomach and duodenum, perforations, or gastrointestinal hemorrhage, melena, hematemesis, sometimes fatal (particularly in elderly patients), ulcerative stomatitis, gastritis;

Frequency not known: exacerbation of colitis and Crohn's disease.

Hepatic disorders:

Very rare: liver function abnormalities.

Skin and subcutaneous tissue disorders:

Uncommon: various skin rashes;

Very rare: severe skin reactions, including Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, and toxic epidermal necrolysis;

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis, photosensitivity reactions.

Respiratory, thoracic and mediastinal disorders:

Frequency not known: respiratory tract reactivity, including asthma, bronchospasm, or dyspnea.

Renal and urinary disorders:

Very rare: acute renal impairment, papillary necrosis, particularly with prolonged use, associated with increased serum urea levels, and edema; frequency not known: renal failure.

Investigations:

Very rare: decreased hemoglobin levels.

Description of selected adverse reactions.

Reports exist of hypersensitivity reactions following ibuprofen treatment. These include (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactions, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea, or (c) 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).
The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, available data on aseptic meningitis associated with NSAIDs suggest a hypersensitivity reaction (based on temporal association with drug intake and resolution of symptoms after discontinuation). In particular, 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 (e.g., systemic lupus erythematosus, mixed connective tissue disease) during ibuprofen treatment.

Reporting of suspected adverse reactions after drug registration is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

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

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister, 1, 2, 3, 4, 5, or 6 blisters per carton.

7 tablets in a blister, 1 or 2 blisters per carton.

Availability. Over-the-counter.

Manufacturer.

JSC "VITAMINS".

Manufacturer's address.

31 Uspenska Street, Uman, Cherkasy Oblast, 20300, Ukraine.

Marketing Authorization Holder.

JSC "VITAMINS".

Address of the Marketing Authorization Holder and/or its representative.

31 Uspenska Street, Uman, Cherkasy Oblast, 20300, Ukraine.