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

Composition:

Active substance: ibuprofen;

1 capsule contains 400 mg of ibuprofen;

Excipients: potato starch, hypromellose, colloidal anhydrous silicon dioxide, crospovidone, magnesium stearate; the capsule shell contains titanium dioxide (E 171), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: white hard gelatin capsules. The capsule contents are a mixture containing granules and powder ranging from white to almost white. The presence of particle agglomerates is acceptable.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. ATC code M01AE01.

Pharmacological Properties

Pharmacodynamics

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a propionic acid derivative, which exerts analgesic, antipyretic, and anti-inflammatory effects by inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively reduce the effect of low-dose acetylsalicylic acid on platelet aggregation when these drugs are administered concomitantly. In some pharmacodynamic studies, administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) resulted in reduced effects of acetylsalicylic acid on thromboxane production or platelet aggregation. Although the clinical relevance of these findings is not fully established, there remains a possibility that regular, long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. Such a clinically significant interaction is considered unlikely with occasional, intermittent use of ibuprofen.

Pharmacokinetics

Ibuprofen is well absorbed in the gastrointestinal tract and binds to plasma proteins.

Maximum serum concentration (Cmax) is reached within 45 minutes after administration (when taken on an empty stomach). When the drug is taken with food, Cmax is observed 1–2 hours after intake. Ibuprofen is metabolized in the liver and excreted by the kidneys either unchanged or as metabolites. The elimination half-life is approximately 2 hours. No significant differences in pharmacokinetic profile have been observed in elderly patients.

Clinical characteristics.

Indications.

Symptomatic treatment of headache, including migraine, 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 component of the medicinal product.
History of hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) following administration of ibuprofen, acetylsalicylic acid, or other NSAIDs.
Active peptic ulcer/gastrointestinal bleeding or history of recurrent episodes (two or more confirmed episodes of peptic ulcer or bleeding).
History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
Severe heart failure [NYHA (New York Heart Association) Class IV], severe hepatic and/or renal impairment.
Third trimester of pregnancy.
Cerebrovascular or other bleeding disorders.
Disorders of blood coagulation or haemostasis.

Interaction with other medicinal products and other forms of interaction.

Ibuprofen, as well as other NSAIDs, should not be used in combination with the following medicinal products:

Acetylsalicylic acid — risk of adverse reactions may increase. Should be used only when acetylsalicylic acid (in doses not exceeding 75 mg per day) has been prescribed by a physician.

Data indicate that concomitant use of ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. Although the possibility of extrapolating these data to clinical situations is uncertain, it cannot be excluded that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Such a clinically significant effect is considered unlikely with occasional, non-systematic use of ibuprofen.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors.

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

Anticoagulants. NSAIDs may enhance the therapeutic effect of anticoagulants such as warfarin.
Antihypertensive agents (ACE inhibitors and angiotensin II antagonists) and diuretics. NSAIDs may attenuate the effects of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed with caution, especially in elderly patients. If prolonged treatment is necessary, adequate hydration of the patient should be ensured, and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.
Corticosteroids. Increase the risk of gastrointestinal ulcers and bleeding.
Lithium. Evidence exists for a potential increase in plasma lithium levels.
Methotrexate. Evidence exists for a potential increase in plasma methotrexate levels.
Zidovudine. Increased risk of hematological toxicity is known when zidovudine is used concomitantly with NSAIDs. Evidence indicates an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.
Cardiac glycosides. NSAIDs may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma levels of glycosides.
Antiplatelet agents and selective serotonin reuptake inhibitors. Increased risk of gastrointestinal bleeding.
Cyclosporine, tacrolimus. Possible increased risk of nephrotoxicity.
Mifepristone. NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, as they reduce its efficacy.
Quinolone antibiotics. Concurrent administration with ibuprofen may increase the risk of seizures.
Sulfonylurea derivatives and phenytoin. Possible potentiation of effect.

Special precautions for use.

Adverse reactions of ibuprofen, as with all NSAIDs, can generally be reduced by using the lowest effective dose required to treat symptoms for the shortest possible duration.

Caution is necessary when treating patients with:

systemic lupus erythematosus and mixed connective tissue disorders;
gastrointestinal disorders and chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease);
arterial hypertension and (or) heart failure;
impaired kidney function;
impaired liver function;
coagulation disorders (ibuprofen may prolong bleeding time).

Effects on the cardiovascular and cerebrovascular systems.

Patients with arterial hypertension and/or a history of moderate to severe congestive heart failure should be treated with caution when initiating long-term therapy (medical consultation is required), as fluid retention, arterial hypertension, and edema have been reported during treatment with ibuprofen and other NSAIDs.

Evidence indicates that ibuprofen use, particularly at high doses (2400 mg daily), is associated with a certain increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). However, low-dose ibuprofen (e.g., ≤1200 mg daily) is generally not expected to increase the risk of arterial thrombotic complications.

Patients with uncontrolled arterial hypertension, congestive heart failure (NYHA class II–III), ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful clinical assessment. High doses (2400 mg daily) should be avoided. Clinical evaluation should also be carefully performed before initiating long-term treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high-dose ibuprofen (2400 mg daily) is required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen. 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 the respiratory system.

Bronchospasm may occur in patients with bronchial asthma or allergic diseases, or with a history of such conditions.

Other NSAIDs.

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

Systemic lupus erythematosus and mixed connective tissue disorders.

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

Effects on the kidneys.

Prolonged use of NSAIDs may lead to dose-dependent reduction in prostaglandin synthesis and may provoke the development of renal failure. Patients at high risk include those with impaired kidney function, cardiac disorders, impaired liver function, patients taking diuretics, and elderly patients. Renal function should be monitored in such patients.

There is a risk of renal failure in dehydrated children and adolescents.

Effects on the liver.

Caution is necessary when treating patients with impaired liver function.

Effects on female fertility.

Some data suggest that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible upon discontinuation of treatment. Long-term use of ibuprofen (involving a daily dose of 2400 mg and treatment duration exceeding 10 days) may impair female fertility and is therefore not recommended for women attempting to conceive. This medicinal product should not be used in women experiencing difficulties in becoming pregnant or undergoing infertility investigations.

Effects on the gastrointestinal tract.

NSAIDs should be used with caution in patients with chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease), as these conditions may worsen. Cases of gastrointestinal bleeding, perforation, and ulcers, sometimes fatal, have been reported at any stage of NSAID treatment, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should start treatment with the lowest possible doses. Caution is required when treating patients receiving concomitant medications that may increase the risk of gastotoxicity or bleeding, such as oral corticosteroids or anticoagulants (e.g., warfarin) or antiplatelet agents (e.g., acetylsalicylic acid). For patients undergoing long-term treatment, as well as those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, physicians should consider prescribing combination therapy with misoprostol or proton pump inhibitors.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should report any unusual gastrointestinal symptoms (especially bleeding), particularly gastrointestinal bleeding at the beginning of treatment. If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, treatment should be discontinued immediately.

Serious skin adverse reactions (SSARs)

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

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

In rare cases, varicella may lead to severe skin and soft tissue infections. At present, a potential influence of NSAIDs on the development of these complications cannot be excluded; therefore, the use of this medicinal product is not recommended in cases of varicella.

Masking symptoms of underlying infections.

NSAIDs may mask symptoms of infectious diseases and fever, potentially interfering with diagnosis and timely treatment, thereby complicating the disease course. Such cases have been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When NSAIDs are used for fever or pain relief during infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Study data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following 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.

Preclinical studies in animals have shown that prostaglandin synthesis inhibitors increase the incidence of pre- and post-implantation miscarriages and embryonic/fetal mortality. Additionally, increased frequency 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 condition may occur soon after starting treatment and is usually reversible upon discontinuation. There have also been reports of arterial duct constriction after second-trimester treatment, which in most cases resolved after stopping treatment. NSAIDs should not be used during the first two trimesters of pregnancy unless the expected benefit to the patient outweighs the potential risk to the fetus. If ibuprofen is used by a woman attempting to conceive or during the first or second trimester of pregnancy, the lowest possible dose for the shortest possible duration should be applied. Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable if ibuprofen exposure occurred for several days starting from the 20th gestational week. Treatment should be discontinued if oligohydramnios or arterial duct 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 arterial duct and pulmonary hypertension); impaired kidney function, which may progress to renal failure accompanied by oligohydramnios (see above);
to the mother near term and the newborn: possible prolongation of bleeding time, antiplatelet effect that may occur even at very low doses; inhibition of uterine contractions, leading to delayed or prolonged labor.

The medicinal product is contraindicated during the third trimester of pregnancy.

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

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

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

Dosage and Administration

Administer orally. For short-term use only.

Adults and children aged 12 years and older: Take 1 capsule every 4 hours. Capsules should be taken with water. Do not exceed 3 capsules within 24 hours. The maximum daily dose is 1200 mg.

Use the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special Precautions"). If symptoms persist for more than 3 days after initiation of treatment or worsen, consult a physician.

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 12 years of age.

Overdose

Administration of more than 400 mg/kg of the drug in children may cause symptoms of intoxication. The effect of overdose is less pronounced in adults. The half-life during overdose is 1.5–3 hours.

Symptoms: In most patients, ingestion of large amounts of NSAIDs causes only nausea, vomiting, epigastric pain, and very rarely diarrhea. Tinnitus, headache, dizziness, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, manifesting as drowsiness, nystagmus, visual disturbances, and occasionally excitement, disorientation, or coma. Seizures may rarely occur. In severe poisoning, hyperkalemia and metabolic acidosis, acute renal failure, liver damage, arterial hypotension, respiratory failure, and cyanosis may develop. In patients with bronchial asthma, exacerbation of asthma may occur.

Treatment: Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring vital signs until condition stabilizes. 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, alkaline agents may be administered to enhance urinary excretion of acidic ibuprofen.

In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. In bronchial asthma, bronchodilators should be used.

Adverse Reactions

Adverse reactions most commonly affect the gastrointestinal tract and are mostly dose-dependent. Adverse reactions occur least frequently when the maximum daily dose is 1200 mg.

Available data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), is associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Adverse reactions of ibuprofen are classified by organ systems and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated due to limited available data).

Cardiac system:

Frequency not known: heart failure, edema, Coon's syndrome.

Gastrointestinal tract:

Uncommon: abdominal pain, dyspepsia, nausea.

Rare: diarrhea, flatulence, constipation, vomiting.

Very rare: peptic ulcer, gastrointestinal perforations or hemorrhages, melena, hematemesis, sometimes fatal (especially in elderly patients), ulcerative stomatitis, gastritis, pancreatitis, exacerbation of colitis and Crohn's disease.

Nervous system:

Uncommon: headache.

Rare: vertigo.

Very rare: aseptic meningitis¹, individual symptoms of which (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) may occur in patients with pre-existing autoimmune disorders such as systemic lupus erythematosus or mixed connective tissue disease.

Frequency not known: paresthesia, drowsiness.

Renal and urinary system:

Very rare: acute renal impairment, papillary necrosis—especially with prolonged use—associated with increased plasma urea levels and development of edema; hypernatremia (sodium retention), oliguria.

Frequency not known: renal failure, nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

Hepatic system:

Very rare: liver function abnormalities.

Frequency not known: hepatitis and jaundice may occur during prolonged treatment.

Vascular system:

Very rare: arterial hypertension.

Frequency not known: arterial thrombosis (myocardial infarction or stroke).

Skin and subcutaneous tissue:

Rare: various skin rashes.

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

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

Blood and lymphatic system:

Very rare: anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis—may occur during prolonged treatment, with initial symptoms including fever, sore throat, superficial oral ulcers, flu-like symptoms, severe fatigue, unexplained bleeding, and bruising.

Psychiatric disorders:

Rare: psychiatric disorders (including depression, insomnia, restlessness, hallucinations, confusion) only during prolonged use.

Visual system:

Frequency not known: visual disturbances, optic neuritis may occur during prolonged treatment.

Auditory system:

Rare: tinnitus and dizziness may occur during prolonged treatment.

Immune system:

Rare: hypersensitivity reactions², including urticaria and pruritus.

Very rare: severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal swelling, dyspnea, tachycardia, hypotension, anaphylactic reactions, angioedema, or severe shock.

Frequency not known: respiratory tract reactivity, including bronchial asthma, asthma exacerbation, bronchospasm.

General disorders:

Malaise and increased fatigue.

Laboratory investigations:

Very rare: decreased hemoglobin levels.

¹ 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 (symptoms occurred during drug intake and resolved upon 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) treated with ibuprofen.

² Hypersensitivity reactions have been reported following ibuprofen treatment. These include: (a) non-specific allergic reactions and anaphylaxis; (b) respiratory tract reactions, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea; (c) various skin disorders, including rashes of different types, pruritus, urticaria, purpura, angioedema, and less frequently, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Shelf life. 3 years from the date of manufacture for bulk-packaged product.

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

Keep out of reach of children.

Packaging. Capsules: No. 10 (10×1), No. 20 (10×2) in blisters, in a box.

Supply category. Over-the-counter (without prescription).

Manufacturer. Limited Liability Company "Pharmaceutical Company "Vertex".

Manufacturer's address and location of business operations.

33, Astronomichna Street, lit. "V-1", Kharkiv, Kharkiv Oblast, 61085, Ukraine.