Ibuprofen

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

Composition:

Active substance: ibuprofen;

1 capsule contains 200 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: hard gelatin capsules of white color. The capsule contents are a mixture containing granules and powder ranging from white to almost white. The presence of particle agglomerates is permissible.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. ATC code M01A E01.

Pharmacological Properties.

Pharmacodynamics.

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

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

Ibuprofen relieves pain, reduces inflammation, and lowers fever.

Pharmacokinetics.

Ibuprofen is rapidly absorbed after administration and quickly distributed throughout the body. It is eliminated via the kidneys. Elimination is rapid and complete.

Maximum plasma concentration (Cmax) is reached within 45 minutes after oral administration on an empty stomach. When administered with food, Cmax occurs within 1–2 hours. This time may vary depending on different pharmaceutical formulations.

The elimination half-life is approximately 2 hours.

In limited studies, ibuprofen has been detected in breast milk at very low concentrations.

Clinical characteristics.

Indications.

Symptomatic treatment of headache and 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 of the excipients.
• History of hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) following administration of ibuprofen, acetylsalicylic acid, or other NSAIDs.
• Active peptic ulceration or 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 Class IV (New York Heart Association)], severe renal impairment, or severe hepatic 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 impaired renal function.

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

• Acetylsalicylic acid. Concomitant use of ibuprofen with acetylsalicylic acid is generally not recommended due to the potential for increased adverse reactions, except when low-dose acetylsalicylic acid (not exceeding 75 mg daily) has been prescribed by a physician.

Evidence indicates that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. Although the clinical relevance of these data is not fully established, there remains a possibility 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, intermittent use of ibuprofen.

• Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors. Concomitant administration of two or more NSAIDs should be avoided, as this may increase the risk of adverse effects.

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

• Corticosteroids. Increased risk of gastrointestinal ulceration and bleeding.
• Antihypertensive agents and diuretics. NSAIDs may reduce the effectiveness of these drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. These interactions should be considered in patients receiving cyclooxygenase inhibitors together with ACE inhibitors or angiotensin II receptor blockers. Therefore, such combinations should be used with caution, particularly in elderly patients. If treatment is necessary, adequate hydration should be ensured, and monitoring of renal function should be considered at the start of combined therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.
• Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin.
• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding.
• Cardiac glycosides. NSAIDs may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma levels of glycosides.
• Lithium. Evidence suggests a potential increase in plasma lithium levels.
• Methotrexate. Evidence suggests a potential increase in plasma methotrexate levels.
• Cyclosporine. Increased risk of nephrotoxicity.
• Mifepristone. NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, as NSAIDs may reduce the efficacy of mifepristone.
• Tacrolimus. Possible 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 indicates an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia who are receiving concomitant treatment with zidovudine and ibuprofen.
• Quinolone antibiotics. Data from animal studies indicate that NSAIDs may increase the risk of convulsions associated with quinolone antibiotics. Patients receiving ibuprofen and quinolone antibiotics concomitantly may have an increased risk of developing convulsions.

Special precautions for use.

Adverse reactions associated with ibuprofen can be minimized by using the lowest effective dose required to treat symptoms for the shortest duration possible.

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

Respiratory effects.

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

Other NSAIDs.

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

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. 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 diseases, cases have also been reported in some patients without chronic conditions. Therefore, this should be considered when using the 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 advice from a physician or pharmacist is required), as fluid retention, hypertension, and edema have been reported with NSAID therapy.

Evidence indicates that the use of ibuprofen, particularly at high doses (2400 mg daily) and over prolonged periods, may be 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 hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful clinical assessment. High doses (2400 mg daily) should be avoided.

Careful clinical evaluation should also be performed 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 daily) 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 potentially may lead to myocardial infarction.

Effects on kidneys/liver.

Caution is advised in patients with renal impairment due to the potential for worsening kidney 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 impairment in children (aged 6 years and older) and adolescents who are dehydrated.

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 impairment, heart failure, or hepatic impairment, and in those receiving diuretic or angiotensin-converting enzyme (ACE) inhibitor therapy. After discontinuation of NSAID therapy, renal function usually returns to the pre-treatment state.

Like other NSAIDs, ibuprofen may cause mild, transient increases in certain liver function parameters, as well as significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. If substantial increases in these parameters occur, treatment should be discontinued.

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

Effects on female fertility.

Some 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 effects.

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

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

The risk of gastrointestinal bleeding, perforation, or ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer disease, particularly complicated by bleeding or perforation, and in elderly patients. These patients should initiate treatment with the lowest dose. For these patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid or other medicinal products that may increase the risk of gastrointestinal adverse reactions, 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 report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly at the beginning of treatment.

Prolonged use of any analgesic for headache treatment may worsen this condition. In such cases, treatment should be discontinued and medical advice sought. Medication-overuse headache should be considered in patients suffering from frequent or daily headaches, despite (or because of) regular use of headache medications.

Caution should be exercised when treating patients who are concurrently using medicinal products that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid).

In case of gastrointestinal bleeding or ulcers 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 reaction with eosinophilia and 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 indicating these reactions appear, ibuprofen should be discontinued immediately, and alternative treatment should be considered (if necessary).

In rare cases, varicella may lead to severe skin and soft tissue infections. At present, the influence of NSAIDs on the development of these complications cannot be excluded; therefore, it is recommended to avoid using the medicinal product in case of varicella.

Masking symptoms of underlying infections.

NSAIDs may mask symptoms of infectious diseases and fever, which could interfere with diagnosis and timely treatment, thereby complicating the course of the disease. 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 for 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 negatively affect pregnancy and/or embryonic/fetal development. Study data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following the 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 lead to increased rates of pre- and post-implantation losses and embryonic/fetal mortality. In addition, increased incidences 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, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction after treatment in the second trimester, which in most cases resolved after treatment cessation. NSAIDs should not be used during the first and second trimesters of pregnancy unless the expected benefit to the patient outweighs the potential risk to the fetus. If ibuprofen is used by a woman trying to conceive or during the first and second trimesters 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 over 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); renal dysfunction, which may progress to renal failure accompanied by oligohydramnios (see above);
• to the mother at the end of pregnancy and the 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 medicinal product is contraindicated during the third trimester of pregnancy.

In some 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 affect reaction speed when driving or operating machinery.

When used according to recommended doses and treatment duration, the medicinal product is not expected to affect reaction speed when driving or operating machinery.

Dosage and Administration.

For oral use only. For short-term treatment only. Capsules should be taken with water and must not be chewed.

The lowest effective dose required to control symptoms should be used for the shortest possible duration (see section "Special Warnings and Precautions for Use"). If symptoms persist for more than 5 days from the start of treatment or worsen, medical advice should be sought.

The medicine is intended for adults and children with body weight above 20 kg (approximately 6 years of age). The recommended daily dose is 20–30 mg/kg of body weight. The maximum daily dose must not exceed 30 mg/kg of body weight.

Children with body weight between 20 and 30 kg (aged 6 to 11 years): 200 mg (1 capsule) per dose. Repeat the dose as needed every 6 hours. Maximum daily dose: 600 mg (3 capsules).

Adults and children with body weight above 30 kg: 200–400 mg (1–2 capsules) per dose. Repeat the dose as needed every 4–6 hours. Maximum daily dose: 1200 mg (6 capsules).

Elderly patients do not require any special dosage adjustment.

Children.

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

Overdose.

Most reported cases of overdose were asymptomatic. Risk of symptoms arises when ibuprofen dose exceeds 80–100 mg/kg. Administration of doses exceeding 400 mg/kg in children may lead to symptoms of intoxication. The effect of overdose in adults is generally less pronounced. Elimination half-life in overdose is 1.5–3 hours.

Symptoms.

Symptoms of overdose typically occur within 4 hours after ingestion. In most patients, ingestion of clinically significant amounts of NSAIDs results in mild symptoms, including nausea, vomiting, epigastric pain, and less frequently, diarrhea. Other possible symptoms include tinnitus, headache, and gastrointestinal bleeding. In more severe poisoning, toxic effects on the central nervous system may occur, manifesting as vertigo, dizziness, lethargy, drowsiness, occasionally excitement, ataxia, disorientation, or coma. Seizures may occasionally develop. Severe intoxication may also lead to hyperkalemia, metabolic acidosis, and prolonged prothrombin time/international normalized ratio (INR), likely due to interaction with circulating blood coagulation factors.

Rarely, moderate to severe symptoms have been observed, such as acute renal failure, liver injury, hypotension, hypothermia, cyanosis, dyspnea/acute respiratory distress syndrome, and transient episodes of apnea (particularly 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. Management should be symptomatic and supportive, including maintenance of airway patency and continuous monitoring of cardiac function and vital signs until the patient stabilizes. In cases of ingestion of small amounts (less than 50 mg/kg of ibuprofen), drinking water is recommended to minimize gastrointestinal disturbances. In cases of ingestion of larger amounts, oral activated charcoal or gastric lavage is recommended if less than 1 hour has passed since ingestion of a potentially toxic dose and if the amount ingested is not life-threatening. If ibuprofen has already been absorbed, alkalinizing agents may enhance renal excretion of the acidic ibuprofen. The benefit of interventions such as forced diuresis, hemodialysis, and hemoperfusion has not been proven, as ibuprofen is highly protein-bound in plasma. For frequent or prolonged seizures, intravenous diazepam or lorazepam is recommended. Bronchodilators should be used in cases of bronchial asthma. Immediate medical attention should be sought.

Adverse reactions.

Adverse reactions observed during the use of ibuprofen are listed below by organ systems and frequency of occurrence. The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), rare (from ≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

The adverse reactions listed below were observed during short-term use of ibuprofen at over-the-counter doses. Additional adverse reactions may occur during treatment of chronic conditions or with long-term therapy.

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

Blood and lymphatic system disorders:

Very rare: blood disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, and agranulocytosis). Initial signs of such disorders include malaise, sore throat, oral ulcerations, influenza-like symptoms, severe fatigue, unexplained bleeding, and unexplained bruising or hematoma.

Immune system disorders:

Hypersensitivity reactions¹:

Uncommon: urticaria and pruritus.

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

Frequency not known: bronchospasm, asthma, worsening of asthma, or dyspnea.

Nervous system disorders:

Uncommon: headache.

Very rare: aseptic meningitis².

Cardiac disorders:

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

Data indicate that the use of ibuprofen, especially at high doses (2400 mg daily) and over prolonged periods, is associated with a small 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, vomiting.

Very rare: peptic ulcer, gastrointestinal perforation or bleeding, 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 types of skin rashes.

Very rare: severe skin reactions may occur (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.

Respiratory, thoracic and mediastinal disorders:

Frequency not known: bronchospasm, asthma, or dyspnea.

Renal and urinary disorders:

Very rare: acute renal failure, papillary necrosis, particularly with prolonged use of NSAIDs, associated with increased blood urea levels and edema.

Frequency not known: renal failure.

Investigations:

Very rare: decreased hemoglobin levels.

¹ Hypersensitivity reactions have been reported following treatment with ibuprofen. These include: (a) non-specific allergic reactions and anaphylaxis; (b) respiratory tract reactions, including bronchial asthma, worsening of asthma, bronchospasm, or dyspnea; (c) various skin disorders, including rashes of different types, pruritus, urticaria, purpura, angioedema; 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 NSAIDs suggest a hypersensitivity reaction (symptoms occurred during drug administration and resolved upon discontinuation). In particular, isolated cases of aseptic meningitis symptoms (such as nuchal rigidity, headache, nausea, vomiting, malaise, or disorientation) have been observed in patients with pre-existing autoimmune disorders (e.g., systemic lupus erythematosus, mixed connective tissue disease) during ibuprofen treatment.

Shelf life. 3 years from the date of manufacture when stored in bulk packaging.

Storage conditions. Store in 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 carton.

Prescription status. Over-the-counter.

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

Manufacturer's address and place of business.

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