INSTRUCTIONS for medical use of the medicinal product IBUPROFEN (IBUPROFEN)

Composition:

Active ingredient: ibuprofen;

One film-coated tablet contains 200 mg of ibuprofen;

Excipients: potato starch, hypromellose (hydroxypropylmethylcellulose), magnesium stearate, povidone, colloidal anhydrous silicon dioxide, titanium dioxide (E 171), talc, polysorbate 80, polyethylene glycol 6000 (macrogol 6000), carmoisine (E 122).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round, film-coated, pink-colored tablets with convex upper and lower surfaces. When broken and examined under a magnifying glass, a core surrounded by a single continuous layer is visible.

Pharmacotherapeutic group. Nonsteroidal 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 has demonstrated its 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 aspirin (acetylsalicylic acid) on platelet aggregation when these drugs are used concomitantly. Some pharmacodynamic studies have shown that administration of single doses of ibuprofen 400 mg within 8 hours before or 30 minutes after immediate-release aspirin (acetylsalicylic acid) 81 mg resulted in reduced effects of aspirin (acetylsalicylic acid) on thromboxane formation or platelet aggregation. Although there is uncertainty regarding extrapolation of these data to the clinical setting, 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-systematic use of ibuprofen, such a clinically significant effect is considered unlikely.

Ibuprofen relieves pain, reduces inflammation, and lowers body temperature.

Pharmacokinetics.

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

Maximum plasma concentrations are reached within 45 minutes after oral administration on an empty stomach. When administered with food, peak levels are observed 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 of the medicinal product.
History of hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) observed after taking acetylsalicylic acid (aspirin) or other NSAIDs.
Active peptic ulcer or gastrointestinal bleeding, or history of recurrent episodes (two or more confirmed episodes of peptic ulcer or bleeding).
History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.
Severe heart failure (NYHA Class IV), 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.

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

aspirin (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 aspirin (not exceeding 75 mg per day) is prescribed by a physician.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose aspirin (acetylsalicylic acid) on platelet aggregation. Although uncertainty exists regarding the extrapolation of these data to clinical settings, 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-regular use of ibuprofen;

other NSAIDs, including selective cyclooxygenase-2 inhibitors: simultaneous use of two or more NSAIDs should be avoided, as this may increase the risk of adverse reactions.

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

corticosteroids: increased risk of gastrointestinal ulcers or 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 individuals), 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 possible acute renal failure, which is usually reversible. The appropriateness of using such combinations in patients receiving coxibs together with ACE inhibitors or angiotensin II antagonists should be considered. Therefore, such combinations should be used with caution, particularly in elderly patients. If treatment is necessary, ensure adequate hydration of the patient and consider the need for monitoring renal function at the start of combination 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. Increased risk of hemarthrosis and hematoma has been observed in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen;
quinolone antibiotics: patients receiving NSAIDs and quinolone antibiotics concomitantly may have an increased risk of seizures.

Special precautions for use.

Adverse effects can be minimized by using the lowest effective dose required to relieve symptoms for the shortest possible duration.

Elderly individuals have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforations, which can 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 COX-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 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, such cases have also been reported in some patients without chronic diseases; therefore, this should be taken into account when using this medicinal product.

Cardiovascular and cerebrovascular effects.

Patients with a history of arterial hypertension and/or heart failure should start ibuprofen treatment with caution (medical consultation is required), as cases of fluid retention, arterial hypertension, and edema associated with NSAID therapy have been reported.

Clinical trial data indicate that the use of ibuprofen, especially at high doses (2400 mg daily), may be associated with a slightly increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (e.g., <1200 mg daily) is associated with an increased 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 be treated with ibuprofen only after careful clinical evaluation. High doses of the drug (2400 mg daily) should be avoided.

A careful clinical assessment should also be performed 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 daily) are 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 kidneys/liver.

Caution is advised in patients with renal impairment due to the possibility of 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. In cases of dehydration, adequate fluid intake should be ensured. There is a risk of renal failure 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 persistent 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, as well as in those receiving diuretic therapy or angiotensin-converting enzyme (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. If substantial increases in these parameters occur, treatment should be discontinued.

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

Effect on female fertility.

Limited data suggest that medicinal products which 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 (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated.

Cases of gastrointestinal bleeding, ulcers, or perforations, which may be fatal, have been reported during treatment with all NSAIDs, regardless of the presence of warning symptoms or prior gastrointestinal disorders.

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 initiate treatment with the lowest available dose. These patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid or other medicinal products that may increase gastrointestinal risk, should be prescribed combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors).

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

Prolonged use of any analgesic for headache treatment may worsen the condition. In such cases, medical advice should be sought and treatment discontinued. 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 receiving concomitant 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., aspirin).

In case of gastrointestinal bleeding or ulceration 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 (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 with ibuprofen use (see section "Adverse reactions"). Most of these reactions occurred within the first month of treatment.

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

In rare cases, varicella may lead to severe skin and soft tissue infections. The influence of NSAIDs on worsening these infections cannot be excluded during varicella infection. Therefore, the use of ibuprofen is not recommended in cases of varicella.

Masking symptoms of underlying infections. Ibuprofen may mask symptoms of infectious diseases, potentially delaying the initiation of appropriate treatment and thereby complicating disease progression. This has been observed in bacterial community-acquired 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.

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 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 treatment.

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

First and second trimesters. 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, there have been reports of fetal arterial duct constriction after treatment during the second trimester, which in most cases resolved after treatment cessation. Therefore, ibuprofen should not be prescribed during the first and second trimesters unless clearly necessary.

If ibuprofen is used by a woman trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

Prenatal monitoring for oligohydramnios and fetal arterial duct constriction may be appropriate if ibuprofen exposure occurred for several days starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or arterial duct constriction is detected.

Third trimester. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors pose risks:

for the fetus:

cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
renal dysfunction (see above);

for the mother at the end of pregnancy and for the newborn:

prolonged bleeding time, anti-aggregatory 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 (see section "Contraindications").

In some studies, ibuprofen has been detected in breast milk at very low concentrations; therefore, it is unlikely to have a negative effect on a 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 the ability to drive or operate machinery.

Method of Administration and Dosage

For oral use. Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

The lowest effective dose should be used for the brief period needed to relieve pain (no more than 5 days) or symptoms of fever (3 days). If treatment longer than 5 days is required (if symptoms persist), medical advice should be sought.

The drug is indicated for adults and children with body weight above 20 kg (approximately from 6 years of age).

The usual dosage is 20 to 30 mg/kg body weight per day. The daily dose should not exceed 30 mg/kg body weight.

Children with body weight from 20 to 30 kg (from 6 to 11 years of age): 200 mg (1 tablet), repeated if necessary after 6 hours, but not more than 600 mg (3 tablets) per day.

Adults and children with body weight above 30 kg: 200–400 mg (1–2 tablets) every 4–6 hours as needed. Tablets should be taken with water. Do not exceed 1200 mg (6 tablets) within 24 hours.

Elderly patients do not require special dosage adjustment.

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

Children

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

Overdose

Most reported cases of overdose were asymptomatic. Symptoms are expected 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 relationship is less pronounced. The half-life in overdose is 1.5–3 hours.

Symptoms
Symptoms of overdose occur within 4 hours after ingestion. In most patients, ingestion of a clinically significant amount of NSAIDs causes mild symptoms, including nausea, vomiting, epigastric pain, or less commonly, diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, such as vertigo, dizziness, lethargy, drowsiness, occasionally excitability, ataxia, disorientation, or coma. Seizures may occasionally occur. Severe intoxication may lead to hyperkalemia, metabolic acidosis, and prolonged prothrombin time/INR (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 apnea episodes (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 should be symptomatic and supportive, including maintenance of airway patency and monitoring of cardiac and vital functions until stabilization. After ingestion of small amounts of the drug (less than 50 mg/kg of ibuprofen), drinking water is recommended to minimize gastrointestinal irritation. After 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 a life-threatening amount has been ingested. If ibuprofen has already been absorbed, alkalizing agents may be used to enhance urinary excretion of acidic ibuprofen. The benefit of interventions such as forced diuresis, hemodialysis, or hemoperfusion has not been proven, as ibuprofen is highly protein-bound. In cases of frequent or prolonged seizures, treatment should include intravenous administration of diazepam or lorazepam. In bronchial asthma, bronchodilators should be administered. Medical help should be sought immediately.

Adverse reactions.

The 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 (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

The list of adverse reactions below refers to those observed with ibuprofen used at over-the-counter doses and 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 gastrointestinal. Adverse reactions are generally dose-dependent; in particular, the risk of gastrointestinal bleeding increases with dose and duration of treatment.

Blood and lymphatic system disorders:

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

Immune system disorders:

Hypersensitivity reactions¹; uncommon: urticaria and pruritus; very rare: severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal swelling, dyspnea, tachycardia, and hypotension (anaphylactic reaction, angioedema, or severe shock); frequency not known: respiratory tract reactions, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea.

Nervous system disorders:

Uncommon: headache; very rare: aseptic meningitis².

Cardiac disorders:

Frequency not known: heart failure, edema, Cozzio’s syndrome.

Clinical trial data and epidemiological evidence suggest that the use of ibuprofen, particularly at high doses of 2400 mg per day 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 ulcer, perforation, or gastrointestinal bleeding, melena, hematemesis, sometimes fatal (especially 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: serious skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis); frequency not known: drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP).

Respiratory, thoracic and mediastinal disorders:

Frequency not known: respiratory tract reactions, 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

1 There have been reports of hypersensitivity reactions following treatment with ibuprofen. 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, angioedema, 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 administration and resolution of symptoms after drug 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 (such as systemic lupus erythematosus or mixed connective tissue disease) during ibuprofen treatment.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets in blisters;

10 tablets in a blister; 5 blisters in a cardboard pack;

10 tablets in a blister; 90 blisters in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

JSC "Tekhnolog".

Manufacturer's address and location of manufacturing site.

8 Stara Prorizna Street, Uman, Cherkasy Oblast, 20300, Ukraine.