Ibuprofen-zdorovya

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

Composition:

Active ingredient: 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: hard gelatin capsules of white color. The capsule contents are a mixture of granules and powder ranging from white to almost white. The presence of particle agglomerates is acceptable.

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 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 inhibit the effect of low-dose 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 acetylsalicylic acid (81 mg) was associated with reduced effects of acetylsalicylic acid on thromboxane formation or platelet aggregation. Although uncertainty exists regarding extrapolation of these data to clinical settings, it cannot be excluded that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. Such a clinically significant effect is considered unlikely with occasional use of ibuprofen.

Pharmacokinetics.

Ibuprofen is well absorbed from 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 within 1–2 hours after intake. Ibuprofen is metabolized in the liver and excreted by the kidneys either unchanged or as metabolites. 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 of the components of the drug.
• History of hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) observed after taking ibuprofen, acetylsalicylic acid, or other NSAIDs.
• Active peptic ulcer disease or gastrointestinal bleeding, or history of recurrence (two or more episodes of confirmed peptic ulcer or bleeding).
• History of gastrointestinal bleeding or perforation associated with the use of NSAIDs.
• Severe heart failure (NYHA 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.

Like other NSAIDs, ibuprofen should not be used in combination with the following medicinal products:

• Acetylsalicylic acid, as this may increase the risk of adverse reactions, except when acetylsalicylic acid (at a dose 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 uncertainty remains regarding 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.

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 reduce the efficacy 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 ACE inhibitors or angiotensin II antagonists with cyclooxygenase-inhibiting drugs may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be used 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 beginning of combined 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 suggests a potential increase in plasma lithium levels.
• Methotrexate. Evidence suggests 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. Concomitant use with ibuprofen may increase the risk of seizures.
• Sulfonylurea derivatives and phenytoin. Possible potentiation of effect.

Special precautions for use.

Adverse reactions associated with the use of ibuprofen and nonsteroidal anti-inflammatory drugs (NSAIDs) in general can usually be minimized by using the lowest effective dose required to relieve 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 renal function;
• impaired hepatic 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.

Data indicate that the use of ibuprofen, particularly at high doses (2400 mg daily), may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, 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 arterial hypertension, congestive heart failure (NYHA class II–III), ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful assessment of the clinical condition. High doses (2400 mg daily) should be avoided.

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

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

Effects on the respiratory system.

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

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 renal function, cardiac disorders, hepatic dysfunction, those taking diuretics, and elderly patients. Renal function should be monitored in such patients.

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

Effects on the liver.

Caution is required when treating patients with impaired hepatic function.

Effects on female fertility.

Limited 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 (doses of 2400 mg daily and treatment duration exceeding 10 days) may impair female fertility and is therefore not recommended for women attempting to conceive. This medicine should not be used in women experiencing difficulty 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 be exacerbated. Cases of gastrointestinal bleeding, perforation, and ulcers, sometimes fatal, have been reported at any stage of NSAID therapy, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, and ulceration increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly 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, or those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, combined therapy with misoprostol or proton pump inhibitors should be considered by the physician.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about 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 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 suggestive of these reactions occur, ibuprofen should be discontinued immediately and alternative treatment options 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 such 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 delaying the initiation of appropriate treatment and thereby worsening the course of the disease. This has 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 adversely affect pregnancy and/or embryonic/fetal development. 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 data show that in animals, prostaglandin synthesis inhibitors led to increased pre- and post-implantation loss 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, the use of ibuprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Moreover, there have been reports of arterial duct constriction following treatment in the second trimester, most of which resolved after stopping treatment. Therefore, ibuprofen 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 in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose should be used for the shortest possible duration. Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of ibuprofen exposure 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 renal function, which may progress to renal failure associated with oligohydramnios (see above);
• to the mother and neonate near term: prolonged bleeding time, antiplatelet effect, which may occur 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.

In limited studies, ibuprofen has been detected in breast milk at very low concentrations, making it unlikely to adversely affect the breastfed infant.

Ability to influence reaction speed when driving or operating machinery.

When used according to the 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 or operating machinery.

Dosage and Administration.

For oral use 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 take more than 3 capsules within 24 hours. The maximum daily dose is 1200 mg.

The lowest effective dose should be used for the shortest possible duration necessary to relieve symptoms (see section "Special Instructions"). If symptoms persist for more than 3 days from the start of treatment or worsen, consult a physician.

Elderly patients do not require special dosage adjustment.

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 the drug to children in doses exceeding 400 mg/kg may cause symptoms of intoxication. In adults, the effect of overdose is less pronounced. The elimination half-life in 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 agitation, disorientation, or coma. Seizures may sometimes occur. In severe poisoning, hyperkalemia and metabolic acidosis, acute renal failure, liver damage, arterial hypotension, respiratory depression, and cyanosis may develop. In patients with bronchial asthma, asthma exacerbation may occur.

Treatment. Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of vital functions until the condition normalizes. 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, alkalizing agents may be administered to accelerate urinary excretion of acidic ibuprofen.

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

Side effects

Gastrointestinal adverse reactions are the most commonly observed 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 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10,000 – < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated due to limited available data).

Cardiac system:

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

Gastrointestinal system:

Uncommon: abdominal pain, dyspepsia, nausea;

Rare: diarrhea, flatulence, constipation, vomiting;

Very rare: peptic ulcer, gastrointestinal perforation or gastrointestinal hemorrhage, 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, with individual symptoms (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) occurring in patients with pre-existing autoimmune disorders such as systemic lupus erythematosus or mixed connective tissue disease;

Frequency not known: paresthesia, somnolence.

Renal and urinary system:

Very rare: acute renal impairment, papillary necrosis, particularly 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: hepatic function abnormalities;

Frequency not known: hepatitis and jaundice may occur with 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-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis, photosensitivity reactions.

Blood and lymphatic system:

Very rare: anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, which may occur during prolonged treatment; initial signs include fever, sore throat, oral ulcers, influenza-like symptoms, severe fatigue, unexplained bleeding, and bruising.

Psychiatric disorders:

Rare: only with prolonged use – psychiatric disorders, depression, insomnia, agitation, hallucinations, confusion.

Visual system:

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

Auditory system:

Rare: tinnitus and dizziness may occur with prolonged treatment.

Immune system:

Rare: hypersensitivity reactions², including urticaria and pruritus;

Very rare: severe hypersensitivity reactions, with symptoms possibly including 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.

Description of selected adverse reactions

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 (based on temporal association with drug intake and resolution of symptoms upon 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 (e.g., systemic lupus erythematosus, mixed connective tissue disease) during ibuprofen therapy.

2 There have been reports 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, angioedema, and less frequently, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Shelf life. 3 years.

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

Keep out of reach of children.

Packaging. Capsules, № 10, № 10x2 in blisters in a box.

Dispensing category. Over-the-counter.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

22 Shevchenka Street, Kharkiv, Kharkiv region, 61013, Ukraine.