Ibuprofen-zdorovya

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

Composition:

Active substance: ibuprofen;

1 capsule contains ibuprofen 200 mg;

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 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 M01AE01.

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. Some pharmacodynamic studies have shown that administration of single doses of ibuprofen 400 mg 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 there is uncertainty regarding extrapolation of these data to the clinical setting, it cannot be excluded 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 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 concentration (C_max) is reached within 45 minutes after oral administration on an empty stomach. When administered with food, C_max occurs within 1–2 hours. This time may vary depending on different dosage forms.

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, 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 or duodenal ulcer/bleeding, or history of recurrent episodes (two or more episodes of confirmed peptic ulcer or bleeding).
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Severe heart failure (NYHA class IV), severe renal failure, or severe hepatic failure.
• Third trimester of pregnancy.
• Active inflammatory bowel disease.
• Hemorrhagic diathesis or other coagulation disorders.

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 renal impairment.

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 in cases where acetylsalicylic acid (at a dose not exceeding 75 mg per day) has been prescribed by a physician.

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

• Other NSAIDs, including selective cyclooxygenase-2 inhibitors. Concomitant use 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 an ACE inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients receiving cyclooxygenase inhibitors together with ACE inhibitors or angiotensin II antagonists. 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 of renal function at the start of combination therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.
• Anticoagulants. NSAIDs may potentiate the effect 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 receiving concomitant treatment with zidovudine and ibuprofen.
• Quinolone antibiotics. Animal data suggest that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. In patients receiving concomitant ibuprofen and quinolone antibiotics, an increased risk of seizures may occur.

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 possible duration.

In elderly patients, there is 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 such 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 disorders, such cases have also been reported in some patients without chronic conditions; therefore, this should be considered when using this medicinal product.

Cardiovascular and cerebrovascular effects.

Caution is advised 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 associated with NSAID therapy have been reported.

Data indicate that the use of ibuprofen, especially at high doses (2400 mg daily) and with prolonged treatment, may be associated with a slightly increased risk of arterial thrombotic complications (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 hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful assessment of the clinical picture. 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., 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 characterized by cardiovascular symptoms related to coronary artery spasm due to an allergic or hypersensitivity reaction, which may potentially 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. Such patients should receive the lowest possible dose of ibuprofen, and renal function should be monitored regularly. Adequate fluid intake should be ensured in cases of dehydration. There is a risk of renal failure in 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 permanent kidney damage with a risk of renal failure (analgesic nephropathy). The highest risk of this reaction occurs in elderly patients, patients with renal, heart, or liver impairment, and those receiving diuretic or ACE inhibitor therapy. 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 therapy, regular monitoring of liver function, kidney function, and hematological parameters/blood count is necessary.

Effect on female fertility.

Limited data suggest that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may impair fertility in women 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 prior warning symptoms or gastrointestinal disorders in the patient’s history.

The risk of gastrointestinal bleeding, perforation, or ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer disease, 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 drugs that may increase gastrointestinal risk, should be considered for combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors).

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should be advised to report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly 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 with frequent or daily headaches despite (or because of) regular use of headache medications.

Caution is advised when treating patients who are concurrently using medications 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).

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 during 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, chickenpox may lead to severe skin and soft tissue infections. At present, the influence of NSAIDs on the occurrence of these complications cannot be excluded; therefore, the use of this medicinal product is not recommended in cases of chickenpox.

Masking symptoms of underlying infections.

NSAIDs may mask symptoms of infectious diseases and fever, potentially delaying appropriate treatment and thereby complicating the course of the disease. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. When NSAIDs are used for fever or pain relief during infection, monitoring for infection 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 caused increased pre- and post-implantation loss 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, 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. Additionally, there have been reports of arterial duct constriction after treatment in the second trimester, most of which resolved after stopping treatment. Therefore, ibuprofen 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 women attempting to become pregnant 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); renal dysfunction, which may progress to renal failure associated with oligohydramnios (see above);
• to the mother and newborn near term: prolonged bleeding time, antiplatelet effects that 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; therefore, it is unlikely to have a negative effect on a breastfed infant.

Ability to influence reaction speed when driving or operating machinery.

When used according to recommended doses and treatment duration, the drug is not expected to affect the ability to drive or operate machinery.

Method of Administration and Dosage

For oral use. For short-term use only. Capsules should be swallowed with water; do not chew. During short-term use, if symptoms persist or worsen, the patient should consult a physician.

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

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

Children with body weight from 20 to 30 kg (aged 6 to 11 years): 200 mg (1 capsule) per dose. Repeat the dose as needed every 6 hours. Do not exceed 600 mg (3 capsules) per day.

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. Do not exceed 1200 mg (6 capsules) per day.

Elderly patients do not require 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 the drug to children at doses exceeding 400 mg/kg may cause intoxication symptoms. In adults, the dose effect is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms.

Symptoms of overdose occur within 4 hours after ingestion.

In most patients, clinically significant intake of NSAIDs causes mild overdose symptoms, including nausea, vomiting, epigastric pain, and less frequently, diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic central nervous system effects may develop, manifesting as vertigo, dizziness, lethargy, drowsiness, occasionally excitement, ataxia, disorientation, or coma. Seizures may occasionally occur. In more severe poisoning, hyperkalemia, metabolic acidosis, and prolonged prothrombin time/international normalized ratio (INR) may develop (likely due to interaction with circulating blood coagulation factors).

Rarely, moderate to severe symptoms such as acute renal failure, liver damage, hypotension, hypothermia, cyanosis, dyspnea/acute respiratory distress syndrome, and brief episodes of apnea (in children after ingestion of large amounts of the drug) have been observed. 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 ensuring airway patency and monitoring cardiac function and vital signs until the patient's condition normalizes. After ingestion of small amounts of the drug (less than 50 mg/kg ibuprofen), drinking water is recommended to minimize gastrointestinal disturbances. After ingestion of larger amounts, oral activated charcoal or gastric lavage is recommended, but only within 1 hour after ingestion of a potentially toxic dose and only if the ingested amount does not pose a life-threatening risk. If ibuprofen has already been absorbed, alkalizing agents may be used to promote urinary excretion of acidic ibuprofen. The benefit of measures such as forced diuresis, hemodialysis, and hemoperfusion has not been proven, as ibuprofen is highly protein-bound in plasma. In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam is recommended. In bronchial asthma, bronchodilators should be administered. Seek immediate medical attention.

Side effects

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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), 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 are gastrointestinal. Most adverse reactions are 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, and agranulocytosis). Early signs of such disorders include malaise, sore throat, oral mucosal ulcers, flu-like symptoms, severe fatigue, unexplained bleeding, and hematomas of unknown etiology.

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 reactivity, 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, Kounis syndrome.

Data indicate that the use of ibuprofen (particularly at high doses of 2400 mg daily and with long-term treatment) may be associated with a slightly increased risk of arterial thrombotic complications (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 ulceration of the stomach and duodenum, gastrointestinal perforation or hemorrhage, melena, hematemesis, sometimes fatal (particularly in elderly patients), ulcerative stomatitis, gastritis;

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

Hepatic disorders:

Very rare: liver function abnormalities.

Skin and subcutaneous tissue disorders:

Uncommon: various 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-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis, photosensitivity reactions.

Respiratory, thoracic and mediastinal disorders:

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

Renal and urinary disorders:

Very rare: acute renal impairment, papillary necrosis, particularly with prolonged use of NSAIDs, 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 Reports exist 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 intake and symptom resolution after drug discontinuation). In particular, isolated cases of aseptic meningitis symptoms (such as nuchal rigidity, headache, nausea, vomiting, malaise, or disorientation) have been observed during ibuprofen treatment in patients with pre-existing autoimmune disorders (such as systemic lupus erythematosus or mixed connective tissue disease).

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 pieces, 10x2 in blisters in a carton.

Category of supply. Over-the-counter.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

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