INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMET® (IMET®)

Composition:

Active substance: ibuprofen;

One film-coated tablet contains 400 mg of ibuprofen;

Excipients: maize starch, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, hypromellose, polyethylene glycol 4000, povidone (K 30), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: white or almost white, elongated film-coated tablets, with a dividing line on both sides and an embossing "E" on both sides of the line on the upper side.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. 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 when administered concomitantly, ibuprofen may interfere with the effect of low-dose acetylsalicylic acid (aspirin) on platelet aggregation. 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) reduces the effect of acetylsalicylic acid on thromboxane production or platelet aggregation. Although uncertainty remains regarding the applicability of these findings to clinical situations, it cannot be ruled out that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. With occasional (intermittent) use of ibuprofen, a clinically significant effect is considered unlikely.

Pharmacokinetics.

Absorption.

After oral administration, ibuprofen is partially absorbed in the stomach and then completely absorbed in the small intestine. Following oral administration of the immediate-release dosage form, peak plasma concentrations are achieved within 1–2 hours. When administered on an empty stomach, maximum serum concentration may be reached within 45 minutes after dosing.

Distribution.

Plasma protein binding is approximately 99%.

Biotransformation.

Ibuprofen is metabolized in the liver (hydroxylation, carboxylation).

Elimination.

Pharmacologically inactive metabolites are excreted completely, primarily via urine (90%) and also via bile. The elimination half-life in healthy individuals and patients with hepatic or renal disease ranges from 1.8 to 3.5 hours.

Linearity/Non-linearity.

Linear kinetics of ibuprofen were observed at doses between 200 and 400 mg. Non-linear kinetics were observed at higher doses.

No significant differences in the pharmacokinetic profile have been observed in elderly patients.

Clinical characteristics.

Indications.

Symptomatic treatment of headache, including migraine, toothache, dysmenorrhea, neuralgia, back pain, joint pain, muscle pain, as well as symptoms of cold and flu.

Contraindications.

Hypersensitivity to ibuprofen or to any of the excipients of the drug.
Hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) previously observed after taking ibuprofen, acetylsalicylic acid, or other NSAIDs.
Active peptic ulcer or gastrointestinal bleeding, or history of recurrent episodes (two or more documented episodes of peptic ulcer or bleeding).
History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
Severe impairment of liver or kidney function; heart failure (NYHA Class IV).
Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").
Cerebrovascular or other bleeding disorders.
Disorders of blood coagulation or hemostasis.

Interaction with other medicinal products and other forms of interaction.

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

Acetylsalicylic acid: concomitant use of ibuprofen and acetylsalicylic acid is generally not recommended due to the potential for increased risk of adverse reactions.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. However, uncertainty regarding the extrapolation of these data to clinical settings prevents definitive conclusions about whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Clinically significant interaction is considered unlikely with occasional use of ibuprofen.

Other NSAIDs (including selective cyclooxygenase-2 inhibitors): concomitant use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects.

Ibuprofen should be used with caution in combination with the following drugs:

Anticoagulants: NSAIDs may enhance the anticoagulant effect of drugs such as warfarin.

Antihypertensive agents (ACE inhibitors and angiotensin II antagonists, beta-blockers, and diuretics): NSAIDs may attenuate the effects of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised kidney function), concomitant use of ACE inhibitors, beta-blockers, or angiotensin II antagonists with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be prescribed cautiously, particularly in elderly patients. In cases of prolonged treatment, adequate hydration should be ensured, and monitoring of renal function should be considered at the initiation of combination therapy and periodically thereafter. Concomitant use of ibuprofen and potassium-sparing diuretics may lead to hyperkalemia. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.

Corticosteroids: may increase the risk of gastrointestinal ulcers and bleeding.

Digoxin, phenytoin, lithium: concomitant use of ibuprofen with digoxin, phenytoin, or lithium may increase plasma concentrations of these drugs. Routine monitoring of serum levels of lithium, digoxin, and phenytoin is generally not required with appropriate use.

Methotrexate: administration of ibuprofen within 24 hours before or after methotrexate may increase methotrexate plasma concentrations and enhance its toxic effects.

Zidovudine: increased risk of hematological toxicity is known when zidovudine is used concomitantly with NSAIDs. Evidence suggests an increased risk of hemarthrosis and hematomas 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 cardiac glycosides.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

Cyclosporine, tacrolimus: increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, as they may reduce its efficacy.

Quinolone antibiotics: concomitant use with ibuprofen may increase the risk of seizures.

Sulfonylurea agents and phenytoin: clinical studies indicate interactions between NSAIDs and antidiabetic sulfonylurea drugs. Although interaction between ibuprofen and sulfonylureas has not been fully described, monitoring of blood glucose levels is recommended as a precaution when these drugs are used concomitantly.

Probenecid and sulfinpyrazone: drugs containing probenecid or sulfinpyrazone may delay the elimination of ibuprofen from the body.

Special precautions for use.

The adverse effects associated with the use of ibuprofen can generally be minimized by using the lowest effective dose required to relieve symptoms for the shortest duration necessary.

Caution should be exercised when treating patients with:

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

Effects on the cardiovascular and cerebrovascular systems.

Patients with a history of arterial hypertension and/or mild to moderate 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 with ibuprofen and other NSAIDs.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), may lead to a small increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (e.g., ≤1200 mg per day) increases the risk of arterial thrombotic complications.

Patients with uncontrolled arterial 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 consideration. High doses of the drug (2400 mg per day) should be avoided. Patients with risk factors for cardiovascular complications (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) should initiate long-term therapy only after careful evaluation, especially if high doses of ibuprofen (2400 mg per day) 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 the respiratory system.

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

Other NSAIDs.

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

Systemic lupus erythematosus (SLE) and mixed connective tissue disorders.

Ibuprofen should be used with caution in patients with manifestations of SLE and mixed connective tissue disorders due to an increased risk of aseptic meningitis.

Effects on the kidneys.

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

In dehydrated children and adolescents, there is a risk of developing renal failure.

Effects on the liver.

Caution should be exercised when treating patients with impaired liver 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 (referring to a dose of 2400 mg per day and treatment duration exceeding 10 days) may impair female fertility and is not recommended for women attempting to conceive. This medication should be discontinued in women experiencing difficulties in conceiving 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, ulcers, or perforation, which may be fatal, have been reported and may occur 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, 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. These patients should start treatment with the lowest doses. Caution is advised in patients receiving concomitant medications that may increase the risk of gastropathy or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), or antiplatelet agents (e.g., acetylsalicylic acid). For long-term treatment, combined therapy with misoprostol or proton pump inhibitors should be considered by the physician for these patients, as well as for patients requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk.

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

Severe skin adverse reactions (SSARs).

Severe 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 such reactions occurred within the first month. If signs or symptoms suggestive of these reactions appear, ibuprofen should be discontinued immediately, and alternative treatment should be considered (if necessary).

Regular monitoring of liver function, kidney function, and blood tests should be performed during prolonged use of ibuprofen.

Prolonged use of any analgesic used for headaches may lead to worsening of headaches. In such cases, the patient should consult a physician, and the medication should be discontinued. Medication-overuse headache may be suspected in patients who experience frequent or daily headaches despite regular analgesic use or as a result of such use.

Masking symptoms of underlying infections.

Imet® may mask symptoms of infectious disease, potentially delaying the initiation of appropriate treatment and thereby complicating the course of the illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Imet® is used for fever or pain relief in infections, monitoring of the infectious condition is recommended. In home treatment, the patient should consult a physician if symptoms persist or worsen (see also section "Adverse reactions. Infections and infestations").

In rare cases, varicella may lead to serious skin and soft tissue infections. It is currently not possible to completely rule out a potential link between NSAID use and worsening of such infections. Therefore, it is advisable to avoid the use of ibuprofen in cases of varicella.

Concomitant alcohol consumption during NSAID therapy may increase the risk of adverse reactions related to the active substance, particularly affecting the gastrointestinal tract or central nervous system.

This medicinal product contains less than 1 mmol of sodium (23 mg) per film-coated tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest 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. In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryonic/fetal mortality. Additionally, increased incidences of various developmental abnormalities, including cardiovascular defects, 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 may occur soon after initiation of treatment and is usually reversible upon discontinuation. Furthermore, cases of arterial duct constriction have been reported after second-trimester treatment, most of which resolved after stopping treatment. Therefore, ibuprofen should not be used during the first two trimesters of pregnancy unless absolutely necessary. Women attempting to conceive or during the first and second trimesters of pregnancy should use the lowest possible dose of ibuprofen 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. Ibuprofen use should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, the use of any prostaglandin synthesis inhibitor may pose the following risks:

to the fetus:
- cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
- impaired kidney function, which may progress to renal failure with manifestations of oligohydramnios (see above);
to the mother towards the end of pregnancy and to the newborn:
- prolonged bleeding time, antiplatelet 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 studies, ibuprofen has been detected in breast milk in very low amounts; thus, 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 drug does not affect reaction speed when driving or operating machinery. Patients who experience dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving or operating machinery. These effects are intensified when the drug is combined with alcohol consumption.

Method of Administration and Dosage

For oral use, intended for short-term use only.

Adults and children aged 12 years and older.

Take 1 tablet every 4 hours. Tablets should be swallowed whole with a large amount of liquid, taken during or after a meal.

Do not take more than 3 tablets within 24 hours. The maximum daily dose is 1200 mg.

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

If symptoms persist for more than 3 days in children or more than 4 days when treating pain in adults, a physician should be consulted.

Patients with sensitive stomachs are advised to take Imed® during meals.

Elderly patients do not require special dosage adjustments.

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

Children.

Do not use in children under 12 years of age.

Overdose.

In children, ingestion of more than 40 mg/kg of ibuprofen may cause symptoms of intoxication. In adults, the dose-response relationship is less pronounced. The half-life in overdose is 1.5–3 hours.

Symptoms.

In most patients participating in clinical trials, ingestion of large amounts of NSAIDs caused only nausea, vomiting, epigastric pain, or 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 also occur. Severe intoxication may lead to hyperkalemia and metabolic acidosis, acute renal failure, liver damage, arterial hypotension, respiratory depression, and cyanosis. In patients with bronchial asthma, exacerbation of asthma symptoms may occur.

Prolonged use at doses exceeding the recommended levels or overdose may lead to the development of renal tubular acidosis and hypokalemia.

Treatment.

Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of vital functions until the patient's 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 enhance urinary excretion of the acidic ibuprofen.

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

Side effects.

Gastrointestinal reactions are the most commonly observed, and they are mostly dose-dependent. Side effects are least common when the maximum daily dose is 1200 mg.

Clinical trial data indicate that the use of ibuprofen, especially at high doses (2400 mg per day), slightly increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

Side effects associated with ibuprofen use are classified by organ systems and frequency of occurrence: very common (> 1/10), common (> 1/100 – < 1/10), uncommon (> 1/1000 – < 1/100), rare (> 1/10000 – < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated due to limited available data).

Cardiac disorders.

Very rare: palpitations, heart failure, myocardial infarction.

Frequency not known: Kounis syndrome.

Gastrointestinal disorders.

Common: gastrointestinal complaints such as heartburn, abdominal pain, nausea, vomiting, flatulence, diarrhea, constipation, and minor gastrointestinal bleeding, which in exceptional cases may lead to anemia.

Uncommon: gastrointestinal ulcers with possible risk of bleeding and perforation (sometimes fatal, especially in elderly patients), ulcerative stomatitis, exacerbation of colitis and Crohn’s disease, gastritis.

Very rare: esophagitis, pancreatitis, formation of diaphragm-like intestinal strictures.

Frequency not known: dyspepsia, melena, hematemesis, jaundice.

Nervous system disorders.

Uncommon: central nervous system disturbances such as headache, dizziness, insomnia, restlessness, irritability, or increased fatigue.

Rare: vertigo.

Very rare: aseptic meningitis (see below); individual symptoms (nuchal rigidity, headache, nausea, vomiting, fever, or confusion) may occur 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 disorders.

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

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

Hepatobiliary disorders.

Very rare: liver function abnormalities, liver damage—especially during prolonged therapy—liver failure, acute hepatitis.

Vascular disorders.

Very rare: arterial hypertension.

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

Skin and subcutaneous tissue disorders.

Rare: various skin rashes.

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

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

Blood and lymphatic system disorders.

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

Psychiatric disorders.

Rare: psychiatric disorders, depression, insomnia, restlessness, hallucinations, confusion.

Eye disorders.

Uncommon: visual disturbances, optic neuritis—may occur during prolonged treatment.

Ear and labyrinth disorders.

Rare: tinnitus and dizziness—may occur during prolonged treatment.

Immune system disorders.

Uncommon: hypersensitivity reactions accompanied by skin rash, urticaria, and pruritus, as well as asthma attacks (in some cases associated with decreased blood pressure).

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

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

Infections and infestations.

Very rare: exacerbations of inflammation associated with infection (e.g., development of necrotizing fasciitis) have been reported in temporal association with NSAID use. This may be related to the mechanism of action of NSAIDs.

If signs of infection appear or worsen during ibuprofen use, patients are advised to seek immediate medical attention. The need for anti-infective/antibacterial therapy should be evaluated.

General disorders.

Malaise and fatigue, irritability.

Laboratory findings.

Very rare: decreased hemoglobin levels.

Description of selected adverse reactions.

There have been reports of hypersensitivity reactions following ibuprofen treatment. These include non-specific allergic reactions and anaphylaxis, respiratory tract reactions such as bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea, and 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).

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 after drug discontinuation). In particular, isolated cases of aseptic meningitis symptoms (such as nuchal rigidity, headache, nausea, vomiting, fever, or confusion) have been reported in patients with autoimmune disorders (e.g., systemic lupus erythematosus, mixed connective tissue disease) during ibuprofen treatment.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep the medicinal product out of the reach of children.

Packaging. 10 tablets per blister; 1, 2, or 3 blisters per cardboard box.

Classification. Over-the-counter (without prescription).

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's address and place of business.

Glienicker Weg 125, 12489 Berlin, Germany.

Date of last revision.