Brufen® retard

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRUFEN® RETARD (BRUFEN® RETARD)

Composition:

Active ingredient: ibuprofen;

Each tablet contains 800 mg of ibuprofen;

Excipients: xanthan gum, povidone, stearic acid, colloidal anhydrous silicon dioxide;
Tablet coating: hypromellose, talc, titanium dioxide (E 171).

Pharmaceutical form. Prolonged-release tablets, film-coated.

Main physicochemical properties: white, capsule-shaped tablets, film-coated.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Ibuprofen. ATC code M01A E01.

Pharmacological Properties

Pharmacodynamics

Ibuprofen is a propionic acid derivative and a nonsteroidal anti-inflammatory drug (NSAID) that exerts analgesic, anti-inflammatory, and antipyretic effects. The therapeutic effects of the drug are believed to be due to its inhibitory action on the cyclooxygenase enzyme, resulting in a marked reduction in prostaglandin synthesis. These properties provide relief from inflammation, pain, and fever.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid/aspirin on platelet aggregation when both drugs are administered concomitantly. Some pharmacodynamic studies have shown that a single 400 mg dose of ibuprofen taken 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid/aspirin (81 mg) reduced the effect of acetylsalicylic acid/aspirin on thromboxane formation or platelet aggregation. Although there is uncertainty about extrapolating these findings to clinical situations, the possibility cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid/aspirin. Clinically significant effects are unlikely with occasional, non-regular use of ibuprofen (see section "Interaction with other medicinal products and other forms of interaction").

Pharmacokinetics

The pharmacokinetic profile of BRUFEN® RETARD in the form of prolonged-release film-coated tablets, compared to the pharmacokinetic profile of the immediate-release tablet formulation at a dose of 400 mg, demonstrated that the prolonged-release (slow-release) formulation smooths out the peak increases and decreases in active substance concentration characteristic of immediate-release tablets and provides higher levels of the active substance at 5, 10, 15, and 24 hours. The area under the plasma concentration-time curve (AUC) after administration of the prolonged-release tablets was nearly identical to that observed with immediate-release tablets.

Mean plasma profiles and plasma concentrations prior to the next dose were not significantly different between young and elderly subjects. According to several studies, BRUFEN® RETARD demonstrated a plasma profile with two peak concentrations when administered on an empty stomach. The elimination half-life of ibuprofen is approximately 2 hours. Ibuprofen is metabolized in the liver into two inactive metabolites, which are excreted by the kidneys along with unchanged ibuprofen, either in free form or as conjugates. Renal excretion is rapid and complete. Ibuprofen is highly bound to plasma proteins.

Clinical characteristics

Indications

• Rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, osteoarthritis, and other non-rheumatoid (seronegative) arthropathies.
• Non-articular rheumatic and periarticular disorders such as periarthritis of the shoulder (capsulitis), bursitis, tendinitis, tenosynovitis, and low back pain; soft tissue injuries such as sprains and strains.
• Relief of mild to moderate pain, such as dysmenorrhea, dental pain, and postoperative pain, as well as symptomatic relief of headache, including migraine.

Contraindications

Known hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Hypersensitivity reactions (e.g., asthma, urticaria, angioedema, or rhinitis) that occurred following administration of ibuprofen, acetylsalicylic acid/aspirin, or other nonsteroidal anti-inflammatory drugs (NSAIDs) in the patient's history.

Severe heart failure (NYHA functional class IV).

Severe hepatic impairment.

Severe renal impairment (glomerular filtration rate < 30 mL/min).

Conditions associated with an increased risk of bleeding or active bleeding.

Gastrointestinal bleeding or perforation due to previous use of NSAIDs in the patient's history.

Acute or previously experienced ulcerative colitis, Crohn's disease, recurrent peptic ulcer, or gastrointestinal bleeding (two or more separate episodes of confirmed ulceration or bleeding).

Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

Concomitant use with the following medications requires caution due to possible drug interactions observed in some patients.

Antihypertensive agents, β-blockers, and diuretics. NSAIDs may reduce the effect of antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, and diuretics. Diuretics may also increase the risk of nephrotoxicity associated with NSAIDs.

Cardiac glycosides. NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides.

Cholestyramine. Concomitant administration of ibuprofen and cholestyramine may reduce the absorption of ibuprofen in the gastrointestinal tract (GI tract). However, the clinical significance of this interaction is unknown.

Lithium. NSAIDs may reduce lithium excretion.

Methotrexate. NSAIDs may inhibit tubular secretion of methotrexate and reduce methotrexate clearance.

Cyclosporine. Increased risk of nephrotoxicity when used concomitantly with NSAIDs.

Mifepristone. Reduced efficacy of the drug is theoretically possible due to the anti-prostaglandin properties of NSAIDs, including acetylsalicylic acid. Limited data suggest that concomitant use of NSAIDs on the day of prostaglandin administration does not adversely affect mifepristone or prostaglandin effects on cervical ripening or uterine contractility, and does not reduce their clinical efficacy in medical termination of pregnancy.

Other analgesics/NSAIDs, including selective COX-2 inhibitors. Concomitant administration of two or more NSAIDs, including selective inhibitors of cyclooxygenase-2, should be avoided due to increased risk of adverse effects (see section "Special precautions for use**"**).

Acetylsalicylic acid/aspirin. As with other NSAID-containing products, concomitant use of ibuprofen and acetylsalicylic acid/aspirin is generally not recommended due to the risk of increased adverse reactions.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid/aspirin on platelet aggregation when used concomitantly. Although uncertainties exist regarding the extrapolation of these data to clinical situations, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Clinically significant effects are unlikely with occasional use of ibuprofen (see section "Pharmacological properties. Pharmacodynamics").

Corticosteroids. Increased risk of gastrointestinal ulceration or bleeding when used concomitantly with NSAIDs (see section "Special precautions for use**"**).

Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use**"**).

Quinolone antibiotics. Data from animal studies indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients receiving NSAIDs and quinolones concomitantly have an increased risk of developing seizures.

Sulfonylureas. NSAIDs may potentiate the effects of sulfonylurea agents. Rare cases of hypoglycemia have been reported in patients taking sulfonylureas during ibuprofen therapy.

Antiplatelet agents and selective serotonin reuptake inhibitors (e.g., clopidogrel and ticlopidine). Increased risk of gastrointestinal bleeding when used concomitantly with NSAIDs (see section "Special precautions for use**"**).

Tacrolimus. Possible increased risk of nephrotoxicity when NSAIDs are administered concomitantly with tacrolimus.

Zidovudine. NSAIDs increase the risk of hematological toxicity when administered concomitantly with zidovudine. Evidence exists for increased risk of hemarthrosis and hematomas in HIV-positive patients with hemophilia receiving ibuprofen while on zidovudine therapy.

Aminoglycosides. NSAIDs may reduce the elimination of aminoglycosides.

Herbal extracts. Ginkgo biloba may potentiate the risk of bleeding associated with NSAID use.

CYP2C9 inhibitors. Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase ibuprofen exposure (CYP2C9 substrate). One study demonstrated that voriconazole and fluconazole (CYP2C9 inhibitors) increased S(+)-ibuprofen exposure by approximately 80–100%. Dose reduction of ibuprofen should be considered when co-administered with potent CYP2C9 inhibitors, particularly when high doses of ibuprofen are used concomitantly with voriconazole or fluconazole.

Special precautions for use

General warnings

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration", as well as information on gastrointestinal and cardiovascular risks and masking of symptoms of underlying infections below).

Prolonged use of any analgesic may lead to medication-overuse headache, which should not be treated by increasing the dose of the medicinal product.

Concomitant use of NSAIDs with alcohol may increase adverse effects related to the active substance, particularly those affecting the gastrointestinal tract or central nervous system.

Elderly patients

The frequency of adverse reactions during NSAID use is higher in elderly patients, especially gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

Children

In dehydrated children and adolescents, there is a risk of impaired renal function.

Gastrointestinal bleeding, ulceration and perforation

NSAIDs should be used with caution in patients with a history of peptic ulcer or other gastrointestinal disorders, as their condition may worsen (see section "Contraindications").

Gastrointestinal bleeding, ulceration or perforation have been reported during treatment with all NSAIDs at any time during therapy. These adverse reactions may be fatal and may occur with or without warning symptoms or serious gastrointestinal disorders in history.

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest available dose. Consideration should be given to concomitant use of protective agents (e.g. misoprostol or proton pump inhibitors) in these patients, as well as in those concurrently taking low-dose acetylsalicylic acid/aspirin or other drugs increasing the risk of gastrointestinal injury (see below and section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided due to increased risk of ulceration or bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Patients, especially elderly individuals, with a history of gastrointestinal disorders should report any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially during initial stages of treatment.

Ibuprofen should be prescribed with caution to patients receiving concomitant therapy with drugs that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g. warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid/aspirin (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in a patient receiving ibuprofen, treatment with the drug should be discontinued.

Respiratory disorders and hypersensitivity reactions

Ibuprofen should be used with caution in patients with bronchial asthma, chronic rhinitis, or allergic conditions, or with a history thereof, as NSAIDs have been reported to induce bronchospasm, urticaria or angioedema in such patients.

Cardiac, renal and hepatic function disorders

NSAID use may cause dose-dependent reduction in prostaglandin formation and lead to renal impairment. Regular concomitant use of such analgesics further increases this risk. Patients at highest risk of such reactions include those with impaired renal, cardiac or hepatic function, those taking diuretics, and elderly patients. These patients should use the lowest effective dose for the shortest possible duration, and renal function should be monitored, especially during prolonged treatment (see section "Contraindications").

Ibuprofen should be prescribed with caution in patients with a history of heart failure or arterial hypertension, as edema has been reported during ibuprofen therapy.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and medical supervision are required in patients with a history of hypertension and/or mild to moderate congestive heart failure, as fluid retention and edema have been reported during NSAID therapy.

Clinical studies indicate that ibuprofen use, especially at high doses (2400 mg daily), may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Overall, epidemiological studies do not suggest a clear association between low-dose ibuprofen use (i.e. ≤ 1200 mg daily) and increased risk of arterial thrombotic events.

Ibuprofen should be prescribed to patients with uncontrolled hypertension, congestive heart failure (NYHA functional class II–III), diagnosed ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease only after careful consideration, and high doses (2400 mg daily) should be avoided.

Careful consideration is also required before initiating long-term ibuprofen therapy in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes, smoking), particularly if high-dose ibuprofen (2400 mg daily) is required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen therapy. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Renal effects

Treatment with ibuprofen should be initiated with caution in patients with significant dehydration. There is a risk of impaired renal function, particularly in dehydrated children, adolescents and elderly patients.

As with other NSAIDs, prolonged use of ibuprofen may lead to renal papillary necrosis and other pathological renal changes. Nephrotoxic effects have also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. Administration of NSAIDs to such patients may cause dose-dependent reduction in prostaglandin formation and, consequently, reduced renal blood flow, potentially leading to renal failure. High-risk patients include those with impaired renal, cardiac or hepatic function, those taking diuretics or angiotensin-converting enzyme (ACE) inhibitors, and elderly patients. Discontinuation of NSAIDs is usually followed by recovery to the pre-treatment condition.

Renal tubular acidosis and hypokalemia may occur after acute overdose and with long-term use of high-dose ibuprofen (typically longer than 4 weeks), including doses exceeding the recommended daily dose.

Systemic lupus erythematosus and mixed connective tissue disorders

Patients with systemic lupus erythematosus and mixed connective tissue disorders may have an increased risk of aseptic meningitis (see below and section "Adverse reactions").

Cutaneous effects

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 during ibuprofen use (see section "Adverse reactions"). Most such reactions occurred within the first month of therapy. If signs or symptoms suggestive of these reactions occur, ibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

In rare cases, serious skin and soft tissue infections may occur during chickenpox. Currently, a potential role of NSAIDs in worsening these infections cannot be excluded. Therefore, it is recommended to avoid ibuprofen use in active chickenpox.

Hematological effects

Ibuprofen, like other NSAIDs, may inhibit platelet aggregation and prolong bleeding time in healthy volunteers.

Aseptic meningitis

Rarely, aseptic meningitis has been observed in patients treated with ibuprofen. Although aseptic meningitis is more likely to occur in patients with systemic lupus erythematosus and related connective tissue disorders, cases have been reported in patients without these chronic conditions.

Masking symptoms of underlying infections

Like other NSAIDs, ibuprofen may mask symptoms of infectious disease, potentially delaying initiation of appropriate treatment and thereby complicating the course of illness. This has been observed in bacterial community-acquired pneumonia and bacterial complications of chickenpox. When ibuprofen is used for fever or pain relief during infection, monitoring for infectious disease progression is recommended. In outpatient settings, patients should seek medical advice if symptoms persist or worsen.

Use during pregnancy or breastfeeding

Fertility

Ibuprofen use may impair female fertility and is not recommended for women attempting to conceive. Women experiencing infertility or undergoing fertility investigations should consider discontinuing ibuprofen.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. This risk is believed to increase with dose and duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryo/fetal mortality. Furthermore, increased incidence of various malformations, including cardiovascular, has been reported in animals exposed to prostaglandin synthesis inhibitors during organogenesis. From the 20th week of gestation, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there are reports of ductus arteriosus constriction after second-trimester treatment, which in most cases resolves after treatment cessation. Therefore, ibuprofen should be used during the first and second trimesters only if clearly necessary. In women attempting conception or during the first or second trimester of pregnancy, the dose should be as low as possible and duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be appropriate after several days of ibuprofen exposure starting from the 20th gestational week. The use of ibuprofen-containing medicinal products should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus, leading to:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension),
• renal dysfunction (see above).

At the end of pregnancy, prostaglandin synthesis inhibitors in the mother and newborn may lead to:

• possible prolongation of bleeding time, antiplatelet effect, which may occur even at very low doses;
• inhibition of uterine contractions, potentially leading to delayed or prolonged labor.

Therefore, ibuprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Labour and delivery

Ibuprofen is not recommended during labour and delivery.

Onset of labour may be delayed, its duration prolonged, and the risk of bleeding in both mother and child may increase.

Breastfeeding

Available limited studies show that NSAIDs are excreted in breast milk in very low concentrations. Use of NSAIDs in breastfeeding women should be avoided, if possible.

Ability to affect driving and operating machinery

Ibuprofen may impair patients' reaction speed, which should be considered when performing activities requiring high concentration, such as driving or operating machinery. This effect is significantly enhanced when combined with alcohol.

Adverse events such as dizziness, somnolence, malaise/fatigue and visual disturbances may occur after NSAID use. If such events occur, patients should refrain from driving and operating machinery.

Method of Administration and Dosage

Doses

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").

Adults and children aged 12 years and older

The recommended dose of BRUFEN® RETARD is two tablets taken simultaneously once daily, preferably in the early evening, well before bedtime. Tablets should be swallowed whole with sufficient fluid. Tablets must not be chewed, divided, crushed, or sucked to avoid oral discomfort and throat irritation. In severe or acute conditions, the total daily dose may be increased to three tablets, divided into two doses throughout the day.

Elderly patients

There is an increased risk of serious adverse reactions in elderly patients. If NSAID therapy is necessary, the lowest effective dose should be used for the shortest possible duration. Patients should be monitored regularly for gastrointestinal bleeding during NSAID therapy. In cases of renal or hepatic impairment, dosage should be individually adjusted.

Renal impairment

For information on use in patients with mild or moderate renal impairment, see section "Special Warnings and Precautions for Use"; for patients with severe renal impairment, see section "Contraindications".

Hepatic impairment

For information on use in patients with mild or moderate hepatic impairment, see section "Special Warnings and Precautions for Use"; for patients with severe hepatic impairment, see section "Contraindications".

Method of administration

For oral use. It is preferable to take the medication during or after a meal. Taking the drug shortly after food intake may delay the onset of effect. Patients with a sensitive gastrointestinal tract should take the medication during meals.

Children

BRUFEN® RETARD is not intended for use in children under 12 years of age.

Overdose

Toxicity

Signs and symptoms of toxicity are generally not observed at doses below 100 mg/kg in children and adults. However, supportive measures may be required in some cases. In children, signs and symptoms of toxicity have been reported after ingestion of 400 mg/kg or more.

Symptoms

In most patients, symptoms of overdose develop within 4–6 hours after ingestion of a significant amount of ibuprofen.

The most common symptoms of overdose include nausea, vomiting, abdominal pain, lethargy, and drowsiness. Central nervous system (CNS) manifestations: headache, tinnitus, dizziness, seizures, and loss of consciousness. Rarely reported are nystagmus, metabolic acidosis, hypothermia, renal symptoms, gastrointestinal bleeding, coma, apnea, diarrhea, and CNS and respiratory depression. In severe poisoning, metabolic acidosis may occur and prothrombin time/international normalized ratio (INR) may increase, likely due to interaction with circulating coagulation factors. Cases of disorientation, agitation, unconsciousness, and cardiovascular toxicity including arterial hypotension, bradycardia, and tachycardia have been reported.

Significant overdose may lead to renal failure and hepatic injury. Substantial overdose is generally well tolerated if no other drugs have been co-ingested.

Prolonged use at doses exceeding recommendations may lead to severe hypokalemia and renal tubular acidosis. Symptoms may include decreased level of consciousness and generalized weakness (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects").

Treatment

There is no specific antidote for ibuprofen overdose. Treatment should be symptomatic as needed. Activated charcoal should be administered within one hour of ingestion of a potentially toxic amount of ibuprofen. If the ingested dose exceeds 400 mg/kg, gastric lavage or gastric emptying is recommended within one hour of ingestion, along with supportive measures. Ensure adequate diuresis.

Renal and hepatic function should be closely monitored. If necessary, correct serum electrolyte imbalances.

After ingestion of a potentially toxic amount, the patient should be observed for at least four hours.

Frequent or prolonged seizures should be treated with intravenous diazepam. Other interventions may be indicated depending on the patient's clinical condition.

For the most up-to-date information, contact the local poison control center.

Adverse Reactions

The nature of adverse reactions to ibuprofen is similar to that observed with other NSAIDs.

Gastrointestinal system

Adverse reactions affecting the gastrointestinal tract (GIT) are the most commonly observed. Peptic ulcers, gastrointestinal perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, gastrointestinal bleeding, and exacerbation of colitis and Crohn’s disease have been reported during ibuprofen use (see section "Contraindications"). Gastritis, duodenal ulcer, gastric ulcer, and gastrointestinal perforation have been observed less frequently.

Immune system

Hypersensitivity reactions have been reported with NSAID use. These include: non-specific allergic reactions and anaphylaxis; respiratory tract reactivity, including asthma, worsening of asthma, bronchospasm, or dyspnea; various skin manifestations, including rashes of different types, pruritus, urticaria, purpura, angioedema, and very rarely, erythema multiforme, bullous dermatoses (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

Cardiovascular system

Edema, hypertension, and heart failure have been reported in association with NSAID therapy. Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), may slightly increase the risk of arterial thrombotic events such as myocardial infarction or stroke (see section "Special precautions").

Infections and infestations

Rhinitis and aseptic meningitis (particularly in patients with pre-existing autoimmune disorders such as systemic lupus erythematosus and mixed connective tissue diseases) with symptoms such as neck stiffness, headache, nausea, vomiting, fever, or disorientation have been reported (see section "Special precautions").

Cases of worsening of skin infections (e.g., development of necrotizing fasciitis) have been described during NSAID therapy. If signs of infection appear or worsen during ibuprofen treatment, the patient should seek immediate medical attention.

Skin and subcutaneous tissue disorders

In rare cases, severe skin infections and soft tissue complications may occur during varicella (chickenpox) (see also "Infections and infestations").

The following adverse reactions, potentially associated with ibuprofen, are classified by frequency and organ systems according to MedDRA.

Adverse reactions are categorized by frequency 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 from available data).

Infections and infestations: uncommon – rhinitis; rare – aseptic meningitis (see section "Special precautions").

Blood and lymphatic system disorders: rare – leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Immune system disorders: uncommon – hypersensitivity; rare – anaphylactic reaction.

Psychiatric disorders: uncommon – insomnia, anxiety disorders; rare – depression, confusion.

Nervous system disorders: common – headache, dizziness; uncommon – paresthesia, somnolence; rare – optic neuritis.

Eye disorders: uncommon – visual disturbances; rare – toxic optic neuropathy.

Ear and labyrinth disorders: uncommon – hearing impairment, tinnitus, vertigo.

Respiratory, thoracic and mediastinal disorders: uncommon – bronchial asthma, bronchospasm, dyspnea.

Gastrointestinal disorders: common – dyspepsia, diarrhea, nausea, vomiting, abdominal pain, flatulence, constipation, melena, hematemesis, gastrointestinal bleeding; uncommon – gastritis, duodenal ulcer, gastric ulcer, ulcerative stomatitis, gastrointestinal perforation; very rare – pancreatitis; frequency not known – exacerbation of colitis and Crohn’s disease.

Hepatobiliary disorders: uncommon – hepatitis, jaundice, liver function abnormalities; very rare – liver failure.

Skin and subcutaneous tissue disorders: common – rash; uncommon – urticaria, pruritus, purpura, angioedema; very rare – serious skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis); frequency not known – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions.

Metabolism and nutrition disorders: frequency not known – decreased appetite, hypokalemia*.

Renal and urinary disorders: uncommon – toxic nephropathy in various forms, including tubulointerstitial nephritis, nephrotic syndrome, and renal failure; very rare – acute renal failure; frequency not known – ureteric colic, dysuria, renal tubular acidosis*.

General disorders and administration site conditions: common – malaise/fatigue; rare – edema.

Cardiac disorders: very rare – heart failure, myocardial infarction (also see section "Special precautions"); frequency not known – Kounis syndrome.

Vascular disorders: very rare – arterial hypertension.

* Renal tubular acidosis and hypokalemia have been reported during the post-marketing period, usually after prolonged use of ibuprofen at doses higher than recommended.

Reporting suspected adverse reactions after a medicinal product is authorized is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 10 tablets in a blister, 1 or 2 blisters per cardboard box; 14 tablets in a blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. Famar A.V.E. Anthoussa Plant, Greece / Famar A.V.E. Anthoussa Plant, Greece.

Manufacturer's address and location of its business activity. Anthousa Avenue 7, Anthousa Attiki, 15349, Greece / Anthousa Avenue 7, Anthousa Attiki, 15349, Greece.