Eurofast combo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUROFAST COMBI (EUROFAST COMBI)

Composition:

Active substances: ibuprofen; paracetamol;

1 soft capsule contains ibuprofen 200 mg and paracetamol 500 mg;

Excipients: polyethylene glycol 400 (macrogol 400), propylene glycol, potassium hydroxide, purified water;

capsule shell: gelatin 180 Bloom, glycerin, sorbitol solution, partially dehydrated (Polysorb® 85/70/00), titanium dioxide, iron oxide red, iron oxide yellow, purified water.

Pharmaceutical form. Soft capsules.

Main physicochemical properties: soft gelatin capsules of oval shape, opaque white on one side and opaque light brown on the other, containing a suspension ranging from almost white to white in color.

Pharmacotherapeutic group.

Drugs for treatment of the musculoskeletal system, anti-inflammatory and antirheumatic agents, non-steroidal agents, propionic acid derivatives. Ibuprofen, combinations.

ATC code M01AE51.

Pharmacological Properties

Pharmacodynamics

The pharmacological effects of ibuprofen and paracetamol differ in site and mechanism of action, but are synergistic, resulting in enhanced analgesic and antipyretic properties compared to either substance used alone.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a propionic acid derivative, which has demonstrated efficacy in inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. Ibuprofen exerts analgesic, antipyretic, and anti-inflammatory effects. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively reduce the effect of low-dose acetylsalicylic acid on platelet aggregation when both agents are used 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 impact of acetylsalicylic acid on thromboxane formation or platelet aggregation. Although uncertainty exists regarding extrapolation of these findings 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 interaction is considered unlikely with occasional, non-systematic use of ibuprofen.

The mechanism of action of paracetamol is not yet fully elucidated, but there is strong evidence for central nervous system analgesic activity. Biochemical studies suggest inhibition of cyclooxygenase-2 (COX-2) activity in the central nervous system. Paracetamol may also stimulate descending serotonergic (5-hydroxytryptamine) pathways that suppress pain signal transmission in the spinal cord.

This medication is particularly suitable for treating pain requiring stronger analgesia than that provided by ibuprofen 400 mg or paracetamol 1000 mg alone. Studies using this combination in models of acute pain (postoperative dental pain) and chronic knee joint pain have demonstrated high efficacy in reducing intensity of acute pain (93.2%) and in long-term management of chronic pain (60.2%). This drug has a rapid onset of action, with confirmed noticeable pain relief occurring on average within 18.3 minutes. Significant pain reduction occurs on average within 44.6 minutes. The analgesic effect of this medication is substantially longer (9.1 hours) compared to paracetamol 500 mg (4 hours).

Pharmacokinetics

Ibuprofen is rapidly absorbed from the gastrointestinal tract and is highly bound to plasma proteins. Ibuprofen is detectable in plasma within 5 minutes and reaches peak plasma concentration within 1–2 hours after fasting administration. It is metabolized in the liver and excreted by the kidneys. The elimination half-life is approximately 2 hours.

Paracetamol is rapidly absorbed from the gastrointestinal tract. At therapeutic concentrations, plasma protein binding is low, although it is dose-dependent. Paracetamol is detectable in plasma within 5 minutes and reaches peak plasma concentration within 0.5–0.67 hours after fasting administration.

Paracetamol is metabolized in the liver and excreted in urine primarily as conjugated metabolites. Less than 5% is excreted unchanged. A hydroxylated metabolite, formed in very small amounts in the liver via mixed-function oxidases and normally detoxified by conjugation with hepatic glutathione, may accumulate in cases of paracetamol overdose and cause hepatotoxicity. The elimination half-life is approximately 3 hours. No significant differences in the pharmacokinetic profiles of paracetamol and ibuprofen have been observed in elderly patients. The bioavailability and pharmacokinetic profiles of ibuprofen and paracetamol in this formulation are not altered following single or repeated doses of this combination.

The formulation of this medication utilizes a technology designed to ensure simultaneous release of ibuprofen and paracetamol, thereby potentiating the effects of each active ingredient.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain associated with migraine, headache, back pain, menstrual pain, dental pain, rheumatic and muscular pain, mild forms of arthritis, symptoms of cold and flu, sore throat, and fever. This medication is particularly suitable for managing pain requiring stronger analgesic effect than that provided by ibuprofen or paracetamol when used separately.

Contraindications.

This medication is contraindicated:

• in patients with known hypersensitivity to ibuprofen, paracetamol, or any other component of the formulation;
• in patients with a history of hypersensitivity reactions (e.g., bronchospasm, angioedema, bronchial asthma, rhinitis, or urticaria) following the intake of ibuprofen, acetylsalicylic acid, or other NSAIDs;
• in active or history of peptic ulcer or gastrointestinal bleeding (two or more documented episodes of peptic ulcer or bleeding);
• in patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy;
• in patients with coagulation disorders;
• in patients with severe hepatic, renal, or cardiac failure (NYHA Class IV);
• when used concomitantly with other paracetamol-containing medications due to increased risk of serious adverse reactions;
• when used concomitantly with other NSAID-containing medications, including COX-2 inhibitors and acetylsalicylic acid at daily doses exceeding 75 mg, due to increased risk of adverse effects;
• during the third trimester of pregnancy due to the risk of premature closure of the fetal ductus arteriosus with potential pulmonary hypertension.

Interaction with other medicinal products and other forms of interaction.

This medication, like other paracetamol-containing products, is contraindicated when used concomitantly with other paracetamol-containing medications due to increased risk of serious adverse reactions.

This medication (like other ibuprofen-containing and NSAID-containing products) should not be used in combination with the following medicinal agents:

Acetylsalicylic acid, as it may increase the risk of adverse effects, except when acetylsalicylic acid (at a dose not exceeding 75 mg per day) is prescribed by a physician.

Experimental data indicate that ibuprofen may inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. However, the clinical relevance of these findings is limited, and there is no conclusive evidence that regular long-term use of ibuprofen reduces the cardioprotective effect of low-dose acetylsalicylic acid. Clinically significant interactions are considered unlikely with occasional ibuprofen use.

Other NSAIDs (including selective COX-2 inhibitors), as their concomitant use may lead to an increased frequency of adverse effects.

This medication (like other paracetamol-containing products) should be used with caution in combination with the following medicinal agents:

Cholestyramine: The absorption rate of paracetamol is reduced by cholestyramine; therefore, paracetamol should be administered at least 1 hour before cholestyramine if maximum analgesia is required.

Metoclopramide and domperidone: The absorption of paracetamol is increased when co-administered with metoclopramide or domperidone; however, concomitant administration should not be avoided.

Warfarin: The anticoagulant effect of warfarin and other coumarins may be enhanced during prolonged regular use of paracetamol, increasing the risk of bleeding; occasional use has no significant effect.

This medication (like other ibuprofen-containing and NSAID-containing products) should be used with caution in combination with the following medicinal agents:

Anticoagulants: NSAIDs may potentiate the therapeutic effect of anticoagulants such as warfarin. The anticoagulant effect of warfarin and other coumarins may be enhanced during prolonged regular daily use of paracetamol, with a possible increased risk of bleeding.

Antihypertensive agents (ACE inhibitors and angiotensin II antagonists) 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 reduced renal function), concomitant use of an ACE inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be prescribed with caution, particularly in elderly patients. Adequate hydration should be ensured during prolonged therapy, and monitoring of renal function should be considered at the initiation of combination therapy and periodically thereafter. Diuretics may increase the risk of NSAID-induced nephrotoxicity.

Concomitant use of ibuprofen and potassium-sparing diuretics may lead to hyperkalemia (serum potassium monitoring is recommended).

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

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

Cyclosporine: Increased risk of nephrotoxicity.

Corticosteroids: May increase the risk of gastrointestinal adverse effects (gastrointestinal ulcers or bleeding).

Lithium: Reduced lithium excretion.

Methotrexate: Reduced methotrexate excretion.

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

Quinolone antibiotics: Animal studies suggest that NSAIDs may increase the risk of seizures associated with quinolone antibiotics; the risk of seizures increases when NSAIDs are used concomitantly with quinolones.

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 suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia who are receiving concomitant therapy with zidovudine and ibuprofen.

Flucloxacillin.

Caution should be exercised when paracetamol is used concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with an increased anion gap due to 5-oxoproline (pyroglutamic acid) accumulation, particularly in patients with risk factors (see section "Special precautions").

Special precautions for use.

Do not exceed recommended doses.

If symptoms worsen, medical advice should be sought.

Paracetamol should be administered with caution in patients with severe renal or hepatic impairment. The risk of paracetamol overdose is higher in patients with non-cirrhotic alcoholic liver disease. In case of overdose, immediate medical attention is required, even if the patient feels well, due to the risk of delayed severe liver damage.

Do not use other medications containing paracetamol. If this occurs, immediate medical advice should be sought, even if the patient feels well, as it may lead to overdose.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoprolinuria have been reported in patients with severe conditions such as severe renal dysfunction, sepsis, malnutrition, or other sources of glutathione deficiency (e.g., chronic alcoholism) who were treated long-term with therapeutic doses of paracetamol or a combination of paracetamol and flucloxacillin.

In suspected cases of HAGMA due to pyroglutamic acidosis, immediate discontinuation of paracetamol and close patient monitoring are recommended. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Adverse effects can be minimized by using the lowest effective dose needed to relieve symptoms, for the shortest duration necessary to control symptoms, and taken with food.

Respiratory effects. In patients with bronchial asthma or allergic disorders following NSAID use, or with such conditions in their medical history, bronchospasm may occur after administration.

Cardiovascular, hepatic, and renal impairment. NSAID use may cause dose-dependent reduction in prostaglandin synthesis and may lead to renal impairment. Patients at increased risk include those with impaired renal function, cardiac dysfunction, hepatic dysfunction, those taking diuretics, and elderly patients. Renal function should be monitored in such patients.

Effects on cardiovascular and cerebrovascular systems. Patients with a history of hypertension and/or heart failure should begin treatment cautiously (medical consultation is required), as fluid retention, hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs.

Clinical trial data indicate that ibuprofen use, especially at high doses (2400 mg daily), may be associated with an increased 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 daily) is associated with an increased risk of arterial thrombotic complications.

Ibuprofen should only be used in patients with uncontrolled hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease 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., 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 Eurofast Combi. 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.

Gastrointestinal effects.

Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported with NSAIDs, occurring at any stage of treatment, 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, a history of peptic ulcer (especially with complications such as bleeding or perforation), and in elderly patients. For these patients, treatment should be initiated with the lowest effective dose.

Concomitant therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered for these patients, as well as for those requiring concomitant low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk. Patients with a history of gastrointestinal disorders, particularly elderly patients, should be advised to report any adverse gastrointestinal symptoms (especially bleeding), particularly at the beginning of treatment.

The drug should be prescribed with caution to patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, or antiplatelet agents such as acetylsalicylic acid.

The occurrence of gastrointestinal bleeding or ulcers in patients receiving an ibuprofen-containing medication requires immediate discontinuation of the drug.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis and Crohn’s disease), as these conditions may worsen.

Systemic lupus erythematosus and mixed connective tissue disease. In patients with systemic lupus erythematosus and mixed connective tissue disease, the risk of aseptic meningitis may be increased.

Serious skin adverse reactions

Serious skin adverse reactions (SSARs), including exfoliative dermatitis, erythema multiforme, Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported with ibuprofen use (see section "Adverse reactions"). Most 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 therapy considered (if necessary).

Masking symptoms of underlying infections. The drug may mask symptoms of infectious disease, potentially delaying appropriate treatment and thereby complicating the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When the drug is used for fever or pain relief in infections, monitoring for infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Effect on female fertility. Limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible upon discontinuation of treatment. Women experiencing infertility or undergoing fertility investigations should avoid using the drug.

Elderly patients. The frequency of adverse reactions associated with NSAID use, particularly gastrointestinal bleeding or perforation (which may be fatal), is increased in elderly patients. If NSAID use is necessary, the lowest effective dose for the shortest possible duration should be used.

Patients should be regularly monitored for possible gastrointestinal bleeding during NSAID therapy.

Use during pregnancy or breastfeeding.

Pregnancy.

There is no experience with the use of the drug in pregnant women.

Extensive pregnancy data do not indicate either malformative or fetal/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have not yielded conclusive results. Paracetamol may be used during pregnancy if clinically necessary, but only at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Congenital anomalies have been reported after NSAID use in humans, but they are rare and usually lack a clear pattern. From the 20th week of gestation, the use of Eurofast Combi may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there are reports of arterial duct constriction after second-trimester treatment, most of which resolved after stopping treatment. Therefore, Eurofast Combi should not be prescribed during the first and second trimesters unless clearly necessary. If Eurofast Combi is used by a woman trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to Eurofast Combi for several days starting from the 20th gestational week. Eurofast Combi should be discontinued if oligohydramnios or arterial duct constriction is detected. Due to the known effects of NSAIDs on the fetal cardiovascular system (risk of premature closure of the arterial duct), the use of Eurofast Combi is contraindicated in the third trimester. Prolonged labor or increased duration of labor with a tendency to bleeding in both mother and child may occur. The drug should be avoided during the first and second trimesters and during labor; it is contraindicated during the third trimester of pregnancy.

Breastfeeding period.

Ibuprofen and its metabolites may pass into breast milk in very low concentrations (0.0008% of the maternal dose). Harmful effects on infants are unknown. Paracetamol is excreted in breast milk but in clinically insignificant amounts. Available published data do not contraindicate the use of the drug during breastfeeding. Therefore, there is no need to discontinue breastfeeding during short-term therapy with this drug at recommended doses.

Fertility.

The use of the drug may affect female fertility. This effect is reversible upon discontinuation of treatment. Therefore, the drug is not recommended for women with difficulty conceiving.

Ability to affect reaction speed when driving or operating machinery.

Adverse effects such as dizziness, drowsiness, fatigue, and visual disturbances may occur after taking NSAIDs. Patients experiencing such side effects should not drive or operate machinery.

Method of Administration and Dosage

For short-term oral use only.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Precautions").

Adults should take 1 capsule up to 3 times daily, with intervals between doses of at least 6 hours. Swallow capsules with water.

If 1 capsule does not relieve symptoms, 2 capsules per dose may be taken, but not more than 3 times daily. The interval between doses must be at least 6 hours. Do not exceed 6 capsules (3000 mg paracetamol, 1200 mg ibuprofen) per day.

If symptoms persist for more than 3 days, consult a physician for diagnosis clarification and treatment adjustment. The duration of treatment should be determined individually by a physician, depending on the course of the disease and the patient's condition.

To reduce the likelihood of adverse effects, it is recommended to take the medication during food intake.

Elderly Patients

Dosage adjustment is not required. However, elderly patients should be monitored particularly carefully due to the potential for adverse effects. If NSAID therapy is necessary, the lowest effective dose should be used for the shortest possible duration. Patients should regularly monitor for signs of possible gastrointestinal bleeding during NSAID therapy.

Children

Not recommended for children under 18 years of age.

Overdose

Paracetamol. Liver damage is possible in adults who have ingested 10 g (equivalent to 20 capsules) or more of paracetamol. Liver damage may occur with ingestion of 5 g (equivalent to 10 capsules) or more of paracetamol if:

• the patient has been receiving long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other enzyme-inducing drugs;
• the patient regularly consumes alcohol;
• the patient likely has glutathione deficiency, e.g., cystic fibrosis, HIV infection, cachexia, or fasting.

Symptoms. Symptoms of paracetamol overdose within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may manifest 12–48 hours after overdose, indicated by abnormal liver function tests. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may be fatal. Acute renal failure with acute tubular necrosis may present with severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment. Prompt medical intervention is required in cases of paracetamol overdose. The patient should be taken immediately to a hospital for medical evaluation, even if early symptoms are absent. Symptoms such as nausea and vomiting may be mild and do not necessarily reflect the severity of overdose or risk of organ damage. Treatment should be conducted according to established guidelines.

Consider administering activated charcoal within 1 hour of paracetamol ingestion. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier measurements are unreliable).

N-acetylcysteine treatment may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours of overdose. The efficacy of the antidote decreases sharply after this time.

If required, N-acetylcysteine should be administered intravenously according to established dosing regimens. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Patients with severe liver dysfunction within 24 hours of paracetamol ingestion should be treated according to established guidelines.

Ibuprofen. Ibuprofen overdose may occur with doses exceeding 400 mg/kg in children. In adults, dose-dependent effects are less pronounced. The half-life in overdose is 1.5–3 hours.

Symptoms. In most patients who have ingested clinically significant amounts of NSAIDs, symptoms may include nausea, vomiting, epigastric pain, and very rarely diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may manifest as drowsiness, occasionally nervous excitation, disorientation, or coma. Seizures may occasionally be observed. Metabolic acidosis may develop in severe poisoning; prothrombin index/international normalized ratio (INR) may be elevated, likely due to effects on blood coagulation factors. Acute renal failure and liver damage may occur, particularly in the presence of dehydration. In patients with bronchial asthma, disease exacerbation may occur.

Treatment. Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring cardiac function and vital signs until stabilization. Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic dose. For frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used for the management of bronchial asthma.

Adverse reactions.

The results of clinical studies conducted with this medicinal product do not indicate any adverse reactions other than those observed with ibuprofen or paracetamol when used separately.

Below are the adverse reactions observed in patients treated with ibuprofen or paracetamol separately during short-term and long-term use.

Adverse reactions reported with ibuprofen or paracetamol used separately are listed by organ systems and frequency of occurrence. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Description of individual adverse reactions

1 Examples include agranulocytosis, anemia, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, and thrombocytopenia. Initial signs are: fever, sore throat, oral ulcers, flu-like symptoms, severe fatigue, unexplained bleeding, bruising, and epistaxis.

2 There have been reports of hypersensitivity reactions. Such reactions include: (a) non-specific allergic reactions; (b) respiratory tract reactions, particularly bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea; or (c) various skin reactions, including rashes of different types, pruritus, urticaria, purpura, angioneurotic edema, and rarely exfoliative and bullous dermatoses (including epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme).

3 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 symptom onset during drug administration and symptom resolution after discontinuation of the drug). In particular, during treatment with ibuprofen, isolated cases of aseptic meningitis symptoms have been observed in patients with pre-existing autoimmune diseases (such as systemic lupus erythematosus, mixed connective tissue disease), including symptoms such as nuchal rigidity, headache, nausea, vomiting, fever, or disorientation (see section "Special precautions for use").

4 Clinical studies suggest that the use of ibuprofen, especially at high doses (2400 mg per day), may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special precautions for use").

5 The most commonly observed adverse effects are gastrointestinal in nature.

6 Sometimes fatal, particularly in elderly individuals.

7 See section "Special precautions for use".

8 In overdose, paracetamol can cause hepatic insufficiency, including acute liver failure, hepatic necrosis, and liver damage (see section "Overdose").

9 Especially with prolonged use, associated with increased serum urea levels and edema. Also includes papillary necrosis.

Metabolic acidosis with high anion gap

Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors during paracetamol use (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after drug authorization. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

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. 10 capsules in a blister; 1 or 2 blisters in a cardboard box labeled in Ukrainian and English.

Category of supply. Over-the-counter.

Manufacturer. Oliv Healthcare.

Manufacturer's address and location of its operations.

Unit-II, Plot No. 163/2, Mahatma Gandhi Udhyog Nagar, Dabhel Village, Nani Daman, Daman - 396 210, India.