Darfen® long

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DAFREN® LONG (DARFENLONG)

Composition:

Active substances: ibuprofen, paracetamol;

One film-coated tablet contains 200 mg of ibuprofen and 500 mg of paracetamol;

Excipients: maize starch, crospovidone (Type A) (E 1202), colloidal anhydrous silicon dioxide (E 551), povidone K-30 (E 1201), pregelatinized maize starch, talc (E 553b), stearic acid (50); film coating: polyvinyl alcohol (E 1203), talc (E 553b), macrogol 3350 (E 1521), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, film-coated tablets, white to almost white in color.

Pharmacotherapeutic group.

Medicinal products 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 actions of ibuprofen and paracetamol differ in site and mechanism of action, yet are synergistic, resulting in enhanced analgesic and antipyretic effects compared to either substance administered 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 through peripheral inhibition of the cyclooxygenase-2 (COX-2) isoenzyme, thereby reducing the sensitization of nociceptive nerve terminals. It has also been shown that ibuprofen inhibits leukocyte migration into inflamed tissues. Ibuprofen has a pronounced effect in the spinal cord, partly due to COX inhibition. The antipyretic effect of ibuprofen is mediated by central inhibition of prostaglandin synthesis in the hypothalamus. Additionally, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. Some pharmacodynamic studies have shown that when single doses of ibuprofen 400 mg are administered within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg), a reduction in the effect of acetylsalicylic acid on thromboxane formation or platelet aggregation is observed. Despite uncertainty regarding the extrapolation of these data to clinical settings, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. However, such a clinically significant effect is considered unlikely with occasional, non-systematic use of ibuprofen.

The precise mechanism of action of paracetamol is not fully established, but convincing evidence supports its central nervous system (CNS) analgesic effect. Biochemical studies indicate inhibition of cyclooxygenase-2 (COX-2) activity in the CNS. Paracetamol may also stimulate the activity of descending serotonergic (5-hydroxytryptamine) pathways, which inhibit pain signal transmission in the spinal cord.

This medicinal product is particularly suitable for the treatment of pain requiring stronger analgesia than that provided by either 400 mg ibuprofen or 1000 mg paracetamol alone. Studies conducted using this combination in models of acute pain (postoperative dental pain) and chronic knee joint pain have demonstrated high efficacy in reducing the intensity of acute pain (93.2%) and in long-term management of chronic pain (60.2%). This medicinal product has a rapid onset of action, with a confirmed noticeable reduction in pain occurring on average within 18.3 minutes. Significant pain relief is observed on average within 44.6 minutes. The analgesic effect of this medicinal product is considerably 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 administration on an empty stomach. Ibuprofen 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 administration on an empty stomach.

Paracetamol is metabolized in the liver and excreted in urine primarily as conjugates. Less than 5% of paracetamol is excreted unchanged. A hydroxylated metabolite, formed in very small amounts in the liver via mixed-function oxidases and 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 medicinal product are not altered following single or repeated doses of this combination.

The formulation of this medicinal product employs 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, pain associated with mild forms of arthritis, symptoms of cold and flu, sore throat, and fever.

This medicinal product is particularly suitable for the treatment of pain requiring stronger analgesic effect than that provided by ibuprofen or paracetamol used separately.

Contraindications.

The medicinal product is contraindicated:

− in patients with known hypersensitivity to ibuprofen, paracetamol, or any other component of the medicinal product;

− in patients with a history of hypersensitivity reactions (e.g., bronchospasm, angioneurotic edema, bronchial asthma, rhinitis, or urticaria) after taking ibuprofen, acetylsalicylic acid, or other NSAIDs;

− in active peptic ulcer or gastrointestinal bleeding, or history of recurrent episodes (two or more separate 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, severe renal, or severe cardiac insufficiency (NYHA class IV);

− during concomitant use of other medicinal products containing NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors, and acetylsalicylic acid at daily doses exceeding 75 mg due to increased risk of adverse reactions;

− during concomitant use with other medicinal products containing paracetamol due to increased risk of serious adverse reactions;

− during the third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

This medicinal product (like other paracetamol-containing products) is contraindicated with concomitant use of other medicinal products containing paracetamol due to increased risk of serious adverse reactions.

This medicinal product (like other ibuprofen-containing products and NSAIDs) should not be used in combination with:

− acetylsalicylic acid, as this may increase the risk of adverse reactions, except when acetylsalicylic acid (at a dose not exceeding 75 mg per day) has been prescribed by a physician.

Experimental data indicate that ibuprofen may inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. However, extrapolation of these data to clinical settings is limited; therefore, it is not conclusively established whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. For occasional use of ibuprofen, such clinically significant effects are considered unlikely;

− other NSAIDs (including selective COX-2 inhibitors), as this may lead to increased frequency of adverse effects.

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

− cholestyramine: cholestyramine reduces the rate of paracetamol absorption; therefore, paracetamol should be administered at least 1 hour before cholestyramine if maximum analgesia is required;

− metoclopramide and domperidone: absorption of paracetamol is increased by metoclopramide and 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 medicinal product (like other ibuprofen-containing products and NSAIDs) should be used with caution in combination with the following medicinal products:

Anticoagulants. NSAIDs may enhance the effect of anticoagulants (increased risk of bleeding). The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol, increasing the risk of bleeding.

Antihypertensive and diuretic agents. NSAIDs may reduce the therapeutic effect of these agents and increase the risk of nephrotoxicity. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II receptor 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, especially in elderly patients. If long-term treatment is necessary, adequate hydration should be ensured, and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter. Diuretics may increase the risk of NSAID-induced nephrotoxicity.

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

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

Cyclosporine. Increased risk of nephrotoxicity is possible.

Corticosteroids may increase the risk of gastrointestinal adverse reactions (gastrointestinal ulcers or bleeding).

INH (isoniazid): toxicity of paracetamol may be enhanced when used concomitantly with isoniazid.

Li (lithium) and methotrexate. Evidence suggests a potential increase in plasma levels of lithium and methotrexate.

Mifepristone. NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, 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 with concomitant use of NSAIDs and quinolones.

Flucloxacillin. Paracetamol should be used with caution when administered concomitantly with flucloxacillin, as co-administration has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions for use").

Tacrolimus. Increased risk of nephrotoxicity may occur with concomitant use of NSAIDs and tacrolimus.

Zidovudine. Increased risk of hematological toxicity with concomitant use of zidovudine and NSAIDs. Evidence indicates an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

Antiemetics. The absorption rate of paracetamol may be increased by metoclopramide or domperidone.

Special precautions for use.

Do not exceed recommended doses.

If symptoms worsen, consult a physician.

Keep out of reach of children.

Paracetamol.

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 should be sought, even if the patient feels well, due to the risk of delayed severe liver damage.

Cases of high anion gap metabolic acidosis (HAGMA) resulting from pyroglutamic acidosis have been reported in critically ill patients, such as those with severe renal failure or sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring are recommended. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Do not take other medications containing paracetamol. If this occurs, seek immediate medical attention, even if the patient feels well, as it may lead to overdose.

Ibuprofen.

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

Elderly patients.

The frequency of adverse reactions associated with NSAIDs, particularly gastrointestinal bleeding or perforation, which may be fatal, increases in elderly patients. If NSAID use is necessary, the lowest effective dose for the minimal duration should be used.

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

Respiratory effects.

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

Systemic lupus erythematosus and mixed connective tissue disease.

Patients with systemic lupus erythematosus or mixed connective tissue disease may have an increased risk of developing aseptic meningitis.

Cardiovascular and cerebrovascular effects.

Patients with a history of hypertension and/or heart failure should begin treatment cautiously (medical consultation required), as fluid retention, hypertension, and edema have been reported during ibuprofen and other NSAID therapies.

Cases of Kounis syndrome have been reported in patients receiving Darfen® Long. 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.

Clinical trial data indicate that ibuprofen use, especially at high doses (2400 mg per day), may be associated with a small 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 per day) 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 only be treated with ibuprofen after careful clinical assessment. High doses (2400 mg per day) should be avoided. Careful clinical evaluation is also required before initiating long-term treatment in patients with cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes, smoking), especially if high-dose ibuprofen (2400 mg per day) is required.

Cardiovascular, hepatic, and renal impairment.

NSAID use may cause dose-dependent reduction in prostaglandin synthesis and development of renal impairment. Patients at increased risk include those with impaired renal, cardiac, or hepatic function, patients taking diuretics, and elderly patients. Renal function should be monitored in such patients. Renal tubular acidosis and hypokalemia may occur after acute overdose and in patients taking ibuprofen for prolonged periods at high doses (usually more than 4 weeks), including doses exceeding the recommended daily dose.

Gastrointestinal effects.

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

Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported at any stage of NSAID therapy, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, 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 begin with the lowest effective dose. For these patients, as well as for those taking low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about any adverse gastrointestinal symptoms (especially bleeding), particularly at the beginning of treatment.

The drug should be used cautiously in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as acetylsalicylic acid.

If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen-containing medications, treatment with this drug must be discontinued immediately.

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 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 considered (if necessary).

Masking symptoms of underlying infections.

Darfen® Long 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. If ibuprofen is used for fever or pain relief during infection, monitoring for infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Effect on female fertility.

Limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible after discontinuation of treatment. Women experiencing fertility problems or undergoing infertility evaluation should avoid taking the drug.

Use during pregnancy or breastfeeding.

Pregnancy

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

Extensive data in pregnant women do not indicate teratogenic or fetal/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have yielded inconclusive results. If clinically necessary, paracetamol may be used during pregnancy, but it should be administered at the lowest effective dose, for the shortest possible duration, and with the lowest possible frequency.

From the 20th week of gestation, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of ductus arteriosus constriction after second-trimester treatment, most of which resolved after stopping treatment. Therefore, ibuprofen should not be prescribed during the first and second trimesters unless necessary. If ibuprofen 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 ductus arteriosus constriction should be considered after several days of ibuprofen exposure starting from the 20th gestational week. Darfen® Long treatment should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors pose risks to the fetus:

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

Risks to the mother at the end of pregnancy and to the newborn:

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

Cases of congenital malformations associated with NSAID use in humans have been reported, but their frequency is low and no clear pattern has been established.

Due to the known effects of NSAIDs on the fetal cardiovascular system (risk of premature ductus arteriosus closure), the use of the drug is contraindicated during the third trimester of pregnancy (see section "Contraindications").

NSAID use during this period may delay the onset of labor, prolong its duration, and increase the risk of bleeding in both mother and newborn.

NSAID use during the first and second trimesters of pregnancy and during labor is only acceptable if the expected benefit to the mother outweighs the potential risk to the fetus.

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 passes into breast milk but in clinically insignificant amounts. Available published data do not preclude 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.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

For short-term oral use only.

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

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

Adults should take 1 tablet up to 3 times daily, with at least 6 hours between doses. Tablets should be taken with water.

If 1 tablet does not relieve symptoms, 2 tablets 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 tablets (3000 mg paracetamol, 1200 mg ibuprofen) within 24 hours.

To minimize the risk of adverse effects, the medicinal product should be taken during meals.

Elderly patients

Dose adjustment is not required.

Due to the potential risk of adverse effects, elderly patients should be monitored particularly closely. If NSAID therapy is necessary, the lowest effective dose should be used for the shortest possible duration. Patients should be regularly monitored for gastrointestinal bleeding throughout NSAID therapy.

Children

Do not use in children under 18 years of age.

Overdose

Paracetamol. Liver damage may occur in adults who have taken 10 g (equivalent to 20 tablets) or more of paracetamol. Liver damage may also occur after ingestion of 5 g (equivalent to 10 tablets) 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 drugs that induce liver enzymes;

− the patient regularly consumes alcohol;

− the patient is likely to have 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 become apparent 12–48 hours after overdose, manifested by abnormal liver function tests. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, cerebral edema, 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. In case of paracetamol overdose, prompt medical attention is required. The patient should be taken immediately to hospital for medical evaluation, even if early symptoms are absent. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Treatment should be carried out according to established treatment guidelines.

Consider administration of activated charcoal within 1 hour of ingestion of an excessive dose of paracetamol. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable).

N-acetylcysteine treatment may be administered within 24 hours after paracetamol ingestion, but the maximum protective effect is achieved when administered within 8 hours after overdose. The efficacy of the antidote decreases sharply after this time. If necessary, N-acetylcysteine should be administered intravenously according to the established dosing regimen. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Treatment of patients who develop severe liver dysfunction within 24 hours after paracetamol ingestion should follow established guidelines.

Ibuprofen. Ibuprofen doses exceeding 400 mg/kg in children may cause overdose symptoms. In adults, the dose-dependent effect is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms. In most patients who have ingested a clinically significant amount of NSAIDs, only nausea, vomiting, epigastric pain, or very rarely diarrhea may occur. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, central nervous system (CNS) toxicity may develop, manifesting as drowsiness, occasionally nervous excitation, disorientation, or coma. Seizures may occasionally be observed. Severe poisoning may lead to metabolic acidosis; 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 in the setting of dehydration. In patients with bronchial asthma, disease exacerbation may occur.

Treatment. Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of 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 treatment of bronchial asthma.

Side effects.

Clinical studies conducted with this medicinal product have not revealed any additional adverse reactions other than those observed with ibuprofen or paracetamol used separately.

The adverse reactions listed below were observed in patients receiving ibuprofen or paracetamol individually, during both short-term and long-term use.

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), frequency not known (cannot be estimated from available data).

Eye disorders: very rare – visual disturbances.

Ear and labyrinth disorders: very rare – tinnitus and vertigo.

Respiratory system disorders: very rare – respiratory hypersensitivity, including asthma, worsening of asthma, bronchospasm, and dyspnea.\textsuperscript{2}

Gastrointestinal disorders: common – abdominal pain, vomiting, diarrhoea, nausea, dyspepsia, and gastrointestinal discomfort\textsuperscript{5}; uncommon – peptic ulcer, gastrointestinal perforation, gastrointestinal haemorrhage, melaena, haematemesis\textsuperscript{6}, oral ulcers, exacerbation of colitis and Crohn’s disease\textsuperscript{7}, gastritis, pancreatitis, flatulence, and constipation.

Hepatobiliary disorders: very rare – liver function abnormalities, hepatitis, and jaundice.\textsuperscript{8}

Renal and urinary disorders: very rare – nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome; acute and chronic renal failure.\textsuperscript{9}

Metabolism and nutrition disorders: metabolic acidosis with high anion gap, frequency not known (cannot be estimated from available data)\textsuperscript{10}.

Nervous system disorders: uncommon – headache and dizziness; very rare – aseptic meningitis\textsuperscript{3}, paraesthesia, optic neuritis, and somnolence.

Psychiatric disorders: very rare – confusion, depression, and hallucinations.

Cardiovascular disorders: very rare – heart failure, oedema, arterial hypertension\textsuperscript{4}; frequency not known – Coats’ syndrome.

Blood and lymphatic system disorders: very rare – blood dyscrasias.\textsuperscript{1}

Immune system disorders: uncommon – hypersensitivity reactions including urticaria and pruritus\textsuperscript{2}; very rare – severe hypersensitivity reactions. Symptoms may include facial, tongue, and laryngeal swelling, dyspnoea, tachycardia, and hypotension (anaphylaxis, angioneurotic oedema, or severe shock).\textsuperscript{2}

Skin and subcutaneous tissue disorders: common – hyperhidrosis; uncommon – skin rash\textsuperscript{2}; very rare – severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis), purpura; frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions.

General disorders: very rare – fatigue and malaise.

Laboratory findings: common – increased alanine aminotransferase (ALT) levels, increased gamma-glutamyl transferase levels, worsening of liver function tests due to paracetamol, increased blood creatinine levels, increased blood urea levels; uncommon – increased aspartate aminotransferase (AST) levels, increased blood alkaline phosphatase levels, increased blood creatine kinase levels, decreased haemoglobin levels, and increased platelet count.

Description of selected adverse reactions

\textsuperscript{1}Examples include agranulocytosis, anaemia, aplastic anaemia, haemolytic anaemia, leucopenia, neutropenia, pancytopenia, and thrombocytopenia. Initial signs include: fever, sore throat, superficial oral ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding, bruising, and epistaxis.

\textsuperscript{2}There have been reports of hypersensitivity reactions, including:

• non-specific allergic reactions and anaphylaxis;
• respiratory tract reactions, such as bronchial asthma, worsening of asthma, bronchospasm, or dyspnoea;
• various skin reactions, including rashes of different types, pruritus, urticaria, purpura, angioneurotic oedema, and, less frequently, exfoliative and bullous dermatoses (including epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme).

\textsuperscript{3}The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, available data on aseptic meningitis associated with NSAIDs suggest a hypersensitivity reaction (based on symptom onset during drug intake and symptom resolution after discontinuation). In particular, isolated cases of aseptic meningitis symptoms, such as nuchal rigidity, headache, nausea, vomiting, fever, 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) (see section "Special precautions").

\textsuperscript{4}Clinical studies suggest that ibuprofen use, especially at high doses (2400 mg/day), may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions").

\textsuperscript{5}The most frequently observed adverse effects are gastrointestinal.

\textsuperscript{6}Sometimes fatal, particularly in elderly patients.

\textsuperscript{7}See section "Special precautions".

\textsuperscript{8}Paracetamol overdose may cause acute liver failure, hepatic failure, hepatic necrosis, and liver damage (see section "Overdose").

\textsuperscript{9}Especially with long-term use, associated with increased serum urea levels and oedema. Also includes papillary necrosis.

\textsuperscript{10}Metabolic acidosis with high anion gap. Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors taking paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. 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/or lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

10 tablets in a blister; 1 blister per carton.

Prescription status. Over-the-counter.

Manufacturer. Rontis Hellas Medical and Pharmaceutical Products S.A.

Manufacturer's address.

P.O. Box 3012 Larissa Industrial Area, Larissa, 41004, Greece.

Marketing Authorization Holder. JSC "Pharmaceutical company "Darnytsia".

Address of the Marketing Authorization Holder.

13, Boryspilska Street, Kyiv, 02093, Ukraine.