Nurofen® cold & flu

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NUROFEN® COLD & FLU

Composition:

Active substances: ibuprofen, phenylephrine hydrochloride;

1 film-coated tablet contains 200 mg of ibuprofen and 5 mg of phenylephrine hydrochloride;

Excipients: hypromellose, microcrystalline cellulose, magnesium stearate, sodium starch glycolate (type A), talc, hypromellose;

coating: Masterkote Yellow FA 0156, black ink S-1277001 Black (for logo printing).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex film-coated tablets with a black printed identification logo on one side.

Pharmacotherapeutic group.

Medicines for the treatment of the musculoskeletal system, anti-inflammatory and antirheumatic agents, nonsteroidal agents, propionic acid derivatives. Ibuprofen, combinations.

ATC code M01AE51.

Pharmacological properties.

Pharmacodynamics.

Ibuprofen

Ibuprofen is a propionic acid derivative, and its mechanism of action is based on inhibition of prostaglandin synthesis. Ibuprofen has analgesic, anti-inflammatory, and antipyretic properties. In addition, ibuprofen reversibly inhibits platelet aggregation.

The therapeutic effect of ibuprofen on symptoms associated with cold and flu lasts up to 8 hours.

Experimental data indicate that ibuprofen may competitively reduce the effect of low-dose aspirin (acetylsalicylic acid) on platelet aggregation when these drugs are used concomitantly. In some pharmacodynamic studies, administration of single 400 mg doses of ibuprofen either 8 hours before or 30 minutes after immediate-release aspirin (acetylsalicylic acid, 81 mg) resulted in reduced effects of aspirin (acetylsalicylic acid) on thromboxane formation or platelet aggregation. Although uncertainty exists regarding extrapolation of these data to clinical situations, it cannot be excluded that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. With occasional use of ibuprofen, such a clinically significant effect is considered unlikely (see section "Interaction with other medicinal products and other forms of interaction").

Phenylephrine

Phenylephrine is a postsynaptic alpha-receptor agonist with low stimulation of cardiovascular beta-receptors and minimal central effects. It is a recognized decongestant that relieves nasal swelling and congestion by vasoconstriction.

Pharmacokinetics.

Ibuprofen

After administration, ibuprofen is rapidly absorbed and quickly distributed throughout the body. Renal elimination is rapid and complete.

Maximum plasma concentrations are achieved within 45 minutes after oral administration on an empty stomach. When taken with food, peak levels occur within 1–2 hours. This time may vary depending on different pharmaceutical forms.

The elimination half-life is approximately 2 hours.

In some studies, ibuprofen was detected in breast milk at very low concentrations.

Phenylephrine

Phenylephrine is absorbed in the gastrointestinal tract, but its bioavailability is reduced after oral administration due to presystemic metabolism.

After oral intake, it retains its activity as a decongestant, reaching the blood vessels of the nasal mucosa via systemic circulation.

When administered orally as a nasal decongestant, phenylephrine is taken at intervals of 4–6 hours.

Combination of ibuprofen and phenylephrine

Ibuprofen contained in this medicinal product (ibuprofen 200 mg and phenylephrine hydrochloride 5 mg) is absorbed faster than standard 200 mg ibuprofen tablets, with therapeutic levels being achieved within 26.4 minutes, compared to 55.2 minutes for standard ibuprofen tablets.

Clinical characteristics.

Indications.

For the relief of symptoms of cold and flu, such as body aches and pains, headache, fever, sore throat, nasal and sinus congestion.

Contraindications.

Hypersensitivity to ibuprofen, phenylephrine, or to any of the excipients of the medicinal product.

History of hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, urticaria) following administration of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).

Active peptic ulceration or gastrointestinal bleeding, or history of recurrent peptic ulcer or bleeding (two or more documented episodes of peptic ulcer disease or bleeding).

History of gastrointestinal bleeding or perforation related to previous NSAID therapy.

Hypertensive disease and severe ischemic heart disease or cardiovascular disorders.

Severe heart failure (NYHA class IV [New York Heart Association]), renal or hepatic impairment.

Third trimester of pregnancy.

Concomitant use with other NSAIDs, including selective cyclooxygenase-2 inhibitors.

Active cerebrovascular or other hemorrhages.

Hematological disorders of unknown etiology.

Hemorrhagic diathesis or coagulation disorders.

Active inflammatory bowel disease.

Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).

Not to be used in children under 12 years of age and weighing less than 40 kg.

Hyperthyroidism.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of such therapy.

Do not use in patients with benign prostatic hyperplasia.

Pheochromocytoma: phenylephrine should not be used in patients with pheochromocytoma.

Interaction with other medicinal products and other forms of interaction.

This medicinal product is contraindicated in combination with:

• Monoamine oxidase inhibitors (MAOIs): interaction between sympathomimetic amines such as phenylephrine hydrochloride and MAOIs may lead to hypertensive effects.

This medicinal product is not recommended for use in combination with:

• Aspirin (acetylsalicylic acid): concomitant use of ibuprofen with acetylsalicylic acid is generally not recommended due to the potential for increased adverse reactions, except when low-dose aspirin (not exceeding 75 mg per day) is prescribed by a physician.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose aspirin (acetylsalicylic acid) on platelet aggregation. Although uncertainty exists regarding 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. Occasional, short-term use of ibuprofen is considered unlikely to produce a clinically significant effect.

• Other NSAIDs, including selective cyclooxygenase-2 inhibitors: concomitant use of two or more NSAIDs should be avoided, as this increases the risk of adverse reactions.

This medicinal product should be used with caution in combination with the following medicinal products:

• Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin.
• Antihypertensive agents (ACE inhibitors and angiotensin II antagonists), diuretics: NSAIDs may attenuate the effects of these agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced renal function), concomitant use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered when co-administering coxibs with ACE inhibitors or angiotensin II antagonists. Therefore, such combinations should be prescribed with caution, particularly in elderly patients. Adequate hydration and monitoring of renal function should be performed at the start of combined therapy and periodically thereafter. Diuretics increase the risk of nephrotoxic effects. Phenylephrine may reduce the effectiveness of beta-blockers and other antihypertensive agents, increasing the risk of arterial hypertension and other cardiovascular adverse reactions.
• Corticosteroids: increased risk of gastrointestinal ulcers or bleeding.
• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.
• Digoxin and cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of glycosides; concomitant use of phenylephrine may lead to arrhythmias or myocardial infarction.
• Tricyclic antidepressants (e.g., amitriptyline): increased risk of phenylephrine-related adverse reactions in patients with cardiovascular disease.
• Sympathomimetics: concomitant use with phenylephrine increases the risk of cardiovascular adverse reactions.
• Lithium: evidence suggests a potential increase in plasma lithium levels.
• Methotrexate: evidence suggests a potential increase in plasma methotrexate levels.
• Cyclosporine: increased risk of nephrotoxicity.
• Mifepristone: NSAIDs should not be used earlier than 8–12 days after mifepristone administration, as NSAIDs may reduce the efficacy of mifepristone.
• Tacrolimus: increased risk of nephrotoxicity when used concomitantly with NSAIDs.
• 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 receiving concomitant treatment with zidovudine and ibuprofen.
• Quinolone antibiotics: animal studies indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients receiving NSAIDs and quinolones concomitantly may have an increased risk of seizures.
• Sulfonylurea agents and phenytoin: possible potentiation of the effects of these agents. Rare cases of hypoglycemia have been reported in patients taking sulfonylureas during ibuprofen therapy. Blood glucose levels should be monitored during concomitant use.
• Aminoglycosides: NSAIDs may reduce the elimination of aminoglycosides.
• Probenecid and sulfinpyrazone: concomitant use with ibuprofen may delay their excretion.
• Potassium-sparing diuretics: concomitant use of ibuprofen with potassium-sparing diuretics may lead to hyperkalemia (plasma potassium levels should be monitored).
• Baclofen: increased risk of toxic effects of baclofen after initiation of ibuprofen therapy.
• Cytochrome CYP2C9 inhibitors: concomitant administration of ibuprofen with CYP2C9 inhibitors may increase ibuprofen exposure (ibuprofen is a CYP2C9 substrate). One study demonstrated that voriconazole and fluconazole (CYP2C9 inhibitors) increased S(+)-ibuprofen exposure by approximately 80–100%. Consideration should be given to reducing the dose of ibuprofen when co-administered with strong CYP2C9 inhibitors, especially when high doses of ibuprofen are prescribed along with voriconazole or fluconazole.
• Oral hypoglycemic agents: inhibition of metabolism of sulfonamide agents, prolonged elimination half-life, and increased risk of hyperglycemia.
• Antacids and cholestyramine: concomitant use of cholestyramine and ibuprofen delays and reduces ibuprofen absorption by 25%. Ibuprofen should be administered with a several-hour interval.
• Caffeine: concomitant use may enhance the analgesic effect.

Special precautions for use.

Ibuprofen

Adverse effects can be minimized by using the lowest effective dose required to relieve symptoms for the shortest duration necessary (see gastrointestinal and cardiovascular risks below).

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

Respiratory effects

Bronchospasm may occur in patients suffering from bronchial asthma or allergic disorders, or with a history of these conditions.

Other NSAIDs

Concomitant use of this product with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Systemic lupus erythematosus and mixed connective tissue disease

Systemic lupus erythematosus and mixed connective tissue disease increase the risk of aseptic meningitis.

Renal effects

Ibuprofen may impair renal function, particularly in dehydrated children and adolescents.

Renal tubular acidosis and hypokalemia may develop after acute overdose or after prolonged intake of high doses of ibuprofen (usually more than 4 weeks), especially when exceeding the recommended daily dose.

Hepatic effects

Ibuprofen may cause disturbances in liver function.

Surgical procedures

Caution should be exercised immediately after major surgical procedures.

Cardiovascular and cerebrovascular effects

Patients with a history of hypertension and/or heart failure should start treatment with caution (medical or pharmacist consultation is required), as cases of fluid retention, hypertension, and edema associated with NSAID therapy have been reported.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg daily), slightly increases the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). However, overall, epidemiological studies have not shown evidence of an association between low-dose ibuprofen use (e.g., ≤1200 mg daily) and an increased risk of arterial thrombotic complications.

Patients with uncontrolled hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful clinical assessment. High doses (2400 mg daily) should be avoided.

Clinical evaluation should also be carefully performed before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., hypertension, hyperlipidemia, diabetes, smoking), especially if high doses of ibuprofen (2400 mg daily) are required.

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

Effect on female fertility

According to some data, medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Gastrointestinal effects

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

Cases of gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported during treatment with all NSAIDs, occurring at any stage of treatment, regardless of prior warning symptoms or gastrointestinal disorders in history.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly complicated by bleeding or perforation, and in elderly patients. Such patients should initiate treatment with the lowest possible dose.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly at the beginning of treatment.

Caution should be exercised when treating patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., aspirin).

In case of gastrointestinal bleeding or ulceration in patients receiving ibuprofen, treatment should be discontinued immediately.

Severe skin adverse reactions

Severe skin adverse reactions have been reported with ibuprofen use, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis, which may be life-threatening or fatal (see section "Adverse reactions"). Most such reactions occurred within the first month. If signs or symptoms suggesting these reactions appear, ibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

Allergic reactions

Caution should be exercised in patients with allergic reactions to other substances, as such patients have a higher risk of hypersensitivity reactions during ibuprofen use.

Patients with hay fever, nasal polyps, chronic obstructive respiratory diseases, or a history of allergic disorders have an increased risk of allergic reactions, which may manifest as asthma attacks (so-called analgesic asthma), Quincke's edema, or urticaria.

Masking symptoms of underlying infections

Nurofen® Cold & Flu may mask symptoms of infectious disease, potentially delaying appropriate treatment and thereby complicating the course of illness. Such symptom masking has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Nurofen® Cold & Flu is used for fever or pain relief during infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Porphyria

Caution should be exercised in patients with inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria).

Ibuprofen may temporarily inhibit platelet function (affect platelet aggregation). Therefore, careful monitoring of patients with coagulation disorders is recommended.

During long-term ibuprofen use, regular monitoring of blood laboratory parameters, liver, and kidney function is required.

Prolonged use of analgesics, especially in combination, may lead to impaired kidney function with a risk of renal failure (analgesic nephropathy). This risk may be increased by low salt concentration and dehydration. Such patients should use the lowest possible dose of ibuprofen and have kidney function monitored regularly. In cases of dehydration, adequate fluid intake should be ensured.

Concomitant use of NSAIDs and alcohol increases the risk of adverse effects on the gastrointestinal tract or central nervous system.

Phenylephrine

Phenylephrine should be used with caution in patients with cardiovascular diseases, diabetes, closed-angle glaucoma, Raynaud's syndrome, and hypertensive disease.

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

Use during pregnancy or breastfeeding.

Pregnancy

The use of this medicinal product is contraindicated during the third trimester of pregnancy. During the first and second trimesters, the product may be used only if absolutely necessary.

Ibuprofen

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital malformations after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation loss and embryonic/fetal mortality. Additionally, increased frequency of various developmental abnormalities, including cardiovascular malformations, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of pregnancy, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This effect may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of ductus arteriosus constriction have been reported after second-trimester treatment, which mostly resolved after stopping treatment. Therefore, ibuprofen should not be prescribed during the first and second trimesters unless clearly 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. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be required after ibuprofen exposure for several days starting from the 20th gestational week. If oligohydramnios or ductus arteriosus constriction is detected, ibuprofen use should be discontinued.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors cause:

Risks for the fetus:

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

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

• prolonged bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, ibuprofen is contraindicated during the third trimester of pregnancy.

Phenylephrine

The safety of this product during pregnancy has not been established. Due to the potential for fetal abnormalities caused by phenylephrine exposure in the first trimester of pregnancy, its use should be avoided during pregnancy. Additionally, since phenylephrine may reduce placental perfusion, the product should not be used in patients with a history of pre-eclampsia.

Breastfeeding

The use of this medicinal product is contraindicated during breastfeeding.

Ibuprofen

In limited studies, ibuprofen was detected in breast milk at very low concentrations, making it unlikely to adversely affect the breastfed infant.

Phenylephrine

Due to the lack of data on phenylephrine use during breastfeeding, this product should not be taken during breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

This medicinal product does not affect or has a negligible effect on reaction speed when driving or operating machinery.

Method of Administration and Dosage

Administer orally. The medicinal product is intended for short-term treatment.

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

If symptoms persist for more than 3–4 days from the start of treatment or worsen, medical advice should be sought.

Adults, elderly patients, and children aged 12 years and older

Take 2 tablets 3 times a day. Repeat the dose no more frequently than every 4 hours, and do not exceed 6 tablets within 24 hours.

Children. Do not use for treatment of children under 12 years of age.

Overdose

Ibuprofen

Administration of doses exceeding 400 mg/kg in children may lead to symptoms of intoxication. In adults, the effect of overdose is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms. In most patients who have ingested clinically significant amounts of NSAIDs, only nausea, vomiting, epigastric pain, or very rarely diarrhea have been observed. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, manifesting as drowsiness, occasionally agitation, disorientation, or coma. Seizures may sometimes occur in patients. Severe intoxication may lead to metabolic acidosis and prolonged prothrombin time / increased prothrombin index, possibly due to effects on circulating blood coagulation factors. Acute renal failure and liver damage may develop. Prolonged use at doses higher than recommended or overdose may result in renal tubular acidosis and hypokalemia. In patients with bronchial asthma, disease exacerbation may occur.

Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of cardiac and vital functions until stabilization. Oral activated charcoal is recommended or gastric lavage 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 to treat exacerbations of bronchial asthma.

Phenylephrine

Symptoms. A characteristic feature of severe phenylephrine overdose is hemodynamic changes and cardiovascular collapse with respiratory insufficiency. Treatment includes symptomatic and supportive measures. The hypertensive effect can be counteracted by intravenous administration of alpha-blockers.

Phenylephrine overdose may cause nervousness, headache, dizziness, insomnia, elevated arterial pressure, nausea, vomiting, mydriasis, acute angle-closure glaucoma (more commonly occurring in patients with pre-existing angle-closure glaucoma), tachycardia, palpitations, allergic reactions (e.g., rash, urticaria, allergic dermatitis), dysuria, and urinary retention (more commonly observed in patients with bladder outlet obstruction, such as bladder hypertrophy).

Additional symptoms may include hypertension and reflex bradycardia. In severe cases, confusion, hallucinations, seizures, and arrhythmias may occur.

Treatment should be based on the clinical presentation. Severe hypertension may require administration of alpha-blockers such as phentolamine.

Adverse Reactions

The adverse reactions listed below were observed during the use of ibuprofen at over-the-counter doses (maximum 1200 mg per day) and phenylephrine hydrochloride during short-term use. Additional adverse effects may occur with long-term treatment of chronic conditions.

Adverse reactions associated with ibuprofen and phenylephrine hydrochloride are listed by organ systems and frequency of occurrence. Frequency of adverse reactions is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Eye disorders: uncommon: visual disturbances (toxic optic neuropathy, blurred vision or diplopia, scotoma, dryness and irritation of eyes, allergic edema of conjunctiva and eyelids).

Ear and labyrinth disorders: rare: hearing disturbances (hearing loss, tinnitus or ringing in the ears).

Blood and lymphatic system disorders: very rare: blood disorders^1.

Immune system disorders: uncommon: hypersensitivity reactions including urticaria and pruritus^2; very rare: severe hypersensitivity reactions, including facial, tongue and laryngeal swelling, dyspnea, tachycardia, and hypotension (anaphylactic reaction, angioedema, or severe shock)^2.

Nervous system disorders: uncommon: headache; very rare: aseptic meningitis^3.

Cardiac disorders: frequency not known: heart failure, edema^4, palpitations, Kounis syndrome.

Vascular disorders: frequency not known: arterial hypertension^4.

Respiratory, thoracic and mediastinal disorders: frequency not known: respiratory tract reactivity, including bronchial asthma, bronchospasm, or dyspnea^2.

Gastrointestinal disorders: uncommon: abdominal pain, nausea, and dyspepsia^5; rare: diarrhea, flatulence, constipation, heartburn, and vomiting; very rare: peptic ulcer, gastrointestinal perforation or gastrointestinal hemorrhage, melena, hematemesis^6, ulcerative stomatitis, gastritis, esophagitis, formation of intestinal diaphragm-like strictures, pancreatitis; frequency not known: exacerbation of colitis and Crohn’s disease^7.

Hepatobiliary disorders: very rare: liver dysfunction.

Renal and urinary disorders: rare: acute renal impairment, papillary necrosis, particularly with prolonged use of NSAIDs, associated with increased serum urea levels; very rare: fluid retention and edema, particularly in patients with hypertension or renal impairment^8, nephrotic syndrome, interstitial nephritis which may lead to acute renal failure, ureteric colic, dysuria, renal tubular acidosis. Therefore, renal function should be monitored regularly.

Nervous system disorders: uncommon: headache, dizziness, insomnia, psychomotor agitation, irritability, fatigue; very rare: aseptic meningitis^2.

Psychiatric disorders: very rare: psychotic reactions, depression.

Skin and subcutaneous tissue disorders: uncommon: skin rash^2; very rare: severe skin reactions including Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis^2; frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis; photosensitivity reactions.

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

Laboratory investigations: very rare: decreased hemoglobin levels.

Description of selected adverse reactions

1 Reports include anemia, leukopenia, thrombocytopenia, pancytopenia, and agranulocytosis. Initial signs include high fever, sore throat, oral ulcers, flu-like symptoms, severe fatigue, unexplained bleeding, and unexplained bruising.

2 There are reports of hypersensitivity reactions following ibuprofen treatment. These include: (a) non-specific allergic reactions and anaphylaxis; (b) respiratory tract reactivity, particularly bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea; (c) various skin reactions, including pruritus, urticaria, angioedema, and, less frequently, exfoliative and bullous dermatoses (including epidermal necrolysis 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 temporal association with drug intake and resolution of symptoms after drug discontinuation). In particular, isolated cases of aseptic meningitis symptoms (such as nuchal rigidity, headache, nausea, vomiting, fever, or confusion) have been observed in patients with pre-existing autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during ibuprofen therapy.

4 Clinical studies indicate that the use of ibuprofen (particularly at high doses of 2400 mg per day) and long-term treatment slightly increases the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

5 Most frequently observed gastrointestinal adverse reactions.

6 Sometimes fatal, especially in elderly individuals.

7 See section "Special precautions for use".

8 Particularly with prolonged use, associated with increased blood urea and edema. Also includes papillary necrosis.

* Renal tubular acidosis and hypokalemia have been reported under post-marketing conditions, typically after prolonged use of ibuprofen at doses higher than recommended.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

6 or 12 tablets in a blister; 1 or 2 blisters per cardboard box with the instruction for medical use.

Prescription status.

Over-the-counter.

Manufacturer. Reckitt Benckiser Healthcare International Limited.

Manufacturer's address.

Nottingham site, Taymount Way, Nottingham, NG90 2DB, United Kingdom.