Nurofen® 12+

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NUROFEN® 12+ (NUROFEN® 12+)

Composition:

Active substance: ibuprofen;

One coated tablet contains 200 mg of ibuprofen as ibuprofen sodium salt;

Excipients: sodium croscarmellose, xylitol (E 967), microcrystalline cellulose, magnesium stearate, colloidal anhydrous silicon dioxide, sodium carmellose, talc, acacia, sucrose, titanium dioxide (E 171), macrogol 6000, printing ink.

Pharmaceutical form. Coated tablets.

Main physicochemical properties: round, biconvex, sugar-coated tablet, white to almost white in color, with a black identification logo printed on one side.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01AE01.

Pharmacological Properties

Pharmacodynamics. Ibuprofen is a non-steroidal anti-inflammatory analgesic, whose action is associated with inhibition of prostaglandin synthesis. Ibuprofen exerts analgesic, antipyretic, and anti-inflammatory effects. Clinical studies have demonstrated that, in the treatment of pain, ibuprofen in tablet form as sodium ibuprofen begins to act significantly faster compared to ibuprofen in its acid form. When administered at a dose of 400 mg, pain relief lasts up to 8 hours. In a study on the treatment of dental pain, significant pain relief was observed within 15 minutes after administration of 2 tablets of the medicinal product NURUFEN® 12+ compared to placebo. In this study, significantly more patients experienced substantial pain relief after taking 2 tablets of NURUFEN® 12+ compared to taking 2 tablets of paracetamol 500 mg each. These patients also showed a significant reduction in pain intensity and more pronounced pain relief over 6 hours compared to paracetamol.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose aspirin (acetylsalicylic acid) on platelet aggregation when both drugs 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 aspirin (acetylsalicylic acid) 81 mg resulted in reduced effects of aspirin on thromboxane formation or platelet aggregation. Therefore, it cannot be ruled out that regular, long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. However, such a clinically significant effect is considered unlikely with occasional, non-systematic use of ibuprofen.

Pharmacokinetics. After oral administration, ibuprofen is rapidly absorbed from the gastrointestinal tract and reaches maximum plasma concentration within 45 minutes when administered on an empty stomach. When ibuprofen is taken with food, maximum plasma concentration is achieved within 1–2 hours. The elimination half-life of ibuprofen is approximately 2 hours. Following administration of NURUFEN® 12+ tablets, maximum plasma concentration is reached within 35 minutes after dosing on an empty stomach.

Ibuprofen is highly bound (90%) to plasma proteins and slowly penetrates into synovial cavities, where its concentration may remain high even as plasma concentrations decline.

Metabolism of ibuprofen occurs in the liver. Ibuprofen is rapidly and completely eliminated from the body. Over 90% of the administered dose is excreted by the kidneys as metabolites and their conjugates.

It should be noted that the bioavailability of sodium ibuprofen is significantly higher, and the onset of action is twice as fast compared to conventional ibuprofen tablets.

No differences in pharmacokinetics depending on patient age have been observed.

Clinical characteristics.

Indications. Symptomatic treatment of mild to moderate pain, including headache, migraine, back pain, neuralgia, muscle pain, rheumatic pain, menstrual pain, and toothache. Symptomatic treatment of symptoms associated with colds, influenza, and fever.

Contraindications.

Hypersensitivity to ibuprofen or to any of the excipients.

History of hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) after administration of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs).

Active or past history of gastric or duodenal ulcer, gastrointestinal bleeding (two or more documented episodes of ulceration or bleeding).

History of gastrointestinal bleeding or perforation associated with prior NSAID therapy.

Severe impairment of liver function, severe renal dysfunction, severe heart failure (NYHA Class IV ‒ New York Heart Association).

Cerebrovascular or other bleeding conditions.

Disorders of blood coagulation or haemostasis.

Glucose-galactose malabsorption syndrome, sucrase-isomaltase deficiency, or fructose intolerance.

Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

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

• acetylsalicylic acid (aspirin), as this increases the risk of adverse reactions, except when aspirin (at a dose not exceeding 75 mg daily) has been prescribed by a physician.

Experimental data indicate that concomitant use of ibuprofen may inhibit the effect of low-dose acetylsalicylic acid (aspirin) on platelet aggregation. However, the possibility of extrapolating these data to clinical practice is limited; therefore, there are no definitive conclusions regarding whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. With occasional use of ibuprofen, such clinically significant effects are considered unlikely;

• other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors: concurrent use of two or more NSAIDs should be avoided, as this increases the risk of adverse reactions.

Ibuprofen 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 (angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists) and diuretics: NSAIDs may reduce the therapeutic effect of these drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of ACE inhibitors or angiotensin II antagonists with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. These interactions should be considered when combining a selective COX-2 inhibitor with ACE inhibitors or angiotensin II antagonists. Such combinations should be prescribed cautiously, particularly in elderly patients. In cases of long-term treatment, adequate hydration of the patient should be ensured, and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter.

Diuretics increase the risk of nephrotoxic effects of NSAIDs.

Corticosteroids: increased risk of gastrointestinal ulcers and bleeding.

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

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

Lithium: possible increase in plasma lithium levels.

Metotrexate: potential for increased plasma methotrexate levels.

Cyclosporine: increased risk of nephrotoxicity.

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

Tacrolimus: increased risk of nephrotoxicity with concomitant use of NSAIDs and tacrolimus.

Zidovudine: increased risk of hematological toxicity is known with concomitant use of zidovudine and NSAIDs. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia who are receiving concomitant treatment with zidovudine and ibuprofen.

Quinolone antibiotics: concomitant use with NSAIDs increases the risk of seizures.

Sulfonylurea derivatives and phenytoin: possible potentiation of drug effects.

Special precautions for use.

Adverse effects associated with ibuprofen can be minimized by using the lowest effective dose required to treat symptoms, for the shortest possible duration.

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 diseases, or with a history of such conditions.

Other NSAIDs.

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

Systemic lupus erythematosus and mixed connective tissue disease.

Ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue disease due to an increased risk of aseptic meningitis.

Renal effects.

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

There is a risk of renal impairment in dehydrated children and adolescents.

Hepatic effects.

Hepatic function disorders.

Cardiovascular and cerebrovascular effects.

Patients with arterial hypertension or a history of moderate heart failure should begin treatment with caution (medical consultation is required), as fluid retention, arterial hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), may increase the risk of arterial thrombotic complications (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 arterial hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful assessment of the clinical picture. High doses (2400 mg per day) should be avoided.

Long-term treatment with NSAIDs, particularly at high doses of ibuprofen (2400 mg per day), should be prescribed to patients with risk factors for cardiovascular complications (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful consideration.

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

Gastrointestinal effects.

NSAIDs should be used with caution in patients with chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease), as these conditions may worsen. Cases of gastrointestinal bleeding, perforation, and ulcers, sometimes fatal, have been reported at any stage of NSAID treatment, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should start treatment with the lowest doses. Caution 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). For long-term treatment, and in patients requiring concomitant use of low-dose acetylsalicylic acid (aspirin) or other drugs increasing gastrointestinal risk, the physician should consider the appropriateness of combination therapy with misoprostol or proton pump inhibitors.

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

If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, treatment should be discontinued immediately.

Serious skin adverse reactions.

Serious 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 result in death (see section "Adverse reactions"). Most such reactions occurred within the first month.

If signs or symptoms indicating these reactions appear, ibuprofen should be discontinued immediately and alternative treatment (if necessary) should be considered.

Masking symptoms of underlying infections.

Nurofen® 12+ may mask symptoms of infectious disease, potentially delaying appropriate treatment and thereby complicating the course of the illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Nurofen® 12+ is used for fever or pain relief in infections, monitoring for infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Effect on female fertility.

There is some evidence that medicinal products which inhibit cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of therapy.

Each tablet contains approximately 24.3 mg (1.06 mmol) of sodium, which should be considered when prescribing the medicinal product to patients on a low-sodium diet.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryonic mortality.

From the 20th week of pregnancy, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction following treatment in the second trimester, most of which resolved after stopping treatment. Therefore, ibuprofen should not be prescribed during the first and second trimesters of pregnancy unless clearly necessary. If ibuprofen is used by women attempting 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 several days of ibuprofen exposure starting from the 20th gestational week. Nurofen® 12+ should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose the following risks:

Risks to the fetus:

• Cardio-pulmonary toxicity (premature constriction/closure of the arterial duct 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, 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 (see section "Contraindications").

In some studies, ibuprofen has been detected in breast milk at very low concentrations. It is unlikely that this would adversely affect the breastfed infant. NSAIDs are not recommended during breastfeeding.

Ability to influence reaction speed when driving or operating machinery.
Under conditions of adherence to recommended dosage and treatment duration, the medicinal product is not expected to affect reaction speed when driving or operating machinery. However, patients who experience dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving and operating machinery.

Dosage and Administration

For oral use in adults and children aged 12 years and older. For short-term use only.

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

The single dose for children aged 12 years and older and adults is 1–2 tablets (200–400 mg of ibuprofen) up to 3 times daily, every 4–6 hours as needed. The maximum daily dose is 1200 mg (6 tablets per day).

Elderly patients do not require special dose adjustment, except in cases of severe renal or hepatic impairment.

The medicinal product should be taken during or after meals, without chewing, and with water if necessary.

If symptoms persist for more than 3 days or worsen in children and adolescents, consult a physician for diagnosis clarification and treatment adjustment.

If symptoms in adults do not improve or worsen, or if the medicinal product needs to be used for longer than 10 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.

Children. The drug is indicated for children aged 12 years and older.

Overdose.

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

Symptoms. 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 develop, manifesting as vertigo, drowsiness, sometimes excitement, disorientation, or coma. Seizures may occasionally occur. Severe poisoning may lead to hyperkalemia and metabolic acidosis, as well as prolonged prothrombin time/international normalized ratio (likely due to interaction with circulating blood coagulation factors). Acute renal failure, hepatic injury, arterial hypotension, respiratory depression, and cyanosis may also occur. In patients with bronchial asthma, asthma exacerbation is possible.

Treatment. Management should be symptomatic and supportive, including ensuring airway patency and continuous monitoring of cardiac function and vital signs until the patient's condition stabilizes. Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic dose. In cases of frequent or prolonged muscle spasms, treatment should include intravenous administration of diazepam or lorazepam. Bronchodilators should be used in cases of bronchial asthma.

Side effects

Side effects associated with the use of ibuprofen are classified by organ systems and frequency. Frequency is defined as follows: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10,000 and < 1/1000; very rare: < 1/10,000; frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in decreasing order of severity.

The adverse reactions listed below were observed during short-term use of ibuprofen doses not exceeding 1200 mg per day. Additional adverse effects may occur during treatment of chronic conditions or with long-term use.

Gastrointestinal adverse reactions are the most commonly observed and are mostly dose-dependent; in particular, the risk of gastrointestinal bleeding increases with higher doses and longer duration of treatment.

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

Blood and lymphatic system disorders

Very rare: blood disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial signs of such disorders include sore throat, oral mucosal ulcers, flu-like symptoms, severe fatigue, bleeding, and unexplained bruising or haematomas.

Immune system disorders

Uncommon: hypersensitivity reactions accompanied by urticaria and pruritus¹;

Very rare: severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal oedema, dyspnoea, tachycardia, hypotension (anaphylaxis, angioneurotic oedema, or severe shock);

Frequency not known: respiratory tract reactivity, including asthma, bronchospasm, or dyspnoea.

Nervous system disorders

Uncommon: headache;

Very rare: aseptic meningitis²

Cardiac disorders

Frequency not known: heart failure, oedema, Cozzarelli syndrome.

Vascular disorders

Frequency not known: arterial hypertension

Gastrointestinal disorders

Uncommon: abdominal pain, nausea, dyspepsia

Rare: diarrhoea, flatulence, constipation, vomiting

Very rare: peptic ulcer, gastrointestinal perforation, or gastrointestinal haemorrhage, melena, haematemesis, sometimes fatal, especially in elderly patients. Ulcerative stomatitis, gastritis

Frequency not known: exacerbation of colitis and Crohn’s disease

Hepatic disorders

Very rare: liver function abnormalities

Skin and subcutaneous tissue disorders

Uncommon: various skin rashes

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

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

Renal and urinary disorders

Very rare: acute renal dysfunction, papillary necrosis, particularly with prolonged use, associated with elevated serum urea levels and oedema

Frequency not known: acute renal failure

Laboratory investigations

Very rare: decreased haemoglobin levels

Description of selected adverse reactions

1 Hypersensitivity reactions may include: non-specific allergic reactions and anaphylaxis; respiratory tract reactivity, including asthma, asthma exacerbation, bronchospasm, and dyspnoea; various skin reactions, including pruritus, urticaria, purpura, angioneurotic oedema, and less commonly exfoliative and bullous dermatoses (including toxic epidermal necrolysis and erythema multiforme).

2 The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. Available data on aseptic meningitis associated with NSAIDs suggest a hypersensitivity reaction (based on temporal association with drug intake and resolution of symptoms after discontinuation). Cases of aseptic meningitis (manifested by nuchal rigidity, headache, nausea, vomiting, malaise, or disorientation) have been reported in patients with autoimmune disorders (systemic lupus erythematosus and mixed connective tissue disease).

Shelf life. 2 years.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 12 tablets per blister pack, 1 or 2 blister packs in a cardboard box.

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

Manufacturer. Reckitt Benckiser Healthcare International Limited.

Manufacturer's address.
Nottingham site, Taymount Way, Nottingham, NG90 2DB, United Kingdom.