Nurofen

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

Composition:

Active substance: ibuprofen;

One coated tablet contains 200 mg of ibuprofen;

Excipients: sodium croscarmellose, sodium lauryl sulfate, sodium citrate, stearic acid, colloidal anhydrous silicon dioxide, sodium carmellose, talc, acacia, sucrose, titanium dioxide (E 171), macrogol 6000, printing ink (shellac, black iron oxide (E 172), propylene glycol (E 1520)).

Pharmaceutical form. Coated tablets.

Main physicochemical properties: white or almost white, biconvex tablets in a sugar coating with a black identifying mark on one side.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. ATC code M01AE01.

Pharmacological properties.

Pharmacodynamics.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a propionic acid derivative, which has demonstrated efficacy by inhibiting the synthesis of prostaglandins. In humans, ibuprofen reduces pain associated with inflammation, swelling, and fever. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose aspirin (acetylsalicylic acid) on platelet aggregation when these agents are used concomitantly. Some pharmacodynamic studies have shown that administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release aspirin (acetylsalicylic acid) 81 mg resulted in reduced effect of aspirin (acetylsalicylic acid) on thromboxane formation or 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. With occasional, non-systematic use of ibuprofen, such a clinically significant effect is considered unlikely.

Nurofen® relieves pain, reduces inflammation, and lowers fever.

Pharmacokinetics.

Ibuprofen is rapidly absorbed after administration and quickly distributed throughout the body. Elimination is rapid and complete, occurring via the kidneys.

Maximum plasma concentrations are reached within 45 minutes after oral administration on an empty stomach. When administered 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 limited studies, ibuprofen has been detected in breast milk at very low concentrations.

Clinical characteristics.

Indications. Symptomatic treatment of headache and toothache, menstrual pain, neuralgia, back pain, joint and muscle pain, rheumatic pain, as well as symptoms of cold and flu.

Contraindications.

• Hypersensitivity to ibuprofen or to any of the excipients of the medicinal product.
• History of hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) following administration of aspirin or other NSAIDs.
• Active or history of recurrent peptic ulcer (two or more documented episodes of confirmed peptic ulceration or gastrointestinal bleeding).
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Severe heart failure (NYHA class IV), severe renal impairment, or severe hepatic impairment.
• Third trimester of pregnancy.
• Active inflammatory bowel disease.
• Hemorrhagic diathesis or other coagulation disorders.

Interaction with other medicinal products and other forms of interaction.

In general, caution should be exercised when using NSAIDs in combination with other medicinal products that may increase the risk of gastrointestinal ulcers, gastrointestinal bleeding, or worsening of renal function.

Ibuprofen, like other NSAIDs, should not be used 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) has been 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 the clinical setting, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. Such a clinically significant effect is considered unlikely with occasional, short-term use of ibuprofen.

• other NSAIDs, including selective cyclooxygenase-2 inhibitors: simultaneous use of two or more NSAIDs should be avoided, as this may increase the risk of adverse reactions.

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

• corticosteroids: increased risk of gastrointestinal ulcers or bleeding;
• antihypertensive agents and diuretics: NSAIDs may reduce the effectiveness of these medicinal products. 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 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 in patients receiving coxibs concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, such combinations should be used with caution, particularly in elderly patients. If treatment is necessary, adequate hydration of the patient should be ensured, and monitoring of renal function should be considered at the start of combined therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs;
• anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin;
• 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: 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 administration of mifepristone, as NSAIDs may reduce the efficacy of mifepristone;
• 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 treatment with zidovudine and ibuprofen;
• quinolone antibiotics: animal data indicate that NSAIDs may increase the risk of convulsions associated with quinolone antibiotics. An increased risk of convulsions may occur in patients receiving NSAIDs and quinolone antibiotics concomitantly.

Special precautions for use.

Adverse effects can be minimized by using the lowest effective dose required to relieve symptoms for the shortest duration necessary.

In elderly individuals, there is an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforations, which may be fatal.

Respiratory effects.

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

Other NSAIDs.

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

Cases of aseptic meningitis have been reported during ibuprofen therapy. Although this effect is more likely in patients with systemic lupus erythematosus and other connective tissue disorders, such cases have also been reported in some patients without chronic diseases; therefore, this should be considered when using this medicinal product.

Effects on the cardiovascular and cerebrovascular systems.

Patients with a history of hypertension and/or heart failure should begin treatment cautiously (medical or pharmacist consultation is required), as 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), may be associated with a slightly 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.

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 assessment of the clinical condition. High doses (2400 mg daily) should be avoided.

The clinical condition should also be carefully evaluated before initiating long-term treatment in patients with cardiovascular risk factors (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 therapy. Kounis syndrome presents with cardiovascular symptoms related to coronary artery spasm due to an allergic or hypersensitivity reaction, which may lead to myocardial infarction.

Effects on kidneys/liver.

Caution is advised in patients with renal impairment due to the potential for worsening kidney function. Ibuprofen should be used with caution in patients with kidney or liver disease, particularly when used concomitantly with diuretics, as prostaglandin inhibition may lead to fluid retention and further deterioration of renal function. Such patients should receive the lowest possible dose of ibuprofen, and renal function should be monitored regularly. Adequate fluid intake should be ensured in cases of dehydration. There is a risk of renal failure in children (aged 6 years and older) and adolescents who are dehydrated.

Generally, chronic use of analgesics, especially combinations of different painkillers, may lead to chronic kidney injury with a risk of renal failure (analgesic nephropathy). The highest risk of this reaction occurs in elderly patients, patients with renal impairment, heart failure, or hepatic insufficiency, and in those receiving diuretic or ACE inhibitor therapy. Renal function typically returns to pre-treatment levels after discontinuation of NSAID therapy.

Like other NSAIDs, ibuprofen may cause mild, transient increases in certain liver function parameters, as well as significant elevations in AST and ALT levels. If substantial increases in these parameters occur, treatment should be discontinued.

During prolonged ibuprofen therapy, liver function, kidney function, and hematological parameters/blood counts should be monitored regularly.

Effects on female fertility.

Limited data suggest that medicinal products which 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, ulcers, or perforations, which may be fatal, have been reported during NSAID therapy at any stage of treatment, regardless of prior gastrointestinal symptoms or history.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should start treatment with the lowest available dose. These patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, should be prescribed concomitant protective therapy (e.g., misoprostol or proton pump inhibitors).

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

Prolonged use of any analgesic for headache treatment may worsen this condition. In such cases, patients should consult a physician and discontinue treatment. Medication-overuse headache should be considered in patients suffering from frequent or daily headaches, despite (or due to) regular use of headache medications.

Caution should be exercised when treating 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, 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 of treatment.

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

In rare cases, chickenpox may lead to severe skin and soft tissue infections. At present, the influence of NSAIDs on worsening these infections cannot be excluded; therefore, the use of Nurofen® is not recommended in cases of chickenpox.

Masking symptoms of underlying infections.

Nurofen® may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. When Nurofen® 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.

Sugar intolerance advice for patients.

Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product.

Advice for patients on controlled sodium diets.

This medicinal product contains 1.1 mmol (or 25.3 mg) of sodium per 2 doses (2 tablets). This should be taken into account by patients on a controlled 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 increased from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of treatment.

In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation losses and embryonic/fetal mortality. Additionally, increased frequencies of various developmental abnormalities, including cardiovascular defects, have 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 may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct 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 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® should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose 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 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 (see section "Contraindications").

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

Ability to affect reaction speed when driving or operating machinery.

When used according to recommended doses and treatment duration, the medicinal product is not expected to affect the ability to drive or operate machinery.

Method of Administration and Dosage

For oral use only. For short-term use only.

The tablets should be swallowed whole with water, not chewed. During short-term use, if symptoms persist or worsen, the patient should consult a physician.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The lowest effective dose should be used for the shortest time required to relieve symptoms (see section "Special Instructions"). If symptoms persist for more than 5 days from the start of treatment or worsen, medical advice should be sought.

The drug is indicated for adults and children with body weight above 20 kg (approximately 6 years of age). The recommended daily dose is 20–30 mg/kg of body weight. Do not exceed 30 mg/kg body weight per day.

Children with body weight from 20 to 30 kg (aged 6 to 11 years): 200 mg (1 tablet) per dose. A repeat dose may be taken if needed after 6 hours. Do not exceed 600 mg (3 tablets) per day.

Adults and children with body weight above 30 kg: 200–400 mg (1–2 tablets) per dose. A repeat dose may be taken if needed after 4–6 hours. Do not exceed 1200 mg (6 tablets) per day.

Elderly patients do not require special dosage adjustment.

Children. Do not use in children with body weight less than 20 kg or under 6 years of age.

Overdose.

Most reported cases of overdose were asymptomatic. Risk of symptoms arises with ibuprofen doses exceeding 80–100 mg/kg. Administration of ibuprofen to children in doses exceeding 400 mg/kg may cause symptoms of intoxication. In adults, the dose effect is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms. Symptoms of overdose typically appear within 4 hours after ingestion. In most patients, ingestion of clinically significant amounts of NSAIDs results in mild symptoms, including nausea, vomiting, epigastric pain, or less commonly, diarrhea. Other possible symptoms include tinnitus, headache, and gastrointestinal bleeding. In more severe poisoning, toxic effects on the central nervous system may occur, such as vertigo, dizziness, lethargy, drowsiness, occasionally excitability, ataxia, disorientation, or coma. Seizures may occasionally develop. Severe intoxication may lead to hyperkalemia, metabolic acidosis, and prolonged prothrombin time/INR (likely due to interaction with circulating blood coagulation factors). Rarely, moderate to severe symptoms such as acute renal failure, liver damage, hypotension, hypothermia, cyanosis, dyspnea/acute respiratory distress syndrome, and transient episodes of apnea (in children after large doses) have been observed. In patients with bronchial asthma, asthma exacerbation may occur. Nystagmus, visual disturbances, and loss of consciousness are also possible.

Treatment. There is no specific antidote. Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring cardiac and vital functions until stabilization. After ingestion of small amounts of the drug (less than 50 mg/kg of ibuprofen), drinking water is recommended to minimize gastrointestinal irritation. After ingestion of larger amounts, oral activated charcoal or gastric lavage is recommended if less than 1 hour has passed since ingestion of a potentially toxic dose and if a life-threatening amount has been ingested. If ibuprofen has already been absorbed, alkalizing agents may be used to enhance renal excretion of acidic ibuprofen. The benefit of interventions such as forced diuresis, hemodialysis, or hemoperfusion has not been proven, as ibuprofen is highly protein-bound. In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. In bronchial asthma, bronchodilators should be used. Immediate medical attention should be sought.

Adverse Reactions

The adverse reactions observed during the use of ibuprofen are listed below 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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

The following list of adverse reactions refers to those observed with over-the-counter doses of ibuprofen used for short-term treatment. Additional adverse effects may occur during treatment of chronic conditions or with long-term therapy.

The most commonly observed adverse reactions are gastrointestinal. Most adverse reactions are dose-dependent; in particular, the risk of gastrointestinal bleeding depends on both the dose and duration of treatment.

Blood and lymphatic system disorders:

Very rare: blood dyscrasias (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms include malaise, sore throat, superficial oral ulcers, influenza-like symptoms, severe exhaustion, unexplained bleeding, and unexplained bruising or petechiae.

Immune system disorders:

Hypersensitivity reactions¹; uncommon: urticaria and pruritus; very rare: severe hypersensitivity reactions, the symptoms of which may include facial, tongue, and laryngeal swelling, dyspnea, tachycardia, and hypotension (anaphylactic reaction, angioedema, or severe shock); frequency not known: respiratory tract reactivity, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea.

Nervous system disorders:

Uncommon: headache; very rare: aseptic meningitis².

Cardiac disorders:

Frequency not known: heart failure, edema, Cozzio’s syndrome.

Clinical trial data and epidemiological evidence suggest that the use of ibuprofen, particularly at high doses of 2400 mg daily and during long-term treatment, may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Vascular disorders:

Frequency not known: arterial hypertension.

Gastrointestinal disorders:

Uncommon: abdominal pain, nausea, dyspepsia; rare: diarrhea, flatulence, constipation, and vomiting; very rare: peptic ulceration of the stomach and duodenum, gastrointestinal perforation or bleeding, melena, hematemesis, sometimes fatal (particularly in elderly patients), ulcerative stomatitis, gastritis;

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

Hepatic disorders:

Very rare: hepatic function abnormalities.

Skin and subcutaneous tissue disorders:

Uncommon: various skin rashes; very rare: severe cutaneous adverse reactions (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis).

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

Respiratory, thoracic and mediastinal disorders:

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

Renal and urinary disorders:

Very rare: acute renal impairment, papillary necrosis, particularly with prolonged use, associated with increased serum urea levels and edema; frequency not known: renal failure.

Investigations:

Very rare: decreased hemoglobin levels.

Description of selected adverse reactions

¹ There have been reports of hypersensitivity reactions following treatment with ibuprofen. These include (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactions, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnea, or (c) various skin disorders, including rashes of different types, pruritus, urticaria, purpura, angioedema, and less frequently exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

² 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 relationship to drug intake and resolution of symptoms after discontinuation). In particular, isolated cases of aseptic meningitis symptoms (such as nuchal rigidity, headache, nausea, vomiting, malaise, or disorientation) have been observed in patients with pre-existing autoimmune disorders (such as systemic lupus erythematosus or mixed connective tissue disease) during ibuprofen therapy.

Shelf life. 3 years.

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

Packaging. 6, 8, or 12 tablets in a blister; 1 blister with 6 tablets, 1 blister with 8 tablets, or 1 or 2 blisters with 12 tablets in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

Reckitt Benckiser Healthcare International Limited.

Manufacturer's address and place of business.

Tame Road, Nottingham, Nottinghamshire, NG90 2DB, United Kingdom.