NUROFEN

200mg 24 COATED TABLETS

It relieves pain of various kinds: headache, toothache, neuralgia, muscle and joint pain, menstrual pain.
Adjuvant in the symptomatic treatment of feverish and influenza states for adults and adolescents over 12 years of age.

ACTIVE INGREDIENTS
Coated tablets 200 mg: Each tablet contains 200 mg ibuprofen.
Coated tablets 400 mg: Each tablet contains 400 mg ibuprofen.

CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients listed in paragraph 6.1.
Patients who have previously shown hypersensitivity reactions (e.g.
bronchospasm, asthma, rhinitis, angioedema or urticaria) resulting from the use of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs).
Patients with severe hepatic or renal impairment (see section 4.4).
Severe heart failure (NYHA class IV) Patients with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy.
Patients with active or previous recurrent peptic ulcers/haemorrhages (two or more distinct episodes of proven ulceration or bleeding).
During the last trimester of pregnancy (see section 4.6).
Children under 12 years old.
Before or after cardiac surgery.

DOSAGE
Dosage: for short-term treatment only.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
If symptoms persist or worsen after a short period of treatment, consult your doctor.
If the use of the medicine is necessary for more than 3 days in adolescents, or in case of worsening of the symptoms, the doctor should be consulted.
Nurofen 200 mg coated tablets.
Paediatric population: Do not administer to children under 12 years of age.
Adults and adolescents over 12 years: 1-2 tablets, 2-3 times a day.
The interval between doses should not be less than 4 hours.
Do not exceed the dose of 1200 mg (6 tablets) in 24 hours.
Elderly: No changes to the dosage regimen are required.
Nurof en 400 mg coated tablets.
Paediatric population: Do not administer to children under 12 years of age.
Adults and adolescents over 12 years: one tablet 2-3 times a day.
The interval between doses must not be less than 4 hours.
Do not exceed the dose of 1200 mg (3 tablets) in 24 hours.
Elderly: No changes to the dosage regimen are required.
Method of administration: oral use.
Patients with gastric sensitivity problems are advised to take Nuro fen on a full stomach.

CONSERVATION
Nurofen 400 mg coated tablets: store below 30 degrees C.

WARNINGS:
Caution is required in patients with coagulation defects.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see gastrointestinal and cardiovascular risks below).
Elderly: Elderly patients have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal (see section 4.2).
Paediatric population: There is a risk of impaired renal function in dehydrated adolescents.
Respiratory disorders: bronchospasm may occur in patients with bronchial asthma or current or previous allergic diseases.
Other NSAIDs: The use of Nurofen should be avoided in conjunction with other NSAIDs, including cyclooxygenase-2 selective inhibitors.
(see paragraph 4.5).
SLE and mixed connective tissue disease Systemic lupus erythematosus and mixed connective tissue disease due to increased risk of aseptic meningitis (see section 4.8).
Cardiovascular and cerebrovascular effects: Caution is advised (discuss with your doctor or pharmacist) before initiating treatment in patients with a history of hypertension and/or heart failure since fluid retention, hypertension and edema have been reported in association with NSAID treatment.
Clinical trials suggest that use of ibuprofen, particularly at high doses (2400 mg/day), may be associated with a modest increased risk of arterial thrombotic events (e.g.
myocardial infarction or stroke).
Overall, epidemiological studies do not suggest that low doses of ibuprofen (e.g.
<= 1200 mg/day) are associated with an increased risk of arterial thrombotic events.
Patients with uncontrolled hypertension, congestive heart failure (NYHA class II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful consideration and high doses (2400 mg/day) should be avoided.
Careful consideration should also be exercised before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g.
hypertension, hyperlipidemia, diabetes mellitus, smoking habits), especially if high doses (2400 mg/day) of ibuprofen are required.
Hepatic or renal function: renal insufficiency, as renal function may be impaired (see sections 4.3 and 4.8).
In general, the habitual use of analgesics, especially combinations of several analgesic active ingredients, can lead to permanent renal damage with risk of onset of renal failure (analgesic nephropathy); liver dysfunction (see paragraphs 4.3 and 4.8).
Particular caution should be exercised when treating patients with impaired hepatic or renal function.
In such patients, periodic monitoring of clinical and laboratory parameters is advisable, especially in case of prolonged treatment.
Impaired female fertility: Nurofen should be avoided in women planning pregnancy (see section 4.6).
Gastrointestinal safety: NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).
Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.
In the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increased doses of NSAIDs.
These patients should start treatment on the lowest available dose.
The use of protective agents with a companion (e.g.
misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low dose acetylsalicylic acid or other drugs likely to increase the risk of gastrointestinal events (see section 4.5).
Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding) promptly, particularly in the initial stages of treatment.
Caution should be advised in patients taking concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (see section 4.5).
If gastrointestinal bleeding or ulceration occurs in patients taking Nurofen, the treatment should be withdrawn.
Severe skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported rarely in association with the use of NSAIDs (see section 4.8).
Patients appear to be at highest risk early in the course of therapy: the onset of the reaction occurs in the majority of cases within the first month of treatment.
Generalized cutaneous exanthematous pustulosis (AGEP) has been reported in relation to medicinal products containing ibuprofen.
Ibuprofen should be discontinued at the first appearance of signs and symptoms of severe skin reactions, such as rash, mucosal lesions or any other sign of hypersensitivity.
Masking of symptoms of underlying infections: Nurofen may mask the symptoms of infection, which may delay the initiation of adequate treatment and therefore worsen the outcome of the infection.
This has been observed in community-acquired bacterial pneumonia and in bacterial complications of chickenpox.
When Nurofen is given for the relief of fever or pain related to infection, monitoring for infection is advised.

INTERACTIONS:
Ibuprofen should be avoided in association with acetylsalicylic acid: the concomitant administration of ibuprofen and acetylsalicylic acid is generally not recommended due to the potential increase in adverse effects (see section 4.4).
Experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when the two drugs are administered concomitantly.
Although there are uncertainties regarding the extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded.
No clinically relevant effect is considered likely following occasional use of ibuprofen (see section 5.1).
Other NSAIDs including cyclooxygenase-2 selective inhibitors: Concomitant use of two or more NSAIDs should be avoided as they may increase the risk of adverse reactions affecting the gastrointestinal tract (see section 4.4).
Ibuprofen (like other NSAIDs) should be used with caution in combination with corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4); anticoagulants: NSAIDs may increase the effects of anticoagulants, such as warfarin (see section 4.4); antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).
Antihypertensives (ACE inhibitors and Angiotensin II antagonists), diuretics and beta blockers: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or an angiotensin II antagonist and agents that inhibit the cyclo-oxygenase system may lead to a further deterioration of renal function, including possible acute renal failure, which is usually reversible.
These interactions should be considered in patients taking a coxib (such as Nurofen) concomitantly with ACE inhibitors or angiotensin II antagonists.
Therefore, the combination should be administered with caution, especially in elderly patients.
Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and at regular intervals thereafter.
Diuretics may increase the risk of nephrotoxicity of NSAIDs.
Cardiac glycosides: NSAIDs may worsen heart failure, reduce GFR (glomerular filtration rate), and increase plasma glycoside levels.
Lithium: There is evidence of the possibility of a potential increase in lithium levels in the blood, with the possibility of reaching the toxic threshold.
If this combination is necessary, monitor blood lithium levels in order to adapt the lithium dosage during concomitant treatment with ibuprofen.
Methotrexate: There is evidence of the possibility of an increase in plasma levels of methotrexate.
Cyclosporins: increase the risk of nephrotoxicity.
Mifepristone: NSAIDs should not be taken for 8-12 days after administration of Mifepristone as NSAIDs may reduce the effects of Mifepristone.
Tacrolimus: possible increased risk of nephrotoxicity when NSAIDs are administered with Tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are administered with Zidovudine.
There is evidence of an increased risk of haemarthrosis and haematoma in HIV-seropositive haemophilic patients treated concomitantly with zidovudine and ibuprofen.
Quinolone antibiotics: Data from animal studies indicate that NSAIDs may increase the risk of convulsions associated with quinolone antibiotics.
Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
Alcohol, bisphosphonates and pentoxifylline: may enhance gastrointestinal side effects and the risk of bleeding and ulceration.
Baclofen: high toxicity of baclofen.

SIDE EFFECTS:
The list of side effects below includes adverse reactions that have been observed during treatment with ibuprofen at self-medication doses (up to a maximum of 1200 mg per day).
In case of chronic conditions during long-term treatment, further side effects may occur.
Undesirable effects associated with the administration of ibuprofen are listed below according to system organ class and frequency.
For the frequency of occurrence of adverse reactions, the following expressions are used: very common (>= 1/10); common (>= 1/100, <1/10); uncommon (>= 1/1000, <1/100); rare (>= 1/10,000, <1/1000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in decreasing order of seriousness.
Pathologies of the haemolymphopoietic system.
Very rare: haematopoietic disorders¹.
Immune system disorders.
Uncommon: hypersensitivity reactions including urticaria and pruritus²; very rare: severe hypersensitivity reactions including swelling of the face, tongue and throat, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock)².
Pathologies of the nervous system.
Uncommon: headache, dizziness; rare: cerebrovascular accident9; very rare: aseptic meningitis³.
Eye pathologies.
Very rare: visual disturbances.
Heart disease.
Very rare: cardiac failure and oedema4.
Vascular pathologies.
Very rare: hypertension4.
Respiratory, thoracic and mediastinal disorders.
Not known: respiratory tract reactivity including asthma, worsening of asthma, bronchospasm or dyspnoea.
Gastrointestinal disorders.
Uncommon: dyspepsia, abdominal pain and nausea5; rare: diarrhoea, flatulence, constipation and vomiting; very rare: peptic ulcers, gastrointestinal perforation or haemorrhage, melaena, haematemesis6, ulcerative stomatitis, gastritis; not known: exacerbation of colitis and Crohn's disease7, pancreatitis.
Hepatobiliary pathologies.
Rare: hepatotoxicity; very rare: hepatic disorders, especially following long-term treatment, hepatitis, jaundice.
Skin and subcutaneous tissue disorders.
Uncommon: skin rashes²; very rare: erythema multiforme, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.²; not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions.
Renal and urinary disorders.
Very rare: acute renal failure8, haematuria, nephritis, nephrotic syndrome9.
Diagnostic tests.
Rare: increased transaminases, increased alkaline phosphatase, decreased haematocrit, prolonged bleeding time, decreased blood calcium, increased uric acid; very rare: decreased haemoglobin level in the blood.
Description of some adverse effects: ^1 Examples include anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis).
The first symptoms are: fever, sore throat, superficial ulcers of the oral cavity, flu-like symptoms, severe fatigue, unexplained bruising and bleeding.
^2 Hypersensitivity reactions: These reactions may include a) non-specific allergic reactions and anaphylaxis, b) respiratory tract reactivity including asthma, worsening of asthma, bronchospasm or dyspnoea, or c) various skin disorders such as various rashes, pruritus, urticaria, purpura, angioedema and very rarely bullous and exfoliative dermatitis including toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme.
^3 The pathogenesis of drug-induced aseptic meningitis is not fully understood.
However, the available data on aseptic meningitis related to the administration of NSAIDs suggest an immune hypersensitivity reaction (due to a temporary relationship with the intake of the drug and the disappearance of symptoms after the suspension of treatment).
Of note, single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever and disorientation) have been observed during treatment with ibuprofen in patients with autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).
^4 Clinical trials suggest that use of ibuprofen, particularly at high doses (2400 mg/day) may be associated with a modest increased risk of arterial thrombotic events (e.g.
myocardial infarction or stroke) (see section 4.4).
^5 The most commonly observed adverse reactions are gastrointestinal in nature.
^6 sometimes fatal, particularly in the elderly.
^7 see paragraph 4.4.
^8 particularly following long-term treatments, associated with an increase in serum urea concentrations.
Decreased urea excretion and edema.
Also includes papillary necrosis ^9 reported as an effect of the NSAID class.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions that occur after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni averse.

PREGNANCY AND BREASTFEEDING:
Pregnancy: inhibition of prostaglandin synthesis may negatively affect the pregnant woman and/or embryo/fetal development.
Data from epidemiological studies suggest an increased risk of miscarriage, cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor during early pregnancy.
The absolute risk of heart defects increased from less than 1% to approximately 1.5%.
The risk is believed to increase with dose and duration of therapy.
In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased pre- and post-implantation loss and embryo-fetal mortality.
Furthermore, an increased incidence of various malformations, including cardiovascular, has been reported in animals given prostaglandin synthesis inhibitors during the organogenetic period.
From the twentieth week of pregnancy onwards, the use of ibuprofen may cause oligohydramnios resulting from fetal renal dysfunction.
This condition may be observed shortly after starting treatment and is usually reversible upon discontinuation of treatment.
Additionally, cases of constriction of the ductus arteriosus have been reported following treatment in the second trimester, most of which resolved after discontinuation of treatment.
Therefore, during the first and second trimester of pregnancy, ibuprofen should not be administered unless strictly necessary.
If ibuprofen is used by a woman who is planning to become pregnant, or during the first and second trimester of pregnancy, the lowest possible dose should be used for the shortest possible time.
Following exposure to ibuprofen for several days from the twentieth week of gestation onwards, antenatal monitoring for oligohydramnios and constriction of the ductus arteriosus should be considered.
In case of oligohydramnios or constriction of the ductus arteriosus, treatment with ibuprofen should be discontinued.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to: cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction (see above); the mother and neonate, at the end of pregnancy, to: possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labor.
Consequently, Nurofen is contraindicated during the third trimester of pregnancy (see sections 4.3 and 5.3).
Breastfeeding: Ibuprofen and its metabolites may pass into breast milk in low concentrations.
No dangerous effects for newborns are known to date, therefore for short treatments with the recommended dose for pain and fever, interruption of breastfeeding is generally not necessary.
Fertility: There is evidence that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may cause impairment of female fertility by affecting ovulation.
This effect is reversible after discontinuation of treatment.
Nurofen should be discontinued in women who have fertility problems or who are undergoing investigation of fertility.

NUROFEN

400mg 12 COATED TABLETS

It relieves pain of various kinds: headache, toothache, neuralgia, muscle and joint pain, menstrual pain.
Adjuvant in the symptomatic treatment of feverish and influenza states for adults and adolescents over 12 years of age.

ACTIVE INGREDIENTS
Coated tablets 200 mg: Each tablet contains 200 mg ibuprofen.
Coated tablets 400 mg: Each tablet contains 400 mg ibuprofen.

CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients listed in paragraph 6.1.
Patients who have previously shown hypersensitivity reactions (e.g.
bronchospasm, asthma, rhinitis, angioedema or urticaria) resulting from the use of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs).
Patients with severe hepatic or renal impairment (see section 4.4).
Severe heart failure (NYHA class IV) Patients with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy.
Patients with active or previous recurrent peptic ulcers/haemorrhages (two or more distinct episodes of proven ulceration or bleeding).
During the last trimester of pregnancy (see section 4.6).
Children under 12 years old.
Before or after cardiac surgery.

DOSAGE
Dosage: for short-term treatment only.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
If symptoms persist or worsen after a short period of treatment, consult your doctor.
If the use of the medicine is necessary for more than 3 days in adolescents, or in case of worsening of the symptoms, the doctor should be consulted.
Nurofen 200 mg coated tablets.
Paediatric population: Do not administer to children under 12 years of age.
Adults and adolescents over 12 years: 1-2 tablets, 2-3 times a day.
The interval between doses should not be less than 4 hours.
Do not exceed the dose of 1200 mg (6 tablets) in 24 hours.
Elderly: No changes to the dosage regimen are required.
Nurof en 400 mg coated tablets.
Paediatric population: Do not administer to children under 12 years of age.
Adults and adolescents over 12 years: one tablet 2-3 times a day.
The interval between doses must not be less than 4 hours.
Do not exceed the dose of 1200 mg (3 tablets) in 24 hours.
Elderly: No changes to the dosage regimen are required.
Method of administration: oral use.
Patients with gastric sensitivity problems are advised to take Nuro fen on a full stomach.

CONSERVATION
Nurofen 400 mg coated tablets: store below 30 degrees C.

WARNINGS:
Caution is required in patients with coagulation defects.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see gastrointestinal and cardiovascular risks below).
Elderly: Elderly patients have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal (see section 4.2).
Paediatric population: There is a risk of impaired renal function in dehydrated adolescents.
Respiratory disorders: bronchospasm may occur in patients with bronchial asthma or current or previous allergic diseases.
Other NSAIDs: The use of Nurofen should be avoided in conjunction with other NSAIDs, including cyclooxygenase-2 selective inhibitors.
(see paragraph 4.5).
SLE and mixed connective tissue disease Systemic lupus erythematosus and mixed connective tissue disease due to increased risk of aseptic meningitis (see section 4.8).
Cardiovascular and cerebrovascular effects: Caution is advised (discuss with your doctor or pharmacist) before initiating treatment in patients with a history of hypertension and/or heart failure since fluid retention, hypertension and edema have been reported in association with NSAID treatment.
Clinical trials suggest that use of ibuprofen, particularly at high doses (2400 mg/day), may be associated with a modest increased risk of arterial thrombotic events (e.g.
myocardial infarction or stroke).
Overall, epidemiological studies do not suggest that low doses of ibuprofen (e.g.
<= 1200 mg/day) are associated with an increased risk of arterial thrombotic events.
Patients with uncontrolled hypertension, congestive heart failure (NYHA class II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful consideration and high doses (2400 mg/day) should be avoided.
Careful consideration should also be exercised before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g.
hypertension, hyperlipidemia, diabetes mellitus, smoking habits), especially if high doses (2400 mg/day) of ibuprofen are required.
Hepatic or renal function: renal insufficiency, as renal function may be impaired (see sections 4.3 and 4.8).
In general, the habitual use of analgesics, especially combinations of several analgesic active ingredients, can lead to permanent renal damage with risk of onset of renal failure (analgesic nephropathy); liver dysfunction (see paragraphs 4.3 and 4.8).
Particular caution should be exercised when treating patients with impaired hepatic or renal function.
In such patients, periodic monitoring of clinical and laboratory parameters is advisable, especially in case of prolonged treatment.
Impaired female fertility: Nurofen should be avoided in women planning pregnancy (see section 4.6).
Gastrointestinal safety: NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).
Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.
In the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increased doses of NSAIDs.
These patients should start treatment on the lowest available dose.
The use of protective agents with a companion (e.g.
misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low dose acetylsalicylic acid or other drugs likely to increase the risk of gastrointestinal events (see section 4.5).
Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding) promptly, particularly in the initial stages of treatment.
Caution should be advised in patients taking concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (see section 4.5).
If gastrointestinal bleeding or ulceration occurs in patients taking Nurofen, the treatment should be withdrawn.
Severe skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported rarely in association with the use of NSAIDs (see section 4.8).
Patients appear to be at highest risk early in the course of therapy: the onset of the reaction occurs in the majority of cases within the first month of treatment.
Generalized cutaneous exanthematous pustulosis (AGEP) has been reported in relation to medicinal products containing ibuprofen.
Ibuprofen should be discontinued at the first appearance of signs and symptoms of severe skin reactions, such as rash, mucosal lesions or any other sign of hypersensitivity.
Masking of symptoms of underlying infections: Nurofen may mask the symptoms of infection, which may delay the initiation of adequate treatment and therefore worsen the outcome of the infection.
This has been observed in community-acquired bacterial pneumonia and in bacterial complications of chickenpox.
When Nurofen is given for the relief of fever or pain related to infection, monitoring for infection is advised.

INTERACTIONS:
Ibuprofen should be avoided in association with acetylsalicylic acid: the concomitant administration of ibuprofen and acetylsalicylic acid is generally not recommended due to the potential increase in adverse effects (see section 4.4).
Experimental data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when the two drugs are administered concomitantly.
Although there are uncertainties regarding the extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded.
No clinically relevant effect is considered likely following occasional use of ibuprofen (see section 5.1).
Other NSAIDs including cyclooxygenase-2 selective inhibitors: Concomitant use of two or more NSAIDs should be avoided as they may increase the risk of adverse reactions affecting the gastrointestinal tract (see section 4.4).
Ibuprofen (like other NSAIDs) should be used with caution in combination with corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4); anticoagulants: NSAIDs may increase the effects of anticoagulants, such as warfarin (see section 4.4); antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).
Antihypertensives (ACE inhibitors and Angiotensin II antagonists), diuretics and beta blockers: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or an angiotensin II antagonist and agents that inhibit the cyclo-oxygenase system may lead to a further deterioration of renal function, including possible acute renal failure, which is usually reversible.
These interactions should be considered in patients taking a coxib (such as Nurofen) concomitantly with ACE inhibitors or angiotensin II antagonists.
Therefore, the combination should be administered with caution, especially in elderly patients.
Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and at regular intervals thereafter.
Diuretics may increase the risk of nephrotoxicity of NSAIDs.
Cardiac glycosides: NSAIDs may worsen heart failure, reduce GFR (glomerular filtration rate), and increase plasma glycoside levels.
Lithium: There is evidence of the possibility of a potential increase in lithium levels in the blood, with the possibility of reaching the toxic threshold.
If this combination is necessary, monitor blood lithium levels in order to adapt the lithium dosage during concomitant treatment with ibuprofen.
Methotrexate: There is evidence of the possibility of an increase in plasma levels of methotrexate.
Cyclosporins: increase the risk of nephrotoxicity.
Mifepristone: NSAIDs should not be taken for 8-12 days after administration of Mifepristone as NSAIDs may reduce the effects of Mifepristone.
Tacrolimus: possible increased risk of nephrotoxicity when NSAIDs are administered with Tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are administered with Zidovudine.
There is evidence of an increased risk of haemarthrosis and haematoma in HIV-seropositive haemophilic patients treated concomitantly with zidovudine and ibuprofen.
Quinolone antibiotics: Data from animal studies indicate that NSAIDs may increase the risk of convulsions associated with quinolone antibiotics.
Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
Alcohol, bisphosphonates and pentoxifylline: may enhance gastrointestinal side effects and the risk of bleeding and ulceration.
Baclofen: high toxicity of baclofen.

SIDE EFFECTS:
The list of side effects below includes adverse reactions that have been observed during treatment with ibuprofen at self-medication doses (up to a maximum of 1200 mg per day).
In case of chronic conditions during long-term treatment, further side effects may occur.
Undesirable effects associated with the administration of ibuprofen are listed below according to system organ class and frequency.
For the frequency of occurrence of adverse reactions, the following expressions are used: very common (>= 1/10); common (>= 1/100, <1/10); uncommon (>= 1/1000, <1/100); rare (>= 1/10,000, <1/1000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in decreasing order of seriousness.
Pathologies of the haemolymphopoietic system.
Very rare: haematopoietic disorders¹.
Immune system disorders.
Uncommon: hypersensitivity reactions including urticaria and pruritus²; very rare: severe hypersensitivity reactions including swelling of the face, tongue and throat, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock)².
Pathologies of the nervous system.
Uncommon: headache, dizziness; rare: cerebrovascular accident9; very rare: aseptic meningitis³.
Eye pathologies.
Very rare: visual disturbances.
Heart disease.
Very rare: cardiac failure and oedema4.
Vascular pathologies.
Very rare: hypertension4.
Respiratory, thoracic and mediastinal disorders.
Not known: respiratory tract reactivity including asthma, worsening of asthma, bronchospasm or dyspnoea.
Gastrointestinal disorders.
Uncommon: dyspepsia, abdominal pain and nausea5; rare: diarrhoea, flatulence, constipation and vomiting; very rare: peptic ulcers, gastrointestinal perforation or haemorrhage, melaena, haematemesis6, ulcerative stomatitis, gastritis; not known: exacerbation of colitis and Crohn's disease7, pancreatitis.
Hepatobiliary pathologies.
Rare: hepatotoxicity; very rare: hepatic disorders, especially following long-term treatment, hepatitis, jaundice.
Skin and subcutaneous tissue disorders.
Uncommon: skin rashes²; very rare: erythema multiforme, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.²; not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions.
Renal and urinary disorders.
Very rare: acute renal failure8, haematuria, nephritis, nephrotic syndrome9.
Diagnostic tests.
Rare: increased transaminases, increased alkaline phosphatase, decreased haematocrit, prolonged bleeding time, decreased blood calcium, increased uric acid; very rare: decreased haemoglobin level in the blood.
Description of some adverse effects: ^1 Examples include anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis).
The first symptoms are: fever, sore throat, superficial ulcers of the oral cavity, flu-like symptoms, severe fatigue, unexplained bruising and bleeding.
^2 Hypersensitivity reactions: These reactions may include a) non-specific allergic reactions and anaphylaxis, b) respiratory tract reactivity including asthma, worsening of asthma, bronchospasm or dyspnoea, or c) various skin disorders such as various rashes, pruritus, urticaria, purpura, angioedema and very rarely bullous and exfoliative dermatitis including toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme.
^3 The pathogenesis of drug-induced aseptic meningitis is not fully understood.
However, the available data on aseptic meningitis related to the administration of NSAIDs suggest an immune hypersensitivity reaction (due to a temporary relationship with the intake of the drug and the disappearance of symptoms after the suspension of treatment).
Of note, single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever and disorientation) have been observed during treatment with ibuprofen in patients with autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).
^4 Clinical trials suggest that use of ibuprofen, particularly at high doses (2400 mg/day) may be associated with a modest increased risk of arterial thrombotic events (e.g.
myocardial infarction or stroke) (see section 4.4).
^5 The most commonly observed adverse reactions are gastrointestinal in nature.
^6 sometimes fatal, particularly in the elderly.
^7 see paragraph 4.4.
^8 particularly following long-term treatments, associated with an increase in serum urea concentrations.
Decreased urea excretion and edema.
Also includes papillary necrosis ^9 reported as an effect of the NSAID class.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions that occur after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni averse.

PREGNANCY AND BREASTFEEDING:
Pregnancy: inhibition of prostaglandin synthesis may negatively affect the pregnant woman and/or embryo/fetal development.
Data from epidemiological studies suggest an increased risk of miscarriage, cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor during early pregnancy.
The absolute risk of heart defects increased from less than 1% to approximately 1.5%.
The risk is believed to increase with dose and duration of therapy.
In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased pre- and post-implantation loss and embryo-fetal mortality.
Furthermore, an increased incidence of various malformations, including cardiovascular, has been reported in animals given prostaglandin synthesis inhibitors during the organogenetic period.
From the twentieth week of pregnancy onwards, the use of ibuprofen may cause oligohydramnios resulting from fetal renal dysfunction.
This condition may be observed shortly after starting treatment and is usually reversible upon discontinuation of treatment.
Additionally, cases of constriction of the ductus arteriosus have been reported following treatment in the second trimester, most of which resolved after discontinuation of treatment.
Therefore, during the first and second trimester of pregnancy, ibuprofen should not be administered unless strictly necessary.
If ibuprofen is used by a woman who is planning to become pregnant, or during the first and second trimester of pregnancy, the lowest possible dose should be used for the shortest possible time.
Following exposure to ibuprofen for several days from the twentieth week of gestation onwards, antenatal monitoring for oligohydramnios and constriction of the ductus arteriosus should be considered.
In case of oligohydramnios or constriction of the ductus arteriosus, treatment with ibuprofen should be discontinued.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to: cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction (see above); the mother and neonate, at the end of pregnancy, to: possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labor.
Consequently, Nurofen is contraindicated during the third trimester of pregnancy (see sections 4.3 and 5.3).
Breastfeeding: Ibuprofen and its metabolites may pass into breast milk in low concentrations.
No dangerous effects for newborns are known to date, therefore for short treatments with the recommended dose for pain and fever, interruption of breastfeeding is generally not necessary.
Fertility: There is evidence that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may cause impairment of female fertility by affecting ovulation.
This effect is reversible after discontinuation of treatment.
Nurofen should be discontinued in women who have fertility problems or who are undergoing investigation of fertility.