4.1. Therapeutic indications

Children aged 7 to 12 years

Rheumatic or muscular pain, headache, dental pain, feverishness, symptoms of cold and influenza.

4.2. Posology and method of administration

For oral administration and short-term use only.

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

Children 7 to 12 years

For children weighing more than 20kg, the daily dosage is 20mg/kg bodyweight in divided doses. Using the oral syringe provided, this can be achieved as follows;

7 to 9 years: 5ml up to three times in 24 hours

10 to 12 years: 7.5ml up to three times in 24 hours

Leave at least four hours between doses and do not give more than 1200mg in any 24-hour period. The recommended dose should not be exceeded.

If in children aged 7 to 12 years this medicinal product is required for more than three days, or if symptoms worsen, a doctor should be consulted. This product should only be given to children who weigh more than 20kg.

Method of administration

For oral administration. The bottle should be shaken vigorously before use.

The oral suspension can be taken with food. The package includes an oral syringe for oral administration or Ibuprofen oral suspension. The oral syringe is graduated in 0.25ml steps up to 5ml. 5ml oral suspension corresponds to 200mg ibuprofen.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin (acetylsalicylic acid) or other non-steroidal anti-inflammatory drugs (NSAIDs).

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

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

Severe hepatic failure, severe renal failure or severe heart failure (see section 4.4).

Last trimester of pregnancy (see section 4.6)

Children under seven years of age.

Children weighing less than 20kg.

Patients with rare hereditary problems of fructose intolerance should not take this medicine

4.4. Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, Gastrointestinal and cardiovascular risks below).

Masking of symptoms of underlying infections:

Ibuprofen oral suspension can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When Ibuprofen is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Other NSAIDs:

The use of Ibuprofen Oral Suspension with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systematic lupus erythematosus and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8)

Renal:

Renal impairment as renal function may further deteriorate (see section 4.3 and 4.8). There is a risk of renal impairment in dehydrated children and adolescents.

Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients taking ibuprofen products over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

Hepatic:

Hepatic dysfunction (see section 4.3 and 4.8)

Cardiovascular and cerebrovascular effects

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical studies and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤1200 mg daily) is associated with an increased risk of myocardial function.

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided.

Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg/day) are required.

Cases of Kounis syndrome have been reported in patients treated with Ibuprofen oral suspension. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.

Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8 – undesirable effects).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving 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 aspirin acetylsalicylic acid) (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving Ibuprofen Oral Suspension, the treatment should be withdrawn.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with the use of ibuprofen (see section 4.8). Most of these reactions occurred within the first month.

If signs and symptoms suggestive of these reactions appear ibuprofen should be withdrawn immediately and an alternative treatment considered (as appropriate).

Exceptionally, varicella can be at the origin of serious cutaneous and soft tissues infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of ibuprofen in case of varicella (chickenpox).

Advice for patients with sugar-related disorders:

This medicinal product contains maltitol liquid. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Advice for patients on a controlled sodium diet:

This medicinal product contains 57.9 mg (2.52 mmol) sodium per 400 mg (10 ml) dose, equivalent to 2.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

Ibuprofen should be avoided in combination with:

Aspirin (acetylsalicylic acid): Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects (see section 4.4).

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDs including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse reactions (see section 4.4).

Ibuprofen (like other NSAIDs) should be used with caution in combination with:

Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increase in plasma levels of lithium

Methotrexate: There is evidence for the potential increase in plasma levels of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of hemarthrosis and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions

4.6. Fertility, pregnancy and lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development.

Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1 %, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

During the first and second trimester of pregnancy, Ibuprofen Oral Suspension should not be given unless clearly necessary. If Ibuprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

From the 20th week of pregnancy onward, Ibuprofen Oral Suspension use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, Ibuprofen Oral Suspension should not be given unless clearly necessary. If Ibuprofen Oral Suspension is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to Ibuprofen Oral Suspension for several days from gestational week 20 onward. Ibuprofen Oral Suspension should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose

▪ the foetus to:

- cardiopulmonary toxicity (constriction/closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction (see above)

▪ the mother and the 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 labour.

Consequently, Ibuprofen Oral Suspension is contraindicated during the third trimester of pregnancy (see section 4.3 and 5.3).

Breast-feeding

In limited studies, ibuprofen appears in the breast milk in very low concentrations and is unlikely to affect the breast-fed infant adversely.

Fertility

There is some evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment (see section 4.4).

4.7. Effects on ability to drive and use machines

None expected at recommended doses and duration of therapy.

4.8. Undesirable effects

Adverse events which have been associated with Ibuprofen are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100, rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

The list of the following adverse events relates to those experienced with ibuprofen at OTC doses for short term use. In the treatment of chronic conditions, under long-term treatment, additional adverse events may occur. The adverse events observed most often are gastrointestinal in nature. Adverse events are mostly dose-dependent, in particular the risk of occurrence of gastrointestinal bleeding is dependent on the dosage range and duration of treatment.

Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke), (see section 4.4).

System Organ Class

Frequency

Adverse Event

Blood and Lymphatic System Disorders

Very rare

Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis)1.

Immune System Disorders

Uncommon

Hypersensitivity reactions consisting of: urticaria and pruritus2

Very rare

Severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angiodema or severe shock)2

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed.

Respiratory, Thoracic and Mediastinal Disorders

Not Known

Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea2.

Nervous System Disorders

Uncommon

Headache

Very rare

Aseptic meningitis3.

Cardiac Disorders

Not Known

Cardiac failure and oedema4

Kounis syndrome

Vascular Disorders

Not Known

Hypertension4

Gastrointestinal Disorders

Uncommon

Abdominal pain, nausea, dyspepsia5

Rare

Diarrhoea, flatulence, constipation and vomiting

Very rare

Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haemotemesis6, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis. Exacerbation of colitis and Crohn's disease7 (section 4.4).

Hepatobiliary Disorders

Very rare

Liver disorders

Skin and Subcutaneous Tissue Disorders

Uncommon

Various skin rashes2

Very rare

Severe cutaneous adverse reactions (SCARs) (including Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis).

Not Known

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Acute generalised exanthematous pustulosis (AGEP).

Photosensitivity reactions.

Renal and Urinary Disorders

Very rare

Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema8

Not Known

Ureteric colic, dysuria, Renal tubular acidosis9

Investigations

Very rare

Decreased haemoglobin levels

Infections and infestations

Not Known

Exacerbation of infections related inflammation has been described, in exceptional cases, severe skin infections and soft tissue complications may occur during a varicella infection.

Metabolic and Nutritional Disorders

Not Known

Decreased appetite, Hypokalaemia9

Description of Selected Adverse Reactions

1First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

2Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) nonspecific allergic reactions and anaphylaxis, (b) respiratory tract activity comprising asthma, aggravated asthma, bronchospasm, dyspnoea or (c) assorted skin disorders, including rashes of various types pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

3The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, the available data on NSAID-related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). Of note, single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever or disorientation) have been observed during treatment with ibuprofen, in patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).

4Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke), (see section 4.4).

5The adverse events observed most often are gastrointestinal in nature.

6Sometimes fatal.

8Especially in long-term use, associated with increased serum urea and oedema. Also includes papillary necrosis.

9Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of the ibuprofen component at higher than recommended doses.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions 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 Yellow Card Scheme (www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store).

4.9. Overdose

In children ingestion of more than 400mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms:

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness (see section 4.4 and section 4.8).

Management:

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.