IBUPROFEN 100 MG / 5ML ORAL SUSPENSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Ibuprofen 100mg/5ml Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient is ibuprofen.

5ml of oral suspension contains 100mg of ibuprofen.

Excipients with known effect:

5ml of oral suspension contains 2g of maltitol liquid.

5ml of oral suspension contains 0.00075mg of benzyl alcohol.

5ml of oral suspension contains 10.0mg of sodium benzoate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral suspension

White to almost white suspension with orange-vanilla flavour.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Children 3 months to 12 years (> 5 kg):

the reduction of fever, including post immunisation pyrexia

the relief of the symptoms of colds and influenza

the relief of mild to moderate pain, such as a sore throat, teething pain, toothache, earache, headache, minor aches and sprains.

4.2 Posology and method of administration

Posology

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

Children from 3 months of age

For post immunisation pyrexia: One 2.5 ml dose followed by one further 2.5 ml dose 6 hours later if necessary. No more than two 2.5 ml doses in 24 hours. If the fever is not reduced, consult your doctor.

For pain, fever and symptoms of cold and influenza: The daily dosage of Ibuprofen oral suspension is 20–30 mg/kg bodyweight in divided doses. Using the oral dosing syringe provided this can be achieved as follows:

Infants 3 – 6 months weighing more than 5 kg: One 2.5ml dose may be taken 3 times in 24 hours.

Infants 6 – 12 months (7 – 10 kg): One 2.5 ml dose may be taken 3 to 4 times in 24 hours.

Children 1 – 3 years (10 – 15 kg): One 5 ml dose may be taken 3 times in 24 hours.

Children 4 – 6 years (15 – 20 kg): 7.5 ml may be taken 3 times in 24 hours.

Children 7 – 9 years (20 – 30 kg): 10 ml may be taken 3 times in 24 hours.

Children 10 – 12 years (30 – 40 kg): 15 ml may be taken 3 times in 24 hours.

Doses should be given approximately every 6 to 8 hours, (or with a minimum of 6 hours between each dose if required).

Infants under 3 months of age or weighing less than 5 kg should not take Ibuprofen due to lack of data on safety and efficacy.

Duration of treatment

For short-term use only.

Children aged over 6 months: If symptoms worsen or persist for more than 3 days, consult a doctor.

Children aged under 6 months: If symptoms worsen or persist for more than 24 hours, seek medical advice.

Renal impairment

Caution should be taken with ibuprofen dosage in patients with renal impairment. The dosage should be assessed individually. The dose should be kept as low as possible and renal function should be monitored (see sections 4.3, 4.4 and 5.2).

Hepatic impairment

Caution should be taken with dosage in patients with hepatic impairment. The dosage should be assessed individually and the dose should be kept as low as possible (see sections 4.3, 4.4 and 5.2).

Method of administration

For oral administration.

Shake well before use.

4.3 Contraindications

Ibuprofen oral suspension is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.

Ibuprofen oral suspension should not be used in patients who have previously shown hypersensitivity reactions (e.g. asthma, urticaria, angioedema or rhinitis) after taking ibuprofen, aspirin or other NSAIDs.

Ibuprofen oral suspension is also contraindicated in patients with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy. Ibuprofen oral suspension should not be used in patients with active, or history of, recurrent peptic ulcer or gastrointestinal haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

Ibuprofen oral suspension should not be given to patients with conditions involving an increased tendency to bleeding.

Ibuprofen oral suspension is contraindicated in patients with severe heart failure (NYHA Class IV), hepatic failure and renal failure (see section 4.4).

Ibuprofen oral suspension is contraindicated during the last trimester of pregnancy (see section 4.6).

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, and GI and cardiovascular risks below).

Masking of symptoms of underlying infections

Ibuprofen 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 nonhospital settings, the patient should consult a doctor if symptoms persist or worsen.

The use of Ibuprofen oral suspension with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the increased risk of ulceration or bleeding (see section 4.5).

The concomitant consumption of excessive alcohol with NSAIDs, including ibuprofen, may increase the risk of adverse effects on the gastrointestinal tract, such as GI haemorrhage or the central nervous system possibly due to an additive effect.

Elderly

The elderly 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 renal impairment in dehydrated children and adolescents.

Gastrointestinal bleeding, ulceration and perforation

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. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of gastrointestinal disease, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal 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 (see section 4.5).

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

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

Respiratory disorders and hypersensitivity reactions

Caution is required if Ibuprofen oral suspension is administered to patients suffering from, or with a previous history of, bronchial asthma, chronic rhinitis or allergic diseases since NSAIDs have been reported to precipitate bronchospasm, urticaria or angioedema in such patients.

Cardiac, renal and hepatic impairment

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. The habitual concomitant intake of various similar painkillers further increases this risk. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. For these patients, use the lowest effective dose, for the shortest possible duration and monitor renal function especially in long-term treated patients (see also section 4.3).

Ibuprofen oral suspension should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with ibuprofen administration.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. 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 such as myocardial infarction or stroke. Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. < 1200mg/day) is associated with an increased risk of arterial thrombotic events.

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

Renal effects

Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration. There is a risk of renal impairment especially in dehydrated children, adolescents and the elderly.

Monitoring of renal function is necessary, especially in high risk patients.

As with other NSAIDs, long-term administration of ibuprofen has resulted in renal papillary necrosis and other renal pathologic changes. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependant reduction in prostaglandin formation and, secondarily, in renal blood flow, which may cause renal failure. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.

SLE and mixed connective tissue disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see below and section 4.8).

Severe skin reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring within the first month of treatment in the majority of cases. Acute generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen-containing products. Brufen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Varicella

In exceptional cases, 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.

Haematological effects

Ibuprofen, like other NSAIDs, can interfere with platelet aggregation and prolong bleeding time in normal subjects.

Aseptic meningitis

Aseptic meningitis has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease.

Impaired female fertility

The use of Ibuprofen oral suspension may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Ibuprofen oral suspension should be considered.

Due to the presence of maltitol liquid in the composition of Ibuprofen oral suspension, patients with rare hereditary problems of fructose intolerance should not take this medicine. Maltitol liquid may have a mild laxative effect. Each 5ml spoonful contains 2g of maltitol liquid. This provides 4.6 kcal per 5ml spoonful.

This medicine contains 0.00075mg of benzyl alcohol in each 5ml spoonful. Benzyl alcohol may cause allergic reactions.

Increased risk due to accumulation in young children.

High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

This medicine contains 10.0mg of sodium benzoate in each 5ml spoonful.

This medicine contains less than 1mmol sodium (23mg) per 5ml spoonful, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Care should be taken in patients treated with any of the following drugs as interactions have been reported in some patients.

Antihypertensives, beta-blockers and diuretics: NSAIDs may reduce the effect of anti-hypertensives, such as ACE inhibitors, angiotensin-II receptor antagonists, betablockers and diuretics.

Diuretics can also increase the risk of nephrotoxicity of NSAIDs.

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

Cholestyramine: The concomitant administration of ibuprofen and cholestyramine may reduce the absorption of ibuprofen in the gastrointestinal tract. However, the clinical significance is unknown.

Lithium: Decreased elimination of lithium.

Methotrexate: NSAIDs may inhibit the tubular secretion of methotrexate and reduce clearance of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: A decrease in the efficacy of the medicinal product can theoretically occur due to the antiprostaglandin properties of NSAIDs. Limited evidence suggests that coadministration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medicinal termination of pregnancy.

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

Aspirin (Acetylsalicylic acid): As with other products containing NSAIDs, concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential of increased adverse effects.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding 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 to be likely for occasional use (see section 5.1).

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

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

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.

Sulfonylureas: NSAIDs may potentiate the effects of sulfonylurea medications. There have been rare reports of hypoglycaemia in patients on sulfonylurea medications receiving ibuprofen.

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

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 haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Aminoglycosides: NSAIDs may decrease the excretion of aminoglycosides.

Herbal extracts: Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

CYP2C9 Inhibitors: Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase the exposure to ibuprofen (CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors), an increased S(+)-ibuprofen exposure by approximately 80 to 100% has been shown. Reduction of the ibuprofen dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, particularly when high-dose ibuprofen is administered with either voriconazole or fluconazole.

4.6 Fertility, pregnancy and lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. 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 losses 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 should not be given unless clearly necessary. If ibuprofen is used by a woman attempting to conceive, or during the first or second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to the following:

Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)

Renal dysfunction, which may progress to renal failure with oligohydramnios.

At the end of pregnancy, prostaglandin synthesis inhibitors may expose the mother and the neonate to the following:

Possible prolongation of bleeding time

Inhibition of uterine contractions, which may result in delayed or prolonged labour.

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

Breastfeeding

In the limited studies so far available, NSAIDs can appear in the breast milk in very low concentrations. NSAIDs should if possible be avoided when breast-feeding.

Fertility

See section 4.4 regarding female fertility.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, gastrointestinal haemorrhage and exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following ibuprofen administration.

Less frequently, gastritis, duodenal ulcer, gastric ulcer and gastrointestinal perforation have been observed

A transient sensation of burning in the mouth or throat may occur with Brufen Syrup.

Immune system disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reaction and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or © assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, very rarely, erythema multiforme, bullous dermatoses (including Stevens- Johnson syndrome and toxic epidermal necrolysis).

Cardiac disorders and vascular disorders: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical studies suggest that use of ibuprofen, particularly at high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke (see section 4.4).

Infections and infestations: Rhinitis and aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus and mixed connective tissue disease) with symptoms of stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4).

Exacerbation of infection-related inflammations (e.g. development of necrotising fasciitis) coinciding with the use of NSAIDs has been described. If signs of an infection occur or get worse during use of Ibuprofen the patient is therefore recommended to go to a doctor without delay.

Skin and subcutaneous tissue disorders: In exceptional cases, severe skin infections and soft-tissue complications may occur during a varicella infection (see also „Infections and infestations“)

The following adverse reactions possibly related to ibuprofen and displayed by MedDRA frequency convention and system organ classification. Frequency groupings are classified according to the subsequent conventions: 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).

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Toxicity

Signs and symptoms of toxicity have generally not been observed at doses below 100 mg/kg in children or adults. However, supportive care may be needed in some cases. Children have been observed to manifest signs and symptoms of toxicity after ingestion of 400 mg/kg or greater.

Symptoms

Most patients who have ingested significant amounts of ibuprofen will manifest symptoms within 4 to 6 hours.

The most frequently reported symptoms of overdose include nausea, vomiting, abdominal pain, lethargy and drowsiness.

Central nervous system (CNS) effects include headache, tinnitus, dizziness, convulsion, and loss of consciousness. Nystagmus, metabolic acidosis, hypothermia, renal effects, gastrointestinal bleeding, coma, apnoea, diarrhoea and depression of the CNS and respiratory system have also been rarely reported.

In serious poisoning metabolic acidosis may occur. Disorientation, excitation, fainting and cardiovascular toxicity, including hypotension, bradycardia and tachycardia have been reported.

In cases of significant overdose, acute renal failure and liver damage are possible. Large overdoses are generally well tolerated when no other drugs are being taken.

Therapeutic measures

Patients should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

Other measures may be indicated by the patient's clinical condition.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, nonsteroids; propionic acid derivatives. ATC code: M01AE01

Ibuprofen is a propionic acid derivative NSAID that possesses anti-inflammatory, analgesic and antipyretic activity. Animal models for pain and inflammation indicate that ibuprofen effectively inhibits the synthesis of prostaglandins. In humans, ibuprofen reduces pain possibly caused by inflammation or connected with it, swelling and fever. Ibuprofen exerts an inhibitory effect on prostaglandin synthesis by inhibiting the activity of cyclo-oxygenase. In addition ibuprofen has an inhibitory effect on ADP (adenosine diphosphate) or collagen-stimulated platelet aggregation.

Ibuprofen has been shown to have an onset of both analgesic and antipyretic action within 30 minutes.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies show that, when single doses of ibuprofen 400 mg were taken within 8 h before or within 30 min after immediate release acetylsalicylic acid dosing (81 mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. Although there are uncertainties regarding 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 acetysalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

Ibuprofen inhibits prostaglandin synthesis in the uterus, thereby reducing intrauterine rest and active pressure, the periodic uterine contractions and the amount of prostaglandins released into the circulation. These changes are assumed to explain the alleviation of menstrual pain. Ibuprofen inhibits renal prostaglandin synthesis which can lead to renal insufficiency, fluid retention and heart failure in risk patients (see section 4.3).

Prostaglandins are connected with ovulation and the use of medicinal products inhibiting prostaglandin synthesis may therefore affect the fertility of women (see section 4.4, 4.6 and 5.3).

5.2 Pharmacokinetic properties

Absorption

Ibuprofen is rapidly absorbed from the gastrointestinal tract with a bioavailability of 80–90%. Peak serum concentrations occur one to two hours after administration. If administered with food, peak serum concentrations are lower and achieved more slowly than when taken on an empty stomach. Food does not affect markedly total bioavailability.

Distribution

Ibuprofen is rapidly distributed throughout the whole body. Ibuprofen is extensively bound to plasma proteins (99%). Ibuprofen has a small volume of distribution being about 0.12–0.2 L/kg in adults.

Biotransformation

Ibuprofen is rapidly metabolized in the liver through cytochrome P450, preferentially CYP2C9, to two primary inactive metabolites, 2-hydroxyibuprofen and 3-carboxyibuprofen. Following oral ingestion of the drug, slightly less than 90% of an oral dose of ibuprofen can be accounted for in the urine as oxidative metabolites and their glucuronic conjugates. Very little ibuprofen is excreted unchanged in the urine.

Elimination

The elimination half-life is approximately 2.5 hours in healthy individuals.

Pharmacologically inactive metabolites are mainly excreted (90%) by the kidneys but also in bile.

Special populations

Elderly

Given that no renal impairment exists, there are only small, clinically insignificant differences in the pharmacokinetic profile and urinary excretion between young and elderly.

Children

The systemic exposure of ibuprofen following weight adjusted therapeutic dosage (5 mg/kg to 10 mg/kg bodyweight) in children aged 1 year or over, appears similar to that in adults. Children 3 months to 2.5 years appeared to have a higher volume of distribution (L/kg) and clearance (L/kg/h) of ibuprofen than did children >2.5 to 12 years of age.

Renal impairment

For patients with mild renal impairment increased unbound (S)-ibuprofen, higher AUC values for (S)-ibuprofen and increased enantiomeric AUC (S/R) ratios as compared with healthy controls have been reported.

In end-stage renal disease patients receiving dialysis the mean free fraction of ibuprofen was about 3% compared with about 1% in healthy volunteers. Severe impairment of renal function may result in accumulation of ibuprofen metabolites. The significance of this effect is unknown. The metabolites can be removed by haemodialysis (see sections 4.2, 4.3 and 4.4).

Hepatic impairment

Alcoholic liver disease with mild to moderate hepatic impairment did not result in substantially altered pharmacokinetic parameters.

In cirrhotic patients with moderate hepatic impairment (Child Pugh’s score 6–10) treated with racemic ibuprofen an average 2-fold prolongation of the half-life was observed and the enantiomeric AUC ratio (S/R) was significantly lower compared to healthy controls suggesting an impairment of metabolic inversion of ®-ibuprofen to the active (S)-enantiomer (see sections 4.2, 4.3 and 4.4).

5.3 Preclinical safety data

As a well established and widely used product, the pre-clinical safety of ibuprofen is well documented.

Ibuprofen’s sub­chronic and chronic toxicity was mainly shown by animal tests as gastric tract damage and ulcers.

The vitro and in vivo tests have not shown any clinically significant signs about ibuprofen’s mu­tagenicity. Furthermore no carcinogenic effects have been observed in mice and rats.

Ibuprofen inhibits ovulation in rabbits and impairs implantation in various animal species (rabbit, rat, and mouse). In reproduction tests undertaken with rats and rabbits, ibuprofen passed across the placenta. When using doses toxic to the mother, malformations occur more frequently (i.e. ventricular septum defects).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium benzoate (E211)

Citric acid

Maltitol liquid

Xanthan gum

Hypromellose

Glycerol

Sodium chloride

Polysorbate 80

Sodium cyclamate

Acesulfame potassium

Sucralose

Orange flavour (Orange Juice 055604 TEU) containing:

– Flavouring components (flavouring preparations, flavouring substances, natural flavouring substances)

– Alpha-tocopherol (E307)

– Benzyl alcohol

Vanillin

Purified Water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

Shelf life after first opening the bottle: 6 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Ibuprofen oral suspension is supplied in an amber glass bottle containing 60 ml, 100 ml or 200 ml, or an amber PET bottle containing 100 ml. The bottle is closed with a child-resistant HDPE screw cap with a PP outer cap and a PE adaptor.

Each pack also contains an oral dosing syringe with a capacity of 5 ml and marked with dosing graduations every 0.5ml. Each syringe consists of a PP syringe body and an HDPE plunger.

Not all pack sizes may be marketed.