Ibuprofen 100 Mg/5 Ml Oral Suspension
PL 36390/0042 a2
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Ibuprofen 100 mg/5 ml oral suspension
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Per 5 ml of suspension contains 100 mg of ibuprofen Excipients with known effects:
- per 5 ml of suspension contains 1375 mg liquid maltitol
- per 5 ml of suspension contains 8.60 mg sodium methyl parahydroxybenzoate
- per 5 ml of suspension contains 2.25 mg sodium propyl parahydroxybenzoate
- per 5 ml of suspension contains 0.48 mmol sodium For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Oral suspension.
White-coloured, orange-flavoured oral suspension.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Ibuprofen oral suspension is indicated for its analgesic and anti-inflammatory effects in the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, osteoarthritis and other nonrheumatoid (seronegative) arthropathies.
In the treatment of non-articular rheumatic conditions, Ibuprofen oral suspension is indicated in peri-articular conditions such as frozen shoulder (capsulitis), bursitis, tendinitis, tenosynovitis and low back pain; Ibuprofen oral suspension can also be used in soft tissue injuries such as sprains and strains.
Ibuprofen oral suspension is also indicated for its analgesic effect in the relief of mild to moderate pain such as dysmenorrhoea, dental and post-operative pain and for symptomatic relief of headache; including migraine headache.
Ibuprofen oral suspension is indicated in short-term use for the treatment of pyrexia in children over one year of age.
4.2 Posology and method of administration
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
Posology
Adults
The recommended dosage of Ibuprofen oral suspension is 1200-1800 mg daily in divided doses. Some patients can be maintained on 600-1200 mg daily. Total daily dose does not exceed 2400 mg in divided doses.
Children
Not recommended for children weighing less than 7 kg. For The daily dosage of Ibuprofen oral suspension is 20 mg/kg of bodyweight in divided doses. This can be achieved as follows:
Children 1-2 years
One 2.5 ml spoonful (50 mg) to be taken three to four times in 24 hours. Children 3- 7 years
One 5 ml spoonful (100 mg) to be taken three to four times in 24 hours. Children 8-12 years
Two 5 ml spoonfuls (200 mg) three to four times in 24 hours.
In juvenile rheumatoid arthritis, up to 40 mg/kg/ in divided doses may be taken.
Elderly
The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be
monitored regularly for GI bleeding during NS AID therapy. If renal or hepatic function is impaired the dosage should be assessed individually.
Method of administration
For oral administration, preferably with or after food.
A transient sensation of burning in the mouth or throat may occur with Ibuprofen oral suspension ; ensure the bottle is thoroughly shaken before use.
4.3. Contraindications
Hypersensitivity to ibuprofen or to any of the excipients listed in section 6.1.
Ibuprofen 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 used in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) after taking ibuprofen, aspirin or other non-steroidal antiinflammatory drugs (NSAIDs).
Ibuprofen oral suspension is contraindicated in patients with severe heart failure (NYHA Class IV), renal failure and hepatic failure (see section 4.4).
Ibuprofen is contraindicated during the last trimester of pregnancy (see section 4.6).
Ibuprofen is also contraindicated in patients with a history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Ibuprofen should not be given to patients with conditions involving an increased tendency to bleeding.
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).
The use of ibuprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to increased risk of ulceration or bleeding (see section 4.5).
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).
Respiratory disorders
Caution is required if ibuprofen is administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.
Cardiovascular, renal and hepatic impairment
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see section 4.3).
Ibuprofen 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.
Gastrointestinal bleeding, ulceration and perforation
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious gastrointestinal 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 corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).
Where gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of ulcerative colitis, Crohn’s disease as these conditions may be exacerbated (see section 4.8).
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 (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 arterial thrombotic events.
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.
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 section 4.8).
Dermatological
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 higher risk for these reactions early in the course of therapy; the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofen suspension should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Impaired _ female _ fertility
The use of ibuprofen 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 should be considered.
Renal effects
Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration.
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 precipitate overt renal decompensation. 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.
Haematological effects
Ibuprofen, like other NSAIDs, can interfere with platelet aggregation and has been shown to prolong bleeding time in normal subjects.
Asceptic 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.
Paediatric population
There is a risk of renal impairment in dehydrated children and adolescents. Excipients of Ibuprofen oral suspension Liquid maltitol
Due to the presence of liquid maltitol, patients with rare hereditary problems of fructose intolerance should not take this medicine.
Sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate
Sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).
Sodium
This medicinal product contains 0.48 mmol of sodium per 5 ml of suspension. This should be taken into consideration for patients on a controlled sodium diet.
4.5. Interactions with other medicinal products and other forms of interaction
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).
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, beta-blockers and diuretics.
Diuretics
Diuretics can 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..
Corticosteroids
Increased risk of gastrointestinal ulceration or bleeding with NSAIDs (see section 4.4).
Anticoagulants
NSAIDs may enhance the effects of anti-coagulants, 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.
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.
Sulfonylureas
NSAIDs may potentiate the effects of sulfonylurea medications. There have been rare reports of hypoglycaemia in patients on sulfonylurea medications receiving ibuprofen.
Acetylsalicylic acid
Concomitant administration of ibuprofen and acetylsalicylic acid 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 acetylsalicylic acid 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 ibuprofen use (see section 5.1).
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. In animals, the 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.
Breast-feeding
In the limited studies so far available, NSAIDs can appears in the breast milk in very low concentrations, NSAIDs should, if possible, be avoided when breast-feeding..
See section 4.4, regarding female fertility.
4.7. Effects on ability to drive and use machines
Undesirable effects such as dizziness, drowsiness, visual disturbances, fatigue or headaches are possible undesirable effects 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 and ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following ibuprofen administration. Less frequently, gastritis has been observed. Gastrointestinal perforation has been rarely reported with ibuprofen use. Pancreatitis has been reported very rarely.
A transient sensation of burning in the mouth or throat may occur with ibuprofen.
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 (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely, exfoliative and bullous dermatoses (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme).
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 (for example myocardial infarction or stroke) (see section 4.4).
Other adverse reactions reported less commonly and for which causality has not necessarily been established include:
Renal and urinary disorders
Impaired renal function and toxic nephropathy in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.
Hepatobiliary disorders
Abnormal liver function, hepatitis failure, hepatitis and jaundice.
Nervous system disorders
Optic neuritis, headaches, paraesthesia, dizziness, somnolence. Infections and infestations
Rhinitis and aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4).
Psychiatric disorders
Insomnia, anxiety, depression, confusional state, hallucinations
Ear and labyrinth disorders
Hearing impaired, tinnitus and vertigo
Eye disorders
Visual impairment and toxic optic neuropathy Blood and lymphatic system disorders
Leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
Skin and subcutaneous tissue disorders
Bullous reactions including photosensitivity reaction, Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).
General disorders and administration site conditions
Malaise, fatigue
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 at: www.mhra.gov.uk/yellowcard.
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 frequent reported symptoms of overdose include nausea, vomiting, abdominal pain, lethargy and drowsiness. Central nervous systems (CNS) effects includes dizziness, tinnitus, headache, 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. Disorientation, excitation, fainting and cardiovascular toxicity, including hypotension, bradycardia and tachycardia have been reported. In cases of significant overdose, renal failure and liver damage are possible. Large overdoses are generally well tolerated when no other drugs are being taken.
Management
Patient should be treated symptomatically as required. Within 1 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. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Anti-inflammatory and anti-rheumatic product, non-steroid, propionic acid derivative.
ATC code: MO1A EO1.
Ibuprofen is a propionic acid derivative with analgesic, anti-inflammatory and anti-pyretic activity. The drug's therapeutic effects as an NSAID are thought to result from its inhibitory effect on the enzyme cyclo-oxygense, which results in a marked reduction in prostaglandin synthesis.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Some pharmacodynamics studies show that when single doses of ibuprofen 400mg were taken within 8 hours before or within 30 minutes after immediate release acetylsalicylic acid dosing (81mg), 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 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 ibuprofen use (see section 4.5).
5.2. Pharmacokinetic properties
Ibuprofen is rapidly absorbed from the gastrointestinal tract. Peak serum concentrations occur 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed 1-2 hours after administration. The elimination half-life is approximately 2 hours.
Ibuprofen is metabolised in the liver to two inactive metabolites and these, together with unchanged ibuprofen, are excreted by the kidney either as such or as conjugates. Excretion by the kidney is both rapid and complete.
Ibuprofen is extensively bound to plasma proteins.
5.3. Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.
6. Pharmaceutical particulars
6.1. List of excipients
Sodium methyl parahydroxybenzoate (E219)
Sodium propyl parahydroxybenzoate (E217)
Xanthan gum
Carboxymethylcellulose sodium Microcrystalline cellulose Liquid maltitol (E965)
Citric acid monohydrate Sodium citrate
Sodium benzoate Saccharin sodium Polysorbate 80 Natural Orange Flavour
Orange Sweet No 1 Flavour (which contains propylene glycol) Purified water
6.2 Incompatibilities
Not to be mixed with other medicinal products.
6.3 Shelf life
24 months.
6.4. Special precautions for storage
Do not store above 25°C.
Keep container in the outer carton and protect from light.
6.5. Nature and contents of container
An amber-coloured polyethylene terephthalate (PET) bottle containing 500 ml Ibuprofen suspension sealed with a polypropylene, tamper-evident child resistant cap fitted with a low density polyethylene liner.
6.6 Special precautions for disposal
Shake well before use.
7 MARKETING AUTHORISATION HOLDER
Cipla (EU) Limited Hillbrow House Hillbrow Road Esher Surrey
KT10 9NW
8 MARKETING AUTHORISATION NUMBER(S)
PL 36390/0042
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/09/2011
10 DATE OF REVISION OF THE TEXT
12/05/2016
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