Ibuprofen Tablets Bp 400mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ibuprofen Tablets BP 400mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 400mg Ibuprofen PhEur.
3 PHARMACEUTICAL FORM
White film-coated tablets.
White oval, biconvex film-coated tablets plain on one side and breakline on
the other side.
The tablet can be divided into equal halves.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Ibuprofen is a non-steroidal anti-inflammatory agent with analgesic and
antipyretic activity. It is indicated for:
• The treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, juvenile chronic arthritis (Still’s disease) and other nonrheumatoid (seronegative) arthropathies.
• The treatment of non-articular rheumatic conditions and soft-tissue injuries including capsulitis, tendinitis, tenosynovitis, bursitis, low-back pain, strains and sprains.
• The relief of mild to moderate pain such as dysmenorrhoea, dental and post-operative pain and the relief of migraine.
• Reduction of fever and pain in children over 8 years old.
4.2 Posology and method of administration
Posology
To be taken with or preferably after food.
Adults and children aged 12 and over: The recommended dose is 12001800mg daily in divided doses. In acute or severe conditions the dosage may be increased until the acute phase has been brought under control, providing the dosage does not exceed 2400mg in any 24 hour period. The 600mg tablet offers a convenient dosage form where higher dosages are required. Some patients may be maintained on 600-1200mg daily.
Elderly: The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose and shortest possible treatment duration should be used and the patient should be regularly monitored for GI bleeding during NSAID therapy.
Children aged 11 years and under: Daily dose of 20-30mg/kg in divided doses.
Juvenile chronic arthritis: 30-40mg/kg daily in divided doses. Not recommended for children under 7kg.
A more suitable dosage form will be required for young/light children or where swallowing of tablets is impractical or inappropriate.
Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
Method of Administration For oral administration
4.3 Contra-Indications
• Ibuprofen is contraindicated in patients with a history of, or existing gastrointestinal ulceration/perforation or bleeding, including that associated with NSAIDs (see section 4.4)
• Ibuprofen should not be given to patients who have a hypersensitivity to ibuprofen, acetylsalicylic acid or other NSAIDs (whereby the symptoms of asthma, rhinitis, angioedema or urticaria are induced), or to any of the other ingredients in the tablet.
• Severe hepatic failure
• Renal failure
• Severe heart failure (NYHA Class IV) (See section 4.4).
• During the last trimester of pregnancy as there is a risk of premature closure of the fetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. (See section 4.6).
• Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or 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).
Elderly - the elderly have an increased frequency of adverse drug reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (See section 4.2).
• Gastrointestinal bleeding, ulceration and perforation:
GI bleeding, ulceration or perforation, which can be fatal has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of 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 acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).
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, or anticoagulants such as warfarin or selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (see section 4.5).
When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.
Ibuprofen 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).
• 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/day) 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 longterm 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.
Respiratory disorders:
Bronchospasm may be precipitated in patients suffering from, or with a previous history of, bronchial asthma; therefore NSAIDs should be used with extreme caution in these patients.
• Cardiovascular, Renal and Hepatic Impairment:
Long-term administration of ibuprofen to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with haematuria, proteinuria, and occasionally nephrotic syndrome (see section 4.8). Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In addition, the administration of a 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, heart failure, liver dysfunction (see Section 4.3), those taking diuretics and ACE inhibitors and the elderly. Discontinuation of the NSAID is typically followed by recovery to the pre-treatment state.
Since ibuprofen is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored and a reduction in dosage should be anticipated to avoid drug accumulation.
Patients at high risk of developing renal dysfunction during long-term treatment should have renal function monitored periodically.
There is a risk of renal impairment in dehydrated children and adolescents.
Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration.
• Haematological:
Ibuprofen, can inhibit platelet aggregation but the effect is quantitatively less and of shorter duration than that seen with acetylsalicylic acid. Ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal subjects. Because this prolonged bleeding effect may be exaggerated in patients with underlying haemostatic defects, Ibuprofen should be used with caution in persons with intrinsic coagulation defects and those on anticoagulant therapy.
• 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 highest 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 should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
• 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 fertilty:
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.
Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors should be avoided due to the increased risk of adverse reactions, such as ulceration or bleeding (see section 4.5).
• Medication-overuse headache
Where analgesics are used long-term (>3 months) with administration every two days or more frequently, headache may develop or worsen. Headache induced by overuse of analgesics (MOH medication-overuse headache) should not be treated by dose increase. In such cases, the use of analgesics should be discontinued in consultation with the doctor.
As with other NSAIDs, ibuprofen may mask the signs of infection.
4.5 Interactions 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:
• Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).
• Anti-platelet agents: Increased risk of gastrointestinal bleeding (see section
4.4).
• Bisphosphonates (alendronate): Since NSAIDs and bisphosphonates are associated with gastrointestinal irritation, monitoring of the concurrent use of NSAIDs and bisphosphonates is advised.
• Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
• Ciclosporin: The risk of kidney damage is increased.
• Colestyramine: The concomitant administration of ibuprofen and colestyramine may reduce the absorption of ibuprofen in the gastrointestinal tract. However, the clinical significance is unknown.
• Corticosteroids: Increased risk of GI bleeding and ulceration (see section
4.4).
• Diuretics and antihypertensives: NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. The risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients or elderly patients) when angiotensin II receptor antagonists are combined with NSAIDs. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
• Lithium: NSAIDs can increase the serum level of lithium, by reducing renal excretion of lithium.
• Methotrexate: Decreased elimination of methotrexate may occur; increased risk of toxicity. The dose of methotrexate should be closely monitored.
• Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
• Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs or in combination as this may increase the risk of adverse effects (see section 4.4)
• Other NSAIDs: The concurrent use of several NSAIDs can increase the risk of gastrointestinal ulcers and haemorrhage.
• 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.
• Selective Serotonin Reuptake Inhibitors (SSRIs): Increased risk of gastrointestinal bleeding with NSAIDs.
• Sulfonylureas: NSAIDs may potentiate the effects of sulfonylurea medications. There have been rare reports of hypoglycaemia in patients on sulfonylurea medications receiving ibuprofen.
• Ritonavir: Plasma concentrations of NSAIDs are possibly increased by ritonavir.
• 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.
• ACE inhibitors: NSAIDs may reduce the antihypertensive affect and increase the risk of nephrotoxicity and hyperkalaemia.
• Aminoglycosides: NSAIDs may decrease the excretion of aminoglycosides.
• Herbal extracts: Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.
• Acetysalicylic 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 this 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. 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, 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 and 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:
- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
- renal dysfunction, which may progress to renal failure with oligo-hydramniosis;
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 is contraindicated during the last trimester of pregnancy.
Lactation:
Ibuprofen can appear in breast milk
In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.
See section 4.4 Special warnings and precautions for use, regarding female fertility.
Fertility
The use of ibuprofen may impair 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.
4.7 Effects on ability to drive and use machines
As ibuprofen can cause visual disturbances, drowsiness, dizziness and fatigue, patients should make sure they are not affected before driving or operating machinery.
4.8 Undesirable Effects
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, heamatemesis, ulcerative stomatits, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed.
Clinical trial 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).
Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.
Hypersensitivity:
Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of:
a) non-specific allergic reactions and anaphylaxis
b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, rhinitis or
c) assorted skin disorders, including rashes of various types, pruritis, urticaria, purpura, angiodema and, more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme
d) aseptic meningitis.
Assessment of adverse reactions is normally based on the following occurrence frequency:
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), not known (cannot be estimated from the available data)
Blood and lymphatic system disorders
Very rare: Haematopoietic disorders (anaemia, haemolytic anaemia, aplastic anaemia), leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, nose and skin bleeding.
Frequency not known: neutropenia, pure white cell aplasia.
Immune system disorders
Uncommon: Hypersensitivity reactions (e.g urticaria, pruritus, and exanthema as well as asthma attacks and hypotension)
Rare: Lupus erythematosus syndrome
Very rare: In patients with existing auto-immune disorders (such as 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.
Severe hypersensitivity reactions. (e.g. facial oedema, swelling of the tongue, internal laryngeal swelling, dyspnoea, tachycardia, fall of blood pressure, (life threatening shock).
Exacerbation of asthma and bronchospasm.
Metabolic and nutrition disorders:
Frequency not known: hyponatraemia
Psychiatric disorders:
Very rare: Nervousness
Frequency not known: hallucinations, insomnia depression, confusional state
Nervous system disorders:
Common: Headache, dizziness
Frequency not known: paraesthesia, drowsiness, aseptic meningitis
Eye disorders
Rare: Visual disturbance Frequency not known: optic neuritis
Ear and labyrinth disorders
Very rare: Tinnitus and vertigo Frequency not known: hearing loss
Cardiac disorders
Very rare: Cardiac failure
Vascular disorders
Very rare: Hypertension
Respiratory, thoracic and mediastinal disorders
Very rare: Asthma, bronchospasm, dyspnoea and wheezing Frequency not known: pulmonary eosinophilia.
Gastrointestinal disorders
Very common: Abdominal pain, dyspepsia and nausea.
Common: Gastrointestinal ulcers
Rare: Diarrhoea, flatulence, constipation and vomiting.
Very rare: Perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly (see section 4.4). Exacerbation of ulcerative colitis and Crohn's disease (see section 4.4). Mouth ulceration.
Frequency not known: ulcerative stomatitis, gastritis, pancreatitis, induction of colitis, heartburn.
Hepatobiliary disorders
Very rare: Liver disorders, especially in long-term treatment, hepatitis and jaundice.
Frequency not known: Abnormal liver function, liver failure, hepatotoxicty.
Skin and subcutaneous tissue disorders
Uncommon: Various skin rashes.
Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.
Frequency unknown: exacerbation of psoriasis, photosensitivity, alopecia.
Renal and urinary disorders:
Uncommon: Renal failure
Very rare: Papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.
Frequency not known: Increased serum creatinine, nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.
General disorders and administration site conditions:
Very rare: Oedema, malaise, fatigue, peripheral oedema.
Investigations:
Very rare: Decreased hematocrit and hemoglobin levels.
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
4.9 Overdose
a) 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.
b) 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. Metabolic acidosis, hypothermia, renal effects, gastrointestinal bleeding, coma, 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.
c) Treatment
Treatment should be symptomatic and supportive Gastric emptying or oral administration of activated charcoal is indicated. 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, non-steroids; propionic acid derivatives.
ATC CODE: M01A E01
Ibuprofen is a 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.
Experimental data suggests 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 a single dose of ibuprofen 400mg was taken within 8 h before or within 30 min 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 this data to the clinical situation, the possibility that regular, long-term us may reduce the cardioprotective effect of low-dose acetylsalcyclic 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:
Peak serum levels of Ibuprofen occur approximately 45 minutes after ingestion when taken on an empty stomach, whereas the peak is delayed up to 90 minutes when taken after a meal.
Ibuprofen is absorbed from the gastrointestinal tract and peak plasma concentrations occur about 1-2 hours after ingestion.
Distribution:
Ibuprofen is rapidly distributed throughout the whole body. The plasma protein binding is approximately 99%.
Metabolism:
Ibuprofen is metabolised in the liver (hydroxylation, carboxylation). 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.
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
Also contains:
Croscarmellose sodium Colloidal silicon dioxide Macrogol
Sodium lauryl sulphate
E171
E460
E463
E464
E553b
6.2 Incompatibilities
None known
6.3 Shelf life
Shelf-life
Three years from the date of manufacture.
Shelf-life after dilution/reconstitution Not applicable.
Shelf-life after first opening Not applicable.
6.4 Special precautions for storage
Store below 25°C in a dry place.
6.5 Nature and contents of container
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps. An alternative closure for polyethylene containers is a polypropylene, twist on, push down and twist off child-resistant, tamper-evident lid.
Blister packs:
(i) 250pm white or clear PVC
(ii) 25 pm aluminium foil
High density polyethylene tablet container with a polypropylene closure and a Al foil inner seal.
Pack sizes: 50, 84
Pack sizes: 28’s, 30’s, 50’s, 56’s, 60’s, 84’s, 90’s, 100's, 112’s, 120’s, 250’s, 168’s, 180’s, 500’s, 1000’s.
Product may also be supplied in bulk packs for reassembly, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material.
Maximum size of bulk packs: 10,000.
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley BARNSTAPLE N Devon EX32 8NS
MARKETING AUTHORISATION NUMBER
PL 00142/0195
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/11/1985 / 18/03/2009
10
DATE OF REVISION OF THE TEXT
13/05/2016