Ibuprofen Tablets Bp 400mg (Apsifen-F)
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ibuprofen Tablets BP 400 mg.
Apsifen-F Tablets 400 mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 400 mg of Ibuprofen BP.
Excipient(s) with known effect:
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Pink, biconvex film coated tablets with APS on one side, plain on reverse.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Rheumatoid arthritis including Still's Disease, osteoarthritis and seronegative (non-rheumatoid) arthropathies, ankylosing spondylitis, non-articular rheumatic conditions, soft-tissue injuries, mild to moderate pain (such as dysmenorrhoea, dental and post-operative pain).
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 the symptoms (see section 4.4).
Method of administration
For oral administration. To be taken preferably with or after food.
Adults (all indications)
Initially 1200 mg per day in divided doses.
In severe conditions up to 1800 mg per day may be given until the acute phase of the condition has been brought under control.
Some patients may be maintained on doses in the range of 600 - 1200 mg per day.
Under no circumstances should the dose of ibuprofen exceed 2400 mg in any 24 hours.
Special populations
Paediatric population Children (all indications)
20 mg/kg of body weight given daily in divided doses.
The tablets are not suitable for children weighing less than 20 kg and no more than two 200 mg tablets should be given in 24 hours to those weighing less than 30 kg.
Elderly people
Elderly people are at an increased risk of the serious consequences from adverse reactions. If an NSAID is considered necessary, the lowest dose should be used and the patient should be monitored for GI bleeding for 4 weeks following initiation of NSAID therapy.
• in children (age range: > 6 months to < 12 years) and/or in adolescents (age range: > 12 years to < 18 years):
If in children aged from 6 months and in adolescents this medicinal product is required for more than 3 days, or if symptoms worsen a doctor should be consulted.
4.3 Contraindications
Ibuprofen is contraindicated in patients with hypersensitivity to ibuprofen or to any of the excipients listed in section 6.1.
Ibuprofen is also contraindicated in patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy. Ibuprofen should not be used in patients with active or history of recurrent peptic ulcer/ haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
Ibuprofen should not be used in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.
Ibuprofen should not be given to patients with conditions involving an increased tendency to bleeding.
Ibuprofen is contraindicated in patients with severe heart failure (NYHA Class IV), hepatic failure and renal failure (See section 4.4).
Ibuprofen is contraindicated during the last trimester of pregnancy (See section 4.6).
4.4 Special warnings and precautions for use
Paediatric population
There is a risk of renal impairment in dehydrated children and adolescents.
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).
As with other NSAIDs, ibuprofen may mask the signs of infection. Gastrointestinal safety
The use of ibuprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the increased risk of ulceration or bleeding (see section 4.5).
Elderly people:
Elderly people have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal (GI) bleeding and perforation which may be fatal (see section 4.2).
Respiratory disorders:
Caution is required if administration to patients suffering from, or with a previous history of bronchial asthma since NSAIDs have been reported to precipitate bronchospasms 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 older people.
Renal function should be monitored in these patients (see also 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.
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 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.
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-dependent 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 older people. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.
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. When GI bleeding or ulceration occurs in patients receiving ibuprofen tablets, the treatment should be withdrawn.
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 older people. 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 aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).
Patients with a history of gastrointestinal toxicity, 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 Interactions).
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).
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 effects:
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 the 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.
Haematological effects:
Ibuprofen, like other NSAIDs, can interfere with platelet aggregation and has been shown to prolong bleeding time in normal patients.
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 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 fertility, withdrawal of ibuprofen should be considered.
4.5 Interaction with other medicinal products and other forms of interaction
Anti-hypertensives, beta-blockers and diuretics:
NSAID’s may reduce anti-hypertensive effect, such as ACE inhibitors, beta-blockers and diuretics.
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Diuretics: |
Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. |
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Cardiac glycosides: |
NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels. |
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Cholestyramine: |
The concomitant administration of ibuprofen and cholestyramine may reduce the absorption of ibuprofen in the gastrointestinal tract. However, the clinical significance is unknown. |
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Lithium: |
Decreased elimination of lithium. |
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Methotrexate: |
NSAIDs may inhibit the tubular secretion of methotrexate and decreased elimination of methotrexate. |
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Ciclosporin: |
Increased risk of nephrotoxicity. |
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Mifepristone: |
NSAIDs should not be used for 8 - 12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone. Limited evidence suggests that co-administration 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
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Acetylsalicylic acid |
including Cox-2 inhibitors, as this may increase the risk of adverse effects (see section 4.4). 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).
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Corticosteroids: |
Increased risk of gastrointestinal ulceration or bleeding (See section 4.4). |
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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.
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Sulfonylureas: |
Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions. 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);
Increase risk of gastrointestinal bleeding (see section
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Tacrolimus: |
4.4) Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. |
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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. |
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Aminoglycosides: aminoglycosides. |
NSAIDs may decrease the excretion of |
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Herbal extracts: |
Ginkgo biloba may potentiate the risk of bleeding with NSAIDs. |
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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 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 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 the following:
• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)
• renal dysfunction, which may progress to renal failure with oligohydroamnios.
At the end of pregnancy, prostaglandin synthesis inhibitors may expose the mother and the neonate to the following:
• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
• inhibition of uterine contractions, which may result in delayed or prolonged labour.
Consequently, ibuprofen is contraindicated during the third trimester of pregnancy.
Breastfeeding:
In limited studies so far available, ibuprofen can appear in breast milk in very low concentrations and is unlikely to adversely affect the breast-fed infant. NSAIDs should, if possible, be avoided when breast feeding.
Fertility
See section 4.4 Special warnings and precautions for use, 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 of GI bleeding, sometimes fatal, particularly in elderly people, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, 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.
Immune system disorders: 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, or (c) assorted skin disorders, including rashes of various types, pruritis, urticaria, purpura, angioedema and, more rarely, exfoliative and, bullous dermatoses (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme).
Cardiac disorders: Oedema and cardiac failure have been reported in association with NSAID treatment.
Vascular disorders: hypertension has been reported in association with NSAID 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).
Other adverse events reported less commonly and for which causality has not necessarily been established include:
Psychiatric disorders: Insomnia, anxiety, depression, confusional state, hallucination
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).
Renal and urinary disorders: Impaired renal failure and toxic nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and renal failure.
Hepatobiliary disorders: Abnormal liver function, hepatitis and jaundice.
Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune 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), depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.
Blood and lymphatic system disorders: Leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
Skin and subcutaneous tissue disorders: Bullous reactions including Steven Johnson Syndrome and toxic epidermal necrosis (very rare), and photosensitivity.
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
Paediatric population
In children ingestion of more than 400 mg/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 symptoms within 4 to 6 hours.
The most frequently reported symptoms of overdose include nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more 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.
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
The active ingredient is a non-steroidal anti-inflammatory agent with analgesic and anti-pyretic activity. The analgesic activity of ibuprofen is thought to be due to inhibition of 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 pharmacodynamic studies show that when a single dose of ibuprofen 400 mg 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 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 4.5).
5.2 Pharmacokinetic Properties
Ibuprofen is well absorbed (>80%) from the gastro-intestinal tract. Peak plasma levels occur 1 to 2 hours after ingestion with a half life of 2 hours (+/-0.5 hours). It is extensively bound to plasma proteins (>99%). It is rapidly excreted in the urine mainly as metabolites and their conjugates.
5.3 Preclinical Safety Data
Preclinical information has not been included because the safety data of ibuprofen has been established after many years of clinical use. Please refer to Section 4.
Pharmaceutical Particulars
6.1 List of Excipients
The tablet contains Starch Ph. Eur., Pregelled Starch BP, Colloidal Silicon Dioxide USNF, Sodium Starch Glycollate BP, Stearic Acid BP, hydroxypropylmethylcellulose and Talc Ph. Eur. The coating contains titanium dioxide E 171, erythrosine aluminium lake E127 and hydroxypropylmethylcellulose E464.
6.2 Incompatibilities
None known.
6.3 Shelf Life
36 months
6.4 Special Precautions for Storage
Store in a dry place at or below 25°C. Protect from light.
6.5 Nature and contents of container
In polypropylene securitainers with polyethylene security closures or amber glass bottles with finoplas or plastissue as cushioning agent or HDPE containers with LDPE lids or child resistant caps, pack size 100, 250.
250 pm PVC / 40 gsm PVdC with 20 pm hard tempered aluminium foil strip, pack sizes, 7, 10, 12, 14, 21, 28. 30, 56, 60, 84, 90, 100, 110, 112, 120, 150, 160 and 168
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG
8. MARKETING AUTHORISATION NUMBER
PL 00289/0063
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27.09.1983 / 12.03.2009
10 DATE OF REVISION OF THE TEXT
08/01/2016