SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL    PRODUCT

Ibuprofen tablets BP 400mg Mandafen 400 mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains:

Ibuprofen 400mg

3    PHARMACEUTICAL FORM

Coated tablet

Appearance: pink, biconvex sugar-coated tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Tubs (POM)

Mild to moderate pain including dysmenorrhoea, headache including migraine, dental and post-operative pain.

Rheumatoid arthritis (including juvenile rheumatoid arthritis or Still’s disease)

Ankylosing Spondylitis

Osteoarthritis

Sero-negative arthropathies Pain relief of periarticular disorders Pain relief of soft tissue injuries.

Blister packs (Pharmacy only)

Rheumatic and muscular pain, pain of non-serious arthritic conditions, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness and the symptoms of cold and influenza.

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).

Tubs (POM)

Adults: Initially 1.2-1.8 g daily in 3 to 4 divided doses preferably after food; increased if necessary to a maximum of 2.4 g daily. Ibuprofen is usually administered in doses of 0.6 to 2.4 g daily in divided doses. Maintenance dose of 0.6-1.2 g daily may be adequate.

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 for the shortest possible duration and the patient should be monitored for GI bleeding for 4 weeks following initiation of the NSAID therapy. If renal or hepatic function is impaired, dosage should be assessed individually.

Children: 20 mg per kg body weight daily, in divided doses. For juvenile rheumatoid arthritis, up to 40 mg per kg daily, in divided doses.

Children under 30 kg must not receive more than 500 mg per day even in divided doses.

Not recommended for children weighing less than 7 kg Method of Administration - Oral

The tablets should be swallowed with a drink of water or milk, preferable with or after food. Ibuprofen tablets should be swallowed whole and not chewed, broken, crushed or sucked on to avoid oral discomfort and throat irritation.

Blister packs (Pharmacy only)

Adults and elderly: One tablet every 4 - 6 hours after food to a maximum of 3 tablets in any 24 hour period.

Children under 12 years: Not to be given.

Method of Administration - Oral

The tablets should be swallowed with a drink of water or milk, preferable with or after food. Ibuprofen tablets should be swallowed whole and not chewed, broken, crushed or sucked on to avoid oral discomfort and throat irritation.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the other constituents.

Ibuprofen 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 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 or gastrointestinal haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

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

Ibuprofen is contraindicated in patients with severe heart failure, 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

This medicine contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

As with other NSAIDs, ibuprofen may mask the signs of infection.

The use of Ibuprofen with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive effects (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).

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 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, 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

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 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. Epidemiological data suggest that use of ibuprofen, particularly at a high dose (2400 mg/ daily) and in long term treatment, 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 daily) is associated with an increased risk of arterial thrombotic events, particularly myocardial infarction.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

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.

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).

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 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. 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 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 systematic 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 infertility, withdrawal of Ibuprofen should be considered.

The pharmacy label will state:

“Do not use, if you have ever had a stomach ulcer or are allergic to ibuprofen or aspirin. If you are allergic to, or taking any other pain killer, pregnant or suffer from asthma, speak to your doctor before taking ibuprofen. Do not exceed the stated dose. Keep out of the reach of children. If symptoms persist, consult your doctor.”

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, beta-blockers and diuretics. Diuretics : reduced diuretic effect ; diuretics can increase the risk of nephrotoxicity of NSAIDs.

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

Colestyramine: The concomitant administration of ibuprofen and colestyramine 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 with NSAIDs.

Mifepristone : A decrease in the efficacy of the medicinal product can theoretically occur due to the antiprostaglandin properties of NSAIDs. 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 including Cox-2 inhibitors, as this may increase the risk of adverse effects (see section 4.4).

Corticosteroids : increased risk of gastrointestinal ulceration or bleeding (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 quinilones may have an increased risk of developing convulsions.

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

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. 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.

Lactation In the limited studies so far available, NSAIDs can appear in the breast milk in very low concentrations and is unlikely to adversely affect the breast-fed infant. NSAIDs should, if possible, be avoided when breastfeeding.

See section 4.4 Special warnings and precautions for use, regarding female fertility.

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, 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 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. Epidemiological data suggest that use of ibuprofen, particularly at high dose (2400 mg/ daily), and in long term treatment, may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke (see section 4.4).

Other adverse events 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, hepatic failure, hepatitis and jaundice.

Psychiatric disorders: Insomnia, anxiety, depression, confusional state, hallucination Nervous system disorders: Optic neuritis, headache, paraesthesia, dizziness, somnolence

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).

Eye disorders: Visual disturbance and toxic optic neuropathy

Ear and labyrinth disorders: Hearing impairment, tinnitus, vertigo

Skin and subcutaneous tissue disorders: Bullous reactions, including Stevens-Johnson

syndrome and toxic epidermal necrolysis (very rare), and photosensitivity reaction.

Blood and lymphatic disorders: Leukopenia, thrombocytopenia, neutropenia,

agranulocytosis, aplastic anaemia and haemolytic anaemia.

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 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. Disorientation, excitation, fainting and cardiovascular toxicity, including hypotension, bradycardia and tachycardia have been reported. In cases of significant poisoning, 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 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Ibuprofen is a propionic acid derivative with analgesic, anti-inflammatory and antipyretic activity. The therapeutic effects of the drug as an NSAID are thought to result from its inhibitory effect on the enzyme cyclo-oxygenase, which results in a marked reduction in prostaglandin synthesis.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be like for occasional ibuprofen use.

5.2    Pharmacokinetic properties

Ibuprofen is rapidly absorbed from the gastro-intestinal tract, peak serum concentrations occurring 1 to 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

Not relevant.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Each tablet contains:

Tablet core:

Maize starch

Cellulose microcrystalline Sodium starch glycollate (Type A)

Povidone Alginic acid

Silica, colloidal anhydrous Magnesium stearate Croscarmellose sodium Sodium lauryl sulphate

Coating:

Opadry

Sucrose

Titanium dioxide (E171) Erythrosine lake (E127) Sodium benzoate (E211) White beeswax Carnauba wax

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

36 months

6.4    Special precautions for    storage

Do not store above 25 °C.

6.5    Nature and contents    of    container

HDPE (High Density Polyethylene) tubs with HDPE Tamper evident, child resistant closure.

Pack sizes: 12, 16, 24, 36, 48, 50, 60, 72, 84, 96, 100, 250 and 500 tablets

Blister pack strips, constructed from 250 micron PVC film lidded with aluminium foil containing 8, 10 or 12 tablets per strip.

Pack sizes: 12, 16, 24, 32, 36, 48, 60, 72, 84, or 96 tablets.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

M. & A. Pharmachem Limited

Allenby Laboratories

Wigan Road

Westhoughton

Bolton

BL5 2AL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04077/0177

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11 May 2001

10 DATE OF REVISION OF THE TEXT

19/07/2013