Rofen

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ibuprofen Tablets BP 400 mg Rofen™

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ibuprofen BP 400 mg per tablet.

3 PHARMACEUTICAL FORM

The product is presented in the form of a sugar coated, deep convex tablet imprinted with the marking IBU 400.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Prescription only medicine:

Ibuprofen is indicated in the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis), ankylosing spondylitis, osteoarthritis, non-articular rheumatism, soft tissue injuries and conditions such as frozen shoulder, seronegative (nonrheumatoid) arthropathies, bursitis, tendinitis, tenosynovitis. Its analgesic activity is of benefit in treating dental and post operative pain, dysmenorrhoea, headaches including migraine headache, rheumatic and muscular pain, backache, sprains, lumbago and fibrositis.

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).

Adults: Initially 1.2 to 1.8g daily in 3 to 4 divided doses. This may be increased if necessary to a maximum of 2.4 g daily.

Maintenance doses of 0.6g to 1.2g may be useful for some patients.

Children under 12years: 20mg/kg bodyweight daily in divided doses. In juvenile rheumatoid arthritis up to 40mg/kg bodyweight daily in divided doses may be taken. The total daily dose given in 24 hours for children weighing less than 30kg should not exceed 500mg.

Nor recommended for children weighing less than 7kg.

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 NSAID therapy. If renal or hepatic function is impaired, dosage should be assessed individually.

Route of administration: Oral. To be taken preferably with or after food.

4.3 Contraindications

Hypersensitivity to ibuprofen or to any of the excipients.

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.

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.

Severe heart failure (NYHA Class IV), hepatic failure and renal failure (see section 4.4).

During the last trimester of pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

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 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).

Paediatric population:

There is a risk of renal impairment in dehydrated children and adolescents.

Gastrointestinal bleeding, ulceration and perforation:

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of gastrointestinal disease, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5)

When GI bleeding or ulceration occurs in patients receiving ibuprofen, 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.

Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400mg/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. < 1200mg/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 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 pretreatment 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 section 4.8).

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.

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 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.

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.

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.

Anti-hypertensives: reduced anti-hypertensive effect.

Beta-blockers: NSAIDs may reduce the effect of beta-blockers.

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 glycoside levels.

Lithium: decreased elimination of lithium.

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

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

Ciclosporin: increased risk of nephrotoxicity.

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

Other analgesics including cyclooxygenase-2 selective inhibitors: avoid concomitant use of two or more NSAIDs, (including Cox-2 inhibitors), as this may result in an increased risk of adverse reactions (see section 4.4).

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).

Corticosteroids: increased risk of GI bleeding or ulceration (see section 4.4).

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

Quinolone antibiotics: animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

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

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (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: Ginko 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 breast milk in very low concentration. NSAIDs should, if possible, be avoided when breastfeeding.

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 gastro-intestinal 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. Gastrointestinal perforation has been rarely reported with ibuprofen use. Less frequently, gastritis has been observed. 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, pruritus, urticaria, purpura, angiodema 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.

Other adverse effects reported less commonly include:

Blood and lymphatic system disorders: leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Psychiatric disorders: anxiety, depression, confusion, hallucinations, insomnia.

Nervous system disorders: optic neuritis, nervousness, headache, paraesthesia, dizziness, drowsiness.

Infections and infestations; rhinitis and 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).

Eye disorders: visual disturbance, toxic optic neuropathy, blurred vision.

Ear and labyrinth disorders: hearing impaired, tinnitus, vertigo.

Hepatobiliary disorders: abnormal liver function, hepatic failure, hepatitis and jaundice.

Skin and subcutaneous tissue disorders: bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare). Photosensitivity.

Renal and urinary disorders: impaired renal function and nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, papillary necrosis and renal failure.

General disorders and administrative site conditions: malaise, fatigue. Investigations: abnormalities of liver function tests

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.

a) 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 rarely been 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.

b) 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 patients clinical condition.

5.1 Pharmacodynamic properties

Ibuprofen is a non-steroidal anti-inflammatory analgesic inhibiting the activity of the enzyme cyclo-oxygenase, resulting in decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid. Decrease in prostaglandin synthesis and activity in various tissues may be responsible for many of the therapeutic (and adverse) effects of ibuprofen. Anti-inflammatory action of ibuprofen may result from peripheral action in inflamed tissues probably reducing the prostaglandin activity in these tissues and possibly by inhibiting the synthesis and/or actions of other local mediators of the inflammatory response.

Inhibition of leucocytes migration, inhibition of the release and/or actions of lysosomal enzymes and actions on the other cellular and immunological processes in mesenchymal and connective tissues may be involved. Analgesic action of ibuprofen may result by blocking pain impulse generation via a peripheral action that may involve reduction of the activity of prostaglandins and possibly inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.

Antipyretic action of ibuprofen is due to central action on the hypothalamic heat regulating centre to produce peripheral vasodilation, hence increased blood flow through the skin, sweating and heat loss.

The central action probably involves reduction of prostaglandin activity in the hypothalamus.

Antidysmenorrhoeal action may be due to inhibition of synthesis and activity of intrauterine prostaglandins which are thought to be responsible for pain and other symptoms of primary dysmenorrhoea. It decreases uterine contractility and uterine pressure, increased uterine perfusion thus relieving ischaemia as well as spasmodic pain. Ibuprofen may also alleviate extrauterine symptoms associated with excessive prostaglandin production.

Platelet aggregation is also inhibited reversibly.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies show that when single doses of ibuprofen 400mg were 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 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 absorbed from the gastrointestinal tract. Following oral administration, absorption, it is extensively bound to plasma proteins. Peak plasma concentrations are attained 1 to 2 hours following ingestion. Onset of action of ibuprofen is 0.5 hour, the duration of action being 4 to 6 hours. Halflife of the drug is approximately 2 hours.

It is rapidly excreted in the urine, mainly excreted as metabolites and their conjugates. Approximately 1% is excreted as unchanged drug and 14% conjugated ibuprofen.

5.3 Preclinical safety data

Not applicable.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Colloidal silicon dioxide USNF

Maize starch BP

Pregelatinised maize starch BP

Potable water HSE

Sodium starch glycollate BP

Stearic acid BP

Dextrin HSE

Talc BP

Gelatin EP

Syrup BP

Nipasept sodium HSE Sucrose BP Heavy kaolin BP Titanium dioxide BP

6.2 Incompatibilities

None known.

6.3 Shelf life

5 years for opaque plastic containers and 2 years for blister packs.

6.4 Special precautions for storage

Protect from heat, light and moisture. Keep out of reach of children.

6.5 Nature and contents of container

The product marketed in pack sizes of 28, 42, 50, 56, 84, 100, 112, 250, 500, 1000 and bulk tablets are packed in opaque plastic containers (securitainers) and/or in opaque plastic containers composed of either, high density polypropylene or high density polyethylene with tamper evident or child resistant tamper evident closure composed of high density polyethylene with a packing inclusion of standard polyether foam or polyethylene or polypropylene made filler. The product is also marketed in blister packs of aluminium/opaque PVC, it is subsequently packed in printed box board cartons in pack sizes of 12, 24, 28, 42, 48, 56, 84, 96 and 112 tablets.

6.6 Special precautions for disposal

No special instructions for use/handling.

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Ltd

Units 3 & 4, Quidhampton Business Units

Polhampton Lane

Overton

Hampshire

RG25 3ED

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0272

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/03/2009

DATE OF REVISION OF THE TEXT

12/11/2015