SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Apsifen-F

Ibuprofen 600 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 600 mg Ibuprofen Ph. Eur.

Excipient(s) with known effect:

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Pink, capsule shaped film-coated tablets, plain on one side and coded "600/0531" on the reverse.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Ibuprofen is indicated for rheumatoid arthritis including Still's disease, osteoarthrosis, seronegative (non-rheumatoid) arthropothies, ankylosing spondylitis, non-articular rheumatic conditions, soft-tissue injuries and 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 symptoms (see section 4.4).

Method of administration For oral administration.

Adults: 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: 600 mg tablets are not recommended for children.

Elderly: Elderly people 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.

4.3 Contraindications

Ibuprofen is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Ibuprofen should not be used in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) after taking aspirin or other NSAID’s.

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 (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

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

Elderly people have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding (GI) 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 elderly 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 dose 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).

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 NSAID’s 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 elderly 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. 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).

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 elderly people. 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 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 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 such as interactions have been reported in some patients.

Anti-hypertensives, beta-blockers and diuretics:

NSAID’s may reduce the effect of anti-hypertensive, such as ACE inhibitors, beta-blockers and diuretics.

Diuretics can also increase the risk of nephrotoxicity of NSAIDs.

Cardiac glycosides:

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

Cholestyramine:

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

Lithium:

Decreased elimination of lithium.

Methotrexate:

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

Ciclosporin:

Increased risk of nephrotoxicity.

Mifepristone:

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 including Cox-2 inhibitors, as this may increase the risk of adverse effects (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 suggests that ibuprofen may competitively inhibit the effect of low dose aspirin on platelet aggregation when they are used 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 gastrointestinal ulceration or bleeding with NSAID’s (see section 4.4).

Anticoagulants:

NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4).

Quinolone antibiotics:

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

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 haemarthrosis 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, 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 the limited studies so far available, ibuprofen appears 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.

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

Gastro-intestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or 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 and gastrointestinal haemorrhage exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following ibuprofen administration. Less frequently, gastritis, duodenal ulcer, gastric ulcer, and gastrointestinal perforation have been observed. Pancreatitis has also 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 trial and 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 (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:

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

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 impairment and toxic optic neuropathy

Ear and labyrinth disorders: Hearing impaired, tinnitus and vertigo

Hepatobiliary disorders: Abnormal liver function, hepatitis and jaundice.

Skin and subcutaneous tissue disorders: Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), and photosensitivity reaction.

Renal and urinary disorders: Impaired renal failure and nephrotoxicity in various

forms, including interstitial nephritis, nephrotic syndrome and renal failure. 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.

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, 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 overdose, renal failure and liver damage are possible. Prothrombin time/INR may also be prolonged, probably due to interference with the actions of circulating clotting factors. Large overdoses are generally well tolerated when no other drugs are being taken. 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 single doses of ibuprofen 400 mg were taken within 8 h before or within 30 min after immediate release acetylsalicylic acid dosing (81 mg), 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 or 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 profile 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 Maize Starch Ph. Eur., Pregelatinised Maize Starch Ph. Eur., Colloidal Silicon Dioxide USNF, Sodium Starch Glycollate Ph. Eur. and Stearic Acid BP.

The coating contains opaspray pink (hydroxypropyl methylcellulose (E464), titanium dioxide (E171), erythrosine (E127)) and Talc Ph. Eur.

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

HDPE or polypropylene containers with caps or child resistant closures in packs of 100, 250, 500 and 1000 tablets.

PVdC coated PVC film with hard temper aluminium foil blister strips in packs of 7, 10, 14, 21, 28, 30, 56, 60, 84, 90, 100, 110, 112, 120, 150, 160 and 168 tablets.

Polypropylene containers with HDPE child resistant caps in pack sizes of 84 tablets.

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 000289/0280

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29.11.1993 / 04.03.2009

10    DATE OF REVISION OF THE TEXT

08/01/2016