Hedex Ibuprofen Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ibuprofen EP 200.0mg

3 PHARMACEUTICAL FORM

White, film-coated tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the relief of headaches including tension headaches and migraine, rheumatic and muscular pains, period pains, backache, neuralgia, toothache, feverishness and symptoms of colds and flu.

4.2 Posology and method of administration

Adults, the elderly and children over 12 years:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

200mg - 400mg, up to three times a day, as required, preferably with or after food.

Leave at least four hours between doses and do not take more than 1200mg in any 24 hour period.

Children:

Not recommended for children under twelve.

Elderly:

Non-steroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in elderly patients who are more prone to adverse events.

Method of Administration

For oral administration and short-term use only.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the constituents in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/ haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Severe heart failure, renal failure or hepatic failure (see section 4.4).

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 GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Patients should be advised to consult their doctor if their headaches become persistent.

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.

Respiratory:

Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.

Other NSAIDs:

The use of Hedex Ibuprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Renal:

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 the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state. (see sections 4.3 and 4.8).

Hepatic:

Hepatic dysfunction (see sections 4.3 and 4.8).

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (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). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. < 1200 mg daily) is associated with an increased risk of myocardial infarction.

Impaired female fertility

There is limited evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.

Gastrointestinal:

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).

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.

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

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, 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.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at higher risk of these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Hedex Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The label will include:

Read the enclosed leaflet before taking this product.

Do not take if you:

• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding

• are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg.

Speak to a pharmacist or your doctor before taking if you:

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems

• are a smoker

are pregnant.

If symptoms persist or worsen, consult your doctor.

4.5 Interaction with other medicinal products and other forms of interaction Ibuprofen should be avoided in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (See section 4.4).

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).

Other NSAIDS including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Aminoglycosides: Reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Antihypertensives and diuretics: NSAIDS may diminish the effects of these drugs. Diuretics can increase the risk of nephrotoxicity.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).

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

Hypoglycaemic agents: Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Lithium: There is evidence for potential increases in plasma levels of lithium. Methotrexate: There is a potential for an increase in plasma 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.

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.

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

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 trimesters 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 trimesters of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (with premature closure of the ductus

arteriosus and pulmonary hypertension);

• renal dysfunction, which may progress to renal failure with oligo-

hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

• possible prolongation of bleeding time, an anti-aggregating effect

which may occur even at very low doses.

• inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, ibuprofen is contraindicated during the third trimester of pregnancy (see section 4.3).

Lactation

In limited studies, ibuprofen appears in the breast milk in very low concentrations and is unlikely to affect the breast-fed infant adversely.

Fertility

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

Adverse reactions reported from extensive post-marketing experience are tabulated below by System Organ Class and frequency. The following convention has been utilised for the classification of undesirable effects: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from available data).

Adverse events are more likely to occur with increasing dose and duration of use.

Body System	Undesirable effect	Frequency
Gastrointestinal disorders	Abdominal pain, nausea and dyspepsia.	Uncommon
	Diarrhoea, flatulence, constipation and vomiting.	Rare
	Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis. Exacerbation of ulcerative colitis and Crohn’s disease (see section 4.4).	Very rare
Nervous system disorders	Headache, drowsiness, dizziness, hearing disturbance (tinnitus).	Common
Body System	Undesirable effect	Frequency

Renal and urinary disorders	Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.	Very rare
Hepatobiliary disorders	Liver disorders, hepatic failure, hepatitis.	Very rare
Blood and lymphatic system disorders	Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.	Very rare
Cardiac disorders	Oedema, hypertension and cardiac failure	Unknown
Vascular disorders	Arterial thrombotic events e.g. myocardial infarction or stroke	Unknown
Skin and subcutaneous tissue disorders	Skin rashes	Uncommon
Skin and subcutaneous tissue disorders	Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.	Very rare
Immune system disorders	Hypersensitivity reactions including: • Urticaria and pruritus	Uncommon
Immune system disorders	• Severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock). • Exacerbation of asthma and bronchospasm.	Very rare
Infections and infestations	In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4).	Unknown

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 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).

4.9 Overdose

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 no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible.

In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In 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

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

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 absorbed from the gastrointestinal tract and peak concentrations in the circulation occur about 1.5 hours after ingestion. Ibuprofen is extensively bound to plasma proteins and has a half life of about 2 hours. It is rapidly excreted in the urine; about 60% of a dose is recovered in the urine as metabolites and their conjugates. It is believed that some ibuprofen may be excreted in the faeces possibly after excretion in the bile.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize starch, microcrystalline cellulose, magnesium stearate, spray dried lactose, colloidal silicon dioxide, croscarmellose sodium, hypromellose (HPMC, 6CPS), triacetin.

6.2 Incompatibilities

None stated.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

The product should be stored below 25°C.

6.5 Nature and contents of container

PVC 250pm/Aluminium foil 20pm blisters in cardboard cartons containing 12, 18 or 24 tablets.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Omega Pharma Ltd.

1^st Floor

32 Vauxhall Bridge Road LONDON, SW1V 2SA United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 02855/0068

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/03/2009

26/04/2013