4.1. Therapeutic indications

Ibuprofen 400 mg Soft Capsules are indicated in children and adolescents between 12 and 18 years and adults for:

Symptomatic treatment for the relief of non-serious arthritic conditions, rheumatic or muscular pain, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness, colds and influenza symptoms.

4.2. Posology and method of administration

Posology

For short-term use only.

The dosage should be adjusted to the severity of the disorder and the complaints of the patient. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

If in children and adolescents between 12 and 18 years this medicinal product is required for more than 3 days, or if symptoms worsen a doctor should be consulted.

Children and Adolescents between 12 and 18 years: Take 1 soft capsule with water, up to three times a day as required.

Adults should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

Adults: Take 1 soft capsules with water, up to three times a day as required.

The maximum single dose is 400 mg, the maximum daily dose is 1200 mg ibuprofen with dosage frequency of up to three times a day.

Leave at least 4 hours between doses.

Do not take more than 3 capsules, soft containing 400 mg ibuprofen in any 24 hour period.

Method of administration

Ibuprofen capsule is for oral use. Capsule should not be chewed.

4.3. Contraindications

Ibuprofen capsules must not be administered in patients:

- with hypersensitivity to ibuprofen, to any other NSAID, or to any of the excipients of the product (see section 6.1.)

- in whom substances with a similar action (e.g. acetylsalicylic acid or other NSAIDs) precipitate attacks of asthma, rhinitis, or cause urticaria or angioneurotic oedema.

- with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy.

- with active, or a history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

- with severe heart failure (NYHA Class IV).

- with renal failure.

- with hepatic failure.

- during the third trimester of pregnancy (see section 4.6).

- Ibuprofen capsules, lecithin (soya lecithin). If you are allergic to soya, do not use this medicinal product.

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).

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

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.

Respiratory

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

Other NSAIDs

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

SLE and mixed connective tissue disease

Systemic lupus erythematosus as well as mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8)

Renal

Renal impairment as renal function may further deterioriate (see sections 4.3 and 4.8).

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

Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients taking ibuprofen products over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

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 as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Cases of Kounis syndrome have been reported in patients treated with ibuprofen. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.

Patients with uncontrolled hypertension, congestive heart failure (NYHA IIIII), 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.

Impaired female fertility

There is some evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on 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 any time during treatment, with or without warning symptoms or a previous history of 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 the 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

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs),, including exfoliative dermatitis, erythema multiforme, Steven-Johnson syndrome (SJS) Toxic Epidermal Necrolysis(TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with the use of ibuprofen (see section 4.8). Most of these reactions occurred within the first month.

If signs and symptoms suggestive of these reactions appear ibuprofen should be withdrawn immediately and an alternative treatment considered (as appropriate).

Masking of symptoms of underlying infections

This medicinal product can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When this medicine is administered for pain or fever in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

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, to any of the ingredients of the product, aspirin or other painkillers

• are taking other NSAID pain killers or aspirin with a daily dose above 75mg

• are in the last 3 months of pregnancy

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 do not get better or get worse or if you get new symptoms, talk to your doctor.

This medicine contains 28 mg potassium per capsule. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

Contains Sorbitol (E 420). Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

The information in this section is based upon previous experience with other NSAIDs. In general, NSAIDs should be used with caution with other drugs that can increase the risk of gastrointestinal ulceration or gastrointestinal bleeding or renal impairment.

Concomitant use not recommended:

Acetylsalicylic acid (as antiplatelet treatment):

Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects, unless low-dose aspirin (not above 75 mg daily) has been advised by a doctor (see section 4.4).

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).

Other NSAIDs including cyclooxygenase-2 selective inhibitors: The concomitant use with other NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided, since simultaneous administration of different NSAIDs can increase the risk of adverse effects (see section 4.4).

Ibuprofen should be used with caution in combination with Precautions:

Antihypertensives (ACE inhibitors and Angiotensin II Antagonists) and diurectics

Since NSAIDs may diminish the effects of these drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking a coxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Anticoagulants

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

Cardiac glycosides:

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

Ciclosporin

Concomitant administration with NSAIDs may increase the risk of nephrotoxicity.

Tacrolimus

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Mifepristone

NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids

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

Lithium

There is evidence for potential increase in plasma levels of lithium.

Methotrexate

There is evidence for the potential increase in plasma levels of methotrexate.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding.

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.

Zidovudine (Azidothymidine)

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

4.6. Fertility, pregnancy and lactation

Pregnancy:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal development.

Data from epidemiological studies suggest an increased risk of miscarriage, 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 postimplantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period (see section 5.3).

From the 20th week of pregnancy onward, ibuprofen use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy NSAIDs should not be given unless clearly necessary. If NSAIDs are used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ibuprofen for several days from gestational week 20 onward. ibuprofen should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

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

- cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension),

- renal dysfunction (see above);

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

- possible prolongation of bleeding time, an antiaggregating 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 and 5.3).

Breast-feeding:

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

See section 4.4 regarding female fertility.

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 dexibuprofen should be considered.

4.7. Effects on ability to drive and use machines

None expected at recommended dose and duration of therapy.

4.8. Undesirable effects

Adverse events which have been associated with Ibuprofen are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

The list of the following adverse effects relates to those experienced with ibuprofen at OTC doses (maximum 1200mg per day), for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

The adverse events observed most often are gastrointestinal in nature. Adverse events are mostly dose-dependent, in particular the risk of occurrence of gastrointestinal bleeding is dependent on the dosage range and duration of treatment.

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) see section 4.4).

System Organ Class

Frequency

Adverse Event

Blood and Lymphatic System Disorders

Very rare:

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.

Immune System Disorders

Uncommon

Hypersensitivity reactions consisting of1:

Urticaria and pruritus

Very rare

Severe hypersensitivity reactions.

Symptoms could be facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).

Not Known

Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea.

Nervous System Disorders

Uncommon

Headache

Very rare

Aseptic meningitis2

Cardiac Disorders

Not Known

Cardiac failure and oedema

Kounis syndrome

Vascular Disorders

Not Known

Hypertension

Gastrointestinal Disorders

Uncommon

Abdominal pain, nausea, dyspepsia

Rare

Diarrhoea, flatulence, constipation and vomiting

Very rare

Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis

Not Known

Exacerbation of colitis and Crohn's disease (section 4.4).

Hepatobiliary Disorders

Very rare

Liver disorders

Skin and Subcutaneous Tissue Disorders

Uncommon

Various skin rashes

Very rare

Severe cutaneous adverse reactions (SCARs) (including Erythema multiforme, exfoliative dermatitis, Bullous reactions including Stevens-Johnson syndrome, and toxic epidermal necrolysis)

Not known

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) Acute generalised exanthematous pustulosis (AGEP).

Photosensitivity reactions

Metabolism and Nutrition Disorders

Not known

Decreased Appetite, Hypokalaemia*

Renal and Urinary Disorders

Very rare

Acute renal failure, papillary necrosis, especially in longterm use, associated with increased serum urea and oedema.

Not Known

Renal insufficiency, Ureteric colic, dysuria Renal tubular acidosis*

Investigations

Very rare

Decreased haemoglobin levels

1 Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract activity comprising asthma, aggravated asthma, bronchospasm, dyspnoea or (c) assorted skin disorders, including rashes of various types pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme). 2 The pathogenic mechanism of drug-Induced aseptic meningitis is not fully understood. However, the available data on NSAID-related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). Of note, single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever or disorientation) have been observed during treatment with ibuprofen, in patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).

*Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of the ibuprofen component at higher than recommended doses.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

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.

Prolonged use at higher than recommended doses or overdose may result in renal tubular acidosis and hypokalaemia. Symptoms may include reduced level of consciousness and generalised weakness (see section 4.4 and section 4.8).

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.