4.1. Therapeutic indications

For the relief of migraine-headaches, backache, dental pain, neuralgia and period pains as well as rheumatic and muscular pains.

Ibuprofen relieves pain and reduces inflammation and temperature as well as relieving headaches and other types of pain. It also relieves cold and flu symptoms.

4.2. Posology and method of administration

For oral administration and short-term use only.

The lowest effective dose should be used for the shortest duration necessary to relieve the symptoms (see section 4.4).

During short-term use, if symptoms persist or worsen the patient should be advised to consult a doctor.

Adults and children and adolescents between 12 and 18 years:

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

If in adults the product is required for more than 10 days, or if the symptoms worsen the patient should consult a doctor.

Children and Adolescents between 12 and 18 years: Take 1 or 2 capsules with water, up to three times a day as required.

Adults: Take 1 or 2 capsules with water, up to three times a day as required.

Leave at least four hours between doses.

Do not take more than 6 capsules in any 24 hour period.

Not for use by children under 12 years of age.

4.3. Contraindications

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

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 (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).

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

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

SLE and mixed connective tissue disease:

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

Renal:

Renal impairment as renal function may further deteriorate (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:

Cases of Kounis syndrome have been reported in patients treated with Ibuprofen capsules 200 mg Capsules. 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.

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.

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.

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 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.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), and acute generalised 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 occured 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, or to aspirin or other related painkillers

• are taking other NSAID pain killers 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, or if new symptoms occur, consult your doctor or pharmacist.

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

Ibuprofen (like other NSAIDs) should be avoided in combination with:

Aspirin (Acetylsalicylic Acid): 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 75mg daily) has been advised by a doctor (see Section 4.4).

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin (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: 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:

Corticosteroids: as these may increase the risk of gastrointestinal ulceration or bleeding (see Section 4.4)

Antihypertensives and diuretics: 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 anti-coagulants, such as warfarin (See section 4.4).

Ant-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.

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.

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 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 quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

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 embryofoetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

From the 20th week of pregnancy onward, Ibuprofen capsules 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, Ibuprofen capsules should not be given unless clearly necessary. If Ibuprofen capsules is 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 capsules for several days from gestational week 20 onward.

Ibuprofen capsules should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

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

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

• Renal dysfunction, which may progress to renal failure with oligohydramnios (see above).

At the end of pregnancy, prostaglandin synthesis inhibitors may expose the mother and the neonate to the following:

• Possible prolongation of bleeding time, 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.

Lactation

In the limited studies so far available, NSAIDs can appear in the breast milk in very low concentrations. 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 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, gastrointestinal haemorrhage and 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.

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 very rarely, erythema multiforme, bullous dermatoses (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

Cardiac disorders and vascular disorders: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical studies suggest that use of ibuprofen, particularly at high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke (see section 4.4)

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).

Exacerbation of infection-related inflammations coinciding with the use of NSAIDs has been described. If signs of an infection occur or get worse during use of Ibuprofen the patient is therefore recommended to go to a doctor without delay.

Skin and subcutaneous tissue disorders: In exceptional cases, severe skin infections and soft-tissue complications may occur during a varicella infection (see also "Infections and infestations").

The following adverse reactions possibly related to ibuprofen and displayed by MedDRA frequency convention and system organ classification. Frequency groupings are classified according to the subsequent conventions: very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000) and Not known (cannot be estimated from the available data

System Organ Class

Frequency

Adverse Event

Infections and infestations

Uncommon

Rhinitis

Rare

Meningitis aseptic (see section 4.4)

Blood and Lymphatic System Disorders

Rare

Leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia , haemolytic anaemia

Immune System Disorders

Uncommon

Hypersensitivity

Rare

Anaphylactic reaction

Psychiatric disorders

Uncommon

Insomnia, anxiety

Rare

Depression, confusional state

Nervous System Disorders

Common

Headache, dizziness

Uncommon

Paraesthesia, somnolence

Rare

Optic neuritis

Eye disorders

Uncommon

Visual impairment

Rare

Toxic optic neuropathy

Ear and labyrinth disorders

Uncommon

Hearing impaired, tinnitus, vertigo

Respiratory, thoracic and mediastinal disorders

Uncommon

Asthma, bronchospasm, dyspnoea

Gastrointestinal Disorders

common

Dyspepsia, diarrhoea, nausea, vomiting, abdominal pain, flatulence, constipation, melaena, haematemesis, gastrointestinal haemorrhage

Uncommon

Gastritis, duodenal ulcer, gastric ulcer, mouth ulceration, gastrointestinal perforation

Very rare

Pancreatitis

Not known

Exacerbation of Colitis and Crohn´s disease

Hepatobiliary Disorders

Uncommon

Hepatitis, jaundice, hepatic function abnormal

Very Rare

Hepatic failure

Skin and Subcutaneous Tissue Disorders

common

Rash

Uncommon

Urticaria, pruritus, purpura, angioedema, photosensitivity reaction

Very rare

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

Not known

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Acute generalised exanthematous pustulosis (AGEP).

Renal and Urinary Disorders

Uncommon

Nephrotoxicity in various forms e.g. Tubulointerstitial nephritis, nephrotic syndrome and renal failure

Not known

Renal tubular acidosis*

General disorders and administration site conditions

Common

Fatigue

Rare

Oedema

Cardiac disorders

Very rare

Cardiac failure, myocardial infarction (also see section 4.4)

Not known

Kounis Syndrome

Vascular disorders

Very rare

Hypertension

Metabolism and Nutritional Disorders

Not known

Hypokalaemia*

*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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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. 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. 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.

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

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.