Ibuprofen

The use of ibuprofen with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the increased risk of ulceration or bleeding

Increased risk of gastrointestinal ulceration or bleeding with NSAIDs.

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.

Increased risk of gastrointestinal bleeding with NSAIDs.

The concomitant consumption of excessive alcohol with NSAIDs, including ibuprofen may increase the risk of adverse effects on the gastrointestinal tract, such as GI haemorrhage or the central nervous system, possibly due to an additive effect.

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. The habitual concomitant intake of various similar painkillers further increases this risk. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. For these patients, use the lowest effective dose, for the shortest possible duration and monitor renal function especially in long-term treated patients.

Brufen 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.

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

NSAIDs may enhance the effects of anticoagulants, such as warfarin.

Increased risk of gastrointestinal bleeding with NSAIDs.

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

NSAIDs may reduce the effect of anti-hypertensives, such as ACE inhibitors, angiotensin-II receptor antagonists, beta-blockers and diuretics. Diuretics can also increase the risk of nephrotoxicity of NSAIDs.

NSAIDs can counteract the diuretic effect of furosemide and bumetanide, possibly through inhibition of prostaglandin synthesis. They can also counteract the antihypertensive effect of thiazides.

There is an increased risk of acute renal failure, usually reversible, in patients with renal impairment (e.g. dehydrated and/or elderly patients) when treatment with ACE inhibitors or angiotensin-II antagonists is given at the same time as NSAIDs, including selective cyclooxygenase-2 inhibitors. The combination should, therefore, be given with care to patients with renal impairment, especially elderly patients. Patients should be adequately hydrated and a check of renal function should be considered after the initiation of combination treatment and at regular intervals during treatment.

NSAIDs may reduce the excretion of aminoglycosides.

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.

The use of ibuprofen may impair 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.

Experimental studies indicate that ibuprofen counteracts the effect of captopril on sodium excretion.

The concomitant administration of ibuprofen and colestyramine retards and reduces (by 25%) the absorption of ibuprofen. These drugs should be given at an interval of at least 2 hours.

Increased risk of nephrotoxicity.

Decreased elimination of lithium.

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

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.

An interaction with pemetrexed as there is an increased risk of its toxicity by decreased renal clearance. In patients with an impaired renal function displaying a creatinine clearance between 45-80 ml/min, this combination is to be avoided. In patients with normal renal function, a precaution for use is sufficient based on laboratory tests of the renal function.

Probenecid slows the excretion of NSAIDs, with possible increase of their plasma concentrations.

In co-administration of ibuprofen (NSAIDs) with ritonavir it is a possible increase in the concentration of NSAIDs.

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

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.

Caution is required if ibuprofen is administered to patients suffering from, or with a previous history of, bronchial asthma, chronic rhinitis or allergic diseases since NSAIDs have been reported to precipitate bronchospasm, urticaria or angioedema in such patients.

NSAIDs should be given with care to patients with a history of ulcerative colitis or Crohn’s disease as these conditions may be exacerbated.

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 such as 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. 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.

Masking of symptoms of underlying infections

Ibuprofen 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 bacteria complications to varicella. When ibuprofen tablets is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In nonhospital settings, the patient should consult a doctor if symptoms persist or worsen.

Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration. There is a risk of renal impairment especially in dehydrated children, adolescents and the elderly.

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Caution is required in patients suffering from allergic rhinitis, nasal polyps or chronic obstructive respiratory disorders, as there is an increased risk of allergic reactions, which may present as asthma attacks (so-called analgesic-induced asthma), Quincke’s edema or urticaria.

Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

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. The risk is believed to increase with dose and duration of therapy. 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. 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, 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. 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 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
• Inhibition of uterine contractions, which may result in delayed or prolonged labour.

Consequently, ibuprofen is contraindicated during the third trimester of pregnancy.

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.

After systemic application, only small amounts of ibuprofen and its metabolites pass into the breast milk.

As no harmful effects to infants are known to date, it is not usually necessary to interrupt breast-feeding during short-term treatment with the medicated plaster at the recommended dose. However, as a precautionary measure, the medicated plaster should not be applied directly onto the breast area of women who are breast-feeding.

Fertility

The use of ibuprofen may impair 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.

Following treatment with ibuprofen, the reaction time of certain patients may be affected. This should be taken into account where increased vigilance is required. Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

Ibuprofen medicated plasters has noor negligible influence on the ability to drive and use machines.

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. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, gastrointestinal haemorrhage and exacerbation of colitis and Crohn’s disease 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 © assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and very rarely, erythema multiforme, bullous dermatoses (including StevensJohnson 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.

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.

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.

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).

^* 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.

IV administration

Data are currently available on approximately 1,000 preterm newborn from both the literature concerning ibuprofen and clinical trials with ibuprofen solution for injection. Causality of adverse events reported in the preterm newborn is difficult to assess since they may be related to the haemodynamic consequences of the patent ductus arteriosus as well as to direct effects of ibuprofen.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10) and uncommon (≥1/1,000, <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

^* see below

In a clinical curative trial involving 175 preterm newborn infants less than 35 weeks of gestational age, the incidence of bronchopulmonary dysplasia at 36 weeks post-conceptional age was 13/81 (16%) for indomethacin versus 23/94 (24%) for ibuprofen.

In a clinical trial where ibuprofen was administered prophylactically during the first 6 hours of life, severe hypoxemia with pulmonary hypertension was reported in 3 newborn infants less than 28 weeks of gestational age. This occurred within one hour of the first infusion and was reversed within 30 minutes after the inhalation of nitric oxide. There have also been post-marketing reports of pulmonary hypertension where ibuprofen was administered to premature neonates in the therapeutic setting.