Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Baldoyle Industrial Estate, Dublin 13, Ireland
Pharmacotherapeutic classification: Anti-inflammatory and anti-rheumatic products, non-steroidal, propionic acid derivatives.
ATC Code: M01AE01
Ibuprofen is a propionic acid derivative, non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory and antipyretic effect. The drug’s therapeutic effects as a NSAID are thought to result from its inhibitory effect on the enzyme cyclooxygenase, which results in a marked reduction in prostaglandin synthesis. These properties provide symptomatic relief of inflammation, pain and fever.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid/aspirin on platelet aggregation when they are dosed concomitantly. Some pharmacodynamics studies show that when single doses of ibuprofen 400mg were taken within 8 h before or within 30 min after immediate release acetylsalicylic acid/aspirin dosing (81mg), a decreased effect of acetylsalicylic acid/aspirin 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/aspirin cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).
Ibuprofen is a racemic mixture of [+]S- and [-]R-enantiomers.
Studies including a standard meal, show that food does not markedly affect total bioavailability.
Ibuprofen is rapidly absorbed from the gastrointestinal tract with a bioavailability of 80-90%. Peak serum concentrations occur one to two hours after administration of immediate release formulations.
Ibuprofen is extensively bound to plasma proteins (99%). Ibuprofen has a small volume of distribution being about 0.12-0.2 L/kg in adults.
Ibuprofen is rapidly metabolized in the liver through cytochrome P450, preferentially CYP2C9, to two primary inactive metabolites, 2-hydroxyibuprofen and 3-carboxyibuprofen. Following oral ingestion of the drug, slightly less than 90% of an oral dose if ibuprofen can be accounted for in the urine as oxidative metabolites and their glucuronic conjugates. Very little ibuprofen is excreted unchanged in the urine.
Excretion by the kidney is both rapid and complete. The elimination half-life of immediate release formulations is approximately two hours. The excretion of ibuprofen is virtually complete 24 hours after the last dose.
Given that no renal impairment exists, there are only small, clinically insignificant differences in the pharmacokinetic profile and urinary excretion between young and elderly.
The systemic exposure of ibuprofen following weight adjusted therapeutic dosage (5mg/kg to 10mg/kg bodyweight) in children aged 1 year or over, appears similar to that in adults. Children 3 months to 2.5 years appeared to have a higher volume of distribution (L/kg) and clearance (l/kg/h) of ibuprofen than did children ˃2.5 to 12 years of age.
For patients with mild renal impairment, increased plasma level of (S)-ibuprofen, higher AUC values for (S)-ibuprofen and increased enantiomeric AUC ratios as compared with healthy controls have been reported. In end-stage renal disease patients receiving dialysis, the mean free fraction of ibuprofen was about 3% compared with about 1% in healthy volunteers. Severe impairment of renal function may result in accumulation of ibuprofen metabolites. The significance of this effect is unknown. The metabolites can be removed by haemodialysis (see sections 4.2, 4.3 and 4.4).
Alcoholic liver disease with mild to moderate hepatic impairment did not result in substantially altered pharmacokinetic parameters.
In cirrhotic patients with moderate hepatic impairment (Child Pugh’s score 6-10) treated with racemic ibuprofen, an average 2-fold prolongation of the half-life was observed and the enantiomeric AUC ratio (S.R) was significantly lower compared to healthy controls, suggesting an impairment of metabolic inversion of (R)-ibuprofen to the active (S)-enantiomer (see sections 4.2, 4.3 and 4.4).
There are no preclinical data of relevance for the safety assessments, apart from what has already been taken into account.
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