IBUPROFEN- ibuprofen suspension
Pharmaceutical Associates, Inc.
Cardiovascular Thrombotic Events
- Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS).
- Ibuprofen Oral Suspension is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS).
- NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).
The active ingredient in Ibuprofen Oral Suspension USP, 100 mg/5 mL is ibuprofen, which is a member of the propionic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Ibuprofen is a racemic mixture of [+]S- and [-]R-enantiomers. It is a white to off-white crystalline powder, with a melting point of 74° to 77°C. It is practically insoluble in water (<0.1 mg/mL), but readily soluble in organic solvents such as ethanol and acetone. Ibuprofen has a pKa of 4.43±0.03 and an n-octanol/water partition coefficient of 11.7 at pH 7.4. The chemical name for ibuprofen is (±)-2-(p-isobutylphenyl) propionic acid. The molecular weight of ibuprofen is 206.28. Its molecular formula is C 13 H 18 O 2 and it has the following structural formula:
Ibuprofen Oral Suspension is a sweetened, orange colored, berry flavored suspension containing 100 mg of ibuprofen in 5 mL (20 mg/mL). Inactive ingredients include: anhydrous citric acid, artificial berry flavor, butylparaben, D&C red #33, FD&C yellow #6, glycerin, high fructose corn syrup, hypromellose, polysorbate 80, propylene glycol, purified water, sodium benzoate, sorbitol solution, xanthan gum.
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that possesses anti-inflammatory, analgesic and antipyretic activity. Its mode of action, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition. After absorption of the racemic ibuprofen, the [-]R-enantiomer undergoes interconversion to the [+]S-form. The biological activities of ibuprofen are associated with the [+]S-enantiomer.
Ibuprofen is a racemic mixture of [-]R-and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S-isomer is responsible for clinical activity. The [-]R-form, while thought to be pharmacologically inactive, is slowly and incompletely (~60%) interconverted into the active [+]S species in adults. The degree of interconversion in children is unknown, but is thought to be similar. The [-]R-isomer serves as a circulating reservoir to maintain levels of active drug. Ibuprofen is well absorbed orally, with less than 1% being excreted in the urine unchanged. It has a biphasic elimination time curve with a plasma half-life of approximately 2 hours. Studies in febrile children have established the dose-proportionality of 5 and 10 mg/kg doses of ibuprofen. Studies in adults have established the dose-proportionality of ibuprofen as a single oral dose from 50 to 600 mg for total drug and up to 1200 mg for free drug.
In vivo studies indicate that ibuprofen is well absorbed orally from the suspension formulation, with peak plasma levels usually occurring within 1 to 2 hours (see Table 1).
|Dose||200 mg (2.8 mg/kg) in Adults||10 mg/kg in Febrile Children|
|Legend: AUCinf = Area-under-the-curve to infinity Tmax = Time-to-peak plasma concentration Cmax = Peak plasma concentration Cl/F = Clearance divided by fraction of drug absorbed|
|Number of Patients||24||18|
|AUCinf (µg∙h/mL)||64 (27%)||155 (24%)|
|Cmax (µg/mL)||19 (22%)||55 (23%)|
|Tmax (h)||0.79 (69%)||0.97 (57%)|
|Cl/F (mL/h/kg)||45.6 (22%)||68.6 (22%)|
A bioavailability study in adults has shown that there was no interference with the absorption of ibuprofen when given in conjunction with an antacid containing both aluminum hydroxide and magnesium hydroxide.
In studies with human volunteers, coadministration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.
Absorption is most rapid when ibuprofen is given under fasting conditions. Administration of ibuprofen oral suspension with food affects the rate but not the extent of absorption. When taken with food, T max is delayed by approximately 30 to 60 minutes, and peak levels are reduced by approximately 30 to 50%.
Ibuprofen, like most drugs of its class, is highly protein bound (>99% bound at 20 µg/mL). Protein binding is saturable and at concentrations >20 µg/mL binding is non-linear. Based on oral dosing data there is an age- or fever-related change in volume of distribution for ibuprofen. Febrile children <11 years old have a volume of approximately 0.2 L/kg while adults have a volume of approximately 0.12 L/kg. The clinical significance of these findings is unknown.
Following oral administration, the majority of the dose was recovered in the urine within 24 hours as the hydroxy-(25%) and carboxypropyl-(37%) phenylpropionic acid metabolites. The percentages of free and conjugated ibuprofen found in the urine were approximately 1% and 14%, respectively. The remainder of the drug was found in the stool as both metabolites and unabsorbed drug.
Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually complete 24 hours after the last dose. It has a biphasic plasma elimination time curve with a half-life of approximately 2.0 hours. There is no difference in the observed terminal elimination rate or half-life between children and adults, however, there is an age- or fever-related change in total clearance. This suggests that the observed change in clearance is due to changes in the volume of distribution of ibuprofen (see Table 1 for Cl/F values).
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