"The the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC) will review the risks and benefits of modified- and prolonged-release paracetamol (acetaminophen) tablets, the agency said today.
Mechanism Of Action
Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Ibuprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
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 [-]R-isomer serves as a circulating reservoir to maintain levels of active drug. The pharmacokinetic parameters of CALDOLOR determined in a study with volunteers are presented below.
Table 4: Pharmacokinetic Parameters of Intravenous
|400 mg* CALDOLOR Mean (CV%)||800 mg* CALDOLOR Mean (CV%)|
|Number of Patients||12||12|
|AUC (mcg•h/mL)||109.3 (26.4)||192.8 (18.5)|
|Cmax (mcg/mL)||39.2 (15.5)||72.6 (13.2)|
|KEL (1/h)||0.32 (17.9)||0.29 (12.8)|
|T½ (h)||2.22 (20.1)||2.44 (12.9)|
|AUC = Area-under-the-curve
Cmax = Peak plasma concentration
CV = Coefficient of Variation
KEL = First-order elimination rate constant
T½ = Elimination half-life
* = 60 minute infusion time
The pharmacokinetic parameters of CALDOLOR determined in a study with febrile pediatric patients are presented in Table 5. It was observed that the median Tmax was at the end of the infusion and that CALDOLOR had a shorter elimination half-life in pediatric patients compared to adults. The volume of distribution and clearance increased with age.
Table 5: Pharmacokinetic Parameters of 10 mg/kg
Intravenous Ibuprofen, Pediatric Patients, by Age Group
|6 months to < 2 years Mean (CV%)||2 years to < 6 years Mean (CV%)||6 years to 16 years Mean (CV%)|
|Number of Patients||5||12||25|
|AUC (mcgh/mL)||71.1 (37.1)||79.2 (37.0)||80.7 (36.9)|
|Cmax (mcg/mL)||59.2 (34.8)||64.2 (34.3)||61.9 (26.6)|
|Tmax (min)*||10 (10-30)||12 (10-46)||10 (10-40)|
|T½ (h)||1.8 (29.9)||1.5 (41.8)||1.55 (26.4)|
|Cl (mL/h)||1172.5 (38.9)||1967.3 (56.0)||4878.5 (71.0)|
|Vz (mL)||2805.7 (20.1)||3695.8 (30.0)||10314.2 (67.4)|
|Cl/WT# (mL/hr/kg)||133.7 (58.6)||130.1 (82.4)||109.2 (41.6)|
|Vz/WT# (mL/kg)||311.2 (35.4)||227.2 (41.7)||226.8 (30.4)|
#WT: body weight (kg)
Ibuprofen, like most NSAIDs, is highly protein bound ( > 99% bound at 20 mcg/mL). Protein binding is saturable, and at concentrations > 20 mcg/mL binding is nonlinear. Based on oral dosing data, there is an age- or fever-related change in volume of distribution for ibuprofen.
Drug Interaction Studies
Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see DRUG INTERACTIONS].
The effect of CALDOLOR on acute pain was evaluated in two multi-center, randomized, double-blind, placebo-controlled studies.
In a study of women who had undergone an elective abdominal hysterectomy, 319 patients were randomized and treated with CALDOLOR 800 mg or placebo administered every 6 hours (started intra-operatively) and morphine administered on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the mean morphine consumption through 24 hours in patients who received CALDOLOR as compared to those receiving placebo (47 mg and 56 mg, respectively). The clinical relevance of this finding is supported by a greater reduction in pain intensity over 24 hours for patients treated with CALDOLOR, even though morphine was available on an as needed basis.
In a study of patients who had undergone an elective abdominal or orthopedic surgery, 406 patients (87 men, 319 women) were randomized to receive CALDOLOR 400 mg, CALDOLOR 800 mg, or placebo administered every 6 hours (started intra-operatively), and morphine on an as needed basis. This study failed to demonstrate a statistically significant difference in outcome between patients receiving CALDOLOR 800 mg or 400 mg and placebo, although there were trends favoring the active treatments.
The effect of CALDOLOR on fever was evaluated in two randomized, double-blind studies in adults and in one open-label study in pediatric patients.
In a multi-center study, 120 hospitalized patients (88 men, 32 women) with temperatures of 101°F or greater were randomized to CALDOLOR 400 mg, 200 mg, 100 mg or placebo, administered every 4 hours for 24 hours. Each of the three CALDOLOR doses, 100 mg, 200 mg, and 400 mg, resulted in a statistically greater percentage of patients with a reduced temperature ( < 101°F) after 4 hours, compared to placebo (65%, 73%, 77% and 32%, respectively). The dose response is shown in the figure below.
Figure 1: Temperature Reduction by Treatment Group,
Hospitalized Febrile Patients NDA 022348 Caldolor
In a single-center study, 60 hospitalized patients (48 men, 12 women) with uncomplicated P. falciparum malaria having temperatures ≥ 100.4°F were randomized to CALDOLOR 400 mg or placebo, administered every 6 hours for 72 hours of treatment. There was a significant reduction in fever within the first 24 hours of treatment, measured as the area above the temperature 98.6°F vs. time curve for patients treated with CALDOLOR.
In a multi-center, open-label study, 100 hospitalized pediatric patients 6 months of age and older with temperatures of 101.0°F or greater were randomized and treated with 10 mg/kg of CALDOLOR or a low dose of an active comparator every 4 hours as needed for fever.
Efficacy was demonstrated as a statistically significant greater reduction in temperature for the primary endpoint, an area under the curve analyses of temperature versus time for the first 2 hours, as well as over the entire dosing interval. Seventy-four percent of CALDOLOR treated patients became afebrile (temperature < 99.5°F) by the end of first dosing interval.
Last reviewed on RxList: 6/7/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Caldolor Information
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