Motrin (Ibuprofen) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Pharmacodynamics-- 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.

In clinical studies in adult patients with rheumatoid arthritis and osteoarthritis, ibuprofen has been shown to be comparable to aspirin in controlling pain and inflammation, though causing fewer of the mild gastrointestinal side effects (see ADVERSE REACTIONS). MOTRIN may be well tolerated in some patients who have had gastrointestinal side effects with aspirin, but these patients, when treated with MOTRIN, should be carefully followed for signs and symptoms of gastrointestinal ulceration and bleeding. Although it is not definitely known whether ibuprofen causes less peptic ulceration than aspirin, in one study involving 885 adult patients with rheumatoid arthritis treated for up to one year (438 patients on ibuprofen and 447 patients on aspirin), there were no reports of gastric ulceration with ibuprofen whereas frank ulceration was reported in 13 patients in the aspirin group (statistically significant p<.001).

Gastroscopic studies at varying doses of ibuprofen showed an increased tendency toward endoscopic lesions at higher doses. However, at clinically comparable doses (2,400 mg of ibuprofen vs. 3,600 mg of aspirin), endoscopic lesions were approximately half that seen with aspirin. Studies using⁵¹ Cr-tagged red cells indicate that fecal blood loss associated with ibuprofen in doses up to 2400 mg daily did not exceed the range of normal, and was significantly less than that seen in aspirin-treated patients. The clinical significance of these findings is unknown.

Pharmacokinetics-- As noted in the DESCRIPTION section, ibuprofen is a racemic mixture of [-]R-and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S-isomer is responsible for clinial 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.

Absorption-- In vivo studies indicate that ibuprofen is well absorbed orally from the suspension, drops, caplet and chewable tablet formulations, with peak plasma levels usually occurring within 1 to 2 hours. The pharmacokinetic differences between the products in adults (see Table 1) are due to differences in the rate of absorption of ibuprofen from the various dosage forms. The observed differences in the table between adults and children, in terms of AUC and C_max, are due to both differences in dose per body weight and age-or fever-related change in volume of distribution (Vd/F). All of the formulations are equally bioavailable in terms of peak plasma levels (C_max) and extent of absorption (AUC), however, the time-to-peak (T_max) is different between the products. Clinically, this has been shown to have no effect on either onset or peak fever reduction in children.

Antacid-- 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.

Food Effects-- Absorption is most rapid when MOTRIN is given under fasting conditions. Administration of MOTRIN Suspension, MOTRIN Oral Drops, MOTRIN Chewable Tablets and MOTRIN Caplets 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%.

Distribution-- Ibuprofen, like most other 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.

Metabolism-- 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.

Elimination-- 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).

Clinical Studies-- Controlled clinical trials comparing doses of 5 and 10 mg/kg ibuprofen suspension and 10-15 mg/kg of acetaminophen elixir have been conducted in children 6 months to 12 years of age with fever primarily do to viral illnesses. In these studies there were no differences between treatments in fever reduction for the first hour and maximum fever reduction occurred between 2 and 4 hours. Response after 1 hour was dependent on both the level of temperature elevation as well as the treatment. In children with baseline temperatures at or below 102.5°F both ibuprofen doses and acetaminophen were equally effective in their maximum effect. In children with temperatures above 102.5°F, the ibuprofen 10 mg/kg dose was more effective. By 6 hours, children treated with ibuprofen 5mg/kg tended to have recurrence of fever, whereas children treated with ibuprofen 10 mg/kg still had significant fever reduction at 8 hours. In control groups treated with 10 mg/kg acetaminophen, fever reduction resembled that seen in children treated with 5 mg/kg of ibuprofen, with the exception that temperature elevation tended to return 1-2 hours earlier.

A comparison of MOTRIN Chewable Tablets and MOTRIN Suspension in febrile children showed similar antipyretic effects of the two formulations, lasting between 6 and 8 hours. No clinical studies of fever reduction in children have been performed with MOTRIN Caplets or MOTRIN Oral Drops.

Controlled single-dose clinical analgesia trials comparing doses of 5 and 10 mg/kg ibuprofen suspension with acetaminophen suspension 12.5 mg/kg and placebo, have been conducted in children 5 to 12 years of age, with sore throat pain due to an infectious agent, or ear pain due to acute otitis media. Onset of pain relief provided by ibuprofen was similar to that of acetaminophen, occurring within the first hour, usually around the half-hour mark. All active treatments showed significant pain relief versus placebo, and the 10 mg/kg dose of ibuprofen had a duration of analgesic effect of 6 to 8 hours. Ibuprofen 10 mg/kg provided more overall pain relief than the 5 mg/kg dose.

Controlled studies have demonstrated that ibuprofen is a more effective analgesic than propoxyphene for the relief of episiotomy pain, pain following dental extraction procedures, and for the relief of the symptoms of primary dysmenorrhea.

In patients with primary dysmenorrhea, ibuprofen has been shown to reduce elevated levels of prostaglandin activity in the menstrual fluid and to reduce resting and active intrauterine pressure, as well as the frequency of uterine contractions. The probable mechanism of action is to inhibit prostaglandin synthesis rather than simply to provide analgesia.

In clinical studies in adult patients with rheumatoid arthritis, ibuprofen has been shown to be comparable to indomethacin in controlling the signs and symptoms of disease activity, with a lower incidence of milder gastrointestinal and CNS side effects than indomethacin.

MOTRIN may be used in combination with gold salts and/or corticosteroids.