Ibuprofen in Water for Injection

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events [see WARNINGS AND PRECAUTIONS]
• GI Bleeding, Ulceration and Perforation [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Heart Failure and Edema [see WARNINGS AND PRECAUTIONS]
• Renal Toxicity and Hyperkalemia [see WARNINGS AND PRECAUTIONS]
• Anaphylactic reactions [see WARNINGS AND PRECAUTIONS]
• Serious Skin Reactions [see WARNINGS AND PRECAUTIONS]
• Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical development, 560 patients were exposed to CALDOLOR, 438 in pain and 122 with fever. In the pain studies, CALDOLOR was started intra-operatively and administered at a dose of 400 mg or 800 mg every six hours for up to three days. In the fever studies, CALDOLOR was administered at doses of 100 mg, 200 mg, or 400 mg every four or six hours for up to 3 days. The most frequent type of adverse reaction occurring with oral ibuprofen is gastrointestinal.

The incidence rates of adverse reactions listed in the following table were derived from multi-center, controlled clinical studies in post-operative patients comparing CALDOLOR to placebo in patients also receiving morphine as needed for post-operative pain.

Table 1: Post-operative Patients with Adverse Reactions Observed in ≥ 3% of Patients in any CALDOLOR Treatment Group in Pain Studies*

Fever studies were conducted in febrile hospitalized patients with malaria and febrile hospitalized patients with varying causes of fever. In hospitalized febrile patients with malaria, the adverse reactions observed in at least two CALDOLOR-treated patients included abdominal pain and nasal congestion.

In hospitalized febrile patients (all causes), adverse reactions observed in more than two patients in any given treatment group are presented in the table below.

Table 2: Patients with Adverse Reactions Observed in ≥ 3% of Patients in any CALDOLOR Treatment Group in All-Cause Fever Study

A total of 143 pediatric patients ages 6 months and older have received CALDOLOR in controlled clinical trials. The most common adverse reactions (incidence greater than or equal to 2%) in pediatric patients treated with CALDOLOR were infusion site pain, vomiting, nausea, anemia and headache.

Included as part of the PRECAUTIONS section.

Mechanism Of Action

Ibuprofen has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of CALDOLOR, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

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.

Pharmacokinetics

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 Ibuprofen

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

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].

Clinical Studies

Analgesia (Pain)

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.

Antipyretic (Fever)

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.

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). Ibuprofen works by reducing hormones that cause inflammation and pain in the body.

Ibuprofen injection is used to reduce fever and treat pain.

Ibuprofen may also be used for purposes not listed in this medication guide.

Ibuprofen may increase your risk of heart attack or stroke, especially if you use it long term or have heart disease. You should not receive this medicine just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Ibuprofen may also cause stomach or intestinal bleeding, which can be fatal. These conditions can occur without warning while you are receiving ibuprofen injection.

You should not use this medication if you are allergic to ibuprofen (Advil, Motrin), aspirin or other NSAIDs.

To make sure ibuprofen is safe for you, tell your doctor if you have:

• a history of heart attack, stroke, or blood clot;
• heart disease, high blood pressure;
• a history of stomach ulcer or bleeding;
• liver or kidney disease;
• a connective tissue disease such as Marfan syndrome, Sjogren's syndrome, lupus, scleroderma, or rheumatoid arthritis;
• a bleeding or blood clotting disorder; or
• asthma, or a history of severe allergic reaction to aspirin, especially aspirin triad syndrome.

FDA pregnancy category D. Using ibuprofen during the last 3 months of pregnancy may harm the unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while receiving ibuprofen.

It is not known whether ibuprofen injection passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Because you will receive ibuprofen injection in a clinical setting, you are not likely to miss a dose.