Included as part of the "PRECAUTIONS" Section
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial
infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV
thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events
over baseline conferred by NSAID use appears to be similar in those with and without known CV
disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a
higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate.
Some observational studies found that this increased risk of serious CV thrombotic events began as
early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest
effective dose for the shortest duration possible. Physicians and patients should remain alert for the
development of such events, throughout the entire treatment course, even in the absence of previous CV
symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such
as ibuprofen, increases the risk of serious gastrointestinal (GI) events [see Gastrointestinal Bleeding, Ulceration, And Perforation].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS].
Observational studies conducted in the Danish National Registry have demonstrated that patients treated
with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and allcause
mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the
first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100
person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat
after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least
the next four years of follow-up.
Avoid the use of CALDOLOR in patients with a recent MI unless the benefits are expected to outweigh
the risk of recurrent CV thrombotic events. If CALDOLOR is used in patients with a recent MI, monitor
patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And Perforation
NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large
intestine, which can be fatal. These serious adverse events can occur at any time, with or without
warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious
upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or
perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months and in
about 2%-4% of patients treated for one year. However, even short-term therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration And Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater
than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors.
Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer
duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or
selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general
health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients.
Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI
Strategies To Minimize The GI Risks In NSAID-Treated Patients
- Use the lowest effective dosage for the shortest possible duration.
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of
bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies
other than NSAIDs.
- Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue
CALDOLOR until a serious GI adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more
closely for evidence of GI bleeding [see DRUG INTERACTIONS].
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in
approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases
of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with
NSAIDs, including ibuprofen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy,
diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs
and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g.,
eosinophilia, rash, etc.), discontinue CALDOLOR immediately, and perform a clinical evaluation of the
NSAIDs, including CALDOLOR, can lead to new onset of hypertension or worsening of preexisting
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired
response to these therapies when taking NSAIDs [see DRUG INTERACTIONS].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of
Heart Failure And Edema
The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials
demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2
selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.
In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI,
hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use
of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical
conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see DRUG INTERACTIONS].
Avoid the use of CALDOLOR in patients with severe heart failure unless the benefits are expected to
outweigh the risk of worsening heart failure. If CALDOLOR is used in patients with severe heart
failure, monitor patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose
dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired
renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and
ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of CALDOLOR in
patients with advanced renal disease. The renal effects of CALDOLOR may hasten the progression of
renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating CALDOLOR. Monitor
renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia
during use of CALDOLOR [see DRUG INTERACTIONS]. Avoid the use of CALDOLOR in patients with
advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal
function. If CALDOLOR is used in patients with advanced renal disease, monitor patients for signs of
worsening renal function.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of
NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these
effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Ibuprofen has been associated with anaphylactic reactions in patients with and without known
hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma [see CONTRAINDICATIONS and Exacerbation Of Asthma Related To Aspirin Sensitivity].
Seek emergency help if anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic
rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to
aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been
reported in such aspirin-sensitive patients, CALDOLOR is contraindicated in patients with this form of
aspirin sensitivity [see CONTRAINDICATIONS]. When CALDOLOR is used in patients with preexisting
asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of
Serious Skin Reactions
NSAIDs, including ibuprofen, can cause serious skin adverse reactions such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
seriousevents may occur without warning. Inform patients about the signs and symptoms of serious skin
reactions, and to discontinue the use of CALDOLOR at the first appearance of skin rash or any other
sign of hypersensitivity. CALDOLOR is contraindicated in patients with previous serious skin reactions
to NSAIDs [see CONTRAINDICATIONS].
Premature Closure Of Fetal Ductus Arteriosus
Ibuprofen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including
CALDOLOR, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use In Specific Populations].
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross GI blood loss,
fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with
CALDOLOR has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including CALDOLOR may increase the risk of bleeding events. Co-morbid conditions such
as coagulation disorder, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g.,
aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)
may increase this risk. Monitor these patients for signs of bleeding [see DRUG INTERACTIONS].
CALDOLOR must be diluted prior to use. Infusion of the drug product without dilution can cause
hemolysis [see DOSAGE AND ADMINISTRATION].
Masking Of Inflammation And Fever
The pharmacological activity of CALDOLOR in reducing inflammation, and possibly fever, may
diminish the utility of diagnostic signs in detecting infections.
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or
signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile
periodically [see Gastrointestinal Bleeding, Ulceration, And Perforation, Hepatotoxicity, Renal Toxicity And Hyperkalemia].
Blurred or diminished vision, scotomata, and changes in color vision have been reported with oral
ibuprofen. Discontinue ibuprofen if a patient develops such complaints, and refer the patient for an
ophthalmologic examination that includes central visual fields and color vision testing.
Aseptic meningitis with fever and coma has been observed in patients on oral ibuprofen therapy.
Although it is probably more likely to occur in patients with systemic lupuserythematosus and related
connective tissue diseases, it has been reported in patients who do not have underlying chronic disease.
If signs or symptoms of meningitis develop in a patient on ibuprofen, give consideration to whether or
not the signs or symptoms are related to ibuprofen therapy.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of ibuprofen have not been
In published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames
Impairment Of Fertility
In a published study, dietary administration of ibuprofen to male and female rats 8-weeks prior to and
during mating at dose levels of 20 mg/kg (0.06-times the MRHD based on body surface area
comparison) did not impact male or female fertility or litter size.
In other studies, adult mice were administered ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day
(0.0085-times the MRHD based on body surface area comparison) for 35 or 60 days in males and 35
days in females. There was no effect on sperm motility or viability in males but decreased ovulation
was reported in females.
Use In Specific Populations
Use of NSAIDs, including CALDOLOR, during the third trimester of pregnancy increases the risk of
premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including CALDOLOR, in
pregnant women starting at 30 weeks gestation (third trimester).
There are no adequate and well-controlled studies of CALDOLOR in pregnant women. Data from
observational studies regarding potential embryofetal risks of NSAID use in women in the first or
second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically
recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major
malformations, and 15-20% for pregnancy loss. In published animal reproduction studies, there were no
clear developmental effects at doses up to 0.4-times the maximum recommended human dose (MRHD)
in the rabbit and 0.5-times in the MRHD rat when dosed throughout gestation. In contrast, an increase in
membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 0.8-
times the MRHD. Based on animal data, prostaglandins have been shown to have an important role in
endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies,
administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and
post-implantation loss. Advise a pregnant woman of the potential risk to a fetus.
Labor or Delivery
There are no studies on the effects of CALDOLOR during labor or delivery. In animal studies,
NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase
the incidence of stillbirth.
In a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.04, 0.12, or 0.36-times the
maximum recommended human daily dose of 3200 mg of ibuprofen based on body surface area) from
Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted. This dose
was associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same
publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.02, 0.06, 0.18, 0.54-
times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity
(gastrointestinal lesions) was noted at 20 mg/kg and above.
In a published study, rats were orally dosed with 300 mg/kg ibuprofen (0.912-times the maximum human
daily dose of 3200 mg based on body surface area) during Gestation Days 9 and 10 (critical time points
for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of
membranous ventricular septal defects. This dose was associated with significant maternal toxicity
including gastrointestinal toxicity. One incidence each of a membranous ventricular septal defect and
gastroschisis was noted in fetuses from rabbits treated with 500 mg/kg (3-times the maximum human
daily dose) from Gestation Day 9-11.
No lactation studies have been conducted with CALDOLOR; however, limited published literature
reports that, following oral administration, ibuprofen is present in human milk at relative infant doses of
0.06% to 0.6% of the maternal weight-adjusted daily dose. There are no reports of adverse effects on
the breastfed infant and no effects on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need for CALDOLOR and any
potential adverse effects on the breastfed infant from the CALDOLOR or from the underlying maternal
Females And Males Of Reproductive Potential
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including CALDOLOR,
may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility
in some women. Published animal studies have shown that administration of prostaglandin synthesis
inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation.
Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider
withdrawal of NSAIDs, including CALDOLOR in women who have difficulties conceiving or who are
undergoing investigation of infertility.
The safety and effectiveness of CALDOLOR for the treatment of pain and fever in pediatric patients
ages 6 months and older is supported by evidence of fever reduction from a multi-center, open-label
study of hospitalized febrile pediatric patients along with safety data from exposure to CALDOLOR in
143 pediatric patients ages 6 months and older in two pediatric fever studies and one pediatric pain
study, supportive data from other ibuprofen products approved in pediatric patients, and evidence from
adequate and well controlled studies in adults. The effectiveness of CALDOLOR for the treatment of
pain and fever has not been studied in pediatric patients less than 6 months of age. [see DOSAGE AND ADMINISTRATION , Clinical Study Experience, Pharmacokinetics , Clinical Studies].
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious
cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly
patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor
patients for adverse effects [see WARNINGS AND PRECAUTIONS].
Clinical studies of CALDOLOR did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Elderly patients are at increased risk for serious GI adverse events.