"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.
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
|Any Reaction||118 (88%)||260 (86%)||258 (90%)|
|Nausea||77 (57%)||161 (53%)||179 (62%)|
|Vomiting||30 (22%)||46 (15%)||50 (17%)|
|Flatulence||10 (7%)||49 (16%)||44 (15%)|
|Headache||12 (9%)||35 (12%)||31 (11%)|
|Hemorrhage||13 (10%)||13 (4%)||16 (6%)|
|Dizziness||8 (6%)||13 (4%)||5 (2%)|
|Edema peripheral||1 ( < 1%)||9 (3%)||4 (1%)|
|Urinary retention||7 (5%)||10 (3%)||10 (3%)|
|Anemia||5 (4%)||7 (2%)||6 (2%)|
|Decreased hemoglobin||4 (3%)||6 (2%)||3 (1%)|
|Dyspepsia||6 (4%)||4 (1%)||2 ( < 1%)|
|Wound hemorrhage||4 (3%)||4 (1%)||4 (1%)|
|Abdominal discomfort||4 (3%)||2 ( < 1%)||0|
|Cough||4 (3%)||2 ( < 1%)||1 ( < 1%)|
|Hypokalemia||5 (4%)||3 ( < 1%)||8 (3%)|
|* All patients received concomitant morphine during these 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
|Any Reaction||27 (87%)||25 (83%)||23 (74%)||25 (89%)|
|Anemia||5 (17%)||6 (20%)||11 (36%)||4 (14%)|
|Eosinophilia||7 (23%)||7 (23%)||8 (26%)||7 (25%)|
|Hypokalemia||4 (13%)||4 (13%)||6 (19%)||5 (18%)|
|Hypoproteinemia||3 (10%)||0||4 (13%)||2 (7%)|
|Neutropenia||2 (7%)||2 (7%)||4 (13%)||2 (7%)|
|Blood urea increased||0||0||3 (10%)||0|
|Hypernatremia||2 (7%)||0||3 (10%)||0|
|Hypoalbuminemia||3 (10%)||1 (3%)||3 (10%)||1 (4%)|
|Hypotension||0||2 (7%)||3 (10%)||1 (4%)|
|Diarrhea||3 (10%)||3 (10%)||2 (7%)||2 (7%)|
|Pneumonia bacterial||3 (10%)||1 (3%)||2 (7%)||0|
|Blood LDH increased||3 (10%)||2 (7%)||1 (3%)||1 (4%)|
|Thrombocythemia||3 (10%)||2 (7%)||1 (3%)||0|
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.
Read the Caldolor (ibuprofen in water for injection) Side Effects Center for a complete guide to possible side effects
See Table 3 for clinically significant drug interactions with ibuprofen.
Table 3: Clinically Significant Drug Interactions with
|Drugs That Interfere with Hemostasis|
|Clinical Impact:||Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
|Intervention:||Monitor patients with concomitant use of CALDOLOR with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS].|
|Clinical Impact:||Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see WARNINGS AND PRECAUTIONS].|
|Intervention:||Concomitant use of CALDOLOR and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS]. CALDOLOR is not a substitute for low dose aspirin for cardiovascular protection.|
|ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers|
|Clinical Impact:||Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.|
|Intervention:||During concomitant use of CALDOLOR with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS].|
|Clinical Impact:||The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.|
|Intervention:||During concomitant use of CADOLOR and digoxin, monitor serum digoxin levels.|
|Clinical Impact:||NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.|
|Intervention:||During concomitant use of CALDOLOR and lithium, monitor patients for signs of lithium toxicity.|
|Clinical Impact:||Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).|
|Intervention:||During concomitant use of CALDOLOR and methotrexate, monitor patients for methotrexate toxicity.|
|Clinical Impact:||Concomitant use of CALDOLOR and cyclosporine may increase cyclosporine’s nephrotoxicity.|
|Intervention:||During concomitant use of CALDOLOR and cyclosporine, monitor patients for signs of worsening renal function.|
|NSAIDs and Salicylates|
|Clinical Impact:||Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS].|
|Intervention:||The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended.|
|Clinical Impact:||Concomitant use of CALDOLOR and pemetrexed, may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).|
|Intervention:||During concomitant use of CALDOLOR and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Last reviewed on RxList: 6/7/2016
Additional Caldolor Information
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