Label: CALDOLOR- ibuprofen injection
- NDC Code(s): 66220-247-04, 66220-287-08
- Packager: Cumberland Pharmaceuticals Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: New Drug Application
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- BOXED WARNING(What is this?)
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CALDOLOR ® safely and effectively. See full prescribing information for CALDOLOR.
CALDOLOR (ibuprofen) Injection, for intravenous use
Initial U.S. Approval: 1974
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
See full prescribing information for complete boxed warning
- Non-steroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1)
- CALDOLOR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1)
- NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2)
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
- Use the lowest effective dose for shortest duration consistent with individual patient treatment goals
- Adult Pain: 400 mg to 800 mg intravenously over 30 minutes every 6 hours as necessary. (2.2)
- Adult Fever: 400 mg intravenously over 30 minutes, followed by 400 mg every 4 to 6 hours or 100-200 mg every 4 hours as necessary. (2.2)
- Pediatric (pain and fever) ages 12 to 17 years of age: 400 mg intravenously over 10 minutes every 4 to 6 hours as necessary (2.3)
- Pediatric (pain and fever) ages 6 months to 12 years of age: 10 mg/kg intravenously over 10 minutes up to a maximum single dose of 400 mg every 4 to 6 hours as necessary (2.3)
- CALDOLOR must be diluted before administration. (2.1)
DOSAGE FORMS AND STRENGTHS
CALDOLOR (ibuprofen) Injection: 800 mg/8 mL (3)
WARNINGS AND PRECAUTIONS
- Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3)
- Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7)
- Heart Failure and Edema: Avoid use of CALDOLOR in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5)
- Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of CALDOLOR in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6)
- Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7)
- Exacerbation of Asthma Related to Aspirin Sensitivity: CALDOLOR is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8)
- Serious Skin Reactions: Discontinue CALDOLOR at first appearance of skin rash or other signs of hypersensitivity (5.9)
- Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation (5.10, 8.1)
- Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.11, 7)
The most common adverse reactions are nausea, flatulence, vomiting, headache, hemorrhage and dizziness (>5%).
The most common adverse reactions in pediatric patients are infusion site pain, vomiting, nausea, anemia and headache (≥2%). (6)
To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
- Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking CALDOLOR with drugs that interfere with hemostasis. Concomitant use of CALDOLOR and analgesic doses of aspirin is not generally recommended (7)
- ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with CALDOLOR may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7)
- ACE Inhibitors and ARBs: Concomitant use with CALDOLOR in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7)
- Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7)
- Digoxin: Concomitant use with CALDOLOR can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7)
USE IN SPECIFIC POPULATIONS
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1)
Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of CALDOLOR in women who have difficulties conceiving (8.3)
See 17 for PATIENT COUNSELING INFORMATION.
- FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
- 2 DOSAGE AND ADMINISTRATION
2.1 Important Dosage and Administration Instructions
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
To reduce the risk of renal adverse reactions, patients must be well hydrated prior to administration of CALDOLOR.
CALDOLOR must be diluted prior to administration.
Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.
Diluted solutions are stable for up to 24 hours at ambient temperature (approximately 20 to 25° C) and room lighting.
2.3 Pediatric Patients
Pediatric Dosing as Necessary for Fever and Pain
* Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less
Age Group Dose Dosing Interval Min infusion time Max daily dose 6 months to less than 12 years 10 mg/kg up to 400 mg max Every 4 to 6 hours as necessary 10 minutes *40 mg/Kg or 2,400 mg 12 to 17 years 400 mg Every 4 to 6 hours as necessary 10 minutes 2,400 mg
- 3 DOSAGE FORMS AND STRENGTHS
CALDOLOR (ibuprofen) Injection is a clear, colorless, non-pyrogenic, aqueous solution intended for intravenous use available in an 800 mg/8 mL (100 mg/mL) single-dose vial.Close
- 4 CONTRAINDICATIONS
CALDOLOR is contraindicated in the following patients:
- Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ibuprofen or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]
- History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]
- In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]
- 5 WARNINGS AND PRECAUTIONS
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including ibuprofen, cause serious gastrointenstinal (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 CALDOLOR. 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 for 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 bleeding.
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 high risk 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 (7)].
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 reported.
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 "flulike" 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 patient.
NSAIDs, including CALDOLOR, can lead to new onset or worsening of pre-existing 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 (7)].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
5.6 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 was 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 pre-existing 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 (7)]. 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.
5.7 Anaphylactic Reactions
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 (4) and Warnings and Precautions (5.8)].
Seek emergency help if anaphylactic reaction occurs.
5.8 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 (4)]. When CALDOLOR is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
5.9 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 serious events 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 (4)].
5.10 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 (8.1)].
5.11 Hematologic Toxicity
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. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].
Caldolor must be diluted prior to use. Infusion of the drug product without dilution can cause hemolysis [see Dosage and Administration (2.3)].
5.12 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.
5.13 Laboratory Monitoring
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 Warnings and Precautions (5.2, 5.3, 5.6)].
- 6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
- GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
- Hepatotoxicity [see Warnings and Precautions (5.3)]
- Hypertension [see Warnings and Precautions (5.4)]
- Heart Failure and Edema [see Warnings and Precautions (5.5)]
- Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
- Anaphylactic reactions [see Warnings and Precautions (5.7)]
- Serious Skin Reactions [see Warnings and Precautions (5.9)]
- Hematologic Toxicity [see Warnings and Precautions (5.11)]
6.1 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*
* All patients received concomitant morphine during these studies.
Event Caldolor Placebo
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%)
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 Event CALDOLOR Placebo
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 Hypertension 0 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 Bacteremia 4 (13%) 0 0 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.
- 7 DRUG INTERACTIONS
See Table 3 for clinically significant drug interactions with ibuprofen.
Table 3: Clinically Significant Drug Interactions with Ibuprofen 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 (5.11)]. Aspirin 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 (5.2)]. 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 (5.11)]. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers Clinical Impact:
- NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
- During concomitant use of CALDOLOR and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
- During concomitant use of CALDOLOR and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
Diuretics 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 (5.6)]. Digoxin 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. Lithium 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. Methotrexate 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. Cyclosporine 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 (5.2)]. Intervention: The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended. Pemetrexed 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 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.
- 8 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 condition.
8.3 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.
8.4 Pediatric Use
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 (2), Clinical Study Experience (6.1), Pharmacokinetics (12.3), CLINICAL STUDIES (14)].
8.5 Geriatric Use
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 (5.1, 5.2, 5.3, 5.6, 5.13)].
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.
- 10 OVERDOSAGE
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2)].
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center at 1-800-222-1222.Close
- 11 DESCRIPTION
CALDOLOR (ibuprofen) Injection is a nonsteroidal anti-inflammatory drug, available as an 800 mg/8 mL single-dose vial (100 mg.mL) for intravenous administration. The chemical name is ibuprofen, which is (±)-2-(p-isobutylphenyl) propionic acid. Ibuprofen is a white powder with a melting point of 74-77°C. It has a molecular weight of 206.28. It is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. The structural formula of ibuprofen is represented below:
Each 1 mL of solution contains 100 mg of ibuprofen in Water for Injection, USP. The inactive ingredients in CALDOLOR include: 78 mg/mL arginine at a molar ratio of 0.92:1 arginine:ibuprofen. The solution pH is about 7.4.
Caldolor is sterile and is intended for intravenous administration only.Close
- 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
CALDOLOR 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.
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
AUC = Area-under-the-curve
Cmax = Peak plasma concentration
CV = Coefficient of Variation
KEL = First-order elimination rate constant
T1/2 = Elimination half-life
* = 60 minute infusion time
400 mg* CALDOLOR
800 mg* CALDOLOR
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) T1/2 (h) 2.22 (20.1) 2.44 (12.9)
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
#WT: body weight (kg)
6 months to
2 years to
6 years to
Number of Patients 5 12 25 AUC (mcg·h/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) T1/2 (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)
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 (7)].
- 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of ibuprofen have not been conducted.
In published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay).
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.
- 14 CLINICAL STUDIES
14.1 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.
14.2 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
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 101.0ºF 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 <99.5ºF) by the end of first dosing interval.
- 16 HOW SUPPLIED/STORAGE AND HANDLING
CALDOLOR (ibuprofen) Injection is a clear, colorless, non-pyrogenic, aqueous solution intended for intravenous use available in an 800 mg/8 mL (100 mg/mL) single-dose vial.
Carton of 25 vials, NDC 66220-287-08
Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
The stopper in the Caldolor vial does not contain natural rubber latex, dry natural rubber, or blends of natural rubber.
- 17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with CALDOLOR and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop CALDOLOR and seek immediate medical therapy [see Warnings and Precautions (5.3)].
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)].
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].
Serious Skin Reactions
Advise patients to stop CALDOLOR immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)].
Inform pregnant women to avoid use of CALDOLOR and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of CALDOLOR with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with CALDOLOR until they talk to their healthcare provider [see Drug Interactions (7)].
Cumberland Pharmaceuticals Inc.
Nashville, TN 37203
US Patent Number 6,727,286, 8,871,810, 8,735,452, 9,012,508, 9,114,068 and 9,138,404
CALDOLOR® is a registered trademark of Cumberland Pharmaceuticals Inc.
- PRINCIPAL DISPLAY PANEL
Principal Display Panel - 8 mL Vial Label
NDC 66220-287-08 Rx Only
800 mg/8 mL
FOR INTRAVENOUS USE. MUST DILUTE BEFORE USE.
Store at controlled room temperature,
20°C - 25°C (68° - 77°F).
Single dose vial, discard unused portion.
DOSAGE: See package insert for dosage,Close
dilution, and administration information.
- PRINCIPAL DISPLAY PANEL
Principal Display Panel - 8 mL Carton Label
25 x 8 mL Vials
800 mg/8 mL
For Intravenous Use
Must Dilute Before Use
800 mg/8 mL
- INGREDIENTS AND APPEARANCE
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:66220-247 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ibuprofen (UNII: WK2XYI10QM) (ibuprofen - UNII:WK2XYI10QM) ibuprofen 400 mg in 4 mL Inactive Ingredients Ingredient Name Strength water (UNII: 059QF0KO0R) arginine (UNII: 94ZLA3W45F) hydrochloric acid (UNII: QTT17582CB) nitrogen (UNII: N762921K75) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:66220-247-04 25 in 1 CARTON 1 4 mL in 1 VIAL; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022348 06/11/2009 12/01/2011 CALDOLOR
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:66220-287 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ibuprofen (UNII: WK2XYI10QM) (ibuprofen - UNII:WK2XYI10QM) ibuprofen 800 mg in 8 mL Inactive Ingredients Ingredient Name Strength water (UNII: 059QF0KO0R) arginine (UNII: 94ZLA3W45F) hydrochloric acid (UNII: QTT17582CB) nitrogen (UNII: N762921K75) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:66220-287-08 25 in 1 CARTON 1 8 mL in 1 VIAL; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022348 06/11/2009 Labeler - Cumberland Pharmaceuticals Inc. (069532880)