Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 05 January 2017

Indication(s)

1 INDICATIONS AND USAGE CALDOLOR is indicated in adults and pediatric patients six months and older for the: management of mild to moderate pain and the management of moderate to severe pain as an adjunct to opioid analgesics reduction of fever CALDOLOR is a nonsteroidal anti-inflammatory drug indicated in adults and pediatric patients six months and older for the: Management of mild to moderate pain and the management of moderate to severe pain as an adjunct to opioid analgesics (1) Reduction of fever (1)

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Advisory information

contraindications

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)] Known hypersensitivity to ibuprofen or any component of the drug product (4) History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs (4) In the setting of CABG surgery (4)

Adverse reactions

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)] 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.

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 can not be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Population 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.

Pain Studies 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 (N=287) 400 mg (N=134) 800 mg (N=304) 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 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 N=28 100 mg N=30 200 mg N=30 400 mg N=31 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 Pediatric Population 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.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage 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) 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)].

After observing the response to initial therapy with

CALDOLOR , the dose and frequency should be adjusted to suit an individual patient 's needs.

Do not exceed 3200 mg total daily dose in adults.

Do not exceed 40 mg/kg or 2,400 mg, whichever is less, total daily dose in pediatric patients less than 17 years of age.

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.

Dilute to a final concentration of 4 mg /mL or less.

Appropriate diluents include 0.9 % Sodium Chloride Injection USP (normal saline), 5 % Dextrose Injection USP (D5W), or Lactated Ringers Solution.

100 mg dose: Dilute 1 mL of CALDOLOR in at least 100 mL of diluent 200 mg dose: Dilute 2 mL of CALDOLOR in at least 100 mL of diluent 400 mg dose: Dilute 4 mL of CALDOLOR in at least 100 mL of diluent 800 mg dose: Dilute 8 mL of CALDOLOR in at least 200 mL of diluent For weight-based dosing at 10 mg/kg ensure that the concentration of CALDOLOR is 4 mg /mL or less.

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° C to 25° C) and room lighting.

2.2 Adults For Analgesia (pain): The dose is 400 mg to 800 mg intravenously every 6 hours as necessary.

Infusion time must be at least 30 minutes.

Maximum daily dose is 3,200 mg.

For Fever: The dose is 400 mg intravenously, followed by 400 mg every 4 to 6 hours or 100 mg to 200 mg every 4 hours as necessary.

Infusion time must be at least 30 minutes.

Maximum daily dose is 3,200 mg.

2.3 Pediatric Patients For Analgesia (pain) and Fever Ages 12 to 17 years of age The dose is 400 mg intravenously every 4 to 6 hours as necessary.

Infusion time must be at least 10 minutes.

Maximum daily dose is 2,400 mg.

Ages 6 months to 12 years of age The dose is 10 mg/kg intravenously up to a maximum single dose of 400 mg every 4 to 6 hours as necessary.

Infusion time must be at least 10 minutes.

Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less.

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

Use in special populations

8 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) 8.1 Pregnancy Risk Summary 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.

Clinical Considerations 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.

Animal Data 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.

8.2 Lactation Risk Summary 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 Infertility Females 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.

Interactions

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)].

CALDOLOR is not a substitute for low dose aspirin for cardiovascular protection.

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.

Intervention: 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)].

When these drugs are administered concomitantly, patients should be adequately hydrated.

Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

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 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.

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)

More information

Category Value
Authorisation number NDA022348
Agency product number WK2XYI10QM
Orphan designation No
Product NDC 66220-287,66220-247
Date Last Revised 22-04-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 854187
Storage and handling Storage 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.
Marketing authorisation holder Cumberland Pharmaceuticals Inc.
Warnings

WARNING:

RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events 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.

[see Warnings and Precautions (5.1)].

CALDOLOR is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].

Gastrointestinal Bleeding, Ulceration and Perforation 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 [see Warnings and Precautions (5.2)].

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)