Caldolor

Description

CALDOLOR (ibuprofen injection) is a nonsteroidal anti-inflammatory drug available in two formulations: an 800 mg/8 mL single dose vial (100 mg/mL) and an 800 mg/200 mL (4 mg/mL) polypropylene single dose, ready-to-use flexible bag for intravenous administration. The chemical name of ibuprofen is (±)-2-(p-isobutylphenyl) propionic acid, with a molecular weight of 206.28. Ibuprofen appears as a white powder with a melting point ranging from 74°C to 77°C.

The solubility profile of ibuprofen indicates it is very slightly soluble in water (<1 mg/mL) but readily soluble in organic solvents such as ethanol and acetone. The structural formula of ibuprofen is provided in the accompanying documentation.

In the CALDOLOR 800 mg/8 mL vial, each 1 mL of solution contains 100 mg of ibuprofen, USP, along with 78 mg of arginine (at a molar ratio of 0.92:1 arginine to ibuprofen), and hydrochloric acid as a pH adjuster in Water for Injection, USP, resulting in a solution with a pH of approximately 7.4. In the CALDOLOR 800 mg/200 mL flexible bag, each 1 mL of solution contains 4 mg of ibuprofen, USP, 3.11 mg of dibasic sodium phosphate as a buffering agent, 6.30 mg of sodium chloride as a tonicity agent, and sodium hydroxide as a pH adjuster in Water for Injection, USP, yielding an iso-osmotic solution with an approximate pH of 7.4. CALDOLOR is sterile and intended for intravenous administration only.

Uses and Indications

CALDOLOR is indicated for the management of mild to moderate pain in adults and pediatric patients aged 3 months and older. It is also indicated for the management of moderate to severe pain as an adjunct to opioid analgesics. Additionally, CALDOLOR is indicated for the reduction of fever.

There are no teratogenic or nonteratogenic effects associated with CALDOLOR.

Dosage and Administration

The lowest effective dosage of CALDOLOR should be utilized for the shortest duration consistent with individual patient treatment goals.

CALDOLOR Injection vials require dilution prior to administration, while CALDOLOR Injection bags are available as ready-to-use formulations.

For adult patients experiencing pain, the recommended dosage is 400 mg to 800 mg administered intravenously over a period of 30 minutes, with a frequency of every 6 hours as necessary. In cases of fever, adults should receive an initial dose of 400 mg intravenously over 30 minutes, followed by subsequent doses of 400 mg every 4 to 6 hours, or alternatively, 100-200 mg every 4 hours as needed.

For pediatric patients aged 12 to 17 years, the dosage for pain and fever is 400 mg administered intravenously over 10 minutes, with a frequency of every 4 to 6 hours as necessary. For children aged 6 months to less than 12 years, the recommended dosage is 10 mg/kg intravenously over 10 minutes, with a maximum single dose of 400 mg, administered every 4 to 6 hours as necessary. In infants aged 3 months to less than 6 months, the dosage is 10 mg/kg intravenously over 10 minutes, with a maximum single dose of 100 mg, given every 4 to 6 hours as necessary.

Contraindications

Use of this product is contraindicated in patients with known hypersensitivity to ibuprofen or any component of the drug product. Additionally, it is contraindicated in individuals with a history of asthma, urticaria, or allergic-type reactions following the administration of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Furthermore, the use of this product is contraindicated in the setting of coronary artery bypass graft (CABG) surgery due to potential complications.

Warnings and Precautions

Non-steroidal anti-inflammatory drugs (NSAIDs), including CALDOLOR, are associated with an increased risk of serious cardiovascular thrombotic events, such as myocardial infarction and stroke, which may be fatal. This risk can manifest early in treatment and is likely to escalate with prolonged use. CALDOLOR is contraindicated in patients undergoing coronary artery bypass graft (CABG) surgery.

NSAIDs also pose a significant risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events may occur at any time during treatment and can arise without warning symptoms. Elderly patients and those with a history of peptic ulcer disease or GI bleeding are at an elevated risk for these serious GI complications.

Patients should be informed of the warning signs and symptoms of hepatotoxicity, and CALDOLOR should be discontinued if abnormal liver tests persist or worsen, or if clinical signs and symptoms of liver disease develop. Blood pressure should be monitored in patients taking antihypertensive medications, as NSAIDs may impair the effectiveness of these therapies.

In patients with severe heart failure, the use of CALDOLOR should be avoided unless the anticipated benefits outweigh the risks of exacerbating heart failure. Renal function must be monitored in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. CALDOLOR should not be used in patients with advanced renal disease unless the benefits are expected to outweigh the risks of worsening renal function.

Anaphylactic reactions can occur; therefore, emergency medical assistance should be sought immediately if such a reaction is suspected. CALDOLOR is contraindicated in patients with aspirin-sensitive asthma, and those with preexisting asthma (without aspirin sensitivity) should be closely monitored.

Serious skin reactions may arise, necessitating the discontinuation of CALDOLOR at the first sign of a skin rash or other hypersensitivity symptoms. In cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), CALDOLOR should be discontinued, and the patient should be evaluated clinically.

Fetal toxicity is a concern with NSAIDs, including CALDOLOR. Use should be limited between approximately 20 to 30 weeks of gestation due to the risk of oligohydramnios and fetal renal dysfunction. NSAIDs should be avoided in women at approximately 30 weeks gestation and later due to the risks of oligohydramnios, fetal renal dysfunction, and premature closure of the fetal ductus arteriosus.

Hematologic toxicity should also be monitored; hemoglobin or hematocrit levels should be assessed in patients exhibiting any signs or symptoms of anemia. Regular monitoring of renal function is advised for patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia, as well as monitoring hemoglobin or hematocrit in patients with signs of anemia.

Side Effects

Patients receiving treatment with this medication may experience a range of adverse reactions. The most common adverse reactions, occurring in more than 5% of patients, include nausea, flatulence, vomiting, headache, hemorrhage, and dizziness. In clinical trials, the incidence of nausea was reported as high as 57% with a 400 mg dose, while vomiting occurred in 22% of patients at the same dosage. Flatulence was noted in 7% of patients receiving 400 mg, and headache was reported in 9%. Hemorrhage was observed in 10% of patients taking 400 mg, and dizziness was reported in 6%.

In pediatric patients, common adverse reactions (≥2%) include infusion site pain, vomiting, nausea, anemia, and headache.

Serious adverse reactions associated with the use of this medication include an increased risk of serious cardiovascular thrombotic events, such as myocardial infarction and stroke, which can be fatal. This risk may manifest early in treatment and is likely to increase with prolonged use. Additionally, there is a significant risk of serious gastrointestinal adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can also be fatal. These gastrointestinal events can occur at any time during treatment and may present without warning symptoms. Elderly patients and those with a history of peptic ulcer disease or gastrointestinal bleeding are at a heightened risk for these serious events.

Postmarketing experience has revealed serious skin reactions, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Patients should be informed of the warning signs and symptoms of hepatotoxicity, and the medication should be discontinued if abnormal liver tests persist or worsen, or if clinical signs of liver disease develop.

Other important considerations include the potential for hypertension, particularly in patients taking antihypertensive medications, as NSAIDs may impair the effectiveness of these therapies. Renal function should be monitored in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. The use of this medication is not recommended in patients with advanced renal disease unless the benefits outweigh the risks.

Patients should be advised to seek emergency help if an anaphylactic reaction occurs and to monitor for exacerbation of asthma related to aspirin sensitivity, as this medication is contraindicated in such cases. The risk of fetal toxicity necessitates limiting the use of NSAIDs during pregnancy, particularly between 20 to 30 weeks of gestation, and avoiding use after 30 weeks due to risks of oligohydramnios and premature closure of the fetal ductus arteriosus.

Finally, hematologic toxicity should be monitored, particularly hemoglobin or hematocrit levels in patients exhibiting signs or symptoms of anemia.

Drug Interactions

Concomitant use of CALDOLOR with drugs that interfere with hemostasis, such as warfarin, aspirin, and SSRIs/SNRIs, necessitates careful monitoring for signs of bleeding. The use of CALDOLOR alongside analgesic doses of aspirin is generally not recommended.

When CALDOLOR is administered with ACE inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers, there is a potential for diminished antihypertensive effects. Blood pressure should be monitored in patients receiving this combination.

In elderly patients, those who are volume depleted, or individuals with renal impairment, the concomitant use of CALDOLOR with ACE inhibitors or ARBs may lead to a deterioration of renal function. It is advisable to monitor these high-risk patients for any signs of worsening renal function.

The use of CALDOLOR in conjunction with diuretics, such as furosemide and thiazide diuretics, may reduce their natriuretic effect. Patients should be monitored to ensure the efficacy of diuretics, including their antihypertensive effects.

Additionally, CALDOLOR may increase the serum concentration and prolong the half-life of digoxin when used together. Therefore, it is important to monitor serum digoxin levels in patients receiving this combination.

Packaging & NDC

The table below lists all NDC Code configurations of Caldolor (ibuprofen), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of CALDOLOR have been established for the treatment of pain and fever in pediatric patients aged 3 months and older. However, the safety and effectiveness of CALDOLOR in pediatric patients less than 3 months of age for the treatment of pain and fever have not been established.

Geriatric Use

Elderly patients, defined as those aged 65 and older, are at an increased risk for serious cardiovascular, gastrointestinal, and renal adverse reactions associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Due to this heightened risk, it is essential that healthcare providers exercise caution when prescribing these medications to geriatric patients.

When considering treatment with CALDOLOR for elderly patients, it is recommended to initiate dosing at the low end of the dosing range. This approach is advised to mitigate potential risks, particularly given the greater frequency of decreased hepatic, renal, or cardiac function in this population, as well as the likelihood of concomitant diseases or other drug therapies. Continuous monitoring for adverse effects is crucial to ensure patient safety.

It is important to note that clinical studies of CALDOLOR did not include a sufficient number of subjects aged 65 and over to ascertain whether this demographic responds differently compared to younger patients. Therefore, healthcare providers should remain vigilant and tailor treatment plans accordingly, weighing the anticipated benefits against the potential risks for each individual elderly patient. Additionally, the increased risk for serious gastrointestinal adverse events in this population necessitates careful consideration and monitoring throughout the course of treatment.

Pregnancy

Use of NSAIDs, including CALDOLOR, during pregnancy is associated with significant risks, particularly when administered around 20 to 30 weeks of gestation. The use of CALDOLOR can lead to premature closure of the fetal ductus arteriosus and fetal renal dysfunction, which may result in oligohydramnios and, in some cases, neonatal renal impairment. Therefore, it is recommended to limit the dose and duration of CALDOLOR use between approximately 20 and 30 weeks of gestation and to avoid its use at around 30 weeks of gestation and later in pregnancy.

Observational studies have shown that the use of NSAIDs at about 20 weeks gestation or later is linked to fetal renal dysfunction leading to oligohydramnios, with some instances of neonatal renal impairment reported. These adverse outcomes typically occur after days to weeks of treatment, although oligohydramnios has been infrequently noted as early as 48 hours after initiation of NSAID therapy. While the decrease in amniotic fluid has often been transient and reversible upon cessation of the drug, there have been limited case reports of irreversible neonatal renal dysfunction, with some cases necessitating invasive interventions such as exchange transfusion or dialysis.

Animal studies indicate that prostaglandins play a crucial role in fetal kidney development and that the administration of prostaglandin synthesis inhibitors, such as ibuprofen, can impair kidney development at clinically relevant doses. Additionally, there is evidence that NSAIDs can delay parturition and increase the incidence of stillbirth.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2% to 4% and 15% to 20%, respectively. However, the specific background risk associated with CALDOLOR use during pregnancy remains unknown. Given the potential risks, if an NSAID is deemed necessary after 20 weeks of gestation, it should be used at the lowest effective dose for the shortest duration possible. If CALDOLOR treatment extends beyond 48 hours, monitoring with ultrasound for oligohydramnios is advised. Should oligohydramnios be detected, CALDOLOR should be discontinued, and follow-up should be conducted according to clinical practice.

There are no studies assessing the effects of CALDOLOR during labor or delivery, and the methodological limitations of existing postmarketing studies hinder the establishment of a reliable estimate of the risk of adverse fetal and neonatal outcomes associated with maternal NSAID use. Consequently, healthcare professionals should exercise caution when prescribing CALDOLOR to pregnant patients, particularly during the later stages of pregnancy.

Lactation

No lactation studies have been conducted with CALDOLOR; however, limited published literature indicates 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 breastfed infants, and no effects on milk production have been observed.

When considering the use of CALDOLOR in lactating mothers, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for CALDOLOR and any potential adverse effects on the breastfed infant from CALDOLOR or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment should have their renal function closely monitored, particularly in those with concurrent hepatic impairment, heart failure, dehydration, or hypovolemia. The use of CALDOLOR is not recommended in patients with advanced renal disease unless the potential benefits are anticipated to outweigh the risks associated with worsening renal function.

Hepatic Impairment

Patients with hepatic impairment should be informed of the warning signs and symptoms of hepatotoxicity. It is essential to discontinue treatment if abnormal liver tests persist or worsen, or if clinical signs and symptoms of liver disease develop.

Additionally, renal function must be monitored in patients with hepatic impairment, particularly in those who also have renal impairment, heart failure, dehydration, or hypovolemia. The use of CALDOLOR is not recommended in patients with advanced renal disease unless the potential benefits are expected to outweigh the risks of worsening renal function.

Overdosage

Acute overdosage of nonsteroidal anti-inflammatory drugs (NSAIDs) may present with a range of symptoms, primarily including lethargy, drowsiness, nausea, vomiting, and epigastric pain. These symptoms are generally reversible with appropriate supportive care. However, more severe complications such as gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression, and coma have been reported, albeit infrequently.

Management of NSAID overdosage should focus on symptomatic and supportive care, as there are no specific antidotes available. Healthcare professionals are advised to monitor the patient closely and provide necessary interventions to alleviate symptoms. It is important to note that methods such as forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion may not be effective due to the high protein binding characteristics of NSAIDs.

For further guidance on the management of NSAID overdosage, healthcare providers can contact a poison control center at 1-800-222-1222 for additional information and support.

Nonclinical Toxicology

Long-term studies in animals to evaluate the carcinogenic potential of ibuprofen have not been conducted.

In published studies, ibuprofen was not found to be mutagenic in the in vitro bacterial reverse mutation assay (Ames assay).

In terms of impairment of fertility, a published study demonstrated that dietary administration of ibuprofen to male and female rats for 8 weeks prior to and during mating at dose levels of 20 mg/kg (0.06-times the maximum recommended human dose based on body surface area comparison) did not affect male or female fertility or litter size. Additionally, in other studies, adult mice received ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day (0.0085-times the maximum recommended human dose based on body surface area comparison) for 35 or 60 days in males and 35 days in females. While there was no effect on sperm motility or viability in males, decreased ovulation was reported in females.

Postmarketing Experience

During postapproval use of ibuprofen, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and appendages-related adverse reactions include exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. It is important for patients, their families, or caregivers to be informed of specific information before initiating therapy with CALDOLOR and periodically during the course of ongoing therapy.

Patients should be alert for symptoms of cardiovascular thrombotic events, which may include chest pain, shortness of breath, weakness, or slurring of speech. They should be instructed to report any of these symptoms to their healthcare provider immediately. Additionally, patients must report any symptoms of ulcerations and bleeding, such as epigastric pain, dyspepsia, melena, and hematemesis, to their healthcare provider. In cases where low-dose aspirin is used for cardiac prophylaxis, patients should be informed of the increased risk for gastrointestinal bleeding and the associated signs and symptoms.

It is essential to inform patients about the warning signs and symptoms of hepatotoxicity, which may include nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms. If any of these occur, patients should be instructed to stop taking CALDOLOR and seek immediate medical attention. Furthermore, patients should be vigilant for symptoms of congestive heart failure, such as shortness of breath, unexplained weight gain, or edema, and should contact their healthcare provider if these symptoms arise.

Patients must be informed of the signs of an anaphylactic reaction, including difficulty breathing and swelling of the face or throat, and should seek immediate emergency help if these symptoms occur. They should also be advised to stop taking CALDOLOR immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible.

Females of reproductive potential who desire pregnancy should be informed that NSAIDs, including CALDOLOR, may be associated with a reversible delay in ovulation. Pregnant women should be advised to avoid the use of CALDOLOR and other NSAIDs starting at 30 weeks gestation due to the risk of premature closure of the fetal ductus arteriosus. If treatment with CALDOLOR is necessary for a pregnant woman between approximately 20 to 30 weeks gestation, she may need to be monitored for oligohydramnios if treatment continues for longer than 48 hours.

Patients should be informed 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 minimal or no increase in efficacy. Patients should also be alerted that NSAIDs may be present in over-the-counter medications for the treatment of colds, fever, or insomnia. Lastly, patients should be advised not to use low-dose aspirin concomitantly with CALDOLOR until they have discussed it with their healthcare provider.

Storage and Handling

The product is supplied in configurations that include specific NDC numbers, which are essential for identification and inventory management. It should be stored at a controlled room temperature of 20 °C to 25 °C (68 °F to 77 °F). Temporary excursions are permissible within the range of 15 °C to 30 °C (59 °F to 86 °F), in accordance with USP Controlled Room Temperature guidelines.

Any unused portion of the product must be discarded to ensure safety and efficacy.

Additional Clinical Information

Postmarketing experience has revealed several adverse reactions associated with the use of ibuprofen. These reactions, reported voluntarily from a population of uncertain size, may not allow for reliable frequency estimation or causal relationship determination to drug exposure.

Notable skin and appendage-related adverse reactions include exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Clinicians should be aware of these potential reactions when prescribing ibuprofen to patients.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Caldolor as submitted by Cumberland Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)