Ibuprofen

Description

Ibuprofen tablets, USP contain the active ingredient ibuprofen, which is chemically defined as (±) - 2 - (p - isobutylphenyl) propionic acid. Ibuprofen appears as a white powder with a melting point of 74-77°C. It is characterized by very slight solubility in water (less than 1 mg/mL) and is readily soluble in organic solvents such as ethanol and acetone. The structural formula of ibuprofen is provided below.

This nonsteroidal anti-inflammatory drug (NSAID) is formulated for oral administration and is available in tablet strengths of 300 mg, 400 mg, 600 mg, and 800 mg. The tablets contain several inactive ingredients, including colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, sodium starch glycoate, stearic acid, talc, and titanium dioxide.

Uses and Indications

Ibuprofen tablets are indicated for the relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Additionally, these tablets are indicated for the relief of mild to moderate pain and for the treatment of primary dysmenorrhea.

Limitations of Use: Controlled clinical trials to establish the safety and effectiveness of ibuprofen tablets in children have not been conducted. Therefore, the use of ibuprofen in pediatric populations should be approached with caution.

Dosage and Administration

For the treatment of rheumatoid arthritis and osteoarthritis, including flare-ups of chronic disease, the suggested dosage ranges from 1200 mg to 3200 mg daily, administered as 400 mg, 600 mg, or 800 mg three to four times a day (tid or qid). Individual patient responses may vary, with some patients potentially benefiting from a higher dosage of 3200 mg daily compared to 2400 mg. It is essential to tailor the dose to each patient, adjusting based on the severity of symptoms, while employing the smallest effective dose.

For the management of mild to moderate pain, a dosage of 400 mg may be administered every 4 to 6 hours as needed for pain relief.

In cases of dysmenorrhea, a dosage of 400 mg can be given every 4 hours as necessary for pain relief.

General administration instructions indicate that the total daily dose should not exceed 3200 mg. In instances where gastrointestinal complaints arise, it is recommended to administer ibuprofen tablets with meals or milk to mitigate discomfort.

Contraindications

Ibuprofen tablets are contraindicated in patients with known hypersensitivity to ibuprofen. They should not be administered to individuals who have experienced asthma, urticaria, or allergic-type reactions following the use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), as severe, potentially fatal, anaphylactic-like reactions have been reported in these patients. Additionally, the use of ibuprofen tablets is contraindicated in the context of coronary artery bypass graft (CABG) surgery.

Caution is advised when considering ibuprofen for patients with preexisting asthma, particularly those with aspirin-sensitive asthma.

Warnings and Precautions

Nonsteroidal anti-inflammatory drugs (NSAIDs), including Ibuprofen tablets, are associated with significant risks that healthcare professionals must consider when prescribing and monitoring treatment.

Cardiovascular Risks NSAIDs are linked to 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 escalate with prolonged use. Patients with existing cardiovascular disease or risk factors are at a heightened risk for these adverse events. It is crucial to monitor patients closely for any signs of cardiovascular complications during NSAID therapy.

Gastrointestinal Adverse Events The use of NSAIDs, including Ibuprofen tablets, poses a risk of serious gastrointestinal complications, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur unexpectedly and without warning symptoms, particularly in elderly patients who are at greater risk. Physicians should remain vigilant for signs or symptoms of gastrointestinal bleeding in patients undergoing long-term NSAID treatment. Regular monitoring of hemoglobin or hematocrit levels is recommended for patients exhibiting any signs of anemia.

Renal and Hypertensive Concerns Long-term administration of NSAIDs has been associated with renal complications, including renal papillary necrosis and other forms of renal injury. Additionally, NSAIDs can lead to the onset of new hypertension or exacerbate preexisting hypertension. Regular assessment of renal function and blood pressure is advised for patients on prolonged NSAID therapy.

Allergic Reactions and Skin Reactions Anaphylactoid reactions may occur in patients without prior exposure to Ibuprofen tablets. Healthcare professionals should instruct patients to seek emergency medical assistance if such reactions occur. Furthermore, NSAIDs can cause serious skin adverse reactions, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be educated on the signs and symptoms of serious skin reactions and advised to discontinue Ibuprofen tablets at the first appearance of a rash or any other hypersensitivity signs.

Pregnancy Considerations The use of NSAIDs, including Ibuprofen tablets, is contraindicated in pregnant women at approximately 30 weeks gestation and later due to the risk of premature closure of the fetal ductus arteriosus.

Corticosteroid Considerations Ibuprofen tablets are not a substitute for corticosteroids and should not be used to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids can lead to exacerbation of the underlying condition. For patients on long-term corticosteroid therapy, a gradual tapering of corticosteroids is recommended if discontinuation is necessary.

Laboratory Monitoring Patients on long-term NSAID therapy should have their complete blood count (CBC) and chemistry profile checked periodically. If any clinical signs or symptoms indicative of liver or renal disease develop, or if systemic manifestations such as eosinophilia or rash occur, or if abnormal liver tests persist or worsen, Ibuprofen tablets should be discontinued.

Healthcare professionals are urged to maintain a high index of suspicion for these potential adverse effects and to monitor patients accordingly throughout the course of NSAID therapy.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication, which can be categorized by seriousness and frequency.

Serious adverse reactions include an increased risk of cardiovascular thrombotic events, such as myocardial infarction and stroke, which can be fatal. This risk may manifest early in treatment and is known to increase with prolonged use. Additionally, there is a significant risk of serious gastrointestinal events, including bleeding, ulceration, and perforation of the stomach or intestines, which can also be fatal. These gastrointestinal complications can occur at any time during treatment and may present without warning symptoms, particularly in elderly patients who are at greater risk.

Gastrointestinal adverse reactions are common and may include nausea, epigastric pain, heartburn, diarrhea, abdominal distress, vomiting, indigestion, constipation, and abdominal cramps or pain. More severe gastrointestinal issues such as gastric or duodenal ulcers with bleeding and/or perforation, gastrointestinal hemorrhage, melena, gastritis, hepatitis, jaundice, abnormal liver function tests, and pancreatitis have also been reported.

Central nervous system reactions may present as dizziness, headache, and nervousness. More serious effects can include depression, insomnia, confusion, emotional liability, somnolence, and aseptic meningitis, which may be accompanied by fever and coma. Other neurological symptoms reported include paresthesias, hallucinations, dream abnormalities, and pseudotumor cerebri.

Dermatologic reactions are also notable, with common manifestations including rash (including maculopapular types) and pruritus. Serious skin reactions such as vesiculobullous eruptions, urticaria, erythema multiforme, Stevens-Johnson syndrome, alopecia, toxic epidermal necrolysis, and photoallergic skin reactions have been observed, particularly in postmarketing experiences.

Adverse reactions affecting the special senses include tinnitus, hearing loss, amblyopia (blurred and/or diminished vision), conjunctivitis, diplopia, optic neuritis, and cataracts.

Hematologic adverse reactions can be serious, including neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (sometimes Coombs positive), and thrombocytopenia with or without purpura. Patients may also experience bleeding episodes such as epistaxis and menorrhagia.

Metabolic and endocrine reactions may include decreased appetite, gynecomastia, hypoglycemic reactions, and acidosis. Cardiovascular reactions can manifest as edema, fluid retention (which generally responds promptly to drug discontinuation), congestive heart failure in patients with marginal cardiac function, elevated blood pressure, palpitations, and arrhythmias (including sinus tachycardia and sinus bradycardia).

Allergic reactions may present as a syndrome characterized by abdominal pain, fever, chills, nausea, and vomiting, as well as anaphylaxis and bronchospasm. Other allergic manifestations include serum sickness, lupus erythematosus syndrome, Henoch-Schonlein vasculitis, and angioedema.

Renal adverse reactions can include acute renal failure, decreased creatinine clearance, polyuria, azotemia, cystitis, hematuria, and renal papillary necrosis. Miscellaneous reactions may involve dry eyes and mouth, gingival ulcer, and rhinitis.

In summary, the adverse reactions associated with this medication range from common gastrointestinal and central nervous system effects to serious cardiovascular and gastrointestinal risks, necessitating careful monitoring and management of patients during treatment.

Drug Interactions

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and other medications may lead to significant drug interactions that require careful consideration.

Pharmacodynamic Interactions

• ACE-Inhibitors: NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be considered in patients receiving both NSAIDs and ACE-inhibitors.

• Aspirin: Pharmacodynamic studies indicate that ibuprofen can interfere with the antiplatelet activity of aspirin. This interaction is particularly pronounced when ibuprofen (400 mg) is administered three times daily or even once daily, especially if ibuprofen is taken prior to aspirin. To mitigate this interaction, immediate-release low-dose aspirin should be administered at least 2 hours before ibuprofen. However, this timing does not apply to enteric-coated low-dose aspirin. Due to the potential increased risk of cardiovascular events, patients taking low-dose aspirin for cardioprotection who require analgesics should consider using an NSAID that does not interfere with aspirin's antiplatelet effect or opt for non-NSAID analgesics when appropriate.

• Anticoagulants: Although several short-term controlled studies have not shown significant effects of ibuprofen on prothrombin times or other clotting factors in patients on coumarin-type anticoagulants, caution is advised. The concomitant use of ibuprofen and anticoagulants may increase the risk of gastrointestinal bleeding, which is synergistic with the effects of warfarin and NSAIDs.

Pharmacokinetic Interactions

• Diuretics: Clinical studies and post-marketing observations have demonstrated that ibuprofen can reduce the natriuretic effect of furosemide and thiazides in some patients, likely due to inhibition of renal prostaglandin synthesis. Patients receiving NSAIDs alongside diuretics should be closely monitored for signs of renal failure and to ensure diuretic efficacy.

• Lithium: Ibuprofen has been shown to elevate plasma lithium levels and reduce renal lithium clearance, with a mean increase in minimum lithium concentration of 15% and a 19% decrease in renal clearance during concurrent administration. This effect is attributed to the inhibition of renal prostaglandin synthesis by ibuprofen. Therefore, careful observation for signs of lithium toxicity is warranted when these drugs are used together.

• Methotrexate: NSAIDs may competitively inhibit the accumulation of methotrexate in renal tissues, potentially enhancing its toxicity. Caution is advised when administering NSAIDs in conjunction with methotrexate.

• Cimetidine and Ranitidine: Studies indicate that co-administration of cimetidine or ranitidine with ibuprofen does not significantly affect ibuprofen serum concentrations.

In summary, healthcare providers should exercise caution and consider appropriate monitoring or dosage adjustments when prescribing NSAIDs alongside these medications to mitigate potential interactions and adverse effects.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness of Ibuprofen tablets in pediatric patients have not been established. Therefore, caution should be exercised when considering the use of this medication in children. Further studies are needed to determine appropriate dosing and outcomes in this population.

Geriatric Use

Caution should be exercised when treating elderly patients (65 years and older) with this medication, as with any nonsteroidal anti-inflammatory drugs (NSAIDs). It is important for healthcare providers to consider the increased risk of adverse effects in this population. Monitoring for potential side effects and adjusting dosages as necessary may be warranted to ensure the safety and efficacy of treatment in geriatric patients.

Pregnancy

Use of NSAIDs, including Ibuprofen tablets, during pregnancy is associated with significant risks, particularly when administered around 20 to 30 weeks of gestation. The use of these medications 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 Ibuprofen tablets use between approximately 20 and 30 weeks of gestation, and to avoid their use at around 30 weeks of gestation and later in pregnancy.

Observational studies have indicated that the use of NSAIDs at about 30 weeks gestation or later increases the risk of premature closure of the fetal ductus arteriosus. Additionally, the use of NSAIDs at about 20 weeks gestation or later has been 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 soon as 48 hours after initiation of NSAID therapy. In many cases, the decrease in amniotic fluid was transient and reversible upon discontinuation of the drug; however, there have been limited reports of irreversible neonatal renal dysfunction requiring invasive interventions.

Data from animal studies suggest that prostaglandins play a crucial role in fetal kidney development and that the administration of prostaglandin synthesis inhibitors, such as Ibuprofen, may impair this development. While reproductive studies in rats and rabbits have not shown evidence of developmental abnormalities, the predictive value of animal studies for human outcomes is uncertain. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2-4% and 15-20%, respectively, and the background risk for the indicated population(s) remains unknown.

There are no adequate, well-controlled studies in pregnant women, and Ibuprofen tablets should only be used during pregnancy if the potential benefits justify the potential risks to the fetus. If NSAID treatment is deemed necessary after 20 weeks of gestation, it is advised to use the lowest effective dose for the shortest duration possible. If treatment extends beyond 48 hours, monitoring with ultrasound for oligohydramnios should be considered. In the event that oligohydramnios occurs, Ibuprofen tablets should be discontinued, and follow-up should be conducted according to clinical practice.

Lactation

It is not known whether this drug is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from Ibuprofen tablets, lactating mothers should consider the importance of the drug to their health when making a decision to either discontinue nursing or discontinue the drug.

Renal Impairment

Long-term administration of NSAIDs has been associated with renal papillary necrosis and other forms of renal injury. In patients with reduced kidney function, renal prostaglandins play a compensatory role in maintaining renal perfusion; therefore, the use of NSAIDs may lead to a dose-dependent reduction in prostaglandin formation and, subsequently, renal blood flow. This can precipitate overt renal decompensation, particularly in patients at greater risk, including those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly.

Discontinuation of NSAID therapy typically results in recovery to the pretreatment state. However, there is no information from controlled clinical studies regarding the use of Ibuprofen tablets in patients with advanced renal disease, and treatment with Ibuprofen tablets is not recommended in this population. If initiation of Ibuprofen tablet therapy is deemed necessary, close monitoring of renal function is advised.

Additionally, the use of NSAIDs, including Ibuprofen tablets, during pregnancy, particularly around 20 weeks gestation or later, may lead to fetal renal dysfunction, resulting in oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes may occur after days to weeks of treatment, although oligohydramnios has been reported as early as 48 hours after NSAID initiation. While oligohydramnios is often reversible upon discontinuation of treatment, if NSAID use is required between 20 and 30 weeks of gestation, it is recommended to limit Ibuprofen tablets to the lowest effective dose and shortest duration possible. Ultrasound monitoring of amniotic fluid should be considered if treatment extends beyond 48 hours, and Ibuprofen tablets should be discontinued if oligohydramnios occurs, with follow-up according to clinical practice.

Hepatic Impairment

Patients with hepatic impairment may experience altered pharmacokinetics and increased risk of adverse effects when treated with NSAIDs, including Ibuprofen tablets. Long-term administration of NSAIDs has been associated with renal papillary necrosis and other forms of renal injury, particularly in individuals where renal prostaglandins play a critical role in maintaining renal perfusion. In patients with compromised liver function, the administration of NSAIDs may lead to a dose-dependent reduction in prostaglandin formation, which can subsequently decrease renal blood flow and potentially precipitate renal decompensation.

Patients at heightened risk for these adverse reactions include those with impaired renal function, heart failure, liver dysfunction, individuals taking diuretics and ACE inhibitors, and the elderly. Due to the lack of controlled clinical study data regarding the use of Ibuprofen tablets in patients with advanced renal disease, treatment with Ibuprofen is not recommended for this population. If therapy with Ibuprofen tablets is deemed necessary, close monitoring of renal function is advised to mitigate the risk of renal toxicity. Discontinuation of NSAID therapy typically results in recovery to the pretreatment state.

Overdosage

In cases of ibuprofen overdosage, clinical manifestations and management strategies are critical for effective treatment.

Clinical Presentation A notable case involved a 19-month-old child weighing 12 kg, who presented to the emergency department approximately 1½ hours after ingesting 7 to 10 ibuprofen tablets (400 mg). Upon arrival, the child was apneic and cyanotic, responding only to painful stimuli, which was sufficient to induce respiration. Initial management included the administration of oxygen and parenteral fluids. Gastric aspiration yielded a greenish-yellow fluid, with no evidence of ibuprofen detected. Two hours post-ingestion, the child's condition stabilized, although she continued to respond solely to painful stimuli and experienced intermittent apnea lasting 5 to 10 seconds. The child was subsequently admitted to intensive care, where sodium bicarbonate, along with dextrose and normal saline infusions, were administered. By four hours post-ingestion, the child could be easily aroused, sit independently, and respond to verbal commands. A blood level of ibuprofen measured 102.9 mcg/mL approximately 8½ hours after ingestion, and by 12 hours, the child appeared to have fully recovered.

In two additional cases involving children weighing approximately 10 kg who accidentally ingested about 120 mg/kg of ibuprofen, no signs of acute intoxication or late sequelae were observed. One child exhibited a blood level of 700 mcg/mL 90 minutes post-ingestion, approximately ten times the peak levels noted in absorption-excretion studies.

A separate case involving a 19-year-old male who ingested 8,000 mg of ibuprofen over several hours reported dizziness, with nystagmus observed during examination. Following hospitalization, the patient received parenteral hydration and underwent three days of bed rest, ultimately recovering without any reported sequelae.

Management Strategies In instances of acute ibuprofen overdosage, it is recommended to empty the stomach through vomiting or gastric lavage; however, it is important to note that minimal drug recovery is likely if more than one hour has passed since ingestion. Given the acidic nature of ibuprofen and its urinary excretion, administering alkali and inducing diuresis may be beneficial. Supportive measures should be prioritized, and the use of oral activated charcoal may assist in reducing both the absorption and reabsorption of ibuprofen tablets.

Healthcare professionals should remain vigilant in monitoring patients for potential symptoms and complications associated with ibuprofen overdosage, ensuring appropriate interventions are implemented promptly.

Nonclinical Toxicology

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including Ibuprofen tablets, during pregnancy, particularly after approximately 20 weeks of gestation, has been associated with an increased risk of fetal renal dysfunction, leading to oligohydramnios and, in some instances, neonatal renal impairment. Furthermore, administration of NSAIDs around 30 weeks gestation or later may elevate the risk of premature closure of the fetal ductus arteriosus.

In animal studies, the administration of prostaglandin synthesis inhibitors, such as Ibuprofen, has resulted in increased pre- and post-implantation loss. Prostaglandins play a crucial role in fetal kidney development, and evidence from published animal studies indicates that prostaglandin synthesis inhibitors can impair kidney development when given at clinically relevant doses.

Data from observational studies regarding other potential embryofetal risks associated with NSAID use during the first or second trimesters of pregnancy remain inconclusive. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. It is acknowledged that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2-4% and 15-20%, respectively.

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, it is important to note that animal reproduction studies are not always predictive of human response.

Postmarketing Experience

During postapproval use of ibuprofen, the following adverse reactions have been identified through voluntary reports and surveillance programs: exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). These events were reported in the context of routine pharmacovigilance activities and do not imply a causal relationship with the medication.

Patient Counseling

Patients should be informed of essential information before initiating therapy with an NSAID, such as Ibuprofen tablets, and periodically during the course of ongoing therapy. Healthcare providers should encourage patients to read the NSAID Medication Guide that accompanies each prescription dispensed.

Patients should be advised to remain vigilant 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.

It is important to inform patients that Ibuprofen tablets, like other NSAIDs, can cause gastrointestinal discomfort and, in rare cases, serious gastrointestinal side effects such as ulcers and bleeding, which may lead to hospitalization or even death. Patients should be made aware that serious gastrointestinal tract ulcerations and bleeding can occur without warning symptoms. They should be alert for signs and symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis, and should seek medical advice if they observe any indicative signs or symptoms.

Patients should be advised to discontinue the use of Ibuprofen tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible.

Healthcare providers should also inform patients to be alert for symptoms of congestive heart failure, such as shortness of breath, unexplained weight gain, or edema, and to contact their healthcare provider if such symptoms occur.

Patients should be educated about the warning signs and symptoms of hepatotoxicity, which may include nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms. If these symptoms occur, patients should be instructed to stop therapy and seek immediate medical attention.

Additionally, patients should be informed of the signs of an anaphylactoid reaction, such as difficulty breathing and swelling of the face or throat. If these symptoms occur, patients should be instructed to seek immediate emergency help.

In late pregnancy, as with other NSAIDs, Ibuprofen tablets should be avoided due to the risk of premature closure of the ductus arteriosus. Pregnant women should be advised to avoid the use of Ibuprofen tablets and other NSAIDs starting at 30 weeks gestation. If treatment with Ibuprofen tablets is necessary for a pregnant woman between approximately 20 to 30 weeks gestation, she should be informed that monitoring for oligohydramnios may be required if treatment continues for longer than 48 hours.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F), as defined by the United States Pharmacopeia (USP). Care should be taken to avoid exposure to excessive heat, specifically temperatures exceeding 40°C (104°F). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Clinicians should be vigilant in monitoring patients for signs or symptoms of gastrointestinal (GI) bleeding, as there is a risk of serious GI tract ulcerations and bleeding associated with the use of NSAIDs. For patients undergoing long-term treatment with NSAIDs, it is recommended that complete blood counts (CBC) and chemistry profiles be checked periodically to assess for potential adverse effects.

In cases where patients exhibit clinical signs and symptoms indicative of liver or renal disease, or if systemic manifestations such as eosinophilia or rash occur, it is crucial to discontinue Ibuprofen tablets. Additionally, if abnormal liver tests persist or worsen, discontinuation of the medication is advised.

FDA Insert (PDF)

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

View full prescribing information (PDF)