Ibuprofen

Description

Ibuprofen tablets contain the active ingredient ibuprofen, which is (±)-2-(p-isobutylphenyl) propionic acid. Ibuprofen is a white powder with a melting point of 74 to 77°C. It is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. Ibuprofen is available in 400 mg, 600 mg, and 800 mg tablets for oral administration. The inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hypromellose 2910, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, pregelatinized starch, povidone k-90, sodium lauryl sulphate, 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 management of rheumatoid arthritis and osteoarthritis, including flare-ups of chronic disease, the suggested dosage ranges from 1,200 mg to 3,200 mg daily. This can be administered as 300 mg four times a day, or as 400 mg, 600 mg, or 800 mg three to four times a day. It is imperative not to exceed a total daily dose of 3,200 mg. The dosage should be individualized for each patient and may be adjusted according to the severity of symptoms.

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

In cases of dysmenorrhea, a dosage of 400 mg is recommended every 4 hours as necessary for pain relief.

To minimize gastrointestinal discomfort, it is advised to administer ibuprofen tablets with meals or milk.

Contraindications

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

Warnings and Precautions

Increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, has been associated with the use of NSAIDs. These events can be fatal and may occur early in treatment, with the risk potentially increasing with prolonged use. It is recommended to use the lowest effective dose for the shortest duration possible. Healthcare professionals should monitor patients for symptoms indicative of serious cardiovascular events.

For patients who have undergone coronary artery bypass graft (CABG) surgery, there is an increased incidence of myocardial infarction and stroke associated with NSAID treatment. Therefore, NSAIDs are contraindicated in this patient population.

In individuals with a history of myocardial infarction, NSAID treatment is linked to an elevated risk of reinfarction, cardiovascular-related death, and all-cause mortality. Close monitoring for signs of cardiac ischemia is advised in patients with a recent MI.

NSAIDs may also contribute to the development of new hypertension or exacerbate preexisting hypertension. Blood pressure should be monitored closely throughout the duration of NSAID therapy.

Patients with heart failure are at an increased risk of hospitalization and mortality when treated with NSAIDs. Monitoring for signs of worsening heart failure is essential.

Serious gastrointestinal adverse events, such as inflammation, bleeding, ulceration, and perforation, can occur at any time during NSAID therapy. Caution is advised when prescribing to patients with a history of ulcer disease or gastrointestinal bleeding. Healthcare professionals should monitor for signs and symptoms of gastrointestinal ulcerations and bleeding.

Long-term use of NSAIDs may lead to renal injury. It is advisable to closely monitor renal function, particularly in patients with impaired renal function, heart failure, liver dysfunction, or those concurrently taking diuretics and ACE inhibitors.

In cases of anaphylactoid reactions, emergency medical assistance should be sought immediately. Patients should be informed about the signs and symptoms of serious skin reactions and advised to discontinue use at the first appearance of a rash or any signs of hypersensitivity.

If signs or symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) occur, ibuprofen tablets should be discontinued, and the patient should be evaluated promptly.

Regarding fetal toxicity, the use of NSAIDs in pregnant women at approximately 30 weeks gestation and later should be avoided due to the risk of premature closure of the fetal ductus arteriosus. If treatment is necessary between 20 and 30 weeks gestation, it should be limited to the lowest effective dose and shortest duration possible, with discontinuation if oligohydramnios occurs.

Healthcare professionals should ensure that patients understand the importance of seeking emergency medical help in the event of an anaphylactoid reaction and the necessity to discontinue ibuprofen tablets at the first sign of a skin rash or any other indication of hypersensitivity. Immediate evaluation is warranted if signs or symptoms of DRESS are present.

Side Effects

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

Common adverse reactions, occurring in greater than 1% but less than 3% of patients, include gastrointestinal symptoms such as nausea, epigastric pain, heartburn, diarrhea, abdominal distress, and constipation. Central nervous system effects may manifest as dizziness, headache, and nervousness. Dermatologic reactions may include rash (including maculopapular types) and pruritus. Other reported reactions include tinnitus, decreased appetite, edema, and fluid retention, which generally respond promptly to discontinuation of the drug.

Adverse reactions with a precise incidence unknown but occurring in less than 1% of patients include more serious gastrointestinal issues such as gastric or duodenal ulcers with bleeding and/or perforation, gastrointestinal hemorrhage, and pancreatitis. Central nervous system effects may include depression, insomnia, confusion, emotional liability, somnolence, and aseptic meningitis with fever and coma. Dermatologic reactions may involve vesiculobullous eruptions, urticaria, erythema multiforme, Stevens-Johnson syndrome, and alopecia. Hematologic reactions can include neutropenia, agranulocytosis, aplastic anemia, and thrombocytopenia. Cardiovascular issues may present as congestive heart failure in patients with marginal cardiac function, elevated blood pressure, and palpitations. Renal adverse reactions may include acute renal failure and decreased creatinine clearance.

There are also adverse reactions with a causal relationship unknown, occurring in less than 1% of patients. These include central nervous system effects such as paresthesias, hallucinations, and dream abnormalities. Dermatologic reactions may consist of toxic epidermal necrolysis and photoallergic skin reactions. Special senses may be affected by conjunctivitis, diplopia, and optic neuritis. Hematologic issues may present as bleeding episodes, while metabolic/endocrine reactions can include gynecomastia and hypoglycemic reactions. Cardiovascular reactions may involve arrhythmias, such as sinus tachycardia and sinus bradycardia.

Postmarketing experience has revealed additional skin and appendage reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and fixed drug eruption.

Drug Interactions

The following drug interactions have been identified, categorized primarily by the class of drug involved and the type of interaction.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Antihypertensive Agents (ACE-Inhibitors): The concomitant use of NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. Monitoring of blood pressure is recommended when these medications are used together.

• Antiplatelet Agents (Aspirin): Ibuprofen can interfere with the antiplatelet activity of aspirin, particularly when ibuprofen is administered prior to aspirin. This interaction may increase the risk of cardiovascular events due to reduced antiplatelet efficacy.

• Diuretics (Furosemide and Thiazides): Ibuprofen may reduce the natriuretic effect of furosemide and thiazides. Close monitoring for renal function is advised in patients receiving these combinations to prevent renal failure.

• Lithium: Ibuprofen elevates plasma lithium levels and decreases renal clearance, which may heighten the risk of lithium toxicity. Regular monitoring of lithium levels is recommended when these drugs are co-administered.

• Methotrexate: NSAIDs may enhance the toxicity of methotrexate by competitively inhibiting its renal accumulation. Caution is warranted when these agents are used together, and monitoring for signs of methotrexate toxicity is advised.

• Anticoagulants (Warfarin): Caution is advised when ibuprofen is used in conjunction with warfarin-type anticoagulants due to an increased risk of serious gastrointestinal bleeding. Regular monitoring of coagulation parameters is recommended.

Other Interactions

• Cimetidine and Ranitidine: Co-administration of cimetidine or ranitidine with ibuprofen does not significantly affect ibuprofen serum concentrations, indicating no major interaction in this context.

No additional drug interactions or laboratory test interactions have been reported.

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

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

Geriatric Use

Caution should be exercised when treating elderly patients, specifically those aged 65 years and older. Due to the potential for altered pharmacokinetics and increased sensitivity to medications in this population, careful consideration of dosage adjustments and monitoring is essential. Healthcare providers are advised to assess the individual health status and comorbidities of geriatric patients to ensure safe and effective treatment.

Pregnancy

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen tablets, during pregnancy is associated with potential risks to the fetus. Specifically, the use of NSAIDs 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. Due to these risks, 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.

The estimated background risk of major birth defects and miscarriage in the general population is 2 to 4% and 15 to 20%, respectively. However, the specific background risk associated with ibuprofen use in the indicated population is unknown. Observational studies regarding other potential embryo-fetal risks of NSAID use during the first or second trimesters of pregnancy have yielded inconclusive results. There are no adequate and well-controlled studies in pregnant women, and ibuprofen should only be used during pregnancy if the potential benefits justify the potential risks to the fetus.

Animal studies have shown that administration of prostaglandin synthesis inhibitors, such as ibuprofen, can lead to increased pre- and post-implantation loss and may impair kidney development when administered at clinically relevant doses. Prostaglandins play a crucial role in fetal kidney development, and the use of NSAIDs at around 20 weeks of gestation or later has been associated with fetal renal dysfunction leading to oligohydramnios, with some cases resulting in neonatal renal impairment. These adverse outcomes have typically been observed after days to weeks of treatment, although oligohydramnios has been reported as early as 48 hours after NSAID initiation.

If the use of ibuprofen tablets is deemed necessary after 20 weeks of gestation, it is advised to limit the use to the lowest effective dose for the shortest duration possible. If treatment extends beyond 48 hours, monitoring with ultrasound for oligohydramnios should be considered. In cases where oligohydramnios occurs, ibuprofen tablets should be discontinued, and follow-up should be conducted according to clinical practice guidelines.

Published literature indicates that maternal NSAID use at around 30 weeks of gestation or later may cause premature closure of the fetal ductus arteriosus. Additionally, there have been limited case reports of maternal NSAID use leading to neonatal renal dysfunction without oligohydramnios, some of which were irreversible and required invasive treatments such as exchange transfusion or dialysis. However, methodological limitations in postmarketing studies, including the lack of control groups and limited information on dose, duration, and timing of drug exposure, hinder the establishment of a reliable estimate of the risk of adverse fetal and neonatal outcomes associated with maternal NSAID use. The effects of ibuprofen tablets on labor and delivery in pregnant women remain unknown.

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. The use of NSAIDs may lead to a dose-dependent reduction in prostaglandin formation, which can subsequently decrease renal blood flow and precipitate overt renal decompensation.

Patients at greatest risk for these adverse reactions include those with impaired renal function, heart failure, liver dysfunction, individuals taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy typically results in recovery to the pretreatment state.

There is no available information from controlled clinical studies regarding the use of ibuprofen tablets in patients with advanced renal disease; therefore, treatment with ibuprofen tablets is not recommended in this population. If initiation of ibuprofen tablet therapy is deemed necessary, close monitoring of the patient's 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 infrequently reported as early as 48 hours after NSAID initiation. While oligohydramnios is often reversible upon discontinuation of treatment, if NSAID therapy is required between 20 and 30 weeks 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. Long-term administration of NSAIDs has been associated with renal papillary necrosis and other forms of renal injury, particularly in individuals with compromised renal function. In patients with hepatic dysfunction, the risk of renal toxicity is heightened, especially in those who also have impaired renal function, heart failure, or are taking diuretics and ACE inhibitors.

Due to the potential for dose-dependent reductions in prostaglandin formation and subsequent renal blood flow, patients with hepatic impairment should be monitored closely for signs of renal decompensation. If NSAID therapy is deemed necessary, it is crucial to initiate treatment with caution and to conduct regular assessments of renal function throughout the course of therapy.

Furthermore, there is no available data from controlled clinical studies regarding the use of ibuprofen tablets in patients with advanced renal disease. Therefore, the use of ibuprofen tablets is not recommended in this population. If treatment with ibuprofen tablets is initiated in patients with hepatic impairment, close monitoring of renal function is advised to mitigate the risk of adverse effects. Discontinuation of NSAID therapy typically leads to recovery to the pretreatment state, underscoring the importance of careful management in this patient group.

Overdosage

In cases of ibuprofen overdosage, clinical manifestations can vary significantly based on the amount ingested and the patient's age and weight.

A notable case involved a 19-month-old child who ingested between 7 to 10 ibuprofen tablets (400 mg). This child presented with apneic and cyanotic symptoms, necessitating the administration of oxygen and fluids. Blood analysis approximately 8½ hours post-ingestion revealed a concentration of 102.9 mcg/mL.

Conversely, in two separate instances, children weighing around 10 kg ingested approximately 120 mg/kg of ibuprofen without exhibiting acute intoxication. Notably, one child's blood level was measured at 700 mcg/mL just 90 minutes after ingestion, yet no immediate symptoms were observed.

In an adult case, a 19-year-old male consumed 8,000 mg of ibuprofen over a few hours. He experienced dizziness but ultimately recovered following parenteral hydration and three days of bed rest.

For the management of acute overdosage, it is critical to empty the stomach through vomiting or gastric lavage within one hour of ingestion, as little drug will likely be recovered after this timeframe. The administration of alkali and the induction of diuresis may be advantageous due to the acidic nature of ibuprofen and its urinary excretion. Additionally, oral activated charcoal can be utilized to reduce both absorption and reabsorption of the drug.

Healthcare professionals should closely monitor patients for signs of toxicity and provide supportive care as necessary. If symptoms worsen or do not improve, it is imperative to seek emergency medical assistance.

Nonclinical Toxicology

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen tablets, during pregnancy has been associated with teratogenic effects, particularly when administered around 30 weeks gestation or later. This use increases the risk of premature closure of the fetal ductus arteriosus. Additionally, administration of NSAIDs at approximately 20 weeks gestation or later may lead to fetal renal dysfunction, resulting in oligohydramnios and, in some instances, neonatal renal impairment. While oligohydramnios is often reversible upon discontinuation of treatment, prolonged cases may lead to complications such as limb contractures and delayed lung maturation.

Non-teratogenic effects of NSAID use during the first or second trimesters of pregnancy remain inconclusive based on observational studies. Animal reproductive studies conducted in rats and rabbits have not shown evidence of developmental abnormalities; however, it is important to note that findings from animal studies are not always predictive of human outcomes.

There are no adequate and well-controlled studies in pregnant women, and ibuprofen should be utilized during pregnancy only if the potential benefits outweigh the potential risks to the fetus. Animal data indicate that prostaglandins play a crucial role in endometrial vascular permeability, blastocyst implantation, and decidualization. In studies involving animals, the administration of prostaglandin synthesis inhibitors, such as ibuprofen, has been linked to increased pre- and post-implantation loss.

In terms of animal pharmacology and toxicology, studies have reported that prostaglandin synthesis inhibitors can impair kidney development when administered at clinically relevant doses.

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 pharmacovigilance and are included for informational purposes.

Patient Counseling

Patients should be informed of essential information before initiating therapy with an NSAID, such as ibuprofen, and periodically throughout the course of treatment. It is important for patients to read the NSAID Medication Guide that accompanies each prescription dispensed.

Healthcare providers should advise patients to be vigilant for 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 healthcare provider immediately. Patients should be made aware that ibuprofen, like other NSAIDs, may cause serious cardiovascular side effects, such as myocardial infarction or stroke, which could lead to hospitalization or even death. Although serious cardiovascular events can occur without warning, patients should be alert for the signs and symptoms mentioned and seek medical advice if they observe any indicative signs.

Patients should also be apprised of the potential gastrointestinal discomfort associated with ibuprofen tablets, as well as the risk of serious gastrointestinal side effects, such as ulcers and bleeding, which may result in hospitalization or death. Serious gastrointestinal complications can occur without warning symptoms; therefore, patients should be vigilant for signs of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis, and should seek medical advice if they experience any of these symptoms.

Healthcare providers should instruct patients to discontinue ibuprofen tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible. Additionally, patients should be alert for symptoms of congestive heart failure, such as shortness of breath, unexplained weight gain, or edema, and should contact their healthcare provider if such symptoms occur.

Patients must be informed 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 occur, patients should be instructed to stop therapy and seek immediate medical attention.

It is crucial to inform patients about the signs of an anaphylactoid reaction, such as difficulty breathing or swelling of the face or throat. If these symptoms occur, patients should be advised to seek immediate emergency help.

Pregnant women should be cautioned to avoid the use of ibuprofen tablets and other NSAIDs starting at 30 weeks of gestation due to the risk of premature closure of the fetal ductus arteriosus. If treatment with ibuprofen tablets is necessary for a pregnant woman between approximately 20 to 30 weeks of gestation, healthcare providers should advise that she may need monitoring for oligohydramnios 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 20º to 25ºC (68º to 77ºF), as defined by the United States Pharmacopeia (USP) guidelines. Care should be taken to avoid exposure to excessive heat, specifically temperatures exceeding 40ºC (104ºF). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Borderline elevations of liver tests may occur in up to 15% of patients taking non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen tablets. Notable elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST), approximately three or more times the upper limit of normal, have been reported in about 1% of patients in clinical trials. Clinicians should monitor hemoglobin or hematocrit levels in patients on long-term NSAID therapy, including ibuprofen, if they exhibit any signs or symptoms of anemia.

Patients should be counseled to read the NSAID Medication Guide accompanying their prescription and to remain vigilant for symptoms of cardiovascular thrombotic events, such as chest pain, shortness of breath, weakness, or slurring of speech, reporting any such symptoms to their healthcare provider immediately. Additionally, postmarketing studies have indicated a higher incidence of decreased hemoglobin levels than previously reported, with decreases of 1 gram or more observed in 17.1% of patients taking 1,600 mg of ibuprofen daily for osteoarthritis and in 22.8% of patients taking 2,400 mg daily for rheumatoid arthritis. Positive stool occult blood tests and elevated serum creatinine levels were also noted in these studies.

FDA Insert (PDF)

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

View full prescribing information (PDF)