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

The lowest effective dose should be utilized for the shortest duration consistent with individual patient treatment goals. After assessing the response to initial therapy, healthcare professionals are advised to adjust the dose and frequency to meet the specific needs of the patient. The total daily dose must not exceed 3200 mg. In cases where gastrointestinal complaints arise, it is recommended to administer Ibuprofen tablets with meals or milk to mitigate these effects.

For the management of rheumatoid arthritis and osteoarthritis, the suggested dosage ranges from 1200 mg to 3200 mg daily, which can be administered as 400 mg, 600 mg, or 800 mg three times a day (tid) or four times a day (qid). 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 the case of dysmenorrhea, a dosage of 400 mg can be administered every 4 hours as necessary for pain relief.

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 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. It is crucial to note that Ibuprofen tablets are contraindicated in patients undergoing coronary artery bypass graft (CABG) surgery.

NSAIDs can also lead to severe gastrointestinal (GI) adverse events, including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which may be fatal. These serious adverse events can occur at any time, with or without warning symptoms. Therefore, healthcare professionals should monitor patients on long-term NSAID therapy for signs or symptoms of GI bleeding.

Anaphylactoid reactions may occur in patients who have not previously been exposed to Ibuprofen tablets. In such cases, emergency medical assistance should be sought immediately. Additionally, serious skin adverse reactions, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal, have been reported. Patients should be informed about the signs and symptoms of serious skin reactions and advised to discontinue Ibuprofen tablets at the first appearance of a skin rash or any other sign of hypersensitivity.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has also been documented in patients taking NSAIDs like Ibuprofen tablets. If any signs or symptoms indicative of DRESS arise, Ibuprofen tablets should be discontinued, and the patient should be evaluated immediately. Furthermore, the use of NSAIDs, including Ibuprofen tablets, is not recommended for pregnant women at approximately 30 weeks of gestation and later due to the risk of premature closure of the fetal ductus arteriosus.

In terms of general precautions, Ibuprofen tablets should not be considered a substitute for corticosteroids or used to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of the underlying disease. For patients on prolonged corticosteroid therapy, a gradual tapering of the corticosteroid dosage is advised if discontinuation is necessary. It is also important to recognize that the pharmacological effects of Ibuprofen tablets in reducing fever and inflammation may obscure diagnostic signs that are critical for detecting complications of presumed noninfectious, painful conditions.

Healthcare professionals should conduct periodic monitoring of complete blood count (CBC) and chemistry profiles in patients receiving long-term NSAID treatment. If clinical signs or symptoms consistent with 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.

Patients should be instructed to seek emergency medical help if they experience an anaphylactoid reaction. They should also be advised to stop taking Ibuprofen tablets at the first sign of a skin rash or any other indication of hypersensitivity, and to discontinue use and seek evaluation if signs or symptoms of DRESS are present.

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. Elderly patients are particularly at heightened risk for these serious gastrointestinal events.

Common gastrointestinal reactions reported include nausea, epigastric pain, heartburn, diarrhea, abdominal distress, and constipation. Other gastrointestinal issues may involve gastric or duodenal ulcers with bleeding and/or perforation, gastrointestinal hemorrhage, melena, gastritis, hepatitis, jaundice, abnormal liver function tests, and pancreatitis.

Central nervous system reactions may include dizziness, headache, nervousness, and more severe effects such as depression, insomnia, confusion, emotional liability, somnolence, and aseptic meningitis, which can present with fever and coma. Patients may also report paresthesias, hallucinations, dream abnormalities, and pseudotumor cerebri.

Dermatologic reactions can range from rash (including maculopapular types) and pruritus to more severe conditions such as vesiculobullous eruptions, urticaria, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Photoallergic skin reactions and alopecia have also been noted.

In the realm of special senses, tinnitus, hearing loss, amblyopia (blurred and/or diminished vision), conjunctivitis, diplopia, optic neuritis, and cataracts have been reported.

Hematologic adverse reactions include 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 involve decreased appetite, gynecomastia, hypoglycemic reactions, and acidosis.

Cardiovascular reactions can include 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 (such as sinus tachycardia and sinus bradycardia).

Allergic reactions may present as a syndrome of abdominal pain, fever, chills, nausea, and vomiting; anaphylaxis; bronchospasm; serum sickness; lupus erythematosus syndrome; Henoch-Schonlein vasculitis; and angioedema.

Renal adverse reactions 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.

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

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, particularly when ibuprofen (400 mg) is administered three times daily or prior to aspirin. This interaction is less pronounced if immediate-release low-dose aspirin is taken at least 2 hours before ibuprofen; however, this 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 a NSAID that does not interfere with aspirin's antiplatelet effect or opt for non-NSAID analgesics when appropriate.

• Anticoagulants: While several short-term 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, leading to a higher risk of serious bleeding compared to either drug alone.

Pharmacokinetic Interactions

• Diuretics: Ibuprofen has been shown to reduce the natriuretic effect of furosemide and thiazides in some patients, likely due to inhibition of renal prostaglandin synthesis. Patients should be closely monitored for signs of renal failure and to ensure diuretic efficacy during concurrent NSAID therapy.

• Lithium: Co-administration of ibuprofen has been associated with elevated plasma lithium levels and reduced renal clearance of lithium, with a mean increase of 15% in minimum lithium concentration and a 19% decrease in renal clearance. Careful observation for signs of lithium toxicity is recommended when these drugs are used together.

• Methotrexate: NSAIDs may competitively inhibit the accumulation of methotrexate, potentially enhancing its toxicity. Caution is warranted when administering NSAIDs alongside methotrexate.

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

In summary, careful monitoring and consideration of alternative therapies are advised when NSAIDs are used in conjunction with the aforementioned drug classes to mitigate potential adverse effects and interactions.

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 this medication in children. Further studies are necessary 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 is recommended to ensure the safety and efficacy of treatment in geriatric patients.

Pregnancy

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including Ibuprofen tablets, during pregnancy is associated with significant risks, particularly when used after approximately 20 weeks of gestation. The use of NSAIDs at about 30 weeks gestation or later can lead to premature closure of the fetal ductus arteriosus, which may have serious implications for fetal cardiovascular health. Additionally, NSAID use during this period has been linked to fetal renal dysfunction, resulting in oligohydramnios and, in some cases, neonatal renal impairment.

Healthcare professionals are advised to limit the dose and duration of Ibuprofen tablets use between approximately 20 and 30 weeks of gestation. If NSAID treatment is deemed necessary after 20 weeks, it should be restricted to the lowest effective dose for the shortest duration possible. Should treatment extend beyond 48 hours, monitoring with ultrasound for oligohydramnios is recommended. In instances where oligohydramnios is detected, discontinuation of Ibuprofen tablets should be considered, followed by appropriate clinical follow-up.

Data from observational studies regarding the risks of NSAID use during the first and second trimesters remain inconclusive. While animal reproduction studies in rats and rabbits have not shown evidence of developmental abnormalities, these findings may not be predictive of human outcomes. Prostaglandins, which are inhibited by NSAIDs like Ibuprofen, play a crucial role in various reproductive processes, including endometrial vascular permeability and fetal kidney development. Animal studies have indicated that the use of prostaglandin synthesis inhibitors can lead to increased pre- and post-implantation loss and may impair kidney development at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2-4% and 15-20%, respectively. However, the specific background risk associated with Ibuprofen tablets use in pregnant patients is 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.

Published literature indicates that adverse outcomes, such as fetal renal dysfunction leading to oligohydramnios, may occur after days to weeks of NSAID treatment, although some cases of oligohydramnios have been reported as soon as 48 hours after initiation. While many instances of decreased amniotic fluid have been transient and reversible upon cessation of the drug, there are limited case reports of irreversible neonatal renal dysfunction requiring invasive interventions.

Due to methodological limitations in postmarketing studies, including the absence of control groups and limited data on dosing and timing, establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use remains challenging. Consequently, the generalizability of reported risks to full-term infants exposed to NSAIDs through maternal use is uncertain.

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 greatest 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 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. If NSAID treatment is required between approximately 20 weeks and 30 weeks gestation, it is recommended to limit the use of 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 compensatory 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 the highest risk for these adverse reactions include those with impaired renal function, heart failure, liver dysfunction, individuals taking diuretics and ACE inhibitors, and the elderly. Therefore, it is crucial to exercise caution when considering NSAID therapy in this population.

Currently, there is no available information from controlled clinical studies regarding the use of Ibuprofen tablets in patients with advanced renal disease. Consequently, treatment with Ibuprofen tablets is not recommended for patients with advanced renal disease. If therapy with Ibuprofen tablets is deemed necessary, close monitoring of renal function is advised to mitigate potential risks. Discontinuation of NSAID therapy typically results in recovery to the pretreatment state, underscoring the importance of careful patient management.

Overdosage

In cases of ibuprofen overdosage, clinical manifestations can vary significantly based on the amount ingested and the time elapsed since ingestion.

Clinical Presentation A notable case involved a 19-month-old child who ingested between 7 to 10 ibuprofen tablets (400 mg each). Approximately 1½ hours post-ingestion, the child presented to the emergency department in an apneic and cyanotic state, 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. Despite stabilization after two hours, the child continued to exhibit periods of apnea lasting 5 to 10 seconds and was subsequently admitted to intensive care. Treatment included sodium bicarbonate, dextrose, and normal saline infusions. By four hours post-ingestion, the child was more responsive, able to sit independently, and follow verbal commands. Blood levels of ibuprofen measured 102.9 mcg/mL approximately 8½ hours after ingestion, and the child appeared fully recovered by the 12-hour mark.

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

Management of Overdosage For adults, a case was reported involving a 19-year-old male who ingested 8,000 mg of ibuprofen over several hours. He experienced dizziness and exhibited nystagmus. Following hospitalization, he received parenteral hydration and was placed on bed rest for three days, after which he recovered without any reported sequelae.

In the event of acute ibuprofen overdosage, it is recommended that the stomach be emptied through vomiting or gastric lavage, although recovery of the drug may be minimal 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 implemented, and the use of oral activated charcoal may assist in reducing both absorption and reabsorption of ibuprofen.

Healthcare professionals should remain vigilant for potential symptoms and manage cases of overdosage with appropriate interventions tailored to the severity of the clinical presentation.

Nonclinical Toxicology

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including Ibuprofen tablets, during pregnancy has been associated with several teratogenic effects. Specifically, administration around 30 weeks gestation or later increases the risk of premature closure of the fetal ductus arteriosus. Additionally, use of NSAIDs at approximately 20 weeks gestation or later has been linked to fetal renal dysfunction, which can lead to oligohydramnios and, in some instances, neonatal renal impairment. Observational studies regarding other potential embryofetal risks associated with NSAID use during the first or second trimesters have yielded inconclusive results.

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 published animal studies indicate that prostaglandin synthesis inhibitors can impair kidney development when administered at clinically relevant doses.

Oligohydramnios, a condition that may arise from NSAID use, is often reversible upon discontinuation of treatment; however, complications from prolonged oligohydramnios can include limb contractures and delayed lung maturation. In certain postmarketing cases of impaired neonatal renal function, invasive interventions such as exchange transfusion or dialysis have been necessary.

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. Nonetheless, it is important to note that animal reproduction studies do not always predict human responses.

Postmarketing Experience

During postmarketing surveillance of ibuprofen, several adverse reactions have been reported voluntarily. Notable skin and appendage reactions include exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

Reactions occurring in 3% to 9% of patients treated with ibuprofen tablets have been documented. Adverse reactions are classified under "Probable Causal Relationship (PCR)" if there has been one positive rechallenge or if three or more cases occur that may be causally related. Conversely, reactions are classified as having a "Causal Relationship Unknown" if seven or more events have been reported without meeting the criteria for PCR.

Patient Counseling

Patients should be informed of essential information before initiating therapy with an NSAID, such as Ibuprofen tablets, and periodically throughout the course of treatment. 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, including chest pain, shortness of breath, weakness, or slurring of speech, and 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. Although serious gastrointestinal tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for signs and symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of seeking medical advice upon observing 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 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 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 symptoms occur, patients should be instructed to stop therapy and seek immediate medical attention.

Patients should also be made aware 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 informed to avoid the use of Ibuprofen tablets and other NSAIDs starting at 30 weeks gestation for the same reason. If treatment with Ibuprofen tablets is necessary for a pregnant woman between approximately 20 to 30 weeks gestation, she should be advised 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 Westminster Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)