Ibuprofen

Description

Ibuprofen tablets 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 very slightly soluble in water, with a solubility of less than 1 mg/mL, but is readily soluble in organic solvents such as ethanol and acetone. The structural formula of ibuprofen is provided below.

These tablets are classified as a nonsteroidal anti-inflammatory drug (NSAID) and are available in dosages of 400 mg, 600 mg, and 800 mg for oral administration. The formulation includes several inactive ingredients: silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, polyethylene glycols, polyvinyl alcohol, pregelatinized starch, 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 of ibuprofen tablets should be utilized for the shortest duration consistent with individual patient treatment goals. After assessing the response to initial therapy, healthcare professionals should adjust the dose and frequency to meet the specific needs of each patient.

The total daily dose must not exceed 3200 mg. In cases where gastrointestinal complaints arise, it is advisable 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 300 mg four times a day (qid) or as 400 mg, 600 mg, or 800 mg three to four times a day (tid or qid). It is important to tailor the dose to each patient, with adjustments made based on the severity of symptoms. Generally, patients with rheumatoid arthritis may require higher doses compared to those with osteoarthritis.

For mild to moderate pain, a dosage of 400 mg may be given every 4 to 6 hours as needed for pain relief. In the case of dysmenorrhea, a dosage of 400 mg every 4 hours may be administered as necessary for pain relief. The smallest effective dose that provides acceptable control should always be employed.

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 reported in these patients. Furthermore, ibuprofen tablets are contraindicated in the context of coronary artery bypass graft (CABG) surgery.

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 important to note that ibuprofen tablets are contraindicated in patients undergoing coronary artery bypass graft (CABG) surgery.

In addition to cardiovascular risks, NSAIDs pose a significant threat of serious gastrointestinal adverse 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 arise without warning symptoms. Elderly patients are particularly vulnerable to these serious gastrointestinal events.

Ibuprofen tablets are not intended to replace corticosteroids or to address corticosteroid insufficiency. Abrupt cessation of corticosteroids can lead to exacerbation of the underlying disease. Therefore, patients receiving prolonged corticosteroid therapy should have their medication tapered gradually if discontinuation is deemed necessary.

The pharmacological effects of ibuprofen in alleviating fever and inflammation may obscure diagnostic signs that are critical for identifying complications in presumed noninfectious, painful conditions.

Healthcare professionals should monitor patients for signs or symptoms indicative of gastrointestinal bleeding. For those on long-term NSAID therapy, it is advisable to periodically assess complete blood count (CBC) and chemistry profiles. Should any clinical signs or symptoms suggestive of liver or renal disease arise, or if systemic manifestations such as eosinophilia or rash occur, or if abnormal liver tests persist or worsen, ibuprofen tablets should be discontinued.

In cases of an anaphylactoid reaction, immediate emergency medical assistance should be sought. Patients should be educated on the signs and symptoms of serious skin reactions and instructed to discontinue ibuprofen tablets at the first indication of a skin rash or any other signs of hypersensitivity. If symptoms consistent with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) are observed, ibuprofen tablets should be discontinued, and the patient should be evaluated without delay.

Side Effects

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

Serious adverse reactions include cardiovascular thrombotic events, such as myocardial infarction and stroke, which can be fatal. The risk of these events may arise early in treatment and is known 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, particularly in elderly patients who are at greater risk.

Gastrointestinal 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 manifest as dizziness, headache, nervousness, depression, insomnia, confusion, emotional liability, somnolence, and in rare cases, aseptic meningitis with fever and coma. Other neurological effects include paresthesias, hallucinations, dream abnormalities, and pseudo-tumor cerebri.

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

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

Hematologic reactions may include neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (sometimes Coombs positive), thrombocytopenia with or without purpura, eosinophilia, and decreases in hemoglobin and hematocrit. Patients may also experience bleeding episodes such as epistaxis and menorrhagia.

Metabolic and endocrine reactions can present as decreased appetite, gynecomastia, hypoglycemic reactions, and acidosis.

Cardiovascular reactions may 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 (sinus tachycardia and sinus bradycardia).

Allergic reactions can manifest 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 may include acute renal failure, decreased creatinine clearance, polyuria, azotemia, cystitis, hematuria, and renal papillary necrosis.

Miscellaneous reactions reported include dry eyes and mouth, gingival ulcer, and rhinitis.

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

Drug Interactions

Concomitant use of certain medications with ibuprofen may lead to significant drug interactions, which can affect therapeutic outcomes and safety. The following interactions have been identified:

Pharmacodynamic Interactions

• ACE-Inhibitors: Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, may reduce the antihypertensive effect of ACE-inhibitors. Clinicians should monitor blood pressure in patients receiving both medications.

• Aspirin:

  • Ibuprofen may interfere with the antiplatelet activity of aspirin, particularly when ibuprofen is administered shortly before aspirin. This interaction is more pronounced with enteric-coated low-dose aspirin. To mitigate this risk, it is advisable to administer immediate-release low-dose aspirin at least 2 hours prior to ibuprofen.

  • Due to the potential for increased cardiovascular events, patients taking low-dose aspirin for cardioprotection who require analgesics should consider alternative NSAIDs that do not affect aspirin's antiplatelet effect or non-NSAID analgesics when appropriate.

  • Co-administration of ibuprofen with aspirin may reduce the protein binding of ibuprofen, although it does not alter the clearance of free ibuprofen. The clinical significance of this interaction remains unclear, but concomitant use is generally not recommended due to the risk of increased adverse effects.

• Diuretics: Ibuprofen may diminish the natriuretic effect of diuretics such as furosemide and thiazides, 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 therapy.

• Warfarin-type Anticoagulants: While short-term studies have not shown significant effects on prothrombin times or clotting factors, caution is warranted when administering ibuprofen to patients on coumarin-type anticoagulants. The combination may increase the risk of gastrointestinal bleeding, which is synergistic in nature.

Pharmacokinetic Interactions

• Lithium: Ibuprofen has been shown to elevate plasma lithium levels and decrease renal clearance of lithium. Specifically, a study indicated a 15% increase in mean minimum lithium concentration and a 19% reduction in renal clearance during concurrent administration. Patients should be monitored for signs of lithium toxicity when these drugs are used together.

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

• H-2 Antagonists: Co-administration of ibuprofen with H-2 antagonists such as cimetidine or ranitidine does not appear to significantly affect ibuprofen serum concentrations, indicating no major pharmacokinetic interaction.

In summary, careful consideration and monitoring are recommended when ibuprofen is used in conjunction with these medications to mitigate potential adverse effects and ensure therapeutic efficacy.

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 (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 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 result in serious fetal complications. Additionally, NSAID use during this period has been linked to fetal renal dysfunction, leading to 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. If treatment extends beyond 48 hours, monitoring with ultrasound for oligohydramnios is recommended. Should oligohydramnios occur, ibuprofen tablets should be discontinued, and follow-up should be conducted according to clinical practice guidelines.

Data from observational studies regarding the potential embryofetal risks of NSAID use in the first or second trimesters are inconclusive. While reproductive studies in rats and rabbits have not shown evidence of developmental abnormalities, animal studies are not always predictive of human outcomes. Furthermore, prostaglandins play a crucial role in endometrial vascular permeability, blastocyst implantation, and fetal kidney development. Animal studies have indicated that the administration of prostaglandin synthesis inhibitors, such as ibuprofen, can impair kidney development and increase pre- and post-implantation loss.

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 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.

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

Due to methodological limitations in postmarketing studies, including the lack of control groups and limited information on dosing and timing, establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use remains challenging. The generalizability of reported risks to full-term infants exposed to NSAIDs through maternal use is also 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 breastfeeding 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 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 can occur after days to weeks of treatment, although oligohydramnios has been infrequently reported as early as 48 hours after initiation. If NSAID treatment is required between approximately 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. 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 overt 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 the initiation of ibuprofen tablet therapy 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. Two hours after ingestion, the child's condition stabilized, although she continued to respond solely to painful stimuli and experienced intermittent apnea lasting 5 to 10 seconds. Following admission to intensive care, sodium bicarbonate, along with dextrose and normal saline infusions, were administered. By four hours post-ingestion, the child was more alert, able to sit independently, and responsive to verbal commands. A blood level of ibuprofen measured 102.9 µg/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 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 µg/mL 90 minutes post-ingestion, which is approximately ten times the peak levels noted in absorption-excretion studies.

A separate case involved a 19-year-old male who ingested 8,000 mg of ibuprofen over several hours. He reported dizziness, and nystagmus was observed. After hospitalization, he received parenteral hydration and underwent three days of bed rest, ultimately recovering without any reported sequelae.

Management Recommendations

In instances 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 prioritized, and the use of oral activated charcoal may assist in reducing both absorption and reabsorption of ibuprofen tablets.

Healthcare professionals should remain vigilant for potential symptoms and manage accordingly, ensuring that supportive care is provided throughout the treatment process.

Nonclinical Toxicology

No teratogenic or non-teratogenic effects have been reported in the available nonclinical studies. Additionally, there is no information regarding animal pharmacology and toxicology. The absence of data in these areas limits the understanding of the compound's potential effects in nonclinical settings.

Postmarketing Experience

Postmarketing experience has identified the following adverse reactions reported voluntarily or through surveillance programs: gastrointestinal bleeding, renal impairment, and hypersensitivity reactions. The hypersensitivity reactions include cases of anaphylaxis and angioedema.

Patient Counseling

Patients should be advised to take ibuprofen with food or milk to minimize gastrointestinal irritation. It is important for patients to be informed about the potential for gastrointestinal bleeding, particularly if they have a history of ulcers or gastrointestinal bleeding. Healthcare providers should instruct patients to avoid alcohol while taking ibuprofen, as it may increase the risk of stomach bleeding.

Patients should be advised to consult their healthcare provider if they experience any signs of allergic reactions, such as rash, itching, or difficulty breathing. Additionally, they should be informed to seek medical attention if they experience symptoms of liver problems, including yellowing of the skin or eyes, dark urine, or persistent nausea.

Healthcare providers should counsel patients to keep ibuprofen out of reach of children and to seek immediate medical attention in the event of an overdose. It is also essential for patients to be instructed to inform their healthcare provider of all medications they are taking, including over-the-counter drugs and supplements, to avoid potential drug interactions.

Finally, patients should be counseled on the importance of adhering to the prescribed dosage and not exceeding the recommended dose.

Storage and Handling

The product is supplied in well-closed containers to ensure integrity and stability. It should be stored at a temperature range of 20 ° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the quality 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 ibuprofen. For patients undergoing long-term treatment with nonsteroidal anti-inflammatory drugs (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, ibuprofen tablets should be discontinued. Additionally, if abnormal liver tests persist or worsen, immediate cessation of the medication is advised.

FDA Insert (PDF)

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

View full prescribing information (PDF)