Ibuprofen

Uses and Indications

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

In pediatric patients, ibuprofen oral suspension is indicated for the reduction of fever in patients aged 6 months up to 2 years of age, for relief of mild to moderate pain in the same age group, and for relief of signs and symptoms of juvenile arthritis. In adults, ibuprofen oral suspension is indicated for the treatment of primary dysmenorrhea and for the relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Controlled clinical trials to establish the safety and effectiveness of ibuprofen tablets in children have not been conducted.

Dosage and Administration

The recommended dosage of ibuprofen tablets for adults varies based on the condition being treated. For rheumatoid arthritis and osteoarthritis, including flare-ups of chronic disease, the suggested dosage is 1200 mg to 3200 mg daily, administered as follows: 300 mg four times a day (qid), or 400 mg, 600 mg, or 800 mg three times a day (tid) or four times a day (qid). The total daily dose should not exceed 3200 mg. It is important to tailor the dose to each patient, adjusting based on the severity of symptoms and individual response to therapy. Generally, patients with rheumatoid arthritis may require higher doses than those with osteoarthritis.

For mild to moderate pain, the recommended dosage is 400 mg every 4 to 6 hours as necessary for pain relief. In controlled clinical trials, doses greater than 400 mg were not shown to be more effective than this dose. For the treatment of dysmenorrhea, ibuprofen should be administered at a dose of 400 mg every 4 hours as necessary, starting at the earliest onset of pain.

If gastrointestinal complaints occur, ibuprofen tablets should be taken with meals or milk to minimize discomfort. After observing the response to initial therapy, the dose and frequency should be adjusted to suit the individual patient's needs. A therapeutic response is often seen within a few days to a week, but most commonly by two weeks. After achieving a satisfactory response, the patient's dose should be reviewed and adjusted as required. The smallest effective dose should be used for the shortest duration consistent with individual patient treatment goals.

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 after taking aspirin or other NSAIDs, as severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Additionally, ibuprofen tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery, including for the treatment of peri-operative pain associated with this procedure.

Warnings and Precautions

Cardiovascular Effects Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are associated with an increased risk of serious cardiovascular thrombotic events, such as myocardial infarction (MI) and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. Patients with known cardiovascular disease or risk factors may be at greater risk. The lowest effective dose should be used for the shortest duration possible. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Avoid use in patients with a recent MI unless the benefits outweigh the risks; monitor for signs of cardiac ischemia.

Gastrointestinal Effects NSAIDs can cause serious gastrointestinal (GI) adverse events, including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and those with a prior history of peptic ulcer disease or GI bleeding are at greater risk. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate evaluation and treatment if a serious GI event is suspected.

Renal Effects Long-term administration of NSAIDs has resulted in renal injury, including renal papillary necrosis. Patients at greatest risk include those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Close monitoring of renal function is advisable, especially in patients with advanced renal disease.

Anaphylactoid Reactions Anaphylactoid reactions may occur in patients without known prior exposure to ibuprofen. Emergency help should be sought in cases of such reactions.

Skin Reactions Serious skin adverse events, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), can occur without warning. Discontinue use at the first appearance of skin rash or any other sign of hypersensitivity.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) DRESS has been reported in patients taking NSAIDs, including ibuprofen. If signs or symptoms of DRESS are present, discontinue ibuprofen and evaluate the patient immediately.

Fetal Toxicity Avoid use of NSAIDs, including ibuprofen, in pregnant women at about 30 weeks gestation and later due to the risk of premature closure of the fetal ductus arteriosus. Use of NSAIDs at about 20 weeks gestation or later may cause fetal renal dysfunction leading to oligohydramnios; discontinue if oligohydramnios occurs.

General Precautions Ibuprofen cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of ibuprofen in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Laboratory Tests Physicians should monitor for signs or symptoms of GI bleeding in patients on long-term treatment with NSAIDs. Patients on long-term treatment should have their CBC and chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, ibuprofen should be discontinued.

Get Emergency Medical Help Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Stop Taking and Call Your Doctor Patients should discontinue ibuprofen at the first appearance of skin rash or any other sign of hypersensitivity. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ibuprofen should be discontinued.

Side Effects

Patients using ibuprofen may experience a range of adverse reactions, which can be categorized by incidence and seriousness.

Common Adverse Reactions (Incidence Greater than 1% but less than 3%)

• Gastrointestinal: Nausea, epigastric pain, heartburn, diarrhea, abdominal distress, nausea and vomiting, indigestion, constipation, abdominal cramps or pain, fullness of the GI tract (bloating and flatulence).

• Central Nervous System: Dizziness, headache, nervousness.

• Dermatologic: Rash (including maculopapular type), pruritus.

• Special Senses: Tinnitus.

• Metabolic/Endocrine: Decreased appetite.

• Cardiovascular: Edema, fluid retention (generally responds promptly to drug discontinuation).

Serious Adverse Reactions (Precise Incidence Unknown but less than 1%)

• Gastrointestinal: Gastric or duodenal ulcer with bleeding and/or perforation, gastrointestinal hemorrhage, melena, gastritis, hepatitis, jaundice, abnormal liver function tests, pancreatitis.

• Central Nervous System: Depression, insomnia, confusion, emotional lability, somnolence, aseptic meningitis with fever and coma.

• Dermatologic: Vesiculobullous eruptions, urticaria, erythema multiforme, Stevens-Johnson syndrome, alopecia, toxic epidermal necrolysis, photoallergic skin reactions.

• Hematologic: Neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (sometimes Coombs positive), thrombocytopenia with or without purpura, eosinophilia, decreases in hemoglobin and hematocrit.

• Cardiovascular: Congestive heart failure in patients with marginal cardiac function, elevated blood pressure, palpitations, arrhythmias (sinus tachycardia, sinus bradycardia).

• Renal: Acute renal failure, decreased creatinine clearance, polyuria, azotemia, cystitis, hematuria, renal papillary necrosis.

• Allergic: Anaphylaxis, bronchospasm, syndrome of abdominal pain, fever, chills, nausea, and vomiting.

Additional Adverse Reactions (Causal Relationship Unknown)

• Central Nervous System: Paresthesias, hallucinations, dream abnormalities, pseudotumor cerebri.

• Special Senses: Hearing loss, amblyopia (blurred and/or diminished vision, scotomata and/or changes in color vision), conjunctivitis, diplopia, optic neuritis, cataracts.

• Hematologic: Bleeding episodes (e.g., epistaxis, menorrhagia).

• Metabolic/Endocrine: Gynecomastia, hypoglycemic reaction, acidosis.

• Miscellaneous: Dry eyes and mouth, gingival ulcer, rhinitis.

Boxed Warnings

• Cardiovascular Risk: NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may increase with duration of use, particularly in patients with cardiovascular disease or risk factors.

• Gastrointestinal Risk: NSAIDs can lead to serious gastrointestinal adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.

Postmarketing Experience

• Reports of serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE), have been noted.

Patients should be monitored for these adverse reactions, and ibuprofen should be discontinued if serious side effects occur.

Drug Interactions

Patients taking ibuprofen should be aware of several significant drug interactions that may affect their treatment outcomes.

Pharmacokinetic Interactions

• ACE-Inhibitors: Ibuprofen may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be considered in patients using both medications concurrently, as it may lead to inadequate blood pressure control.

• Aspirin: When ibuprofen is administered with aspirin, its protein binding is reduced, although the clearance of free ibuprofen remains unchanged. This interaction can interfere with the antiplatelet activity of aspirin, particularly when ibuprofen is taken before aspirin. The clinical significance of this interaction is not fully understood, but it is generally recommended to avoid concomitant use due to the potential for increased adverse effects. For patients taking low-dose aspirin for cardiovascular protection, alternative analgesics that do not interfere with aspirin's effects should be considered.

• Diuretics: Ibuprofen can reduce the natriuretic effect of diuretics such as furosemide and thiazides. This effect is attributed to the inhibition of renal prostaglandin synthesis, which may lead to decreased diuretic efficacy. Patients should be monitored closely for signs of renal failure during concurrent therapy.

• Lithium: Ibuprofen can elevate plasma lithium levels and reduce renal clearance of lithium, increasing the risk of lithium toxicity. Careful monitoring is advised when these medications are used together.

• Methotrexate: Ibuprofen may enhance the toxicity of methotrexate by competitively inhibiting its accumulation in the kidneys. Caution is warranted when these drugs are administered concurrently.

• Warfarin-Type Anticoagulants: While short-term studies have not shown significant effects on prothrombin times or other clotting factors, caution is advised when administering ibuprofen to patients on warfarin-type anticoagulants. The combination may increase the risk of serious gastrointestinal bleeding due to synergistic effects.

• H-2 Antagonists: Co-administration of cimetidine or ranitidine with ibuprofen does not significantly affect ibuprofen serum concentrations, indicating that these medications can be used together without concern for altered ibuprofen levels.

Pharmacodynamic Interactions

• Asthma: Patients with aspirin-sensitive asthma should avoid ibuprofen, as it may provoke severe bronchospasm. Caution is also advised in patients with preexisting asthma.

• Visual Disturbances: Blurred vision, scotomata, and changes in color vision have been reported with ibuprofen use. If such symptoms occur, discontinuation of the drug and an ophthalmologic examination are recommended.

In summary, careful consideration and monitoring are essential when ibuprofen is used in conjunction with other medications, particularly those affecting blood pressure, renal function, and hemostasis.

Pediatric Use

The safety and effectiveness of ibuprofen tablets in pediatric patients have not been established. No specific pediatric use information, recommended ages, dosing differences, safety concerns, or special precautions for children are provided for ibuprofen tablets.

For ibuprofen oral suspension, safety and effectiveness have not been established in pediatric patients below the age of 6 months. Dosing in children 6 months or older should be guided by their body weight.

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

Geriatric Use

Elderly patients (65 years and older) may experience increased sensitivity to the side effects of ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID). Caution is advised when prescribing ibuprofen to this population due to a higher risk of serious cardiovascular, gastrointestinal, and renal adverse reactions.

When initiating treatment, it is recommended to start at the low end of the dosing range, reflecting the potential for decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Monitoring for adverse effects is essential, particularly for gastrointestinal complications, which are more prevalent in geriatric patients.

Clinical studies have not included sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Therefore, dosage adjustments may be necessary based on individual patient assessments, particularly considering the potential for reduced kidney function in elderly patients.

Pregnancy

Use of NSAIDs, including ibuprofen tablets, is generally not recommended during pregnancy, particularly in the third trimester. The use of ibuprofen can lead to significant fetal risks, including premature closure of the fetal ductus arteriosus and fetal renal dysfunction, which may result in oligohydramnios and, in some cases, neonatal renal impairment.

Pregnant patients should be advised to avoid ibuprofen and other NSAIDs starting at approximately 30 weeks of gestation due to the increased risk of premature closure of the ductus arteriosus. If treatment with ibuprofen is deemed necessary between about 20 and 30 weeks of gestation, it is crucial to limit the use to the lowest effective dose and the shortest duration possible. Monitoring for oligohydramnios with ultrasound is recommended if ibuprofen treatment extends beyond 48 hours. Should oligohydramnios occur, ibuprofen should be discontinued, and appropriate follow-up should be conducted according to clinical practice.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is approximately 2% to 4% and 15% to 20%, respectively. While animal studies have not demonstrated evidence of developmental abnormalities, they are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women, and ibuprofen should only be used if the potential benefit justifies the potential risk to the fetus.

Data from observational studies regarding other potential embryofetal risks of NSAID use during the first or second trimesters are inconclusive. Prostaglandins play a critical role in fetal kidney development, and the administration of prostaglandin synthesis inhibitors like ibuprofen has been associated with increased pre- and post-implantation loss in animal studies.

In summary, the use of ibuprofen during pregnancy should be approached with caution, and healthcare providers should be consulted to evaluate the risks and benefits before prescribing this medication to pregnant patients.

Lactation

It is not known whether ibuprofen is excreted in human milk. Given that many drugs can be present in breast milk and the potential for serious adverse reactions in breastfed infants, healthcare providers should carefully consider the risks and benefits when prescribing ibuprofen to lactating mothers. A decision should be made regarding whether to discontinue breastfeeding or to discontinue the medication, taking into account the importance of ibuprofen to the mother's health.

Limited published literature indicates that, following oral administration, ibuprofen may be present in human milk at relative infant doses ranging from 0.06% to 0.6% of the maternal weight-adjusted daily dose. However, there are no reports of adverse effects on breastfed infants or impacts on milk production associated with ibuprofen use.

Healthcare providers should weigh the developmental and health benefits of breastfeeding against the mother's clinical need for ibuprofen and any potential adverse effects on the breastfed infant.

Renal Impairment

Long-term administration of nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, has been associated with renal papillary necrosis and other forms of renal injury. Renal toxicity may occur particularly in patients where renal prostaglandins play a compensatory role in maintaining renal perfusion. In such cases, the use of NSAIDs can lead to a dose-dependent reduction in prostaglandin formation and, consequently, a decrease in renal blood flow, which may precipitate overt renal decompensation.

Patients with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly are at the highest risk for these adverse reactions. 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 in patients with advanced renal disease; therefore, treatment with ibuprofen is not recommended for these patients. If ibuprofen therapy must be initiated in patients with renal impairment, close monitoring of renal function is essential.

Additionally, caution is advised when administering ibuprofen to patients with decreased creatinine clearance, and dosage adjustments may be necessary. Regular renal function tests should be conducted to ensure patient safety.

In pregnant patients, particularly between 20 and 30 weeks of gestation, the use of ibuprofen 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 reported as early as 48 hours after initiation. If ibuprofen treatment is necessary during this period, it should be limited to the lowest effective dose and shortest duration possible, with ultrasound monitoring of amniotic fluid recommended if treatment extends beyond 48 hours. Discontinuation of ibuprofen should occur if oligohydramnios is detected, with appropriate follow-up according to clinical practice.

Hepatic Impairment

Patients with hepatic impairment may experience altered drug metabolism and clearance when using ibuprofen. Caution is advised when administering ibuprofen to these patients, as they may be at increased risk for adverse effects.

Monitoring of liver function tests is recommended periodically for patients with liver dysfunction. Dosage adjustments may be necessary based on the severity of liver impairment. In cases of significant deterioration in liver function tests, ibuprofen should be discontinued.

Additionally, patients should be informed of the warning signs and symptoms of hepatotoxicity, such as nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms. If any of these symptoms occur, patients should be instructed to stop therapy and seek immediate medical attention.

There is no specific information regarding dosage adjustments or special monitoring requirements for patients with mild to moderate hepatic impairment, but the use of ibuprofen is generally approached with caution in this population. Avoidance of ibuprofen in patients with severe hepatic impairment is recommended due to the potential for increased adverse effects.

Overdosage

Approximately 1½ hours after the ingestion of 7 to 10 ibuprofen tablets (400 mg), a 19-month-old child weighing 12 kg presented to the emergency room in an apneic and cyanotic state, responding only to painful stimuli, which was sufficient to induce respiration. The child received oxygen and parenteral fluids, and a greenish-yellow fluid was aspirated from the stomach, with no evidence of ibuprofen detected. Two hours post-ingestion, the child's condition stabilized, although she continued to respond only to painful stimuli and experienced periods of apnea lasting 5 to 10 seconds. She was admitted to intensive care, where sodium bicarbonate, dextrose, and normal saline infusions were administered. By four hours post-ingestion, she could be easily aroused, sit independently, and respond to verbal commands. The blood level of ibuprofen was measured at 102.9 mcg/mL approximately 8½ hours after ingestion, and by 12 hours, she appeared to have fully recovered.

In two additional cases involving children weighing approximately 10 kg who ingested about 120 mg/kg of ibuprofen, there were no signs of acute intoxication or late sequelae. One child's blood level was recorded at 700 mcg/mL 90 minutes after ingestion, which is about ten times the peak levels observed in absorption-excretion studies. A 19-year-old male who ingested 8,000 mg of ibuprofen over a few hours reported dizziness and exhibited nystagmus. After hospitalization, he received parenteral hydration and three days of bed rest, ultimately recovering without any reported sequelae.

In cases of acute ibuprofen overdosage, the stomach should be emptied by vomiting or gastric lavage within one hour of ingestion, as little drug will likely be recovered after this time. Given the acidic nature of ibuprofen and its urinary excretion, administering alkali and inducing diuresis may be beneficial. Supportive measures are essential, and the use of oral activated charcoal may help reduce the absorption and reabsorption of ibuprofen tablets. Monitoring for signs of toxicity is crucial, and appropriate care should be provided based on the clinical presentation.

Nonclinical Toxicology

Teratogenic Effects

The use of nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, during pregnancy, particularly at approximately 20 weeks of gestation or later, has been associated with an increased risk of fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Additionally, the use of NSAIDs at around 30 weeks of gestation or later may increase the risk of premature closure of the fetal ductus arteriosus. Data from observational studies regarding other potential embryofetal risks of NSAID use in women during the first or second trimesters of pregnancy are inconclusive.

Animal reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities; however, these studies are not always predictive of human response. Based on animal data, prostaglandins play a crucial role in fetal kidney development, and the administration of prostaglandin synthesis inhibitors such as ibuprofen has been shown to result in increased pre- and post-implantation loss.

Non-Teratogenic Effects

Oligohydramnios, which may occur as a result of fetal renal dysfunction, is often reversible with the discontinuation of treatment, although complications from prolonged oligohydramnios can include limb contractures and delayed lung maturation. In some postmarketing cases, impaired neonatal renal function has necessitated invasive procedures such as exchange transfusion or dialysis.

Nonclinical Toxicology Section

There are no adequate and well-controlled studies in pregnant women. Ibuprofen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Long-term administration of NSAIDs has been associated with renal papillary necrosis and other renal injuries. Renal toxicity has been observed in patients where renal prostaglandins have a compensatory role in maintaining renal perfusion. In these patients, NSAID administration may lead to a dose-dependent reduction in prostaglandin formation and, consequently, renal blood flow, potentially precipitating overt renal decompensation.

Patients at greatest risk for this reaction include those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.

Animal Pharmacology and Toxicology

In animal studies, the administration of prostaglandin synthesis inhibitors such as ibuprofen has resulted in increased pre- and post-implantation loss. Prostaglandins have also been shown to play an important role in fetal kidney development, with published studies indicating that prostaglandin synthesis inhibitors can impair kidney development when administered at clinically relevant doses. Additionally, in rat studies involving NSAIDs, there has been an increased incidence of dystocia, delayed parturition, and decreased pup survival. The effects of ibuprofen on labor and delivery in pregnant women remain unknown.

Storage and Handling

Ibuprofen is supplied in various forms, including tablets, film-coated tablets, and suspensions. The product should be stored at a controlled room temperature of 20° to 25°C (68° to 77°F), in accordance with USP guidelines. Excursions in temperature are permitted between 15° to 30°C (59° to 86°F) for certain formulations.

It is essential to avoid exposure to excessive heat, defined as temperatures above 40°C (104°F). All forms of ibuprofen should be preserved in well-closed, tight, and light-resistant containers as specified in the USP. For suspensions, it is recommended to shake well before use.

Proper storage conditions are crucial to maintain the integrity and efficacy of the product.