IBUPROFEN: 87,008 Adverse Event Reports & Safety Profile

CALDOLOR (ibuprofen injection) is a nonsteroidal anti-inflammatory drug, available as an 800 mg/8 mL single dose vial (100 mg/mL) and 800 mg/200 mL (4 mg/mL) polypropylene, single dose, ready-to-use, flexible bag for intravenous administration. The chemical name is ibuprofen, which is (±)-2-( p -isobutylphenyl) propionic acid. Ibuprofen is a white powder with a melting point of 74°C to 77°C. It has a molecular weight of 206.28. It is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. The structural formula of ibuprofen is represented below: Structural Formula of Ibuprofen CALDOLOR 800 mg/8 mL (100 mg/mL) vial: Each 1 mL of solution contains 100 mg of ibuprofen, USP, 78 mg of arginine (at a molar ratio of 0.92:1 arginine:ibuprofen), and 10% arginine solution and hydrochloric acid as pH adjusters in Water for Injection, USP. The solution pH is about 7.4. CALDOLOR 800 mg/200 mL (4 mg/mL) polypropylene flexible bag: Each 1 mL of solution contains 4 mg of ibuprofen, USP, 3.11 mg of dibasic sodium phosphate, as a buffering agent; 6.30 mg sodium chloride as a tonicity agent; and sodium hydroxide as a pH adjuster in Water for Injection, USP. The solution is iso-osmotic with an approximate pH of 7.4. CALDOLOR is sterile and is intended for intravenous administration only.

Uses temporarily relieves minor aches and pains due to: muscular aches, backache, toothache, menstrual cramps, headache, the common cold, minor pain of arthritis temporarily reduces fever Warnings Allergy alert: Ibuprofen may cause severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: facial swelling, blisters, hives, shock, skin reddening, asthmas (wheezing), rash If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you: take more or for a longer time than directed take a blood thinning (anticoagulant) or steroid drug are age 60 or older take other drugs containing prescription or nonprescription NSAIDs [aspirin, ibuprofen, naproxen, or others] have had stomach ulcers or bleeding problems have 3 or more alcoholic drinks every day while using this product Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or for longer than directed. Stop use and ask a doctor if you experience any of the following signs of stomach bleeding: feel faint, have bloody or black stools, vomit blood, have stomach pain that does not get better you have symptoms of heart problems or stroke: chest pain, slurred speech, leg swelling, trouble breathing, weakness in one part or side of body pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present in the painful area any new symptoms appear Do not use if you have ever had an allergic reaction to any other pain reliever/fever reducer right before or after heart surgery Ask a doctor before use if stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, kidney disease, asthma, or had a stroke you are taking a diuretic you have problems or serious side effects from taking pain relievers or fever reducers Ask a doctor or pharmacist before use if you are under a doctor's care for any serious condition taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin taking any other drug When using this product take with food or milk if stomach upset occurs If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen at 20 weeks or later in pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Directions do not take more than directed the smallest effective dose should be used adults and children 12 years and over: take 1 tablet every 4 to 6 hours while symptoms persist; if pain or fever dose not respond to 1 tablet, 2 tablets may be used; do not exceed 6 tablets in 24 hours, unless directed by a doctor children under 12 years: ask a doctor Other information do not use if packet is torn, cut, or opened Store between 20 ° -25 ° C (68 ° -77 ° F) avoid excessive heat above 40 ° C (104 ° F) Inactive ingredients carnauba wax, colloidal silicon dioxide, corn starch, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, red iron oxide, sodium starch glycolate, stearic acid, titanium dioxide, Questions? 1-877-973-2811 Monday-Friday 8:00am-5:00pm

AND ADMINISTRATION Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. ( 2.1 )

Caldolor

Injection vials must be diluted before administration. ( 2.1 )

Caldolor

Injection bags are ready to use. ( 2.1 )

Adult

Pain: 400 mg to 800 mg intravenously over 30 minutes every 6 hours as necessary. ( 2.2 )

Adult

Fever: 400 mg intravenously over 30 minutes, followed by 400 mg every 4 to 6 hours or 100-200 mg every 4 hours as necessary. ( 2.2 ) Pediatric (pain and fever) ages 12 to 17 years of age: 400 mg intravenously over 10 minutes every 4 to 6 hours as necessary. ( 2.3 ) Pediatric (pain and fever) aged 6 months to less than 12 years of age: 10 mg/kg intravenously over 10 minutes up to a maximum single dose of 400 mg every 4 to 6 hours as necessary. ( 2.3 ) Pediatric (pain and fever) aged 3 months to less than 6 months: 10 mg/kg intravenously over 10 minutes up to a maximum single dose of 100 mg. ( 2.3 )

2.1 Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ]. After observing the response to initial therapy with CALDOLOR, the dose and frequency should be adjusted to suit an individual patient&apos;s needs. Do not exceed 3200 mg total daily dose in adults. Do not exceed 40 mg/kg or 2,400 mg, whichever is less, total daily dose in pediatric patients 6 months to 17 years of age. The dosage is limited to a single dose not to exceed 10 mg/kg or 100 mg, whichever is less, in pediatric patients 3 months to less than 6 months of age. To reduce the risk of renal adverse reactions, patients must be well hydrated prior to administration of CALDOLOR. CALDOLOR injection 800 mg/8 mL (100 mg/mL) vials MUST BE DILUTED prior to administration. Dilute to a final concentration of 4 mg/mL or less. Appropriate diluents include 0.9% Sodium Chloride Injection USP (normal saline), 5% Dextrose Injection USP (D5W), or Lactated Ringers Solution. 100 mg dose: Dilute 1 mL of CALDOLOR in at least 100 mL of diluent 200 mg dose: Dilute 2 mL of CALDOLOR in at least 100 mL of diluent 400 mg dose: Dilute 4 mL of CALDOLOR in at least 100 mL of diluent 800 mg dose: Dilute 8 mL of CALDOLOR in at least 200 mL of diluent CALDOLOR injection 800 mg/200 mL (4 mg/mL) polypropylene flexible bags are ready to use, intended for 800 mg doses only. For weight-based dosing at 10 mg/kg ensure that the concentration of CALDOLOR is 4 mg/mL or less. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used. Diluted solutions are stable for up to 24 hours at ambient temperature (approximately 20° C to 25° C) and room lighting.

2.2 Adults For Analgesia (pain) : The dose is 400 mg to 800 mg intravenously every 6 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200 mg.

For

Fever : The dose is 400 mg intravenously, followed by 400 mg every 4 to 6 hours or 100 mg to 200 mg every 4 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200 mg.

2.3 Pediatric Patients For Analgesia (pain) and Fever: Ages 12 to 17 years The dose is 400 mg intravenously every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less.

Ages

6 months to less than 12 years The dose is 10 mg/kg intravenously up to a maximum single dose of 400 mg every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less.

Pediatric

Dosing as Necessary for Fever and Pain * Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less.

Age Group Dose Dosing Interval

Min infusion time Max daily dose 6 months to less than 12 years 10 mg/kg up to 400 mg max Every 4 to 6 hours as necessary 10 minutes *40 mg/kg or 2,400 mg 12 to 17 years 400 mg Every 4 to 6 hours as necessary 10 minutes *40 mg/kg or 2,400 mg Ages 3 months to less than 6 months The dose is a single dose at 10 mg/kg intravenously up to a maximum single dose of 100 mg. Infusion time must be at least 10 minutes.

CALDOLOR is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ibuprofen or any components of the drug product [ see Warnings and Precautions ( 5.7 , 5.9 ) ] History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [ see Warnings and Precautions ( 5.7 , 5.8 ) ] In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.1 ) ] Known hypersensitivity to ibuprofen or any component of the drug product ( 4 ) History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) In the setting of CABG surgery ( 4 )

REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions ( 5.1 )] GI Bleeding, Ulceration and Perforation [see Warnings and Precautions ( 5.2 )] Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] Hypertension [ see Warnings and Precautions ( 5.4 ) ]

Heart

Failure and Edema [ see Warnings and Precautions ( 5.5 ) ]

Renal

Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] Anaphylactic reactions [ see Warnings and Precautions ( 5.7 ) ]

Serious Skin

Reactions [ see Warnings and Precautions ( 5.9 ) ]

Hematologic

Toxicity [ see Warnings and Precautions ( 5.11 ) ] The most common adverse reactions are nausea, flatulence, vomiting, headache, hemorrhage and dizziness (>5%). The most common adverse reactions in pediatric patients are infusion site pain, vomiting, nausea, anemia and headache (≥2%). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Population

During clinical development, 560 patients were exposed to CALDOLOR, 438 in pain and 122 with fever. In the pain studies, CALDOLOR was started intra-operatively and administered at a dose of 400 mg or 800 mg every six hours for up to three days. In the fever studies, CALDOLOR was administered at doses of 100 mg, 200 mg, or 400 mg every four or six hours for up to 3 days. The most frequent type of adverse reaction occurring with oral ibuprofen is gastrointestinal.

Pain Studies

The incidence rates of adverse reactions listed in the following table were derived from multi-center, controlled clinical studies in post-operative patients comparing CALDOLOR to placebo in patients also receiving morphine as needed for post-operative pain.

Table

1: Post-operative Patients with Adverse Reactions Observed in ≥ 3% of Patients in any CALDOLOR Treatment Group in Pain Studies * * All patients received concomitant morphine during these studies. Event CALDOLOR Placebo (N=287) 400 mg (N=134) 800 mg (N=304)

Any Reaction

118 (88%) 260 (86%) 258 (90%)

Nausea

77 (57%) 161 (53%) 179 (62%)

Vomiting

30 (22%) 46 (15%) 50 (17%)

Flatulence

10 (7%) 49 (16%) 44 (15%)

Headache

12 (9%) 35 (12%) 31 (11%)

Hemorrhage

13 (10%) 13 (4%) 16 (6%)

Dizziness

8 (6%) 13 (4%) 5 (2%) Edema peripheral 1 (<1%) 9 (3%) 4 (1%) Urinary retention 7 (5%) 10 (3%) 10 (3%)

Anemia

5 (4%) 7 (2%) 6 (2%) Decreased hemoglobin 4 (3%) 6 (2%) 3 (1%)

Dyspepsia

6 (4%) 4 (1%) 2 (<1%) Wound hemorrhage 4 (3%) 4 (1%) 4 (1%) Abdominal discomfort 4 (3%) 2 (<1%) 0 Cough 4 (3%) 2 (<1%) 1 (<1%)

Hypokalemia

5 (4%) 3 (<1%) 8 (3%)

Fever Studies

Fever studies were conducted in febrile hospitalized patients with malaria and febrile hospitalized patients with varying causes of fever. In hospitalized febrile patients with malaria, the adverse reactions observed in at least two CALDOLOR-treated patients included abdominal pain and nasal congestion. In hospitalized febrile patients (all causes), adverse reactions observed in more than two patients in any given treatment group are presented in the table below.

Table

2: Patients with Adverse Reactions Observed in ≥ 3% of Patients in any CALDOLOR Treatment Group in All-Cause Fever Study Event CALDOLOR Placebo N=28 100 mg N=30 200 mg N=30 400 mg N=31 Any Reaction 27 (87%) 25 (83%) 23 (74%) 25 (89%)

Anemia

5 (17%) 6 (20%) 11 (36%) 4 (14%)

Eosinophilia

7 (23%) 7 (23%) 8 (26%) 7 (25%)

Hypokalemia

4 (13%) 4 (13%) 6 (19%) 5 (18%)

Hypoproteinemia

3 (10%) 0 4 (13%) 2 (7%)

Neutropenia

2 (7%) 2 (7%) 4 (13%) 2 (7%) Blood urea increased 0 0 3 (10%) 0 Hypernatremia 2 (7%) 0 3 (10%) 0 Hypertension 0 0 3 (10%) 0 Hypoalbuminemia 3 (10%) 1 (3%) 3 (10%) 1 (4%)

Hypotension

0 2 (7%) 3 (10%) 1 (4%)

Diarrhea

3 (10%) 3 (10%) 2 (7%) 2 (7%) Pneumonia bacterial 3 (10%) 1 (3%) 2 (7%) 0 Blood LDH increased 3 (10%) 2 (7%) 1 (3%) 1 (4%)

Thrombocythemia

3 (10%) 2 (7%) 1 (3%) 0 Bacteremia 4 (13%) 0 0 0 Pediatric Population A total of 143 pediatric patients ages 6 months and older have received CALDOLOR in controlled clinical trials. The most common adverse reactions (incidence greater than or equal to 2%) in pediatric patients treated with CALDOLOR were infusion site pain, vomiting, nausea, anemia and headache. Twenty-one hospitalized patients ages 3 months to less than 6 months were treated with CALDOLOR for pain or fever in an open-label, non-controlled clinical study; 18 of 21 patients were treated with a single dose.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ibuprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

5. Warnings and Precautions CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events [see WARNINGS].

Status Post Coronary Artery Bypass

Graft (CABG)

Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ibuprofen tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ibuprofen tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs including ibuprofen tablets can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ibuprofen tablets should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Heart

Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of Ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] [see DRUG INTERACTIONS]. Avoid the use of ibuprofen tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ibuprofen tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Gastrointestinal

Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including ibuprofen tablets 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 serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with a NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal

Disease No information is available 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 these patients with advanced renal disease. If ibuprofen tablets therapy must be initiated, close monitoring of the patients renal function is advisable.

Anaphylactoid

Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ibuprofen tablets. Ibuprofen tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see CONTRAINDICATIONS and PRECAUTIONS, PREEXISTING ASTHMA]. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin

Reactions NSAIDs, including ibuprofen tablets can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ibuprofen tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ibuprofen tablets and evaluate the patient immediately.

Fetal Toxicity Premature

Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including ibuprofen tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs including ibuprofen tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal

Renal Impairment: Use of NSAIDs, including ibuprofen tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ibuprofen tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ibuprofen tablets treatment extends beyond 48 hours. Discontinue ibuprofen tablets if oligohydramnios occurs and follow up according to clinical practice [see PRECAUTIONS, PREGNANCY].

General

Ibuprofen tablets 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 tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including ibuprofen tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ibuprofen tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ibuprofen tablets should be discontinued. Hematological effects Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ibuprofen tablets should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. In two postmarketing clinical studies the incidence of a decreased hemoglobin level was greater than previously reported. Decrease in hemoglobin of 1 gram or more was observed in 17.1% of 193 patients on 1600 mg ibuprofen daily (osteoarthritis), and in 22.8% of 189 patients taking 2400 mg of ibuprofen daily (rheumatoid arthritis). Positive stool occult blood tests and elevated serum creatinine levels were also observed in these studies. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ibuprofen tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants should be carefully monitored. Preexisting asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and NSAIDs has been reported in such aspirin-sensitive patients, ibuprofen tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Ophthalmological effects Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a patient develops such complaints while receiving ibuprofen tablets, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing.

Aseptic Meningitis

Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on ibuprofen tablets, the possibility of its being related to ibuprofen tablets should be considered. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

Cardiovascular Thrombotic Events

Advise patients to be alert for the 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 health care provider immediately [see WARNINGS]. Ibuprofen tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up [see WARNINGS, GASTROINTESTINAL EFFECTS-RISK OF ULCERATION, BLEEDING AND PERFORATION].

Serious Skin

Reactions, including DRESS Advise patients to stop taking ibuprofen tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see WARNINGS]. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

Heart Failure And Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see WARNINGS]. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., 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 therapy. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see WARNINGS].

Fetal Toxicity

Inform pregnant women to avoid use of ibuprofen tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with ibuprofen tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS, FETAL TOXICITY and PRECAUTIONS, PREGNANCY].

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash etc.), or abnormal liver tests persist or worsen, ibuprofen tablets should be discontinued.

Drug

Interactions ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Aspirin

Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric-coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once-daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see CLINICAL PHARMACOLOGY, Pharmacodynamics]. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate. When ibuprofen tablets are administered with aspirin, its protein binding is reduced, although the clearance of free ibuprofen tablets is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential for increased adverse effects.

Diuretics

Clinical studies, as well as post marketing observations, have shown that ibuprofen tablets can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure [see WARNINGS, RENAL EFFECTS], as well as to assure diuretic efficacy.

Lithium

Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of eleven normal volunteers. The mean minimum lithium concentration increased 15% and the renal clearance of lithium was decreased by 19% during this period of concomitant drug administration. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. (Read circulars for lithium preparation before use of such concurrent therapy.) Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin-type anticoagulants Several short-term controlled studies failed to show that ibuprofen tablets significantly affected prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. However, because bleeding has been reported when ibuprofen tablets and other NSAIDs have been administered to patients on coumarin-type anticoagulants, the physician should be cautious when administering ibuprofen tablets to patients on anticoagulants. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. H-2 Antagonists In studies with human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.

Pregnancy Risk Summary

Use of NSAIDs, including ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ibuprofen tablets use between about 20 and 30 weeks of gestation, and avoid ibuprofen tablets use at about 30 weeks of gestation and later in pregnancy [see WARNINGS, FETAL TOXICITY].

Premature

Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ibuprofen tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus [see WARNINGS, FETAL TOXICITY].

Oligohydramnios/Neonatal

Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If ibuprofen tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue ibuprofen tablets and follow up according to clinical practice [see WARNINGS, FETAL TOXICITY].

Data Human Data

There are no adequate, well-controlled studies in pregnant women. Ibuprofen tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Premature

Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of ibuprofen tablets on labor and delivery in pregnant women are unknown.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ibuprofen tablets, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of ibuprofen tablets in pediatric patients have not been established.

Geriatric

Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

PRECAUTIONS General Ibuprofen tablets 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 tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including Ibuprofen tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/ or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Ibuprofen tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, reaction, etc.), Ibuprofen tablets should be discontinued. Hematological effects Anemia is sometimes seen in patients receiving NSAIDs, including Ibuprofen tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Ibuprofen tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. In two postmarketing clinical studies the incidence of a decreased hemoglobin level was greater than previously reported. Decrease in hemoglobin of 1 gram or more was observed in 17.1% of 193 patients on 1600 mg ibuprofen daily (osteoarthritis), and in 22.8% of 189 patients taking 2400 mg of ibuprofen daily (rheumatoid arthritis). Positive stool occult blood tests and elevated serum creatinine levels were also observed in these studies. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Ibuprofen tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants should be carefully monitored. Preexisting asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and NSAIDs has been reported in such aspirin-sensitive patients, Ibuprofen tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Ophthalmological effects Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a patient develops such complaints while receiving Ibuprofen tablets, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing.

Aseptic Meningitis

Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on Ibuprofen tablets, the possibility of its being related to Ibuprofen tablets should be considered. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

• CARDIOVASCULAR THROMBOTIC EVENTS Advise patients to be alert for the 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 health care provider immediately [see Error! Hyperlink reference not valid. ].
• Ibuprofen tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up [see Error! Hyperlink reference not valid. ].
• Ibuprofen tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin Reaction and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to stop the drug immediately if they develop any type of reaction and contact their physicians as soon as possible.
• Serious Skin Reactions, including DRESS: Advise patients to stop taking Ibuprofen tablets immediately if they develop any type of reaction or fever and to contact their healthcare provider as soon as possible [see Error! Hyperlink reference not valid. ].
• Heart failure and Edema: Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Error! Hyperlink reference not valid. ].
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., 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 therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see Error! Hyperlink reference not valid. ].
• In late pregnancy, as with other NSAIDs, Ibuprofen tablets should be avoided because it may cause premature closure of the ductus arteriosus.

Fetal Toxicity

Inform pregnant women to avoid use of Ibuprofen tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with Ibuprofen tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ].

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, reaction etc.), or abnormal liver tests persist or worsen, Ibuprofen tablets should be discontinued.

Drug

Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Aspirin

Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric-coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once-daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Error! Hyperlink reference not valid. ]. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardio protection who require analgesics, consider use of a NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate.

When

Ibuprofen tablets are administered with aspirin, its protein binding is reduced, although the clearance of free Ibuprofen tablets is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential for increased adverse effects.

Diuretics

Clinical studies, as well as post marketing observations, have shown that Ibuprofen tablets can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure [see PRECAUTIONS, Renal Effects ], as well as to assure diuretic efficacy.

Lithium

Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of eleven normal volunteers. The mean minimum lithium concentration increased 15% and the renal clearance of lithium was decreased by 19% during this period of concomitant drug administration. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. (Read circulars for lithium preparation before use of such concurrent therapy.) Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin-type anticoagulants Several short-term controlled studies failed to show that Ibuprofen tablets significantly affected prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. However, because bleeding has been reported when Ibuprofen tablets and other NSAIDs have been administered to patients on coumarin-type anticoagulants, the physician should be cautious when administering Ibuprofen tablets to patients on anticoagulants. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. H-2 Antagonists In studies with human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.

Pregnancy Risk Summary

Use of NSAIDs, including Ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of Ibuprofen tablets use between about 20 and 30 weeks of gestation, and avoid Ibuprofen tablets use at about 30 weeks of gestation and later in pregnancy [see Error! Hyperlink reference not valid. ].

Premature

Closure of Fetal Ductus Arteriosus Use of NSAIDs, including Ibuprofen tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as Ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including Ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus [see Error! Hyperlink reference not valid. ].

Oligohydramnios/Neonatal

Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible.

If

Ibuprofen tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue Ibuprofen tablets and follow up according to clinical practice [see Error! Hyperlink reference not valid. ].

Data Human Data

There are no adequate, well-controlled studies in pregnant women. Ibuprofen tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Premature

Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Ibuprofen tablets on labor and delivery in pregnant women are unknown.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human-milk and because of the potential for serious adverse reactions in nursing infants from Ibuprofen tablets, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Ibuprofen tablets in pediatric patients have not been established.

Geriatric

Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

DRUG INTERACTION ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Aspirin

Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology /Pharmacodynamics]. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardio protection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate. When ibuprofen tablets are administered with aspirin, its protein binding is reduced, although the clearance of free ibuprofen tablets is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential for increased adverse effects.

Diuretics

Clinical studies, as well as post marketing observations, have shown that ibuprofen tablets can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects ), as well as to assure diuretic efficacy.

Lithium

Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of eleven normal volunteers. The mean minimum lithium concentration increased 15% and the renal clearance of lithium was decreased by 19% during this period of concomitant drug administration. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. (Read circulars for lithium preparation before use of such concurrent therapy.) Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin-type anticoagulants Several short-term controlled studies failed to show that ibuprofen tablets significantly affected prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. However, because bleeding has been reported when ibuprofen tablets and other NSAIDs have been administered to patients on coumarin-type anticoagulants, the physician should be cautious when administering ibuprofen tablets to patients on anticoagulants. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. H-2 Antagonists In studies with human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.

Pregnancy Risk Summary

Use of NSAIDs, including ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ibuprofen tablets use between about 20 and 30 weeks of gestation, and avoid ibuprofen tablets use at about 30 weeks of gestation and later in pregnancy [ see WARNINGS; Fetal Toxicity ].

Premature

Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ibuprofen tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal Toxicity ) .

Oligohydramnios/Neonatal

Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If ibuprofen tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue ibuprofen tablets and follow up according to clinical practice (see WARNINGS; Fetal Toxicity ) .

Data Human Data

There are no adequate, well-controlled studies in pregnant women. Ibuprofen tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Premature

Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of ibuprofen tablets on labor and delivery in pregnant women are unknown.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human-milk and because of the potential for serious adverse reactions in nursing infants from ibuprofen tablets, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of ibuprofen tablets in pediatric patients have not been established.

Geriatric

Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

Active Ingredient Advil Tablets (in each tablet)

Ibuprofen

200 mg (NSAID)* *nonsteroidal anti-inflammatory drug Advil Caplets (in each caplet)

Ibuprofen

200 mg (NSAID)* *nonsteroidal anti-inflammatory drug Advil Gel Caplets (in each gel caplet)

Ibuprofen

200 mg (NSAID)* *nonsteroidal anti-inflammatory drug

Advil Tablets (in each tablet)

Ibuprofen

200 mg (NSAID)* *nonsteroidal anti-inflammatory drug

Advil Caplets (in each caplet)

Ibuprofen

200 mg (NSAID)* *nonsteroidal anti-inflammatory drug

Advil Gel Caplets (in each gel caplet)

Ibuprofen

200 mg (NSAID)* *nonsteroidal anti-inflammatory drug

Inactive ingredients Advil Tablets acetylated monoglycerides, colloidal silicon dioxide, corn starch, croscarmellose sodium, methylparaben, microcrystalline cellulose, pharmaceutical glaze, pharmaceutical ink, povidone, pregelatinized starch, propylparaben, sodium benzoate, sodium lauryl sulfate, stearic acid, sucrose, synthetic iron oxide, titanium dioxide, white wax Advil Caplets acetylated monoglycerides, colloidal silicon dioxide, corn starch, croscarmellose sodium, methylparaben, microcrystalline cellulose, pharmaceutical glaze, pharmaceutical ink, povidone, pregelatinized starch, propylparaben, sodium benzoate, sodium lauryl sulfate, stearic acid, sucrose, synthetic iron oxide, titanium dioxide, white wax Advil Gel Caplets colloidal silicon dioxide, corn starch, croscarmellose sodium, FD&C red no. 40, FD&C yellow no. 6, fractionated coconut oil, gelatin, glycerin, hypromellose, pharmaceutical ink, pregelatinized starch, propyl gallate, purified water, sodium lauryl sulfate, stearic acid, synthetic iron oxides, titanium dioxide, triacetin Questions or comments? call toll free 1-800-88-ADVIL

Advil Tablets acetylated monoglycerides, colloidal silicon dioxide, corn starch, croscarmellose sodium, methylparaben, microcrystalline cellulose, pharmaceutical glaze, pharmaceutical ink, povidone, pregelatinized starch, propylparaben, sodium benzoate, sodium lauryl sulfate, stearic acid, sucrose, synthetic iron oxide, titanium dioxide, white wax

Advil Caplets acetylated monoglycerides, colloidal silicon dioxide, corn starch, croscarmellose sodium, methylparaben, microcrystalline cellulose, pharmaceutical glaze, pharmaceutical ink, povidone, pregelatinized starch, propylparaben, sodium benzoate, sodium lauryl sulfate, stearic acid, sucrose, synthetic iron oxide, titanium dioxide, white wax

Advil Gel Caplets colloidal silicon dioxide, corn starch, croscarmellose sodium, FD&C red no. 40, FD&C yellow no. 6, fractionated coconut oil, gelatin, glycerin, hypromellose, pharmaceutical ink, pregelatinized starch, propyl gallate, purified water, sodium lauryl sulfate, stearic acid, synthetic iron oxides, titanium dioxide, triacetin