nimize 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. pregnancy in late pregnancy, as with other nsaids, ibuprofen tablets should be avoided because it may cause premature closure of the ductus arteriosus.

3200 mg/day, the physician should observe sufficient increased clinical benefits to offset potential increased risk. the dose should be tailored to each patient, and may be lowered or raised depending on the severity of symptoms either at time of initiating drug therapy or as the patient responds or fails to respond. in general, patients with rheumatoid arthritis seem to require higher doses of ibuprofen tablets than do patients with osteoarthritis. the smallest dose of ibuprofen tablets that yields acceptable control should be employed. a linear blood level dose-response relationship exists with single doses up to 800 mg [see clinical pharmacology for effects of food on rate of absorption]. the availability of four tablet strengths facilitates dosage adjustment. in chronic conditions, a therapeutic response to therapy with ibuprofen tablets is sometimes seen in a few days to a week but most often is observed by two weeks. after a satisfactory response has been achieved, the patient's dose should be reviewed and adjusted as required. mild to moderate pain: 400 mg every 4 to 6 hours as necessary for relief of pain. in controlled analgesic clinical trials, doses of ibuprofen tablets greater than 400 mg were no more effective than the 400 mg dose. dysmenorrhea: for the treatment of dysmenorrhea, beginning with the earliest onset of such pain, ibuprofen tablets should be given in a dose of 400 mg every 4 hours as necessary for the relief of pain.

lists reactions with therapy with ibuprofen tablets where the probability of a causal relationship exists: for the reactions in column three, a causal relationship with ibuprofen tablets has not been established. reported side effects were higher at doses of 3200 mg/day than at doses of 2400 mg or less per day in clinical trials of patients with rheumatoid arthritis. the increases in incidence were slight and still within the ranges reported in the table. incidence greater than 1% (but less than 3%) probable causal relationship precise incidence unknown (but less than 1%) probable causal relationship** precise incidence unknown (but less than 1%) causal relationship unknown** * reactions occurring in 3% to 9% of patients treated with ibuprofen tablets. (those reactions occurring in less than 3% of the patients are unmarked.) ** reactions are classified under “ probable causal relationship (pcr) ” if there has been one positive rechallenge or if three or more cases occur which might be causally related. reactions are classified under “ causal relationship unknown ” if seven or more events have been reported but the criteria for pcr have not been met. gastrointestinal nausea*, epigastric pain*, heartburn*, diarrhea, abdominal distress, nausea and vomiting, indigestion, constipation, abdominal cramps or pain, fullness of gi tract (bloating and flatulence) gastric or duodenal ulcer with bleeding and/or perforation, gastrointestinal hemorrhage, melena, gastritis, hepatitis, jaundice, abnormal liver function tests; pancreatitis central nervous system dizziness*, headache, nervousness depression, insomnia, confusion, emotional liability, somnolence, aseptic meningitis with fever and coma (see precautions ) paresthesias, hallucinations, dream abnormalities, pseudo-tumor cerebri dermatologic rash* (including maculopapular type), pruritus vesiculobullous eruptions, urticaria, erythema multiforme, stevens-johnson syndrome, alopecia toxic epidermal necrolysis, photoallergic skin reactions neuritis, cataracts special senses tinnitus hearing loss, amblyopia (blurred and/or diminished vision, scotomata and/or changes in color vision) (see precautions ) conjunctivitis, diplopia, optic neuritis, cataracts hematologic neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (sometimes coombs positive), thrombocytopenia with or without purpura, eosinophilia, decreases in hemoglobin and hematocrit (see precautions ) bleeding episodes (eg epistaxis, menorrhagia) metabolic/endocrine decreased appetite gynecomastia, hypoglycemic reaction, acidosis cardiovascular edema, fluid retention (generally responds promptly to drug discontinuation) (see precautions) congestive heart failure in patients with marginal cardiac function, elevated blood pressure, palpitations arrhythmias (sinus tachycardia, sinus bradycardia) allergic syndrome of abdominal pain, fever, chills, nausea and vomiting; anaphylaxis; bronchospasm (see contraindications ) serum sickness, lupus erythe- matosus syndrome. henoch-schonlein vasculitis, angioedema renal acute renal failure (see precautions ), decreased creatinine clearance, polyuria, azotemia, cystitis, hematuria renal papillary necrosis miscellaneous dry eyes and mouth, gingival ulcer, rhinitis tests to report suspected adverse reactions, contact avkare, inc. at 1-855-361-3993; email drugsafety@avkare.com; or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

for up to one year, there were no reports of gastric ulceration with ibuprofen tablets whereas frank ulceration was reported in 13 patients in the aspirin group (statistically significant p<0.001). gastroscopic studies at varying doses show an increased tendency toward gastric irritation at higher doses. however, at comparable doses, gastric irritation is approximately half that seen with aspirin. studies using 51 cr-tagged red cells indicate that fecal blood loss associated with ibuprofen tablets in doses up to 2400 mg daily did not exceed the normal range, and was significantly less than that seen in aspirin-treated patients. in clinical studies in patients with rheumatoid arthritis, ibuprofen tablets have been shown to be comparable to indomethacin in controlling the signs and symptoms of disease activity and to be associated with a statistically significant reduction of the milder gastrointestinal [see adverse reactions ] and cns side effects. ibuprofen tablets may be used in combination with gold salts and/or corticosteroids. controlled studies have demonstrated that ibuprofen tablets are a more effective analgesic than propoxyphene for the relief of episiotomy pain, pain following dental extraction procedures, and for the relief of the symptoms of primary dysmenorrhea. in patients with primary dysmenorrhea, ibuprofen tablets have been shown to reduce elevated levels of prostaglandin activity in the menstrual fluid and to reduce resting and active intrauterine pressure, as well as the frequency of uterine contractions. the probable mechanism of action is to inhibit prostaglandin synthesis rather than simply to provide analgesia. the ibuprofen in ibuprofen tablets is rapidly absorbed. peak serum ibuprofen levels are generally attained one to two hours after administration. with single doses up to 800 mg, a linear relationship exists between amount of drug administered and the integrated area under the serum drug concentration vs time curve. above 800 mg, however, the area under the curve increases less than proportional to increases in dose. there is no evidence of drug accumulation or enzyme induction. the administration of ibuprofen tablets either under fasting conditions or immediately before meals yields quite similar serum ibuprofen concentration-time profiles. when ibuprofen tablets are administered immediately after a meal, there is a reduction in the rate of absorption but no appreciable decrease in the extent of absorption. the bioavailability of the drug is minimally altered by the presence of food. a bioavailability study has shown that there was no interference with the absorption of ibuprofen when ibuprofen tablets were given in conjunction with an antacid containing both aluminum hydroxide and magnesium hydroxide. ibuprofen is rapidly metabolized and eliminated in the urine. the excretion of ibuprofen is virtually complete 24 hours after the last dose. the serum half-life is 1.8 to 2.0 hours. studies have shown that following ingestion of the drug, 45% to 79% of the dose was recovered in the urine within 24 hours as metabolite a (25%), (+)-2-[ p -(2hydroxymethyl-propyl) phenyl] propionic acid and metabolite b (37%), (+)-2-[ p -(2carboxypropyl)phenyl] propionic acid; the percentages of free and conjugated ibuprofen were approximately 1% and 14%, respectively.

° to 25°c (68° to 77°f) [see usp controlled room temperature]. avoid excessive heat 40°c (104°f). dispense in a tight, light-resistant container as defined in the usp. rx only manufactured for: avkare, inc. pulaski, tn 38478 mfg. rev. 06-2016-02 av rev. 08/18 (p)