Carefully consider the potential benefits and risks of a ketoprofen immediate-release capsules and ketoprofen extended-release capsules and other treatment options before deciding to use ketoprofen immediate-release capsules and ketoprofen extended-release capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals . After observing the response to initial therapy with ketoprofen immediate-release capsules and ketoprofen extended-release capsules, the dose and frequency should be adjusted to suit an individual patient's needs. Concomitant use of ketoprofen immediate-release capsules and ketoprofen extended-release capsules is not recommended. If minor side effects appear, they may disappear at a lower dose which may still have an adequate therapeutic effect. If well tolerated but not optimally effective, the dosage may be increased. Individual patients may show a better response to 300 mg of ketoprofen immediate-release capsules daily as compared to 200 mg, although in well controlled clinical trials patients on 300 mg did not show greater mean effectiveness. They did, however, show an increased frequency of upper and lower GI distress and headaches. It is of interest that women also had an increased frequency of these adverse effects compared to men. When treating patients with 300 mg/day, the physician should observe sufficient increased clinical benefit to offset potential increased risk. In patients with mildly impaired renal function, the maximum recommended total daily dose of ketoprofen immediate-release capsules or ketoprofen extended-release capsules is 150 mg. In patients with a more severe renal impairment (GFR less than 25 mL/min/1.73 mor end-stage renal impairment), the maximum total daily dose of ketoprofen immediate-release capsules or ketoprofen extended-release capsules should not exceed 100 mg. In elderly patients, renal function may be reduced with apparently normal serum creatinine and/or BUN levels. Therefore, it is recommended that the initial dosage of ketoprofen immediate-release capsules or ketoprofen extended-release capsules should be reduced for patients over 75 years of age . It is recommended that for patients with impaired liver function and serum albumin concentration less than 3.5 g/dL, the maximum initial total daily dose of ketoprofen immediate-release capsules or ketoprofen extended-release capsules should be 100 mg. All patients with metabolic impairment, particularly those with both hypoalbuminemia and reduced renal function,may have increased levels of free (biologically active) ketoprofen and should be closely monitored. The dosage may be increased to the range recommended for the general population, if necessary, only after good individual tolerance has been ascertained. Because hypoalbuminemia and reduced renal function both increase the fraction of free drug (biologically active form), patients who have both conditions may be at greater risk of adverse effects. Therefore, it is recommended that such patients also be started on lower doses of ketoprofen immediate-release capsules or ketoprofen extended-release capsules and closely monitored.<br/>Rheumatoid Arthritis and Osteoarthritis: The recommended starting dose of ketoprofen in otherwise healthy patients is for ketoprofen immediate-release capsules 75 mg three times or 50 mg four times a day, or for ketoprofen extended-release capsules 200 mg administered once a day. Smaller doses of ketoprofen immediate-release capsules or ketoprofen extended-release capsules should be utilized initially in small individuals, or in debilitated or elderly patients. The recommended maximum daily dose of ketoprofen is 300 mg/day for ketoprofen immediate-release capsules or 200 mg/day for ketoprofen extended-release capsules. Dosages higher than 300 mg/day of ketoprofen immediate-release capsules or 200 mg/day of ketoprofen extended-release capsules are not recommended because they have not been studied. Concomitant use of ketoprofen immediate-release capsules and ketoprofen extended-release capsules is not recommended. Relatively smaller people may need smaller doses. As with other non-steroidal anti-inflammatory drugs, the predominant adverse effects of ketoprofen are gastrointestinal. To attempt to minimize these effects, physicians may wish to prescribe that ketoprofen immediate-release capsules or ketoprofen extended-release capsules be taken with antacids, food, or milk. Although food delays the absorption of both formulations in most of the clinical trials ketoprofen was taken with food or milk. Physicians may want to make specific recommendations to patients about when they should take ketoprofen immediate-release capsules or ketoprofen extended-release capsules in relation to food and/or what patients should do if they experience minor GI symptoms associated with either formulation.<br/>Management of Pain and Dysmenorrhea: The usual dose of ketoprofen immediate-release capsules recommended for mild to moderate pain and dysmenorrhea is 25 to 50 mg every 6 to 8 hours as necessary. A smaller dose should be utilized initially in small individuals, in debilitated or elderly patients, or in patients with renal or liver disease . A larger dose may be tried if the patient's response to a previous dose was less than satisfactory, but doses above 75 mg have not been shown to give addedanalgesia. Daily doses above 300 mg are not recommended because they have not been adequately studied. Because of its typical non-steroidal anti-inflammatory drug-side effect profile, including as its principal adverse effect GI side effects , higher doses of ketoprofen immediate-release capsules should be used with caution and patients receiving them observed carefully. Ketoprofen extended-release capsules are not recommended for use in treating acute pain because of its extended-release characteristics.
Ketoprofen is a non-steroidal anti-inflammatory drug with analgesic and antipyretic properties. The anti-inflammatory, analgesic, and antipyretic properties of ketoprofen have been demonstrated in classical animal and in vitro test systems. In anti-inflammatory models ketoprofen has been shown to have inhibitory effects on prostaglandin and leukotriene synthesis, to have antibradykinin activity, as well as to have lysosomal membrane-stabilizing action. However, its mode of action, like that of other non-steroidal anti-inflammatory drugs, is not fully understood.<br/>Pharmacodynamics: Ketoprofen is a racemate with only the S enantiomer possessing pharmacological activity. The enantiomers have similar concentration time curves and do not appear to interact with one another. An analgesic effect-concentration relationship for ketoprofen was established in an oral surgery pain study with ketoprofen immediate-release capsules. The effect-site rate constant (K) was estimated to be 0.9 hour(95% confidence limits: 0 to 2.1), and the concentration (Ce) of ketoprofen that produced one-half the maximum PID (pain intensity difference) was 0.3 mcg/mL (95% confidence limits: 0.1 to 0.5). Thirty-three (33) to 68% of patients had an onset of action (as measured by reporting some pain relief) within 30 minutes following a single oral dose in postoperative pain and dysmenorrhea studies. Pain relief (as measured by remedication) persisted for up to 6 hours in 26 to 72% of patients in these studies.<br/>Pharmacokinetics:<br/>General: Ketoprofen immediate-release capsules and ketoprofen extended-release capsules both contain ketoprofen. They differ only in their release characteristics. Ketoprofen immediate-release capsules release drug in the stomach whereas ketoprofen extended-release capsules are designed to resist dissolution in the low pH of gastric fluid but release drug at a controlled rate in the higher pH environment of the small intestine . Irrespective of the pattern of release, the systemic availability (F) when either oral formulation is compared with IV administration is approximately 90% in humans. For 75 mg to 200 mg single doses, the area under the curve has been shown to be dose proportional. The figure depicts the plasma time curves associated with both products. Ketoprofen is>99% bound to plasma proteins, mainly to albumin. Separate sections follow which delineate differences between ketoprofen immediate-release capsules and ketoprofen extended-release capsules.<br/>Absorption: Ketoprofen immediate-release capsules are rapidly and well absorbed, with peak plasma levels occurring with 0.5 to 2 hours. Ketoprofen extended-release capsules are also well absorbed from this dosage form, although an observable increase in plasma levels does not occur until approximately 2 to 3 hours after taking the formulation. Peak plasma levels are usually reached 6 to 7 hours after dosing. (See Figure and Table, below). When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption from either dosage form is slowed. Ketoprofen immediate-release capsules���Food intake reduces Cby approximately one-half and increases the mean time to peak concentration (t) from 1.2 hours for fasting subjects (range, 0.5 to 3 hours) to 2.0 hours for fed subjects (range, 0.75 to 3 hours). The fluctuation of plasma peaks may also be influenced by circadian changes in the absorption process. Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with absorption of ketoprofen immediate-release capsules. Ketoprofen extended-release capsules���Administration of ketoprofen extended-release capsules with a high fat meal causes a delay of about 2 hours in reaching the C; neither the total bioavailability (AUC) nor the Cis affected. Circardian changes in the absorption process have not been studied. The administration of antacids or other drugs which may raise stomach pH would not be expected to change the rate or extent of absorption of ketoprofen extended-release capsules.<br/>Multiple Dosing: Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with ketoprofen immediate-release capsules or ketoprofen extended-release capsules. In studies with healthy male volunteers, trough levels at 24 hours following administration of ketoprofen 200 mg extended-release capsules were 0.4 mg/L compared with 0.07 mg/L at 24 hours following administration of ketoprofen 50 mg immediate-release capsules QID (12 hours), or 0.13 mg/L following administration of ketoprofen 75 mg immediate-release capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of ketoprofen immediate-release capsules or ketoprofen extended-release capsules is minimal. The figure below shows a reduction in peak height and area after the second 50 mg dose. This is probably due to a combination of food effects, circadian effects, and plasma sampling times. It is unclear to what extent each factor contributes to the loss of peak height and area. The shaded area represents��1 standard deviation (S.D.) around the mean for ketoprofen immediate-release capsules or ketoprofen extended-release capsules. KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING 200 MG OF KETOPROFEN EXTENDED-RELEASE CAPSULES ONCE A DAY (QD), OR 50 MG OF KETOPROFEN IMMEDIATE-RELEASE CAPSULES EVERY 4 HOURS FOR 16 HOURS<br/>Metabolism: The metabolic fate of ketoprofen is glucuronide conjugation to form an unstable acyl-glucuronide. The glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a potential reservoir for parent drug, and this may be important in persons with renal insufficiency, whereby the conjugate may accumulate in the serum and undergo deconjugation back to the parent drug . The conjugates are reported to appear only in trace amounts in plasma in healthy adults, but are higher in elderly subjects���presumably because of reduced renal clearance. It has been demonstrated that in elderly subjects following multiple doses (50 mg every 6 h), the ratio of conjugated to parent ketoprofen AUC was 30% and 3%, respectively, for the S&R enantiomers. There are no known active metabolites of ketoprofen. Ketoprofen has been shown not to induce drug metabolizing enzymes.<br/>Elimination: The plasma clearance of ketoprofen is approximately 0.08 L/kg/h with a Vof 0.1 L/kg after IV administration. The elimination half-life of ketoprofen has been reported to be 2.05��0.58 h (Mean��S.D.) following IV administration, from 2 to 4 h following administration of ketoprofen immediate-release capsules, and 5.4��2.2 h after administration of ketoprofen 200 mg extended-release capsules. In cases of slow drug absorption, the elimination rate is dependent on the absorption rate and thus trelative to an IV dose appears prolonged. After a single 200 mg dose of ketoprofen extended-release capsules, the plasma levels decline slowly, and average 0.4 mg/L after 24 hours (see Figure above). In a 24 hour period, approximately 80% of an administered dose of ketoprofen is excreted in the urine, primarily as the glucuronide metabolite. Enterohepatic recirculation of the drug has been postulated, although biliary levels have never been measured to confirm this.<br/>Special Populations:<br/>Elderly:<br/>Renally Impaired: Studies of the effects of renal function impairment have been small. They indicate a decrease in clearance in patients with impaired renal function. In 23 patients with renal impairment, free ketoprofen peak concentration was not significantly elevated, but free ketoprofen clearance was reduced from 15 L/kg/h for normal subjects to 7 L/kg/h in patients with mildly impaired renal function, and to 4 L/kg/h in patients with moderately to severely impaired renal function. The elimination twas prolonged from 1.6 hours in normal subjects to approximately 3 hours in patients with mild renal impairment, and to approximately 5 to 9 hours in patients with moderately to severely impaired renal function. No studies have been conducted in patients with renal impairment taking ketoprofen extended-release capsules .<br/>Hepatically Impaired: For patients with alcoholic cirrhosis, no significant changes in the kinetic disposition of ketoprofen immediate-release capsules were observed relative to age-matched normal subjects: the plasma clearance of drug was 0.07 L/kg/h in 26 hepatically impaired patients. The elimination half-life was comparable to that observed for normal subjects. However, the unbound (biologically active) fraction was approximately doubled, probably due to hypoalbuminemia and high variability which was observed in the pharmacokinetics for cirrhotic patients. Therefore, these patients should be carefully monitored and daily doses of ketoprofen kept at the minimum providing the desired therapeutic effect. No studies have been conducted in patients with hepatic impairment taking ketoprofen extended-release capsules .<br/>Clinical Trials:<br/>Rheumatoid Arthritis and Osteoarthritis: The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis. Using standard assessments of therapeutic response, there were no detectable differences in effectiveness or in the incidence of adverse events in crossover comparison of ketoprofen immediate-release capsules and ketoprofen extended-release capsules. In other trials, ketoprofen demonstrated effectiveness comparable to aspirin, ibuprofen, naproxen, piroxicam, diclofenac and indomethacin. In some of these studies there were more dropouts due to gastrointestinal side effects among patients on ketoprofen than among patients on other NSAIDs. In studies with patients with rheumatoid arthritis, ketoprofen was administered in combination with gold salts, antimalarials, low dose methotrexate, d-penicillamine, and/or corticosteroids with results comparable to those seen with control non-steroidal drugs.<br/>Management of Pain: The effectiveness of ketoprofen immediate-release capsules as a general purpose analgesic has been studied in standard pain models which have shown the effectiveness of doses of 25 mg to 150 mg. Doses of 25 mg were superior to placebo. Doses larger than 25 mg generally could not be shown to be significantly more effective, but there was atendency toward faster onset and greater duration of action with 50 mg, and, in the case of dysmenorrhea, a significantly greater effect overall with 75 mg. Doses greater than 50 mg to 75 mg did not have increased analgesic effect. Studies in postoperative pain have shown that ketoprofen immediate-release capsules in doses of 25 mg to 100 mg was comparable to 650 mg of acetaminophen with 60 mg of codeine, or 650 mg of acetaminophen with 10 mg of oxycodone. Ketoprofen tended to be somewhat slower in onset; peak pain relief was about the same and the duration of the effect tended to be 1 to 2 hours longer, particularly with the higher doses of ketoprofen. The use of ketoprofen extended-release capsules in patients with acute pain is not recommended, since, in comparison to ketoprofen immediate-release capsules, ketoprofen extended-release capsules would be expected to have a delayed analgesic response due to its extended-release characteristics.
Ketoprofen Immediate-release Capsules are available containing 50 mg or 75 mg of ketoprofen, USP. The 50 mg capsule is a hard-shell gelatin capsule with a light celery opaque cap and a light celery opaque body filled with a white to off-white powder. The capsule is axially printed with MYLAN over 4070 in black ink on both the body and cap. They are available as follows: NDC 0378-4070-01bottles of 100 capsules The 75 mg capsule is a hard-shell gelatin capsule with a light aqua opaque cap and a light aqua opaque body filled with a white to off-white powder. The capsule is axially printed with MYLAN over 5750 in black ink on both the body and cap. They are available as follows: NDC 0378-5750-01bottles of 100 capsules Ketoprofen Extended-release Capsules are available containing 200 mg of ketoprofen, USP. The 200 mg extended-release capsule is a hard-shell gelatin capsule with a blue green opaque cap and a iron gray opaque body axially printed with MYLAN over 8200 in black ink on both the cap and body. They are available as follows: NDC 0378-8200-01bottles of 100 capsules NDC 0378-8200-05bottles of 500 capsules Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Protect from direct light and excessive heat and humidity. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.
Cardiovascular Risk Gastrointestinal Risk
dailymed-ingredient:D&C_Yellow_No._10_Aluminum_Lake, dailymed-ingredient:FD&C_Blue_No.1_Aluminum_Lake, dailymed-ingredient:FD&C_Blue_No.2_Aluminum_Lake, dailymed-ingredient:FD&C_Red_No._40_Aluminum_Lake, dailymed-ingredient:FD&C_Yellow_No._6_Aluminum_Lake, dailymed-ingredient:colloidal_silicon_dioxide, dailymed-ingredient:corn_starch, dailymed-ingredient:gelatin, dailymed-ingredient:lactose_monohydrate, dailymed-ingredient:magnesium_stearate, dailymed-ingredient:pharmaceutical_glaze, dailymed-ingredient:propylene_glycol, dailymed-ingredient:sodium_lauryl_sulfate, dailymed-ingredient:sodium_starch_glycolate, dailymed-ingredient:synthetic_black_iron_oxide, dailymed-ingredient:titanium_dioxide
Signs and symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Respiratory depression, coma, or convulsions have occurred following large ketoprofen overdoses. Gastrointestinal bleeding, hypotension, hypertension, or acute renal failure may occur, butare rare. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients with symptoms seen within 4 hours (longer for sustained-release products) or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with a saline cathartic or sorbitol added to the first dose. Forced diuresis, alkalinization of the urine, hemodialysis or hemoperfusion would probably not be useful due to ketoprofen's high protein binding. Case reports include twenty-six overdoses: 6 were in children, 16 in adolescents, and 4 in adults. Five of these patients had minor symptoms (vomiting in 4, drowsiness in 1 child). A 12 year-old girl had tonic-clonic convulsions 1 to 2 hours after ingesting an unknown quantity of ketoprofen and 1 or 2 tablets of acetaminophen with hydrocodone. Her ketoprofen level was 1128 mg/L (56 times the upper therapeutic level of 20 mg/L) 3 to 4 hours post ingestion. Full recovery ensued 18 hours after ingestion following management with intubation, diazepam, and activated charcoal. A 45 year-old woman ingested twelve 200 mg extended-release ketoprofen capsules and 375 mL vodka, was treated with emesis and supportive measures 2 hours after ingestion, and recovered completely with her only complaint being mild epigastric pain.
The incidence of common adverse reactions (above 1%) was obtained from a population of 835 ketoprofen immediate-release capsules treated patients in double-blind trials lasting from 4 to 54 weeks and in 622 ketoprofen extended-release capsules treated (200 mg/day) patients in trials lasting from 4 to 16 weeks. Minor gastrointestinal side effects predominated; upper gastrointestinal symptoms were more common than lower gastrointestinal symptoms. In crossover trials in 321 patients with rheumatoid arthritis or osteoarthritis, there was no difference in either upper or lower gastrointestinal symptoms between patients treated with 200 mg of ketoprofen extended-release capsules once a day or 75 mg of ketoprofen immediate-release capsules TID (225 mg/day). Peptic ulcer or GI bleeding occurred in controlled clinical trials in less than 1% of 1,076 patients; however, in open label continuation studies in 1,292 patients the rate was greater than 2%. The incidence of peptic ulceration in patients on NSAIDs is dependent on many risk factors including age, sex, smoking, alcohol use, diet, stress, concomitant drugs such as aspirin and corticosteroids, as well as the dose and duration of treatment with NSAIDs . Gastrointestinal reactions were followed in frequency by central nervous system side effects, such as headache, dizziness, or drowsiness. The incidence of some adverse reactions appears to be dose related . Rare adverse reactions (incidence less than 1%) were collected from one or more of the following sources: foreign reports to manufacturers and regulatory agencies, publications, U.S. clinical trials, and/or U.S. post-marketing spontaneous reports. Reactions are listed below under body system, then by incidence or number of cases in decreasing incidence.<br/>Incidence Greater than 1% (Probable Causal Relationship): Digestive: Dyspepsia (11%), nausea, abdominal pain, diarrhea, constipation, flatulence, anorexia, vomiting, stomatitis. Nervous System: Headache, dizziness, CNS inhibition (i.e., pooled reports of somnolence, malaise, depression, etc.) or excitation (i.e., insomnia, nervousness, dreams, etc.). Special Senses: Tinnitus, visual disturbance. Skin and Appendages: Rash. Urogenital: Impairment of renal function (edema, increased BUN), signs or symptoms of urinary-tract irritation.<br/>Incidence Less than 1% (Probable Causal Relationship): Body as a Whole: Chills, facial edema, infection, pain, allergic reaction, anaphylaxis. Cardiovascular: Hypertension, palpitation, tachycardia, congestive heart failure, peripheral vascular disease, vasodilation. Digestive: Appetite increased, dry mouth, eructation, gastritis, rectal hemorrhage, melena, fecal occult blood, salivation, peptic ulcer, gastrointestinal perforation, hematemesis, intestinal ulceration, hepatic dysfunction, hepatitis, cholestatic hepatitis, jaundice. Hemic: Hypocoagulability, agranulocytosis, anemia, hemolysis, purpura, thrombocytopenia. Metabolic and Nutritional: Thirst, weight gain, weight loss, hyponatremia. Musculoskeletal: Myalgia. Nervous System: Amnesia, confusion, impotence, migraine, paresthesia, vertigo. Respiratory: Dyspnea, hemoptysis, epistaxis, pharyngitis, rhinitis, bronchospasm, laryngeal edema. Skin and Appendages: Alopecia, eczema, pruritus, purpuric rash, sweating, urticaria, bullous rash, exfoliative dermatitis, photosensitivity, skin discoloration, onycholysis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson Syndrome. Special Senses: Conjunctivitis, conjunctivitis sicca, eye pain, hearing impairment, retinal hemorrhage and pigmentation change, taste perversion. Urogenital: Menometrorrhagia, hematuria, renal failure, interstitial nephritis, nephrotic syndrome.<br/>Incidence Less than 1% (Causal Relationship Unknown): The following rare adverse reactions, whose causal relationship to ketoprofen is uncertain, are being listed to serve as alerting information to the physician. Body as a Whole: Septicemia, shock. Cardiovascular: Arrhythmias, myocardial infarction. Digestive: Buccal necrosis, ulcerative colitis, microvesicular steatosis, pancreatitis. Endocrine: Diabetes mellitus (aggravated). Nervous System: Dysphoria, hallucination, libido disturbance, nightmares, personality disorder, aseptic meningitis. Urogenital: Acute tubulopathy, gynecomastia.
Carefully consider the potential benefits and risks of ketoprofen immediate-release capsules and ketoprofen extended-release capsules before deciding to use ketoprofen immediate-release capsules and ketoprofen extended-release capsules. Use of the lowest effective dose for the shortest duration consistent with individual patient treatment goals . Ketoprofen immediate-release capsules and ketoprofen extended-release capsules are indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Ketoprofen extended-release capsules are not recommended for treatment of acute pain because of its extended-release characteristics . Ketoprofen immediate-release capsules are indicated for the management of pain. Ketoprofen immediate-release capsules are also indicated for treatment of primary dysmenorrhea.