ketoprofen 25 MG Oral Capsule [Kiprofen]

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of ketoprofen extended-release capsules before deciding to use ketoprofen extended-release capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). 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 (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Ketoprofen Capsules, USP and other treatment options before deciding to use Ketoprofen Capsules, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). After observing the response to initial therapy with Ketoprofen Capsules, USP, the dose and frequency should be adjusted to suit an individual patient's needs. Concomitant use of Ketoprofen Capsules, USP 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 Capsules, USP 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 Capsules, USP is 150 mg. In patients with a more severe renal impairment (GFR less than 25 mL/min/1.73 m2 or end-stage renal impairment), the maximum total daily dose of Ketoprofen Capsules, USP 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 Capsules, USP should be reduced for patients over 75 years of age (see Geriatric Use ). 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 Capsules, USP 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 Capsules, USP and closely monitored. Rheumatoid Arthritis and Osteoarthritis The recommended starting dose of Ketoprofen Capsules, USP in otherwise healthy patients is 75 mg three times or 50 mg four times a day. Smaller doses of Ketoprofen Capsules, USP should be utilized initially in small individuals or in debilitated or elderly patients. The recommended maximum daily dose of Ketoprofen Capsules USP is 300 mg/day. Dosages higher than 300 mg/day of Ketoprofen Capsules, USP are not recommended because they have not been studied. Concomitant use of Ketoprofen Capsules, USP 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 ORUDIS be taken with antacids, food, or milk. Although food delays the absorption of Ketoprofen Capsules, USP (see CLINICAL PHARMACOLOGY ), 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 Capsules, USP in relation to food and/or what patients should do if they experience minor GI symptoms associated with Ketoprofen Capsules, USP. Management of Pain and Dysmenorrhea The usual dose of Ketoprofen Capsules, USP 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 (see PRECAUTIONS ). 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 added analgesia. 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 (see WARNINGS and ADVERSE REACTIONS ), higher doses of Ketoprofen Capsules, USP should be used with caution and patients receiving them observed carefully.

WARNINGS 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 ketoprofen, 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 10–14 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 4 years of follow-up. Avoid the use of ketoprofen extended-release capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ketoprofen extended-release capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, including ketoprofen extended-release capsules, can lead to onset of new hypertension or worsening of pre-existing 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 ketoprofen extended-release capsules, 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 ketoprofen 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 ketoprofen extended-release capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ketoprofen extended-release capsules 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 ketoprofen extended-release capsules, 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 2-4% 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 with neither of these risk factors. Other factors that increase the risk for 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 an 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 ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse 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 nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greater 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 ketoprofen extended-release capsules in patients with advanced renal disease. Therefore, treatment with ketoprofen extended-release capsules is not recommended in these patients with advanced renal

CONTRAINDICATIONS Ketoprofen extended-release capsules are contraindicated in patients who have shown hypersensitivity to ketoprofen. Ketoprofen extended-release capsules should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic reactions to ketoprofen have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: General: Preexisting Asthma ). Ketoprofen extended-release capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).

CLINICAL PHARMACOLOGY Ketoprofen is a nonsteroidal 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 nonsteroidal anti-inflammatory drugs, is not fully understood. 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 capsules. The effect-site rate constant (K e0 ) was estimated to be 0.9 hour -1 (95% confidence limits: 0 to 2.1), and the concentration (Ce 50 ) 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. Pharmacokinetics General Ketoprofen extended-release capsules contain ketoprofen. They differ only in their release characteristics. Ketoprofen capsules release drug in 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 (see DESCRIPTION ). Irrespective of the pattern of release, the systemic availability (F s ) when either oral formulation is compared with IV administration is approximately 90% in humans. For 75 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 capsules and ketoprofen extended-release capsules. Absorption Ketoprofen capsules are rapidly and well-absorbed, with peak plasma levels occurring within 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 capsules – Food intake reduces C max by approximately one-half and increases the mean time to peak concentration (t max ) 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 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 max ; neither the total bioavailability (AUC) nor the C max is affected. Circadian 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. Multiple Dosing Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with 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 capsules QID (12 hours), or 0.13 mg/L following administration of ketoprofen 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of 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 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 CAPSULES EVERY 4 HOURS FOR 16 HOURS COMPARISON OF PHARMACOKINETIC PARAMETERS Values expressed are mean ± standard deviation FOR KETOPROFEN CAPSULES AND KETOPROFEN EXTENDED-RELEASE CAPSULES Kinetic Parameters Ketoprofen Immediate-Release (4 x 50 mg) Ketoprofen Extended-Release (1 x 200 mg) Extent of oral absorption (bioavailability) F s (%) ~ 90 ~ 90 Peak plasma levels C max (mg/L) Fasted 3.9 ± 1.3 3.1 ± 1.2 Fed 2.4 ± 1.0 3.4 ± 1.3 Time to peak concentration t max (h) Fasted 1.2 ± 0.6 6.8 ± 2.1 Fed 2.0 ± 0.8 9.2 ± 2.6 Area under plasma concentration-time curve AUC 0-24h (mg•h/L) Fasted 32.1 ± 7.2 30.1 ± 7.9 Fed 36.6 ± 8.1 31.3 ± 8.1 Oral-dose clearance CL/F (L/h) 6.9 ± 0.8 6.8 ± 1.8 Half-life t 1/2 (h) 2.1 ± 1.2 5.4 ± 2.2 [See footnote In the case of ketoprofen extended-release capsules, absorption is slowed, intrinsic clearance is unchanged, but because the rate of elimination is dependent on absorption, the half-life is prolonged. ] KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING 200 MG OF KETOPROFEN EXTENDED-RELEASE CAPSULES ONCE A DAY (QD), OR 50 MG OF KETOPROFEN CAPSULES EVERY 4 HOURS FOR 16 HOURS 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 (see CLINICAL PHARMACOLOGY: Special Populations: Renally Impaired ). 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. Elimination The plasma clearance of ketoprofen is approximately 0.08 L/kg/h with a V d of 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 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 t 1/2 relative 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 abov