Ketoprofen Information
Ketoprofen () Description
Ketoprofen () is a non-steroidal anti-inflammatory drug. The chemical name for Ketoprofen () is 2-(3-benzoylphenyl)-propionic acid with the following structural formula:
CHO M.W. 254.29
It has a pKa of 5.94 in methanol: water (3:1) and an n-octanol: water partition coefficient of 0.97 (buffer pH 7.4).
Ketoprofen () is a white or off-white, odorless, nonhygroscopic, fine to granular powder, melting at about 95°C. It is freely soluble in ethanol, chloroform, acetone, ether and soluble in benzene and strong alkali, but practically insoluble in water at 20°C.
Ketoprofen () capsules contain 50 mg or 75 mg of Ketoprofen () for oral administration.
Ketoprofen () Clinical Pharmacology
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 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.
Ketoprofen () Indications And Usage
Carefully consider the potential benefits and risks of Ketoprofen () capsules and other treatment options before deciding to use Ketoprofen () capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
Ketoprofen () capsules are indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Ketoprofen () capsules are indicated for the management of pain. Ketoprofen () capsules are also indicated for treatment of primary dysmenorrhea.
Ketoprofen () Contraindications
Ketoprofen () capsules are contraindicated in patients who have shown hypersensitivity to Ketoprofen () .
Ketoprofen () 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 , and ,).
Ketoprofen () capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
Ketoprofen () Warnings
NSAIDs, including Ketoprofen () 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 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 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.
Ketoprofen () Precautions
Ketoprofen () capsules 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.
If steroid dosage is reduced or eliminated during therapy, it should be reduced slowly and the patients observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
The pharmacological activity of Ketoprofen () capsules in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Ketoprofen () and other non-steroidal anti-inflammatory drugs cause nephritis in mice and rats associated with chronic administration. Rare cases of interstitial nephritis or nephrotic syndrome have been reported in humans with Ketoprofen () since it has been marketed.
A second form of renal toxicity has been seen in patients with conditions leading to a reduction in renal blood flow or blood volume, where renal prostaglandins have a supportive role in the maintenance of renal blood flow. In these patients, administration of a non-steroidal anti-inflammatory drug results in a dose-dependent decrease in prostaglandin synthesis and, secondarily, in renal blood flow which may precipitate overt renal failure. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of non-steroidal anti-inflammatory drug therapy is typically followed by recovery to the pretreatment state.
Since Ketoprofen () is primarily eliminated by the kidneys and its pharmacokinetics are altered by renal failure (see ), patients with significantly impaired renal function should be closely monitored, and a reduction of dosage should be anticipated to avoid accumulation of Ketoprofen () and/or its metabolites (see ).
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Ketoprofen () capsules. 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, and fatal 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 in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Ketoprofen () capsules. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Ketoprofen () capsules should be discontinued.
In patients with chronic liver disease with reduced serum albumin levels, Ketoprofen () ’s pharmacokinetics are altered (see ). Such patients should be closely monitored, and a reduction of dosage should be anticipated to avoid high blood levels of Ketoprofen () and/or its metabolites (see ).
Anemia is sometimes seen in patients receiving NSAIDs, including Ketoprofen () capsules. 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 Ketoprofen () capsules, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
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 Ketoprofen () capsules who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
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.
NSAIDs are often essential agents in the management of arthritis and have a major role in the treatment of pain, but they also may be commonly employed for conditions which are less serious. Physicians may wish to discuss with their patients the potential risks (see , , and ) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.
Because aspirin causes an increase in the level of unbound Ketoprofen () , patients should be advised not to take aspirin while taking Ketoprofen () (see ). It is possible that minor adverse symptoms of gastric intolerance may be prevented by administering Ketoprofen () capsules with antacids, food, or milk. Because food and milk do affect the rate but not the extent of absorption (see ), physicians may want to make specific recommendations to patients about when they should take Ketoprofen () in relation to food and/or what patients should do if they experience minor GI symptoms associated with Ketoprofen () therapy.
Chronic oral toxicity studies in mice (up to 32 mg/kg/day; 96 mg/m/day) did not indicate a carcinogenic potential for Ketoprofen () . The maximum recommended human therapeutic dose is 300 mg/day for a 60 kg patient with a body surface area of 1.6 m, which is 5 mg/kg/day or 185 mg/m/day. Thus the mice were treated at 0.5 times the maximum human daily dose based on surface area.
A 2 year carcinogenicity study in rats, using doses up to 6.0 mg/kg/day (36 mg/m/day), showed no evidence of tumorigenic potential. All groups were treated for 104 weeks except the females receiving 6.0 mg/kg/day (36 mg/m/day) where the drug treatment was terminated in week 81 because of low survival; the remaining rats were sacrificed after week 87. Their survival in the groups treated for 104 weeks was within 6% of the control group. An earlier 2 year study with doses up to 12.5 mg/kg/day (75 mg/m/day) also showed no evidence of tumorigenicity, but the survival rate was low and the study was therefore judged inconclusive. Ketoprofen () did not show mutagenic potential in the Ames Test. Ketoprofen () administered to male rats (up to 9 mg/kg/day; or 54 mg/m/day) had no significant effect on reproductive performance or fertility. In female rats administered 6 or 9 mg/kg/day (36 or 54 mg/m/day), a decrease in the number of implantation sites has been noted. The dosages of 36 mg/m/day in rats represent 0.2 times the maximum recommended human dose of 185 mg/m/day (see above).
Abnormal spermatogenesis or inhibition of spermatogenesis developed in rats and dogs at high doses, and a decrease in the weight of the testes occurred in dogs and baboons at high doses.
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). In pharmacokinetic studies, Ketoprofen () clearance was reduced in older patients receiving Ketoprofen () capsules, compared with younger patients. Peak Ketoprofen () concentrations and free drug AUC were increased in older patients (see ). The glucuronide conjugate of Ketoprofen () , which can serve as a potential reservoir for the parent drug, is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. It is recommended that the initial dosage of Ketoprofen () capsules should be reduced for patients over 75 years of age and it may be useful to monitor renal function (see ). In addition, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see and ). In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Therefore, caution should be exercised in treating the elderly, and when individualizing their dosage, extra care should be taken when increasing the dose (see ).
In Ketoprofen () capsule clinical studies involving a total of 1540 osteoarthritis or rheumatoid arthritis patients, 369 (24%) were ≥ 65 years of age, and 92 (6%) were ≥ 75 years of age. For Ketoprofen () capsule acute pain studies, 23 (5%) of 484 patients were ≥ 60 years of age. No overall differences in effectiveness were observed between these patients and younger patients.
Ketoprofen () Adverse Reactions
The incidence of common adverse reactions (above 1%) was obtained from a population of 835 Ketoprofen () -treated patients in double-blind trials lasting from 4 to 54 weeks and in 622 patients treated with Ketoprofen () extended-release capsules 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 (255 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 (see ).
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 (see ). 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. postmarketing spontaneous reports.
Reactions are listed below under body system, then by incidence or number of cases in decreasing incidence.
The following rare adverse reactions, whose causal relationship to Ketoprofen () is uncertain, are being listed to serve as alerting information to the physician.
Ketoprofen () Overdosage
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, but are 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 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.
Ketoprofen () Dosage And Administration
Carefully consider the potential benefits and risks of Ketoprofen () capsules and other treatment options before deciding to use Ketoprofen () capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
After observing the response to initial therapy with Ketoprofen () capsules, the dose and frequency should be adjusted to suit an individual patient's needs.
Concomitant use of Ketoprofen () 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 () 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 () capsules is 150 mg. In patients with a more severe renal impairment (GFR less than 25 mL/min/1.73 m or end-stage renal impairment), the maximum total daily dose of Ketoprofen () 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 () capsules should be reduced for patients over 75 years of age (see ).
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 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 and closely monitored.
Ketoprofen () How Supplied
Ketoprofen () capsules are available as follows:
50 mg: Blue cap and light blue body, imprinted “TEVA” on the cap and “3193” on the body, in bottles of 100.
75 mg: Blue cap and white body, imprinted “TEVA” on the cap and “3195” on the body, in bottles of 100 and 500.
Sellersville, PA 18960
Rev. J 10/2010
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