Nonsteroidal Anti-inflammatory – Analgesic
Action And Clinical Pharmacology: Pharmacological studies in animals have demonstrated that ketoprofen is an NSAID that possesses anti-inflammatory, analgesic and antipyretic properties. The anti-inflammatory action is not mediated through the pituitary adrenal axis.
Ketoprofen, like other nonsteroidal anti-inflammatory analgesics is an inhibitor of prostaglandin synthesis. In vivo studies have demonstrated that ketoprofen is 8 times as potent as indomethacin in inhibiting the synthesis of prostaglandin from arachidonic acid.
Ketoprofen’s therapeutic effectiveness has been demonstrated by a reduction in joint swelling, pain and duration of morning stiffness, and by increased grip strength and an improvement in functional capacity.
Clinical trials in rheumatoid arthritis have shown that the antiarthritic activity of ketoprofen 200 mg/day was similar to that of ASA 3.6 g/day and induced less gastrointestinal bleeding.
The effectiveness of ketoprofen as a general purpose analgesic has been studied in standard pain models which have shown the effectiveness of doses of 25 to 150 mg were effective in standard pain models. 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 a tendency towards a faster onset and greater duration of action with a 50 mg dose and, in the case of dysmenorrhea, a significantly greater overall effect with 75 mg. Doses greater than 50 to 75 mg did not have an increased analgesic effect.
Pharmacokinetics: In man, ketoprofen is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma levels are reached within 0.5 to 2 hours after administration of capsules or suppositories; however, peak plasma levels are delayed by a further 1 to 2 hours with enteric-coated tablets and by 5 to 6 hours with sustained-release tablets. Pharmacokinetic studies in both young and elderly adults indicated that the Tmax of ketoprofen is similar for both groups. The t1/2 and AUC, however, were significantly increased in the elderly subjects.
When ketoprofen capsules are administered with food, the total bioavailability (AUC) is not altered; however, the rate of absorption is slowed resulting in delayed and reduced peak concentrations (Cmax). Following a single 50 mg dose of ketoprofen while fasting, the mean Cmax was 4.1 mg/L (at 1.1 hours); when administered after food, it decreased to 2.4 mg/L (at 2.0 hours).
The composition of the diet slightly but significantly alters the extent of absorption of ketoprofen from sustained-release tablets; a high-fat/high-calorie meal (3 000 calories/day) was associated with lower ketoprofen bioavailability values (about 20%) than a low-fat/low-calorie content (1 200 calories/day). Mean trough ketoprofen plasma concentrations were similar after high or low fat meals.
Following administration of slow-release ketoprofen, absorption is gradual reaching a plateau during which plasma levels remain steady from the 5th to the 12th hour after ingestion and decrease with an apparent half-life of 3 to 4 days. No accumulation of ketoprofen was found following repeated once-daily administration of ketoprofen sustained-release tablets. Repeated administration of the drug, in both animals and man, caused no induction of liver enzymes.
To date, studies of the effects of age and renal-function impairment have been small, generally involving 5 to 8 subjects per group, but they indicate modest decreases in clearance in the elderly and in patients with impaired renal function. In normal elderly volunteers (mean age 73 years), the plasma and renal clearance and protein-binding were reduced while the Vd increased when compared to a younger normal population (mean age 27 years). (Plasma clearance and Vd were 0.05 L/kg/h and 0.4 L/kg in elderly and 0.06 L/kg/h and 0.3 L/kg in young subjects, respectively). The mean half-life of ketoprofen in this normal geriatric population, as well as in a rheumatoid elderly population (mean age 64 years), was about 5 hours as compared to 3 hours in the younger population.
Patients with impaired renal function (mean age 44 years) also demonstrate decreases in plasma clearance (0.04 L/kg/h) of drug, with the mean half-life increasing to about 3.5 hours.
Ketoprofen is rapidly and extensively metabolized in the liver, principally by hydroxylation and conjugation, the latter being the main metabolic pathway in man.
Metabolites as well as the unchanged drug are excreted mainly in the urine; fecal excretion is negligible. Following the administration of capsules or enteric coated tablet in man, 25 to 90% of the drug is excreted in the urine within 24 hours, with the major portion being excreted during the first 6 hours. The elimination half-life is approximately 2 hours and the apparent plasma clearance averages approximately 1 to 1.3 mL/min/kg. Repeated administration of the drug, in both animals and man, caused no induction of liver enzymes.
Indications And Clinical Uses: In the treatment of rheumatoid arthritis, ankylosing spondylitis and osteoarthritis.
Ketoprofen is also indicated in the treatment of primary dysmenorrhea and the relief of mild to moderate acute pain associated with musculotendinous trauma (sprains and strains), postoperative (including dental surgery) or postpartum pain.
Contra-Indications: Active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system.
Known or suspected hypersensitivity to the drug or other NSAIDs. The potential for cross-reactivity between different NSAIDs must be kept in mind.
Ketoprofen should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.
Significant hepatic impairment or active liver disease.
Severely impaired or deteriorating renal function (creatinine clearance
Ketoprofen is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.
Ketoprofen suppositories should not be used in patients with any inflammatory lesions of the rectum or anus and in patients with a recent history of rectal or anal bleeding.
Manufacturers’ Warnings In Clinical States: Gastrointestinal System: Serious gastrointestinal toxicity, such as peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms in patients treated with NSAIDs including ketoprofen.
Minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy. Physicians should remain alert for ulceration and bleeding in patients treated with NSAIDs, even in the absence of previous gastrointestinal tract symptoms.
In patients observed in clinical trials of such agents, symptomatic upper gastrointestinal ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months and in about 2 to 4% of patients treated for 1 year. The risk continues beyond 1 year and possibly increases.
The incidence of these complications increases with increasing dose.
Ketoprofen should be given under close medical supervision to patients prone to gastrointestinal tract irritation, particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn’s disease. In these cases, the physician must weigh the benefits of treatment against the possible hazards.
Physicians should inform patients about the signs and/or symptoms of serious gastrointestinal toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.
Because serious gastrointestinal tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this followup.
If ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, ketoprofen should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.
No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious gastrointestinal events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anticoagulant use have been associated with increased risk.
Studies to date show that all NSAIDs can cause gastrointestinal tract adverse events. Although existing data does not clearly identify differences in risk between various NSAIDs, this may be shown in the future.
Geriatrics: Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from NSAIDs: the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal gastrointestinal events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding.
For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision (see Precautions).
Cross-sensitivity: Patients sensitive to any one of the NSAIDs may also be sensitive to any of the other NSAIDs.
Aseptic Meningitis: In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be predisposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.
Pregnancy , Labor and Lactation: The safety of ketoprofen when administered to pregnant or nursing women has not been determined, and therefore such use is not recommended. Pregnant rats who received ketoprofen 6 and 9 mg/kg/day orally from day 15 of gestation, showed dystocia and increased pup mortality.
In rats, ketoprofen did not affect perinatal development at doses of 9 mg/kg (representing approximately 1.5 times the maximum human therapeutic dose). In lactating dogs, ketoprofen concentration in milk was found to be 4 to 5% of the plasma drug level. Data on secretion in human milk after ingestion of ketoprofen do not exist. As with other drugs that are excreted in milk, ketoprofen is not recommended for use in nursing mothers.
Children: The conditions for safe and effective use of ketoprofen in children under 12 years of age have not been established, and the drug is therefore not recommended in this age group.
Precautions: Gastrointestinal System: There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of ketoprofen therapy when and if these adverse reactions appear.
Suppositories should be given with caution to patients with any rectal or anal pathology.
Renal Function: Long-term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and 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 the elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.
Ketoprofen and its metabolites are eliminated primarily by the kidneys; therefore the drug should be used with great caution in patients with impaired renal function. In these cases, utilization of lower doses of ketoprofen should be considered and patients carefully monitored
During long-term therapy kidney function should be monitored periodically.
Genitourinary Tract: Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with ketoprofen must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.
Hepatic function: As with other NSAIDs, borderline elevations of one or more liver function tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Meaningful (3 times the upper limit of normal) elevations of ALT or AST occurred in controlled clinical trials in less than 1% of patients. 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 more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with NSAIDs.
Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), this drug should be discontinued.
During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.
Fluid and Electrolyte Balance: Fluid retention and edema have been observed in patients treated with ketoprofen. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Ketoprofen should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.
With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with b-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.
Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when ketoprofen is administered.
Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.
Anemia is commonly observed in rheumatoid arthritis and is sometimes aggravated by NSAIDs, which may produce fluid retention or minor gastrointestinal blood loss in some patients. Therefore, patients with initial hemoglobin values of 10 g/dL or less who are to receive long-term therapy should have hemoglobin values determined frequently.
Infection: In common with other anti-inflammatory drugs, ketoprofen may mask the usual signs of infection.
Ophthalmology: Blurred and/or diminished vision has been reported with the use of ketoprofen and other NSAIDs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.
CNS: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of ketoprofen. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.
Drug Interactions: ASA or other NSAIDs: The use of ketoprofen in addition to any other NSAID, including those over the counter drugs (such as ASA and ibuprofen) is not recommended due to the possibility of additive side effects.
Concurrent administration of ASA and ketoprofen reduces protein binding of ketoprofen and increases its plasma clearance. The overall result was a 40% reduction in the AUC of ketoprofen. Ketoprofen does not alter ASA absorption.
Anticoagulants: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of gastrointestinal adverse events such as ulceration and bleeding.
Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of ketoprofen with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary.
Ketoprofen has been shown to depress platelet aggregation and it can prolong bleeding time by approximately 3 to 4 minutes from baseline values. However, a study conducted in 20 patients undergoing therapy with coumarin and simultaneously receiving ketoprofen, failed to demonstrate potentiation of anticoagulant effect. Nevertheless, close monitoring of patients is recommended when ketoprofen is given concomitantly with anticoagulants.
Diuretics: Hydrochlorothiazide, given concomitantly with ketoprofen, produces a reduction in urinary potassium and chloride excretion compared to hydrochlorothiazide alone. Patients taking diuretics are at greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition.
Glucocorticoids: Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of gastrointestinal side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.
Antacids: Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen.
Methotrexate: The concomitant administration of ketoprofen and high-dose methotrexate has been associated with prolonged and marked enhancement of serum methotrexate levels resulting in severe methotrexate toxicity. This may also apply to some other NSAIDs. There were no abnormalities in methotrexate kinetics or evidence of toxicity when ketoprofen was given at least 12 hours after completion of high-dose methotrexate infusion. Ketoprofen should not be used in patients receiving high-dose methotrexate.
The potential for severe toxicity should be kept in mind when prescribing ketoprofen and low-dose methotrexate concurrently. Ketoprofen should not be administered within 12 hours of methotrexate infusion.
Lithium: NSAIDs have been reported to increase steady-state plasma lithium levels. It is recommended that plasma lithium levels be monitored when ketoprofen is coadministered with lithium.
Other Drug Interactions : Probenecid: Concurrent administration of probenecid increases both free and bound ketoprofen through reducing the plasma clearance of ketoprofen to about one-third as well as decreasing its protein binding. Ketoprofen is not recommended in association with probenecid.
Ketoprofen is extensively (99%) protein bound to human serum albumin and may compete for binding sites with drugs such as sulfonamides, oral hypoglycemic agents, phenytoin or lithium. Although no significant interaction has been documented, patients with such combination therapy should be monitored.
Clinical Laboratory Tests: The presence of ketoprofen and its metabolites in urine has been shown to interfere with certain tests that are used to detect albumin, bile salts, 17-ketosteroids or 17-hydroxycorticosteroids in urine and which rely upon acid precipitation as an end point or upon color reactions of carbonyl groups. No interference was seen in the tests for proteinuria using Albustix, Hema-Combistix or Labstix Reagent Strips.
Although ketoprofen has been shown to depress platelet adhesion and aggregation and consequently, it can prolong bleeding time by approximately 3 to 4 minutes from baseline values; there has been no observed cases of changes in platelet count, prothrombin time, partial thromboplastin time or thrombin time.
Adverse Reactions: The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly.
In clinical trials involving 1 542 patients treated with ketoprofen, gastrointestinal effects were the most frequently observed adverse reactions and were reported in approximately 22% of patients. Ulceration and gastrointestinal bleeding have been noted in a few patients receiving ketoprofen therapy (less than 1% of 1 076 patients in controlled clinical trials); however, in open label continuation studies in 1 292 patients, the rate was greater than 2%.
A detailed breakdown of side effects with their corresponding frequencies (not indicated when
Gastrointestinal (22%): dyspepsia (12.8%), nausea (4%), indigestion and flatulence (2.8%), vomiting (2%), constipation (2%), diarrhea (1.4%), anorexia, ulcer, gastrointestinal bleeding and perforation, melena, hematemesis, stomatitis.
Rectal administration was associated with a lower incidence of upper gastrointestinal reactions (12%) with the exception of ulceration, the incidence of which was the same. However, anorectal reactions presenting as local pain, burning, pruritus, tenesmus and rare instances of rectal bleeding occurred in 16.5% of patients. Five percent of patients discontinued rectal therapy because of these local reactions.
Allergic: These include angioedema, asthma, life-threatening bronchospasm and anaphylaxis.
CNS (3 to 5%): headache (1.7%), fatigue (1%), dizziness, tension, anxiety, depression, drowsiness, impotence, vertigo, migraine, paresthesia.
Cardiovascular: peripheral edema (2%), palpitation, congestive heart failure, hypertension.
Special Senses: tinnitus, hearing impairment, visual disturbance, conjunctivitis, conjunctivitis sicca, taste perversion.
Hematologic: hypocoagulability, agranulocytosis, anemia, hemolysis, purpura, thrombocytopenia.
Renal: interstitial nephritis, hematuria, nephrotic syndrome, impairment of renal function, acute renal failure.
Hepatic: hepatic dysfunction, jaundice.
Other: Laboratory Tests: abnormal alkaline phosphatase, lactic dehydrogenase, glutamic oxaloacetic transaminase and BUN values were found in some patients receiving ketoprofen therapy. The abnormalities did not lead to discontinuation of treatment and, in some cases, returned to normal while the drug was continued. There have been sporadic reports of decreased hematocrit and hemoglobin values without progressive deterioration on prolonged administration of the drug.
Frequency of Adverse Reactions
- Gastrointestinal Dyspepsia (12.8%), nausea (4%), indigestion and flatulence (2.8%), vomiting (2%), constipation (2%), diarrhea (1.4%).
- CNS Headache (1.7%), fatigue (1%).
- Dermatologic Rash (1.7%).
- Cardiovascular Peripheral edema (2%)
- Special Senses
Symptoms And Treatment Of Overdose: Symptoms: Of 20 cases of overdosage (up to 5 000 mg) reported in Great Britain (5 children, 14 adolescents or young adults and 1 elderly), only 4 had mild symptoms (vomiting in 3, drowsiness in 1 child).
Treatment: Administer gastric lavage or an emetic and treat symptomatically: compensate for dehydration, monitor urinary excretion and correct acidosis if present.
The drug is dialyzable; therefore, hemodialysis may be useful to remove circulating drug and to assist in case of renal failure.
Dosage And Administration: Adults: Rheumatoid Arthritis and Osteoarthritis: Oral: The usual dosage for ketoprofen capsules or enteric coated tablets is 150 to 200 mg/day in 3 or 4 divided doses.
Once the maintenance dosage has been established, patients may be tried on a twice daily dosing regimen. Clinical trials, however, show that some rheumatoid arthritis patients respond better to more frequent dosing. The usual maintenance dose is 100 mg twice daily.
Rectal: Ketoprofen suppositories offer an alternative route of administration for those patients who prefer it. Administer 1 suppository morning and evening or 1 suppository at bedtime supplemented as needed by divided oral doses.
Use whole suppositories. Do not split or use portions of suppositories. Make sure that the wrapping is fully removed before inserting the suppository into the rectum. Do not take suppositories by mouth.
The total daily dose of ketoprofen capsules, tablets and suppositories should not exceed 200 mg/day. When the patient’s response warrants it, the dose may be decreased to the minimum effective level.
In severe cases, during flare-up of rheumatic activity or if a satisfactory response cannot be obtained with the lower dose, a daily dosage in excess of 200 mg may be used. However, a dose of 300 mg/day should not be exceeded.
Primary Dysmenorrhea and Mild to Moderate Pain: Oral: The usual dose for ketoprofen is 25 to 50 mg 3 or 4 times daily as necessary.
A larger dose may be tried if the patient’s response to a previous dose was less than satisfactory, but individual doses above 50 mg have not been shown to give added analgesia. The total daily dose should not exceed 300 mg. In most types of acute pain, a course of 3 to 7 days has been shown to be sufficient.
Elderly and Debilitated Patients: Initial dosage should be reduced by 1/2 to 1/3 in patients with impaired renal function and the elderly.
Children: Ketoprofen is not indicated in children under 12 years of age because clinical experience in this group of patients is insufficient.
Availability And Storage: Each off-white, smooth, torpedo-shaped suppository contains: ketoprofen 100 mg. Nonmedicinal ingredients: semisynthetic glycerides. Boxes of 30. Store below 30°C. Keep away from excessive heat, elevated humidity and light.
ORAFEN® Technilab Ketoprofen Nonsteroidal Anti-inflammatory – Analgesic
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