Ketoprofen

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# Black Box Warning

# Overview
Ketoprofen is a analgesic, anti-inflammatory, antimigraine, antirheumatic, central nervous system agent and musculoskeletal agent that is FDA approved for the treatment of rheumatoid arthritis, osteoarthritis, pain and dysmenorrhea. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include edema, rash, abdominal pain, constipation, diarrhea, flatulence, indigestion, nausea, increased liver function test, CNS depression, CNS stimulation, dizziness, headache, abnormal vision, tinnitus and renal impairment..

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Dosage: 75 mg PO q8h or 50 mg PO q6h
- The recommended maximum daily dose of ketoprofen capsules is 300 mg/day.
- Dosage: 75 mg PO q8h or 50 mg PO q6h
- The recommended maximum daily dose of ketoprofen capsules is 300 mg/day.
- Dosage: 25 to 50 mg every 6 to 8 hours as necessary. A larger dose may be tried if the patients response to a previous dose was less than satisfactory, but doses above 75 mg have not been shown to give added analgesia.
- Dosage: 12.5 mg q4h-q6h
Maximum dose: 75 mg/day (six 12.5mg tablets)
- Maximum dose: 75 mg/day (six 12.5mg tablets)

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults 

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ketoprofen in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
FDA doesn't indicate Ketoprofen for patients under 18 years old

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ketoprofen in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ketoprofen in pediatric patients.

# Contraindications
- Ketoprofen immediate- and extended-release capsules should not be given to patients who have experienced asthma, urticaria, or allergic type reactions after taking aspirin or other NSAIDs.
- Ketoprofen immediate- and extended-release capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft.

# Warnings

### Cardiovascular Effects
- 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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- NSAIDs, including ketoprofen capsules, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. ], including ketoprofen 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.
- Fluid retention and edema have been observed in some patients taking NSAIDs. Peripheral edema has been observed in approximately 2% of patients taking ketoprofen. Ketoprofen capsules should be used with caution in patients with fluid retention or heart failure.

### Gastrointestinal Effects
- 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 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 non-steroidal 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.
- No information is available from controlled clinical studies regarding the use of ketoprofen capsules in patients with advanced renal disease. Therefore, treatment with ketoprofen capsules is not recommended in these patients with advanced renal disease. If ketoprofen capsule therapy must be initiated, close monitoring of the patient's renal function is advisable.

### Anaphylactoid Reactions
- As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ketoprofen capsules. Ketoprofen capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

### Skin Reactions
- NSAIDs, including ketoprofen capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

### Pregnancy
In late pregnancy, as with other NSAIDs, ketoprofen capsules should be avoided because they may cause premature closure of the ductus arteriosus.

# Adverse Reactions

## Clinical Trials Experience

### Incidence > 1% with Probable Causal Relationship
- Dyspepsia
- Nausea
- Abdominal pain
- Diarrhea
- Constipation
- Flatulence
- Anorexia
- Vomiting
- Stomatitis
- Headache
- Dizziness
- CNS inhibition: somnolence, malaise and depression.
- CNS excitation: insomnia and nervousness
- Tinnitus
- Visual disturbances
- Rash
- Renal impairment
- Urinary Tract Infections (UTI's)

### Incidence < 1% with Probable Causal Relationship
- Chills
- Facial edema
- Infections
- Pain
- Anaphylaxis
- Hypertension
- Palpitations
- Tachycardia
- Congestive Heart Failure (CHF)
- Peripheral vascular disease
- Vasodilation
- 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
- Hypocoagulability
- Agranulocytosis
- Anemia
- Hemolysis
- Purpura
- Thrombocytopenia
- Thirst
- Weight gain
- Weight loss
- Hyponatremia
- Myalgia
- Amnesia
- Confusion
- Impotence
- Migraine
- Paresthesia
- Vertigo
- Dyspnea
- Hemoptysis
- Epistaxis
- Pharyngitis
- Rhinitis
- Bronchospasm
- Laryngeal edema
- Alopecia
- Eczema
- Pruritus
- Purpuric rash
- Sweating
- Urticaria
- Bullous rash
- Exfoliative dermatitis
- Photosensitivity
- Skin discoloration
- Onycholysis
- Toxic epidermal necrolysis
- Erythema multiforme
- Stevens-Johnson syndrome
- Conjunctivitis
- Conjunctivitis sicca
- Eye pain
- Hearing impairment
- Retinal hemorrhage and pigmentation change
- Taste perversion
- Menometrorrhagia
- Hematuria
- Renal failure
- Interstitial nephritis
- Nephrotic syndrome

### Incidence < 1% with Unknown Causal Relationship
- Septicemia
- Shock
- Arrhythmia
- Myocardial infarction
- Buccal necrosis
- Ulcerative colitis
- Microvesicular steatosis
- Pancreatitis
- Diabetes Mellitus
- Dysphoria
- Hallucination
- Libido disturbance
- Nightmares
- Personality disorder
- Aseptic meningitis
- Acute tubulopathy
- Gynecomastia

## Postmarketing Experience
There is limited information regarding Ketoprofen Postmarketing Experience in the drug label.

# Drug Interactions

### Drug Interactions
The following drug interactions were studied with ketoprofen doses of 200 mg/day. The possibility of increased interaction should be kept in mind when ketoprofen capsule doses greater than 50 mg as a single dose or 200 mg of ketoprofen per day are used concomitantly with highly bound drugs.
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
- Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen administered as ketoprofen capsules.
- Ketoprofen does not alter aspirin absorption; however, in a study of 12 normal subjects, concurrent administration of aspirin decreased ketoprofen protein binding and increased ketoprofen plasma clearance from 0.07 L/kg/h without aspirin to 0.11 L/kg/h with aspirin. The clinical significance of these changes is not known; however, as with other NSAIDs, concomitant administration of ketoprofen and aspirin is not generally recommended because of the potential of increased adverse effects.
- NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. Hydrochlorothiazide, given concomitantly with ketoprofen, produces a reduction in urinary potassium and chloride excretion compared to hydrochlorothiazide alone. Patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
- In a study in 12 patients with congestive heart failure where ketoprofen and digoxin were concomitantly administered, ketoprofen did not alter the serum levels of digoxin.
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
- Ketoprofen, like other NSAIDs, may cause changes in the elimination of methotrexate leading to elevated serum levels of the drug and increased toxicity. NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
- Probenecid increases both free and bound ketoprofen by reducing the plasma clearance of ketoprofen to about one-third, as well as decreasing its protein binding. Therefore, the combination of ketoprofen and probenecid is not recommended.
- The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. In a short-term controlled study in 14 normal volunteers, ketoprofen did not significantly interfere with the effect of warfarin on prothrombin time. Bleeding from a number of sites may be a complication of warfarin treatment and GI bleeding a complication of ketoprofen treatment. Because prostaglandins play an important role in hemostasis and ketoprofen has an effect on platelet function as well, concurrent therapy with ketoprofen and warfarin requires close monitoring of patients on both drugs.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- In teratology studies ketoprofen administered to mice at doses up to 12 mg/kg/day (36 mg/m2/day) and rats at doses up to 9 mg/kg/day (54 mg/m2/day), the approximate equivalent of 0.2 times the maximum recommended therapeutic dose of 185 mg/m2/day, showed no teratogenic or embryotoxic effects. In separate studies in rabbits, maternally toxic doses were associated with embryotoxicity but not teratogenicity. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Ketoprofen capsules should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ketoprofen in women who are pregnant.

### Labor and Delivery
- The effects of ketoprofen on labor and delivery in pregnant women are unknown. Studies in rats have shown ketoprofen at doses of 6 mg/kg (36 mg/m2/day, approximately equal to 0.2 times the maximum recommended human dose) prolongs pregnancy when given before the onset of labor. Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), use of ketoprofen during late pregnancy should be avoided.

### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Data on secretion in human milk after ingestion of ketoprofen do not exist. In rats, ketoprofen at doses of 9 mg/kg (54 mg/m2/day; approximately 0.3 times the maximum human therapeutic dose) did not affect perinatal development. Upon administration to lactating dogs, the milk concentration of ketoprofen was found to be 4 to 5% of the plasma drug level. As with other drugs that are excreted in milk, ketoprofen is not recommended for use in nursing mothers.

### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 have not been established.

### Geriatic Use
- 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. 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. 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. 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.
- 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.

### Gender
There is no FDA guidance on the use of Ketoprofen with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ketoprofen with respect to specific racial populations.

### Renal Impairment
- 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 t1/2 was 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.

### Hepatic Impairment
- For patients with alcoholic cirrhosis, no significant changes in the kinetic disposition of immediate-release ketoprofen 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.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ketoprofen in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ketoprofen in patients who are immunocompromised.

# Administration and Monitoring

### Administration
There is limited information regarding Ketoprofen Administration in the drug label.

### Monitoring
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, ketoprofen capsules should be discontinued.

# IV Compatibility
There is limited information regarding the compatibility of Ketoprofen and IV administrations.

# 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 ketoprofens 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.

# Pharmacology

## Mechanism of Action
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.

## Structure
- Ketoprofen is a non-steroidal anti-inflammatory drug. The chemical name for ketoprofen is 2-(3-benzoylphenyl)-propionic acid with the following structural formula:
- 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 95C. It is freely soluble in ethanol, chloroform, acetone, ether and soluble in benzene and strong alkali, but practically insoluble in water at 20C.

## 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 immediate-release ketoprofen capsules. The effect-site rate constant (ke0) was estimated to be 0.9 hour-1 (95% confidence limits: 0 to 2.1), and the concentration (Ce50) 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
- The systemic availability (FS) when the 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.
- Ketoprofen is > 99% bound to plasma proteins, mainly to albumin.

### Absorption
- Ketoprofen is rapidly and well-absorbed, with peak plasma levels occurring within 0.5 to 2 hours.
- When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption is slowed.
- Food intake reduces Cmax by approximately one-half and increases the mean time to peak concentration (tmax) 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 from ketoprofen capsules.

### Multiple Dosing
Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with immediate-release ketoprofen capsules. In studies with healthy male volunteers, trough levels at 24 hours following administration of immediate-release ketoprofen 50 mg capsules QID for 12 hours were 0.07 mg/L and 0.13 mg/L at 24 hours following administration of immediate-release ketoprofen 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of immediate-release ketoprofen 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 immediate-release ketoprofen capsules).

### 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.

### Elimination
- The plasma clearance of ketoprofen is approximately 0.08 L/kg/h with a Vd 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 hours following administration of ketoprofen capsules. In cases of slow drug absorption, the elimination rate is dependent on the absorption rate and thus t1/2 relative to an IV dose appears prolonged.
- 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.

### Special Populations
The plasma and renal clearance of ketoprofen is reduced in the elderly (mean age, 73 years) compared to a younger normal population (mean age, 27 years). Hence, ketoprofen peak concentration and AUC increase with increasing age. In addition, there is a corresponding increase in unbound fraction with increasing age. Data from one trial suggest that the increase is greater in women than in men. It has not been determined whether age-related changes in absorption among the elderly contribute to the changes in bioavailability of ketoprofen.
In a study conducted with young and elderly men and women, results for subjects older than 75 years of age showed that free drug AUC increased by 40% and Cmax increased by 60% as compared with estimates of the same parameters in young subjects (those younger than 35 years of age.
Also in the elderly, the ratio of intrinsic clearance/availability decreased by 35% and plasma half-life was prolonged by 26%. This reduction is thought to be due to a decrease in hepatic extraction associated with aging.

## Nonclinical Toxicology
There is limited information regarding Ketoprofen Nonclinical Toxicology in the drug label.

# Clinical Studies

### Rheumatoid Arthritis and Osteoarthritis
- The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis. 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.

### Management of Pain
- The effectiveness of immediate-release ketoprofen capsules as a general-purpose analgesic has been studied in standard pain models which have shown the effectiveness of doses of 25 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 a tendency 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 to 75 mg did not have increased analgesic effect. Studies in postoperative pain have shown that ketoprofen in doses of 25 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.

# How Supplied
Ketoprofen capsules are available as follows:
- 50 mg: Blue cap and light blue body, imprinted 93 over "3193" on the cap and 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.

## Storage
- Store at 20 to 25C (68 to 77F) . Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Ketoprofen Patient Counseling Information in the drug label.

# Precautions with Alcohol
- Alcohol-Ketoprofen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Orudis
- Orudis KT
- Oruvail

# Look-Alike Drug Names
There is limited information regarding Ketoprofen Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price