ketoprofen 200 MG 24 HR Extended Release Oral Capsule
Generic Name: KETOPROFEN
Brand Name: Ketoprofen
- Substance Name(s):
- KETOPROFEN
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 ).
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 disease.
If ketoprofen extended-release capsules 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 extended-release capsules.
Ketoprofen extended-release 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 (see CONTRAINDICATIONS and PRECAUTIONS: General: Preexisting Asthma ).
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions NSAIDs, including ketoprofen extended-release 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.
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ketoprofen extended-release capsules.
Some of these events have been fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling.
Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis.
Sometimes symptoms of DRESS may resemble an acute viral infection.
Eosinophilia is often present.
Because this disorder is variable in its presentation, other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.
If such signs or symptoms are present, discontinue ketoprofen extended-release capsules and evaluate the patient immediately.
Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including ketoprofen extended-release capsules, in pregnant women at about 30 weeks gestation and later.
NSAIDs including ketoprofen extended-release capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including ketoprofen extended-release capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.
These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.
Oligohydramnios is often, but not always, reversible with treatment discontinuation.
Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation.
In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ketoprofen extended-release capsules use to the lowest effective dose and shortest duration possible.
Consider ultrasound monitoring of amniotic fluid if ketoprofen extended-release capsules treatment extends beyond 48 hours.
Discontinue ketoprofen extended-release capsules if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS: Pregnancy ).
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 immediate-release doses greater than 50 mg as a single dose or 200 mg of ketoprofen per day are used concomitantly with highly bound drugs.
ACE Inhibitors 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.
Antacids Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen administered as the immediate-release capsules.
Aspirin 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.
Diuretics NSAIDs can reduce the natriuetic 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 (see PRECAUTIONS ).
During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects ), as well as to assure diuretic efficacy.
Digoxin 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.
Lithium 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.
Methotrexate 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 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.
Warfarin 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 (see PRECAUTIONS: Drug/Laboratory Test Interactions: Effect on Blood Coagulation ), concurrent therapy with ketoprofen and warfarin requires close monitoring of patients on both drugs.
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 (longer for sustained-release products) or following a large overdose (5 to 10 times the usual dose).
This should be accomplished via emesis and/or activated charcoal (60 g 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 1-2 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) 3-4 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.
DESCRIPTION
Ketoprofen is a nonsteroidal anti-inflammatory drug.
The chemical name for ketoprofen is (±)- m -Benzoylhydratropic acid with the following structural formula: Its molecular formula is C 16 H 14 O 3 , with a molecular weight of 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, USP 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.
Each ketoprofen extended-release capsule, USP for oral administration contains 200 mg of ketoprofen, USP.
In addition, each capsule contains the following inactive ingredients: ammonium hydroxide, black iron oxide, colloidal anhydrous silica, dibutyl sebacate, ethylcellulose, FD&C Blue No.
2, gelatin, hypromellose, maltodextrin, methacrylic acid copolymer type B, oleic acid, polyacrylate dispersion, silicon dioxide, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide, triacetin, triethyl citrate and yellow iron oxide.
In addition, the black imprinting ink contains the following: black iron oxide, D&C Yellow No.
10 Aluminum Lake, FD&C Blue No.
1 Aluminum Lake, FD&C Blue No.
2 Aluminum Lake, FD&C Red No.
40 Aluminum Lake, propylene glycol and shellac glaze.
Ketoprofen Structural Formula
CLINICAL STUDIES
Clinical Trials Rheumatoid Arthritis and Osteoarthritis The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis.
Using standard assessments of therapeutic response, there were no detectable differences in effectiveness or in the incidence of adverse events in crossover comparison of ketoprofen capsules and ketoprofen extended-release capsules.
In other trials, ketoprofen demonstrated effectiveness comparable to aspirin, ibuprofen, naproxen, piroxicam, diclofenac and indomethacin.
In some of these studies there were more dropouts due to gastrointestinal side effects among patients on ketoprofen than among patients on other NSAIDs.
In studies with patients with rheumatoid arthritis, ketoprofen was administered in combination with gold salts, antimalarials, low-dose methotrexate, d-penicillamine, and/or corticosteroids with results comparable to those seen with control nonsteroidal drugs.
Management of Pain The effectiveness of 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 capsules 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.
The use of ketoprofen extended-release capsules in patients with acute pain is not recommended, since, in comparison to ketoprofen capsules, ketoprofen extended-release capsules would be expected to have a delayed analgesic response due to its extended-release characteristics.
HOW SUPPLIED
Ketoprofen Extended-Release Capsules, USP are available containing 200 mg of ketoprofen, USP.
The 200 mg capsules are hard-shell gelatin capsules with a blue green opaque cap and an iron gray opaque body filled with white to off-white beads.
The capsules are axially printed with MYLAN over 8200 in black ink on both the cap and body.
They are available as follows: NDC 0378-8200-01 bottles of 100 capsules Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Protect from direct light and excessive heat and humidity.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Dispense a Medication Guide with each prescription.
GERIATRIC USE
Geriatric 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 extended-release capsules, compared with younger patients.
Peak ketoprofen concentrations and free drug AUC were increased in older patients (see PHARMACOKINETICS: Special Populations ).
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 extended-release capsules should be reduced for patients over 75 years of age and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION ).
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 WARNINGS and PRECAUTIONS ).
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 DOSAGE AND ADMINISTRATION ).
In ketoprofen capsules 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 capsules acute pain studies, 23 (5%) of 484 patients were ≥ 60 years of age.
In ketoprofen extended-release capsules clinical studies, 356 (42%) of 840 osteoarthritis or rheumatoid arthritis patients were ≥ 65 years of age, and less than 100 of these were ≥ 75 years of age.
No overall differences in effectiveness were observed between these patients and younger patients.
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 ).
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established.
PREGNANCY
Pregnancy Risk Summary Use of NSAIDs, including ketoprofen extended-release capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.
Because of these risks, limit dose and duration of ketoprofen extended-release capsules use between about 20 and 30 weeks of gestation, and avoid ketoprofen extended-release capsules use at about 30 weeks of gestation and later in pregnancy (see WARNINGS: Fetal Toxicity ).
Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ketoprofen extended-release capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.
Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.
In the general U.S.
population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss.
In animal reproduction studies, ketoprofen administered to mice at doses up to 12 mg/kg/day (36 mg/m 2 /day) and rats at doses up to 9 mg/kg/day (54 mg/m 2 /day), the approximate equivalent of 0.2 times the maximum recommended therapeutic dose of 185 mg/m 2 /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.
Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.
In animal studies, administration of prostaglandin synthesis inhibitors such as ketoprofen, resulted in increased pre- and post-implantation loss.
Prostaglandins also have been shown to have an important role in fetal kidney development.
In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.
Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ketoprofen extended-release capsules, can cause premature closure of the fetal ductus arteriosus (see WARNINGS: Fetal Toxicity ).
Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible.
If ketoprofen extended-release capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios.
If oligohydramnios occurs, discontinue ketoprofen extended-release capsules and follow up according to clinical practice (see WARNINGS: Fetal Toxicity ).
Data Human Data Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.
These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.
In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug.
There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible.
Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.
Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications.
These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use.
Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.
NUSRING MOTHERS
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/m 2 /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.
BOXED WARNING
Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.
This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS ).
• Ketoprofen extended-release capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS ).
Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.
These events can occur at any time during use and without warning symptoms.
Elderly patients are at greater risk for serious gastrointestinal (GI) events (see WARNINGS ).
INFORMATION FOR PATIENTS
Information For Patients 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.
1.
Cardiovascular Thrombotic Events: Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS ).
2.
Ketoprofen extended-release capsules, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death.
Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation ).
3.
Serious Skin Reactions, including DRESS: Advise patients to stop taking ketoprofen extended-release capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see WARNINGS ).
4.
Heart Failure and Edema: Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS ).
5.
Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6.
Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat).
If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS ).
7.
Fetal Toxicity: Inform pregnant women to avoid use of ketoprofen extended-release capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.
If treatment with ketoprofen extended-release capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see WARNINGS: Fetal Toxicity , PRECAUTIONS: Pregnancy ).
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 WARNINGS , PRECAUTIONS: General and ADVERSE REACTIONS ) 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 PRECAUTIONS: Drug Interactions ).
Ketoprofen extended-release capsules have not been studied with antacids.
Because food and milk do affect the rate but not the extent of absorption (see CLINICAL PHARMACOLOGY ), 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.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of ketoprofen extended-release capsules and other treatment options 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 ).
After observing the response to initial therapy with ketoprofen extended-release capsules, the dose and frequency should be adjusted to suit an individual patient’s needs.
Concomitant use of 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 extended-release capsules is 150 mg.
In patients with a more severe renal impairment (GFR less than 25 mL/min/1.73 m 2 or end-stage renal impairment), the maximum total daily dose of ketoprofen extended-release capsules should not exceed 100 mg.
In elderly patients, renal function may be reduced with apparently normal serum creatinine and/or BUN levels.
Therefore, it is recommended that the initial dosage of ketoprofen extended-release capsules should be reduced for patients over 75 years of age (see PRECAUTIONS: 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 extended-release capsules should be 100 mg.
All patients with metabolic impairment, particularly those with both hypoalbuminemia and reduced renal function, may have increased levels of free (biologically active) ketoprofen and should be closely monitored.
The dosage may be increased to the range recommended for the general population, if necessary, only after good individual tolerance has been ascertained.
Because hypoalbuminemia and reduced renal function both increase the fraction of free drug (biologically active form), patients who have both conditions may be at greater risk of adverse effects.
Therefore, it is recommended that such patients also be started on lower doses of ketoprofen extended-release capsules and closely monitored.
Rheumatoid Arthritis and Osteoarthritis The recommended starting dose of ketoprofen in otherwise healthy patients is for ketoprofen extended-release capsules 200 mg administered once a day.
Smaller doses of ketoprofen extended-release capsules should be utilized initially in small individuals, or in debilitated or elderly patients.
The recommended maximum daily dose of ketoprofen is 200 mg/day for ketoprofen extended-release capsules.
Dosages higher than 200 mg/day of ketoprofen extended-release capsules are not recommended because they have not been studied.
Concomitant use of ketoprofen extended-release capsules is not recommended.
Relatively smaller people may need smaller doses.
As with other nonsteroidal anti-inflammatory drugs, the predominant adverse effects of ketoprofen are gastrointestinal.
To attempt to minimize these effects, physicians may wish to prescribe that ketoprofen extended-release capsules be taken with antacids, food, or milk.
Although food delays the absorption of both formulations (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 extended-release capsules in relation to food and/or what patients should do if they experience minor GI symptoms associated with either formulation.
Management of Pain and Dysmenorrhea Ketoprofen extended-release capsules are not recommended for use in treating acute pain because of its extended-release characteristics.