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Ketoprofen

Pronunciation

Pronunciation: KEE-toe-PROE-fen
Class: NSAID

Trade Names

Ketoprofen
- Capsules, oral 50 mg
- Capsules, oral 75 mg
- Capsules, extended-release, oral 200 mg

APO-Keto (Canada)
APO-Keto-E (Canada)
APO-Keto SR (Canada)

Pharmacology

Decreases inflammation, pain, and fever, probably through inhibition of cyclooxygenase activity and prostaglandin synthesis.

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Pharmacokinetics

Absorption

Immediate-release is released in the stomach; T max is 0.5 to 2 h. ER is released in the small intestine; T max is 6 to 7 h. Bioavailability is approximately 90%. Food does not change AUC, but the rate of absorption for either form is slowed.

Distribution

More than 99% protein bound, mainly to albumin. Vd is 0.1 L/kg.

Metabolism

Metabolic pathway is glucuronide conjugation. The metabolite is acylglucuronide, which can be converted back to the parent drug. There are no known active metabolites.

Elimination

Immediate-release half-life is 2 to 4 h. ER half-life is approximately 5.4 h. Cl is approximately 0.08 L/kg/h.

Special Populations

Renal Function Impairment

Cl is decreased and half-life is prolonged. Adjustment of the max total daily dose is recommended.

Hepatic Function Impairment

Unbound fraction is approximately doubled; daily doses should be kept at the minimum.

Elderly

Plasma and renal Cl are reduced and the unbound fraction increases.

Gender

Data suggest that the increase in unbound fraction is greater in women than in men.

Hypoalbuminemia

Patients with this condition may be at greater risk of adverse reactions due to increased fractions of free drug. Give these patients lower doses of the drug, and monitor them closely.

Indications and Usage

Treatment of rheumatoid arthritis and osteoarthritis; management of pain (immediate-release only); treatment of primary dysmenorrhea (immediate-release only).

Unlabeled Uses

Treatment of juvenile idiopathic arthritis; migraine prophylaxis; menstrual migraine.

Contraindications

Hypersensitivity to any component of the product; patients in whom aspirin or other NSAIDs induce asthma, urticaria, or other allergic-type reactions; treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Dosage and Administration

Rheumatoid Arthritis or Osteoarthritis
Adults Immediate release

PO 75 mg 3 times daily or 50 mg 4 times daily. If minor adverse reactions appear, they may disappear with a decrease in dosage. If well tolerated but not optimally effective, the dosage may be increased to a max of 300 mg/day.

ER

PO 200 mg once daily.

Pain Management, Primary Dysmenorrhea
Adults Immediate release

PO 25 to 50 mg every 6 to 8 h as needed; do not exceed 300 mg/day.

Elderly

Use smaller doses initially in elderly or debilitated patients.

Renal Function Impairment

Max recommended total daily dose is 150 mg in patients with mild renal impairment. In patients with more severe renal impairment (glomerular filtration rate less than 25 mL/min or ESRD), the max total daily dose should not exceed 100 mg. Patients with renal impairment and hypoalbuminemia should be started on lower doses and closely monitored.

Hepatic Function Impairment

For patients with impaired hepatic function and serum albumin concentration less than 3.5 g/dL, the max initial total daily dose should be 100 mg. The dose may be increased if necessary but only after good individual tolerance has been ascertained.

General Advice

  • May take with antacids, food, or milk to minimize GI effects.
  • Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Storage/Stability

Store between 68° and 77°F. Protect from light and excessive heat and humidity.

Drug Interactions

ACE inhibitors (eg, captopril, lisinopril)

The antihypertensive effect of ACE inhibitors may be diminished. Also, the risk of nephrotoxicity associated with ACE inhibitors or ketoprofen may be increased. Closely monitor BP. If BP control deteriorates, consider stopping ketoprofen. Periodic measurement of renal function is warranted.

Alcohol

The risk of GI bleeding may be increased. Avoid alcohol.

Aminoglycosides (eg, gentamicin)

Plasma aminoglycoside levels may be elevated. The risk of acute renal failure may be increased. Avoid coadministration.

Anticoagulants (eg, warfarin)

The risk of GI bleeding may be increased. Monitor coagulation status and adjust the anticoagulant dosage as needed. Monitor for signs of GI bleeding.

Aspirin

Ketoprofen Cl may be increased; coadministration is not recommended because of the potential for increased adverse reactions.

Bisphosphonates (eg, alendronate)

Synergistic action may increase the risk of GI adverse reactions (eg, gastric ulceration). Use with caution. Closely monitor for GI adverse reactions.

Clopidogrel, corticosteroids (eg, prednisone), prasugrel

The risk of bleeding may be increased. Use with caution.

Cyclosporine, tacrolimus

The nephrotoxicity of each agent may be increased. Closely monitor renal function and cyclosporine and tacrolimus concentrations. If an interaction is suspected, decrease the cyclosporine and tacrolimus dose or discontinue ketoprofen.

Dabigatran, desirudin

The risk of bleeding may be increased. If coadministration cannot be avoided, instruct patients to report any signs or symptoms of bleeding or gastric discomfort to their health care provider.

Diuretics (eg, loop diuretics [eg, furosemide], thiazide diuretics [chlorothiazide])

Patients treated with ketoprofen may be resistant to the effects of loop diuretics and thiazides. In addition, renal toxicity may occur. Closely observe patients for diuretic efficacy and signs of renal failure.

Heparin

The risk of heparin-induced bleeding may be increased. If coadministration cannot be avoided, close clinical and laboratory monitoring is warranted.

Lithium

Lithium plasma concentrations may be elevated, increasing the risk of toxicity. Monitor lithium plasma concentrations and the clinical response. Monitor for signs of lithium toxicity. Adjust the lithium dose as needed.

Methotrexate

Plasma concentrations and toxic effects of methotrexate may be increased. Severe toxicity characterized by bone marrow suppression, nephrotoxicity, and mucositis has occurred in patients receiving NSAIDs and high-dose methotrexate chemotherapy. Fatal toxicity has occurred. Coadministration of high-doses of methotrexate and ketoprofen should be avoided. Use of low-dose methotrexate for rheumatoid arthritis, commonly used in conjunction with NSAIDs, is considerably less likely to result in a clinically important interaction.

Pemetrexed

Plasma concentrations and toxic effects of pemetrexed may be increased. A 2- to 5-day suspension of ketoprofen before and 2 days after pemetrexed administration may be recommended. Alternatively, ibuprofen may be an acceptable alternative to ketoprofen in patients with healthy renal function who are receiving pemetrexed.

Probenecid

Pharmacologic and toxic effects of ketoprofen may be increased. Closely monitor for signs of ketoprofen toxicity. Adjust the ketoprofen dose as needed.

Quinolones (eg, norfloxacin)

The risk of CNS stimulation and seizures from quinolones may be increased. In addition, plasma concentrations of quinolones may be increased. Coadminister with caution.

Rivaroxaban

Because of additive effects on the inhibition of normal clotting mechanisms, the risk of bleeding may be increased. Coadminister with caution. Careful clinical monitoring is warranted.

Serotonin reuptake inhibitors (eg, fluoxetine, venlafaxine)

The risk of upper GI bleeding may be increased. If coadministration cannot be avoided, close clinical monitoring for signs of GI bleeding is warranted. Use of acid suppression therapy may be considered.

Smoking

The risk of GI bleeding may be increased.

Triamterene

The risk of acute renal failure may be increased. If coadministration cannot be avoided, closely monitor renal function. If renal function decreases, consider stopping one or both drugs.

Adverse Reactions

CNS

CNS excitation (ie, dreams, insomnia, nervousness), headache (3% to 9%); CNS inhibition (ie, depression, malaise, somnolence), dizziness (more than 1% to less than 3%).

EENT

Tinnitus, visual disturbances (more than 1% to less than 3%).

GI

Dyspepsia (11%); abdominal pain, constipation, diarrhea, flatulence, nausea (3% to 9%); anorexia, stomatitis, vomiting (more than 1% to less than 3%).

Genitourinary

Increased BUN (3% to 9%); signs or symptoms of UTI (more than 1% to less than 3%).

Metabolic

Edema (3% to 9%).

Precautions

Warnings

NSAIDs may cause an increased risk of serious CV thrombotic events, MI, and stroke, which can be fatal. This risk may increase with length of therapy. Patients with CV disease or risk factors for CV disease may be at greater risk. NSAIDs are contraindicated for the treatment of perioperative pain in the setting of CABG surgery. NSAIDs cause an increased risk of serious GI adverse reactions, including bleeding, inflammation, perforation of the stomach or intestines, and ulceration, which can be fatal. These events can occur any time during use and without warning symptoms. Elderly patients are at greater risk of serious GI events.


Monitor

Monitor for signs and symptoms of GI bleeding. Periodically check CBC and chemistries in patients on long-term therapy. Closely monitor BP during the initiation and throughout the course of therapy. Closely monitor renal function when using ketoprofen in patients with advanced renal disease. Evaluate patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, for evidence of the development of a more severe hepatic reaction. Monitor Hgb and Hct in patients on long-term treatment with ketoprofen if they exhibit any signs or symptoms of anemia. Carefully monitor patients who may be adversely affected by alterations in platelet function (eg, those with coagulation disorders, patients receiving anticoagulants).


Pregnancy

Category C . Avoid use in late pregnancy because ketoprofen may cause premature closure of the ductus arteriosus.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution. Increased risk of adverse reactions.

Hypersensitivity

Anaphylactoid reactions may occur; use with caution in aspirin-sensitive patients because of possible cross-sensitivity.

Renal Function

Lower doses may be necessary. Use is not recommended in patients with advanced renal disease.

Hepatic Function

Use with caution and at reduced doses.

Special Risk Patients

Use with caution in patients with a history of ulcer disease or GI bleeding.

Asthma

Use ketoprofen with caution in patients with asthma because they may have aspirin-sensitive asthma and there is a chance of cross-reactivity.

Dermatologic effects

Serious skin adverse reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and TEN, may occur and can be fatal.

Fever and inflammation

Activity of ketoprofen in reducing fever and inflammation may diminish the utility of these signs in detecting complications of presumed noninfectious, painful conditions.

Fluid retention/edema

May occur. Use with caution in patients with fluid retention or heart failure.

Hematologic effects

Anemia may occur and could be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect on erythropoiesis. Because ketoprofen inhibits platelet aggregation, bleeding time may be prolonged in some patients.

Hepatic effects

Borderline elevations of 1 or more liver tests may occur; these abnormalities may progress, remain unchanged, or be transient with continuing therapy. Rare cases of severe reactions, including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure, some with a fatal outcome, have been reported.

Hypertension

May lead to onset of new hypertension or worsening of preexisting hypertension.

Renal effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Overdosage

Symptoms

Acute renal failure, coma, convulsions, drowsiness, epigastric pain, GI bleeding, hypertension, hypotension, lethargy, nausea, respiratory depression, vomiting.

Patient Information

  • Instruct patients to read the NSAID Medication Guide prior to starting therapy and to reread it with each refill.
  • Inform patients that ketoprofen, like other NSAIDs, may cause serious CV effects, such as MI or stroke. Alert patients to the signs and symptoms of chest pain, shortness of breath, weakness, and slurring of speech. Advise patients to seek medical advice immediately if any of these symptoms are observed.
  • Inform patients that NSAIDs can cause GI discomfort and, rarely, more serious GI adverse effects, such as ulcers and bleeding, which may result in hospitalization and even death.
  • Inform patients that NSAIDs can cause serious skin adverse reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and TEN, which may result in hospitalization and even death. Advise patients to be alert for skin rash, skin blisters, fever, and itching, and to seek medical advice if any of these occur. Advise patients to stop ketoprofen immediately and contact their health care provider if any type of skin rash develops.
  • Advise patients to promptly report signs or symptoms of unexplained weight gain or edema to their health care provider.
  • Inform patients of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms). If these occur, instruct patients to stop therapy and seek immediate medical attention.
  • Inform patients of the risk of anaphylactoid reaction (eg, difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.
  • Advise women of childbearing potential that use of ketoprofen in late pregnancy should be avoided because of the risk of premature closure of the ductus arteriosus.
  • Advise patients to take medication with food, milk, or antacids.
  • Warn patients not to take aspirin or other NSAIDs.
  • Instruct patients not to ingest alcohol or take OTC medications without notifying their health care provider.

Copyright © 2009 Wolters Kluwer Health.

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