Fenoprofen (Monograph)

Brand name: Nalfon
Drug class: Reversible COX-1/COX-2 Inhibitors

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Prototypical NSAIA;^{100 b} propionic acid derivative;^b structurally and pharmacologically related to flurbiprofen, ibuprofen, ketoprofen, and naproxen.^{b d}

Uses for Fenoprofen

Consider potential benefits and risks of fenoprofen therapy as well as alternative therapies before initiating therapy with the drug.^{100 137 b} Use lowest possible effective dosage and shortest duration of therapy consistent with patient’s treatment goals.^{100 137 b}

Pain

Relief of mild to moderate pain in adults.^{100 b}

Inflammatory Diseases

Symptomatic treatment of osteoarthritis and rheumatoid arthritis.^{100 b d}

Has been used in the symptomatic treatment of juvenile rheumatoid arthritis^{† [off-label]}.^{b c}

Also has been used with some success in the treatment of ankylosing spondylitis^{† [off-label]} and acute gouty arthritis^{† [off-label]}.^{b d}

Fenoprofen Dosage and Administration

General

• Consider potential benefits and risks of fenoprofen therapy as well as alternative therapies before initiating therapy with the drug.^{100 137 b}

Administration

Oral Administration

Administer orally.^{100 b}

Administration with meals, milk, or antacids may minimize adverse GI effects.^{100 b d}

Dosage

Available as fenoprofen calcium; dosage expressed in terms of fenoprofen.^{100 b}

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.^{100 137 b} Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^{100 137 b}

Adults

Pain

Oral

For mild to moderate pain, 200 mg every 4–6 hours as needed.^{100 b}

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

Initially, 400–600 mg 3 or 4 times daily.^{146 508} Adjust dose and frequency as necessary based on severity of symptoms and clinical response (maximum 3.2 g daily).^{100 b}

Patients with rheumatoid arthritis may require higher dosages than those with osteoarthritis.^{100 b}

Symptomatic improvement usually begins in a few days, but an additional 2–3 weeks may be needed to determine response.^{100 b}

Prescribing Limits

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

Maximum 3.2 g daily.^{100 b}

Special Populations

Renal Impairment

No dosage adjustments recommended.¹⁰⁰

Use not recommended in patients with advanced renal disease.¹⁰⁰

Hepatic Impairment

No dosage adjustments recommended.

Cautions for Fenoprofen

Contraindications

• Known hypersensitivity to fenoprofen or any ingredient in the formulation.^{100 d}

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^{100 137 d}

• In the setting of CABG surgery.⁵⁰⁸

• History of significant renal impairment.¹⁰⁰

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.^{500 502 508}

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information^{500 501 502} indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.⁵⁰⁰

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.^{500 502 506 508}

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.^{500 502 505 506 508}

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.⁵⁰⁸

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.^{505 508}

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;^{500 508 511} absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.^{508 511}

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs.^{141 142 143 145 500 501 502 503 506} FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.⁵⁰⁰

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.^{100 137 500 508}

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.^{505 511 512 516} Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.⁵⁰⁸ Contraindicated in the setting of CABG surgery.⁵⁰⁸

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.^{100 137 138 502 508} (See Specific Drugs under Interactions.)

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms;^{100 104 105 108} increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.^{100 124 127 134}

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{107 124 125 126} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)^{107 124 125} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).¹²⁵

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.^{100 137} Use with caution in patients with hypertension; monitor BP.^{100 137}

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.^{100 137 508} (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.^{100 137 508}

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.^{500 501 504 507 508}

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.⁵⁰⁸ (See Specific Drugs under Interactions.)

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.⁵⁰⁸

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.⁵⁰⁷

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.^{100 137}

Potential for overt renal decompensation.^{100 137} Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.^{100 137 140} (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.^{100 137} Immediate medical intervention and discontinuance for anaphylaxis.^{100 137}

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.^{100 137 d}

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs.¹²⁰¹ Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).¹²⁰¹ Symptoms may resemble those of acute viral infection.¹²⁰¹ Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.¹²⁰¹ If signs or symptoms of DRESS develop, discontinue fenoprofen and immediately evaluate the patient.¹²⁰¹

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.^{100 137} Discontinue at first appearance of rash or any other signs of hypersensitivity (e.g., blisters, fever, pruritus).^{100 137}

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.¹⁰⁰

Elevations of serum ALT or AST reported.¹⁰⁰

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.¹⁰⁰ Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.¹⁰⁰

Hematologic Effects

Anemia reported rarely.^{100 137} Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.^{100 137 d}

May inhibit platelet aggregation and prolong bleeding time.^{100 137 d}

CNS Effects

Drowsiness and dizziness reported; may impair ability to perform activities requiring mental alertness.^{100 b}

Ocular Effects

Adverse ocular effects reported in patients receiving NSAIA therapy; ophthalmologic evaluation recommended if visual disturbances occur.^{100 b}

Otic Effects

Safety not established in patients with hearing impairment; auditory function tests should be performed periodically in these patients during prolonged therapy.^{100 b}

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.¹⁰⁰

May mask certain signs of infection.^b

Obtain CBC and chemistry profile periodically during long-term use.¹⁰⁰

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.^{1200 1201}

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.¹²⁰²

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice.^{1200 1201} (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs.^{1200 1201} Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.^{1200 1201} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{1200 1201} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{1200 1201} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{1200 1201} Deaths associated with neonatal renal failure also reported.¹²⁰⁰ Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.¹²⁰¹ Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.¹²⁰¹

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.¹²⁰¹ In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.¹²⁰¹

No evidence of developmental abnormalities in animal reproduction studies with fenoprofen.¹²⁰¹

Effects of fenoprofen on labor and delivery not known.¹²⁰¹ In animal studies, NSAIAs increased incidence of dystocia, delayed parturition, and decreased pup survival.¹²⁰¹

Lactation

Fenoprofen is distributed into milk.^{b d} Discontinue nursing or the drug.^{100 b}

Fertility

NSAIAs may be associated with reversible infertility in some women.¹²⁰³ Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.¹²⁰³

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.¹²⁰³

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹⁰⁰

Geriatric Use

Use with caution in patients ≥65 years of age.¹⁰⁰ Geriatric patients appear to tolerate therapy less well (e.g., possible higher incidence of adverse GI effects, greater risk of developing renal decompensation) than younger individuals.^{100 b} Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{100 b}

Renal Impairment

Has not been evaluated in patients with severe renal impairment.^{100 b} Use not recommended in patients with advanced renal disease.^{100 b}

Common Adverse Effects

Dyspepsia,^{100 d} nausea,^{100 d} constipation,^{100 d} headache,¹⁰⁰ somnolence,¹⁰⁰ dizziness,¹⁰⁰ nervousness,¹⁰⁰ asthenia,¹⁰⁰ peripheral edema.¹⁰⁰

Drug Interactions

Protein-bound Drugs

Possible pharmacokinetic interaction; potential for fenoprofen to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs (e.g., oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas).^{100 b d} Observe for adverse effects if used with other protein-bound drugs.^{100 b}

Specific Drugs

Fenoprofen Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration.^{100 b d} Peak plasma concentrations usually attained within 2 hours.^{100 b}

Onset

Onset of analgesic activity reportedly occurs within 15–30 minutes following oral administration.^b

Duration

Duration of analgesic activity: 4–6 hours.^b

Food

Food delays and diminishes peak plasma fenoprofen concentrations.^{100 a b d}

Distribution

Extent

Distributed into milk;^{b d} does not appear to cross the placenta.^{b d}

Plasma Protein Binding

Approximately 99% (mainly to albumin).^{100 b d}

Elimination

Metabolism

Extensively metabolized in the liver.^{b d} Fenoprofen’s major metabolite, 4′-hydroxyfenoprofen, probably is inactive.^b

Elimination Route

Eliminated principally in urine as unchanged drug (2–5%), 4′-hydroxyfenoprofen (2–5%), their glucuronide or other conjugates (90%), and unidentified conjugates (2–5%).^{100 b d}

Half-life

2.5–3 hours.^{100 b d}

Special Populations

Not substantially removed by hemodialysis or peritoneal dialysis.¹⁰⁰

Stability

Storage

Oral

Capsules and Tablets

Tight containers at 20–25°C.¹⁰⁰

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{118 119 120 121 122 123 b}

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.^{100 118 119 120 121 122 123 b d}

Advice to Patients

• Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.^{100 137}

• Risk of serious cardiovascular events (e.g., MI, stroke).^{100 500 508 b} Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.^{100 500 508 b}

• Risk of GI bleeding and ulceration.^{100 111 115 b} Importance of notifying a clinician if signs and symptoms of serious adverse GI effects occur.^{100 b}

• Risk of serious skin reactions,^{100 b} DRESS,¹²⁰¹ and anaphylactoid and other sensitivity reactions.^{100 b} Advise patients to stop taking fenoprofen immediately if they develop any type of rash or fever and to promptly contact their clinician.¹²⁰¹ Importance of seeking immediate medical attention if an anaphylactic reaction occurs.^{100 b}

• Risk of hepatotoxicity.^{100 b} Importance of discontinuing therapy and contacting a clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.^{100 b}

• Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.^{100 508}

• Risk of dizziness and potential for drug to impair mental alertness; use caution when driving or operating machinery until effects on individual are known.^{100 b}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹⁰⁰

• Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.^{1200 1201}

• Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.¹²⁰³

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant diseases.¹⁰⁰

• Importance of informing patients of other important precautionary information.¹⁰⁰ (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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