PRINCIPAL DISPLAY PANEL

Fenoprofen Calcium Capsules, USP 400 mg - NDC 71993-0308-90 - 90 Capsules Bottle Label


WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

1 INDICATIONS AND USAGE

Fenoprofen calcium is indicated for:

• Relief of mild to moderate pain in adults
• Relief of the signs and symptoms of rheumatoid arthritis
• Relief of the signs and symptoms of osteoarthritis

4 CONTRAINDICATIONS

Fenoprofen calcium is contraindicated in the following patients:

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to fenoprofen or any components of the drug product [ see Warnings and Precautions ( 5.7, 5.9) ]
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [ see Warnings and Precautions ( 5.7, 5.8) ]
• In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions (5.1)]

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events [ see Warnings and Precautions (5.1)]
• GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions (5.2)]
• Hepatotoxicity [ see Warnings and Precautions (5.3)]
• Hypertension [ see Warnings and Precautions (5.4)]
• Heart Failure and Edema [ see Warnings and Precautions (5.5)]
• Renal Toxicity and Hyperkalemia [ see Warnings and Precautions (5.6)]
• Anaphylactic Reactions [ see Warnings and Precautions (5.7)]
• Serious Skin Reactions [ see Warnings and Precautions (5.9)]
• Hematologic Toxicity [ see Warnings and Precautions (5.12)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies.

Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials

Digestive System— During clinical trials with fenoprofen calcium, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving fenoprofen calcium as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% fenoprofen calcium vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarketing studies.

Nervous System— The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. Fenoprofen calcium was discontinued in less than 0.5% of patients because of these side effects during premarketing studies.

Skin and Appendages— Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. Fenoprofen calcium was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies.

Special Senses— Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. Fenoprofen calcium was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies.

Cardiovascular— Palpitations (2.5% vs. 0.4%). Fenoprofen calcium was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies.

Miscellaneous— Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%), and nasopharyngitis (1.2% vs. none).

Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials

Digestive System—Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool. Increases in alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis.

Cardiovascular—Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia.

Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and papillary necrosis.

Hypersensitivity—Angioedema (angioneurotic edema).

Hematologic—Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and pancytopenia.

Nervous System—Depression, disorientation, seizures, and trigeminal neuralgia.

Special Senses—Burning tongue, diplopia, and optic neuritis.

Skin and Appendages—Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and alopecia.

Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality change, lymphadenopathy, mastodynia, and fever.

RECENT MAJOR CHANGES

Warnings and Precautions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) ( 5.10) 04/2021

Warnings and Precautions, Fetal Toxicity ( 5.11) 04/2021

3 DOSAGE FORMS AND STRENGTHS

Fenoprofen calcium capsules, USP:

• The 400 mg capsule is opaque green cap and opaque blue body, imprinted with “SUVEN” on the cap and “400 mg” on the body.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Instructions

Carefully consider the potential benefits and risks of fenoprofen calcium and other treatment options before deciding to use fenoprofen. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Use lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5)].

Fenoprofen calcium may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are delayed and diminished.

Patients with rheumatoid arthritis generally seem to require larger doses of fenoprofen calcium than do those with osteoarthritis. The smallest dose that yields acceptable control should be employed.

Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy.

2.2 Analgesia

For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed.

2.3 Rheumatoid Arthritis and Osteoarthritis

For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Use of NSAIDs, including fenoprofen calcium, 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 fenoprofen calcium use between about 20 and 30 weeks of gestation, and avoid fenoprofen calcium use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data)

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including fenoprofen calcium, 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 animal reproduction studies, embryo-fetal lethality and skeletal abnormalities were noted in offspring of pregnant rabbits following oral administration of fenoprofen during organogenesis at 0.6 times the maximum human daily dose of 3200 mg/day. However, there were no major malformations noted following oral administration of fenoprofen calcium to pregnant rats and rabbits during organogenesis at exposures up to 0.3 and 0.6 times the maximum human daily dose of 3200 mg/day.

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 fenoprofen, 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.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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 fenoprofen calcium, can cause premature closure of the fetal ductus arteriosus ( see Data).

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 fenoprofen calcium treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue fenoprofen calcium and follow up according to clinical practice ( see Data).

Labor or Delivery

There are no studies on the effects of fenoprofen calcium during labor or delivery. In animal studies, NSAIDS, including fenoprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Human Data

There are no adequate and well-controlled studies of fenoprofen calcium in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.

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.

Animal data

Pregnant rats were treated with fenoprofen using oral doses of 50 or 100 mg/kg (0.15 times and 0.3 times the maximum human daily dose (MHDD) of 3200 mg/day based on body surface area comparison) during the period of organogenesis. No major malformations were noted and there was no evidence of maternal toxicity at these doses, however, the exposures were below the exposures that will occur in humans.

Pregnant rabbits were treated with fenoprofen using oral doses of 50 or 100 mg/kg (0.3 times and 0.6 times the MHDD of 3200 mg/day based on body surface area comparison) during the period of organogenesis. Maternal toxicity (mortality) was noted in the high dose animals. Although no major malformations were noted, there was an increased incidence of embryo-fetal lethality and skeletal abnormalities were present at 0.6 times the MHDD.

Pregnant rats were treated from Gestation Day 14 through Post-Natal Day 20 with oral doses of fenoprofen of 6.25, 12.5, 25, 50, or 100 mg/kg (0.02, 0.04, 0.08, 0.15, or 0.3 times the MDD of 3200 mg/day based on body surface area comparison). All doses produced significant toxicity, including vaginal bleeding, prolonged parturition, increased stillbirths, and maternal deaths.

Pregnant rats were treated from Gestation Day 6 through Gestation Day 19 and Post Partum Day 1 to 20 (excluding parturition) with an oral dose of fenoprofen of 100 mg/kg (0.3 times the MDD of 3200 mg/day based on body surface area comparison) demonstrated only a small increase in the incidence of impaired parturition despite the presence of maternal toxicity (gastrointestinal ulceration and renal toxicity).

8.2 Lactation

Risk Summary

In a published study, after a dose of 600 mg every 6 hours for 4 days in postpartum mothers, breastmilk fenoprofen calcium levels were reportedly 1.6% of those in maternal plasma. Because there is little published experience with fenoprofen during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fenoprofen calcium and any potential adverse effects on the breastfed infant from the fenoprofen or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including fenoprofen calcium, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including fenoprofen calcium, in women who have difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients under the age of 18 have not been established.

8.5 Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID- associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14) ].

11 DESCRIPTION

Fenoprofen calcium capsules**,**USP is a nonsteroidal, anti-inflammatory drug available in 400 mg capsule form for oral administration.

The 400 mg capsule is opaque green cap and opaque blue body, imprinted with “SUVEN” on the cap and “400 mg” on the body.

The chemical name is Benzeneacetic acid, α-methyl-3-phenoxy-, calcium salt dihydrate, (±)-. The molecular weight is 558.65. Its molecular formula is C 30H 26CaO 6•2H 2O, and it has the following chemical structure.


Fenoprofen calcium is an arylacetic acid derivative. It is a white crystalline powder. At 25°C, it dissolves to a 15 mg/mL solution in alcohol (95%). It is slightly soluble in water and insoluble in benzene. The pKa of fenoprofen calcium is 4.5 at 25°C.

Fenoprofen calcium capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 400 mg (1.65 mmol) of fenoprofen.

Inactive ingredients in fenoprofen calcium capsules are crospovidone, magnesium stearate, sodium lauryl sulfate, talc, gelatin, iron oxide yellow, FD&C Blue #1, FD&C Red #40, FD&C Yellow #6, and titanium dioxide.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of fenoprofen have not been conducted.

Mutagenesis

Studies to evaluate the genotoxic potential of fenoprofen have not been conducted.

Impairment of Fertility

Female and Male rats were treated with 60 to 70 mg/kg/day or 120 to 150 mg/kg/day fenoprofen calcium via the diet (approximately 0.2 or 0.4 times the maximum human daily dose of 3200 mg/day based on body surface area comparison, respectively). Male rats were treated from 77 days prior to mating and during mating. Female rats were treated from 14 days prior to mating and through gestation. Pregnancy rates were slightly reduced in the low and high dose groups compared to controls. There was no adverse effect on implantations, resorptions, or live fetuses.

14 CLINICAL STUDIES

Fenoprofen is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved.

Results in humans demonstrate that fenoprofen has both anti-inflammatory and analgesic actions. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of fenoprofen calcium, aspirin, and indomethacin were each compared with those of a placebo. All 3 drugs demonstrated antierythemic activity.

In all patients with rheumatoid arthritis, the anti-inflammatory action of fenoprofen calcium has been evidenced by relief of pain, increase in grip strength, and reductions in joint swelling, duration of morning stiffness, and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action of fenoprofen calcium has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion).

The use of fenoprofen calcium in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding fenoprofen calcium to maintenance therapy with gold salts or steroids. Whether or not fenoprofen calcium used in conjunction with partially effective doses of a corticosteroid has a “steroid-sparing” effect is unknown.

In patients with osteoarthritis, the anti-inflammatory and analgesic effects of fenoprofen calcium have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints.

In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown fenoprofen calcium to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with fenoprofen calcium than in aspirin-treated patients. It is not known whether fenoprofen calcium causes less peptic ulceration than does aspirin.

In patients with pain, the analgesic action of fenoprofen calcium has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect.

16 HOW SUPPLIED/STORAGE AND HANDLING

Fenoprofen calcium capsules**,**USP are for oral administration, and are supplied as following:

• The 400 mg capsule is opaque green cap and opaque blue body, imprinted with “SUVEN” on the cap and “400 mg” on the body

NDC 71993-308-90 Bottles of 90.

Storage:

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Preserve in well-closed containers.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with fenoprofen calcium and periodically during the course of ongoing therapy.

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 health care provider immediately [ see Warnings and Precautions (5.1)].

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [ see Warnings and Precautions (5.2)].

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop fenoprofen calcium and seek immediate medical therapy [ see Warnings and Precautions (5.3)].

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 and Precautions (5.5)].

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications (4)and Warnings and Precautions (5.7)].

Serious Skin Reactions, including DRESS

Advise patients to stop taking fenoprofen calcium immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions (5.9), (5.10)].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including fenoprofen calcium, may be associated with a reversible delay in ovulation [ see Use in Specific Populations (8.3)]

Fetal Toxicity

Inform pregnant women to avoid use of fenoprofen calcium and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with fenoprofen calcium 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 and Precautions (5.11)and Use in Specific Populations (8.1)].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of fenoprofen calcium with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions (5.2)and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use of NSAIDS and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with fenoprofen calcium until they talk to their healthcare provider [see Drug Interactions (7)].

Manufactured for:
Atland Pharmaceuticals, LLC
Sylacauga, AL 35150

Made in India

Revised: 02/2024

ATL.308.99

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 02/2024

10 OVERDOSAGE

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions (5.1, 5.2, 5.4, 5.6) ].

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fenoprofen has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of fenoprofen calcium, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Fenoprofen is a potent inhibitor of prostaglandin synthesis in vitro. Fenoprofen concentrations reached during therapy have produced in vivoeffects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because fenoprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics

Absorption

Under fasting conditions, fenoprofen is rapidly absorbed, and peak plasma levels of 50 mcg/L are achieved within 2 hours after oral administration of 600 mg doses. Good dose proportionality was observed between 200 and 600 mg doses in fasting male volunteers.

Distribution

Fenoprofen is highly bound (99%) to albumin.

Elimination

Metabolism

The plasma half-life is approximately 3 hours.

Excretion

About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxyfenoprofen glucuronide, the major urinary metabolites of fenoprofen.

Specific Populations

Geriatrics

Peak plasma levels of fenoprofen in normal elderly volunteers were similar to those observed in normal young volunteers. Elderly volunteers had a mean plasma clearance of 2.2 L/hour while plasma clearance of fenoprofen in normal young volunteers ranged from 3 to 3.5 L/hour. The overall elimination rate constant, plasma half-life and ratio of renal to nonrenal clearance of fenoprofen was the same in elderly and young volunteers. The 30 to 60% decrease in plasma clearance is due to a decrease in the volume of distribution in the body.

Drug Interaction Studies

Aspirin:When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions (7)].

Antacid:The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of fenoprofen.