DESCRIPTION

Nalfon® (Fenoprofen Calcium Capsules, USP) is a nonsteroidal, anti-inflammatory, antiarthritic drug. Nalfon capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) or 300 mg (1.24 mmol) of fenoprofen. The capsules also contain cellulose, gelatin, iron oxides, silicone, titanium dioxide, and other inactive ingredients. The 300 mg capsules also contain D & C Yellow No. 10 and F D & C Yellow No. 6.

Chemically, Nalfon is an arylacetic acid derivative.

The structural formula is as follows:

Nalfon is a white crystalline powder that has the structural formula C ₃₀ H ₂₆ CaO ₆ ·2H ₂ O representing a molecular weight of 558.65. 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 p Ka of Nalfon is a 4.5 at 25°C.

CLINICAL PHARMACOLOGY

Nalfon 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. Nalfon has been shown to inhibit prostaglandin synthetase isolated from bovine seminal vesicles. Reproduction studies in rats have shown Nalfon to be associated with prolonged labor and difficult parturition when given during late pregnancy. Evidence suggests that this may be due to decreased uterine contractility resulting from the inhibition of prostaglandin synthesis. Its action is not mediated through the adrenal gland.

Fenoprofen shows anti-inflammatory effects in rodents by inhibiting the development of redness and edema in acute inflammatory conditions and by reducing soft-tissue swelling and bone damage associated with chronic inflammation. It exhibits analgesic activity in rodents by inhibiting the writhing response caused by the introduction of an irritant into the peritoneal cavities of mice and by elevating pain thresholds that are related to pressure in edematous hindpaws of rats. In rats made febrile by the subcutaneous administration of brewer's yeast, fenoprofen produces antipyretic action. These effects are characteristic of nonsteroidal, anti-inflammatory, antipyretic, analgesic drugs.

The results in humans confirmed the anti-inflammatory and analgesic actions found in animals. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of Nalfon, 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 Nalfon 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 Nalfon has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion).

The use of Nalfon 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 Nalfon to maintenance therapy with gold salts or steroids. Whether or not Nalfon 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 Nalfon 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 Nalfon 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 Nalfon than in aspirin-treated patients. It is not known whether Nalfon causes less peptic ulceration than does aspirin.

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

Under fasting conditions, Nalfon is rapidly absorbed, and peak plasma levels of 50 µg/mL are achieved within 2 hours after oral administration of 600 mg doses. Good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3 hours. 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. Fenoprofen is highly bound (99%) to albumin.

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

There is less suppression of collagen-induced platelet aggregation with single doses of Nalfon than there is with aspirin.

INDICATIONS AND USAGE

Nalfon is indicated for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis. It is recommended for the treatment of acute flare-ups and exacerbations and for the long-term management of these diseases.

Nalfon is also indicated for relief of mild to moderate pain.

CONTRAINDICATIONS

Nalfon is contraindicated in patients who have shown hypersensitivity to it.

The drug should not be administered to patients with a history of significantly impaired renal function.

Nalfon should not be given to patients in whom aspirin and other nonsteroidal anti-inflammatory drugs induce the symptoms of asthma, rhinitis, or urticaria, because cross-sensitivity to these drugs occurs in a high proportion of such patients.

WARNINGS

Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy --Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs, even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to 2 years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for 1 year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.

Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc, no risk factors (e.g. age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.

Since Nalfon has been marketed, there have been reports of genitourinary tract problems in patients taking it. The most frequently reported problems have been episodes of dysuria, cystitis, hematuria, interstitial nephritis, and nephrotic syndrome. This syndrome may be preceded by the appearance of fever, rash, arthralgia, oliguria, and azotemia and may progress to anuria. There may also be substantial proteinuria, and, on renal biopsy, electron microscopy has shown foot process fusion and T-lymphocyte infiltration in the renal interstitium. Early recognition of the syndrome and withdrawal of the drug have been followed by rapid recovery. Administration of steroids and the use of dialysis have also been included in the treatment. Because a syndrome with some of these characteristics has also been reported with other nonsteroidal anti-inflammatory drugs, it is recommended that patients who have had these reactions with other such drugs not be treated with Nalfon. In patients with possibly compromised renal function, periodic renal function examinations should be done.

PRECAUTIONS

General--Renal Effects --There have been reports of acute interstitial nephritis and nephrotic syndrome ( see CONTRAINDICATIONS and WARNINGS ).

A second form of renal toxicity has been seen in patients with prerenal conditions leading to a reduction in renal blood flow or blood volume, in which renal prostaglandins play a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation at any time. Patients at greatest risk for this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.

Since Nalfon is primarily eliminated by the kidneys, patients with possibly compromised renal function (such as the elderly) should be monitored periodically, especially during long-term therapy. For such patients, it may be anticipated that a lower daily dosage will avoid excessive drug accumulation.

Miscellaneous --Peripheral edema has been observed in some patients taking Nalfon; therefore, Nalfon should be used with caution in patients with compromised cardiac function or hypertension. The possibility of renal involvement should be considered.

Studies to date have not shown changes in the eyes attributable to the administration of Nalfon. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking Nalfon.

Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking Nalfon.

Since the safety of Nalfon has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with Nalfon.

Information for Patients --Nalfon, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) 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 , and ADVERSE REACTIONS sections) 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.

Laboratory Tests --In chronic studies in rats, high doses of Nalfon caused elevation of serum transaminase and hepatocellular hypertrophy. In clinical trials, some patients developed elevation of serum transaminase, LDH, and alkaline phosphatase that persisted for some months and usually, but not always, declined despite continuation of the drug. The significance of this is unknown. It is recommended, therefore, that Nalfon be discontinued if any significant liver abnormality occurs.

As with other nonsteroidal anti-inflammatory drugs, borderline elevations in 1 or more liver tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (i.e., 3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reactions while using Nalfon.

Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with Nalfon, as with other nonsteroidal anti-inflammatory drugs. As a result, during long-term therapy, liver function tests should be monitored periodically. Although such reactions are rare, if liver tests continue to be abnormal or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia and rash), Nalfon should be discontinued. If this drug is to be used in the presence of impaired liver function, it must be done under strict observation.

Patients with initial low hemoglobin values who are receiving long-term therapy with Nalfon should have a hemoglobin determination made at reasonable intervals.

Nalfon decreases platelet aggregation and may prolong bleeding time. Patients who may be adversely affected by prolongation of the bleeding time should be carefully observed when Nalfon is administered.

Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up ( see Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy under WARNINGS ).

Laboratory Test Interactions --Amerlex-M kit assay values of total and free triiodothyronine in patients receiving Nalfon have been reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the assay. Thyroid-stimulating hormone, total thyroxine, and thyrotropin-releasing hormone response are not affected.

Drug Interactions --The coadministration of aspirin decreases the biologic half-life of fenoprofen because of an increase in metabolic clearance that results in a greater amount of hydroxylated fenoprofen in the urine. Although the mechanism of interaction between fenoprofen and aspirin is not totally known, enzyme induction and displacement of fenoprofen from plasma albumin binding sites are possibilities. Because Nalfon has not been shown to produce any additional effect beyond that obtained with aspirin alone and because aspirin increases the rate of excretion of Nalfon, the concomitant use of Nalfon and salicylates is not recommended.

Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen. When phenobarbital is added to or withdrawn from treatment, dosage adjustment of Nalfon may be required.

In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their binding sites other drugs that are also albumin bound, and this may lead to drug interaction. Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs. In patients receiving coumarin-type anticoagulants, the addition of Nalfon to therapy could prolong the prothrombin time. Patients receiving both drugs should be under careful observation. Patients treated with Nalfon may be resistant to the effects of loop diuretics.

In patients receiving Nalfon and a steroid concomitantly, any reduction in steroid dosage should be gradual in order to avoid the possible complications of sudden steroid withdrawal.

Usage in Pregnancy --Safe use of Nalfon during pregnancy and lactation has not been established; therefore, administration to pregnant patients and nursing mothers is not recommended. Reproduction studies have been performed in rats and rabbits. When fenoprofen was given to rats during pregnancy and continued until the time of labor, parturition was prolonged. Similar results have been found with other nonsteroidal anti-inflammatory drugs that inhibit prostaglandin synthetase.

Usage in Pediatric Patients --Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

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.

INCIDENCE GREATER THAN 1%

Probable Causal Relationship

Digestive System --During clinical trials with Nalfon, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving Nalfon as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3%, Nalfon, 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% treated vs 7.5% placebo) 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.

Nalfon 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.

Nalfon 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.

Nalfon 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%).

Nalfon 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).

INCIDENCE LESS THAN 1%

Probable Causal Relationship

The following adverse reactions, occurring in less than 1% of patients, were reported in controlled clinical trials and voluntary reports made since Nalfon was initially marketed. The probability of a causal relationship exists between Nalfon and these adverse reactions:

Digestive System --Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool. Increases in alkaline phosphatase, LDH, and SGOT, jaundice, and cholestatic hepatitis were observed (see PRECAUTIONS ).

Genitourinary Tract --Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and papillary necrosis (see WARNINGS ).

Hypersensitivity --Angioedema (angioneurotic edema).

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

Miscellaneous --Anaphylaxis, urticaria, malaise, insomnia, and tachycardia.

INCIDENCE LESS THAN 1%

Causal Relationship Unknown

Other reactions reported either in clinical trials or spontaneously, occurred in circumstances in which a causal relationship could not be established. However, with these rarely reported reactions, the possibility of such a relationship cannot be excluded. Therefore, these observations are listed to alert the physician.

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

Digestive System --Aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis.

Cardiovascular --Atrial filbrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia.

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

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

Miscellaneous --Personality change, lymphadenopathy, mastodynia, and fever.

OVERDOSAGE

Signs and Symptoms --Symptoms of overdose appear within several hours and generally involve the gastrointestinal and central nervous systems. They include dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache, ataxia, tinnitus, tremor, drowsiness, and confusion. Hyperpyrexia, tachycardia, hypotension, and acute renal failure may occur rarely following overdose. Respiratory depression and metabolic acidosis have also been reported following overdose with certain NSAIDs.

Treatment --To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR) . In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.

Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis, and charcoal hemoperfusion do not enhance systemic drug elimination.

DOSAGE AND ADMINISTRATION

Analgesia

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

Rheumatoid Arthritis and Osteoarthritis

The suggested dosage is 300 to 600 mg, 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.

If gastrointestinal complaints occur, Nalfon 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 Nalfon 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.

HOW SUPPLIED

Nalfon® (Fenoprofen Calcium Capsules, USP) are available in:

The 200 mg * capsule is opaque yellow cap and opaque white body, imprinted with "RX681" on the cap and body.

NDC 0884-6600-10 Bottles of 100

The 300 mg * capsule is opaque yellow cap and opaque yellow body, imprinted with "RX682" on the cap and body.

NDC 0884-6700-10 Bottles of 100

Preserve in well-closed containers.

Store at 20°-25° C (68°-77° F). (See USP Controlled Room Temperature).

Manufactured for:

Pedinol Pharmacal Inc.

Farmingdale, NY 11735 USA

By: Ohm Laboratories, Inc.

North Brunswick, NJ 08902 USA

February 2005