NALFON- fenoprofen calcium_capsule

Fernoprofen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of NALFON, 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 vivo effects. 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. Absorption Distribution Elimination Metabolism Excretion Specific Populations Gertatrics Drug Interaction Studies Aspirin: see Drug Interactions ( 7 Antacid:.

NALFON is indicated for: Relief of mild to moderate pain in adults. Relief of the signs and symptoms of rheumatoid arthrites. Relief of the signs and symptoms of osteoarthritis. NALFON is a nonsteroidal anti-inflammatory drug indicated for: Relief of mild to moderate pain in adults. ( 1 Relief of the signs and symptoms of rheumatoid arthritis. ( 1 Relief of the signs and symptoms of osteoarthritis.

Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2. 1 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. 1 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. Carefully consider the potential benefits and risks of NALFON and other treatment options before deciding to use NALFON. Use lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 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. For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. 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 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 Most common adverse reactions (incidence >= 5%) are Dyspepsia, headache, somnolence, nausea, dizziness, constipation, nervousness, asthenia, and peripheral edema. To report SUSPECTED ADVERSE REACTIONS, contact Xspire Pharma at 1-601-990-9497 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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 Nervous System Skin and Appendages Special Senses Cardiovascular Miscellaneous Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials Digestive System Cardiovascular Genitourinary Tract Hypersensitivity Hematologic Nervous System Special Senses Skin and Appendages Miscellaneous.

NALFON is contraindicated in the following patients: Known hypersensitivity (e. , anaphylactic reactions and serious skin reactions) to fenoprofen or any components of the drug product [ see Warnings and Precautions ( 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. 8 In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5. 1 Known hypersensitivity to fenoprofen or any components of the drug product ( 4 History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 In the setting of CABG surgery ( 4.

Infertility: 8. 3 Risk Summary see Clinical Considerations, Data Premature Closure of Fetal Ductus Arteriosus Oligohydramnios/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. 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. 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: Oligohydramnios/Neonatal Renal Impairment: Labor or Delivery Data Human Data Premature Closure of Fetal Ductus Arteriosus: Oligohydramnios/Neonatal Renal Impairment: 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 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. 5, 25, 50, or 100 mg/kg (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). Risk Summary Infertility Females Safety and effectiveness in pediatric patients under the age of 18 have not been established. 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.

See Table 1 for clinically significant drug interactions with fenoprophen. Table 1: Clinically Significant Drug Interactions with Fenoprofen Drugs That Interfere with Hemostasis Clinical Impact: Fenoprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of fenoprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of NALFON with anticoagulants (e. , warfarin), antiplatelet agents (e. , aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5. 12 Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5. 2 Intervention: Concomitant use of NALFON and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5. 12 NALFON is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of NALFON and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of NALFON, ACE-inhibitors, or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5. 6 When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e. , furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NALFON with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5. 6 Digoxin Clinical Impact: The concomitant use of fenoprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of NALFON and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NALFON and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e. , neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of NALFON and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NALFON and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NALFON and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of fenoprofen with other NSAIDs or salicylates (e. , diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5. 2 Intervention: The concomitant use of fenoprofen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NALFON and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NALFON and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e. , diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e. , meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Phenobarbital Clinical Impact: Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen. Intervention: When phenobarbital is added to or withdrawn from treatment, dosage adjustment of NALFON may be required. Hydantoins, sulfonamides, or sulfonylureas Clinical Impact: 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 interactions. Theoretically, fenoprofen could likewise be displaced. Intervention: Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs. Drugs that Interfere with Hemostasis (e. warfarin, aspirin, SSRIs/SNRIs): 7 ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: 7 ACE Inhibitors and ARBs: 7 Diuretics: 7 Digoxin: 7 Drug/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. Thus, results of the Amerlex-M kit assay should be interpreted with caution in these patients.

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).
NONCLINICAL TOXICOLOGY
Carcinogenesis Mutagenesis Impairment of Fertility
CLINICAL STUDIES
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. 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 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.

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NALFON- fenoprofen calcium_capsule Product manual source documgent