fenoprofen (as fenoprofen calcium) 200 MG Oral Capsule
DRUG INTERACTIONS
7.
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 FENORTHO with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 ) ].
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 FENORTHO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 ) ].
FENORTHO 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 FENORTHO and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of FENORTHO 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.g., 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 FENORTHO 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 FENORTHO 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 FENORTHO 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.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of FENORTHO and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine Clinical Impact: Concomitant use of FENORTHO and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of FENORTHO 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.g., 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 FENORTHO and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention: During concomitant use of FENORTHO 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.g., 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.g., 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 FENORTHO 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.g.
warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking FENORTHO with drugs that interfere with hemostasis.
Concomitant use of FENORTHO and analgesic doses of aspirin is not generally recommended ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with FENORTHO may diminish the antihypertensive effect of these drugs.
Monitor blood pressure ( 7 ) ACE Inhibitors and ARBs: Concomitant use with FENORTHO in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function.
In such high risk patients, monitor for signs of worsening renal function ( 7 ) Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics.
Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7 ) Digoxin: Concomitant use with FENORTHO can increase serum concentration and prolong half-life of digoxin.
Monitor serum digoxin levels ( 7 ) Drug/Laboratory Test Interactions Amerlex-M kit assay values of total and free triiodothyronine in patients receiving Fenortho 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
10.
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).
DESCRIPTION
11.
FENORTHO (fenoprofen calcium, USP) capsules is a nonsteroidal, anti-inflammatory drug available in 200 mg and 400 mg capsule form for oral administration.
The 200 mg capsule is opaque yellow No.
97 cap and opaque white body, imprinted with “RX681” on the cap and body.
The 400 mg capsule is opaque green cap and opaque blue body, imprinted with “NALFON 400 mg” on the cap and “EP 123” on the body.
The chemical name is Benzenaecetic acid, α-methyl-3-phenoxy-, calcium salt dihydrate, (±)-.
The molecular weight is 558.65.
Its molecular formula is C 30 H 26 CaO 6 •2H 2 O, 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.
Fenortho capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) or 400 mg (1.65 mmol) of fenoprofen.
Inactive ingredients in Fenortho capsules are crospovidone, magnesium stearate, sodium lauryl sulfate, and talc.
In addition, the 200 mg capsules contain gelatin, titanium dioxide, yellow iron oxide, and red iron oxide, and the 400 mg capsules contain gelatin, D&C Yellow #10, FD&C Blue #1, FD&C Red #40, FD&C Yellow #6, and titanium dioxide.
strucform
CLINICAL STUDIES
14.
FENORTHO 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 FENORTHO, 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 FENORTHO 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 FENORTHO has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion).
The use of FENORTHO 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 FENORTHO to maintenance therapy with gold salts or steroids.
Whether or not FENORTHO 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 FENORTHO 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 FENORTHO 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 FENORTHO than in aspirin-treated patients.
It is not known whether FENORTHO 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.
HOW SUPPLIED
16.
/STORAGE AND HANDLING Fenortho (fenoprofen calcium, USP) are available in capsule form for oral administration, and are supplied as following: ● The 200 mg capsule has an opaque yellow No.
97 cap and an opaque white body, imprinted with “RX681” on the cap and body.
NDC 54288-0131-10 Bottles of 100.
● The 400 mg capsule has an opaque green cap and an opaque blue body, imprinted with “NALFON 400 mg” on the cap and “EP 123” on the body.
NDC 54288-0132-09 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
RECENT MAJOR CHANGES
Boxed Warning 4/2016 Warnings and Precautions, Cardiovascular Thrombotic Events ( 5.1 ) 4/2016 Warnings and Precautions, Heart Failure and Edema ( 5.5 ) 4/2016
GERIATRIC USE
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 , 5.13 ) ].
DOSAGE FORMS AND STRENGTHS
3.
FENORTHO (fenoprofen calcium) capsules: The 200 mg capsule is opaque yellow No.
97 cap and opaque white body, imprinted with “RX681” on the cap and body.
The 400 mg capsule is opaque green cap and opaque blue body, imprinted with “NALFON 400 mg” on the cap and “EP 123” on the body.
Fenortho (fenoprofen calcium, USP) capsules: 200 mg and 400 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Fernoprofen has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of FENORTHO, 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.
INDICATIONS AND USAGE
1.
FENORTHO 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.
FENORTHO 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.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients under the age of 18 have not been established.
PREGNANCY
8.1 Pregnancy Risk Summary Use of NSAIDs, including FENORTHO, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
Avoid use of NSAIDs, including FENORTHO, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of FENORTHO 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.
In the general U.S.
population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss.
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 fenortho 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.
Clinical Considerations Labor or Delivery There are no studies on the effects of FENORTHO 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 FENORTHO 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.
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).
BOXED WARNING
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning Non-Steroidal Anti-Inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.
This risk may occur early in treatment and may increase with duration of use.
( 5.1 ) FENORTHO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ) NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal.
These events can occur at any time during use and without warning symptoms.
Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 ) Cardiovascular Thrombic Events Non-Steroidal Anti-Inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal.
This risk may occur early in treatment and may increase with duration of use.
[ see Warnings and Precautions ( 5.1 ) ].
FENORTHO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications ( 4 ) and Warnings and precautions ( 5.1 ) ].
Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal.
These events can occur at any time during use and without warning symptoms.
Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2 ) ].
WARNING AND CAUTIONS
5.
WARNINGS AND PRECAUTIONS Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity.
Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs.
Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema: Avoid use of FENORTHO in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.
Avoid use of FENORTHO in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity: FENORTHO is contraindicated in patients with aspirin-sensitive asthma.
Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions: Discontinue FENORTHO at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation ( 5.10 , 8.1 ) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.11 , 7 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.
Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.
The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.
However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate.
Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment.
The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.
Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms.
Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.
The concurrent use of aspirin and an NSAID, such as fenoprofen, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions ( 5.2 ) ].
Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
NSAIDs are contraindicated in the setting of CABG [ see Contraindications ( 4 ) ].
Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment.
In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients.
Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of FENORTHO in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.
If FENORTHO is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including FENORTHO, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal.
These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDS.
Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic.
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year.
However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk of developing a GI bleed compared to patients without these risk factors.
Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status.
Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients.
Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated Patients: Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh theincreased risk of bleeding.
For such patients, as well as those with active GIbleeding, consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue FENORTHO until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Drug Interactions ( 7 ) ].
5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials.
In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including fenoprofen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue FENORTHO immediately, and perform a clinical evaluation of the patient.
5.4 Hypertension NSAIDs, including FENORTHO, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events.
Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions ( 7 ) ].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.
In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs.
Use of fenoprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug Interactions ( 7 ) ].
Avoid the use of FENORTHO in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.
If FENORTHO is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.
In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.
Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly.
Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of FENORTHO in patients with advanced renal disease.
The renal effects of FENORTHO may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating FENORTHO.
Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of FENORTHO [ see Drug Interactions ( 7 ) ].
Avoid the use of FENORTHO in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function.
If FENORTHO is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment.
In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
5.7 Anaphylactic Reactions Fenoprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to fenoprofen and in patients with aspirin-sensitive asthma [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 ) ].
Seek emergency help if an anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs.
Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, FENORTHO is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications ( 4 ) ].
When FENORTHO is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
5.9 Serious Skin Reactions NSAIDs, including fenopropfen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.
These serious events may occur without warning.
Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of FENORTHO at the first appearance of skin rash or any other sign of hypersensitivity.
FENORTHO is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ].
5.10 Premature Closure of Fetal Ductus Arteriosus Fenoprofen may cause premature closure of the fetal ductus arteriosus.
Avoid use of NSAIDs, including FENORTHO, in pregnant women starting at 30 weeks of gestation (third trimester) [ see Use in Specific Populations ( 8.1 ) ].
5.11 Hematologic Toxicity Anemia has occurred in NSAID-treated patients.
This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.
If a patient treated with FENORTHO has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including FENORTHO, may increase the risk of bleeding events.
Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk.
Monitor these patients for signs of bleeding [ see Drug Interactions ( 7 ) ].
5.12 Masking of Inflammation and Fever The pharmacological activity of FENORTHO in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions ( 5.2 , 5.3 , 5.6 ) ].
5.14 Ocular Effects Studies to date have not shown changes in the eyes attributable to the administration of FENORTHO.
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 FENORTHO.
5.15 Central Nervous System Effects Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking FENORTHO.
5.16 Impact on Hearing Since the safety of FENORTHO has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with FENORTHO.
INFORMATION FOR PATIENTS
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 FENORTHO 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 FENORTHO 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 Advise patients to stop FENORTHO immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9 ) ].
Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including FENORTHO, 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 FENORTHO and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [ see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 ) ].
Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of FENORTHO 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 FENORTHO until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ].
Manufactured for: BPI Labs, LLC Freehold, NJ 07728 Issued: 04/ 2016
DOSAGE AND ADMINISTRATION
2.
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.
2.1 General Dosing Instructions Carefully consider the potential benefits and risks of FENORTHO and other treatment options before deciding to use FENORTHO.
Use lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ].
Fenortho 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 Fenortho 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.