Use of NSAIDs, including FENOPROFEN CALCIUM, USP, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including FENOPROFEN CALCIUM, USP, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of FENOPROFEN CALCIUM, USP 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 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.
Labor or Delivery
There are no studies on the effects of FENOPROFEN CALCIUM, USP during labor or delivery. In animal studies, NSAIDS, including fenoprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
There are no adequate and well-controlled studies of FENOPROFEN CALCIUM, USP 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.
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).
In a published study, after a dose of 600 mg every 6 hours for 4 days in postpartum mothers, breastmilk fenoprofen levels were reportedly 1.6% of those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FENOPROFEN CALCIUM, USP and any potential adverse effects on the breastfed infant from the FENOPROFEN CALCIUM, USP or from the underlying maternal condition.
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including FENOPROFEN CALCIUM, USP, 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 prostaglandinmediated 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, USP in women who have difficulties conceiving or who are undergoing investigation of infertility.
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 ( 5.1, 5.2, 5.3, 5.6, 5.13) ].
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).
FENOPROFEN CALCIUM, USP capsule 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 “”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.
FENOPROFEN CALCIUM, USP capsules contain fenoprofen calcium as the dihydrate in an amount equivalent 400 mg (1.65 mmol) of fenoprofen.
Inactive ingredients in FENOPROFEN CALCIUM, USP capsules are crospovidone, magnesium stearate, sodium lauryl sulfate, and talc. In addition, 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.
Fernoprofen has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of FENOPROFEN CALCIUM, USP, 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.
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.
Fenoprofen is highly bound (99%) to albumin.
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.
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.
Long-term studies in animals to evaluate the carcinogenic potential of fenoprofen have not been conducted.
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.
FENOPROFEN CALCIUM, USP 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, USP, 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, USP 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, USP has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion).
The use of FENOPROFEN CALCIUM, USP 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, USP to maintenance therapy with gold salts or steroids. Whether or not FENOPROFEN CALCIUM, USP 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, USP 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, USP 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, USP than in aspirin-treated patients. It is not known whether FENOPROFEN CALCIUM, USP causes less peptic ulceration than does aspirin.
In patients with pain, the analgesic action of FENOPROFEN CALCIUM, USP has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect.
FENOPROFEN CALCIUM, USP is available in capsule form for oral administration, and are supplied as following:
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.
NDC 69101-400-01. Bottles of 90.
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.
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, USP and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic EventsAdvise 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) ].
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, USP
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) ].
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 FENOPROFEN CALCIUM, USP immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9) ].
Advise females of reproductive potential who desire pregnancy that NSAIDs, including FENOPROFEN CALCIUM, USP, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3) ]
Inform pregnant women to avoid use of FENOPROFEN CALCIUM, USP 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 FENOPROFEN CALCIUM, USP 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, USP until they talk to their healthcare provider [ see Drug Interactions ( 7) ].
Burke Therapeutics, LLC
Hot Springs, AR, 71913
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