Fluconazol axcount may be available in the countries listed below.
Fluconazole is reported as an ingredient of Fluconazol axcount in the following countries:
International Drug Name Search
Fenofibric Acid tablets are indicated as adjunctive therapy to diet for treatment of severe hypertriglyceridemia (≥ 500 mg/dl). Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention.
Levels of serum triglycerides > 1000 mg/dl may increase the risk of developing pancreatitis. The effect of Fenofibric Acid tablets on reducing this risk has not been studied.
Fenofibric Acid tablets are indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, TG, and Apo B, and to increase HDL-C in patients with primary hypercholesterolemia or mixed dyslipidemia.
Fenofibrate at a dose equivalent to 105 mg of Fenofibric Acid tablets was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus [see Warnings and Precautions (5.6)].
The active moiety of Fenofibric Acid tablets is Fenofibric Acid. The pharmacological effects of Fenofibric Acid have been extensively studied through oral administration of fenofibrate, which is converted in vivo to Fenofibric Acid.
Fenofibric Acid tablets can be given without regard to meals.
Patients should be placed on an appropriate lipid-lowering diet before receiving Fenofibric Acid tablets and should continue this diet during treatment with Fenofibric Acid.
Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting Fenofibric Acid tablets therapy. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy.
Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of Fenofibric Acid tablets. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 105 mg per day.
Consideration should be given to reducing the dosage of Fenofibric Acid tablets if lipid levels fall significantly below the targeted range.
Severe Hypertriglyceridemia: The initial dose is 35 to 105 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.
Primary Hyperlipidemia or Mixed Dyslipidemia: The dose of Fenofibric Acid tablets is 105 mg per day.
The maximum dose of Fenofibric Acid tablets is 105 mg per day.
In patients with mild-to-moderate renal impairment, treatment with Fenofibric Acid tablets should be initiated at a dose of 35 mg/day, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of Fenofibric Acid tablets should be avoided in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.6)].
Fenofibric Acid tablets are contraindicated in patients with:
Fenofibrate (administered over a range of doses with the higher dose equivalent to 105 mg Fenofibric Acid) has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)].
In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal of ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. The incidence of increases in transaminases observed with fenofibrate therapy may be dose related.
Chronic active hepatocellular and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.
Periodic monitoring of liver tests (e.g., ALT) should be performed for the duration of therapy with Fenofibric Acid tablets, and therapy discontinued if enzyme levels persist above three times the normal limit.
Fenofibric Acid tablets, like fenofibrate, clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibric Acid tablets therapy should be discontinued if gallstones are found.
Caution should be exercised when Fenofibric Acid tablets are given in conjunction with oral anticoagulants. Fenofibric Acid tablets may potentiate the anticoagulant effects of these agents resulting in prolongation of the prothrombin time/INR. Frequent monitoring of prothrombin time/INR and dose adjustment of the anticoagulant are recommended until the prothrombin time/INR has stabilized in order to prevent bleeding complications [see Drug Interactions (7.1)].
Fibrates increase the risk for myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism.
Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin).
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels.
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and Fenofibric Acid tablets therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed.
Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Renal monitoring should be considered for patients with renal impairment and for patients at risk for renal insufficiency, such as the elderly and patients with diabetes.
The effect of Fenofibric Acid tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5 year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75–1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80–0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.
Because of chemical, pharmacological, and clinical similarities between fenofibrate, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to Fenofibric Acid.
In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).
In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age – adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p<0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.
The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk =0.91–1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (relative risk=1.29). Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study.
A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (HR 2.2, 95% confidence interval: 0.94–5.05). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, p=0.07). There was a statistically significant difference in the number of appendectomies in the gemfibrozil group (6/311 vs. 0/317, p=0.029).
Pancreatitis has been reported in patients taking fenofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.
In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,875 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p=0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p=0.022).
In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p<0.01).
Acute hypersensitivity reactions including severe skin rashes such as Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrate.
Mild-to-moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of Fenofibric Acid tablets administration.
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 clinical practice.
Adverse reactions reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% treated with placebo. Increases in liver tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients.
| BODY SYSTEM Adverse Reactions | Fenofibrate* (N=439) | Placebo (N=365) |
|---|---|---|
| ||
| BODY AS A WHOLE | ||
| Abdominal Pain | 4.6% | 4.4% |
| Back Pain | 3.4% | 2.5% |
| Headache | 3.2% | 2.7% |
| DIGESTIVE | ||
| Liver Function Tests Abnormal | 7.5%† | 1.4% |
| Nausea | 2.3% | 1.9% |
| Constipation | 2.1% | 1.4% |
| METABOLIC AND NUTRITIONAL DISORDERS | ||
| Abnormal Liver Tests | 7.5% | 1.4% |
| Increased ALT | 3.0% | 1.6% |
| Creatine Phosphokinase Increased | 3.0% | 1.4% |
| Increased AST | 3.4% | 0.5% |
| RESPIRATORY | ||
| Respiratory Disorder | 6.2% | 5.5% |
| Rhinitis | 2.3% | 1.1% |
The following adverse reactions have been identified during postapproval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: myalgia, rhabdomyolysis, increased creatinine phosphokinase, pancreatitis, increased alanine aminotranaminase, increased aspartate aminotranaminase, muscle spasm, acute renal failure, hepatitis, cirrhosis, nausea, abdominal pain, anemia, headache, arthralgia and asthenia.
Caution should be exercised when Fenofibric Acid tablets are given in conjunction with coumarin anticoagulants. Fenofibric Acid tablets may potentiate the anticoagulant effect of these agents resulting in prolongation of the prothrombin time/INR. Frequent monitoring of prothrombin time/INR and dose adjustment of the oral anticoagulant are recommended until the prothrombin time/INR has stabilized in order to prevent bleeding complications [see Warnings and Precautions (5.3)].
Since bile-acid binding resins may bind other drugs given concurrently, patients should take Fenofibric Acid tablets at least 1 hour before or 4 to 6 hours after taking another drug.
Immunosuppressant agents such as cyclosporine and tacrolimus can impair renal function. When immunosuppressants and other potentially nephrotoxic agents are co-administered with Fenofibric Acid tablets, the lowest effective dose of Fenofibric Acid tablets should be employed and renal function should be monitored.
Pregnancy Category C: Safety in pregnant women has not been established. There are no adequate and well controlled studies of Fenofibric Acid tablets in pregnant women. Fenofibric Acid tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at a dose that results in exposure to Fenofibric Acid that is 50 times that at the MRHD of Fenofibric Acid.
In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6–15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (a dose that results in exposure to Fenofibric Acid that is approximately twice that at the MRHD of Fenofibric Acid). At higher multiples of human doses evidence of maternal toxicity was observed.
In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6–18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (20 times that at the MRHD of Fenofibric Acid). No developmental findings were observed at 15 mg/kg/day (an exposure to Fenofibric Acid that is 7 times that at the MRHD of Fenofibric Acid).
In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at an exposure to Fenofibric Acid that is approximately 50 times that at the MRHD of Fenofibric Acid [see Nonclinical Toxicology (13.1)].
Fenofibric Acid tablets should not be used by nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug [see Contraindications (4)].
Safety and effectiveness of Fenofibric Acid tablets in pediatric patients have not been established.
Fenofibric Acid tablets are substantially excreted by the kidney as Fenofibric Acid and Fenofibric Acid glucuronide, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Since elderly patients have a higher incidence of renal impairment, the dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Elderly patients with normal renal function should require no dose modifications.
The use of Fenofibric Acid tablets should be avoided in patients who have severe renal impairment. Dose reduction is required in patients with mild-to-moderate renal impairment. Monitoring renal function in patients with renal impairment is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
The use of Fenofibric Acid tablets has not been evaluated in patients with hepatic impairment [see Contraindications (4)].
There is no specific treatment for overdose with Fenofibric Acid tablets. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because Fenofibric Acid is highly bound to plasma proteins, hemodialysis should not be considered.
Fenofibric Acid is a lipid regulating agent available as tablets for oral administration. Each tablet contains 35 mg or 105 mg of Fenofibric Acid. The chemical name for Fenofibric Acid is 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid with the following structural formula:
Fenofibric Acid is a white to almost white crystalline powder that is stable under ordinary conditions, and has a melting point of 179 – 183°C. Its empirical formula is C17H15ClO4 and molecular weight 318.75. Fenofibric Acid is insoluble in water; its solubility increases with pH in buffered media.
Inactive Ingredients: Each tablet contains copovidone, crospovidone, magnesium stearate and microcrystalline cellulose.
The effects of Fenofibric Acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, Fenofibric Acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.
Elevated levels of Total-C, LDL-C, and Apo B, and decreased levels of HDL-C and its transport complex, Apo AI and Apo AII, are risk factors for atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the levels of Total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined.
Absorption
The absolute bioavailability of Fenofibric Acid tablets has not been determined. Following oral administration of Fenofibric Acid tablets in healthy volunteers, median peak plasma levels of Fenofibric Acid occur by approximately 2.5 hours after administration. Exposure after administration of 3 × 35 mg Fenofibric Acid tablets is comparable to 1 × 105 mg Fenofibric Acid tablets.
A food-effect study involving administration of Fenofibric Acid tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased by approximately 35% while the AUC remained unchanged. This decrease in exposure is not considered clinically significant, and therefore Fenofibric Acid tablets can be taken without regards to meals.
The extent and rate of absorption of Fenofibric Acid after administration of 105 mg Fenofibric Acid tablets are equivalent to those after administration of 145 mg fenofibrate tablets (TriCor®) under fasted conditions.
Distribution
Upon multiple dosing of fenofibrate, Fenofibric Acid steady state is achieved within 9 days. Plasma concentrations of Fenofibric Acid at steady state are slightly more than double those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
Metabolism
Fenofibric Acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of Fenofibric Acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
In vitro and in vivo metabolism data indicate that Fenofibric Acid does not undergo oxidative metabolism (e.g. cytochrome P450) to a significant extent. The enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 do not play a role in the metabolism of Fenofibric Acid.
Elimination
Fenofibric Acid is eliminated with a half-life of approximately 20 hours, allowing once-daily dosing.
Specific Populations
Geriatrics: In five elderly volunteers 77 – 87 years of age, the oral clearance of Fenofibric Acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that an equivalent dose of Fenofibric Acid tablets can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites [see Use in Specific Populations (8.5)].
Pediatrics: Fenofibric Acid tablets have not been investigated in adequate and well-controlled trials in pediatric patients.
Gender: No pharmacokinetic difference between males and females has been observed for fenofibrate.
Race: The influence of race on the pharmacokinetics of Fenofibric Acid has not been studied, however Fenofibric Acid is not metabolized by enzymes known for exhibiting inter-ethnic variability.
Renal Impairment: The pharmacokinetics of Fenofibric Acid were examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl ≤ 30 mL/min) showed a 2.7-fold increase in exposure for Fenofibric Acid and increased accumulation of Fenofibric Acid during chronic dosing compared to that of healthy subjects. Patients with mild (CrCl 50–80 mL/min) to-moderate (CrCl 30–50 mL/min) renal impairment had similar exposure but an increase in the half-life for Fenofibric Acid compared to that of healthy subjects. Based on these findings, the use of Fenofibric Acid should be avoided in patients who have severe renal impairment and dose reduction is required in patients with mild-to-moderate renal impairment.
Hepatic Impairment: No pharmacokinetic studies of Fenofibric Acid have been conducted in patients with hepatic impairment.
Drug-Drug Interactions: An in vitro study using human hepatocytes indicates that Fenofibric Acid does not induce CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
In vitro studies using human liver microsomes indicate that Fenofibric Acid is not an inhibitor of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2.
Table 2 describes the effects of co-administered drugs on Fenofibric Acid systemic exposure. Table 3 describes the effects of co-administered Fenofibric Acid on exposure to other drugs.
| Co-Administered Drug | Dosage Regimen of Co-Administered Drug | Dosage Regimen of Fenofibrate | Changes in Fenofibric Acid Exposure | ||
|---|---|---|---|---|---|
| Auc | Cmax | ||||
| |||||
| No dosing adjustment required for Fenofibric Acid tablets with the following co-administered drugs | |||||
| Lipid-lowering agents | |||||
| Atorvastatin | 20 mg QD for 10 days | Fenofibrate 160 mg* QD for 10 days | ↓ 2% | ↓ 4% | |
| Pravastatin | 40 mg as a single dose | Fenofibrate 3 × 67 mg† as a single dose | ↓ 1% | ↓ 2% | |
| Fluvastatin | 40 mg as a single dose | Fenofibrate 160 mg* as a single dose | ↓ 2% | ↓ 10% | |
| Simvastatin | 80 mg QD for 7 days | Fenofibrate 160 mg* QD for 7 days | ↓ 5% | ↓ 11% | |
| Ezetimibe | 10 mg QD for 10 days | Fenofibrate 145 mg* QD for 10 days | 0% | ↑ 3% | |
| Anti-diabetic agents | |||||
| Glimepiride | 1 mg as a single dose | Fenofibrate 145 mg* QD for 10 days | ↑ 1% | ↓ 1% | |
| Metformin | 850 mg TID for 10 days | Fenofibrate 54 mg* TID for 10 days | ↓ 9% | ↓ 6% | |
| Rosiglitazone | 8 mg QD for 5 days | Fenofibrate 145 mg* QD for 14 days | ↑ 10% | ↑ 3% | |
| Dosage Regimen of Fenofibrate | Dosage Regimen of Co-Administered Drug | Change in Co-Administered Drug Exposure | |||
|---|---|---|---|---|---|
| Analyte | AUC | Cmax | |||
| |||||
| No dosing adjustment required for these co-administered drugs with Fenofibric Acid tablets | |||||
| Lipid-lowering agents | |||||
| Fenofibrate 160 mg* QD for 10 days | Atorvastatin, 20 mg QD for 10 days | Atorvastatin | ↓ 17% | 0% | |
| Fenofibrate 3 × 67 mg† as a single dose | Pravastatin, 40 mg as a single dose | Pravastatin | ↑ 13% | ↑ 13% | |
| 3α-Hydroxyl-iso-pravastatin | ↑ 26% | ↑ 29% | |||
| Fenofibrate 160 mg* QD for 10 days | Pravastatin, 40 mg QD for 10 days | Pravastatin | ↑ 28% | ↑ 36% | |
| 3α-Hydroxyl-iso-pravastatin | ↑ 39% | ↑ 55% | |||
| Fenofibrate 160 mg* as a single dose | Fluvastatin, 40 mg as a single dose | (+)-3R, 5S-Fluvastatin | ↑ 15% | ↑ 16% | |
| Fenofibrate 160 mg* QD for 7 days | Simvastatin, 80 mg QD for 7 days | Simvastatin acid | ↓ 36% | ↓ 11% | |
| Simvastatin | ↓ 11% | ↓ 17% | |||
| Active HMG-CoA Inhibitors | ↓ 12% | ↓ 1% | |||
| Total HMG-CoA Inhibitors | ↓ 8% | ↓ 10% | |||
| Fenofibrate 145 mg* QD for 10 days | Ezetimibe, 10 mg QD for 10 days | Total Ezetimibe | ↑ 43% | ↑ 33% | |
| Free Ezetimibe | ↑ 3% | ↑ 11% | |||
| Ezetimibe Glucuronide | ↑ 49% | ↑ 34% | |||
| Anti-diabetic agents | |||||
| Fenofibrate 145 mg* QD for 10 days | Glimepiride, 1 mg as a single dose | Glimepiride | ↑ 35% | ↑ 18% | |
| Fenofibrate 54 mg* TID for 10 days | Metformin, 850 mg TID for 10 days | Metformin | ↑ 3% | ↑ 6% | |
| Fenofibrate 145 mg* QD for 14 days | Rosiglitazone, 8 mg QD for 5 days | Rosiglitazone | ↑ 6% | ↓ 1% | |
| Anti-viral agents | |||||
| Fenofibric Acid tablets 105 mg QD for 10 days | Efavirenz, 600 mg as a single dose | Efavirenz | ↓ 11% | ↓ 2% | |
Carcinogenesis
Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, (approximately 0.3, 1, and 6 times the maximum recommended human (MRHD) dose on the basis of mg/sq meter surface area). At a dose of 200 mg/kg/day (6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 45, and 200 mg/kg/day (approximately 1, and 6 times the human dose on the basis of mg/sq meter surface area), an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed in males at a dose that results in exposure to Fenofibric Acid that is 6 times the human dose. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (1.2 and 16.5 times the MRHD of Fenofibric Acid, based upon exposure) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 16.5 times the MRHD of fenofibrate (60 mg/kg/day).
A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD of fenofibrate), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose) (multiples based on mg/meter2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.
In a 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 0.7, and 3 times the human dose on the basis of mg/sq meter surface area) significantly increased the liver carcinomas in both sexes at doses that result in exposure to Fenofibric Acid that is 3.7 times the MRHD of Fenofibric Acid. In a second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD of fenofibrate.
Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.
Mutagenesis
Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes and in vivo in the mouse micronucleus assay.
Impairment of Fertility
In fertility studies, rats were given oral dietary doses of fenofibrate. Males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (approximately 10 times the MRHD of fenofibrate, based on mg/m2 surface area comparisons).
The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one protocol entered patients with baseline triglyceride (TG) levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL.
In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 105 mg of Fenofibric Acid tablets decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of some with elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 4).
| ||||||||
| Study 1 | Placebo | Fenofibrate | ||||||
| Baseline TG levels 350 to 499 mg/dL | N | Baseline (Mean) | ||||||
Pravagamma may be available in the countries listed below.
Pravastatin sodium salt (a derivative of Pravastatin) is reported as an ingredient of Pravagamma in the following countries:
International Drug Name Search
Pemirolast Potassium may be available in the countries listed below.
Pemirolast Potassium (USAN) is known as Pemirolast in the US.
International Drug Name Search
Glossary
| USAN | United States Adopted Name |
Rhewlin may be available in the countries listed below.
Diclofenac sodium salt (a derivative of Diclofenac) is reported as an ingredient of Rhewlin in the following countries:
International Drug Name Search
Class: Selective Serotonin Agonists
VA Class: CN105
Chemical Name: (+)-(R)-2,3,4,9-tetrahydro-3-(methylamino)-1H-carbazole-6-carboxamide butanedioate monohydrate
Molecular Formula: C14H17N3O•H2O
CAS Number: 158930-17-7
Brands: Frova
Selective serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptor agonist (“triptan”).1 2
Acute treatment of migraine attacks with or without aura.1 4 5
Not recommended for management of hemiplegic or basilar migraine or for prophylaxis of migraine.1
Safety and efficacy not established for management of cluster headaches.1
Administer orally with fluids without regard to meals.1
Available as frovatriptan succinate; dosage is expressed in terms of frovatriptan.1
2.5 mg as a single dose.1 Higher dosages provide no additional benefit but may increase risk of adverse effects.1 2
If headache recurs, additional doses may be administered at intervals of ≥2 hours, up to a maximum dosage of 7.5 mg in any 24-hour period.1
If patient does not respond to first dose, additional doses are unlikely to provide benefit for the same headache.1
Maximum 7.5 mg in any 24-hour period.1
Safety of treating an average of >4 headaches per 30-day period has not been established.1
No dosage adjustment required in patients with mild to moderate hepatic impairment; not studied in patients with severe hepatic impairment.1
Known or suspected ischemic heart disease (e.g., angina pectoris, history of MI, documented silent ischemia).1
Coronary artery vasospasm (e.g., Prinzmetal variant angina).1
Other serious underlying cardiovascular disease (e.g., uncontrolled hypertension).1
Cerebrovascular syndromes (e.g., stroke syndrome, TIAs).1
Peripheral vascular ischemia (e.g., ischemic bowel disease).1
Hemiplegic or basilar migraine.1
Treatment within previous 24 hours with another 5-HT1 receptor agaonist or an ergot alkaloid.1 (See Specific Drugs under Interactions.)
Known hypersensitivity to frovatriptan or any ingredient in the formulation.1
Use only in patients in whom a clear diagnosis of migraine has been established.1
If first migraine attack treated with frovatriptan fails to respond to the drug, reconsider diagnosis before administering frovatriptan to treat subsequent attacks.1
Risk of myocardial ischemia and/or infarction, coronary vasospasm, life-threatening cardiac rhythm disturbances, and death with use of 5-HT1 receptor agonists.1
Use not recommended in patients with known or suspected ischemic or vasospastic heart disease or in patients in whom unrecognized CAD is likely (e.g., postmenopausal women; men >40 years of age; patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, or family history of CAD) unless there is satisfactory evidence from prior cardiovascular evaluation that patient does not have CAD, ischemic heart disease, or other underlying cardiovascular disease.1
Administer initial dose to patients with risk factors for CAD who have completed satisfactory cardiovascular evaluation under medical supervision (e.g., in clinician’s office, possibly followed by ECG) unless patient previously received the drug.1
Periodic cardiovascular evaluation recommended in patients with risk factors for CAD if receiving intermittent long-term therapy.1
Patients with symptoms suggestive of angina after receiving frovatriptan should be evaluated for presence of CAD or predisposition to Prinzmetal variant angina before receiving additional doses.1
Possible cerebral or subarachnoid hemorrhage, stroke, and other cerebrovascular events, sometimes fatal, with use of 5-HT1 receptor agonists.1
Risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA) may be increased in patients with migraine.1
Peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea reported with use of 5-HT1 receptor agonists.1 Further evaluation recommended if signs or symptoms of decreased arterial flow (e.g., ischemic colitis, Raynaud’s phenomenon) occur following administration.1 6 8
Substantial increases in BP, including hypertensive crises, reported rarely with 5-HT1 receptor agonists in patients with or without history of hypertension;1 6 transient increases in BP observed following administration of recommended dosage of frovatriptan (2.5 mg) in geriatric patients.1
Increases in mean pulmonary artery pressure observed following administration of a 5-HT1 receptor agonist to patients with suspected CAD who were undergoing cardiac catheterization.1
Potentially life-threatening serotonin syndrome reported during concurrent therapy with 5-HT1 receptor agonists (“triptans”) and SSRIs or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).1 11 Symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).11 (See Specific Drugs under Interactions.)
Possible accumulation of frovatriptan and/or its metabolites in melanin-rich tissues (e.g., eye) over time, resulting in potential toxicity in these tissues with extended use.1
Category C.1
Distributed into milk in rats; not known whether distributed into milk in humans.1 Caution advised if frovatriptan is used.1
Safety and efficacy not established in children <18 years of age; use not recommended.1
Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 (See Special Populations under Pharmacokinetics.)
Use with caution in patients with mild to moderate hepatic impairment.8 9 (See Special Populations under Pharmacokinetics.)
Not studied in patients with severe hepatic impairment.1
Dizziness,1 fatigue,1 headache,1 paresthesia,1 flushing,1 dry mouth,1 hot or cold sensation,1 skeletal pain,1 dyspepsia,1 chest pain,1 somnolence,1 nausea.1
Appears to be metabolized principally via CYP1A2.1 3 10
Does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 or MAO isoenzymes in vitro; does not induce drug metabolizing enzymes.1 Pharmacokinetic interaction with drugs metabolized by these isoenzymes unlikely.1 9
Potential pharmacokinetic interaction (increased plasma frovatriptan concentrations) with concomitant use of CYP1A2 inhibitors; however, effects not considered clinically relevant.8 10
Drug | Interaction | Comments |
|---|---|---|
Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) or SNRIs (e.g., duloxetine, venlafaxine) | Potentially life-threatening serotonin syndrome1 11 Potential increase in blood frovatriptan concentrations with concomitant fluvoxamine administration10 | Observe carefully if used concomitantly, particularly during treatment initiation, dosage increases, or when another serotonergic agent is initiated1 11 No dosage adjustment required if fluvoxamine is used concomitantly8 10 |
Ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide) | Additive vasospastic effects1 | Use within 24 hours contraindicated1 |
5-HT1 receptor agonists | Additive vasospastic effects1 | Use within 24 hours contraindicated1 |
Oral contraceptives | Possible increased plasma concentrations of frovatriptan8 9 | No dosage adjustment required8 9 |
Propranolol | Possible increased plasma concentrations of frovatriptan1 3 10 | No dosage adjustment required8 10 |
Incompletely absorbed from GI tract; absolute bioavailability of 20 and 30% in males and females, respectively.1 9
Peak plasma concentrations attained approximately 2–4 hours after oral administration.1 9
Food does not affect bioavailability but may delay time to peak plasma concentration by 1 hour.1
Distributes into cellular fraction of blood, principally erythrocytes (approximately 60% reversibly bound).9
Animal studies indicate limited capacity to cross blood-brain barrier.9
Distributed into milk in rats; not known whether distributed into milk in humans.1
Approximately 15%.1 9
Appears to be metabolized principally via CYP1A2 to numerous metabolites, including desmethyl frovatriptan, which exhibits lower affinity for 5-HT1B/1D receptors compared with frovatriptan.1 3
Excreted in urine (32%) and feces (62%) as unchanged drug and metabolites.1
Approximately 26 hours.1 9
In patient with mild to moderate hepatic impairment, AUC is twofold higher than in healthy individuals; pharmacokinetics not studied in patients with severe hepatic impairment.1
In geriatric patients, AUC is 1.5- to 2-fold higher than in younger adults; half-life and time to peak plasma concentrations unchanged.1
25°C (may be exposed to 15–30°C).1 Protect from moisture and light.1
Binds with high affinity to 5-HT1B and 5-HT1D receptors.1
Structurally distinct from, but pharmacologically related to, other selective 5-HT1B/1D receptor agonists (e.g., almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).2 7 8
Precise mechanism of action not established;6 may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathway.1 2
Importance of immediately informing clinician if tightness, pain, pressure, or heaviness in chest, throat, jaw, or neck occurs1 and of not taking frovatriptan again until evaluated by clinician.8
Importance of taking frovatriptan exactly as prescribed.1
Importance of providing patient a copy of manufacturer’s patient information.1
Risk of dizziness or fatigue; importance of exercising caution when driving or operating machinery.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1
Importance of informing patients of risk of serotonin syndrome with concurrent use of frovatriptan and an SSRI or SNRI.1 11 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.11
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 2.5 mg (of frovatriptan) | Frova | Endo |
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Frova 2.5MG Tablets (ENDO PHARMACEUTICALS): 9/$241.99 or 27/$699.93
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. Endo Pharmaceuticals Inc. Frova (frovatriptan succinate) tablets prescribing information. Chadds Ford, PA; 2006 Jun.
2. Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics, and efficacy. Drugs. 2000; 60:1259-87. [PubMed 11152011]
3. Jhee SS, Shiovitz T, Crawford AW et al. Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review. Clin Pharmacokinet. 2001; 40:189-205. [PubMed 11327198]
4. Matchar DB, Young WB, Rosenberg JH et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. From American Academy of Neurology web site ().
5. Silberstein SD, for the US Headache Consortium. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2000; 55:754-63. [IDIS 453389] [PubMed 10993991]
6. GlaxoWellcome. Amerge (naratriptan hydrochloride) tablets prescribing information. Research Triangle Park, NC; 1999 Nov.
7. Deleu D, Hanssens Y. Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol. 2000; 40:687-700. [IDIS 449430] [PubMed 10883409]
8. Elan Pharmaceuticals, South San Francisco, CA: Personal communication.
9. Buchan P, Keywood C, Wade A et al. Clinical pharmacokinetics of frovatriptan. Headache. 2002; 42(Suppl 2):S54-62.
10. Buchan P, Wade A, Ward C et al. Frovatriptan: a review of drug-drug interactions. Headache. 2002; 42(Suppl 2):S63-73.
11. Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephirne reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website: ( and ).
Migraine headaches, arthritis, menstrual pain, and to reduce fever. It may also have other uses. Check with your pharmacist for more details regarding the particular brand you use.
Feverfew is an herbal product. It works by affecting various chemicals in the body.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Feverfew. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Feverfew. However, no specific interactions are known at this time.
This may not be a complete list of all interactions that may occur. Ask your health care provider if Feverfew may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Feverfew as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Feverfew.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Mouth sores; nausea; stomach upset.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); fast heartbeat.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Feverfew side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Store at room temperature away from heat, moisture, and light unless otherwise directed on the package label. Do not store in the bathroom. Most herbal products are not in childproof containers. Keep Feverfew out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Feverfew. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
