No case of overdosage has been reported. No specific antidote is known. If an overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Controlip cannot be eliminated by haemodialysis.
There is no specific treatment for overdose with Controlip. 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. The usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.
Not applicable
The frequencies of adverse events are ranked according top the following: Very common ( > 1/10), Common (> 1/100, < 1/10), Uncommon (> 1/1,000, < 1/100), Rare (>1/10,000, < 1/1,000), very rare ( < 1/10,000 including isolated reports
Gastrointestinal:
Common: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence) moderate in severity
Uncommon: Pancreatitis *
Hepato-biliary disorders:
Common: Moderately elevated levels of serum transaminases (see Special Precautions for use).
Uncommon: Development of gallstones
Very rare: Episodes of hepatitis. When symptoms (e.g. jaundice, pruritus) indicative of hepatitis occur, laboratory tests are to be conducted for verification and Controlip discontinued, if applicable (see Special Warnings).
Cardiovascular system:
Uncommon: Thromboembolism (pulmonary embolism, deep vein thrombosis*)
Skin and subcutaneous tissue disorder:
Uncommon: rashes, pruritus, urticaria or photosensitivity reactions.
Rare: alopecia
Very rare: cutaneous photosensitivity with erythema, vesiculation or nodulation on parts of the skin expose to sunlight or artificial light (e.g. sunlamp) in individual cases (even after many months of uncomplicated use)
Musculoskeletal, connective tissue and bone disorders:
Rare: diffuse myalgia, myositis, muscular cramps and weakness
Not known: rhabdomyolysis
Blood and lymphatic system disorders:
Rare: decrease in haemoglobin and leukocytes
Nervous system disorder:
Rare: sexual asthenia
Respiratory, thoracic and mediastinal disorders.
Not known: interstitial pneumopathies
Investigation
Uncommon: increases in serum creatinine and urea
* In the FIELD study, a randomised placebo controlled trial performed in 9795 patients with type II diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving Controlip verses patients receiving placebo. (0.8% versus 05% p = 0.031. In the same study, a statistically significant increase was reported in the incidence of pulmonary embolism (0.7% in the placebo group versus 1.1% in the Controlip group; p = 0.022) and a statistically non-significant increase in deep vein thromboses (placebo 1.0% [48/4900 patients] versus Controlip 1.4% [67/4895 patients]; p = 0.074)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
Clinical Trials ExperienceBecause 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 rate 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, regardless of causality, are listed in Table 1 below. Adverse events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.
Table 1: Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials
| BODY SYSTEM Adverse Event | 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 | ||
| Abnormal Liver Function Tests | 7.5%** | 1.4% |
| Nausea | 2.3% | 1.9% |
| Constipation | 2.1% | 1.4% |
| METABOLIC AND NUTRITIONAL DISORDERS | ||
| 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% |
| * Dosage equivalent to 150 mg Controlip ** Significantly different from placebo | ||
The following adverse reactions have been identified during postapproval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL cholesterol levels. 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.
Chronic toxicity studies have yielded no relevant information about specific toxicity of Controlip.
Studies on mutagenicity of Controlip have been negative.
In rats and mice, liver tumours have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man.
Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity.
Prolongation of the gestation period and difficulties during delivery were observed at high doses. No sign of any effect on fertility has been detected.
Serum Lipid Reducing Agents / Cholesterol and Triglycerides Reducers / Fibrates.
ATC code: C10 AB 05
Controlip is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα).
Through activation of PPARα, Controlip increases the lipolysis and elimination of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The above stated effects of Controlip on lipoproteins lead to a reduction in very low- and low density fractions (VLDL and LDL) containing apoprotein B and an increase in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII.
In addition, through modulation of the synthesis and the catabolism of VLDL fractions Controlip increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.
During clinical trials with Controlip, total cholesterol was reduced by 20 to 25%, triglycerides by 40 to 55% and HDL cholesterol was increased by 10 to 30%.
In hypercholesterolaemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effect on cholesterol results in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol, or Apo B to Apo AI, all of which are markers of atherogenic risk.
Because of its significant effect on LDL cholesterol and triglycerides, treatment with Controlip should be beneficial in hypercholesterolaemic patients with or without hypertriglyceridaemia, including secondary hyperlipoproteinaemia such as type 2 diabetes mellitus.
At the present time, no results of long-term controlled clinical trials are available to demonstrate the efficacy of Controlip in the primary or secondary prevention of atherosclerotic complications.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated during Controlip therapy.
Patients with raised levels of fibrinogen treated with Controlip have shown significant reductions in this parameter, as have those with raised levels of Lp (a). Other inflammatory markers such as C Reactive Protein are reduced with Controlip treatment.
The uricosuric effect of Controlip leading to reduction in uric acid levels of approximately 25% should be of additional benefit in those dyslipidaemic patients with hyperuricaemia.
Controlip has been shown to possess an anti-aggregatory effect on platelets in animals and in a clinical study, which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine.
There is evidence that treatment with fibrates may reduce coronary heart disease events but they have not been shown to decrease all cause mortality in the primary or secondary prevention of cardiovascular disease.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus treated with Controlip in addition to simvastatin. Controlip plus simvastatin therapy did not show any significant differences compared to simvastatin monotherapy in the composite primary outcome of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08, p = 0.32 ; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidaemic patients, defined as those in the lowest tertile of HDL-C (≤34 mg/dl or 0.88 mmol/L) and highest tertile of TG (>204 mg/dl or 2.3 mmol/L) at baseline, Controlip plus simvastatin therapy demonstrated a 31% relative reduction compared to simvastatin monotherapy for the composite primary outcome (hazard ratio [HR] 0.69, 95% CI 0.49-0.97, p = 0.03 ; absolute risk reduction: 4.95%). Another prespecified subgroup analysis identified a statistically significant treatment-by-gender interaction (p = 0.01) indicating a possible treatment benefit of combination therapy in men (p=0.037) but a potentially higher risk for the primary outcome in women treated with combination therapy compared to simvastatin monotherapy (p=0.069). This was not observed in the aforementioned subgroup of patients with dyslipidaemia but there was also no clear evidence of benefit in dyslipidaemic women treated with Controlip plus simvastatin, and a possible harmful effect in this subgroup could not be excluded.
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 investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-c, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined.
Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apolipoproteins AI and AII.
Controlip 160 mg is a tablet containing 160 mg of micronised Controlip and is suprabioavailable (larger bioavailability) compared to the previous formulations.
Absorption: Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
The absorption of Controlip is increased when administered with food.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Plasma half-life: The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Metabolism and excretion: No unchanged Controlip can be detected in the plasma where the principal metabolite is fenofibric acid. The drug is excreted mainly in the urine. Practically all the drug is eliminated within 6 days. Controlip is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. In elderly patients, the fenofibric acid apparent total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug does not accumulate. Fenofibric acid is not eliminated by haemodialysis.
The extent and rate of absorption of fenofibric acid after administration of 150 mg Controlip capsules are equivalent under low-fat and high-fat fed conditions to 160 mg TriCor® tablets.
Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation. In a bioavailability study with Controlip capsules 200 mg, following single-dose administration, the plasma concentration (AUC) for the parent compound fenofibrate was approximately 40 μg/mL compared to 204 μg/mL for the metabolite, fenofibric acid. In the same study, the half-life was observed to be 0.91 hrs for the parent compound versus 16.76 hrs for the metabolite.
AbsorptionThe absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabeled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within approximately 5 hours after oral administration.
The absorption of fenofibrate is increased when administered with food. With Controlip, the extent of absorption is increased by approximately 58% and 25% under high-fat fed and low-fat fed conditions as compared to fasting conditions, respectively.
In a single dose and multiple dose bioavailability study with Controlip capsules 200 mg, the extent of absorption (AUC) of fenofibric acid, the principal metabolite of fenofibrate, was 42% larger at steady state compared to single-dose administration. The rate of absorption (Cmax) of fenofibric acid was 73% greater after multiple-dose than after single-dose administration.
The extent of absorption of Controlip in terms of AUC value of fenofibric acid increased in a less than proportional manner while the rate of absorption in terms of Cmax value of fenofibric acid increased proportionally related to dose.
DistributionUpon multiple dosing of fenofibrate, fenofibric acid steady state is achieved after 5 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.
MetabolismFollowing oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; unchanged fenofibrate is detected at low concentrations in plasma compared to fenofibric acid over most of the single dose and multiple dosing periods.
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 neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.
EliminationAfter absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in feces.
Fenofibric acid is eliminated with a half-life of approximately 20 hours allowing once daily dosing.
GeriatricsIn elderly volunteers 77 to 87 years of age, the apparent 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 Controlip can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites.
PediatricsPharmacokinetics of Controlip has not been studied in pediatric patients.
GenderNo pharmacokinetic difference between males and females has been observed for fenofibrate.
RaceThe influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.
Renal ImpairmentThe pharmacokinetics of fenofibric acid was examined in patients with mild, moderate and severe renal impairment. Patients with mild (estimated glomerular filtration rate eGFR 60-89 ml/min/1.73m²) to moderate (eGFR 30-59 mL/min/1.73m²) renal impairment had similar exposure but an increase in the half-life for fenofibric acid was observed as compared to that of healthy subjects. Patients with severe renal impairment (eGFR < 30 mL/min/1.73m²) 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. In patients with mild to moderate renal impairment, treatment with Controlip should be initiated at a dose of 50 mg per day, and increased only after evaluation of the effects on renal function and lipid levels at this dose. Based on these findings, the use of Controlip should be avoided in patients who have severe renal impairment.
Hepatic ImpairmentNo pharmacokinetic studies have been conducted in patients having hepatic impairment.
Drug-Drug InteractionsIn vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome P450 (CYP) isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild to moderate inhibitors of CYP2C9 at therapeutic concentrations.
Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of fenofibrate on coadministered drugs.
Table 2: Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration
| Co-Administered Drug | Dosage Regimen of Co-Administered Drug | Dosage Regimen of Fenofibrate | Changes in Fenofibric Acid Exposure | |
| AUC | Cmax | |||
| Lipid-lowering agents | ||||
| Atorvastatin | 20 mg once daily for 10 days | Fenofibrate 160 mg1 once daily for 10 days | ↓2% | ↓4% |
| Pravastatin | 40 mg as a single dose | Fenofibrate 3 x 67 mg2 as a single dose | ↓1% | ↓2% |
| Fluvastatin | 40 mg as a single dose | Fenofibrate 160 mg1as a single dose | ↓2% | ↓10% |
| Anti-diabetic agents | ||||
| Glimepiride | 1 mg as a single dose | Fenofibrate 145 mg1once daily for 10 days | ↑1% | ↓1% |
| Metformin | 850 mg three times daily for 10 days | Fenofibrate 54 mg1 three times daily for 10 days | ↓9% | 16% |
| Rosiglitazone | 8 mg once daily for 5 days | Fenofibrate 145 mg1 once daily for 14 days | ↑10% | ↑3% |
| 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule | ||||
Table 3. Effects of Fenofibrate on Systemic Exposure of Co-Administered Drugs
| Dosage Regimen of Fenofibrate | Dosage Regimen of Co-Administered Drug | Change in Co-Administered Drug Exposure | |
| Analyte | AUC Cmax | ||
| Lipid-lowering agents | |||
| Fenofibrate 160 mg1 once daily for 10 days | Atorvastatin, 20 mg once daily for 10 days | Atorvastatin | ↓17% 0% |
| Fenofibrate 3 x 67 mg2 as a single dose | Pravastatin, 40 mg as a single dose | Pravastatin | ↑13% ↑13% |
| 3α-Hydroxyl-iso- pravastatin | ↑26% ↑29% | ||
| Fenofibrate 160 mg1 as a single dose | Fluvastatin, 40 mg as a single dose | (+)-3R, 5S-Fluvastatin | ↑15% ↑16% |
| Anti-diabetic agents | |||
| Fenofibrate 145 mg1 once daily for 10 days | Glimepiride, 1 mg as a single dose | Glimepiride | ↑35% ↑18% |
| Fenofibrate 54 mg1 three times daily for 10 days | Metformin, 850 mg three times daily for 10 days | Metformin | ↑3% ↑6% |
| Fenofibrate 145 mg1 once daily for 14 days | Rosiglitazone, 8 mg once daily for 5 days | Rosiglitazone | ↑6% ↓1% |
| 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule | |||
No special requirements.
