Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Laboratoires SMB s.a., Rue de la Pastorale, 26-28, B-1080 Brussels, Belgium Tel. +32 (2) 411 48 28 Fax. +32 (2) 411 28 28
Pharmacotherapeutic group: Lipid modifying agents, HMG CoA reductase inhibitors in combination with other lipid modifying agents
ATC code: C10BA03
Pravafenix contains fenofibrate and pravastatin, which have different modes of action and show additive effects in terms of reduction of serum lipid. The following statements reflect the pharmacodynamic/pharmacokinetic properties of the individual active substances of Pravafenix.
Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα). Studies with fenofibrate on lipoprotein fractions show decreases in levels of LDL and VLDL cholesterol. HDL cholesterol levels are frequently increased. LDL and VLDL triglycerides are reduced. The overall effect is a decrease in the ratio of low and very low-density lipoproteins to high-density lipoproteins.
The lipid-lowering properties of fenofibrate seen in clinical practice have been explained in vivo in transgenic mice and in human hepatocyte cultures by activation of Peroxisome Proliferator Activated Receptor type α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of Apoprotein C-III. Activation of PPARα also induces an increase in the synthesis of Apoproteins A-I, A-II and of HDL cholesterol.
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 5,518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Fenofibrate 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, fenofibrate 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 fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not be excluded.
Plasma uric acid levels are increased in approximately 20% of hyperlipidaemic patients, particularly in those with type IV disease. Fenofibrate has a uricosuric effect and is therefore of additional benefit in such patients.
Pravastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalysing the early rate-limiting step in cholesterol biosynthesis, and produces its lipid-lowering effect in two ways. Firstly, with the reversible and specific competitive inhibition of HMG-CoA reductase, it effects modest reduction in the synthesis of intracellular cholesterol. This results in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL-cholesterol.
Secondly, pravastatin inhibits LDL production by inhibiting the hepatic synthesis of VLDLcholesterol, the LDL-cholesterol precursor.
In both healthy subjects and patients with hypercholesterolaemia, pravastatin lowers the following lipid values: total cholesterol, LDL-cholesterol, apolipoprotein B, VLDL-cholesterol and triglycerides; while HDL-cholesterol and apolipoprotein A are elevated.
The respective effects of pravastatin and fenofibrate are complementary. Pravastatin is more effective in reducing LDL-C and total cholesterol but presents only modest effects on TG and HDL-C while fenofibrate is very effective in decreasing TG and increasing HDL-C, but with few effects on LDL-C. Additionally, fibrates have the properties to modify the size and density of LDL-C particles to make them less atherogenic.
Fibrates and statins in combination have also been shown to synergistically increase the transcriptional activities of PPAR receptors.
Four multicenter studies with either Pravafenix 40 mg/160 mg or Pravastatin 40 mg or Simvastatin 20 mg were conducted: 3 studies included a 12 week randomized, double-blind, active controlled period with an open-label extension phase and one was a 24-week open-label study. In total, these studies enrolled 1,637 patients who have not had an adequate response to treatment with pravastatin 40 mg monotherapy or simvastatin 20 mg in Europe and in the USA.
In the pivotal European multicenter 64-week clinical trial including 12 week randomised, doubleblind, double-dummy, 2-arm, parallel study period, 248 high vascular risk patients with mixed dyslipidaemia were randomised to one of the two treatment groups: Pravafenix 40 mg/160 mg or pravastatin 40 mg. Only patients who had not met their NCEP ATP III target LDL-C and Triglyceride goals (LDL >100 mg/dl and TG >150 mg/dl) after 8 weeks on pravastatin 40 mg (1 tablet, once daily) were randomized. Patients receiving Pravafenix 40 mg/160 mg were compared to those receiving pravastatin 40 mg: Pravafenix significantly lowered non-HDL-C, LDL-C, TG and significantly increased HDL-C to a greater extent than pravastatin 40 mg (table).
Mean percent changes from baseline to week 12 for patients treated with Pravafenix 40 mg/160 mg or Pravastatin 40 mg once daily:
| Pravafenix 40 mg/160 mg Na = 120 | PRAVASTATIN 40 mg Na = 119 | Pravafenix versus PRAVASTATIN | |
|---|---|---|---|
| Mean (%)± SEb | Mean (%)± SEb | p-valuec | |
| Non-HDL-C (mg/dl) | -14.1 ± 1.78 | -6.1 ± 1.79 | 0.0018 |
| LDL-C (mg/dl) | -11.7 ± 1.75 | -5.9 ± 1.76 | 0.019 |
| HDL-C (mg/dl) | +6.5 ± 1.12 | +2.3 ± 1.13 | 0.0089 |
| TG (mg/dl) | -22.6 ± 4.37 | -2.0 ± 4.39 | 0.0010 |
| TC (mg/dl) | -9.9 ± 1.37 | -4.4 ± 1.38 | 0.006 |
| Apo A1 (g/L) | +5.5 ± 0.99 | +2.8 ± 0.97 | 0.058 |
| Apo B (g/L) | -12.6 ± 1.57 | -3.8 ± 1.53 | <0.0001 |
| Apo B/Apo A1 | -16.3 ± 1.66 | -6.0 ± 1.61 | <0.0001 |
| Fibrinogen (g/L) | -8.8 ± 1.80 | +1.4 ± 1.75 | <0.0001 |
| Hs-CRP (mg/L) | -1.1 ± 0.61 | +0.6 ± 0.70 | 0.003 |
a Number of patients
b Mean percent change (least square mean ± standard error) between baseline measured after 8 weeks on Pravastatin 40 mg and 12 additional weeks with Pravafenix 40 mg/160 mg or Pravastatin 40 mg
c Pairwise p-value is significant if <0.05
The effects of Pravafenix 40 mg/160 mg were confirmed in a similar multicenter, 64-week trial including a 12 week randomized, double-blind phase in a study performed in the USA and comparing Pravafenix 40 mg/160 mg to Fenofibrate 160 mg monotherapy and Pravastatin 40 mg monotherapy in patients with mixed dyslipidaemia. The incremental benefit of Pravafenix 40 mg/160 mg on main lipid parameters versus Pravastatin 40 mg and Fenofibrate 160 mg monotherapy was also established.
The European Medicines Agency has waived the obligation to submit the results of studies with Pravafenix in all subsets of the paediatric population in disorders of lipoprotein metabolism and other hyperlipidaemias (see section 4.2 for information on paediatric use).
No clinically significant pharmacokinetic interaction was seen when fenofibrate was coadministered with pravastatin.
Pravafenix is bioequivalent to coadministered fenofibrate and pravastatin in a single dose study. However in a multiple dose study, the results showed that the product is not bioequivalent because its bioavailability after multiple dosing is a 20% lower for the fenofibrate component of the combination. This is due to the fat content of the meal. Therefore the fixed dose combination (Pravafenix) could not be considered interchangeable with the free co-administration of fenofibrate and pravastatin mono-component drug products.
A pharmacokinetic study after a single dose administration of Pravafenix has been performed in fed and fasting condition. The results of this study show that food has effect on the rate and extent of absorption in the fixed dose combination. The bioavailability of fenofibric acid is lower in fasting conditions after a single dose administration of the Fenofibrate-Pravastatin 160/40 mg combination. The decreased in AUCt, AUC∞ and Cmax of fenofibric acid (point estimate) is of 30.94%, 10.9% and 68.71% respectively.
The bioavailability of pravastatin is higher after a single dose administration of the test product Fenofibrate/Pravastatin 160/40 mg in fasting conditions than after a single dose of the product in fed conditions. The increase in AUC∞, AUCt, and Cmax is of 111.88%, 114.06%, and 115.28% respectively. In line with several formulations for fenofibrate, the fixed combination is recommended to be taken with food because the bioavailability of fenofibrate is increased when administered with food and the lipid-lowering efficacy of pravastatin is not altered.
Pravastatin is administered orally in the active form. It is rapidly absorbed; peak serum levels are achieved 1 to 1.5 hours after ingestion. On average, 34% of the orally administered dose is absorbed, with an absolute bioavailability of 17%.
The presence of food in the gastrointestinal tract leads to a reduction in the bioavailability, but the cholesterol-lowering effect of pravastatin is identical whether taken with or without food.
After absorption, 66% of pravastatin undergoes a first-pass extraction through the liver, which is the primary site of its action and the primary site of cholesterol synthesis and clearance of LDLcholesterol. In vitro studies demonstrated that pravastatin is transported into hepatocytes and with substantially less intake in other cells. In view of this substantial first pass through the liver, plasma concentrations of pravastatin have only a limited value in predicting the lipid-lowering effect. The plasma concentrations are proportional to the doses administered.
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 fenofibrate is increased when administered with food. The food effect increases with the fat content: the larger the lipid content the larger the bioavailability of fenofibrate.
About 50% of circulating pravastatin is bound to plasma proteins. The volume of distribution is about 0.5 l/kg. A small quantity of pravastatin passes into the human breast milk.
Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Pravastatin is not significantly metabolised by cytochrome P450 nor does it appear to be a substrate or an inhibitor of P-glycoprotein but rather a substrate of other transport proteins.
Following oral administration, 20% of the initial dose is eliminated in the urine and 70% in the faeces.
Plasma elimination half-life of oral pravastatin is 1.5 to 2 hours.
After intravenous administration, 47% of the dose is eliminated by the renal excretion and 53% by biliary excretion and biotransformation. The major degradation product of pravastatin is the 3-αhydroxy isomeric metabolite. This metabolite has one-tenth to one-fortieth the HMG-CoA reductase inhibitor activity of the parent compound.
The systemic clearance of pravastatin is 0.81 l/h/kg and the renal clearance is 0.38 l/h/kg indicating tubular secretion.
No unchanged fenofibrate 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.
Fenofibrate 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. The plasma elimination half-life of fenofibric acid is approximately 20 hours.
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 safety of concomitant administration of pravastatin and fenofibrate was assessed in rats. Toxicological findings in these co-administration studies were consistent with those seen with pravastatin and fenofibrate administered individually.
Based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity on reproduction, there are no other risks for the patient than those expected due to the pharmacological mechanism of action.
Repeated dose studies indicate that pravastatin may induce varying degrees of hepatotoxicity and myopathy; in general, substantive effects on these tissues were only evident at doses 50 or more times the maximum human mg/kg dose. In vitro and in vivo genetic toxicology studies have shown no evidence of mutagenic potential. In mice, a 2-year carcinogenicity study with pravastatin demonstrates at doses of 250 and 500 mg/kg/day (>310 times the maximum human mg/kg dose), statistically significant increases in the incidence of hepatocellular carcinomas in males and females, and lung adenomas in females only. In rats a 2-year carcinogenicity study demonstrates at a dose of 100 mg/kg/day (125 times the maximum human mg/kg/dose) a statistically significant increase in the incidence of hepatocellular carcinomas in males only.
Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate. Studies on mutagenicity of fenofibrate 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.
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