PRAVAFEN 40/ 160 mg

Indications

• Primary hyperlipidaemia
• Mixed dyslipidaemia
• Prevention of cardiovascular disease in patients with elevated cholesterol levels

Dosage

Children: For children aged 9-17 years, the recommended starting dose is 10 mg daily, with a maximum dose of 80 mg daily, adjusted according to response

Adults: The usual starting dose is 40 mg once daily, which can be adjusted based on the patient's response, with a maximum dose of 80 mg once daily.

Mechanism of action

Pravastatin inhibits HMG-CoA reductase, the rate-limiting enzyme in the cholesterol synthesis pathway. This action reduces the hepatic cholesterol levels, leading to increased uptake of LDL cholesterol from the bloodstream and thereby lowering circulating LDL levels. Additionally, pravastatin enhances endothelial function and has anti-inflammatory properties.

Pharmacodynamics

The pharmacodynamics of pravastatin involve its ability to reduce levels of total cholesterol, LDL cholesterol, and triglycerides while increasing high-density lipoprotein (HDL) cholesterol. The effects are typically seen within a few weeks of starting therapy, with maximum reductions observed after 4 to 6 weeks of treatment. Pravastatin also has pleiotropic effects, which may contribute to its cardiovascular benefits, including improving endothelial function and reducing inflammation.

Pharmacokinetics

Pravastatin is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1 to 1.5 hours after oral administration. It undergoes extensive first-pass metabolism in the liver, primarily via the cytochrome P450 system, and has a relatively short half-life of about 1.5 to 2 hours. The drug is excreted mainly in the bile and feces, with minimal renal excretion. Dose adjustments may be necessary in patients with renal impairment, particularly at higher doses.

Contra-indications

• Active liver disease
• Pregnancy
• Breastfeeding
• Hypersensitivity to pravastatin or any component of the formulation

Adverse effects

• Myopathy
• Rhabdomyolysis
• Elevated liver enzymes
• Gastrointestinal disturbances
• Headache
• Dizziness
• Angioedema
• Lupus-like syndrome

Interactions

• CYP3A4 inhibitors (e.g., erythromycin, azole antifungals) may increase pravastatin levels
• Co-administration with other medications that may lead to muscle toxicity (e.g., other statins, gemfibrozil) should be done with caution
• Warfarin may have increased anticoagulant effects when used with pravastatin

Precautions

• Use cautiously in patients with a history of liver disease
• Monitor for signs of myopathy or rhabdomyolysis
• Regular liver function tests are recommended
• Assess renal function before initiating higher doses

Pregnancy

Pravastatin is contraindicated in pregnancy due to potential harm to the fetus. It is classified as a Category X drug.

Breast-feeding

Manufacturer advises avoiding use during breastfeeding due to insufficient data on safety.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• 10 mg tablets
• 20 mg tablets
• Oral suspension (special-order)

Indications

• Mixed hyperlipidaemia
• Severe hypertriglyceridaemia
• Familial hypercholesterolaemia (under expert advice)

Dosage

Children: For children aged 4–14 years, the dosage is one 67 mg capsule per 20 kg body weight daily, with a maximum of four 67 mg capsules per day

Adults: Initially 200 mg daily, increased if necessary to a maximum of 267 mg daily, or 100 mg to 160 mg daily depending on the formulation and patient needs.

Mechanism of action

Fenofibrate activates PPARα, a nuclear receptor that regulates gene transcription involved in lipid metabolism. This activation increases lipolysis, enhances the activity of lipoprotein lipase, and reduces apoprotein C-III levels. The resultant effect is an alteration in lipid homeostasis, leading to decreased triglyceride levels and improved lipid profiles. Fenofibrate also exhibits anti-inflammatory properties by suppressing the production of inflammatory cytokines.

Pharmacodynamics

Fenofibrate is effective in treating primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Its long half-life of 19-27 hours allows for once-daily dosing, making it convenient for patients. The therapeutic index is wide, but caution is advised due to the risks of rhabdomyolysis and myopathy, especially when used with statins.

Pharmacokinetics

Fenofibrate is absorbed after oral administration, with peak plasma concentrations occurring approximately 4-5 hours post-dose. It is extensively protein-bound and undergoes metabolism in the liver, converting to its active form. The elimination half-life is between 19 to 27 hours, and it is primarily excreted via urine. Dose adjustments may be necessary in cases of renal impairment.

Contra-indications

• Gall bladder disease
• Severe hepatic impairment
• Concurrent use of a statin in patients with risk factors for myopathy
• Hypoalbuminaemia
• Nephrotic syndrome
• Photosensitivity to fibrates

Adverse effects

• Alopecia
• Diarrhoea
• Dizziness
• Drowsiness
• Fatigue
• Gastrointestinal discomfort
• Headache
• Myalgia
• Nausea
• Skin reactions
• Vertigo
• Rhabdomyolysis
• Pancreatitis
• Hepatic disorders
• Sexual dysfunction
• Fatigue
• Interstitial lung disease

Interactions

• Fenofibrate + statins (increased risk of rhabdomyolysis)
• Fenofibrate + pravastatin (severe interaction, increases risk of rhabdomyolysis)
• Fenofibrate + fluvastatin (moderate interaction, increases risk of rhabdomyolysis)
• Fenofibrate + ketoprofen (photosensitivity)

Precautions

• Correct hypothyroidism before initiating treatment
• Monitor liver function and creatine kinase when fibrates are used in combination with a statin
• Use caution in patients with risk factors for myopathy or severe hypertriglyceridaemia

Pregnancy

Manufacturers advise avoiding use due to potential toxicity based on animal studies.

Breast-feeding

Manufacturer advises avoiding use as fenofibrate is present in milk in animal studies.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Modified-release tablets (200 mg)
• Tablets (100 mg)
• Micronised capsules (67 mg)
• Micronised capsules (200 mg)
• Micronised capsules (267 mg)

Indications

• Hyperlipidemia
• Primary prevention of cardiovascular disease
• Secondary prevention following myocardial infarction
• Familial hypercholesterolemia

Dosage

Adults: The usual starting dose is 40 mg once daily, which may be adjusted based

Mechanism of action

Pravastatin acts as a specific inhibitor of the hepatic HMG-CoA reductase enzyme, leading to a reduction in cholesterol biosynthesis. This inhibition increases the number of LDL receptors on cell surfaces, enhancing the receptor-mediated metabolism and clearance of LDL from circulation. Additionally, pravastatin inhibits the production of very low-density lipoproteins (VLDL), which are precursors to LDL.

Pharmacodynamics

Pravastatin primarily reduces total cholesterol, LDL cholesterol, and apolipoprotein B levels in the plasma. Clinical studies indicate that pravastatin can decrease total cholesterol by approximately 18%, LDL cholesterol by 27%, and triglycerides by 6%, while also increasing high-density lipoprotein (HDL) cholesterol levels by 4%. The drug has demonstrated a 24% reduction in the risk of death due to coronary disease in patients with a history of myocardial infarction or angina.

Pharmacokinetics

Pravastatin is well absorbed after oral administration, with peak plasma concentrations occurring within 1 to 1.5 hours. It undergoes extensive first-pass metabolism in the liver, which is primarily mediated by sulfation and to a lesser extent by cytochrome P450 enzymes. The elimination half-life of pravastatin is approximately 1.5 to 2 hours, and it is mainly excreted in the urine as metabolites. Its pharmacokinetics can be affected by factors such as liver function and concomitant use of other medications.

Contra-indications

• Active liver disease
• Pregnancy
• Breastfeeding
• Hypersensitivity to pravastatin or any component of the formulation

Adverse effects

• Headache
• Nausea
• Diarrhea
• Muscle pain
• Rhabdomyolysis
• Elevated liver enzymes

Interactions

• Fenofibrate: Severe (increases risk of rhabdomyolysis)
• Fibrates: Severe (increases risk of rhabdomyolysis)
• Letermovir: Moderate (increases exposure)
• Roxadustat: Moderate (increases exposure)
• Voxilaprevir with sofosbuvir and velpatasvir: Moderate (increases exposure)
• Darolutamide: Unknown (increases concentration)
• Bempedoic acid: Unknown (increases exposure)
• Crizotinib: Unknown (increases exposure)
• Elexacaftor: Unknown (increases exposure)
• HIV protease inhibitors: Unknown (affects exposure)

Precautions

• Monitor liver function tests before and during treatment
• Use caution in patients with a history of liver disease
• Consider risk of myopathy in patients with renal impairment
• Caution in elderly patients and those with hypothyroidism

Pregnancy

Pravastatin is contraindicated in pregnancy due to potential harm to the fetus.

Breast-feeding

Pravastatin is contraindicated during breastfeeding as it may affect the nursing infant.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 10 mg, 20 mg, 40 mg, 80 mg

Mechanism of action

Fenofibrate activates peroxisome proliferator activated receptor alpha (PPARα), increasing lipolysis, activating lipoprotein lipase, and reducing apoprotein C-III. PPARα is a nuclear receptor and its activation alters lipid, glucose, and amino acid homeostasis. Activation of PPARα activates transcription of gene transcription and translation that generates peroxisomes filled with hydrogen peroxide, reactive oxygen species, and hydroxyl radicals that also participate in lipolysis. This mechanism of increased lipid metabolism is also associated with increased oxidative stress on the liver. In rare cases this stress can lead to cirrhosis and chronic active hepatitis. Fenofibrate is a synthetic ligand for the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha and has been widely used in the treatment of metabolic disorders, especially hyperlipemia, due to its lipid-lowering effect. The molecular mechanism of lipid-lowering is relatively well defined: an activated PPARalpha forms a PPAR-RXR heterodimer and this regulates the transcription of genes involved in energy metabolism by binding to PPAR response elements in their promoter regions, so-called "trans-activation". In addition, fenofibrate also has anti-inflammatory and anti-athrogenic effects in vascular endothelial and smooth muscle cells. /There is/ limited information about the anti-inflammatory mechanism of fenofibrate; however, "trans-repression" which suppresses production of inflammatory cytokines and adhesion molecules probably contributes to this mechanism. Furthermore, there are reports that fenofibrate affects endothelial cells in a PPARalpha-independent manner. In order to identify PPARalpha-dependently and PPARalpha-independently regulated transcripts, ... microarray data from human endothelial cells treated with fenofibrate, and with and without siRNA-mediated knock-down of PPARalpha /were obtained/. ... Dynamic Bayesian transcriptome networks /were used/ to reveal PPARalpha-dependent and -independent pathways. Transcriptome network analysis identified growth differentiation factor 15 (GDF15) as a hub gene having PPARalpha-independently regulated transcripts as its direct downstream children. This result suggests that GDF15 may be PPARalpha-independent master-regulator of fenofibrate action in human endothelial cells. 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 a (PPARa). 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 (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 (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARa also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. ... /This study/ investigated whether fenofibrate affects serum levels of retinol-binding protein-4 (RBP4), an adipocytokine that has recently been shown to link obesity and insulin resistance. Fenofibrate treatment significantly decreased serum RBP4 levels of dyslipidemic patients, which correlated with reduced body weight and increased insulin sensitivity. ... the effect of fenofibrate on RBP4 expression in obese rats /were also examined/. Fenofibrate greatly decreased RBP4 mRNA levels in adipose tissue but not in the liver, which correlated with decreased serum RBP4 levels and increased insulin sensitivity in obese rats. Consistent with a direct effect on RBP4 expression, fenofibrate treatment significantly reduced the mRNA expression levels

Pharmacodynamics

Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half life of 19-27 hours so its duration of action is long. Fenofibrate capsules are given at a dose of 50-150mg daily so the therapeutic index is wide. Patients should be counselled about the risk of rhabdomyolysis, myopathy, and cholelithiasis when taking fibrates.

Mechanism of action

Pravastatin is a specific inhibitor of the hepatic HMG-CoA reductase in humans. The inhibition of this enzyme produces a reduction in cholesterol biosynthesis as HMG-CoA reductase activity is an early-limiting step in cholesterol biosynthesis. The inhibitory mechanism of action produces a reduction in cholesterol synthesis which in order has been observed to increase the number of LDL receptors on cell surfaces and an enhancement in receptor-mediated metabolism of LDL and clearance. On the other hand, pravastatin-driven inhibition of LDL production inhibits hepatic synthesis of VLDL as the LDL is the precursor for these molecules. Statins are largely used in clinics in the treatment of patients with cardiovascular diseases for their effect on lowering circulating cholesterol. Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for ox-LDL, plays a central role in the pathogenesis of atherosclerosis and cardiovascular disorders. We have recently shown that chronic exposure of cells to lovastatin disrupts LOX-1 receptor cluster distribution in plasma membranes, leading to a marked loss of LOX-1 function. Here we investigated the molecular mechanism of statin-mediated LOX-1 inhibition and we demonstrate that all tested statins /including pravastatin/ are able to displace the binding of fluorescent ox-LDL to LOX-1 by a direct interaction with LOX-1 receptors in a cell-based binding assay. Molecular docking simulations confirm the interaction and indicate that statins completely fill the hydrophobic tunnel that crosses the C-type lectin-like (CTLD) recognition domain of LOX-1. Classical molecular dynamics simulation technique applied to the LOX-1 CTLD, considered in the entire receptor structure with or without a statin ligand inside the tunnel, indicates that the presence of a ligand largely increases the dimer stability. Electrophoretic separation and western blot confirm that different statins binding stabilize the dimer assembly of LOX-1 receptors in vivo. The simulative and experimental results allow us to propose a CTLD clamp motion, which enables the receptor-substrate coupling. These findings reveal a novel and significant functional effect of statins. Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces very-low-density lipoprotein (VLDL) and triglyceride (TG) and increases high-density lipoprotein cholesterol (HDL-C). The HMG-CoA reductase inhibitors (statins) have been shown to exert several vascular protective effects that are not related to changes in cholesterol profile, and these effects of statins are partly caused by the activation of angiogenesis. Endothelial cell (EC) proliferation and migration are crucial events for angiogenesis and statins are known to enhance these events. However, the molecular mechanism by which statins promote EC proliferation and migration is not fully understood. In this study, we show Akt and its downstream target mammalian target of rapamycin (mTOR) play an important role in pravastatin-induced EC proliferation and migration. We found that pravastatin significantly enhanced the proliferation and migration of rat aortic endothelial cells (rAECs). The addition of pravastatin to rAECs resulted in rapid phosphorylation of Akt and p70 S6 kinase (p70S6K). LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), blocked both Akt and p70S6K phosphorylation, whereas rapamycin, a specific inhibitor of mTOR, suppressed only p70S6K phosphorylation induced by pravastatin. Furthermore, both LY294002 and rapamycin inhibited pravastatin-induced rAEC proliferation and migration. Taken together, our findings indicate that pravastatin activates PI3K/Akt/mTOR /p70S6K signaling in this sequential manner and this pathway contributes to pravastatin-i

Pharmacodynamics

The action of pravastatin on the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase produces an increase in the expression of hepatic LDL receptors which in order decreases the plasma levels of LDL cholesterol. The effect of pravastatin has been shown to significantly reduce the circulating total cholesterol, LDL cholesterol, and apolipoprotein B. As well, it modestly reduces very low-density-lipoproteins (VLDL) cholesterol and triglycerides while increasing the level of high-density lipoprotein (HDL) cholesterol and apolipoprotein A. In clinical trials with patients with a history of myocardial infarction or angina with high total cholesterol, pravastatin decreased the level of total cholesterol by 18%, decreased of LDL by 27%, decreased of triglycerides by 6% and increased of high-density lipoprotein (HDL) by 4%. As well, there was reported a decrease in risk of death due to coronary disease of 24%. When coadministered with [cholestyramine], pravastatin can reduce by 50% the levels of LDL and slow the progression of atherosclerosis and the risk of myocardial infarction and death.