LIPISTAT-10 10MG TABLET

Indications

• Primary hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease
• Familial hypercholesterolemia
• Secondary prevention of coronary heart disease

Dosage

Adults: The usual starting dose

Mechanism of action

Lovastatin is a lactone that is hydrolyzed in vivo to its active β-hydroxyacid form, inhibiting HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early step in cholesterol biosynthesis. This inhibition leads to decreased hepatic cholesterol concentrations, prompting upregulation of hepatic LDL receptors, enhancing LDL uptake from the plasma. The result is a reduction in plasma LDL and very low-density lipoprotein (VLDL), consequently lowering the risk of CVD.

Pharmacodynamics

Lovastatin reversibly inhibits HMG-CoA reductase, effectively lowering total cholesterol, LDL-C, apolipoprotein B, and triglyceride concentrations while increasing HDL-C levels. Elevated levels of LDL-C and triglycerides are linked to increased atherosclerosis and CVD risk, whereas higher HDL-C levels correlate with decreased cardiovascular risk. By achieving these lipid profile modifications, lovastatin significantly reduces cardiovascular morbidity and mortality.

Pharmacokinetics

Lovastatin is absorbed from the gastrointestinal tract, with peak plasma concentrations occurring 1 to 2 hours after administration. It is extensively metabolized in the liver, predominantly via the cytochrome P450 system, particularly CYP3A4. The elimination half-life is approximately 2 to 5 hours. Lovastatin is primarily excreted as metabolites in urine and feces. The bioavailability of lovastatin is low due to extensive first-pass metabolism, hence it is often recommended to be taken in the evening for optimal effects.

Contra-indications

• Active liver disease
• Pregnancy
• Breastfeeding
• Hypersensitivity to lovastatin or any of its components

Adverse effects

• Myopathy
• Rhabdomyolysis
• Elevated liver enzymes
• Gastrointestinal disturbances (e.g., nausea, diarrhea)
• Headache
• Muscle cramps
• Dizziness

Interactions

• CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, grapefruit juice) may increase lovastatin levels and risk of myopathy
• CYP3A4 inducers (e.g., rifampicin, carbamazepine) may reduce effectiveness of lovastatin
• Other lipid-lowering agents (e.g., gemfibrozil) may increase risk of myopathy

Precautions

• Use with caution in patients with a history of liver disease
• Monitor liver function tests before and during treatment
• Assess risk of myopathy when used with other medications that affect muscle metabolism
• Consider risk versus benefit in elderly patients

Pregnancy

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

Breast-feeding

Lovastatin is contraindicated while breastfeeding as it may pass into breast milk and affect the 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

Mechanism of action

Lovastatin is a lactone which is readily hydrolyzed _in vivo_ to the corresponding β-hydroxyacid and strong inhibitor of HMG-CoA reductase, a hepatic microsomal enzyme which catalyzes the conversion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A ) to mevalonate, an early rate-limiting step in cholesterol biosynthesis. At therapeutic lovastatin doses, HMG-CoA reductase is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol, therapy with lovastatin would not be expected to cause an accumulation of potentially toxic sterols. Lovastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increase hepatic uptake of LDL. Lovastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL and a significant reduction in the risk of development of CVD and all-cause mortality. A significant effect on LDL-C reduction was seen within 2 weeks of initiation of lovastatin, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night. When therapy with lovastatin is stopped, total cholesterol has been shown to return to pre-treatment levels. In vitro and in vivo animal studies also demonstrate that lovastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation. Lovastatin has been reported to have beneficial effects on certain cancers. This includes a multi-factorial stress-triggered cell death (apoptosis) and DNA degradation response in breast cancer cells. It has also been shown to inhibit histone deacetylase 2 (HDAC2) activity and increase the accumulation of acetylated histone-H3 and the expression of p21(WAF/CIP) in human cancer cells, suggesting that statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin and simvastatin, reduce atherogenesis and cardiovascular morbidity. Besides, there is growing evidence that statins have immunomodulatory activities. Statins downregulate the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1), on leucocytes and endothelial cells and, through binding to LFA-1, interfere with ICAM-1-LFA-1 interaction, which is crucial for activation of lymphocytes by antigen-presenting cells, ingress of leucocytes into the inflammation sites and immunologic cytotoxicity. Statins inhibit the inducible expression of major histocompatibility complex class II in several cell types including macrophages and downregulate the expression of T-helper-1 (Th1) chemokine receptors on T cells, leading further to inhibition of activation of lymphocytes and their infiltration into the inflammation sites. Statins block the induction of inducible nitric oxide synthase and the expression of several proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma in macrophages and possess antioxidant effects. These agents inhi

Pharmacodynamics

Lovastatin is an oral antilipemic agent which reversibly inhibits HMG-CoA reductase. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, lovastatin reduces the risk of cardiovascular morbidity and mortality. Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. Clinical studies have shown that lovastatin reduces LDL-C and total cholesterol by 25-40%. The 50% inhibitory dose is known to be of 46 mcg/kg which is translated into a reduction of approximately 30% of plasma cholesterol. **Myopathy/Rhabdomyolysis** Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is dose-related and is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20 to 40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may also be at increased risk for myopathy. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. The risk of myopathy during treatment with lovastatin may be increased with concurrent administration of interacting drugs such as [fenofibrate], [niacin], [gemfibrozil], [cyclosporine], and strong inhibitors of the CYP3A4 enzyme. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with [colchicine], and caution should therefore be exercised when prescribing these two medications together. Real-world data from observational studies has suggested that 10-15% of people taking statins may experience muscle aches at some point during treatment. **Liver Dysfunction** Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials. When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment