Lovastatin

Lovastatin is an HMG-CoA reductase inhibitor belonging to Antilipemic Agent.

Lovastatin is an HMG-CoA reductase inhibitor used to lower LDL cholesterol and reduce the risk of cardiovascular disease and associated conditions, including myocardial infarction and stroke.

Lovastatin is 30% absorbed from the GI tract. The time to peak plasma concentration is achieved within 2-4 hours. Lovastatin can cross the blood-brain barrier and placenta. Both lovastatin and its β-hydroxy acid metabolite are highly bound (>95%) to human plasma proteins, largely due to its lipophilicity. Lovastatin is metabolized by the microsomal hepatic enzyme system (Cytochrome P-450 isoform 3A4). The major active metabolites present in human plasma are the β-hydroxy acid of lovastatin, and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. The uptake of lovastatin by the liver is enhanced by the activity of OATP1B1. Lovastatin's half-life is reported to be of 13.37 hours. The elimination half-life of the hydroxy acid form of lovastatin is reported to be of 0.7-3 hours. Lovastatin is excreted Via feces (approximately 85%) and via urine (approximately 10%).

Lovastatin shows common side effects like Constipation, stomach pain, Dizziness, difficulty falling asleep or staying asleep, Depression, joint pain, Headache, memory loss or forgetfulness, and confusion.

Lovastatin is available in the form of an Oral Tablet.

Lovastatin is available in India, the US, the UK, Singapore, Russia, Spain, Canada, Japan, and China.

Lovastatin belongs to the Antilipemic Agent and acts as an HMG-CoA Reductase Inhibitor.

Lovastatin acts by competitively inhibiting 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects.

The Data on the onset and duration of action of Lovastatin is not clinically established.

The Tmax of Lovastatin is approximately Immediate release: 2-4 hours; extended release: 12-14 hours.

Lovastatin is available in the form of Oral Tablet.

Lovastatin Tablet is taken orally, usually once daily.

Lovastatin is used to reduce the levels of bad cholesterol in the body. It is also used in the treatment of long-term heart problems and stroke. Moreover, Lovastatin is used in reducing the amount of cholesterol and also in children between 10 to 17 years of age suffering from hypercholesterolemia.

Lovastatin is an HMG-CoA reductase inhibitor belonging to Antilipemic Agent.

Lovastatin reduces cholesterol by competitively inhibiting HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis.

Lovastatin is approved for use in the following clinical indications

Adult indication

• Heterozygous familial hyperlipidemia
• Prevention of atherosclerotic cardiovascular disease

Pediatric indication

• Dyslipidemia; prevention of coronary artery disease
• Heterozygous familial hypercholesterolemia

Adult Dose

• Heterozygous familial hyperlipidemia

Patients unable to tolerate high-intensity therapy

Moderate-intensity therapy

Immediate release: 40 to 80 mg once daily with the evening meal.

Extended-release: 40 to 80 mg once daily at bedtime.

• Prevention of atherosclerotic cardiovascular disease

Primary prevention:

Patients without diabetes, 40 to 75 years of age, and LDL-C 70 to 189 mg/dL

ASCVD 10-year risk 5% to <7.5%:

Moderate-intensity therapy:

Immediate release: 40 to 80 mg once daily with the evening meal to reduce LDL-C by ~30% to 49%.

Extended-release: 40 to 80 mg once daily at bedtime to reduce LDL-C by ~30% to 49%.

ASCVD 10-year risk ≥7.5% to <20%:

Moderate-intensity therapy:

Immediate release: 40 to 80 mg once daily with the evening meal to reduce LDL-C by ~30% to 49%.

Extended-release: 40 to 80 mg once daily at bedtime to reduce LDL-C by ~30% to 49%.

ASCVD 10-year risk ≥20% (alternative agent)

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy:

Immediate release: 40 to 80 mg once daily with the evening meal.

Extended-release: 40 to 80 mg once daily at bedtime.

Patients with diabetes

40 to 75 years of age without additional ASCVD risk factors:

Moderate-intensity therapy:

Immediate release: 40 to 80 mg once daily with the evening meal to reduce LDL-C by ~30% to 49%.

Extended-release: 40 to 80 mg once daily at bedtime to reduce LDL-C by ~30% to 49%.

ASCVD 10-year risk ≥20% or multiple ASCVD risk factors (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy:

Immediate release: 40 to 80 mg once daily with the evening meal.

Extended-release: 40 to 80 mg once daily at bedtime.

Patients with LDL-C ≥190 mg/dL and 20 to 75 years of age (regardless of ASCVD risk estimate or coexisting diabetes mellitus) (alternative agent)

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy:

Immediate release: 40 to 80 mg once daily with the evening meal.

Extended-release: 40 to 80 mg once daily at bedtime.

Secondary prevention in patients with established atherosclerotic cardiovascular disease (eg, coronary heart disease, cerebrovascular disease [ischemic stroke or transient ischemic attack], peripheral arterial disease) (alternative agent)

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy:

Immediate release: 40 to 80 mg once daily with the evening meal.

Extended-release: 40 to 80 mg once daily at bedtime.

Pediatric Dose

• Dyslipidemia; prevention coronary artery disease

Adolescents ≥18 years: Immediate release

Initial: 20 mg once daily with evening meal, then adjust at 4-week intervals.

Maximum daily dose: 80 mg/day.

• Heterozygous familial hypercholesterolemia

Children ≥10 years and Adolescents ≤17 years: Immediate release

Initial: 10 mg once daily with evening meal; if target LDL-C levels are not reached within 3 months, increase dose in 10 mg increments every 3 months until target LDL-C is achieved; usual effective range: 10 to 40 mg once daily.

Maximum daily dose: 80 mg/day. Lower initial doses or maximum daily doses may be necessary for some concomitant medications (eg, amiodarone, verapamil, danazol, diltiazem).

Lovastatin is available in various strengths as 10 mg, 20 mg, 40 mg, and 60 mg.

Lovastatin is available in the form of an Oral Tablet.

• Dosage Adjustment in Kidney Patient

CrCl <30 mL/minute: Use with caution and carefully consider doses >20 mg/day.

Avoid grapefruit products. Grapefruit products may increase the risk for Lovastatin-related adverse effects such as myopathy and rhabdomyolysis.

Lovastatin is contraindicated in patients with

• Hypersensitivity to any component of this medication.
• Active liver disease or unexplained persistent elevations of serum transaminases.
• Concomitant administration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodone).
• Pregnancy and lactation

• Diabetes mellitus

Increases in HbA_1c and fasting blood glucose have been reported with HMG-CoA reductase inhibitors; however, the benefits of statin therapy far outweigh the risk of dysglycemia. If a patient develops diabetes mellitus during therapy, continue the use of lovastatin and encourage the patient to adhere to healthy lifestyle regimens (eg, heart-healthy dietary patterns, engaging in physical activity, achieving, and maintaining a healthy body weight).

• Endocrine effects

Reduced cholesterol synthesis because of therapy could theoretically lead to reduced adrenal or gonadal steroid hormone production; clinical trial data are inconsistent in regard to the effect on basal steroid hormone levels. Patients with signs/symptoms of endocrine dysfunction should be evaluated as clinically indicated; use caution with concomitant medications (eg, spironolactone, cimetidine, ketoconazole) that may reduce steroid hormone levels/activity.

• Hepatotoxicity

Persistent elevations in serum transaminases have been reported; upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels. Post-marketing reports of fatal and nonfatal hepatic failure are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy promptly. If an alternate etiology is not identified, do not restart lovastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated; routine periodic monitoring of liver enzymes is not necessary. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.

• Myopathy/rhabdomyolysis

Rhabdomyolysis with acute renal failure secondary to myoglobinuria and/or myopathy has been reported; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, protease inhibitors), cyclosporine, fibric acid derivatives (eg, gemfibrozil), or niacin (doses ≥1 g/day); if concurrent use is warranted, consider lower starting and maintenance doses of lovastatin. Use caution in patients with inadequately treated hypothyroidism and those taking other drugs associated with myopathy (eg, colchicine), ≥65 years of age, and women; these patients are predisposed to myopathy. Immune-mediated necrotizing myopathy associated with HMG-CoA reductase inhibitor use has also been reported. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine, particularly if accompanied by malaise or fever. Discontinue therapy if markedly elevated CPK levels occur or if myopathy is diagnosed/suspected; consider treatment with immunosuppressants and additional neuromuscular and serologic testing. Prior to initiating a different HMG-CoA reductase inhibitor, consider the risk of immune-mediated necrotizing myopathy; monitor closely.

Avoid consumption of alcohol while on treatment with Lovastatin as it may increase the risk of liver damage.

It is not known whether Lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking Lovastatin should not nurse their infants.

Lovastatin is contraindicated in pregnant females. There are reports of congenital anomalies following maternal use of HMG-CoA reductase inhibitors in pregnancy; however, maternal disease, differences in specific agents used, and the low rates of exposure limit the interpretation of the available data. Cholesterol biosynthesis may be important in fetal development; serum cholesterol and triglycerides increase normally during pregnancy. The discontinuation of lipid-lowering medications temporarily during pregnancy is not expected to have a significant impact on the long-term outcomes of primary hypercholesterolemia treatment. Lovastatin should be discontinued immediately if an unplanned pregnancy occurs during treatment.

Avoid grapefruit products. Grapefruit products may increase the risk for Lovastatin-related adverse effects such as myopathy and rhabdomyolysis.

Common Adverse effects

• GI disturbances, headache, dizziness, insomnia, myopathy or rhabdomyolysis (dose-related), myalgia, arthralgia, weight gain, blurred vision, rash, and asymptomatic hepatic aminotransferase elevation.

Rare Adverse effects

• Severe rhabdomyolysis w/ acute renal failure. Hepatitis, pancreatitis. Rare: Stevens-Johnson syndrome, anaphylaxis, toxic epidermal necrolysis.

• CYP3A4 Interactions:

Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore, it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Strong inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin), and grapefruit juice increase the risk of myopathy by reducing the elimination of lovastatin.

• Interactions With Lipid-Lowering Drugs that can cause Myopathy when given alone:

The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong CYP3A4 inhibitors but can cause myopathy when given alone.

• Cyclosporine:

The risk of myopathy/rhabdomyolysis is increased by the concomitant administration of cyclosporine.

• Danazol, Diltiazem, Dronedarone or Verapamil:

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol, diltiazem, dronedarone, or verapamil particularly with higher doses of lovastatin.

• Amiodarone:

The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class.

• Coumarin Anticoagulants:

In a small clinical trial in which lovastatin was administered to warfarin-treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended that in patients taking anticoagulants, prothrombin time be determined before starting lovastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

• Colchicine:

Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine.

• Ranolazine:

The risk of myopathy, including rhabdomyolysis, may be increased by the concomitant administration of ranolazine.

• Propranolol:

In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with the concomitant administration of single doses of lovastatin and propranolol.

• Digoxin:

In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.

• Oral Hypoglycemic Agents:

In pharmacokinetic studies of Lovastatin in hypercholesterolemic noninsulin-dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide.

The common side effects of Lovastatin include the following

Common

● Constipation, memory loss or forgetfulness, confusion.

Rare

● Muscle pain, tenderness, or weakness, lack of energy, weakness, fever, dark-colored urine, yellowing of the skin or eyes, pain in the upper right part of the stomach, extreme tiredness, nausea, unusual bleeding or bruising, loss of appetite, flu-like symptoms, rash, hives, itching, difficulty breathing or swallowing, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, hoarseness.

• Pregnancy

Pregnancy Category X

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in the use of the drug in pregnant women clearly outweigh the potential benefits.

• Nursing Mothers

It is not known whether Lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking Lovastatin should not nurse their infants.

• Pediatric Use

As per FDA, the safety and effectiveness in pediatric patients have not been established. Because pediatric patients are not likely to benefit from cholesterol-lowering for at least a decade and because experience with this drug is limited (no studies in subjects below the age of 20 years), treatment of pediatric patients with Lovastatin is not recommended at this time.

• Geriatric Use

A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥ 65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day dosage range.

After oral administration of Lovastatin to mice, the median lethal dose observed was > 15 g/m². Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5-6 g. Until further experience is obtained, no specific treatment for overdosage with Lovastatin can be recommended. The realizability of lovastatin and its metabolites in men is not known at present.

Pharmacodynamic

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 (apo B), non-high-density lipoprotein-cholesterol (non-HDL-C), and triglyceride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C, and high TG concentrations in the plasma are associated with an 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 a 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.

Pharmacokinetics

• Absorption

Lovastatin is 30% absorbed from the GI tract. The time to peak plasma concentration is achieved within 2-4 hours.

• Distribution

Lovastatin can cross the blood-brain barrier and placenta. Both lovastatin and its β-hydroxy acid metabolite are highly bound (>95%) to human plasma proteins, largely due to its lipophilicity.

• Metabolism

Lovastatin is metabolized by the microsomal hepatic enzyme system (Cytochrome P-450 isoform 3A4). The major active metabolites present in human plasma are the β-hydroxy acid of lovastatin, and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. The uptake of lovastatin by the liver is enhanced by the activity of OATP1B1.

• Excretion

Lovastatin's half-life is reported to be of 13.37 hours. The elimination half-life of the hydroxy acid form of lovastatin is reported to be of 0.7-3 hours. Lovastatin is excreted Via feces (approximately 85%) and via urine (approximately 10%).

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