Lovastatin

Mechanism of Action

Lovastatin is metabolized into its active form beta-hydroxy acid in the stomach and functions to competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is involved in the rate-limiting step of cholesterol synthesis. HMG-CoA inhibitors also decrease levels of high-sensitivity C-reactive protein (hsCRP), improve endothelial function, reduce inflammation at coronary plaque sites, inhibit platelet aggregation, and have anticoagulant effects.[2][3] Also, a decrease in serum cholesterol will stimulate LDL receptor expression on hepatocytes, further increasing LDL catabolism.

Pharmacokinetics

Lovastatin has a 30% bioavailability with an extensive first-pass effect; less than 5% reaches the systemic circulation. When administered without food, its bioavailability is reduced by 50%. It has a half-life of 1.1 to 1.7 hours and greater than 95% protein binding. It is metabolized to beta-hydroxy acid (active form) by CYP3A4, with excretion of 80 to 85% in feces and 10% in urine. Therapeutic response is apparent by 2 weeks, and maximal response occurs within 4 to 6 weeks.[4]

Administration

Dosage Formulations

Lovastatin is available in two forms, immediate and extended-release tablets. Immediate-release tablets are recommended for administration in the evening with food, and extended-release taken at bedtime. Both dosage forms are not to be crushed or chewed. Lovastatin immediate release is available in 20 mg and 40 mg tablets. The extended-release tablets are available in 20, 40, or 60 mg. Extended-release tablets are not recommended for patients that only need small amounts of reduction in cholesterol levels.

Adult Dosing

• Lovastatin at a dose of 20 mg per day is considered a low-intensity statin as it normally reduces LDL-C by less than 30%.
• Lovastatin at a dose of 40 - 80 mg per day is considered a moderate-intensity statin as it normally reduces LDL-C by 30% to 50%.

Before initiating treatment with lovastatin, other causes for hypercholesterolemia should be ruled out. These include alcoholism, poorly controlled diabetes mellitus, dysproteinemias, hypothyroidism, obstructive liver disease, nephrotic syndrome, and/or other drug therapy. A complete lipid profile should be investigated to measure total-C, HDL-C, and TG. Lovastatin is indicated for heterozygous familial hyperlipidemia and prevention of atherosclerotic cardiovascular disease (primary prevention in patients with or without diabetes and secondary prevention in patients with established atherosclerotic cardiovascular disease like coronary heart disease, peripheral arterial disease, ischemic stroke, and/or transient ischemic attack).

• Before starting lovastatin, the patient should be started on a standard cholesterol-lowering diet as per NCEP Treatment Guidelines for six weeks and continue this diet throughout treatment. Patients should avoid taking grapefruit juice since it may increase drug toxicity and adverse effects.[5]
• When initiating the treatment, consider the patient’s 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores, LDL-C at baseline, and patient and medicine-specific factors. Lovastatin needs to be used in conjugation with lifestyle changes like exercise and dietary modifications. 
• Recommended starting dose is 20 mg once a day with an evening meal. The maximum recommended dose is 80 mg once daily. Dosages should be individualized to treatment goals and adjusted at 4-week intervals. According to AHA guidelines, reassess patient clinical response after one to three months of treatment initiation with lovastatin and once stabilized reassess annually.[6]
• A lower starting dose of 10 mg of lovastatin may be considered for some when patients require smaller reductions in cholesterol levels. Consider reducing the dose of lovastatin if cholesterol levels fall drastically below the targeted range for individuals.

Specific Patient Population

Adolescent Patients(10 - 17 years ): In patients with heterozygous familial hypercholesterolemia, recommended lovastatin dose ranges between 10 to 40 mg per day, and the maximum recommended dose should not exceed 40 mg per day. Lovastatin dose should be individualized according to the recommended goal of therapy as per NCEP pediatric panel guidelines. Consider starting dose at 10 mg for patients requiring smaller reductions in LDL-C. When reduction in LDL-C of 20% or more desired, then start lovastatin dose at 20 mg per day.

Patients with Renal Impairment: In patients with severe renal impairment with CrCL less than 30 mL/min, use caution when the lovastatin dose is more than 20 mg per day.

Patients with Hepatic Impairment: No dose adjustment is studied/provided in the manufacturer’s prescribing label.

Pregnancy Considerations: After a comprehensive review of all available data, the U.S. FDA has removed the strongest warnings against using HMG-co-A Reductase Inhibitors in pregnant women. However, most women should not take lovastatin once they become pregnant. Assess the risk versus benefits to the pregnant patient.

Breastfeeding Considerations: It is not known whether lovastatin gets 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.[7]

Adverse Effects

Lovastatin is generally well tolerated with mild and transient adverse reactions. There are few report cases of severe adverse effects associated with lovastatin. Below are the reported side effects of the drug: 

• Persistent elevation in serum AST and ALT (more than three times the upper limit of normal)
• Increased creatinine phosphokinase (CK) greater than two times normal
• Headaches, dizziness
• Skin rash
• Gastrointestinal symptoms such as flatulence, constipation, abdominal pain, diarrhea, nausea, dyspepsia
• Myalgia, weakness, muscle cramps
• Blurry vision 

Other serious adverse effects include diabetes mellitus, endocrine dysfunction, hepatotoxicity, and myopathy/rhabdomyolysis. Compared to other statins, lovastatin showed a non-significant upward trend in fasting blood glucose.[8] Rarely reported was cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion), which was non-serious and reversible. The FDA states that the cardiovascular benefits of statins outweigh the small risk of cognitive impairment. 

Lovastatin use requires caution in older patients since they are predisposed to myopathy. Surgical patients should discontinue Lovastatin for elective major surgery or any patients with conditions that may predispose them to renal failure (e.g., sepsis, hypotension, trauma, uncontrolled seizures). Lovastatin use in patients that have renal impairment and/or liver disease merits prescriber caution. 

Drug-Drug Interactions[9]

1. Drugs with strong CYP3A4 inhibition that can increase risks of myopathy/rhabdomyolysis: Itraconazole, ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin.
2. Other drugs that can increase the risk of myopathy if taken with lovastatin: cyclosporine, danazol, diltiazem, verapamil, amiodarone, colchicine, and ranolazine. In patients taking lovastatin concomitantly with danazol, diltiazem, dronedarone, or verapamil, lovastatin treatment should begin at 10 mg of and dose should not exceed 20 mg per day.
3. Drugs to avoid when taking lovastatin: cyclosporine and gemfibrozil.
4. Amiodarone: In patients taking lovastatin and amiodarone concomitantly,  do not use more than 40 mg lovastatin per day as higher doses increase the risk of myopathy and rhabdomyolysis.

Contraindications

Lovastatin is contraindicated in patients with a history of hypersensitivity to lovastatin or any ingredient in its formulation. Other contraindications are listed below[10]: 

• Pregnant women (pregnancy category X)
• Breastfeeding[7]
• Acute liver disease
• Unexplained persistent elevations of serum transaminase
• Taking potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, erythromycin, and cobicistat-containing products)[11]

Monitoring

According to the American College of Cardiology and the American Heart Association Cholesterol Guideline Recommendations[12]:

Lipid panel: Baseline, fasting within 4 to 12 weeks after starting a treatment or dose adjustment, and every 3 to 12 months after that. Consider decreasing the dose if two or more consecutive LDL levels are less than 40 mg/dl.

Liver transaminase levels: Baseline measure of hepatic transaminases. Measurement of the hepatic function if any indication of hepatotoxicity (e.g., unusual fatigue, loss of appetite, abdominal pain, dark-colored urine, jaundice, or scleral icterus) during therapy.

CPK: CPK levels do not require routine monitoring. Baseline CPK may be necessary for patients with a family history of statin intolerance, muscle disease, or other drugs that may increase the risk of myopathy. In addition, patients with muscle pain, weakness, aches, or other symptoms suggestive of myopathy would need CPK levels.

Evaluate for new-onset diabetes: If diabetes develops, the patient is to continue statin therapy and encourage a healthy diet, exercise, maintaining healthy body weight, and cessation of tobacco use.

If the patient develops confusion or memory impairment, further evaluation is needed for non-statin causes, systemic or neuropsychiatric causes, and/or adverse effects of statin therapy.

Toxicity

Researchers gave a single 200 mg dose of lovastatin to 5 healthy volunteers, and there were no clinically significant adverse effects reported. Cases of lovastatin overdose are reported, but none of the patients reported any specific symptoms. All the patients recovered without complications. The patient should discontinue lovastatin use if severe muscle symptoms or fatigue develops. CPK, creatinine, and urinalysis should be done to assess for myoglobinuria. Mild to moderate muscle symptoms should also call for discontinuation of lovastatin, pending a thorough investigation of symptoms.[13]

Enhancing Healthcare Team Outcomes

Like many other statin medications, lovastatin is commonly used to help lower cholesterol levels. Although lovastatin shares several notable side effects with the other drugs in its class, it is generally well-tolerated. Therefore, it could be beneficial for patients that are more sensitive to other statins. Lovastatin is effective in lowering cholesterol and the risk of atherosclerotic cardiovascular disease. Both patients and physicians should discuss the risks and benefits of lovastatin before starting treatment. Patients must also adhere to a heart-healthy diet before and during therapy with lovastatin. Patients should also know that routine checks are needed every four weeks to adjust and monitor serum levels of cholesterol.

Due to its many serious side effects and multiple drug-drug interactions, clinicians, nurses, pharmacists, and patients must openly communicate to optimize treatment with lovastatin. Pharmacists should notify clinicians and patients to discontinue any drugs that may cause harmful adverse effects while taking lovastatin and perform medication reconciliation. Nurses are well-positioned to monitor adverse reactions related to the medication and verify medication compliance on the patient chart. It is important to establish strong communication between all disciplines of care to maximize the benefits of lovastatin; this includes interprofessional team communication between physicians (both primary care and/or cardiologist), nursing (particularly those with cardiovascular specialty training), and pharmacy to achieve optimal results from lovastatin therapy. [Level 5]