Lovastatin

Article Author:
Hanh Duong
Article Editor:
Tushar Bajaj
Updated:
5/13/2019 11:15:06 PM
PubMed Link:
Lovastatin

Indications

Lovastatin is a cholesterol-lowering agent first isolated from a strain of Aspergillus terreus.[1] It has been FDA-approved for the treatment and prevention of coronary heart disease, hypercholesterolemia, and adolescent patients with heterozygous familial hypercholesterolemia. Non-FDA approved uses include cardiac risk reduction for non-cardiac surgery and non-cardioembolic stroke.

Mechanism of Action

Lovastatin is metabolized into its active form beta-hydroxy acid in the stomach and functions to competitively inhibit of 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 has anticoagulant effects.[2][3] Also, a decrease in serum cholesterol will stimulate LDL receptor expression on hepatocytes, further increasing LDL catabolism.

Lovastatin has a 30% bioavailability with an extensive first-pass effect; less than 5% reaches 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

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.

Prior to starting Lovastatin, the patient should be started on a standard cholesterol-lowering diet for 6 weeks and continue this diet throughout treatment. Patients should avoid taking grapefruit juice since it may increase drug toxicity and adverse effects.[5] Recommended starting dose is 20mg once a day with an evening meal. The maximum recommended dose is 80mg in one day. Dosages should be individualized to treatment goal and adjusted at 4-week intervals.

Lovastatin immediate release is available in 20mg and 40mg tablets. The extended-release tablets are available in 20, 40, or 60mg. Extended-release tablets are not recommended for patients that only need small amounts of reduction in cholesterol levels.

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.[6] Rarely reported was cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) which was non-serious and reversible. FDA states that the cardiovascular benefits of statins outweigh the small risk of cognitive impairment. 

Lovastatin should be used with 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, use should be cautioned. 

Drug-drug interactions[7]:

  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.
  3. Drugs to avoid when taking lovastatin: cyclosporine and gemfibrozil.

Contraindications

Lovastatin is contraindicated in patients with a history of hypersensitivity to lovastatin or any ingredient in its formulation. Other contraindications are listed below[8]

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

Monitoring

According to the American College of Cardiology and the American Heart Association Cholesterol Guideline Recommendations[9]:

Lipid panel: baseline, fasting within 4 to 12 weeks after starting treatment or dose adjustment, and every 3 to 12 months after that. If 2 or more consecutive LDL levels are less than 40mg/dl, consider decreasing the dose.

Liver transaminase levels: baseline measure of hepatic transaminases. Measurement of the hepatic function of there is 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 family history of statin intolerance, muscle disease, or taking other drugs that may increase the risk of myopathy. Any 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, may evaluate for non-statin causes, systemic, or neuropsychiatric causes, and adverse effects associated with 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. There also have been cases of lovastatin overdose, 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. 

Enhancing Healthcare Team Outcomes

Lovastatin, like many other statin medications, is commonly used to help lower cholesterol levels. Although lovastatin shares many serious side effects with the other drugs in its class, it is generally well tolerated. 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. It is important that patients should also adhere to a heart-healthy diet before and during therapy with lovastatin. Patients should also know that routine checks are needed every 4 weeks to adjust and monitor serum levels of cholesterol. Due to its many serious side effects and multiple drug-drug interactions, it is important that physicians, pharmacists, and patients communicate with one another to provide optimal therapy. Pharmacists should notify both physicians and patients to discontinue any drugs that may cause harmful side effects while taking lovastatin. 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. [Level V]


References

[1] Hassan A,Saleem Y,Chaudhry MN,Asghar A,Saleem M,Nawaz S,Syed Q,Iqbal MS,Shahzad K, Optimization of process variables for increased production of lovastatin in Aspergillus terreus PU-PCSIR1 and its characterization. Pakistan journal of pharmaceutical sciences. 2019 Jan;     [PubMed PMID: 30829216]
[2] De Denus S,Spinler SA, Early statin therapy for acute coronary syndromes. The Annals of pharmacotherapy. 2002 Nov;     [PubMed PMID: 12398573]
[3] Ray KK,Cannon CP, The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes. Journal of the American College of Cardiology. 2005 Oct 18;     [PubMed PMID: 16226165]
[4] Schachter M, Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundamental     [PubMed PMID: 15660968]
[5] Bailey DG,Dresser GK, Grapefruit juice-lovastatin interaction. Clinical pharmacology and therapeutics. 2000 Jun;     [PubMed PMID: 10872652]
[6] Kim J,Lee HS,Lee KY, Effect of statins on fasting glucose in non-diabetic individuals: nationwide population-based health examination in Korea. Cardiovascular diabetology. 2018 Dec 5;     [PubMed PMID: 30518364]
[7] Watanabe K,Oda S,Matsubara A,Akai S,Yokoi T, Establishment and characterization of a mouse model of rhabdomyolysis by coadministration of statin and fibrate. Toxicology letters. 2019 Mar 7;     [PubMed PMID: 30853469]
[8] Newman CB,Preiss D,Tobert JA,Jacobson TA,Page RL 2nd,Goldstein LB,Chin C,Tannock LR,Miller M,Raghuveer G,Duell PB,Brinton EA,Pollak A,Braun LT,Welty FK, Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association. Arteriosclerosis, thrombosis, and vascular biology. 2019 Feb;     [PubMed PMID: 30580575]
[9] Grundy SM,Stone NJ,Bailey AL,Beam C,Birtcher KK,Blumenthal RS,Braun LT,de Ferranti S,Faiella-Tommasino J,Forman DE,Goldberg R,Heidenreich PA,Hlatky MA,Jones DW,Lloyd-Jones D,Lopez-Pajares N,Ndumele CE,Orringer CE,Peralta CA,Saseen JJ,Smith SC Jr,Sperling L,Virani SS,Yeboah J, 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation. 2018 Nov 10;     [PubMed PMID: 30586774]