Lovastatin


Article Author:
Hanh Duong


Article Editor:
Tushar Bajaj


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


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James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/15/2019 12:47:00 AM

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 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

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.

Before 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 20 mg 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 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.

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. 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[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 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)
  • 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, 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 a 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 several notable 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. 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 4 weeks to adjust and monitor serum levels of cholesterol.

Due to its many serious side effects and multiple drug-drug interactions, physicians, pharmacists, and patients must 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. Nurses are well-positioned for monitoring adverse events related to the medication, as well as verifying medication compliance on the patient's part. 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 V]


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Lovastatin - Questions

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A 67-year-old man with hypertension, hyperlipidemia, and diabetes is brought to the emergency department for sudden onset of right upper quadrant abdominal pain, nausea, and vomiting. The patient reports sharp pain in his right side that started gradually two weeks ago, which initially responded to acetaminophen but now is constant. He also mentions being sick around that time but improved after taking some antibiotics from his primary care provider. He states the pain was so bad this morning when he woke up that he vomited twice. On examination, the patient is diaphoretic with scleral icterus. The abdomen is distended and tender to light touch. Serum results include WBC 9,000/microliter, platelets 150,000/microliter, hemoglobin 15 g/dL, AST 212 U/L, ALT 198 U/L, and hemoglobin A1c 8.3%. The patient reports being adherent to all his medications including lisinopril, metformin, insulin, and lovastatin except for today since he was brought to the emergency department. What other information from the patient's history may help confirm the diagnosis?



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A 30-year-old female with diabetes type 2 presents to the clinic for a routine exam. Her BMI is 34. Her medications include metformin and glipizide. She has been adherent with her medications and her glucose levels have been well controlled. Upon routine blood work, her serum total cholesterol is found to be 300 mg/dl, HDL 55 mg/dl, and LDL level 360 mg/dl. Treatment with lovastatin is being considered. Which of the following should be ordered before starting the patient on the medication?



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A 65-year-old female with osteoarthritis, hyperlipidemia, and type 2 diabetes presents to the clinic for fatigue and leg pain. She has been taking over the counter ibuprofen, metformin, and lovastatin for many years. She complains of worsening pain in her thighs that started a few weeks ago. She originally thought it was due to her age and osteoarthritis, so she did not seek treatment. She says the pain is persistent, achy, tender, and does not improve with ibuprofen. The patient also mentions increased urination at night, possibly due to her diabetes but has been darker in color as well. Which of the following is the next best step in management for this patient?



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A 35-year-old woman with type 2 diabetes and hyperlipidemia comes into the office after a positive pregnancy test. She is adherent to all her medications, including insulin, metformin, and lovastatin. She would like to confirm if she's pregnant. Routine lab work was within normal limits, and serum beta-hCG levels confirmed her pregnancy. Which of the following is the next best step in management for this patient?



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Lovastatin - References

References

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]
De Denus S,Spinler SA, Early statin therapy for acute coronary syndromes. The Annals of pharmacotherapy. 2002 Nov;     [PubMed]
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]
Bailey DG,Dresser GK, Grapefruit juice-lovastatin interaction. Clinical pharmacology and therapeutics. 2000 Jun;     [PubMed]
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]
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]
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]
Schachter M, Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundamental     [PubMed]
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]

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