The P-I-E-N-O Parkinsn's List Drug Database
lovastatin / MevacorTM
CHOLESTEROL CONTROL:
Description: Lovastatin is an oral antilipemic agent produced by fermentation of Aspergillus terreus. Lovastatin represents the first of a new class of lipid-lowering agents, the HMG-CoA reductase inhibitors, which are indicated for the treatment of primary hypercholesterolemia. Lovastatin was also the first HMGCoA reductase inhibitor acknowledged to slow coronary atherosclerosis. Other agents in this class include fluvastatin, pravastatin, and simvastatin. Lovastatin was purposely developed as a prodrug to concentrate active drug in the liver during first-pass circulation. Simvastatin is also a prodrug, but pravastatin is not. Lovastatin was approved by the FDA for the treatment of hypercholesterolemia in August 1987. Its indications were expanded to include slowing the progression of coronary atherosclerosis in February 1995.
Mechanism of Action: Lovastatin is a prodrug with little or no inherent activity but is hydrolyzed in vivo to mevinolinic acid. Mevinolinic acid, one of lovastatin's several active metabolites, is structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, lovastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with the activity of this enzyme reduces the quantity of mevalonic acid, a precursor of cholesterol. This process occurs within the hepatocyte and is one of two mechanisms that generate cholesterol. Cholesterol also can be taken up from LDL by endocytosis. Since de novo synthesis of cholesterol is impaired by lovastatin, the second mechanism is augmented. Thus, lovastatin also enhances clearance of LDL. Lovastatin exerts its effects mainly on total cholesterol and LDL, with minor effects seen on HDL and triglycerides.
Pharmacokinetics: Lovastatin is administered orally. It is incompletely absorbed from the GI tract and undergoes extensive first-pass extraction in the liver. Lovastatin was purposely developed as a prodrug to concentrate active drug in the liver during first-pass circulation. Because less drug reaches the systemic circulation, fewer adverse reactions are believed to occur. Roughly 5% of active drug reaches the systemic circulation. The presence of food in the GI tract enhances oral absorption. Diurnal variation in the activity of the enzyme has been documented; single daily doses are most effective if given in the evening.
Lovastatin is highly bound to plasma proteins. Lovastatin crosses the blood-brain barrier and the placental barrier, and may also be distributed into human milk. It should be noted that, as with the other HMG-CoA reductase inhibitors, lovastatin is classified as a pregnancy category X drug. Although no data exist regarding its use in pregnant women, lovastatin, in high doses, has produced fetal abnormalities in animal models.
As mentioned above, lovastatin is a prodrug that is hydrolyzed to mevinolinic acid and several other active derivatives. The plasma half-life of mevinolinic acid is about 1.1-1.7 hours. Following a single dose to adults with hypercholesterolemia, 83% is excreted in the feces as both active and inactive metabolites. Drug eliminated via the stool represents both unabsorbed drug and drug and metabolites secreted in the bile. Only 10% of a dose is eliminated renally as inactive drug.
CONTRAINDICATIONS/PRECAUTIONS: Lovastatin is absolutely contraindicated in patients with active hepatic disease or unexplained persistent elevations in serum aminotransferase concentrations. In addition, patients should minimize alcohol intake while receiving lovastatin therapy, and lovastatin should be avoided in patients with alcoholism.
Lovastatin is absolutely contraindicated during pregnancy and in patients who are breast-feeding because it has been shown to cause malformations of vertebrae and ribs in fetal rats when given in high doses. No malformations appeared in other animal models at lower doses, but no data exist regarding safe use of lovastatin in pregnant women. Lovastatin has been classified as a category X drug by the FDA for use during pregnancy.
Safe use in pediatric patients has not been established. For this reason, lovastatin should not be used in children (age 1-12 years).
Lovastatin may be contraindicated in conditions that can cause decreased renal perfusion because renal failure is possible if lovastatin-induced rhabdomyolysis occurs. Predisposing conditions include hypotension, acute infection, endocrine disease, electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. Lovastatin should be used with caution in patient with organ transplant on immunosuppressant therapy because of an increased risk of rhabdomyolysis and renal failure.
Lovastatin should be used with caution in patients with renal impairment. Dosage limits are recommended in patients with creatinine clearances < 30 ml/minute. The risk of rhabdomyolysis should be considered in this patient population.
The risk of developing myopathy appears to be increased when HMGCoA reductase inhibitors are used in combination with other drugs. The reader is referred to Drug Interactions for further information. Lovastatin should be discontinued immediately in any patient who develops myopathy or elevations in CPK.
DRUG INTERACTIONS: The risk of developing myopathy is increased if lovastatin is administered concomitantly with cyclosporine or other immunosuppressives, danazol, erythromycin, or gemfibrozil. Antilipemic doses of niacin, vitamin BA may also increase this risk although in some cases lovastatin has been used concomitantly with niacin safely for long periods. One case is noted of a patient who developed rhabdomyolysis when itraconazole was added to a stable regimen of lovastatin and niacin. Concurrent use of lovastatin with any of these drugs may be associated with an increased risk of developing rhabdomyolysis and acute renal failure. Any patient receiving such combined therapy should be carefully monitored for myopathy or rhabdomyolysis. Serum concentrations of CPK can rise to 200,000 or higher but correlate poorly with symptoms. Myopathy or myositis can reverse if therapy is discontinued.
Intake of ethanol should be avoided or minimized during lovastatin therapy to reduce the risk of hepatic injury.
It is unclear if a significant drug interaction exists between lovastatin and warfarin; data are limited and conflicting. Until more data are available, lovastatin should be used cautiously in any patient receiving warfarin.
ADVERSE REACTIONS: Lovastatin was extremely well tolerated in controlled clinical trials. Only 1% of subjects were discontinued from therapy during short-term (14 week) trials due to the adverse effects of lovastatin. With extended use, approximately 3% of patients are discontinued from therapy, usually secondary to alterations in serum transaminase concentrations. Adverse reactions tend to be transient and mild. During clinical trials, lovastatin was compared to placebo, there were no significant differences in their adverse reaction profiles.
Toxicity to the skeletal muscle occurs infrequently but can be a serious adverse reaction to lovastatin therapy. Asymptomatic elevations of CPK occur in approximately 11% of patients, however, more serious manifestations, such as rhabdomyolysis, can also occur. Myalgia (muscle aches or cramps), fever, tiredness, or myasthenia occurs in approximately 1-3% of patients, and myopathy occurs in approximately 1%, although the risk is greater if lovastatin is administered with cyclosporine or other immunosuppressive agents (see Drug Interactions). This toxicity appears to be reversible after discontinuation of therapy. A recently published study of lovastatin therapy in more than 3,300 women revealed that myopathy occurred too infrequently to accurately apply statistical analysis. Clinicians should note that rhabdomyolysis and renal failure (renal intratubular obstruction) have been associated with HMGCoA reductase inhibitor therapy.
Adverse GI effects occur with lovastatin use but are usually mild. They include nausea/vomiting, dyspepsia, constipation or diarrhea, flatulence, and abdominal pain. These reactions were reported in > 3.9% of patients, their incidence was higher, but not significantly different than placebo.
Lovastatin therapy can cause elevated hepatic enzymes. Persistent elevations of serum transaminases have been reported in 1.9% of patients during clinical studies. Enzyme concentrations will decrease to pretreatment concentrations after discontinuation of lovastatin. These elevations were not associated with jaundice or other signs or symptoms of hepatotoxicity. Hepatitis, cholestasis with jaundice anorexia, and pancreatitis have been reported during therapy with other HMG-CoA reductase inhibitors, but a causal relationship has not been established with these agents.
Headache is the most common nervous system effect from lovastatin, occurring in about 9% of patients. Dizziness has also been reported in 2% of patients. These effects appear to occur more often than placebo, although their differences are not significantly different.
Allergic reactions can occur with lovastatin therapy. Rash and pruritus occur in about 5% of patients receiving lovastatin therapy, this incidence is similar to placebo. Rashes can vary in severity from urticaria or purpura to toxic epidermal necrolysis or Stevens-Johnson syndrome.
Cataracts have been reported with lovastatin use, usually occurring after many months of therapy. Patients should report any symptoms of blurred vision.
Lovastatin's other reported side effects include impotence and insomnia.
PATIENT INFORMATION:
What do lovastatin tablets do?
Lovastatin (MevacorTM ) blocks the body's ability to make cholesterol. Lovastatin can help lower blood cholesterol for patients who are at risk of getting heart disease or a stroke. It is only for patients whose cholesterol level is not controlled by diet. It is not a cure. Generic lovastatin tablets are not yet available.
What should my doctor, dentist, or pharmacist know before I take lovastatin?
They need to know if you have any of these conditions:
How should I take this medicine?
Take lovastatin tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Lovastatin works best if taken with food. If you take the tablets once a day, take them with the evening meal. Take your doses at regular intervals. Do not take your medicine more often than directed.
Special precautions for use in children:
This medicine is not for children or adolescents under 18 years old.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.
What other medicines can interact with lovastatin?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking lovastatin?
Serious side effects with lovastatin include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with lovastatin include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take lovastatin?
Visit your doctor for regular checks on your progress. You will need to have regular tests to make sure your liver is working properly.
Tell your doctor as soon as you can if you get any unexplained muscle pain, tenderness, or weakness, especially if you also have a fever and tiredness.
Lovastatin is only part of a total cholesterol-lowering program. Your doctor or dietician can suggest a low-cholesterol and lowfat diet that will reduce your risk of getting heart and blood vessel disease. Avoid alcohol and smoking, and keep a proper exercise schedule.
If you are going to have surgery tell your doctor or dentist that you are taking lovastatin.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between between 5 and 30C (59 and 86F). Protect from light. Throw away any unused medicine after the expiration date.
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