Pro-Lovastatin

Uses

Pro-Lovastatin is recommended in Primary Prevention of Coronary Heart Disease, Coronary Heart Disease, Hypercholesterolemia, Adolescent Patients with Heterozygous Familial Hypercholesterolemia

Pro-Lovastatin is also used to associated treatment for these conditions: Coronary Heart Disease (CHD), Dyslipidemia, Heterozygous Familial Hypercholesterolemia, High Cholesterol, Peripheral Artery Disease (PAD), Primary prevention Coronary artery disease, Primary prevention Myocardial infarction, Primary prevention Unstable angina

How Pro-Lovastatin works

Pro-Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid and strong inhibitor of HMG-CoA reductase, a hepatic microsomal enzyme which catalyzes the conversion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A ) to mevalonate, an early rate-limiting step in cholesterol biosynthesis. At therapeutic lovastatin doses, HMG-CoA reductase is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol, therapy with lovastatin would not be expected to cause an accumulation of potentially toxic sterols.

Pro-Lovastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increase hepatic uptake of LDL. Pro-Lovastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL and a significant reduction in the risk of development of CVD and all-cause mortality.

A significant effect on LDL-C reduction was seen within 2 weeks of initiation of lovastatin, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night. When therapy with lovastatin is stopped, total cholesterol has been shown to return to pre-treatment levels.

In vitro and in vivo animal studies also demonstrate that lovastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response.

Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation.

Pro-Lovastatin has been reported to have beneficial effects on certain cancers. This includes a multi-factorial stress-triggered cell death (apoptosis) and DNA degradation response in breast cancer cells. It has also been shown to inhibit histone deacetylase 2 (HDAC2) activity and increase the accumulation of acetylated histone-H3 and the expression of p21(WAF/CIP) in human cancer cells, suggesting that statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention.

Dosage

Pro-Lovastatin dosage

The patient should be placed on a standard cholesterol-lowering diet before receiving Pro-Lovastatin and should continue on this diet during treatment with Pro-Lovastatin . Pro-Lovastatin should be given with meals.

Adult Patients: The usual recommended starting dose is 20 mg once a day given with the evening meal. The recommended dosing range of Pro-Lovastatin is 10-80 mg/day in single or two divided doses; the maximum recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy. Patients requiring reductions in LDLC of 20% or more to achieve their goal should be started on 20 mg/day of Pro-Lovastatin . A starting dose of 10 mg of Pro-Lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more. The 10 mg dosage is provided for information purposes only. Although Pro-Lovastatin tablets 10 mg are available in the marketplace, Pro-Lovastatin is no longer marketed in the 10 mg strength.

Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of Pro-Lovastatin if cholesterol levels fall significantly below the targeted range.

Dosage in Patients taking Danazol, Diltiazem, Dronedarone or Verapamil: In patients taking danazol, diltiazem, dronedarone or verapamil concomitantly with Pro-Lovastatin , therapy should begin with 10 mg of Pro-Lovastatin and should not exceed 20 mg/day

Dosage in Patients taking Amiodarone: In patients taking amiodarone concomitantly with Pro-Lovastatin , the dose should not exceed 40 mg/day

Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia: The recommended dosing range of Pro-Lovastatin is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy. Patients requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of Pro-Lovastatin . A starting dose of 10 mg of Pro-Lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

Concomitant Lipid-Lowering Therapy: Pro-Lovastatin is effective alone or when used concomitantly with bile-acid sequestrants

Should be taken with food.

Side Effects

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

Toxicity

The median lethal dose of lovastatin is higher than 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 to 6 g.

In carcinogenic studies, there is an increase in the incidence of hepatocellular carcinomas and adenomas, pulmonary adenomas, papilloma in non-glandular mucose in stomach and thyroid neoplasms. However, with respect to effects on fertility, lovastatin has been reported to present testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation which derived into decreased fertility in males. Lastly, there is no evidence of mutagenicity induced by lovastatin.

Precaution

History of liver disease; patients at risk of myopathy;. alcoholism; inadequately controlled hypothyroidism. Severe renal impairment.

Interaction

Increased risk of myopathy/ rhabdomyolysis with amiodarone, colchicine, ranolazine, danazol, diltiazem and verapamil. May increase anticoagulant effect of warfarin.

Food Interaction

• Avoid grapefruit products. Grapefruit products may increase the risk for lovastatin related adverse effects such as myopathy and rhabdomyolysis.
• Take with food. Food increases bioavailability.

[Major] GENERALLY AVOID: Coadministration with grapefruit juice may significantly increase the plasma concentrations of lovastatin and simvastatin and their active acid metabolites.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

When a single 60 mg dose of simvastatin was coadministered with 200 mL of double-strength grapefruit juice three times a day, simvastatin systemic exposure (AUC) increased by 16-fold and simvastatin acid AUC increased by 7-fold.

Administration of a single 20 mg dose of simvastatin with 8 ounces of single-strength grapefruit juice increased the AUC of simvastatin and simvastatin acid by 1.9-fold and 1.3-fold, respectively.

The interaction has also been reported with lovastatin, which has a similar metabolic profile to simvastatin.

Clinically, high levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity.

Myopathy manifested as muscle pain and

Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

ADJUST DOSING INTERVAL: Fibres such as oat bran and pectin may diminish the pharmacologic effects of HMG-CoA reductase inhibitors by interfering with their absorption from the gastrointestinal tract.

Coadministration with green tea may increase the plasma concentrations of simvastatin.

The mechanism of interaction has not been established, but may involve inhibition of organic anion transporting polypeptide (OATP) 1B1- and

The interaction was suspected in a 61-year-old man who experienced muscle intolerance during treatment with simvastatin while drinking an average of 3 cups of green tea daily.

He also experienced similar muscle intolerance (leg cramps without creatine phosphokinase elevation) during treatments with atorvastatin and rosuvastatin while drinking green tea.

Pharmacokinetic studies performed during his usual green tea intake demonstrated an approximately two-fold higher exposure to simvastatin lactone (the administered form of simvastatin) than that observed after stopping green tea intake for a month.

He was also able to tolerate simvastatin after discontinuing green tea consumption.

The authors of the report subsequently conducted two independent studies to assess the effect of different green tea preparations on simvastatin pharmacokinetics.

One study was conducted in 12 Italian subjects and the other in 12 Japanese subjects.

In the Italian study, administration of a single 20 mg dose of simvastatin following pretreatment with 200 mL of a hot green tea standardized infusion 3 times daily for 14 days (estimated daily intake of 335 mg total catechins and 173 mg epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea) was found to have no significant effect on mean peak plasma concentration (Cmax) or systemic exposure (AUC) of simvastatin lactone and simvastatin acid relative to administration with water.

However, green tea increased simvastatin lactone AUC (0-6h) by about two-fold in 3 of the study subjects.

In the Japanese study, administration of a single 10 mg dose of simvastatin following pretreatment with 350 mL of a commercial green tea beverage twice daily for 14 days (estimated daily intake of 638 mg total catechins and 322 mg EGCG) did not affect mean simvastatin lactone Cmax or AUC to a statistically significant extent compared to administration with water, but increased mean simvastatin acid Cmax and AUC by 42% and 22%, respectively.

Similar to the first study, green tea increased simvastatin lactone AUC (0-6h) by two- to three-fold in 4 of the study subjects.

Although not studied, the interaction may also occur with lovastatin due to its similar metabolic profile to simvastatin.

MANAGEMENT: Patients receiving therapy with lovastatin, simvastatin, or red yeast rice (which contains lovastatin) should be advised to avoid the consumption of grapefruit and grapefruit juice.

Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized by other enzymes and may be preferable alternatives in some individuals.

All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and

Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

Also, patients should either refrain from the use of oat bran and pectin, or separate the administration times by at least 2 to 4 hours if concurrent use cannot be avoided.

Caution may be advisable when coadministered with green tea or green tea extracts.

Dosing reduction of the statin and

Pro-Lovastatin Alcohol interaction

[Moderate]

Concomitant use of statin medication with substantial quantities of alcohol may increase the risk of hepatic injury.

Transient increases in serum transaminases have been reported with statin use and while these increases generally resolve or improve with continued therapy or a brief interruption in therapy, there have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins.

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.

Active liver disease or unexplained transaminase elevations are contraindications to statin use.

Patients should be counseled to avoid substantial quantities of alcohol in combination with statin medications and clinicians should be aware of the increased risk for hepatotoxicity in these patients.

Pro-Lovastatin Drug Interaction

Minor: levothyroxineUnknown: fluticasone / salmeterol, aspirin, aspirin, calcium / vitamin d, ubiquinone, duloxetine, omega-3 polyunsaturated fatty acids, insulin glargine, furosemide, pregabalin, metoprolol, metoprolol, clopidogrel, montelukast, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, cetirizine

Pro-Lovastatin Disease Interaction

Major: liver disease, rhabdomyolysis, renal dysfunctionModerate: cognitive impairment, diabetes, renal disease

Volume of Distribution

Pro-Lovastatin is able to cross the blood-brain barrier and placenta.

Elimination Route

Pro-Lovastatin Cmax was found to be 3.013ng/mL with a Tmax of 3.36 hours.

Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin, estimated relative to an intravenous reference dose, in each of four animal species tested, averaged about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues. Pro-Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory activity in the general circulation.

The peak concentrations of lovastatin when a dose of 10-40 mg is administered are reported to range from 1.04-4.03 ng/ml and an AUC of 14-53 ng.h/ml. This indicates that lovastatin presents a dose-dependent pharmacokinetic profile. When lovastatin was given under fasting conditions, plasma concentrations of both active and total inhibitors were on average about two-thirds those found when lovastatin was administered immediately after a standard test meal.

Genetic differences in the OATP1B1 (Organic-Anion-Transporting Polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact lovastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) showed that lovastatin Cmax and AUC were 340 and 286% higher, respectively, for individuals homozygous for 521CC compared to homozygous 521TT individuals. The 521CC genotype is also associated with a marked increase in the risk of developing myopathy, likely secondary to increased systemic exposure. Other statin drugs impacted by this polymorphism include rosuvastatin, pitavastatin, atorvastatin, simvastatin, and pravastatin.

While specific dosage instructions are not included in the available product monographs for lovastatin, individuals with the above-mentioned c.521CC OATP1B1 genotype should be monitored for development of adverse effects from increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis, particularly at higher doses.

Half Life

Pro-Lovastatin 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.

Elimination Route

Following an oral dose of 14C-labeled lovastatin to man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug excreted in bile, together with unabsorbed drug.

Pregnancy & Breastfeeding use

Pregnancy Category X. Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Contraindication

Active liver disease or unexplained persistent elevated serum transaminases. Concomitant use with CYP3A4 inhibitors (e.g. nefazodone, erythromycin, boceprevir, clarithromycin, telithromycin, HIV protease inhibitors, itraconazole, ketoconazole, posaconazole, telaprevir), gemfibrozil, ciclosporin. Pregnancy and lactation.

Special Warning

Dosage in Patients with Renal Insufficiency: In patients with severe renal insufficiency (CrCl< 30 mL/min), dosage increases above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Storage Condition

Store between 20-25° C.

Innovators Monograph

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