Niacin and lovastatin

Uses

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

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atheroscleroticvascular disease due to hyperlipidemia. Niacin therapy is used for an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

• Niacin is used to reduce elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia.
• In patients with a history of myocardial infarction and hyperlipidemia, niacin is used to reduce the risk of recurrent nonfatal myocardial infarction.
• In patients with a history of coronary artery disease (CAD) and hyperlipidemia, niacin, in combination with a bile acid binding resin, is used to slow progression or promote regression of atherosclerotic disease.
• Niacin in combination with a bile acid binding resin is used to reduce elevated TC and LDL-C levels in adult patients with primary hyperlipidemia.
• Niacin is also used as adjunctive therapy for treatment of adult patients with severe hypertriglyceridemia who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them.

Niacin and 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 anginaAtherosclerosis, Mixed Dyslipidemias, Myocardial Infarction, Pellagra, Vitamin Deficiency, Primary Hyperlipidemia, Severe Hyperlipidemia, Dietary supplementation

How Niacin and lovastatin works

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.

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. 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.

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.

Niacin performs a number of functions in the body and so has many mechanisms, not all of which have been fully described. Niacin can decrease lipids and apolipoprotein B (apo B)-containing lipoproteins by modulating triglyceride synthesis in the liver, which degrades apo B, or by modulating lipolysis in adipose tissue.

Niacin inhibits hepatocyte diacylglycerol acyltransferase-2. This action prevents the final step of triglyceride synthesis in hepatocytes, limiting available triglycerides for very low density lipoproteins (VLDL). This activity also leads to intracellular degradation of apo B and decreased production of low density lipoproteins, the catabolic product of VLDL.

Niacin also inhibits a high density lipoprotein (HDL) catabolism receptor, which increases the levels and half life of HDL.

Dosage

Niacin and lovastatin dosage

The patient should be placed on a standard cholesterol-lowering diet before receiving Lovastatin and should continue on this diet during treatment with Lovastatin . 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 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 Lovastatin . A starting dose of 10 mg of 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 Lovastatin tablets 10 mg are available in the marketplace, 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 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 Lovastatin , therapy should begin with 10 mg of Lovastatin and should not exceed 20 mg/day

Dosage in Patients taking Amiodarone: In patients taking amiodarone concomitantly with 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 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 Lovastatin . A starting dose of 10 mg of Lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

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

Niacin can be administered as a single dose at bedtime, after a snack or meal and doses should be individualized according to patient response. Therapy with Niacin must be initiated at 500 mg in order to reduce the incidence and severity of side effects which may occur during early therapy.

Maintenance Dose: The daily dosage of Niacin should not be increased by more than 500 mg in any 4-week period. The recommended maintenance dose is 1000 mg (two 500 mg tablets or one 1000 mg tablet) to 2000 mg (two 1000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2000 mg daily are not recommended. Women may respond at lower Niacin doses than men.

Single-dose bioavailability studies have demonstrated that two of the 500 mg and one of the 1000 mg tablet strengths are interchangeable but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable.

Flushing of the skin may be reduced in frequency or severity by pretreatment with aspirin (up to the recommended dose of 325 mg taken 30 minutes prior to Niacin dose). Tolerance to this flushing develops rapidly over the course of several weeks. Flushing,pruritus, andgastrointestinaldistress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of Niacin ingestion.

Equivalent doses of Niacin should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin. Patients previously receiving other niacin products should be started with the recommended Niacin titration schedule, and the dose should subsequently be individualized based on patient response.

If Niacin therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase.

Should be taken with food.

Niacin tablets should be taken whole and should not be broken, crushed or chewed before swallowing.

Side Effects

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

Niacin is generally well tolerated; adverse reactions have been mild and transient.The most frequent advers effects were flushing, itching, pruritis, nausea and GI upset, jaundice ,hypotension, tachycardia, increased serum blood glucose and uric acid levels, myalgia.

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.

Overdose of niacin may present with severe prolonged hypotension. Patients experiencing an overdose should be treated with supportive measures which may include intravenous fluids.

The oral LD₅₀ in the mouse is 3720mg/kg, in the rabbit is 4550mg/kg, in the rat is 7000mg/kg, and the dermal LD₅₀ in the rat is >2000mg/kg.

Precaution

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

Before instituting therapy with Niacin, an attempt should be made to control hyperlipidemia with appropriate diet, exercise, and weight reduction in obese patients and to treat other underlying medical problems. Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Niacin therapy. Frequent monitoring of liver function tests and blood glucose should be performed to ascertain that the drug is producing no adverse effects on these organ systems. Diabetic patients may experience a dose-related rise in glucose intolerance, the clinical significance of which is unclear. Diabetic or potentially diabetic patients should be observed closely. Adjustment of diet and/or hypoglycemic therapy may be necessary.

Caution should also be used when Niacin is used in patients with unstable angina or in the acute phase of MI, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers or adrenergic blocking agents. Elevated uric acid levels have occurred with Niacin therapy, therefore use with caution in patients predisposed to gout. Niacin has been associated with small but statistically significant dose-related reductions in platelet count and increases in prothrombin time. Caution should be observed when Niacin is administered concomitantly with anticoagulants; prothrombin time and platelet counts should be monitored closely in such patients. Niacin has been associated with small but statistically significant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg). So phosphorus levels should be monitored periodically in patients at risk.

Interaction

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

Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension. Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this finding is unclear. About 98% of available Niacin was bound to colestipol, with 10 to 30% binding to cholestyramine. These results suggest that 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of Niacin.

Volume of Distribution

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

Data regarding the volume of distribution of niacin is not readily available.

Elimination Route

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. 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.

In patients with chronic kidney disease, the C_max is 0.06µg/mL for a 500mg oral dose, 2.42µg/mL for a 1000mg oral dose, and 4.22µg/mL for a 1500mg oral dose. The T_max is 3.0 hours for a 1000mg or 1500mg oral dose. The AUC is 1.44µg*h/mL for a 500mg oral dose, 6.66µg*h/mL for a 1000mg oral dose, and 12.41µg*h/mL for a 1500mg oral dose. These values did not drastically differ in patients requiring dialysis.

Half Life

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.

The half life of niacin is 0.9h, nicotinuric acid is 1.3h, and nicotinamide is 4.3h.

Clearance

Data regarding the clearance of niacin is not readily available.

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.

69.5% of a dose of niacin is recovered in urine. 37.9% of the recovered dose was N-methyl-2-pyridone-5-carboxamide, 16.0% was N-methylnicotinamide, 11.6% was nicotinuric acid, and 3.2% was niacin.

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.

Niacin cannot be used in pregnancy and lactation because of a lack of information.

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.

Niacin is contraindicated in patients with a known hypersensitivity to Niacin or any component of this medication, significant or unexplained hepatic dysfunction, active peptic ulcer disease or arterial bleeding.

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.

Acute Overdose

Supportive measures should be undertaken in the event of an overdosage. Symptoms may include nausea, dizziness, itching, vomiting, upset stomach, and flushing

Storage Condition

Store between 20-25° C.

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