Apo-Lovastatin

Apo-Lovastatin

lovastatin

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Lovastatin.
Description
Each tablet contains 20 mg of Lovastatin.
Action
Pharmacology: Lovastatin is a cholesterol-lowering agent isolated from a strain of Coniothyrium fuckelli. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This principal metabolite is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
Lovastatin reduces cholesterol production by the liver and induces some changes in cholesterol transport and disposition in the blood and tissues. The mechanism(s) of this effect is believed to involve both reduction of the synthesis of Low Density Lipoprotein (LDL), and an increase in LDL catabolism as a result of induction of the hepatic LDL receptors.
Lovastatin has complex pharmacokinetic characteristics.
Indications/Uses
APO-LOVASTATIN (lovastatin) is indicated as an adjuct to diet, at least equivalent to the American Heart Association (AHA) Step 1 diet, for the reduction of elevated total and Low Density Lipoprotein Cholesterol (LDL-C) levels in patients with primary hypercholesterolemia (Types IIa and IIb), when the response to diet and other measures alone has been inadequate.
After establishing that the elevation in plasma lipids represents a primary disorder not due to secondary conditions such as poorly-controlled diabetes mellitus, hypothyroidism, the nephritic syndrome, liver disease, or dysproteinemias, it should be determined that patients for whom treatment with lovastatin is being considered have an elevated LDL-C level as the cause for an elevated total serum cholesterol. This may be particularly relevant for patients with tot al triglycerides over 4.52mmol/L (400mg/dL) or with markedly elevated High Density Lipoprotein Cholesterol (HDL-C) values, where non-LDL lipoprotein fractions may contribute significantly to total cholesterol levels without apparent increase in cardiovascu lar risk. In general, LDL-C may be estimated according to the following equations: (See Equation).

Click on icon to see table/diagram/image

When total triglycerides are greater than 4.52mmol/L (400mg/dL) this equation is not applicable. In such patients, LDL-C may be obtained by ultra-centrifugation.
Dosage/Direction for Use
The patient should be placed on at least an equivalent of the American Heart Association (AHA) Step 1 diet before receiving APO-LOVASTATIN (lovastatin) and should continue on this diet during treatment with APO-LOVASTATIN. If appropriate, a program of weight control and physical exercise should be implemented.
The usual starting dose is 20mg/day given as a single dose with the evening meal. Single daily doses given with the evening meal have been shown to be more effective than the same dose given with the morning meal, perhaps because cholesterol is synthesized mainly at night. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80mg daily given in single doses or divided doses with the morning and evening meals. Divided doses (i.e., twice daily) tend to be slightly more effective than single daily doses.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of APO-LOVASTATIN if cholesterol levels fall below the targeted range, such as that recommended by the Second Report of the U.S. National Cholesterol Education Program (NCEP).
Concomitant Therapy: In patients taking immunosuppressive drugs concomitantly with lovastatin, the maximum recommended dosage of APO-LOVASTATIN is 20mg/day.
Contraindications
Hypersensitivity to any component of this medication. Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and lactation.
Warnings
The effect of lovastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity or mortality or total mortality has not been established.
Hepatic Effects: In the initial controlled clinical trials performed in 695 patients, marked persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.6% of adult patients who received lovastatin for at least a year. When the drug was interrupted or discontinued in these patients, the transaminase levels fell slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with lovastatin. In most cases, they were not associated with jaundice or other clinical signs or symptoms.
In a 48-week expanded clinical evaluation of lovastatin (EXCEL study) performed in 8245 patients suffering from moderate hypercholesterolemia, the incidence of marked (more than 3 times the upper limit of normal) increase in serum transaminases on successive testing was 0.1% in patients receiving a placebo and 0.1% at 20mg/day, 0.9% at 40mg/day and 1.5% at 80mg/day in patients administered lovastatin. A significant lovastatin dose-related trend was noted for confirmed serum transaminase elevation > 3 times the ULN.
It is recommended that liver function tests be performed at baseline and periodically thereafter in all patients. Particular attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently.
If the transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal and are persistent, the drug should be discontinued.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained serum transaminase elevations are contraindications to the use of lovastatin; if such conditions develop during therapy, the drug should be discontinued.
Moderate elevations of serum transaminases (less than three times the upper limit of normal) have been reported following therapy with lovastatin. These changes were not specific to lovastatin and were also observed with comparative lipid metabolism regulators. They generally appeared within the first 3 months after initiation of therapy, were often transient and were not accompanied by any other symptoms. They did not necessitate interruption of treatment.
Muscle Effects: CPK: Transient elevations of creatine phosphokinase (CPK) levels are commonly seen in lovastatin-treated patients but have usually been of no clinical significance.
Myalgia and muscle cramps have also been associated with lovastatin therapy.
Myopathy has occurred rarely and should be considered in any patient with diffuse myalgias, muscle tenderness or weakness and/or marked elevation of creatine phosphokinase (10 times the upper limit of normal). There have been reports of severe rhabdomyolysis that precipitated acute renal failure. Therapy with lovastatin should be discontinued if marked elevation of CPK levels occurs, or if myopathy is diagnosed or suspected.
In the EXCEL study comparing lovastatin to placebo in 8245 patients, myopathy (defined as a CPK elevation >10 times the ULN with associated muscle symptoms) occurred in one patient in the lovastatin 40mg/day group (0.1%) and in four patients in the 80mg/day group (0.2%).
The EXCEL study, however, excluded patients with factors known to be associated with an increased risk of myopathy, including rhabdomyolysis.
These factors include pre-existing renal insufficiency (usually as a consequence of long-standing diabetes), concomitant therapy with cyclosporine, gemfibrozil, or lipid-lowering doses of niacin, and erythromycin.
Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin.
In clinical trials, about 30% of patients on immunosuppressive therapy, including cyclosporine, developed myopathy within a year after starting therapy with lovastatin. The corresponding incidence figures for concomitant therapy with gemfibrozil and niacin were approximately 5% and 2% respectively. Most of these patients were taking lova statin 40-80mg/day. In seven subsequent reports, 148 cyclosporine-treated transplant patients (105 cardiac and 43 renal) received concurrent lovastatin 10-60mg/day (the vast majority receiving 20mg/day) for periods of 3 to 41 months with one reported case of rhabdomyolysis (0.6%) and one case of significant CPK elevations.
Therefore, the benefits and risks of using APO-LOVASTATIN concomitantly with immunosuppressive drugs, erythromycin, fibrates or lipid-lowering doses of niacin should be carefully considered. In patients receiving lovastatin without these concomitant therapies, the incidence of myopathy was approximately 0.1%.
In six patients with cardiac transplants taking immunosuppressive therapy including cyclosporine, concomitantly with lovastatin 20 mg/day, the average plasma level of active metabolites derived from lovastatin was elevated to approximately four times the expected levels. In this group, the therapeutic response also appeared to be proportionately higher, relative to the dosage used.
Because of an apparent relationship between increased plasma levels of active metabolites derived from lovastatin and myopathy, the daily dosage in patients taking immunosuppressants should not exceed 20mg/day (see DOSAGE & ADMINISTRATION). Even at this dosage, the benefits to risks of using lovastatin in patients taking immunosuppresants should be carefully considered.
Rhabdomyolysis with renal failure has been reported in a renal transplant patient receiving cyclosporine and lovastatin shortly after a dose increase in the systemic antifungal agent itraconazole. Another transplant patient on cyclosporine and a different HMG-CoA reductase inhibitor experienced muscle weakness accompanied by marked elevation of CPK following the initiation of systemic itraconazole therapy. The HMG-CoA reductase inhibitors and the azole derivative antifungal agents inhibit cholesterol biosynthesis at different points in the biosynthetic pathway. In patients receiving cyclosporine, lovastatin should be temporarily discontinued if systemic azole derivative antifungal therapy is required; patients not taking cyclosporine should be carefully monitored if systemic azole derivative antifungal is required.
Interruption of therapy with APO-LOVASTATIN should be considered in any patient with an acute, serious condition, suggestive of a myopathy or having a risk factor predisposing to the development of renal failure or rhabdomyolysis, such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disorders and uncontrolled seizures.
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Special Precautions
General: Before instituting therapy with APO-LOVASTATIN (lovastatin), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems. The patient should be advised to inform subsequent physicians of the prior use of lovastatin or any other lipid metabolism regulator.
Use in Homozygous Familial Hypercholesterolemia (FH): APO-LOVASTATIN is not effective or is less effective in patients with rare homozygous familial hypercholesterolemia, because these patients have no or very low levels of LDL receptor activity. Lovastatin appears to be more likely to raise serum transaminases in these homozygous patients.
Effect on the Lens: Current long-term data from clinical trials do not indicate an adverse effect of lovastatin on the human lens.
Effect on Lipoprotein (a) [Lp(a)]: In some patients, the beneficial effect of lowered total cholesterol and LDL cholesterol levels may be partly blunted by a concomitant increase in the Lp(a) levels. Until further experience is obtained from controlled clinical trials, it is suggested, where feasible, that Lp(a) measurements be carried out in patients placed on therapy with APO-LOVASTATIN.
Effect on CoQ10 Levels (Ubiquinone): A significant decrease in plasma CoQ10 levels in patients treated with lovastatin and other statins has been observed in short-term clinical trials. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not yet been established.
Hypersensitivity: Although to date, hypersensitivity syndrome has not been described as such, in few instances eosinophilia and skin eruptions appear to be associated with lovastatin treatment. If hypersensitivity is suspected, APO-LOVASTATIN should be discontinued.
Use in Patients with Impaired Renal Function: Because lovastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with moderate renal insufficiency.
In patients with severe renal insufficiency (creatinine clearance < 30mL/min), dosages above 20mg/day should be carefully considered and, if deemed necessary, implemented cautiously.
Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal an d/or gonadal steroid production. Clinical studies with lovastatin have shown that this agent does not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.
Patients treated lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones.
Use in Pregnancy: APO-LOVASTATIN is contraindicated during pregnancy.
Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as lovastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, APO-LOVASTATIN may cause fetal harm when administered to a pregnant woman.
A few reports have been received of congenital abnormalities in infants whose mothers were treated during a critical period of pregnancy with HMG-CoA reductase inhibitors including lovastatin.
APO-LOVASTATIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, APO-LOVASTATIN should be discontinued and the patient apprised of the potential hazard to the fetus.
Nursing Mothers: It is not known whether APO-LOVASTATIN is excreted in human milk. Because many drugs are excreted in human milk and because of the potential of serious adverse reactions in nursing infants from APO-LOVASTATIN, women taking APO-LOVASTATIN should not nurse their infants.
Pediatric Use: Limited experience is available in children. However, safety and effectiveness in children have not been established.
Geriatric Use: In patients over 60 years, efficacy appeared similar to that seen in the population as a whole, with no apparent increases in the frequency of clinical or laboratory/adverse findings.
Use In Pregnancy & Lactation
Use in Pregnancy: APO-LOVASTATIN is contraindicated during pregnancy.
Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as lovastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, APO-LOVASTATIN may cause fetal harm when administered to a pregnant woman.
A few reports have been received of congenital abnormalities in infants whose mothers were treated during a critical period of pregnancy with HMG-CoA reductase inhibitors including lovastatin.
APO-LOVASTATIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, APO-LOVASTATIN should be discontinued and the patient apprised of the potential hazard to the fetus.
Nursing Mothers: It is not known whether APO-LOVASTATIN is excreted in human milk. Because many drugs are excreted in human milk and because of the potential of serious adverse reactions in nursing infants from APO-LOVASTATIN, women taking APO-LOVASTATIN should not nurse their infants.
Side Effects
Lovastatin was compared to placebo in 8245 patients with hypercholesterolemia (total cholesterol 6.2 – 7.8mmol/L) in a randomized, double-blind, parallel, 48-week expanded clinical evaluation of lovastatin (EXCEL study). Clinical adverse reactions reported as possibly, probably or definitely drug-related in any treatment group is shown in the table as follows. (See table.)

Click on icon to see table/diagram/image

Other clinical adverse reactions reported as possibly, probably or definitely drug-related in 0.5 to 1.0% of patients in any drug-related group are listed as follows. In all these cases, the incidence on drug and placebo was not statistically significant.
Body as a whole: Chest pain.
Gastrointestinal: acid regurgitation, dry mouth, vomiting.
Musculoskeletal: leg pain, shoulder pain, arthralgia.
Nervous system/psychiatric: insomnia, paresthesia.
Skin: alopecia, pruritus.
Special senses: eye irritation.
No significant difference was found among the different treatment groups including placebo in the incidence of serious clinical adverse experiences including death due to CHD, non-fatal myocardial infarction, cancer, and deaths due to all causes. This study was not designed or powered to evaluate the incidence of these serious clinical adverse experiences. The EXCEL study included a minority of patients at risk of or with coronary artery disease; however, its findings cannot be extrapolated in this respect to other segments of the high-risk population.
Laboratory Tests: Marked persistent increases of serum transaminases have been noted.
Other liver function test abnormalities including elevated phosphatase and bilirubin have been reported. In the EXCEL study, 7.3% of the patients on lovastatin had elevations of CPK levels of at least twice the normal value on one or more occasions compared to 6.2% on placebo.
The EXCEL study, however, excluded patients with factors known to be associated with an increased risk of myopathy.
Nervous System: Visual evoked response, nerve conduction measurements and electromyography in 30 patients showed no evidence of neurotoxic effects of lovastatin.
Effect on the Lens: Current long-term data from clinical trials do not indicate an adverse effect of lovastatin on the human lens.
Post Marketing Experience: The following additional side effects have been reported since lovasatin was marketed: hepatitis, cholestatic jaundice, vomiting, anorexia, paresthesia and psychic disturbances including anxiety, erythema multiform, including Stevens-John syndrome; toxic epidermal necrolysis.
An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia, rheumatica, vasculities, thrombocytopenia, leucopenia, eosinophilia, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, flushing, chills, dyspnea and malaise.
There have been rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Increases in HbA1c and fasting serum glucose level have been reported with statins.
Drug Interactions
Concomittant Therapy with Other Lipid Metabolism Regulators: Combined drug therapy should be approached with caution as information from controlled studies is limited.
Bile Acid Sequestrants: Preliminary evidence suggests that the cholesterol-lowering effects of lovastatin and the bile acid sequestrant cholestyramine, are additive.
When APO-LOVASTATIN is used concurrently with cholestyramine or any other resin, an interval of at least two hours should be maintained between the two drugs, since the absorption of lovastatin may be impaired by the resin.
Gemfibrozil, Fenofibrate and Niacin: Myopathy, including rhabdomyolysis, has occurred in patients who were receiving coadministration of lovastatin with fibric acid derivatives and niacin, particularly in subjects with pre-existing renal insufficiency.
Erythromycin: Muscle effects.
Angiotensin-Converting Enzyme Inhibitors: Hyperkalemia associated with myositis (myalgia and elevated CPK) has been reported in the case of a single patient with insulin-dependent diabetes mellitus and mild renal insufficiency who received lovastatin concomitantly with an angiotensin-converting enzyme inhibitor (lisinopril).
Coumarin Anticoagulants: Clinically evident bleeding and/or increased prothrombin time have been rep orted occasionally in patients taking coumarin anticoagulants concomitantly with lovastatin. Careful monitoring of prothrombin time is therefore recommended in such cases.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovas tatin and digoxin resulted in no effect on digoxin plasma concentrations.
Beta-Adrenergic Blocking Drugs: In healthy volunteers, the coadministration of propranolol and lovastatin resulted in a slight decrease of the AUC of lovastatin and its metabolites as well as in a significant decrease of the Cmax for the lovastatin metabolites. The clinical interpretation of this phenomenon is difficult as it may indicate a greater uptake of lovastatin by the liver.
There was no clinically relevant interaction reported in patients who have been receiving lovastatin concomitantly with beta-adrenergic blocking agents.
Antipyrine: Antipyrine was used as a model for drugs metabolized by the microsomal hepatic enzyme system (cytochrome P450 system). Lovastatin had no effect on the pharmacokinetics of antipyrine.
Other Concomitant Therapy: Caution should be exercised with concomitant use of immunosuppresants and itraconazole.
Although specific interaction studies were not performed, in clinical studies, lovastatin was used concomitantly with calcium-channel blockers (such as verapamil HCl, nifedipine and diltiazem HCl), a number of diuretics and nonsteroidal anti-inflammatory drugs (NSAIDS), hypoglycemic drugs (chlorpropamide, glipizide, insulin) without evidence of clinically significant adverse interactions.
Drug/Laboratory Test Interactions: Lovastatin may elevate creatinine phosphokinase and transaminase levels. In the differential diagnosis of chest pain in a patient on therapy with lovastatin, cardiac and non-cardiac fractions of these enzymes should be determined.
Storage
To be stored in a cool place. Protect from light.
ATC Classification
C10AA02 - lovastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
Tab 20 mg x 500's.
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