LOVASTATIN TABLETS USP, 10 mg, Rx only

/LOVASTATIN TABLETS USP, 10 mg, Rx only
LOVASTATIN TABLETS USP, 10 mg, Rx only2018-09-06T09:12:40+00:00

Prescription Drug Name:

LOVASTATIN TABLETS USP, 10 mg, Rx only

ID:

33221ee2-b16c-4ef7-b0b4-083cb76b0bf3

Code:

34391-3

DESCRIPTION


id: a5ec781f-c39c-4b94-8b27-778d235d696a
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Lovastatin is a cholesterol lowering agent isolated from a strain of Aspergillus terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme 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 is [1S-[1α(R*),3α,7β,8β(2S*,4S*),8aβ]]-1,2,3,7, 8,8a-hexahydro-3,7-dimethyl-8-[2(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is: Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile. Lovastatin tablets USP are supplied as 10 mg, 20 mg and 40 mg tablets for oral administration. In addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients: D&C Yellow No. 10, FD&C Blue No. 2, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Butylated hydroxyanisole (BHA) is added as a preservative.

CLINICAL PHARMACOLOGY


id: f6129211-f18e-4627-9a36-79ba7fe8d4f1
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range. Lovastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of lovastatin may involve both reduction of VLDL-C concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with lovastatin. Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that lovastatin does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, lovastatin can produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma triglycerides (TG) (see Tables II-IV under Clinical Studies). The effects of lovastatin on Lp(a), fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown. Lovastatin is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.

INDICATIONS AND USAGE


id: ae687a55-de81-4b5b-ab2b-09812f60e70b
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Therapy with lovastatin tablets USP should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. Lovastatin tablets USP should be used in addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has been inadequate to reduce risk. Primary Prevention of Coronary Heart Disease In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C and LDL-C and below average HDL-C, lovastatin tablets USP are indicated to reduce the risk of: -Myocardial infarction -Unstable angina -Coronary revascularization procedures (See CLINICAL PHARMACOLOGY, Clinical Studies.) Coronary Heart Disease Lovastatin tablets USP are indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels. Hypercholesterolemia Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lovastatin tablets USP are indicated as an adjunct to diet for the reduction of elevated total-C and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb***), when the response to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.

*
*
*Classification of Hyperlipoproteinemias
IDL = intermediate-density lipoprotein
Type Lipoproteins elevated Lipid Elevations
major minor
I chylomicrons TG ↑→C
IIa LDL C
IIb LDL,VLDL C TG
III (rare) IDL C/TG
IV VLDL TG ↑→C
V (rare) chylomicrons,VLDL TG ↑→C
Adolescent Patients with Heterozygous Familial Hypercholesterolemia Lovastatin tablets USP are indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if after an adequate trial of diet therapy the following findings are present: LDL-C remains >189 mg/dL or
LDL-C remains >160 mg/dL and:
there is a positive family history of premature cardiovascular disease or
two or more other CVD risk factors are present in the adolescent patient
General Recommendations Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation: LDL-C = total-C – [0.2 × (TG) + HDL-C] For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated total-C. In such cases, lovastatin tablets USP are not indicated. The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
CHD, coronary heart disease

Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory.


Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
NCEP 
Treatment 
Guidelines
:


LDL


Goals 
and 
Cutpoints 
for 
Therapeutic 
Lifestyle 
Changes 
and 
Drug 
Therapy 
in 
Different 
Risk 
Categories

Risk 
Category

LDL 
Goal


(
mg
/
dL
)

LDL 
Level 
at 
Which 
to 
Initiate 
Therapeutic 
Lifestyle 
Changes


(
mg
/
dL
)

LDL 
Level 
at 
Which 
to 
Consider 
Drug 
Therapy


(
mg
/
dL
)

CHD or CHD risk equivalence (10-year risk >20%) <100 ≥100 ≥130
(100-129: drug optional) 

2+ Risk factors
(10-year risk ≤20%)
<130 ≥130 10-year risk 10-20%: ≥130
10-year risk<10%: ≥160
0-1 Risk factor

<160 ≥160 ≥190
(160-189: LDL-lowering drug optional)
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category. At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines above). Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used to monitor therapy. Although lovastatin tablets  USP  may be useful to reduce elevated LDL-C levels in patients with combined hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality (Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).*** The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:
Category

Total


(
mg
/
dL
)

LDL


(
mg
/
dL
)

Acceptable <170 <110
Borderline 170-199 110-129
High ≥200 ≥130
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.

CONTRAINDICATIONS


id: e9153923-fb0c-42cb-bb7e-c81105129394
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Hypersensitivity to any component of this medication. Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS). Concomitant administration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone) (see WARNINGS, Myopathy/Rhabdomyolysis). Pregnancy and lactation (see PRECAUTIONS, Pregnancy and Nursing Mothers). 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 the cholesterol 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, lovastatin is contraindicated during pregnancy and in nursing mothers. 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, lovastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).

WARNINGS


id: b8554f79-559d-48b0-af0c-a97a5dd2334c
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

Myopathy/Rhabdomyolysis Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily. All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Lovastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Lovastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following: Strong inhibitors of CYP3A4 Lovastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, and posaconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, or the antidepressant nefazodone. Combination of these drugs with lovastatin is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with lovastatin should be suspended during the course of treatment (see CONTRAINDICATIONS; PRECAUTIONS, Drug Interactions). Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of lovastatin. It is recommended that dose adjustment of lovastatin be considered during coadministration. Increased lovastatin concentration in plasma has been associated with an increased risk of myopathy/rhabdomyolysis. Gemfibrozil The combined use of lovastatin with gemfibrozil should be avoided. Other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin) Caution should be used when prescribing other fibrates or lipid-lowering doses (≥1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations. Cyclosporine The use of lovastatin with cyclosporine should be avoided. Danazol, diltiazem or verapamil with higher doses of lovastatin The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with danazol, diltiazem, or verapamil. The benefits of the use of lovastatin in patients receiving danazol, diltiazem, or verapamil should be carefully weighed against the risks of these combinations. Amiodarone The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class. Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine, and caution should be exercised when prescribing lovastatin with colchicine (see PRECAUTIONS, Drug Interactions). Ranolazine The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Dose adjustment of lovastatin may be considered during coadministration with ranolazine. Prescribing recommendations for interacting agents are summarized in Table VII (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).

Table 
VII


Drug 
Interactions 
Associated 
with 
Increased 
Risk 
of 
Myopathy

Rhabdomyolysis

Interacting 
Agents

Prescribing 
Recommendations

Strong CYP3A4 inhibitors, e.g.: 
Ketoconazole 
Itraconazole 
Posaconazole 
Erythromycin 
Clarithromycin 
Telithromycin 
HIV protease inhibitors 
Boceprevir 
Telaprevir 
Nefazodone
Contraindicated with lovastatin 
Gemfibrozil
Cyclosporine
Avoid with lovastatin
Danazol 
Diltiazem 
Verapamil
Do not exceed 20 mg lovastatin daily
Amiodarone Do not exceed 40 mg lovastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice
(>1 quart daily)
Liver Dysfunction Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with lovastatin, symptomatic liver disease has been reported rarely at all dosages (see ADVERSE REACTIONS). In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of lovastatin was 20 mg/day; 50% of the lovastatin treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301). It is recommended that liver enzyme tests be obtained prior to initiating therapy with lovastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with lovastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart lovastatin. 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 transaminase elevations are contraindications to the use of lovastatin. As with other lipid-lowering agents, moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with lovastatin (see ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with lovastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

PRECAUTIONS


id: 15f67a5f-892d-4e1c-bb09-ed57ec1e007f
displayName: PRECAUTIONS SECTION
FDA Article Code: 42232-9

General Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with lovastatin. Homozygous Familial Hypercholesterolemia Lovastatin is less effective in patients with the rare homozygous familial hypercholesterolemia, possibly because these patients have no functional LDL receptors. Lovastatin appears to be more likely to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients. Information for Patients Patients should be advised about substances they should not take concomitantly with lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking lovastatin. It is recommended that liver enzymes be checked before starting therapy, and if signs or symptoms of liver injury occur. All patients treated with lovastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Drug Interactions CYP3A4 Interactions Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Strong inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin), and large quantities of grapefruit juice (>1 quart daily) increase the risk of myopathy by reducing the elimination of lovastatin. (See CONTRAINDICATIONS, WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics) In vitro studies have demonstrated that voriconazole inhibits the metabolism of lovastatin. Adjustment of the lovastatin dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if voriconazole must be used concomitantly with lovastatin. Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong CYP3A4 inhibitors, but which can cause myopathy when given alone. See WARNINGS, Myopathy/Rhabdomyolysis. Gemfibrozil Other fibrates Niacin (nicotinic acid) (≥1 g/day) Other Drug Interactions Cyclosporine: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine (see WARNINGS, Myopathy/Rhabdomyolysis). Danazol, Diltiazem, or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol, diltiazem, or verapamil particularly with higher doses of lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Pharmacokinetics). Amiodarone: The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class (see WARNINGS, Myopathy/Rhabdomyolysis). Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended that in patients taking anticoagulants, prothrombin time be determined before starting lovastatin and frequently enough during early therapy to insure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine. See WARNINGS, Myopathy/Rhabdomyolysis. Ranolazine
: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. See WARNINGS, Myopathy/Rhabdomyolysis.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of lovastatin and propranolol. Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations. Oral Hypoglycemic Agents: In pharmacokinetic studies of lovastatin in hypercholesterolemic non-insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide (see CLINICAL PHARMACOLOGY, Clinical Studies). Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including lovastatin. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the mean testosterone response to HCG was slightly but not significantly reduced after treatment with lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones. CNS Toxicity Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60 mg/kg/day dose. CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels (Cmax) which were about 30 times higher than the mean values in humans taking 80 mg/day. Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class. Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at 60 mg/kg/day. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of lovastatin). There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The human stomach contains only glandular mucosa. In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day). An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors. A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males, with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly increased in mid- and high dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high dose mice than in controls. No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear. Pregnancy Pregnancy Category X See CONTRAINDICATIONS. Safety in pregnant women has not been established. Lovastatin has been shown to produce skeletal malformations in offspring of pregnant mice and rats dosed during gestation at 80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the control group; affected rat fetuses/total: 6/324 compared to 2/308 in the control group). Female rats dosed before mating through gestation at 80 mg/kg/day also had fetuses with skeletal malformations (affected fetuses/total: 1/152 compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7 times the human dose based on body surface area and in rats results in 5 times the human exposure based on AUC. In pregnant rats given doses of 2, 20, or 200 mg/kg/day and treated through lactation, the following effects were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to 0.6% in the control group), decreased pup body weights throughout lactation (up to 5%, 8%, and 38%, respectively, below control), supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and 11/79, respectively, compared to 0/5 in the control group), delays in ossification in dead pups (affected fetuses/total: 0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and delays in pup development (delays in the appearance of an auditory startle response at 200 mg/kg/day and free-fall righting reflexes at 20 and 200 mg/kg/day). Direct dosing of neonatal rats by subcutaneous injection with 10 mg/kg/day of the open hydroxyacid form of lovastatin resulted in delayed passive avoidance learning in female rats (mean of 8.3 trials to criterion, compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects on retention 1 week later) at exposures 4 times the human systemic exposure at 80 mg/day based on AUC. No effect was seen in male rats. No evidence of malformations was observed when pregnant rabbits were given 5 mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body surface area) or a maternally toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day based on body surface area). Rare clinical reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysisof greater than 200 prospectively followed pregnancies exposed during the first trimester to lovastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was sufficient to exclude a 3-fold or greater increase in congenital anomalies over the background incidence. Maternal treatment with lovastatin may reduce the fetal levels of mevalonate, which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, lovastatin should not be used in women who are pregnant, or can become pregnant (see CONTRAINDICATIONS). Lovastatin should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Treatment should be immediately discontinued as soon as pregnancy is recognized. Nursing Mothers It is not known whether lovastatin is 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 (see CONTRAINDICATIONS). Pediatric Use Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In these limited controlled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than 10 years of age. Geriatric Use A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).

ADVERSE REACTIONS


id: b4da3beb-fcde-4885-be7d-f179b3f71614
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Lovastatin is generally well tolerated; adverse reactions usually have been mild and transient. Phase III Clinical Studies In Phase III controlled clinical studies involving 613 patients treated with lovastatin, the adverse experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded Clinical Evaluation of Lovastatin [EXCEL] Study). Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see WARNINGS, Myopathy/Rhabdomyolysis). Expanded Clinical Evaluation of Lovastatin (EXCEL) Study Lovastatin was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300 mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment group are shown in the table below. For no event was the incidence on drug and placebo statistically different.

Placebo



(

=
1663
)


%

Lovastatin


20 
mg 
q
.
p
.
m
.


(


1642
)


%

Lovastatin


40 
mg 
q
.
p
.
m
.


(


1645
)


%

Lovastatin


20 
mg 
b
.
i
.
d
.


(


1646
)


%

Lovastatin


40 
mg 
b
.
i
.
d
.


(


1649
)


%

Body 
As 

Whole

Asthenia 1.4 1.7 1.4 1.5 1.2
Gastrointestinal

   Abdominal pain 1.6 2.0 2.0 2.2 2.5
   Constipation 1.9 2.0 3.2 3.2 3.5
   Diarrhea 2.3 2.6 2.4 2.2 2.6
   Dyspepsia 1.9 1.3 1.3 1.0 1.6
   Flatulence 4.2 3.7 4.3 3.9 4.5
   Nausea 2.5 1.9 2.5 2.2 2.2
Musculoskeletal

   Muscle cramps 0.5 0.6 0.8 1.1 1.0
   Myalgia 1.7 2.6 1.8 2.2 3.0
Nervous 
System


Psychiatric

   Dizziness 0.7 0.7 1.2 0.5 0.5
   Headache 2.7 2.6 2.8 2.1 3.2
Skin

   Rash 0.7 0.8 1.0 1.2 1.3
Special 
Senses

   Blurred vision 0.8 1.1 0.9 0.9 1.2
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different. 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. In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with lovastatin. The value for the placebo group was 2.5%. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605 participants treated with 20-40 mg/day of lovastatin (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with lovastatin was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up. The adverse experiences reported in AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded Clinical Evaluation of Lovastatin (EXCEL) Study). Concomitant Therapy In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin with cyclosporine or gemfibrozil should be avoided. Caution should be used when prescribing other fibrates or lipid-lowering doses (≥1 g/day) of niacin with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis). The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with lovastatin therapy. Skeletal:muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias. Neurological:dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression. There have been rare postmarketing 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 nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Hypersensitivity Reactions:An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Gastrointestinal:pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting, fatal and non-fatal hepatic failure. Skin:alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported. Reproductive: gynecomastia, loss of libido, erectile dysfunction. Eye: progression of cataracts (lens opacities), ophthalmoplegia. Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities. Adolescent Patients (ages 10-17 years) In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the groups treated with lovastatin (10 to 40 mg daily) was generally similar to that of the groups treated with placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS, Pediatric Use).

OVERDOSAGE


id: 77df13a6-9ae6-4522-8324-847d8bdd1656
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

After oral administration of lovastatin to mice, the median lethal dose observed was >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 5-6 g. Until further experience is obtained, no specific treatment of overdosage with lovastatin can be recommended. The dialyzability of lovastatin and its metabolites in man is not known at present.

DOSAGE AND ADMINISTRATION


id: 8a7e82da-0b67-451f-8ba5-477e0a0ba8f6
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

The patient should be placed on a standard cholesterol-lowering diet before receiving lovastatin tablets and should continue on this diet during treatment with lovastatin tablets (see NCEP Treatment Guidelines for details on dietary therapy). Lovastatin tablets 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 to 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 (see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL-C of 20% or more to achieve their goal (see INDICATIONS AND USAGE) 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. 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, or Verapamil In patients taking danazol, diltiazem, or verapamil concomitantly with lovastatin, therapy should begin with 10 mg of lovastatin and should not exceed 20 mg/day (see CLINICAL PHARMACOLOGY, Pharmacokinetics, WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions, Other Drug Interactions). Dosage in Patients taking Amiodarone In patients taking amiodarone concomitantly with lovastatin, the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other Drug Interactions). 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 (see NCEP Pediatric Panel Guidelines ††, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). 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 tablets are effective alone or when used concomitantly with bile-acid sequestrants (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions). Dosage in Patients with Renal Insufficiency In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).

HOW SUPPLIED


id: e588097c-8d39-44a3-bee0-d52fe36a5b66
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Lovastatin Tablets USP, 10 mg are light green colored, oval shaped, uncoated tablets, debossed with ‘LU’ on one side and ‘G01’ on the other side. They are supplied as follows: Bottles of 30  –  NDC 16590-311-30 Bottles of 60  –  NDC 16590-311-60 Bottles of 90  –  NDC 16590-311-90 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Lovastatin tablets must be protected from light and stored in a well-closed, light-resistant container. **    Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4): 397-402 †  Manson, J.M., Freyssinges,C.Ducroq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastating and Simvastatin Exposure During Pregnancy. Reproductive Toxicology. 10(6):439-446, 1996. ††  National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992. Manufactured for Lupin Pharmaceuticals, Inc.   Baltimore, Maryland 21202 United States Manufactured by Lupin Limited   Goa 403722 INDIA August 2012 Relabeling and Repackaging by:

STAT Rx USA LLC
Gainesville, GA  30501

PACKAGE LABEL – LOVASTATIN 10 MG TABLETS


id: 4008184e-9a64-483f-9485-28d3bad16f3a
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

LOVASTATIN TABLETS USP 10 mg Rx only