Lovastatin

MEVACOR® (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 α- 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,7α,8α(2S*,4S*), 8aα]]-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 empiricalformula 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.

Tablets MEVACOR are supplied as 20 mg and 40 mg tablets for oral administration. In addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients: cellulose, lactose, magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a preservative. Tablets MEVACOR 20 mg also contain FD&C Blue 2 aluminum lake. Tablets MEVACOR 40 mg also contain D&C Yellow 10 aluminum lake and FD&C Blue 2 aluminum lake.

No. 8123 — Tablets MEVACOR 20 mg are blue, octagonal tablets, coded MSD 731 on one side and plain on the other. They are supplied as follows:

NDC 0006-0731-61 unit of use bottles of 60.

No. 8124 — Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and plain on the other. They are supplied as follows:

NDC 0006-0732-61 unit of use bottles of 60.

Storage

Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Tablets MEVACOR must be protected from light and stored in a well-closed, light-resistant container.

REFERENCES

2 Classification of Hyperlipoproteinemias

4 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.

By: Mylan Pharmaceuticals Inc. Morgantown, WV 26505, USA OR Mylan Pharmaceuticals ULC, Etobicoke, Ontario, Canada M8Z 2S6. Revised: 10/2012

After oral administration of MEVACOR 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 MEVACOR can be recommended.

The dialyzability of lovastatin and its metabolites in man is not known at present.

MEVACOR 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 MEVACOR, 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

MEVACOR 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.

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 MEVACOR. 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 MEVACOR (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with MEVACOR 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.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use (see WARNINGS, Myopathy/Rhabdomyolysis).

Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular 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 MEVACOR (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).

Read the entire FDA prescribing information for Mevacor (Lovastatin)

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Lovastatin is usually taken at bedtime or with an evening meal. If you take lovastatin several times daily, take it with meals. Follow your doctor's instructions.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

You may need to take lovastatin on a long-term basis for the treatment of high cholesterol. You may need to stop using lovastatin for a short time if you have surgery or a medical emergency. Do not stop taking this medicine unless your doctor tells you to.

You will need frequent blood tests to check your liver function.

Lovastatin is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

Store at room temperature away from moisture, heat, and light.

Contraindications

• Concomitant use with potent CYP3A4 inhibitors (e.g., clarithromycin, cobicistat-containing preparations, erythromycin, HIV protease inhibitors, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, voriconazole).118 119 (See Specific Drugs and Foods under Interactions.)

• Active liver disease or unexplained, persistent elevations of serum aminotransferases.1 118

• Pregnancy or lactation.1 Administer to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards.1 118

• Known hypersensitivity to lovastatin or any ingredient in the formulation.1 118

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis could cause fetal harm.1 118 Skeletal malformations reported in animal reproductive studies.118 Congenital anomalies following intrauterine exposure to statins reported rarely.1 118

Administer to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards.1 118 If the patient becomes pregnant while taking the drug, immediately discontinue therapy and apprise the patient of the potential hazard to the fetus.1 118

Musculoskeletal Effects

Myopathy (manifested as muscle pain, tenderness, or weakness and serum creatine kinase [CK, creatine phosphokinase, CPK] concentration increases >10 times the ULN) reported occasionally.1 118

Rhabdomyolysis (characterized by muscle pain or weakness with marked increases [>10 times the ULN] in serum CK concentrations and increases in Scr [usually accompanied by brown urine and urinary myoglobinuria])437 with or without acute renal failure secondary to myoglobinuria has been reported;1 118 rare fatalities have occurred.1

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported rarely in patients receiving statins.118 119 Characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, necrotizing myopathy without substantial inflammation, and improvement following therapy with immunosuppressive agents.118 119

Risk of myopathy is increased in patients receiving higher dosages of statins; risk also may be increased in geriatric patients (≥65 years of age), women, and patients with renal impairment or uncontrolled hypothyroidism.118 119

Certain drug or food interactions also may increase risk of myopathy and/or rhabdomyolysis.1 118 119 (See Contraindications under Cautions and also see Interactions.)

May consider periodic monitoring of CK concentrations when initiating therapy or increasing dosage; however, there is no assurance that such monitoring will prevent myopathy.118

ACC/AHA cholesterol management guideline does not recommend routine monitoring of CK concentrations in adults; however, may obtain CK concentrations before initiating therapy in adults at increased risk of developing adverse musculoskeletal effects (e.g., patients with personal or family history of statin intolerance or muscle disease, patients receiving concomitant therapy with myotoxic drugs).350 During statin therapy, may measure CK concentrations in adults with muscle symptoms (e.g., pain, tenderness, stiffness, cramping, weakness, generalized fatigue).350

National Heart, Lung, and Blood Institute (NHLBI) expert panel on integrated guidelines cardiovascular health and risk reduction in children and adolescents recommends obtaining CK concentrations before initiating statin therapy and routinely monitoring for muscle toxicity during therapy.357

Discontinue if serum CK concentrations increase markedly or if myopathy is diagnosed or suspected.1 118 119

Temporarily withhold therapy 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; uncontrolled seizures).1 118 119

Hepatic Effects

Associated with increases in serum aminotransferase (AST, ALT) concentrations.1 118 119

Pancreatitis,1 118 hepatitis (including chronic active hepatitis),1 118 cholestatic jaundice,1 118 fatty change in liver,1 118 increased serum alkaline phosphatase concentrations,1 118 increased serum γ-glutamyl transpeptidase concentrations,1 118 increased bilirubin concentrations,1 118 cirrhosis,1 118 fulminant hepatic necrosis,1 118 hepatoma,1 118 and fatal and nonfatal hepatic failure118 119 have been reported.1 118 119

Perform liver function tests before initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage201 ).118 119 Although manufacturers previously recommended more frequent monitoring,1 FDA concluded that serious statin-related liver injury is rare and unpredictable, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.200 ACC/AHA cholesterol management guideline recommends obtaining liver function tests in adults with symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of skin or sclera).350 However, NHLBI expert panel on cardiovascular health and risk reduction in children and adolescents strongly recommends routine monitoring of hepatic function in children and adolescents receiving statins.357

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt lovastatin therapy.118 119 If an alternate etiology is not found, do not restart lovastatin.118 119

Also see Hepatic Impairment under Cautions.

Hyperglycemic Effects

Increases in HbA1c and fasting serum glucose concentrations reported.118 119 200 Possible increased risk of developing diabetes.200 May need to monitor glucose concentrations following initiation of statin therapy.201

FDA states that cardiovascular benefits of statins outweigh these small increased risks.200

ACC/AHA cholesterol management guideline recommends evaluating patients for new-onset diabetes mellitus according to current diabetes screening guidelines.350

If diabetes mellitus develops during statin therapy, encourage patients to adhere to a heart-healthy diet, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of ASCVD.350

Endogenous Steroid Production

Statins interfere with cholesterol synthesis and theoretically may blunt adrenal and/or gonadal steroid production.118 119

No effects on basal plasma cortisol concentrations, testosterone concentrations, or adrenal reserve observed with lovastatin.118 119 Effects on male fertility or on pituitary-gonadal axis in premenopausal women not fully established.118 119

If clinical evidence of endocrine dysfunction is present, evaluate patients appropriately.118 119

Caution advised if a statin or another antilipemic agent is used concomitantly with drugs that may decrease concentrations or activity of endogenous steroid hormones (e.g. spironolactone, cimetidine).118 119

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) reported rarely.118 119

Generally nonserious and reversible, with variable times to symptom onset (1 day to years) and resolution (median of 3 weeks following discontinuance of therapy).118 119 200 Not associated with fixed or progressive dementia (e.g., Alzheimer’s disease) or clinically important cognitive decline.200 Not associated with any specific statin, patient's age, statin dosage, or concomitant drug therapy.200

FDA states that cardiovascular benefits of statins outweigh the small increased risk of cognitive impairment.200

If manifestations consistent with cognitive impairment occur, National Lipid Association (NLA) statin safety assessment task force recommends evaluating and managing patients appropriately.202

If patients present with confusion or memory impairment, ACC/AHA cholesterol management guideline recommends evaluating patient for statin as well as nonstatin causes (e.g., other drugs, systemic or neuropsychiatric causes).350

Role as Adjunct Therapy

Prior to institution of antilipemic therapy, vigorously attempt to control serum cholesterol by appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying disorder that might be the cause of lipid abnormality.1 118

Specific Populations

Category X.1 118 Safety in pregnant women not established.118 119 Discontinue immediately if pregnancy is known or suspected.118 119 (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality, under Cautions.)

Not known whether lovastatin is distributed into milk; however, other statins are distributed into milk.118 119 Use is contraindicated in nursing women; women who require lovastatin therapy should not breast-feed their infants.1 118 119

Safety and efficacy of conventional tablets not established in children <10 years of age or in prepubertal children.1 Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.1

Safety and efficacy of extended-release lovastatin not established in children or adolescents <20 years of age.119

No substantial differences in safety or efficacy relative to younger adults.1 118

Conventional preparation: Mean plasma HMG-CoA reductase inhibitory activity is approximately 45% higher in patients 70–78 years of age than in young adults; however, dosage adjustment based on age-related pharmacokinetic differences not necessary in geriatric patients.118 Because advanced age (≥65 years of age) is a predisposing factor for myopathy, including rhabdomyolysis, use with caution in this population.118

Extended-release preparation: Safety and efficacy appear to be similar to those in younger adults; however, greater sensitivity in some older patients cannot be ruled out.119 (See Geriatric Patients under Dosage and Administration.)

Use with caution.119 437 In patients >75 years of age, consider benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy.350

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1 118

Contraindicated in patients with active liver disease or unexplained, persistent increases in liver function test results.1 118

Because many patients who have developed rhabdomyolysis during lovastatin therapy have had complicated medical histories, including renal impairment secondary to chronic diabetes mellitus, closely monitor such patients.118 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

GI disturbances (e.g., flatulence, diarrhea, abdominal pain, constipation, nausea, dyspepsia), headache, myalgia, asthenia, blurred vision, rash, dizziness, muscle cramps, insomnia.1 118 119

Storage

Oral

Well-closed, light-resistant containers at 5–25°C; protect from light.118

20–25°C (may be exposed to 15–30°C).119 Avoid excessive heat and humidity.119

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For lovastatin, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to lovastatin or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of lovastatin regular tablets for children 10 to 17 years of age. However, safety and efficacy in children younger than 10 years of age have not been established.

Teenage girls taking lovastatin regular tablets should be counseled on appropriate birth control methods to prevent pregnancy.

Appropriate studies have not been performed on the relationship of age to the effects of lovastatin extended-release tablets in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of lovastatin in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require an adjustment in the dose for patients receiving lovastatin.

Pregnancy

Breast Feeding

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using lovastatin.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking lovastatin, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using lovastatin with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amprenavir
• Atazanavir
• Boceprevir
• Clarithromycin
• Cobicistat
• Darunavir
• Erythromycin
• Fosamprenavir
• Idelalisib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Mibefradil
• Mifepristone
• Nefazodone
• Nelfinavir
• Posaconazole
• Ritonavir
• Saquinavir
• Telaprevir
• Telithromycin
• Tipranavir
• Voriconazole

Using lovastatin with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone
• Bezafibrate
• Ceritinib
• Ciprofibrate
• Clofibrate
• Colchicine
• Conivaptan
• Cyclosporine
• Dabigatran Etexilate
• Dalfopristin
• Danazol
• Daptomycin
• Delavirdine
• Diltiazem
• Dronedarone
• Fenofibrate
• Fenofibric Acid
• Fluconazole
• Gemfibrozil
• Lomitapide
• Lumacaftor
• Niacin
• Quinupristin
• Ranolazine
• Verapamil

Using lovastatin with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Azithromycin
• Bosentan
• Clopidogrel
• Oat Bran
• Pectin
• St John's Wort

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using lovastatin with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use lovastatin, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of lovastatin. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of or
• Diabetes, poorly-controlled or
• Hypothyroidism (an underactive thyroid) or
• Liver disease, history of—Use with caution. May cause side effects to become worse.

• Electrolyte disorder, severe or
• Endocrine disorder, severe or
• Epilepsy (seizures), not well-controlled or
• Hypotension (low blood pressure) or
• Kidney disease, severe or
• Metabolic disorder, severe or
• Sepsis (severe infection)—Patients with these conditions may be at risk for muscle or kidney problems.

• Hypercholesterolemia (high cholesterol in the blood), familial homozygous—Less effective in patients with this condition.

• Liver disease, active or
• Liver enzymes, elevated—Should not be used in patients with these conditions.

Take lovastatin only as directed by your doctor. Do not take more or less of it, and do not take more or less often than your doctor ordered.

In addition to lovastatin, your doctor may change your diet to one that is low in fat, sugar, and cholesterol. Carefully follow your doctor's orders about any special diet.

Take the regular tablet with food. Take the extended-release tablet without food.

Swallow the whole. Do not crush, break, or chew it.

If you are taking danazol (Danocrine®), diltiazem (Cardizem®), dronedarone (Multaq®), or verapamil (Calan®, Isoptin®, Verelan®) together with lovastatin, your lovastatin dose should not be higher than 20 milligrams (mg) per day, unless otherwise directed by your doctor. Do not use more than 40 mg per day of lovastatin together with amiodarone (Cordarone®). When used together with higher doses of lovastatin, these medicines may increase your risk of muscle injury and could result in kidney problems.

Tell your doctor if you drink grapefruit juice. Drinking large amounts of grapefruit juice (more than 1 quart each day) while taking lovastatin may increase your risk of muscle injury and could result in kidney problems.

Do not drink large amounts of alcohol with lovastatin. This could cause unwanted effects on the liver.

Dosing

The dose of lovastatin will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of lovastatin. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For high cholesterol:
  • For oral dosage form (extended-release tablets):
    • Adults—At first, 20 to 60 milligrams (mg) once a day, in the evening at bedtime and taken as single dose. Your doctor may increase your dose as needed.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—At first, 20 milligrams (mg) once a day given with the evening meal. Your doctor may increase your dose as needed. However, the dose is usually not more than 80 mg per day.
    • Children 10 to 17 years of age—At first, 10 mg once a day given with the evening meal. Your doctor may increase your dose as needed. However, the dose is usually not more than 40 mg per day.
    • Children younger than 10 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of lovastatin, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Therapy with Lovastatin should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. Lovastatin 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 is indicated to reduce the risk of:

• Myocardial infarction
• Unstable angina
• Coronary revascularization procedures

(See CLINICAL PHARMACOLOGY, Clinical Studies.)

Coronary Heart Disease

Lovastatin is 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 artherosclerotic vascular disease due to hypercholesterolemia. Lovastatin is 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 2), when the response to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.

Adolescent Patients with Heterozygous Familial Hypercholesterolemia

Lovastatin is 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 to 17 years of age, with heFH if after an adequate trial of diet therapy the following findings are present:

1. LDL-C remains >189 mg/dL or
2. 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 is not indicated.

The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:

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 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:

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.

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 particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discountinuing Lovastatin (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

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, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, erythromycin, and cobicistat-containing products), and grapefruit juice increase the risk of myopathy by reducing the elimination of Lovastatin. (See CONTRAINDICATIONS, WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics.)

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, Dronedarone, or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol, diltiazem, dronedarone 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 seconds 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 ).

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 premenopausal 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.

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 (C max) 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 (C max) 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 to 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

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, and11/79, 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 analysis† of 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 childbearing 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 to 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 to 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 to 78 years of age compared with patients between 18 to 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 ). Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, Lovastatin should be prescribed with caution in the elderly.

____________________________________

3 Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.

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.

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 to 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.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see WARNINGS, Myopathy/Rhabdomyolysis].

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.

Respiratory: interstitial lung disease

Adolescent Patients (ages 10 to 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 ).

Noncardioembolic stroke/TIA (secondary prevention)

Based on the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack, statin therapy with intensive lipid-lowering effects is recommended to reduce the risk of recurrent stroke and future cardiovascular events in patients with ischemic stroke or TIA presumed to be of atherosclerotic origin who have an LDL-C concentration ≥100 mg/dL (with or without evidence for other clinical atherosclerotic cardiovascular disease [ASCVD]) or who have an LDL-C concentration <100 mg/dL (without evidence for other clinical ASCVD).

Immediate release: Refer to adult dosing; Extended release: Initial: 20 mg once daily at bedtime

Heterozygous familial hypercholesterolemia: Oral (immediate release tablet): Adolescents 10-17 years:

LDL reduction <20%: Initial: 10 mg daily with evening meal

LDL reduction ≥20%: Initial: 20 mg daily with evening meal

Usual range: 10-40 mg once daily with evening meal, then adjust dose at 4-week intervals; maximum dose per manufacturer: 40 mg daily

Dosage adjustment for lovastatin with concomitant medications (amiodarone, danazol, diltiazem, dronedarone, lomitapide, or verapamil): Refer to adult dosing.

No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Tablet, immediate release: Store at 20°C to 25°C (68°F to 77°F). Protect from light

Tablet, extended release: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Avoid excessive heat and humidity.

Adverse events were observed in animal reproduction studies. There are reports of congenital anomalies following maternal use of HMG-CoA reductase inhibitors in pregnancy; however, maternal disease, differences in specific agents used, and the low rates of exposure limit the interpretation of the available data (Godfrey 2012; Lecarpentier 2012). Cholesterol biosynthesis may be important in fetal development; serum cholesterol and triglycerides increase normally during pregnancy. The discontinuation of lipid lowering medications temporarily during pregnancy is not expected to have significant impact on the long term outcomes of primary hypercholesterolemia treatment.

Use of lovastatin is contraindicated in pregnancy. HMG-CoA reductase inhibitors should be discontinued prior to pregnancy (ADA 2013). If treatment of dyslipidemias is needed in pregnant women or in women of reproductive age, other agents are preferred (Berglund 2012; Stone 2013). The manufacturer recommends administration to women of childbearing potential only when conception is highly unlikely and patients have been informed of potential hazards.

Applies to lovastatin: oral tablet, oral tablet extended release

Hepatic

Persistent elevations in liver function tests to three times normal values have been reported in up to 2% of patients on lovastatin in clinical trials. Overall, 1.5% of patients were withdrawn from study due to elevations in serum transaminases. While most patients remained asymptomatic with these elevations, cases of cholestatic jaundice and hepatitis have been reported.

Liver function tests should be closely monitored. Lovastatin should be discontinued in patients with persistent, significant elevations (three times the upper limit of normal) in liver function parameters.[Ref]

Common (1% to 10%): Elevations in liver function tests
Frequency not reported: Hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in the liver, cirrhosis, fulminant hepatic necrosis[Ref]

Gastrointestinal

Common (1% to 10%): Flatulence, abdominal pain, diarrhea, constipation, nausea
Frequency not reported: Dyspepsia, heartburn, anorexia, vomiting
Postmarketing reports: Abdominal discomfort[Ref]

Gastrointestinal side effects are among the most common complaints in patients on lovastatin. These effects tend to be mild and transient in nature and will often dissipate with continued therapy.[Ref]

Musculoskeletal

HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria, and renal failure. These conditions appear to be dose related, usually occurring with doses greater than 30 mg per day. The incidence and severity of myopathy may be increased by concomitant administration of lovastatin with drugs that can cause myopathy when given alone, such as gemfibrozil and other fibrates, niacin, and potent inhibitors of CYP450 3A4 (i.e., cyclosporine, antifungal azoles, macrolide antibiotics, large amounts of grapefruit juice). Other variables associated with an increased risk of statin-induced myopathy include, advanced age, small body stature, female gender, renal and/or hepatic dysfunction, perioperative periods, hypothyroidism, diabetes mellitus, and alcoholism.

Milder forms of myotoxicity (i.e., myalgia) are commonly reported and occur in approximately 5% to 7% of patients taking a statin drug.

Patients should be instructed to report promptly symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if markedly elevated, lovastatin should be discontinued. The value of routine monitoring of creatine kinase is not known. In some studies up to 11% of patients experienced elevations in creatine kinase while on lovastatin. In most cases these elevations were mild, transient, and not associated with clinical symptoms.

Itraconazole used concomitantly with lovastatin has led to one reported case of severe rhabdomyolysis in a 63-year-old woman. Caution should be exercised when HMG-CoA reductase inhibitors and azole antifungals are prescribed concurrently.

Exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50.[Ref]

Frequency not reported: Elevations in creatine kinase, muscle cramps, myopathy, rhabdomyolysis, arthralgia, myalgia, tendon rupture, dermatomyositis[Ref]

Hematologic

Frequency not reported: Hemolytic anemia, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), leukopenia (These effects may be manifestations of a hypersensitivity reaction)[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness
Frequency not reported: Cranial nerve dysfunction, tremor, vertigo, memory loss, drowsiness, weight loss, decline in cognitive function, paresthesias, peripheral neuropathy, peripheral nerve palsy
Postmarketing reports: Asthenia, fatigue, malaise, hypoesthesia, insomnia[Ref]

Renal

Frequency not reported: Acute renal failure secondary to rhabdomyolysis[Ref]

Dermatologic

Frequency not reported: Rash, pruritus, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, purpura, alopecia (These effects may be manifestations of a hypersensitivity reaction)[Ref]

Endocrine

Frequency not reported: Hypospermia, gynecomastia, thyroid dysfunction, acid maltase deficiency (the genetic disorder also referred to as Pompe's Disease), pancreatitis[Ref]

Hypersensitivity

Frequency not reported: Anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatic, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever (including severe hyperthermia), chills, flushing, malaise, dyspnea, toxic epidermal necrolysis[Ref]

Immunologic

Frequency not reported: Lupus-like syndrome with positive ANA and elevated ESR, polymyalgia rheumatica, vasculitis[Ref]

Ocular

Frequency not reported: Progression of cataracts, ophthalmoplegia[Ref]

Metabolic

Very rare (less than 0.01%): Hyperkalemia[Ref]

Psychiatric

Frequency not reported: Decreased libido, anxiety, insomnia, depression, suicidal thoughts, delusions, paranoia, agitation, nightmares[Ref]

Genitourinary

Halkin, et al report a case in which use of both lovastatin and pravastatin on different occasions in the same patient led to reversible impotence. The impotence resolved within 2 weeks after discontinuation of the HMG-CoA reductase inhibitor.[Ref]

Frequency not reported: Erectile dysfunction, impotence, testicular pain[Ref]

Oncologic

Frequency not reported: Tumor growth, hepatocellular carcinomas and adenomas. pulmonary adenomas (all in rodents)[Ref]

Respiratory

Postmarketing reports: Interstitial lung disease

Some side effects of lovastatin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

It is recommended that liver function tests be performed prior to initiation of therapy in patients with a history of liver disease, or when otherwise clinically indicated. It is also recommended that liver function tests be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated. Discontinuation of lovastatin therapy is recommended if liver function tests (AST or ALT) persist at three times the upper limit of normal or greater.

Consult WARNINGS section for additional precautions.

• Lovastatin, in conjunction with dietary measures, is used to lower total cholesterol and LDL-cholesterol in people at increased risk of cardiovascular disease if initial dietary measures fail to lower cholesterol.
• Lovastatin is also used to reduce the risk of heart attack, unstable angina, and revascularization procedures in people with moderately elevated total cholesterol and LDL-cholesterol, and low HDL-cholesterol.
• Lovastatin may also slow the progression of atherosclerosis in people with preexisting coronary heart disease.
• Lovastatin is also indicated in some genetic lipid disorders (such as heterozygous familial hypercholesterolemia) in adolescents aged 10 to 17 meeting certain criteria.