HMG-CoA Reductase Inhibitors (Systemic)

This monograph includes information on the following:

1) Atorvastatin
2) Cerivastatin#  * 
3) Fluvastatin
4) Lovastatin
5) Pravastatin
6) Simvastatin

VA CLASSIFICATION
Primary: CV351
Secondary: CV900

Commonly used brand name(s): Lescol3; Lipitor1; Mevacor4; Pravachol5; Zocor6.

Other commonly used names are:
Epistatin — Simvastatin
{28} Eptastatin — Pravastatin
{28} Mevinolin — Lovastatin
Synvinolin —Cerivastatin# * 
{28}
#  Products containing cerivastatin were withdrawn from the market by Bayer in August 2001{126}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


HMG-CoA reductase inhibitor—

antihyperlipidemic—

Indications

Note: Cerivastatin was removed from the market by Bayer in August 2001{126}

Accepted

Hyperlipidemia (treatment)—3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are indicated as adjuncts to diet in the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (type IIa and IIb hyperlipoproteinemia) caused by elevated low-density lipoprotein cholesterol (LDL-C) concentrations in patients with a significant risk of coronary artery disease, who have not responded to diet or other measures alone.{56}{57}{58}{59}{106}{107}{108}{109}{110}{111}{112}{113}{114}{115}{116}{117} The HMG-CoA reductase inhibitors may also be useful for the reduction of elevated LDL-C concentrations in patients with combined hypercholesterolemia and hypertriglyceridemia, {01}{06}{26}{27}{32}{34}{45}{57}{58}{106}{107}{108}{109}{110}{111}{112}{113}{114}{115}{116}{117}and for the reduction of total-C, LDL-C, apolipoprotein B (Apo B), and triglyceride (TG), and to increase HDL-C levels in patients with combined hypercholesterolemia and mixed dyslipidemia{106}{123}{124}{125}.
—Atorvastatin1 and simvastatin are indicated as adjunctive therapy with other lipid lowering treatments ( eg, LDL apheresis){123} in homozygous familial hypercholesterolemia to reduce total cholesterol (total-C) and LDL-C.{106}{108}{123}{124}
—Atorvastatin 1and simvastatin 1 are indicated for the treatment of dysbetalipoproteinemia (type III hyperlipoproteinemia) in patients who did not respond adequately to diet.{106}{123}
—Atorvastatin1and simvastatin 1are indicated as adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels (type IV hyperlipoproteinemia).{106}{123}
—For additional information on initial therapeutic guidelines related to the treatment of hyperlipidemia, see Appendix III.

Coronary heart disease (prophylaxis)— Pravastatin and simvastatin are indicated to reduce the risk of total mortality by reducing the incidence of coronary death in patients without symptomatic cardiovascular disease.{108}{109}{114}{115}{123} Lovastatin1, pravastatin, and simvastatin are indicated to reduce the risk of myocardial infarction and the risk of undergoing myocardial revascularization procedures.{108}{109}{110}{114}{115} {123}Lovastatin1 is also indicated to reduce the risk of unstable angina.{110}{110}{111}{116}{117}.
—Fluvastatin and lovastatin are indicated to slow the progression of atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.{107}{108}{109}{110}

Stroke or transient ischemic attack (prophylaxis) 1—Simvastatin is indicated to reduce the risk of stroke or transient ischemic attack in patients with coronary heart disease and hypercholesterolemia{108}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Atorvastatin{106}, cerivastatin{107}, fluvastatin{56}: Synthetic
    Lovastatin, pravastatin, simvastatin: Fungus-derived{71}
Molecular weight—
    Atorvastatin calcium: 1209.42{106}
    Cerivastatin sodium: 481.5{107}
    Fluvastatin sodium: 433.45 {38}
    Lovastatin: 404.55 {38}
    Pravastatin sodium: 446.52 {38}
    Simvastatin: 418.57 {38}

Mechanism of action/Effect:

The active beta-hydroxy acid form of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors competitively inhibits the enzyme HMG-CoA reductase. {57} {58} {59} {100} Atorvastatin, cerivastatin, fluvastatin, and pravastatin are administered in the active (open acid) form, while lovastatin and simvastatin must be hydrolyzed to the beta-hydroxyacid in tissues. {30} {41} {103}

Inhibition of HMG-CoA reductase prevents conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. The primary site of action of HMG-CoA reductase inhibitors is the liver. {63} Inhibition of cholesterol synthesis in the liver leads to upregulation of LDL receptors and an increase in catabolism of LDL cholesterol. There may also be some reduction in LDL production as a result of inhibition of hepatic synthesis of very low-density lipoprotein (VLDL), the precursor of LDL. HMG-CoA reductase inhibitors reduce LDL cholesterol, VLDL cholesterol, and to a lesser extent, plasma triglyceride concentrations, and slightly increase high-density lipoprotein (HDL) concentrations. {01} {26} {27} {63}

Absorption:

Atorvastatin—Rapidly absorbed; bioavailability of parent compound 14%{106}. Grapefruit juice in large amounts has been shown to interfere with the metabolism of atorvastatin, causing increases in Cmaxand AUC{119}{120}

Cerivastatin—Bioavailability 60% (range 39 to 101%){107}

Fluvastatin—Rapidly and almost completely absorbed from the gastrointestinal tract (greater than 90%); bioavailability 19 to 29%. {56} {65} {71}

Lovastatin—Reduced by approximately 30% when administered on an empty stomach rather than with food. {01}

Pravastatin—Approximately 34%; bioavailability approximately 18%. {48} {49} {85}

Simvastatin—Absorption in animal study averaged about 85%; bioavailability less than 5%{108}

Protein binding:

Atorvastatin—Very high (³ 98%){106}

Cerivastatin—Very high (> 99%) (80% to albumin){107}

Fluvastatin—Very high (greater than 98%). {56} {63} {67}

Lovastatin—Very high (greater than 95%). {01} {28}

Pravastatin—Moderate (50%). {27} {46}

Simvastatin—Very high (approximately 95%). {33} {47} {58}

Biotransformation:

Atorvastatin—Administered in active (open acid) form. Biotransformation by ortho- and parahydroxylation and beta-oxidation. Ortho- and parahydroxylated metabolites are pharmacologically active. Their in vitro inhibition of HMG-CoA reductase activity is equivalent to the parent compound.{106}

Cerivastatin—Administered in active (open acid) form. Biotransformation by demethylation and hydroxylation. Certain metabolites (M1 and M23) are pharmacologically active with relative potency of 50% and 100% of the parent compound, respectively{107}

Fluvastatin—Administered in active (open acid) form. Biotransformation by hydroxylation, N-dealkylation, and beta-oxidation; the major metabolic products present in plasma are pharmacologically inactive. {56} {68}

Lovastatin and simvastatin—By hydrolysis in tissues, to several metabolites, including a major active beta-hydroxy metabolite. {01} {28} {33} {57} {58}

Pravastatin—Administered in active (open acid) form and converted to inactive metabolites and active metabolites with minimal activity. {29} {49} {59}

Half-life:

Atorvastatin—Elimination, approximately 14 hours{106}

Cerivastatin—Elimination, 2 to 3 hours{107}

Fluvastatin—Approximately 1.2 hours (range, 0.5 to 3.1 hours). {56} {65}

Lovastatin—3 hours. {30}

Pravastatin—1.3 to 2.7 hours. {30} {49} {50} {51} {85}

Time to peak concentration:

Atorvastatin—1 to 2 hours{106}

Cerivastatin—Approximately 2.5 hours{107}

Fluvastatin—0.5 to 0.7 hour. {56} {65}

Lovastatin—2 to 4 hours. {01}

Pravastatin—Approximately 1 hour. {30}

Simvastatin—1.3 to 2.4 hours. {28} {33} {47}

Duration of action:

Lovastatin—After withdrawal of continuous therapy: 4 to 6 weeks. {06}

Elimination:


Atorvastatin—
        Fecal (biliary): primary route of elimination{106}
        Renal: less than 2%{106}



Cerivastatin—
        Fecal (biliary): 70%{107}
        Renal: 24%{107}



Fluvastatin—
        Fecal (biliary): 90%. {56} {71}
        Renal: 5%. {56} {65}



Lovastatin—
        Fecal (biliary and unabsorbed): 83%.
        Renal: 10%. {01}



Pravastatin—
        Fecal (biliary and unabsorbed): 70%. {27} {46} {49} {50}
        Renal: 20%. {27} {46} {49} {50}



Simvastatin—
        Fecal (biliary and unabsorbed): 60%. {28} {33} {58}
        Renal: 13%. {28} {33} {58}



Precautions to Consider

Carcinogenicity

Atorvastatin—A 2–year carcinogenicity study in rats at doses of 10, 30, and 100 mg per kg of body weight (mg/kg) per day found 2 rare tumors (rhabdomyosarcoma and fibrosarcoma) in the high dose female rats (plasma drug concentration of approximately 16 times the mean human plasma drug concentration after an 80 mg oral dose){106}. Administration of atorvastatin at 100, 200, or 400 mg/kg per day in mice (producing plasma values of 6 times the mean human drug exposure after an 80 mg dose) for 2 years resulted in a significant increase in liver adenomas in males and liver carcinomas in females{106}.

Cerivastatin— A 2-year carcinogenicity study in rats at doses of 0.007, 0.034, or 0.158 mg/kg per day (plasma drug concentrations of the high dosage level equaled that of human exposure after a 0.4 mg daily oral dose) showed tumor incidences were comparable to those in controls. In mice given cerivastatin for 2 years at doses of 0.4, 1.8, 9.1, or 55 mg/kg per day (plasma drug concentrations in the range of human exposure at 0.4 mg/day) hepatocellular adenomas were significantly increased in males and females at doses ³ 9.1 mg/kg, and hepatocellular carcinomas were significantly increased in males at ³ 1.8 mg/kg{107}.

Fluvastatin—A study in rats given fluvastatin in doses of 6, 9, and 18 to 24 mg per kg of body weight (mg/kg) per day (plasma drug concentrations of approximately 9, 13, and 26 to 35 times the mean human plasma drug concentration after a 40-mg dose) found a low incidence of forestomach squamous papillomas and one carcinoma of the forestomach at the 24 mg/kg dose. {56} However, these results were thought to reflect prolonged hyperplasia induced by direct contact with fluvastatin sodium rather than a systemic drug effect. {56} Similar results were found in mice studies. {56} In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was found in male rats treated with the 18 to 24 mg/kg doses. {56}

Lovastatin—Studies in male and female mice given lovastatin in doses of 500 mg/kg per day (a total plasma drug exposure [total HMG-CoA reductase inhibitory activity in extracted plasma] 3 to 4 times that of humans given the highest recommended dose) for 21 months found an increased incidence of hepatocellular carcinomas and adenomas. {45} In female mice, an increase in pulmonary adenomas was observed at approximately 4 times the human drug exposure. {45} The incidence of papillomas in nonglandular mucosa of the stomach was also increased beginning at exposures 1 to 2 times that of humans; however, the human stomach contains only glandular mucosa. {45} In rats given lovastatin for 24 months at drug exposures between 2 and 7 times human exposure at 80 mg per day, a positive dose–response relationship for hepatocellular carcinogenicity was observed in males. {45}

Pravastatin—A study in rats given pravastatin doses producing serum drug concentrations 6 to 10 times higher than those in humans receiving 40 mg showed an increased incidence of hepatocellular carcinomas in male rats at the highest dose. {46} {59} Administration of pravastatin (producing plasma drug concentrations 0.5 to 5 times the human drug concentrations at 40 mg) in mice for 22 months resulted in an increased incidence of malignant lymphomas in females. {46} {59}

Simvastatin—A 72-week study in mice given simvastatin at doses producing serum concentrations 3, 15, and 33 times higher than the mean human plasma drug concentration after a 40-mg dose revealed increased incidences of liver adenomas, liver carcinomas, and lung adenomas in the middle- and high-dose groups. {47} In addition, a higher incidence of Harderian gland (a gland of the eye in rodents) adenomas was observed in the high-dose group. {47}

A 2-year study in rats exposed to simvastatin concentrations 45 times higher than those in humans given 40 mg revealed an increased incidence of thyroid follicular adenomas. {47}

Mutagenicity

Atorvastatin—No evidence of mutagenicity or clastogenicity was found in the following in vitro tests with or without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. In vivo, atorvastatin, was negative in the mouse micronucleus test.{106}

Cerivastatin—No evidence of mutagenicity was found in vitro with or without metabolic activation in the following assays: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli , Chinese Hamster Ovary Forward Mutation Assay, Unscheduled DNA Synthesis in rat primary hepatocytes, chromosome aberrations in Chinese hamster ovary cells, and spindle inhibition in human lymphocytes. There was no evidence of genotoxicity in vivo in a mouse micronucleus test; however, there was equivocal evidence of mutagenicity in a mouse dominant lethal test.{107}

Fluvastatin—No evidence of mutagenicity was observed in in vitro studies with or without rat-liver activation, including microbial mutagen tests, unscheduled DNA synthesis in rat primary hepatocytes, and chromosomal aberration tests. {56} Additionally, there was no evidence of mutagenicity in in vivo rat or mouse micronucleus tests. {56}

Lovastatin and simvastatin —A microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation found no evidence of mutagenicity. {57} {58} There was also no evidence of damage to genetic material in in vitro alkaline elution assays 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. {01} {57} {58}

Pravastatin—No evidence of mutagenicity was observed in in vitro tests with or without liver metabolic activation, including microbial mutagen tests, a chromosomal aberration test, a gene conversion assay, a dominant lethal test in mice, and a micronucleus test in mice. {46}

Pregnancy/Reproduction
Fertility—
Atorvastatin: No changes in fertility in rats were observed at doses up to 175 mg/kg (15 times the human exposure). Aplasia and aspermia in the epididymis and lower epididymal weight were found at doses of 100 mg/kg per day (16 times the human exposure at the 80 mg dose){106}. Lower testis weight was observed at doses of 30 and 100 mg/kg. Decreased sperm motility, decreased spermatid head concentration, and an increased number of abnormal sperms were observed in male rats given 100 mg/kg per day for 11 weeks prior to mating.{106} No adverse effects on semen parameters, or reproductive organ histopathology were found in dogs given dose of 10, 40, or 120 mg/kg for 2 years.{106}

Cerivastatin: No adverse effects on fertility or reproductive performance were observed in male and female rats at doses up to 0.1 mg/kg per day (peak plasma concentration [C max] in the range of human exposure). At a dose of 0.3 mg/kg per day (Cmax about 2 times human exposure), the length of gestation was marginally prolonged, stillbirths were increased, and the survival rate up to day 4 postpartum was decreased. In the fetuses (F1), a marginal reduction in fetal weight and delay in bone development was observed. In dogs given doses of 0.0008 mg/kg per day (Cmax in the range of human exposure), atrophy, vacuolization of the germinal epithelium, spermatidic giant cells, and focal oligospermia were observed. At doses of 0.1 mg/kg per day (Cmax about 20 times human exposure) ejaculate volume was small and libido was decreased in dogs. There was an increased number of morphologically altered spermatozoa, indicating disturbance of epididymal sperm maturation that was reversible when drug administration was discontinued.{107}

Fluvastatin: No adverse effects on fertility or reproductive performance were observed in rats given fluvastatin sodium at doses of up to 6 mg/kg per day in females and 20 mg/kg per day in males. {56}

Lovastatin: Testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation were seen in dogs given lovastatin starting at doses of 20 mg/kg per day. However, no adverse effects on fertility were observed in rats. {45}

Pravastatin: No adverse effects on fertility or general reproductive performance were observed in rats given pravastatin at doses of up to 500 mg/kg per day. {46}

Simvastatin: Decreased fertility was noted in rats given simvastatin for 34 weeks at 15 times the maximum human exposure level. {47} However, this effect was not observed in another study in rats given simvastatin for 11 weeks at the same dosage level. {47} Seminiferous tubule degeneration was observed in rats given simvastatin at a dose of 180 mg/kg per day (44 times the exposure level of humans given 40 mg per day). {47} Testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation were observed in dogs given simvastatin at a dose of 10 mg/kg per day (7 times the human exposure level at a dose of 40 mg per day). {47}

Pregnancy—
HMG-CoA reductase inhibitors are not recommended for use during pregnancy or in women who plan to become pregnant in the near future. {13}

Adequate and well-controlled studies in humans have not been done. However, because HMG-CoA reductase inhibitors interfere with biosynthesis of mevalonic acid, a cholesterol precursor that may have an essential function in DNA replication and, therefore, may be closely tied to fetal development (including synthesis of steroids and cell membranes), there is a possibility that fetal harm may be caused by administration of these medications during pregnancy. {56} {57} {58} {59} Vertebral anomalies, anal atresia, tracheo-esophageal fistula with esophageal atresia, and renal and radial dysplasias occurred in a neonate born to a mother who took lovastatin during the first trimester of pregnancy. {89} However, a direct causal relationship has not been proven. {89}

Use of birth control is recommended during use of these medications. If pregnancy occurs during HMG-CoA reductase inhibitor therapy, it is recommended that the HMG-CoA reductase inhibitor be discontinued for the duration of the pregnancy. {56} {57} {58} {59} Because of the long-term nature of antihyperlipidemic treatment, temporary suspension of therapy is not expected to be deleterious. {01} {26} {27} {57} {58} {59}


Atorvastatin

No evidence of teratogenicity was found in rats at doses up to 300 mg/kg per day or rabbits at doses up to 100 mg/kg per day (30 and 20 times, respectively, the human exposure level based on surface area [mg/m 2]). Decreased rat pup survival at birth, neonate, weaning, and maturity in pups, and pup body weight were observed in the offspring of mothers dosed with 225 mg/kg per day(22 times the human exposure at 80 mg/day). Pup development was delayed at doses of 100 and 225 mg/kg per day{106}.

FDA Pregnancy Category X{106}.



Cerivastatin

Studies in rats given cerivastatin at doses of 0.72 mg/kg (5 times the human exposure of a 0.4 mg oral dose) caused a significant increase in incomplete ossification of the lumbar center of the vertebrae. No anomalies or malformations were found in rabbits given 0.75 mg/kg (3 times the human exposure of a 0.4 mg oral dose). In pregnant rats given a single oral 2 mg/kg dose, cerivastatin crossed the placenta and was found in fetal liver, gastrointestinal tract, and kidneys{107}.

FDA Pregnancy Category X{107}.



Fluvastatin

No evidence of teratogenicity was found in rats or rabbits given doses of up to 36 mg/kg and 10 mg/kg per day, respectively. {56} Administration of fluvastatin at 12 and 24 mg/kg per day to female rats during the third trimester resulted in maternal mortality at or near term and postpartum. {56} Fetal and neonatal deaths were also observed. {56} These results were confirmed by a second study. {56}

FDA Pregnancy Category X. {56}



Lovastatin

Studies in mice and rats at doses producing plasma concentrations 40 (mouse fetus) and 80 (rat fetus) times the human exposure found an increased incidence of skeletal malformations. No changes occurred in rats or mice at multiples of 8 and 4 times, respectively, or in rabbits at exposures up to 3 times the highest tolerated human exposure. {45}

FDA Pregnancy Category X. {01} {45}



Pravastatin

Studies in rats and rabbits given pravastatin at doses of 1000 mg/kg per day (240 times the human exposure based on surface area) and 50 mg/kg per day (20 times the human exposure based on surface area), respectively, did not reveal teratogenic effects. {46}

FDA Pregnancy Category X. {46}



Simvastatin

No teratogenic effects were observed in rats or rabbits given simvastatin at doses of 25 mg/kg per day (6 times the human exposure based on surface area) and 10 mg/kg per day (4 times the human exposure based on surface area), respectively. {47}

FDA Pregnancy Category X. {47}


Breast-feeding

Use of HMG-CoA reductase inhibitors while breast-feeding is not recommended, because of the potential for serious adverse effects in nursing infants. {01} {26} {27} {56} {57} {58} {59}


Atorvastatin:

It is not known if atorvastatin is distributed in the breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother's milk{106}.



Cerivastatin:

Cerivastatin is distributed in the breast milk at a milk to plasma concentration ratio of 1.3 to 1{107}.



Fluvastatin:

Fluvastatin is distributed into breast milk and is present in breast milk in a 2 to 1 ratio (milk to plasma). {56}



Lovastatin:

It is not known whether lovastatin is distributed into human breast milk, but it is distributed into the milk of rats. {01} {57}



Pravastatin:

Trace amounts of pravastatin are distributed into human breast milk. {27} {46}



Simvastatin:

It is not known whether simvastatin is distributed into human breast milk. {26} {47}


Pediatrics

Appropriate studies on the relationship of age to the effects of HMG-CoA reductase inhibitors have not been performed in the pediatric population. Safety and efficacy have not been established. {45} {47}

Limited experience with use of atorvastatin, lovastatin, and simvastatin in children younger than 18 years of age seems to indicate that these medications are well tolerated and may be useful in severely hypercholesterolemic children who need medication therapy. {80} {81} {83}{107} {84} However, the long-term safety of HMG-CoA reductase inhibitor use in children has not been studied. {84} {101} Use of these agents should be reserved for severe cases under the care of a lipid specialist. {101} {102} Caution is recommended in use of cholesterol-lowering agents in children younger than 10 years of age. {82}


Geriatrics


Studies performed to date in a limited number of patients 65 years of age or older have not demonstrated geriatrics-specific problems that would limit the usefulness of HMG-CoA reductase inhibitors in the elderly. {73} {74} {75} {76} {77}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anticoagulants, coumarin- or indandione-derivative    (concurrent use with HMG-CoA reductase inhibitors may increase bleeding or prothrombin time; prothrombin time should be monitored in patients taking HMG-CoA reductase inhibitors with anticoagulants {19} {20} {25} {26} {27} {54}. However, atorvastatin, cerivastatin, fluvastatin, and pravastatin did not significantly affect prothrombin time when co-administered with warfarin{106}{107}{109}{111}; monitor prothrombin time (PT) before and during concurrent therapy with coumarin anticoagulants and simvastatin.{123}{124})


Cholestyramine or
Colestipol    (concurrent use may decrease the bioavailability of HMG-CoA reductase inhibitors; therefore, when these agents are used with HMG-CoA reductase inhibitors for therapeutic advantage, it is recommended that the HMG-CoA reductase inhibitor be given 2{124} to 4 hours after cholestyramine or colestipol {85} {87} {88} {99}{106}{107}{125})


Azole antifungals or{106}{107}{108}{110}{123}{124}{125}
» Cyclosporine or {01} {18} {22} {24} {56}{106}{107}{123}{124}{125}
» Gemfibrozil or {01} {16} {17} {56}{106}{107}
» Fibrates, other or{123}{124}{125}
Immunosuppressants or {01} {56}{106}{107}
Macrolide antibiotics or{01} {18} {22} {23} {40} {56}{106}{107}{108}{110}{123}{124}{125}
» Niacin {01} {21} {24}{106}{107}    (concurrent use with HMG-CoA reductase inhibitors may be associated with an increased risk of rhabdomyolysis and acute renal failure {10} {54}; although cases have been reported only with lovastatin, the potential also exists with other HMG-CoA reductase inhibitors; {26} {27} combined therapy of HMG-CoA reductase inhibitors with gemfibrozil, {39} {54} {86}{123}{124}{125} other fibrates{123}{124}{125}, niacin{123}{124}{125}, or immunosuppressants should include careful monitoring for symptoms of myopathy or rhabdomyolysis {54} {86}{106}{107}{106}{107})

    ( simvastatin dose should not exceed 10 mg/day when administered concurrently with niacin, fibrates, or cyclosporine{123}{124})

    (concurrent use with cerivastatin and gemfibrozil is contraindicated, due to rhabdomyolysis and associated renal failure{125})


For atorvastatin (in addition to those listed above):
Antacids    (concurrent use with atorvastatin may decrease plasma concentrations of atorvastatin approximately 35%{106} )


» Oral contraceptives    (concurrent use with atorvastatin may increase AUC value for norethindrone and ethinyl estradiol by approximately 30% and 20% respectively{106})


For atorvastatin, fluvastatin, and simvastatin (in addition to those listed above)
» Digoxin    (concurrent use with atorvastatin, fluvastatin, or simvastatin may cause an elevation in serum digoxin concentrations {26} {58}{106}{123}{124})


For atorvastatin and simvastatin (in addition to those listed above)
» Grapefruit juice    (concurrent use with large amounts of grapefruit juice has been reported to significantly increase the serum concentrations and the area under the plasma concentration-time curve (AUC){119}{120}. In a study with 12 subjects, administration of grapefruit juice double-strength 200 mL three times a day resulted in a Cmax decrease of about 24% of active atorvastatin compounds. An increase in AUC of active atorvastatin compounds was about 23%. The time to C max(tmax) was increased from 1 hour to 4 hours. Grapefruit juice or other grapefruit products in large doses should not be taken before or after administration of atorvastatin{119})

    (concurrent use with large amounts of grapefruit juice (> 1 quart per day) and simvastatin {123} has been reported to significantly increase the plasma concentrations of simvastatin, increasing the risk of myopathy{123}{124})


For fluvastatin:
Cimetidine or
Omeprazole or
Ranitidine    (concurrent use with fluvastatin results in a significant increase in the peak plasma concentration [Cmax ] of fluvastatin, [43%, 70%, and 50%, respectively] with an 18 to 23% decrease in plasma clearance{111})


Rifampin    (addition of fluvastatin in patients pretreated with rifampin results in significant reduction in Cmax [59%] and area under the curve [AUC] [51%] for rifampin, and a large increase in plasma clearance of rifampin [95%])


For simvastatin (in addition to those listed above)
» HIV protease inhibitors or
» Nefazodone    (concurrent use with simvastatin may be associated with an increased risk of rhabdomyolysis and acute renal failure; concurrent use is not recommended{123}{124})


» Verapamil    (concurrent use with simvastatin may be associated with an increased risk of myopathy; this effect is not seen with other calcium channel blockers)

{123}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Creatine kinase (CK) concentrations    (mild transient increases are common and may not be drug-related {102}; drug-related marked increases, with myositis and possible renal failure {09}, occur in about 0.5 to 1% of patients, although the incidence may be higher in organ transplant patients treated concurrently with immunosuppressants or gemfibrozil {01} {10} {26} {27})


Transaminase, serum    (values may be increased, usually to less than 3 times the upper limit of normal; in slightly less than 1 to 2% of patients receiving HMG-CoA reductase inhibitors for at least 1 year, marked increases to more than 3 times the upper limit of normal have occurred {01} {02} {04} {06} {26} {27} {56})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hepatic disease, active {01} {26} {27} {45} {99}    (condition may be exacerbated)


Risk-benefit should be considered when the following medical problems exist
Alcoholism, active or in remission or
Hepatic disease, history of    (further increases in liver enzymes may occur {01} {26} {27} {99})


» Organ {42} transplant, with immunosuppressant therapy    (increased risk of rhabdomyolysis and renal failure {10} {26} {27})


Sensitivity to any HMG-CoA reductase inhibitor {16} {26} {27}
» Serious conditions predisposing to the development of renal failure secondary to rhabdomyolysis, such as hypotension, severe acute infection, severe metabolic, endocrine, or electrolyte disorders, uncontrolled seizures, major surgery, or trauma    (increased risk of secondary renal failure if rhabdomyolysis occurs {01} {26} {27} {45})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Cholesterol, serum    (determinations recommended 4 weeks after initiation of therapy and at periodic intervals during therapy {01} {33})


» Creatine kinase (CK), serum    (determinations recommended if patient develops muscle tenderness during therapy or during concurrent therapy with niacin or immunosuppressive medications {09} {26} {57} {58}; a level 10 times higher than the upper limit of normal (ULN) in a patient with unexplained muscle symptoms indicates myopathy{123}{124})


» Liver function tests, including serum transaminase    (determinations recommended prior to initiation of therapy, every 6 weeks during the first 3 months of therapy, every 8 weeks during the remainder of the first year of therapy, and then at periodic intervals [approximately every 6 months] {01} {27} {33} {57} {58})


Prothrombin time    (determinations recommended prior to initiation of therapy and frequently enough during early therapy to insure prothrombin time stability in patients patients taking coumarin anticoagulants concomitantly)

{123}{124}


Side/Adverse Effects

Note: Recent data on patients receiving lovastatin do not reveal clinically significant differences between lovastatin and placebo in the incidence, type, or progression of lens opacities. {45} {52} {94} To date, no increased incidence of lens opacities has been found with atorvastatin{106}, cerivastatin{107}, fluvastatin, pravastatin, {95} {96} or simvastatin {72} {78} {79} {97}.
Acute pancreatitis has been reported during clinical use with simvastatin and lovastatin. {90} {91} {92} {93} A causal relationship with the HMG-CoA reductase inhibitors has not been clearly established. However, onset of symptoms appears to occur within 3 months of initiation of therapy. {91} {92} {93} Rapid regression of symptoms and laboratory anomalies has been observed upon discontinuation of the HMG-CoA reductase inhibitor. {90} {91} {92} {93} Patients should be advised to report immediately to physician acute onset of severe abdominal pain. Although reports of fluvastatin- or pravastatin-associated pancreatitis are lacking, patients taking these medications should also be properly advised, since the mechanism of the effect is poorly understood.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Myalgia, myositis, or rhabdomyolysis ( fever; muscle aches or cramps; unusual tiredness or weakness){03}{44}{45}{56}{98}

Note: Rhabdomyolysis may lead to renal failure. Incidence may be increased in patients treated with immunosuppressants, gemfibrozil, erythromycin, or niacin. Onset may occur weeks to months after initiation of treatment. {26} {27} {45} {54} {56} Patients should be advised to report immediately to physician any unexplained muscle pain, tenderness, or weakness, especially if it is accompanied by malaise or fever. {45}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Constipation, diarrhea, gas, heartburn, or stomach pain {01} {02} {04} {20} {26} {27} {56} {72}
    
dizziness {01}
    
headache {01} {04} {26} {27} {32}
    
nausea {01} {26} {27} {56} {72}
    
skin rash {01} {20} {26} {27} {32}

Incidence rare
    
Impotence (decreased sexual ability){36}{56}{57}{58}{59}
    
insomnia (trouble in sleeping ){12}{20}{56}{57}{58}{59}{70}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, HMG-CoA Reductase Inhibitors (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
Diet as preferred therapy; importance of following prescribed diet
»   Conditions affecting use, especially:
Sensitivity to any HMG-CoA reductase inhibitor

Pregnancy—Use not recommended in pregnancy or in women who plan to become pregnant in near future, because inhibited formation of cholesterol may impair fetal development; birth defects reported with lovastatin





Breast-feeding—Use not recommended, because of potentially serious adverse effects in nursing infants
Other medications, especially cyclosporine, gemfibrozil, other fibrates, niacin (with all HMG-CoA reductase inhibitors); digoxin (with atorvastatin, fluvastatin, and simvastatin); oral contraceptives (with atorvastatin only); HIV protease inhibitors, nefazodone (with simvastatin); verapamil (with simvastatin); or grapefruit juice in large amounts (with atorvastatin and simvastatin)
Other medical problems, especially, active hepatic disease; hypotension; major surgery; organ transplant with immunosuppressant therapy; severe infection; severe metabolic, endocrine, or electrolyte disorders; trauma; or uncontrolled seizures

Proper use of this medication

For all HMG-CoA reductase inhibitors
» Importance of not taking more or less medication than the amount prescribed

This medication does not cure the condition but instead helps control it

» Compliance with prescribed diet

» Proper dosing

Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For atorvastatin and simvastatin
Importance of not taking atorvastatin or simvastatin with grapefruit juice in large amounts

For lovastatin
Taking with meals, since medication is more effective with food

Precautions while using this medication
» Importance of close monitoring by physician

» Notifying physician immediately if pregnancy is suspected

» Checking with physician before discontinuing medications; blood lipid levels may increase significantly

» Caution if any kind of surgery (including dental surgery) or emergency treatment is required


Side/adverse effects
Signs of potential side effects, especially myalgia, myositis, or rhabdomyolysis


General Dosing Information
If serum transaminase concentrations increase to 3 times the upper limit of normal, HMG-CoA reductase inhibitor therapy should be withdrawn. {01} {26} {27}

If creatine kinase (CK) concentrations are markedly increased or myositis occurs, HMG-CoA reductase inhibitor therapy should be withdrawn. {01} {26} {27}

Diet/Nutrition
Nonpharmacologic management (dietary and weight control) of hypercholesterolemia is recommended as an adjunct to all pharmacologic therapy.

Concurrent administration of atorvastatin with 200 mL of grapefruit juice has been shown to decrease plasma concentration 24%{119}{120}

ATORVASTATIN

Summary of Differences


Indications:
Indicated for treatment of homozygous familial hypercholesterolemia.

Also indicated in Type III and Type IV hyperlipoproteinemia.



Pharmacology/pharmacokinetics:
Biotransformation—Administered in active form and metabolized by ortho- and parahydroxylation and beta-oxidation to active metabolites.

Time to peak concentration—1 to 2 hours{106}



Precautions:
Drug interaction and/or related problems—Interacts with antacids and oral contraceptives.



Additional Dosing Information
Can be taken at any time of the day, with or without food{106}


Oral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of atorvastatin base (not the calcium salt).{106}


ATORVASTATIN CALCIUM TABLETS

Usual adult and adolescent dose
Antihyperlipidemic


Heterozygous familial and nonfamilial hypercholesterolemia and mixed dyslipidemia (Frederickson type IIa and IIb)::
Initial—Oral, 10 mg (base) once a day{106}. The dosage can be adjusted after assessing treatment response in 2 to 4 weeks.{106}

Maintenance—Oral, 10 to 80 mg (base) once daily{106}.



Homozygous familial hypercholesterolemia::
Oral, 10 to 80 mg a day{106}
Note: Atorvastatin should be used in these patients as an adjunct to other lipid-lowering treatments such as LDL apheresis, or if such treatments are unavailable{106}.





Usual pediatric dose
Antihyperlipidemic
Homozygous familial hypercholesterolemia: Dosage has not been established{106}


Strength(s) usually available
U.S.—


10 mg (base) (Rx) [Lipitor (calcium carbonate) (candelila wax) (croscarmellose sodium ) (hydroxypropyl cellulose) ( lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (hydroxypropylmethylcellulose ) (polyethylene glycol) ( talc) (titanium dioxide) ( polysorbate 80) (simethicone emulsion)]


20 mg (base) (Rx) [Lipitor (calcium carbonate) (candelila wax) (croscarmellose sodium ) (hydroxypropyl cellulose) ( lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (hydroxypropylmethylcellulose ) (polyethylene glycol) ( talc) (titanium dioxide) ( polysorbate 80) (simethicone emulsion)]


40 mg (base) (Rx) [Lipitor (calcium carbonate) (candelila wax) (croscarmellose sodium ) (hydroxypropyl cellulose) ( lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (hydroxypropylmethylcellulose ) (polyethylene glycol) ( talc) (titanium dioxide) ( polysorbate 80) (simethicone emulsion)]

Canada—


10 mg (base) (Rx) [Lipitor (calcium carbonate) (candelila wax) (croscarmellose sodium ) (hydroxypropyl cellulose) ( lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (hydroxypropylmethylcellulose ) (polyethylene glycol) ( talc) (titanium dioxide) ( polysorbate 80) (simethicone emulsion){112}]


20 mg (base) (Rx) [Lipitor (calcium carbonate) (candelila wax) (croscarmellose sodium ) (hydroxypropyl cellulose) ( lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (hydroxypropylmethylcellulose ) (polyethylene glycol) ( talc) (titanium dioxide) ( polysorbate 80) (simethicone emulsion){112}]


40 mg (base) (Rx) [Lipitor (calcium carbonate) (candelila wax) (croscarmellose sodium ) (hydroxypropyl cellulose) ( lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (hydroxypropylmethylcellulose ) (polyethylene glycol) ( talc) (titanium dioxide) ( polysorbate 80) (simethicone emulsion){112}]

Packaging and storage:
Store at controlled room temperature 20 to 25°C (68 to 77°F)


CERIVASTATIN

Note: Products containing cerivastatin were withdrawn from the market by the manufacturer in August 2001.{126}


Summary of Differences


Pharmacology/pharmacokinetics:
Biotransformation—Administered in active form and metabolized by demethylation and hydroxylation to active metabolites{107}

Time to peak concentration—approximately 2.5 hours{107}



Additional Dosing Information
Should be taken in the evening with or without food{107}.


Oral Dosage Forms

CERIVASTATIN SODIUM TABLETS

Usual adult and adolescent dose
Antihyperlipidemic
Heterozygous familial and nonfamilial and mixed dyslipidemia (Fredrickson type IIa and IIb): Initial—Oral, 0.4 mg once daily in the evening. The dosage can be adjusted at four-week intervals after assessing treatment response.{107}

Maintenance—Oral, 0.4 mg to 0.8 mg once daily in the evening{107}{122}.


Note: For patients with significant renal impairment (creatinine clearance less than or equal to 60 mL/min/1.73m2), the starting dose should be 0.2 or 0.3 mg once a day in the evening{107}.




Usual adult prescribing limits
0.8 mg per day.
{125}
Usual pediatric dose
Safety and efficacy have not been established{107}.

Strength(s) usually available
U.S.—
Not commercially available

Canada—
Not commercially available

Packaging and storage:
Store below 25°C (77°F) protected from moisture. Store in a tight container.{107}


FLUVASTATIN

Summary of Differences


Pharmacology/pharmacokinetics:
Biotransformation—By hydroxylation, N-dealkylation, and beta-oxidation to inactive metabolites.

Time to peak concentration—0.5 to 0.7 hour.



Additional Dosing Information
Can be taken with meals or on an empty stomach. {56}


Oral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of fluvastatin base (not the sodium salt).


FLUVASTATIN SODIUM CAPSULES

Usual adult and adolescent dose
Antihyperlipidemic
Initial: Oral, 20 mg (base) once a day at bedtime, the dosage being adjusted at four-week intervals as needed and tolerated. {56} {69}

Maintenance: Oral, 20 to 40 mg (base) once a day in the evening. {56} {69}

Note: A 40-mg (base) daily dose may be split and taken two times a day. {56}



Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


20 mg (base) (Rx) [Lescol (gelatin) ( magnesium stearate) (microcrystalline cellulose ) (pregelatinized starch) ( titanium dioxide)]


40 mg (base) (Rx) [Lescol (gelatin) ( magnesium stearate) (microcrystalline cellulose ) (pregelatinized starch) ( titanium dioxide)]

Canada—


20 mg (base) (Rx) [Lescol (calcium carbonate) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch) (sodium bicarbonate) (talc)]{112}


40 mg (base) (Rx) [Lescol (calcium carbonate) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch) (sodium bicarbonate) (talc)]{112}

Packaging and storage:
Store below 30 °C (86 °F) in a tight container. {56} Protect from light. {56}


LOVASTATIN

Summary of Differences


Pharmacology/pharmacokinetics:
Absorption—Reduced by one-third on empty stomach.

Biotransformation—By hydrolysis to active metabolites.

Time to peak concentration—2 to 4 hours.

Duration of action—After withdrawal of continuous therapy: 4 to 6 weeks.



Additional Dosing Information
Should be taken with meals to maximize absorption.


Oral Dosage Forms

LOVASTATIN TABLETS USP

Usual adult and adolescent dose
Antihyperlipidemic
Initial: Oral, 20 mg once a day with the evening meal, the dosage being adjusted at four-week intervals as needed and tolerated. {45} {57}

Maintenance: Oral, 20 to 80 mg per day, as a single dose or in divided doses, with meals {01} {45} {57}.

Note: For patients on concomitant immunosuppressive therapy, it is recommended that lovastatin therapy begin with 10 mg per day and not exceed 20 mg per day.
For patients with severe renal function impairment (creatinine clearance less than 30 mL per min), doses above 20 mg per day should be carefully considered and dosage titration should proceed cautiously. {57}



Usual adult prescribing limits
80 mg per day {01} {57}.

Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


10 mg (Rx) [Mevacor (cellulose) (lactose ) (magnesium stearate) ( starch) (butylated hydroxyanisole (BHA) as preservative ) (red ferric oxide) ( yellow ferric oxide)]


20 mg (Rx) [Mevacor (cellulose) (lactose ) (magnesium stearate) ( starch) (butylated hydroxyanisole (BHA) as preservative ) (red ferric oxide) ( yellow ferric oxide) (FD&C Blue 2)]


40 mg (Rx) [Mevacor (cellulose) (lactose ) (magnesium stearate) ( starch) (butylated hydroxyanisole (BHA) as preservative ) (red ferric oxide) ( yellow ferric oxide) (FD&C Yellow 10) (FD&C Blue 2)]

Canada—


20 mg (Rx) [Mevacor (butylated hydroxyanisole) (indigotine on alumina) (lactose) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch)]


40 mg (Rx) [Mevacor (butylated hydroxyanisole) (indigotine and quinoline yellow on alumina substratum) (lactose) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer. {54}

Auxiliary labeling:
   • Take with meals.


PRAVASTATIN

Summary of Differences


Pharmacology/pharmacokinetics:
Biotransformation—Administered in active form.

Time to peak concentration—1 hour.



Additional Dosing Information
Can be taken with meals or on an empty stomach.


Oral Dosage Forms

PRAVASTATIN SODIUM TABLETS

Usual adult and adolescent dose
Antihyperlipidemic


Initial:
Oral, 10 to 40 mg once a day at bedtime, the dosage being adjusted at four-week intervals as needed and tolerated.

Note: An initial dose of 10 mg once a day is recommended in patients with significant renal function impairment or hepatic function impairment, and for the elderly. {121}




Maintenance:
10 to 40 mg once a day at bedtime. {46}

Note: In the elderly, maintenance doses of 20 mg a day or less are usually effective. {59}




Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


10 mg (Rx) [Pravachol (croscarmellose sodium) ( lactose) (magnesium oxide) ( magnesium stearate) (microcrystalline cellulose ) (povidone) (red ferric oxide)]


20 mg (Rx) [Pravachol (croscarmellose sodium) ( lactose) (magnesium oxide) ( magnesium stearate) (microcrystalline cellulose ) (povidone) (yellow ferric oxide)]


40 mg (Rx) [Pravachol (croscarmellose sodium) ( lactose) (magnesium oxide) ( magnesium stearate) (microcrystalline cellulose ) (povidone) (Green Lake Blend)]

Canada—


10 mg (Rx) [Pravachol (croscarmellose sodium) ( lactose) (magnesium oxide) ( magnesium stearate) (microcrystalline cellulose ) (povidone) (red ferric oxide)]


20 mg (Rx) [Pravachol (croscarmellose sodium) ( lactose) (magnesium oxide) ( magnesium stearate) (microcrystalline cellulose ) (povidone) (yellow ferric oxide)]


40 mg (Rx) [Pravachol (croscarmellose sodium) ( lactose) (magnesium oxide) ( magnesium stearate) (microcrystalline cellulose ) (povidone) (FD&C yellow no. 10) (FD&C blue no. 1)]{112}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.


SIMVASTATIN

Summary of Differences


Pharmacology/pharmacokinetics:
Biotransformation—By hydrolysis to active metabolites.

Time to peak concentration—1.3 to 2.4 hours.



Precautions:
Drug interactions and/or related problems—Elevation of serum digoxin.



Additional Dosing Information
Can be taken with meals or on an empty stomach.


Oral Dosage Forms

SIMVASTATIN TABLETS

Usual adult and adolescent dose
Antihyperlipidemic
Initial: Oral, 20 mg once a day in the evening, the dosage being adjusted at four-week intervals.{26}{47}{58}{123} Oral, 40 mg once a day in the evening for patients requiring a large LDL-C reduction (more than 45%), dosage adjusted at four-week intervals.{123}

Maintenance: 5 to 80 mg per day . {47} {58}{123}

Note: For patients taking concurrent immunosuppressive medications, it is recommended that simvastatin therapy begin with 5 mg per day and not exceed 10 mg per day.{58}{123} {124}For patients with severe renal insufficiency, begin therapy with 5 mg per day and closely monitor.{123} For patients with homozygous familial hypercholesterolemia, the recommended dose (adjunct therapy to other lipid-lowering treatments or if other therapy not available) is 40 mg per day in the evening or 80 mg per day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg.{123}



Usual adult prescribing limits
80 mg per day. {123}

Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


5 mg (Rx) [Zocor (cellulose) (hydroxypropyl cellulose) (hydroxypropyl methylcellulose) (iron oxides) (lactose) (magnesium stearate) (talc) (titanium dioxide) (butylated hydroxyanisole as preservative)]


10 mg (Rx) [Zocor (cellulose) (hydroxypropyl cellulose) (hydroxypropyl methylcellulose) (iron oxides) (lactose) (magnesium stearate) (talc) (titanium dioxide) (butylated hydroxyanisole as preservative)]


20 mg (Rx) [Zocor (cellulose) (hydroxypropyl cellulose) (hydroxypropyl methylcellulose) (iron oxides) (lactose) (magnesium stearate) (talc) (titanium dioxide) (butylated hydroxyanisole as preservative)]


40 mg (Rx) [Zocor (cellulose) (hydroxypropyl cellulose) (hydroxypropyl methylcellulose) (iron oxides) (lactose) (magnesium stearate) (talc) (titanium dioxide) (butylated hydroxyanisole as preservative)]


80 mg (Rx) [Zocor (cellulose) (hydroxypropyl cellulose) (hydroxypropyl methylcellulose) (iron oxides) (lactose) (magnesium stearate) (talc) (titanium dioxide) (butylated hydroxyanisole as preservative)]

Canada—


5 mg (Rx) [Zocor (ascorbic acid) ( butylated hydroxyanisole) (citric acid) (hydroxypropyl cellulose) (lactose ) (magnesium stearate) ( methylcellulose) (microcrystalline cellulose) (pregelatinized starch) (red ferric oxide) (talc) (titanium dioxide) (yellow ferric oxide)]


10 mg (Rx) [Zocor (ascorbic acid) ( butylated hydroxyanisole) (citric acid) (hydroxypropyl cellulose) (lactose ) (magnesium stearate) ( methylcellulose) (microcrystalline cellulose) (pregelatinized starch) (red ferric oxide) (talc) (titanium dioxide) (yellow ferric oxide)]


20 mg (Rx) [Zocor (ascorbic acid) ( butylated hydroxyanisole) (citric acid) (hydroxypropyl cellulose) (lactose ) (magnesium stearate) ( methylcellulose) (microcrystalline cellulose) (pregelatinized starch) (red ferric oxide) (talc) (titanium dioxide) (yellow ferric oxide)]


40 mg (Rx) [Zocor (ascorbic acid) ( butylated hydroxyanisole) (citric acid) (hydroxypropyl cellulose) (lactose ) (magnesium stearate) ( methylcellulose) (microcrystalline cellulose) (pregelatinized starch) (red ferric oxide) (talc) (titanium dioxide) (yellow ferric oxide)]


80 mg [Zocor (ascorbic acid) (butylated hydroxyanisole ) (citric acid) (hydroxypropyl cellulose) (lactose) ( magnesium stearate) (methylcellulose) (microcrystalline cellulose) (pregelatinized starch) (red ferric oxide) ( talc) (titanium dioxide) ( yellow ferric oxide)]
{124}
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.



Revised: 02/14/2002



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  1. Lovastatin product monograph (Mevacor, Merck Frosst—Canada), Rev 4/91, Rec 1/93.
  1. Simvastatin product monograph (Zocor, Merck Frosst—Canada), Rev 9/93, Rec 4/94.
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  1. Product Information: Lipitor(R), atorvastatin. Parke-Davis, White Plains, NJ, USA, Rev 1/99, Rec 10/99.
  1. Product Information: Baycol (R), cerivastatin. Bayer Corporation, West Haven, CT, USA, Rev 5/99, Rec 10/99.
  1. Product Information: Zocor (R), simvastatin. Merck & Co., Whitehouse Station, NJ, USA, Rev 8/99, Rec 10/99.
  1. Product Information: Pravachol (R), pravastatin. Bristol-Myers Squibb Company, Princeton, NJ, USA, Rev 5/98, Rec 10/99
  1. Product Information: Mevacor (R), lovastatin. Merck & Co., West Point, PA, USA, Rev 3/99, Rec 10/99.
  1. Product Information: Lescol (R), fluvastatin. Novartis Corp., East Hanover, PA, USA, Rev 1/99, Rec 10/99.
  1. Lipitor (Parke-Davis). In: CPS Compendium of pharmaceuticals and specialties (English edition). 34th ed. Canadian Pharmacists Association, Ontario, Canada; 1999. p. 939-941.
  1. Baycol (Bayer). In: CPS Compendium of pharmaceuticals and specialties (English edition). 34th ed. Canadian Pharmacists Association, Ontario, Canada; 1999. p. 199-200.
  1. Zocor (Frosst). In: CPS Compendium of pharmaceuticals and specialties (English edition). 34th ed. Canadian Pharmacists Association, Ontario, Canada; 1999. p. 2031-2033.
  1. Pravachol (Squibb). In: CPS Compendium of pharmaceuticals and specialties (English edition). 34th ed. Canadian Pharmacists Association, Ontario, Canada; 1999. p. 1428-1430.
  1. Mevacor (MSD). In: CPS Compendium of pharmaceuticals and specialties (English edition). 34th ed. Canadian Pharmacists Association, Ontario, Canada; 1999. p. 1045-1047.
  1. Lescol (Novartis). In: CPS Compendium of pharmaceuticals and specialties (English edition). 34th ed. Canadian Pharmacists Association, Ontario, Canada; 1999. p. 917-920.
  1. Product Information: Baycol®, cerivastatin, Bayer, Toronto, Ontario, Canada, rev. 10/99, reviewed 2/2000.
  1. Lilja J, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66:118-127.
  1. Personal Communication: Ana Aymes, Drug Information Services, Parke-Davis, July 2000.
  1. Product Information: Pravachol®, pravastatin. Bristol-Myers-Squibb, Princeton, NJ, (PI revised 7/2000, reviewed 8/2000).
  1. Product Information: Baycol®, cerivastatin. Bayer, West Haven, CT. (PI revised 7/2000, reviewed 8/2000).
  1. Product Information: Zocor®, simvastatin. Merck, Whitehouse Station, NJ. (PI revised 9/2000, reviewed 3/2001).
  1. Product Information: Zocor®, simvastatin. Merck Frosst, Kirkland, Quebec. (PI revised 8/1999, reviewed 6/2001).
  1. Product Information: Baycol®, cerivastatin. Bayer,West Haven, CT (PI revised 5/2001) reviewed 6/2001
  1. FDA Website: Market withdrawal of Baycol® (cerivastatin). United States Food and Drug Administration (08/2001), retrieved 08/09/2001from http://www.fda.gov/medwatch/safety/2001/Baycol2.htm
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