Indications
Adjunctive management of primary hypercholesterolemia
and mixed dyslipidemias. Atorvastatin: Primary
prevention of cardiovascular disease (prisk of MI or
stroke) in patients with multiple risk factors for coronary
heart disease CHD or type 2 diabetes mellitus (also
prisk of angina or revascularization procedures in patients
with multiple risk factors for CHD). Atorvastatin
and pravastatin: Secondary prevention of cardiovascular
disease (prisk of MI, stroke, revascularization
procedures, angina, and hospitalizations for HF) in patients
with clinically evident CHD. Fluvastatin: Secondary
prevention of coronary revascularization procedures
in patients with clinically evident CHD.
Fluvastatin and lovastatin: Slow progression of coronary
atherosclerosis in patients with CHD. Lovastatin:
Primary prevention of CHD (prisk of MI, unstable
angina, and coronary revascularization) in patients
without symptomatic cardiovascular disease withqtotal
and low-density lipoprotein (LDL) cholesterol andp
high-density lipoprotein (HDL) cholesterol. Pravastatin:
Primary prevention of CHD (prisk of MI, coronary
revascularization, and cardiovascular mortality) in patients
without clinically evident CHD. Simvastatin: Secondary
prevention of cardiovascular events (prisk of
MI, coronary revascularization, stroke, and cardiovascular
mortality) in patients with clinically evident CHD
or those at high-risk for CHD (history of diabetes, peripheral
arterial disease, or stroke). Rosuvastatin:
Slow progression of coronary atherosclerosis. Rosuvastatin:
Primary prevention of cardiovascular disease
(reduces risk of stroke, myocardial infarction, and revascularization)
in patients without clinically evident
coronary heart disease but with an increased risk of
cardiovascular disease because of age (50 yr for men;
60 yr for women), hsCRP 2 mg/L, and the presence
of 1 risk factor for cardiovascular disease (hypertension,
low HDL-C, smoking, or premature family history
of coronary heart disease). Rosuvastatin: Adjunctive
therapy to diet and exercise for the reduction of LDL
cholesterol in children 8–17 yrs with heterozygous familial
hypercholesterolemia if after diet therapy fails the
following still exist: LDL cholesterol remains 190 mg/
dL or remains 160 mg/dL [with family history of premature
cardiovascular disease or 2 risk factors for
cardiovascular disease]).
Action
Inhibit an enzyme, 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA) reductase, which is responsible for
catalyzing an early step in the synthesis of cholesterol.
Therapeutic Effects: Lowers total and LDL cholesterol
and triglycerides. Slightly increase HDL. Slows the
progression of coronary atherosclerosis with resultant
decrease in CHD-related events (all agents except rosuvastatin
have indication forpevents).
Pharmacokinetics
Absorption: Atorvastatin—rapidly absorbed but
undergoes extensive GI and hepatic metabolism, resulting
in 14% bioavailability; fluvastatin—98% absorbed
after oral administration, but undergoes extensive firstpass
metabolism resulting in 24% bioavailability; lovastatin,
pravastatin—poorly and variably absorbed after
oral administration; pitavastatin—well absorbed
(51%) after oral administration; rosuvastatin—20%
absorbed following oral administration; simvastatin—
85% absorbed but rapidly metabolized.
Distribution: Atorvastatin—probably enters
breast milk. Fluvastatin—enters breast milk. Lovastatin—
crosses the blood-brain barrier and placenta.
Pravastatin—small amounts enter breast milk. Pitavastatin,
rosuvastatin, and simvastatin—unknown.
Protein Binding: Atorvastatin, fluvastatin, pitavastatin,
and simvastatin—98%.
Metabolism and Excretion: All agents are extensively
metabolized by the liver; amount excreted unchanged in urine: atorvastatin—2%, lovastatin—
10%, fluvastatin—5%, pitavastatin—15%, pravastatin—
20%, and simvastatin—13%.
Half-life: Atorvastatin—14 hr; fluvastatin—1.2
hr; lovastatin—3 hr; pitavastatin—12 hr; pravastatin—
1.3–2.7 hr; rosuvastatin—19 hr; simvastatin—
unknown.
TIME/ACTION PROFILE (cholesterol-lowering
effect)
ROUTE ONSET PEAK DURATION*
Atorvastatin unknown unknown 20–30 hr
Fluvastatin 1–2 wk 4–6 wk unknown
Lovastatin 2 wk 4–6 wk 6 wk
Pitavastatin within 4 wk 4 wk unknown
Pravastatin several days 2–4 wk unknown
Rosuvastatin unknown 2–4 wk unknown
Simvastatin several days 2–4 wk unknown
*After discontinuation.
Contraindications/Precautions
Contraindicated in: Hypersensitivity; Active liver
disease or unexplained persistentqin AST or ALT; Simvastatin
and lovastatin—Concurrent use of strong
CYP3A4 inhibitors (qrisk of myopathy/rhabdomyolysis);
Pitavastatin—Concurrent use of cyclosporine;
Pitavastatin—severe renal impairment (CCr 30
mL/min); Simvastatin—Concurrent use of cyclosporine,
gemfibrozil, or danazol (qrisk of myopathy/rhabdomyolysis);
OB: Avoid use during pregnancy (may
cause fetal harm); Lactation: Avoid breast feeding if
treatment is necessary.
Use Cautiously in: History of liver disease; Alcoholism;
Rosuvastatin—patients with Asian ancestry
(may haveqblood levels andqrisk of rhabdomyolysis);
Atorvastatin—Concurrent use of gemfibrozil,
azole antifungals, erythromycin, clarithromycin, protease
inhibitors, niacin, or cyclosporine (higher risk of
myopathy/rhabdomyolysis); Lovastatin—Concurrent
use of gemfibrozil, niacin, cyclosporine, amiodarone,
danazol, diltiazem, verapamil, colchicine, or ranolazine
(higher risk of myopathy/rhabdomyolysis); Pitavastatin—
Hypothyroidism, concurrent use of fibrates or
lipid-lowering doses of niacin (higher risk of myopathy/
rhabdomyolysis); Rosuvastatin—Concurrent use
of gemfibrozil, azole antifungals, protease inhibitors,
niacin, cyclosporine, amiodarone, or verapamil
(higher risk of myopathy/rhabdomyolysis); Simvastatin—
Concurrent use of amiodarone, amlodipine, diltiazem,
dronedarone, verapamil, lomitapide, or ranolazine
(qrisk of myopathy/rhabdomyolysis);
Simvastatin—Chinese patients receiving 1 g/day of
niacin (qrisk of myopathy; do not use simvastatin 80
mg/day in these patients); Renal impairment; Geri: Pitavastatin—
qrisk of myopathy (age 65 yr); Rep:
Women of reproductive potential (use effective contraception);
Pedi: Children 8 yr (safety and effectiveness
not established); some products approved for use in
older children only.
Adverse Reactions/Side Effects
CNS: amnesia, confusion, dizziness, headache, insomnia,
memory loss, weakness. CV: chest pain, peripheral
edema. EENT: rhinitis; lovastatin, blurred vision.
Resp: bronchitis. GI: abdominal cramps, constipation,
diarrhea, flatus, heartburn, altered taste, drug-induced
hepatitis, dyspepsia, elevated liver enzymes, nausea,
pancreatitis. GU: erectile dysfunction. Derm:
rashes, pruritus. Endo: hyperglycemia. MS: RHABDOMYOLYSIS,
arthralgia, arthritis, immune-mediated
necrotizing myopathy, myalgia, myopathy (qwith simvastatin
80 mg/day dose). Misc: hypersensitivity reactions.
Interactions
Atorvastatin, lovastatin, simvastatin, and rosuvastatin
are metabolized by the CYP3A4 metabolic pathway. Fluvastatin
is metabolized by CYP 2C9. Pravastatin is not
metabolized by the CYP P450 system.
Drug-Drug: Atorvastatin, lovastatin, and simvastatin
may interact with CYP3A4 inhibitors. Risk of myopathy
with lovastatin isqby concurrent use of strong
CYP3A4 inhibitors, including ketoconazole, itraconazole,
posaconazole, voriconazole protease
inhibitors, clarithromycin, erythromycin, nefazodone,
and cobicistat-containing products; concurrent
use contraindicated. Risk of myopathy with simvastatin
isqby concurrent use of cyclosporine,
gemfibrozil, danazol, erythromycin, clarithromycin,
protease inhibitors, nefazodone, ketoconazole,
itraconazole, voriconazole, posaconazole,
and cobicistat-containing products; concurrent use
contraindicated. Risk of myopathy with pitavastatin isq
by concurrent use of cyclosporine; concurrent use
contraindicated. Bioavailability and effectiveness may
bepby cholestyramine and colestipol. Risk of myopathy
with atorvastatin isqby concurrent use of cyclosporine,
gemfibrozil, itraconazole, colchicine,
erythromycin, clarithromycin, nelfinavir, ritonavir/
saquinavir, lopinavir/ritonavir, tipranavir/ritonavir,
saquinavir/ritonavir, darunavir/ritonavir,
fosamprenavir, fosamprenavir/ritonavir, and
large doses of niacin; concurrent use with gemfibrozil,
cyclosporine, or tipranavir/ritonavir should be avoided;
use lowest dose with lopinavir/ritonavir; usepdoses
with nelfinavir, clarithromycin, itraconazole, saquinavir/
ritonavir, darunavir/ritonavir, fosamprenavir, or
fosamprenavir/ritonavir. Risk of myopathy with fluvastatin
isqby concurrent use of gemfibrozil, erythromycin,
colchicine, cyclosporine, azole antifungal
agents, or large doses of niacin mayqrisk of myopathy;
concurrent use with gemfibrozil should be avoided; usepdoses with cyclosporine and fluconazole. Risk of
myopathy with lovastatin isqby concurrent use of amiodarone
cyclosporine, gemfibrozil, diltiazem,
verapamil, danazol, and large doses of niacin; concurrent
use with gemfibrozil or cyclosporine should be
avoided; usepdoses with danazol, amiodarone, diltiazem,
or verapamil. Risk of myopathy with pitavastatin
isqby concurrent use of erythromycin, rifampin,
colchicine, fibrates, or large doses of niacin; usep
doses with erythromycin, rifampin, and niacin; concurrent
use with gemfibrozil should be avoided. Risk of
myopathy with pravastatin isqby concurrent use of cyclosporine,
fibrates, colchicine, erythromycin,
clarithromycin, azithromycin, or large doses of niacin;
concurrent use with gemfibrozil should be
avoided; consider lower dose with niacin. Risk of myopathy
with rosuvastatin isqby concurrent use of cyclosporine,
lopinavir/ritonavir, atazanavir/ritonavir,
simeprevir, colchicine, fibrates, or large
doses of niacin; concurrent use of gemfibrozil should
be avoided, if possible; usepdoses with cyclosporine,
lopinavir/ritonavir, and atazanavir/ritonavir. Risk of
myopathy with simvastatin isqby concurrent use of
amiodarone, amlodipine, diltiazem, dronedarone,
verapamil, lomitapide, ranolazine, or niacin.
Atorvastatin, fluvastatin, and simvastatin may
slightlyqserum digoxin levels. Atorvastatin and rosuvastatin
mayqlevels of hormonal contraceptives.
Atorvastatin, fluvastatin, lovastatin, rosuvastatin, and
simvastatin mayqrisk of bleeding with warfarin. Alcohol,
cimetidine, ranitidine, and omeprazole
mayqfluvastatin levels. Rifampin maypfluvastatin
levels. Antacidspabsorption of rosuvastatin (administer
2 hr after rosuvastatin. Lopinavir/ritonavir mayq
rosuvastatin levels. Fluvastatinqlevels of glyburide.
Drug-Natural Products: St. John’s wort mayp
levels and effectiveness (lovastatin and simvastatin).
Drug-Food: Large quantities of grapefruit juice
mayqblood levels andqrisk of rhabdomyolysis (atorvastatin,
lovastatin, and simvastatin); concurrent use
contraindicated. Foodqblood levels of lovastatin.
Route/Dosage
Atorvastatin
PO (Adults): 10–20 mg once daily initially; (may
start with 40 mg/day if LDL-C needs to bepby 45%);
may beqevery 2–4 wk up to 80 mg/day; Concurrent
nelfinavir therapy—Dose should not exceed 40 mg/
day; Concurrent clarithromycin, itraconazole, saquinavir/
ritonavir, darunavir/ritonavir, fosamprenavir,
or fosamprenavir/ritonavir therapy—Dose
should not exceed 20 mg/day.
PO (Children 10–17 yr): 10 mg/day initially, may be
qevery 4 wk up to 20 mg/day; Concurrent nelfinavir
therapy—Dose should not exceed 40 mg/day; Concurrent
clarithromycin, itraconazole, saquinavir/ritonavir,
darunavir/ritonavir, fosamprenavir, or fosamprenavir/
ritonavir therapy—Dose should not
exceed 20 mg/day.
Fluvastatin
PO (Adults): 20–40 mg (immediate-release) once
daily at bedtime. May beqto 40 mg twice daily (immediate-
release) or 80 mg once daily (extended-release);
Concurrent fluconazole or cyclosporine therapy—
Dose should not exceed 20 mg twice daily.
Lovastatin
PO (Adults): 20 mg once daily with evening meal. May
beqat 4-wk intervals to a maximum of 80 mg/day (immediate-
release) or 60 mg/day (extended-release);
Concurrent danazol, verapamil, or diltiazem therapy—
Initiate at 10 mg/day; do not exceed 20 mg/day;
Concurrent amiodarone therapy—Dose should not
exceed 40 mg/day.
Renal Impairment
PO (Adults): CCr 30 mL/min—Dose should not
exceed 20 mg/day unless carefully titrated.
PO (Children /Adolescents 10–17 yr): Familial
heterozygous hypercholesterolemia—10–40 mg/day
adjusted at 4-wk intervals.
Pitavastatin
PO (Adults): 2 mg once daily initially, may bequp to
4 mg depending on response. Concurrent erythromycin
therapy—Dose should not exceed 1 mg/day; Concurrent
rifampin therapy—Dose should not exceed
2 mg/day.
Renal Impairment
PO (Adults): CCr 30–60 mL/min—1 mg once
daily initially, may bequp to 2 mg daily.
Pravastatin
PO (Adults): 40 mg once daily at bedtime, may beq
after 4 wk, if needed to 80 mg once daily at bedtime);
Concurrent cyclosporine therapy—Initiate therapy
with 10 mg once daily at bedtime; may beqafter 4 wk,
if needed, to 20 mg once daily at bedtime (max dose
20 mg/day); Concurrent clarithromycin therapy—
Dose should not exceed 40 mg/day.
PO (Children 14–18 yrs): 40 mg once daily (max
dose40 mg/day).
PO (Children 8–13 yrs): 20 mg once daily (max
dose20 mg/day).
Renal Impairment
PO (Adults): CCr30 mL/min—Initiate therapy with
10 mg once daily at bedtime; may titrate at 4–wk intervals
as needed (max dose80 mg/day).
Rosuvastatin
PO (Adults): 10 mg once daily initially (range 5–20
mg initially) (20 mg initial dose may be considered for
patients with LDL-C 190 m g/dL or homozygous familial
hypercholesterolemia); dose may be adjusted at 2–
4 wk intervals, some patients may require up to 40 mg/
day, however this dose is associated withqrisk of rhabdomyolysis;
Patients with Asian ancestry—initial
dose should be 5 mg; Concurrent cyclosporine therapy—Dose should not exceed 5 mg/day; Concurrent
lopinavir/ritonavir, atazanavir/ritonavir, or simeprevir
therapy—Dose should not exceed 10 mg/day;
Concurrent gemfibrozil therapy—Dose should not
exceed 10 mg/day (avoid if possible).
PO (Children 10–17 yr): 5–20 mg once daily.
PO (Children 8–10 yr): 5–10 mg once daily.
Renal Impairment
PO (Adults): CCr 30 mL/min—5 mg once daily initially;
dose may beqbut should not exceed 10 mg/day.
Simvastatin
The 80 mg dose should be restricted to
patients who have been taking this dose
for 12 mo without evidence of muscle
toxicity.
PO (Adults): 5–40 mg once daily in the evening; if
LDL goal cannot be achieved with 40 mg/day dose, add
another lipid-lowering therapy (do notqsimvastatin
dose to 80 mg/day). Concurrent verapamil, diltiazem,
or dronedarone therapy—Dose should not exceed
10 mg/day. Concurrent amiodarone, amlodipine,
or ranolazine therapy—Dose should not
exceed 20 mg/day; Concurrent lomitapide therapy—
pdose by 50% (dose should not exceed 20 mg/day or
40 mg/day for patients who previously received 80 mg/
day chronically [for 12 mo] without evidence of myopathy).
PO (Children 10–17 yr): 10 mg once daily initially,
may beqat 4–wk intervals up to 40 mg/day. Concurrent
verapamil or diltiazem therapy—Dose should
not exceed 10 mg/day. Concurrent amiodarone, amlodipine,
or ranolazine therapy—Dose should not
exceed 20 mg/day.
Renal Impairment
PO (Adults): CCr 10 mL/min—5 mg/day initially,
titrate carefully.
Availability
Atorvastatin (generic available)
Tablets: 10 mg, 20 mg, 40 mg, 80 mg. Cost: Generic—
10 mg $33.25/100, 20 mg $48.75/100, 40 mg
$40.42/100, 80 mg $49.20/100. In combination
with: amlodipine (Caduet); see Appendix B.
Fluvastatin (generic available)
Capsules: 20 mg, 40 mg. Cost: Generic—All
strengths $113.40/30. Extended-release tablets: 80
mg. Cost: $194.69/30.
Lovastatin (generic available)
Immediate-release tablets : 10 mg, 20 mg, 40 mg.
Cost: Generic—10 mg $10.83/100, 20 mg $10.83/
100, 40 mg $16.50/100. Extended-release tablets:
20 mg, 40 mg, 60 mg. Cost: All strengths $555.98/30.
Pitavastatin (generic available)
Tablets: 1 mg, 2 mg, 4 mg. Cost: All strengths
$492.48/90.
Pravastatin (generic available)
Tablets: 10 mg, 20 mg, 40 mg, 80 mg. Cost: Generic—
20 mg $10.83/100, 40 mg $29.82/100, 80 mg
$142.06/100.
Rosuvastatin
Tablets: 5 mg, 10 mg, 20 mg, 40 mg. Cost: 5 mg
$609.27/100, 10 mg $600.47/100, 20 mg $609.27/
100, 40 mg $541.62/100.
Simvastatin (generic available)
Tablets: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg. Cost: Generic—
5 mg $7.11/100, 10 mg $10.83/100, 20 mg
$10.83/100, 40 mg $10.83/100, 80 mg $9.83/100. In
combination with: ezetimibe (Vytorin). See
Appendix B.
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