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HMG COA reductase inhibitors, other:

Overview

Mechanism of action: Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Comparative efficiency and pharmacology of the statins.
Drug Reduction in LDL-C (%) Increase in HDL-C (%) Reduction in TG (%) Reduction in TC (%) Metabolism Protein binding (%) T1/2 (h) Hydrophilic
Atorvastatin 26 - 60 5 - 13 17 - 53 25 - 45 CYP3A4 98 13-30 No
Lovastatin 21 - 42 2 - 10 6 - 27 16 - 34 CYP3A4 >95 2 - 4 No
Simvastatin 26 - 47 8 - 16 12 - 34 19 - 36 CYP3A4 95 - 98 1 - 3 No
Fluvastatin 22 - 36 3 - 11 12 - 25 16 - 27 CYP2C9 98 0,5 - 3,0 No
Rosuvastatin 45 - 63 8 - 14 10 - 35 33 - 46 CYP2C9 88 19 Yes
Pravastatin 22 - 34 2 - 12 15 - 24 16 - 25 Sulfation 43 - 67 2 - 3 Yes
Source: Vaughan CJ, Gotto AM Jr. Update on statins: 2003. Circulation. 2004 Aug 17;110(7):886-92.

Comparison of lipophilicity of HMG-CoA Reductase Inhibitors at pH 7.4
Cerivastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin Pravastatin
Log D Class 1,50-1,75 1,50-1,75 1,00-1,25 1,00-1,25 -0,25-(-0,50) -0,75-(-1,0)
          Hydrophilic Hydrophilic
White CM. A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol. 2002 Sep;42(9):963-70.
Atorvastatin (Lipitor ®) Fluvastatin (Lescol ®)
Lovastatin (Mevacor ®) pitavastatin - (LIVALO®
Pravastatin (Pravachol ®) Rosuvastatin (Crestor ®)
Simvastatin (Zocor ®)  

Combination products

Advicor ® (lovastatin + niacin SR) LIPTRUZET™ (ezetimibe and atorvastatin)
Vytorin ® (simvastatin +ezetimibe)  

Other

alirocumab injection - PRALUENT ® evolocumab - REPATHA ™ injection
ezetimibe (Zetia ®) Niacin (Vitamin B3 )

Adult Treatment Panel (ATP) III Analysis

Adult Treatment Panel (ATP) III Calc Impact of drug therapy
Please see package insert for additional information and possible updates. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.    [  Read the disclaimer    |   <<Back     ]

Atorvastatin (Lipitor ®)  top of page

Supplied10 mg, 20 mg, 40 mg, 80 mg
Dosing
Hyperlipidemias:  Adults:  Oral: Initial: 10-20 mg once daily.  Patients requiring >45% reduction in LDL-C may be started at 40 mg once daily.  Range: 10 to 80 mg once daily.
Adjustments should be made at intervals of 2-4 weeks.


Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or a Combination of Ritonavir plus Saquinavir or Lopinavir plus Ritonavir
In patients taking cyclosporine, therapy should be limited to LIPITOR 10 mg once daily. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of ritonavir plus saquinavir or lopinavir plus ritonavir, for doses of LIPITOR exceeding 20 mg, appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPITOR is employed

Fluvastatin (Lescol ®) top of page

Supplied: Capsule: 20 mg, 40 mg. Tablet, extended release (Lescol® XL): 80 mg

Dosing: Dyslipidemia: Oral: (Adults): Patients requiring >/= 25% decrease in LDL-C: 40 mg capsule once daily in the evening, 80 mg XL tablet once daily (anytime), or 40 mg capsule twice daily. Patients requiring <25% decrease in LDL-C: Initial: 20 mg capsule once daily in the evening; may increase based on tolerability and response to a maximum recommended dose of 80 mg/day, given in 2 divided doses (capsule) or as a single daily dose (XL tablet).

Lovastatin (Mevacor ®) top of page

SuppliedTablet: 10 mg, 20 mg, 40 mgTablet, extended release: 20 mg, 40 mg, 60 mg
Dosing
Dyslipidemia: Oral:  (Adults): Initial: 20 mg with evening meal, then adjust at 4-week intervals; maximum: 80 mg/day immediate release tablet or 60 mg/day extended release tablet.

Dosage modification/limits based on concurrent therapy:  Cyclosporine and other immunosuppressant drugs: Initial dose: 10 mg/day with a maximum recommended dose of 20 mg/day.
Concurrent therapy with fibrates, danazol, and/or lipid-lowering doses of niacin (>1 g/day): Maximum recommended dose: 20 mg/day. Concurrent use with fibrates should be avoided unless risk to benefit favors use.  Concurrent therapy with amiodarone or verapamil: Maximum recommended dose: 40 mg/day of regular release or 20 mg/day with extended release.

Pravastatin (Pravachol ®) top of page

Supplied 10 mg, 20 mg, 40 mg, 80 mg
Dosing
Hyperlipidemias: Oral:  (Adults): Initial: 40 mg once daily; titrate dosage to response (usual range: 10-80 mg) (maximum dose: 80 mg once daily).

Dosage adjustment based on concomitant cyclosporine: Oral: Initial: 10 mg/day, titrate with caution (maximum dose: 20 mg/day).

Rosuvastatin (Crestor ®) top of page

Supplied:  5 mg, 10 mg, 20 mg, 40 mg

Dosing
Hypercholesterolemia; mixed dyslipidemia: Oral: (Adults):  Initial dose: 10 mg once daily (20 mg in patients with severe hypercholesterolemia).   Conservative dosing: Patients requiring less aggressive treatment or predisposed to myopathy (including patients of Asian descent): 5 mg once daily.   Titration: After 2 weeks, may be increased by 5-10 mg once daily; dosing range: 5 to 40 mg/day (maximum dose: 40 mg once daily).

Dosage adjustment for persistent, unexplained proteinuria while on 40 mg/day: Reduce dose and evaluate causes.

Use with Concomitant Therapy
Patients taking cyclosporine
The dose of CRESTOR should not exceed 5 mg once daily

Patients taking gemfibrozil
Initiate CRESTOR therapy with 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once daily.

Patients taking lopinavir and ritonavir or atazanavir and ritonavir
Initiate CRESTOR therapy with 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once daily

Simvastatin (Zocor ®) top of page

Dosing
Simvastatin Dose Limitations
When used with simvastatin, the following medications can raise the levels of simvastatin in the body and increase the risk of myopathy. Taking no more than the recommended dose of simvastatin with these medications will help keep simvastatin levels in the body at a safer level.
 

Previous simvastatin label

New simvastatin label

Avoid simvastatin with:
  • Itraconazole
  • Ketoconazole
  • Erythromycin
  • Clarithromycin
  • Telithromycin
  • HIV protease inhibitors
  • Nefazodone
Contraindicated with simvastatin:
  • Itraconazole
  • Ketoconazole
  • Posaconazole (New)
  • Erythromycin
  • Clarithromycin
  • Telithromycin
  • HIV protease inhibitors
  • Nefazodone
  • Gemfibrozil
  • Cyclosporine
  • Danazol
Do not exceed 10 mg simvastatin daily with:
  • Gemfibrozil
  • Cyclosporine
  • Danazol
Do not exceed 10 mg simvastatin daily with:
  • Amiodarone
  • Verapamil
  • Diltiazem
(Note: These drugs are contraindicated with Simcor as Simcor is only available with 20 mg or 40 mg of simvastatin.)
Do not exceed 20 mg simvastatin daily with:
  • Amiodarone
  • Verapamil
Do not exceed 20 mg simvastatin daily with:
  • Amlodipine (New)
  • Ranolazine (New)
Do not exceed 40 mg simvastatin daily with:
  • Diltiazem
 
Avoid large quantities of grapefruit juice (>1 quart daily) Avoid large quantities of grapefruit juice (>1 quart daily




Oral: (Adults):  [See dosage restrictions above]
Prevention of cardiovascular events, hyperlipidemias: Oral: 20-40 mg once daily in the evening; range: 5 to 80 mg/day.
Homozygous familial hypercholesterolemia: Oral: 40 mg once daily in the evening or 80 mg/day (given as 20 mg, 20 mg, and 40 mg evening dose). 
Patients requiring only moderate reduction of LDL-cholesterol: May be started at 10 mg once daily
Patients requiring reduction of >45% in low-density lipoprotein (LDL) cholesterol: May be started at 40 mg once daily in the evening. 
Patients with CHD or at high risk for CHD: Dosing should be started at 40 mg once daily in the evening; simvastatin may be started simultaneously with diet.

Dosage adjustment for simvastatin with concomitant medications:  Cyclosporine or danazol: Patient must first demonstrate tolerance to simvastatin >/= 5 mg once daily: Initial: 5 mg, should not exceed 10 mg/day.  Fibrates or niacin: Dose should not exceed 10 mg/day. Amiodarone or verapamil: Dose should not exceed 20 mg/day.


Mechanism Of Action
Simvastatin is a prodrug and is hydrolyzed to its active beta-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

Supplied 5 mg, 10 mg, 20 mg, 40 mg, 80 mg

Combination products:

Advicor ®  (lovastatin + niacin SR)  top of page

Indicated for the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

Dosing (Adults)
Usual initial dose: 500 mg/20 mg. The dose of Advicor should not be increased by more than 500 mg daily (based on the niacin component) every 4 weeks. Doses > 2000 mg/40 mg daily are not recommended.

Supplied: 20/500, 20/750mg, 20/1000mg tablet.

LIPTRUZET™ (ezetimibe and atorvastatin)  top of page

Drug UPDATES:  LIPTRUZET™ (ezetimibe and atorvastatin) tablets for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2013

Mechanism of Action
LIPTRUZET
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. LIPTRUZET contains ezetimibe and atorvastatin, two lipid-lowering compounds with complementary mechanisms of action.

Ezetimibe
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production.

Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins [see Clinical Studies (14)].

Atorvastatin
In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.


INDICATIONS AND USAGE
LIPTRUZET, which contains a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet to:
reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. (1.1)
reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments. (1.2)

Limitations of Use
No incremental benefit of LIPTRUZET on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established. LIPTRUZET has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias

DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The dosage range of LIPTRUZET is 10/10 mg/day to 10/80 mg/day. The recommended starting dose of LIPTRUZET is 10/10 mg/day or 10/20 mg/day. LIPTRUZET can be administered as a single dose at any time of the day, with or without food. The recommended starting dose for patients who require a larger reduction in LDL-C (greater than 55%) is 10/40 mg/day. After initiation and/or upon titration of LIPTRUZET, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly.

Patients should swallow LIPTRUZET tablets whole. Tablets should not be crushed, dissolved, or chewed.

2.2 Patients with Homozygous Familial Hypercholesterolemia
The dosage of LIPTRUZET in patients with homozygous familial hypercholesterolemia is 10/40 mg/day or 10/80 mg/day. LIPTRUZET should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

2.3 Coadministration with Other Drugs
Bile Acid Sequestrants
Dosing of LIPTRUZET should occur either =2 hours before or =4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.11)].

Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors
In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with LIPTRUZET should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing LIPTRUZET and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with LIPTRUZET should be limited to 10/20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPTRUZET is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with LIPTRUZET should be limited to 10/40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPTRUZET is employed. [See Warnings and Precautions (5.1) and Drug Interactions (7).]

Other Concomitant Lipid-Lowering Therapy
The combination of LIPTRUZET and gemfibrozil is not recommended

HOW SUPPLIED: Tablets (ezetimibe mg/atorvastatin mg): 10/10, 10/20, 10/40, 10/80.

Vytorin ®  (simvastatin + ezetimibe ) top of page

HMG-CoA reductase inhibitor + cholesterol absorption inhibitor.

Dosing (Adults)
Usual initial dose: Ezetimibe 10 mg and simvastatin 20 mg once daily in the evening. Patients who require >55% reduction in LDL-C: Initial: Ezetimibe 10 mg and simvastatin 40 mg once daily.

Renal dosing: In severe dysfunction, start only if patient tolerates 5 mg daily of simvastatin. Monitor closely.

Supplied: ( Ezetimibe / simvastatin) 10/10 , 10/20, 10/40, 10/80.

Other:

alirocumab injection - PRALUENT ®-   top of page


Drug UPDATES:  PRALUENT ®- alirocumab injection, solution
[Drug information  /  PDF]  led  Click link for the latest monograph
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2015

Mechanism of Action: Alirocumab is a human monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.

INDICATIONS AND USAGE:  1.1 Primary Hyperlipidemia
PRALUENT® is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.

1.2 Limitations of Use
The effect of PRALUENT on cardiovascular morbidity and mortality has not been determined.


HOW SUPPLIED:
PRALUENT is a clear, colorless to pale yellow solution available as follows:
Injection: Single-dose pre-filled pen
75 mg/mL
150 mg/mL

Injection: Single-dose pre-filled syringe
75 mg/mL
150 mg/mL

evolocumab - REPATHA™ injection  top of page


Drug UPDATES:  REPATHA ™- evolocumab injection, solution
[Drug information  /  PDF]led    Click link for the latest monograph
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2015

Mechanism of Action: Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.

INDICATIONS AND USAGE:
 1.1 Primary Hyperlipidemia
REPATHA™ is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).

1.2 Homozygous Familial Hypercholesterolemia
REPATHA is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

1.3 Limitations of Use
The effect of REPATHA on cardiovascular morbidity and mortality has not been determined.


HOW SUPPLIED:
REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution available as follows:
Injection: 140 mg/mL solution in a single-use prefilled syringe
Injection: 140 mg/mL solution in a single-use prefilled SureClick® autoinjector

ezetimibe (Zetia ®)  top of page

Selective cholesterol absorption inhibitor.
Adult (usual): Hypercholesterolemia: 10 mg po qd.

Moderate reductions in low-density lipoprotein (LDL) cholesterol (less than 20%) have been reported with monotherapy in patients with hypercholesterolemia. As add-on therapy, it may enable reduced doses of statins. The drug is approved for primary hypercholesterolemia, for homozygous familial hypercholesterolemia (combined with atorvastatin or simvastatin), and for homozygous sitosterolemia.

Supplied: 10 mg tablet.

Niacin  (Vitamin B3 ) top of page


Hyperlipidemia:
Nicotinic acid and nicotinamide are the two common forms of the vitamin most often referred to as niacin. OTC preparations that are marketed as causing "no flush" may have no free nicotinic acid and are ineffective in treating dyslipidemia.

Dosing (Adults)
Regular release formulation (Niacor®): Initial: 250 mg once daily (with evening meal); increase frequency and/or dose every 4-7 days to desired response or first-level therapeutic dose (1.5-2 g/day in 2-3 divided doses); after 2 months, may increase at 2- to 4-week intervals to 3 g/day in 3 divided doses

Extended release formulation (Niaspan®): 500 mg at bedtime for 4 weeks, then 1 g at bedtime for 4 weeks; adjust dose to response and tolerance; can increase to a maximum of 2 g/day, but only at 500 mg/day at 4-week intervals.

Administer with food. Administer Niaspan® at bedtime. Niaspan® tablet strengths are not interchangeable. When switching from immediate release tablet, initiate Niaspan® at lower dose and titrate.
MONITORING— Blood glucose; liver function tests (dyslipidemia, high dose, prolonged therapy) pretreatment and every 6-12 weeks for first year then periodically; lipid profile.

®  top of page

 

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Disclaimer

Listed dosages are for - Adult patients ONLY. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. GlobalRPH does not directly or indirectly practice medicine or provide medical services and therefore assumes no liability whatsoever of any kind for the information and data accessed through the Service or for any diagnosis or treatment made in reliance thereon.

David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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