Simvastatin
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|
| Systematic (IUPAC) name |
| (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate |
| Clinical data |
| Trade names |
Zocor |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a692030 |
| Licence data |
US FDA:link |
| Pregnancy cat. |
D (AU) X (US) |
| Legal status |
Prescription Only (S4) (AU) P (UK) ℞-only (US) |
| Routes |
Oral |
| Pharmacokinetic data |
| Bioavailability |
5% |
| Protein binding |
95% |
| Metabolism |
Hepatic (CYP3A4) |
| Half-life |
2 hours for simvastatin and 1.9 hours for simvastatin acid |
| Excretion |
Renal 13%, faecal 60% |
| Identifiers |
| CAS number |
79902-63-9 Y |
| ATC code |
C10AA01 |
| PubChem |
CID 54454 |
| DrugBank |
DB00641 |
| ChemSpider |
49179 Y |
| UNII |
AGG2FN16EV Y |
| KEGG |
D00434 Y |
| ChEBI |
CHEBI:9150 Y |
| ChEMBL |
CHEMBL1064 Y |
| Chemical data |
| Formula |
C25H38O5 |
| Mol. mass |
418.566 g/mol |
SMILES
- O=C(O[C@@H]1[C@H]3C(=C/[C@H](C)C1)\C=C/[C@@H]([C@@H]3CC[C@H]2OC(=O)C[C@H](O)C2)C)C(C)(C)CC
|
InChI
-
InChI=1S/C25H38O5/c1-6-25(4,5)24(28)30-21-12-15(2)11-17-8-7-16(3)20(23(17)21)10-9-19-13-18(26)14-22(27)29-19/h7-8,11,15-16,18-21,23,26H,6,9-10,12-14H2,1-5H3/t15-,16-,18+,19+,20-,21-,23-/m0/s1 Y
Key:RYMZZMVNJRMUDD-HGQWONQESA-N Y
|
| Y (what is this?) (verify) |
Simvastatin (INN) // is a hypolipidemic drug used with exercise, diet, and weight-loss to control elevated cholesterol, or hypercholesterolemia. It is a member of the statin class of pharmaceuticals.
Simvastatin is a synthetic derivative of a fermentation product of Aspergillus terreus. The drug is marketed generically following the patent expiration, and under the trade name Zocor.
Contents
- 1 Medical uses
- 2 Adverse effects
- 3 Cost/benefit
- 4 Dose
- 5 Pharmacology
- 5.1 Interactions
- 5.2 Contraindications
- 6 Marketing
- 7 Sales
- 8 History
- 9 See also
- 10 References
- 11 External links
Medical uses[edit]
The primary uses of simvastatin are for the treatment of dyslipidemia and the prevention of cardiovascular disease.[1] It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels sufficiently.[1]
Adverse effects[edit]
Common side effects (>1% incidence) may include abdominal pain, diarrhea, indigestion, and a general feeling of weakness. Rare side effects include joint pain, memory loss, and muscle cramps.[2] Cholestatic hepatitis, hepatic cirrhosis, rhabdomyolysis (destruction of muscles and blockade of renal system) and myositis have been reported in patients receiving the drug chronically.[3] Serious allergic reactions to simvastatin are rare.[4] If the following signs of a serious allergic reaction occur seek medical attention immediately: rash, hoarsness itching/swelling, dizziness, difficulty swallowing/breathing.[4]
A type of DNA variant known as a single nucleotide polymorphism (SNP) may help predict individuals prone to developing myopathy when taking simvastatin; a study ultimately including 32,000 patients concluded the carriers of one or two risk alleles of particular SNPs[5] were at a five-fold or 16-fold increased risk, respectively.[6]
On June 8, 2011, the U.S. Food and Drug Administration (FDA) announced new safety recommendations for high-dose simvastatin (80 mg) due to muscle injury risk.[7][8]
In March 2012, the FDA updated its guidance for statin users to address reports of memory loss, liver damage, increased blood sugar, development of type 2 diabetes, and muscle injury.[9] The new guidance indicates:
- FDA has found that liver injury associated with statin use is rare but can occur.
- The reports about memory loss, forgetfulness and confusion span all statin products and all age groups. Egan says these experiences are rare but that those affected often report feeling “fuzzy” or unfocused in their thinking.
- A small increased risk of raised blood sugar levels and the development of type 2 diabetes have been reported with the use of statins.
- Some drugs interact with statins in a way that increases the risk of muscle injury called myopathy, characterized by unexplained muscle weakness or pain.
This advice has caused some controversy, and claims have been made that it is too conservative in its guidance regarding diabetes. In March 2012, Eric J. Topol, the Chief Academic Officer for Scripps Health and Director, Scripps Translational Science Institute, published an op-ed piece in the New York Times entitled 'The Diabetes Dilemma for Statin Users'[10] claiming the trial data had been misunderstood and the risk of diabetes amongst users of simvistatin, atorvastatin, and rosuvastatin was much higher.
Cost/benefit[edit]
Since its introduction, the price of lipid-lowering drugs and their benefits in atherosclerosis has been much debated. Although this has affected the other statins, simvastatin was the first statin drug to be used extensively in clinical practice.
A number of large epidemiological studies were conducted to discover which patients would benefit most from statin drugs; most studies involve simvastatin as the study drug. The most influential studies were the Scandinavian Simvastatin Survival Study (4S) and the Heart protection study (HPS).
It has been suggested that patients with one or more risk factors for cardiovascular disease (such as diabetes mellitus, hypertension, or a positive family history) can benefit from statins, even if they do not have substantially elevated cholesterol levels.[citation needed] This is the hypothetical concept of "total risk", by combining particular risk factors.
Simvastatin was introduced in the late 1980s, and since 2006 in many countries, it is available as a generic preparation. This has led to a decrease of the price of most statin drugs, and a reappraisal of the health economics of preventive statin treatment. In the UK in 2008, the typical per patient cost to the NHS of simvastatin was about £1.50 per month.[11] (40 mg/day costs UK NHS £1.37/month in 2012[12])
Dose[edit]
Simvastatin is a powerful lipid-lowering drug that can decrease low density lipoprotein (LDL) levels by up to 50%.[citation needed] It is used in doses of 5 mg up to 80 mg.
In secondary prevention, 80 mg per day reduced major cardiovascular events by an absolute rate of 1.2% compared with 20 mg per day in a randomized controlled trial.[13]
Pharmacology[edit]
Main article: Statin
|
|
This section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2012) |
All statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase, the rate-limiting enzyme of the HMG-CoA reductase pathway, the metabolic pathway responsible for the endogenous production of cholesterol. Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration, but they are less effective than the fibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration. This is a major evidence that the statins works in another way than the lowering of cholesterol (called pleiotropic effects).[14]
The drug is in the form of an inactive lactone that is hydrolyzed after ingestion to produce the active agent. It is a white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.
Interactions[edit]
Grapefruit contains furanocoumarins, notably bergamottin and 6',7'-dihydroxybergamottin, which inhibit the intestinal cytochrome P450 3A4 isoform. This, in turn, slows metabolization of simvastatin and a large number of other drugs, resulting in higher plasma levels of the drug. Due to the risk of toxicity, patients taking simvastatin should avoid intake of grapefruit and grapefruit-containing products.[15][16][17] A Finnish clinical study on the duration of grapefruit juice and simvastatin interaction was published October 2004 stating the interaction potential of high amounts of grapefruit juice dissipates within 3 to 7 days after the last grapefruit juice dose.[18]
On August 8, 2008, the FDA issued a warning of the risk of rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone. This interaction is dose-dependent with simvastatin doses exceeding 20 mg. This drug combination, especially with higher doses of simvastatin, should be avoided.[19]
On March 19, 2010, the FDA issued another statement regarding simvastatin, saying it increases the risk of muscle injury (myopathy) when taken at high doses (80 mg) or at lower doses in combination with other drugs. This conclusion is supported by the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial.[20] The highest 80-mg dose rate causes muscle damage in 61 of every 1,000 patients, according to the research, in contrast to the lower 40-mg dose, which causes muscle damage in eight of 10,000 patients.[21] The FDA warning, re-released on June 8, 2011, suggested that "Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury (myopathy)" and that "Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug."[22]
Also, a 2010 FDA review of simvastatin drug-drug interactions stated patients should not take simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone. Patients taking 10 mg of simvastatin should not take it with gemfibrozil, cyclosporine, or danazol. If taking 20 mg of simvastatin, do not take it with amiodarone or verapamil. Diltiazem should not be taken with 40 mg of simvastatin.[20] These drugs mentioned are CYP3A4 inhibitors which decrease the metabolism of simvastatin, therefore increasing the plasma activity of simvastatin, which leads to higher risk of developing rhabdomyolysis and myopathy.[4]
Contraindications[edit]
Simvastatin is contraindicated with pregnancy, breast feeding and liver disease.[4] Pregnancy must be avoided while on simvastatin due to potentially severe birth defects. Patients cannot breast feed while on simvastatin due to potentially disrupting the infant's lipid metabolism.[23] Simvastatin is also contraindicated with Amlodipine and should not exceed a dosage greater than 20 mg/day when taken alongside Amlodipine.[24]
Marketing[edit]
Simvastatin was initially marketed by Merck & Co under the trade name Zocor, but is available generically in most countries following the patent expiry. A combination of simvastatin along with ezetimibe is sold under the brand name Vytorin and is jointly marketed by Merck and Schering-Plough.
Brand names include Zocor, Zocor Heart Pro, marketed by the pharmaceutical company Merck & Co. Simlup, Simvotin, Simcard [India], Denan (Germany), Liponorm, Sinvacor, Sivastin (Italy), Lipovas (Japan), Lodales (France), Zocord (Austria and Sweden), Zimstat, Simvahexal (Australia), Lipex (Australia and New Zealand), Simvastatin-Teva, Simvacor, Simvaxon, Simovil (Israel), and others.[citation needed]
The primary U.S. patent for Zocor expired on June 23, 2006.[citation needed] Ranbaxy Laboratories (at the 80 mg strength) and Teva Pharmaceutical Industries through its Ivax Pharmaceuticals unit (at all other strengths) were given approval by the FDA to manufacture and sell simvastatin as a generic drug with 180-day exclusivity. Dr. Reddy's Laboratories also has a license from Merck & Co. to sell simvastatin as an authorized generic drug.[citation needed]
Sales[edit]
Prior to losing U.S. patent protection, simvastatin was Merck & Co.'s largest selling drug and second largest selling cholesterol lowering drug in the world; it recorded US$4.3 billion of sales in 2005.[citation needed]
Zocor had an original patent expiry date of January 2006 but was extended by the United States Patent Trademark Office (PTO) to expire on June 23, 2006.[citation needed] The PTO granted the patent extension after Merck submitted data from studies of the drug’s positive effect on children, a move typically used by drug companies to lengthen exclusivity. In the UK the patent for simvastatin had expired by 2004.[citation needed]
Ordinarily, Merck would have expected a sharp decrease in sales after the generic versions of simvastatin entered the market. However, Merck has slashed the price of Zocor dramatically in an effort to claim sales that would have otherwise gone to the generic versions.[citation needed] At least two major U.S. health insurers, UnitedHealthcare and WellPoint, are now[when?] offering Zocor to their members as generic copays.[25]
In addition, since Merck manufactures some versions of Dr. Reddy's authorized generic simvastatin,[citation needed] Merck is poised to profit from Dr. Reddy's version. An 80 mg, 30-count bottle of Dr. Reddy's simvastatin obtained July 6, 2006 states it is made by Merck Sharp & Dohme (Merck & Co.'s name outside the U.S. to avoid conflicts with Merck KGaA) in the UK, just like 80 mg Zocor, and has a Merck & Co. logo on the bottom; except for omitting the "80" on one side, the tablets are visually identical to 80 mg Zocor, including "543" on the other side which is the key part of the National Drug Code for 80 mg Zocor.[citation needed]
History[edit]
The development of simvastatin was closely linked with lovastatin. Biochemist Jesse Huff and his colleagues at Merck began researching the biosynthesis of cholesterol in the early 1950s.[26] In 1956, mevalonic acid was isolated from a yeast extract by Karl Folkers, Carl Hoffman, and others at Merck; while Huff and his associates confirmed that mevalonic acid was an intermediate in cholesterol biosynthesis.[citation needed] In 1959, the HMG-CoA reductase enzyme (a major contributor of internal cholesterol production) was discovered by researchers at the Max Planck Institute.[citation needed] This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme.[citation needed]
By 1976, Akira Endo had isolated the first inhibitor, mevastatin, from the fungus Penicillium citrinium in Sankyo, Japan.[27] In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus Aspergillus terreus. While developing and researching lovastatin, Merck scientists synthetically derived a more potent HMG-CoA reductase inhibitor from a fermentation product of Aspergillus terreus, which was designated MK-733 (later to be named simvastatin).[28]
See also[edit]
- List of drugs affected by grapefruit
References[edit]
- ^ a b The American Society of Health-System Pharmacists. "Simvastatin". Drugs.com. Retrieved 3 April 2011.
- ^ "Mylan-Simvastatin". Retrieved 2007-08-15.
- ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1431–3.
- ^ a b c d "Zocor". RxList. 14 November 2012. Retrieved 1 December 2012.
- ^ rs4149056
- ^ SEARCH Collaborative Group,, Group; Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008). "SLCO1B1 variants and statin-induced myopathy--a genomewide study" (pdf). N Engl J Med. 359 (8): 789–99. doi:10.1056/NEJMoa0801936. PMID 18650507.
- ^ "FDA announces new safety recommendations for high-dose simvastatin" (Press release). U.S. Food and Drug Administration (FDA). Retrieved 9 June 2011.
- ^ "FDA Restricts Use of High Doses of Cholesterol-Lowering Drug Zocor". Time. June 9, 2011.
- ^ "FDA Expands Advice on Statin Risks". FDA. Retrieved 12 July 2012.
- ^ Topol, Eric (March 4, 2012). "The Diabetes Dilemma for Statin Users". New York Times. Retrieved 12 July 2012.
- ^ "NHS overspends on statins". Jan 2008.
- ^ "Simvastatin 40mg tablets".
- ^ SEARCH Collaborative Group; Armitage, J; Bowman, L; Wallendszus, K; Bulbulia, R; Rahimi, K; Haynes, R; Parish, S et al. (2010). "Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial". The Lancet 376 (9753): 1658–69. doi:10.1016/S0140-6736(10)60310-8. PMC 2988223. PMID 21067805.
- ^ Pedersen, TR (2010). "Pleiotropic effects of statins: Evidence against benefits beyond LDL-cholesterol lowering". American journal of cardiovascular drugs : drugs, devices, and other interventions. 10 Suppl 1: 10–7. doi:10.2165/1158822-S0-000000000-00000. PMID 21391729.
- ^ "Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors". November 1998. Retrieved 25 September 2013.
- ^ "Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin". July 2004. Retrieved 25 September 2013.
- ^ "Cholesterol-lowering medicines, statins - Interactions". NHS. 16 April 2012. Retrieved 25 September 2013.
- ^ "Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin". October 2004. Retrieved 25 September 2013.
- ^ "Information on Simvastatin/Amiodarone". Food and Drug Administration (FDA). Retrieved 2008-09-21.
- ^ a b http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm
- ^ Steve Sternberg (2011-06-09). "Simvastatin can damage muscles in high doses". USA Today. Retrieved 2011-06-09. "The cholesterol-lowering drug simvastatin can cause severe muscle damage and should not be prescribed in high doses to patients who have taken it for less than a year or in any dose to people taking certain drugs, health officials said Tuesday. . . . Research has shown that the highest dose of simvastatin, 80 milligrams, causes muscle damage in 61 of every 1,000 patients, far higher than the eight-per-10,000 rate in patients taking a 40-milligram dose, Rosenblatt says."
- ^ "FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury". U.S. Food and Drug Administration (FDA). June 8, 2011. Retrieved 2011-06-09. "The U.S. Food and Drug Administration (FDA) is recommending limiting the use of the highest approved dose of the cholesterol-lowering medication, simvastatin (80 mg) because of increased risk of muscle damage."
- ^ "Simvastatin". LactMed. U.S. National Library of Medicine. Retrieved 1 December 2012.
- ^ "FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury". Federal Drug Administration. Retrieved 15 January 2013.
- ^ Brin, Dinah Wisenberg (2006-06-22). "Zocor Patent Expiring Means Bidding War". Associated Press. Retrieved 2006-07-09. [dead link]
- ^ Jie Jack Li (2009). Triumph of the Heart : The Story of Statins. Oxford University Press. p. 59. ISBN 0198043511.
- ^ Liao JK, Laufs U (2005). "Pleiotropic effects of statins". Annu. Rev. Pharmacol. Toxicol. 45: 89–118. doi:10.1146/annurev.pharmtox.45.120403.095748. PMC 2694580. PMID 15822172.
- ^ Olivia Williams, Anne-Marie Jacks, Jim Davis, Sabrina Martinez (1998). "Case 10: Merck(A): Mevacor". In Allan Afuah. Innovation Management - Strategies, Implementation, and Profits. Oxford University Press. ISBN 0-19-511346-2. Retrieved 2006-07-19.
External links[edit]
- Simvastatin RxList.com
- U.S. National Library of Medicine: Drug Information Portal - Simvastatin
- "Zocor Prescribing information". Merck & Co.
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Lipid modifying agents (C10)
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Cholesterol absorption inhibitors, NPC1L1
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| Liver |
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Statins (HMG-CoA reductase, LDL)
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- Simvastatin#
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- Fluvastatin
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- Pravastatin
- Rosuvastatin
- Cerivastatin‡
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mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
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k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
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m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
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Merck & Co., Inc.
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Note: 21-Hydroxylase inhibitors may also affect androgen levels as they prevent metabolism of androgen steroid precursors.
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- Isoconazole
- Ketoconazole
- L-39
- Liarozole
- LY-207,320
- MDL-27,302
- Miconazole
- Mifepristone
- Orteronel
- Pioglitazone
- Rosiglitazone
- Spironolactone
- Stanozolol
- SU-10,603
- TGF-β
- Tioconazole
- Troglitazone
- VN/87-1
- YM116
|
|
|
3β-HSD
|
- 4-MA
- Azastene
- Cyanoketone
- Danazol
- Epostane
- Genistein
- Gestrinone
- Metyrapone
- Oxymetholone
- Pioglitazone
- Rosiglitazone
- Trilostane
- Troglitazone
|
|
|
17β-HSD
|
|
|
|
Aromatase
|
- 1,4,6-Androstatriene-3,17-dione
- 4-Androstene-3,6,17-trione
- 4-Cyclohexylaniline
- 4-Hydroxytestosterone
- 5α-DHNET
- Abyssinone II
- Aminoglutethimide
- Anastrozole
- Ascorbic acid (Vitamin C)
- Atamestane
- Bifonazole
- CGP-45,688
- CGS-47,645
- Clotrimazole
- DHT
- Difeconazole
- Econazole
- Exemestane
- Fadrozole
- Fenarimol
- Finrozole
- Formestane
- Imazalil
- Isoconazole
- Ketoconazole
- Letrozole
- Liarozole
- MEN-11066
- Miconazole
- Minamestane
- Nimorazole
- NKS01
- ORG-33,201
- Penconazole
- Plomestane
- Prochloraz
- Propioconazole
- Pyridoglutethimide
- Rogletimide
- Rotenone
- Talarozole
- Testolactone
- Tioconazole
- Triadimefon
- Triadimenol
- Troglitazone
- Vorozole
- YM511
- Zinc
Note: 5α-reductase and 21-hydroxylase inhibitors may also affect estrogen levels as they prevent metabolism of estrogen steroid precursors.
|
|
|
| Other |
|
Endogenous
|
- Estrogens: 5α-Androstane-3β,17β-diol
- DHEA
- Estetrol
- Estradiol
- Estriol
- Estrone
- Antiestrogens: 2-Hydroxyestrone
- 16-Hydroxyestrone
- Precursors: Cholesterol
- 22R-Hydroxycholesterol
- 20α,22R-Dihydroxycholesterol
- Pregnenolone
- 17-Hydroxypregnenolone
- Progesterone
- 17-Hydroxyprogesterone
- Cortodoxone/Deoxycortisol
- DHEA
- DHEA sulfate
- 16-Hydroxy-DHEA
- 16-Hydroxy-DHEA sulfate
- Androstenediol
- Androstenedione
- 16-Hydroxyandrostenedione
- Testosterone
|
|
|
Indirect
|
- Androgens/Antiandrogens (see here)
- Calcitriol (a form of Vitamin D)
- GnRH agonists/antagonists (see here)
- Gonadotropins//Antigonadotropins (see here)
- Plasma proteins (SHBG, ABP, Albumin)
- Progestogens/Antiprogestins (see here)
- Prolactin
|
|
|
Procedures
|
- Adrenalectomy
- Hypophysectomy
- Oophorectomy
- Orchiectomy
|
|
|
