Simvastatin
Encyclopedia
Simvastatin (icon) (Zocor and generics) is a hypolipidemic drug
used to control elevated cholesterol, or hypercholesterolemia
. Simvastatin is a member of the statin
class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus
.
and the prevention of cardiovascular disease
. It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.
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 that carriers of one or two risk allele
s of particular SNPs rs4149056 were at 5x or 16x increased risk, respectively.
On June 8, 2011, the FDA announced new safety recommendations for high-dose simvastatin (80 mg) due to muscle injury risk.
. Although this has affected the other statin
s, 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.
Simvastatin was introduced in the late 1980s, and in many countries it is now 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 approx £1.50 per month.
-lowering drug that can decrease low density lipoprotein
(LDL) levels by up to 50%. It is used in doses of 5 mg up to 80 mg. Higher doses (160 mg) have been found to be too toxic, while giving only minimal benefit in terms of lipid lowering.
In secondary prevention, 80 mg per day reduced major cardiovascular events by an absolute rate of 1.2% compared to 20 mg per day in a randomized controlled trial
.
, 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.
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
.
contains furanocoumarin
s, 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.
On August 8, 2008, the U.S. Food and Drug Administration (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.
On March 19, 2010 the FDA issued another statement regarding simvastatin that said 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. The highest 80 mg dose rate causes muscle damage in 61 out of every 1,000 patients, according to the research, in contrast to the lower 40 mg dose which causes muscle damage in 8 out of every 10,000 patients. 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."
Also, a 2010 FDA review of Simvastatin drug-drug interactions stated that patients should not take a 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. 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.
Simvastatin is contraindicated in pregnancy and liver disease.
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.
The primary U.S. patent for Zocor expired on June 23, 2006. 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.
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. 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.
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. At least two major U.S. health insurers, UnitedHealthcare
and WellPoint
, are now offering Zocor to their members as generic copays.
In addition, since Merck manufactures some versions of Dr. Reddy's authorized generic simvastatin, 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.
. Biochemist Jesse Huff and his colleagues at Merck
began researching the biosynthesis of cholesterol in the early 1950s. 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. In 1959, the HMG-CoA reductase
enzyme (a major contributor of internal cholesterol production) was discovered by researchers at the Max Planck Institute. This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme.
By 1976, Akira Endo had isolated the first inhibitor (Compactin, ML-236B) from the fungus
Penicillium citrinium
in Sankyo
, Japan
. 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).
Hypolipidemic agent
Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs or agents.- Classes of hypolipidemic drugs :...
used to control elevated cholesterol, or hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
. Simvastatin is a member of the statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus
Aspergillus terreus
Aspergillus terreus is a fungus commonly used in industry to produce important organic acids, such as itaconic acid and cis-aconitic acid. It was also the initial source for the drug mevinolin , a drug for lowering serum cholesterol. A. terreus may cause opportunistic infection in people with...
.
Medical uses
The primary uses of simvastatin is for the treatment of dyslipidemiaDyslipidemia
Dyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...
and the prevention of cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.
Adverse effects
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. Cholestatic hepatitis, hepatic cirrhosis, rhabdomyolysis and myositis have been reported in patients receiving the drug chronically.A type of DNA variant known as a single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
(SNP) may help predict individuals prone to developing myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
when taking simvastatin; a study ultimately including 32,000 patients concluded that carriers of one or two risk allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s of particular SNPs rs4149056 were at 5x or 16x increased risk, respectively.
On June 8, 2011, the FDA announced new safety recommendations for high-dose simvastatin (80 mg) due to muscle injury risk.
Cost / benefit
Since its introduction, there has been a large debate surrounding the price for lipid-lowering treatment and its benefits with regard to atherosclerosisAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. Although this has affected the other statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s, simvastatin was the first statin drug to be used extensively in clinical practice.
A number of large epidemiological
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
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
Scandinavian Simvastatin Survival Study
The Scandinavian Simvastatin Survival Study is a multicenter clinical trial that was performed in 1990s in Scandinavia....
(4S) and the Heart protection study
Heart Protection Study
The Heart Protection Study was a large randomized controlled trialrun by the Clinical Trial Service Unit, and fundedby the Medical Research Council and the British Heart Foundation in the United Kingdom...
(HPS).
It has been suggested that patients with one or more risk factors for cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
(such as diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
or a positive family history) can benefit from statins even if they do not have substantially elevated cholesterol levels.
Simvastatin was introduced in the late 1980s, and in many countries it is now available as a generic
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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 approx £1.50 per month.
Dose
Simvastatin is a powerful lipidLipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
-lowering drug that can decrease low density lipoprotein
Low density lipoprotein
Low-density lipoprotein is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of cholesterol within the water-based bloodstream...
(LDL) levels by up to 50%. It is used in doses of 5 mg up to 80 mg. Higher doses (160 mg) have been found to be too toxic, while giving only minimal benefit in terms of lipid lowering.
In secondary prevention, 80 mg per day reduced major cardiovascular events by an absolute rate of 1.2% compared to 20 mg per day in a randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
.
Pharmacology and dosage
All statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductaseHMG-CoA reductase
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...
, the rate-limiting enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
of the HMG-CoA reductase pathway
HMG-CoA reductase pathway
The mevalonate pathway or HMG-CoA reductase pathway or mevalonate-dependent route or isoprenoid pathway, is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria...
, the metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
responsible for the endogenous production of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
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.
The drug is in the form of an inactive lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
that is hydrolyzed
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
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
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
, methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
and ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
.
Interactions
GrapefruitGrapefruit
The grapefruit , is a subtropical citrus tree known for its sour fruit, an 18th-century hybrid first bred in Barbados. When found, it was named the "forbidden fruit"; it has also been misidentified with the pomelo or shaddock , one of the parents of this hybrid, the other being sweet orange The...
contains furanocoumarin
Furanocoumarin
Furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. They are biosynthesized partly through the phenylpropanoid pathway and the mevalonate pathway, which is biosynthesized by a coupling of dimethylallyl pyrophosphate and 7-hydroxycoumarin...
s, notably bergamottin
Bergamottin
Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits...
and 6',7'-dihydroxybergamottin, which inhibit the intestinal cytochrome P450 3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
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.
On August 8, 2008, the U.S. Food and Drug Administration (FDA) issued a warning of the risk of rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
, which can lead to kidney failure or death, when simvastatin is used with amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
. This interaction is dose-dependent with simvastatin doses exceeding 20 mg. This drug combination especially with higher doses of simvastatin should be avoided.
On March 19, 2010 the FDA issued another statement regarding simvastatin that said it increases the risk of muscle injury (myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
) 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. The highest 80 mg dose rate causes muscle damage in 61 out of every 1,000 patients, according to the research, in contrast to the lower 40 mg dose which causes muscle damage in 8 out of every 10,000 patients. 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."
Also, a 2010 FDA review of Simvastatin drug-drug interactions stated that patients should not take a 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. 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.
Simvastatin is contraindicated in pregnancy and liver disease.
Marketing
Reference: Drug Discovery Today editorial, 2005.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
Ezetimibe
Ezetimibe is a drug that lowers cholesterol. It acts by decreasing cholesterol absorption in the intestine. It may be used alone , when other cholesterol-lowering medications are not tolerated, or together with statins when statins alone do not control cholesterol.Even though ezetimibe decreases...
is sold under the brand name Vytorin and is jointly marketed by Merck and Schering-Plough
Schering-Plough
Schering-Plough Corporation was a United States-based pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough to form Schering-Plough. On November 4, 2009 Merck & Co...
.
Brand names include Zocor, Zocor Heart Pro, marketed by the pharmaceutical company
Pharmaceutical company
The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
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.
The primary U.S. patent for Zocor expired on June 23, 2006. Ranbaxy Laboratories
Ranbaxy Laboratories
Ranbaxy Laboratories Limited is a pharmaceutical company that was incorporated in India in 1961. The company went public in 1973 and Japanese pharmaceutical company Daiichi Sankyo gained majority control in 2008...
(at the 80 mg strength) and Teva Pharmaceutical Industries
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...
through its Ivax Pharmaceuticals unit (at all other strengths) were given approval by the FDA to manufacture and sell simvastatin as a generic drug
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
with 180-day exclusivity. Dr. Reddy's Laboratories
Dr. Reddy's Laboratories
Dr. Reddy's Laboratories Ltd. is an integrated pharmaceutical company focused on providing medicines through its three business segments: Global Generics segment, Pharmaceutical Services and Active Ingredients segment and Proprietary Products segment. The company was founded by Dr...
also has a license from Merck & Co. to sell simvastatin as an authorized generic drug.
Sales
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.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. 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.
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. At least two major U.S. health insurers, UnitedHealthcare
UnitedHealth Group
UnitedHealth Group Incorporated is a diversified health and "well-being" company. Headquartered in Minnetonka, Minnesota, UnitedHealth Group offers a spectrum of products and services through two operating businesses: United Healthcare and Optum. Through its family of subsidiaries and divisions,...
and WellPoint
WellPoint
WellPoint, Inc. is the largest health plan company in the Blue Cross and Blue Shield Association. It was formed when WellPoint Health Networks, Inc. merged into Anthem, Inc., with the surviving Anthem adopting the name, WellPoint, Inc...
, are now offering Zocor to their members as generic copays.
In addition, since Merck manufactures some versions of Dr. Reddy's authorized generic simvastatin, 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
Merck KGaA
Merck KGaA is a German chemical and pharmaceutical company. Merck, also known as “German Merck” and “Merck Darmstadt”, was founded in Darmstadt, Germany, in 1668, making it the world's oldest operating chemical and pharmaceutical company. The company was privately owned until going public in 1995...
) 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
National Drug Code
The National Drug Code is a unique product identifier used in the United States for drugs intended for human use. The Drug Listing Act of 1972 requires registered drug establishments to provide the Food and Drug Administration with a current list of all drugs manufactured, prepared, propagated,...
for 80 mg Zocor.
History
The development of simvastatin was closely linked with lovastatinLovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
. Biochemist Jesse Huff and his colleagues at Merck
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
began researching the biosynthesis of cholesterol in the early 1950s. In 1956, mevalonic acid
Mevalonic acid
Mevalonic acid is a key organic compound in biochemistry. The anion of mevalonic acid, the predominant form in biological media, is known as mevalonate. This compound is of major pharmaceutical importance...
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. In 1959, the HMG-CoA reductase
HMG-CoA reductase
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...
enzyme (a major contributor of internal cholesterol production) was discovered by researchers at the Max Planck Institute. This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme.
By 1976, Akira Endo had isolated the first inhibitor (Compactin, ML-236B) from the fungus
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
Penicillium citrinium
Penicillium
Penicillium is a genus of ascomycetous fungi of major importance in the natural environment as well as food and drug production. Members of the genus produce penicillin, a molecule that is used as an antibiotic, which kills or stops the growth of certain kinds of bacteria inside the body...
in Sankyo
Sankyo
means "third one" in Japanese. It may refer to:, a Japanese pharmaceutical company, a Japanese pharmaceutical company and a successor of Sankyo Co. since 2005.* A principle in Aikido referred to as "third teaching"...
, Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
. In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus Aspergillus terreus
Aspergillus
Aspergillus is a genus consisting of several hundred mold species found in various climates worldwide. Aspergillus was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli...
. 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).