Escitalopram
Encyclopedia
Escitalopram is an antidepressant
of the selective serotonin reuptake inhibitor
(SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder and generalized anxiety disorder. Escitalopram is the (S)-stereoisomer (enantiomer
) of the earlier Lundbeck
drug citalopram
, hence the name escitalopram. Escitalopram is noted for its high selectivity with serotonin reuptake inhibition
. Its side effects
are typical for the SSRI class.
Only one independent study has shown that Escitalopram is more effective than citalopram, but in October 2011 it was reported that the company that sponsored the study had links to Lundbeck, the makers. The similarity between Escitalopram and citalopram has led to accusations of 'evergreening
', an accusation that Lundbeck has rejected.
in adults. There is some evidence favouring escitalopram over the antidepressants citalopram
and fluoxetine
in the first two weeks of major depression. Concerns of sponsorship bias with the studies is however noted. In another review escitalopram and sertraline
had the highest rate of efficacy and acceptability among adults receiving treatment for major depression with second-generation antidepressants.
profile of escitalopram is similar to that of other SSRIs. For example, according to the FDA analysis of depression trials common side effects for the highest approved dose of escitalopram are insomnia (14% vs. 4% for placebo), constricted pupils (15% vs. 5% for placebo), dry mouth (9% vs 3% for placebo), somnolence
(9% vs 1% for placebo), dizziness (7% vs 2% for placebo), sweating (8% vs 1% for placebo), constipation (6% vs 1% for placebo), fatigue (6% vs 2% for placebo) and indigestion (6% vs. 1% for placebo). Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido
, delayed ejaculation
, genital anesthesia, and anorgasmia
. Although usually reversible upon discontinuation, these sexual side effects can last for months or years after the drug has been completely withdrawn. This is known as Post SSRI Sexual Dysfunction
. SSRI can rarely cause extrapyramidal side effects including akathisia
through the indirect inhibition of dopamine
.
Escitalopram is not associated with significant weight gain. For example, 0.6 kg mean weight change after 6 months of treatment with escitalopram for depression was insignificant and similar to that with placebo (0.2 kg). 1.4–1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression, and generalized anxiety disorder. A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain. Escitalopram may help reduce weight in those treated for binge eating
associated obesity
.
An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications. Similarly, the UK MHRA
data indicate an 80% increase of suicide-related events, not reaching statistical significance
, in the escitalopram vs placebo patients. The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients. A single case report
described a patient developing suicidal ideations after beginning treatment with escitalopram, and suicidal ideation disappearing after stopping the treatment.
Escitalopram should be taken with caution when using St John's wort
. Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole
. The authors of this study, employed by Lundbeck, suggested that this increase is unlikely to be of clinical concern Caution should be used when taking cough medicine containing dextromethorphan
(DXM) as serotonin syndrome
, liver damage, and other negative side effects have been reported.
s such as "electric shock" sensations (also known as "brain shivers" or "brain zaps"), dizziness
, acute depressions and irritability
,bladder control issues, as well as heightened senses of akathisia
.
, hypertonia
and clonus
may occur in some cases. Plasma escitalopram concentrations are usually in a range of 20-80 μg/L in therapeutic situations and may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolizers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.
Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin
by blocking the reuptake
of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market escitalopram has the highest affinity for the human serotonin transporter
(SERT). The enantiomer of escitalopram ((R)-citalopram) counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram is a more potent antidepressant than citalopram, which is a mixture of escitalopram and (R)-citalopram.
In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.
Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram, and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that R-citalopram decreases binding of escitalopram to the transporter. Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.
In vitro studies using human liver microsomes indicated that CYP3A4
and CYP2C19
are the primary isozymes involved in the N-demethylation of escitalopram. The resulting metabolites, desmethylescitalopram and didesmethylescitalopram, are significantly less active and their contribution to the overall action of escitalopram is negligible.
and Forest Laboratories
. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram
, which has similar pharmacology.
The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. Escitalopram can be considered an example of "evergreening
" (also called "lifecycle management")– the long-term strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an enantiopure compound
of the racemic mixture citalopram
, used for the same indication, and for that reason it required less investment and less time to develop. Two years after escitalopram's launch, when the patent on citalopram expired, the escitalopram sales successfully made up for the loss. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva. On July 14 of that year, however, the U.S. District Court of Delaware
decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.
In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram. This pushed the patent expiry from December 7, 2009 to to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date is March 14, 2012.
, aggressive pharmaceutical marketing
of escitalopram by Forest Laboratories has been controversial: the generic alternatives to the drug are cheaper, but a substantial number of doctors continue to prescribe the more expensive proprietary drug. The United States Senate Special Committee on Aging
has released portions of the "Lexapro Fiscal 2004 Marketing Plan" which gives some of the details of the plans to promote use of the drug by doctors.
In 2004, two separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers, one by a non-practicing physician named Joseph Piacentile, and the other by a Forest salesman named Christopher Gobble who was disturbed by what he witnessed at Forest.
In February 2009, these two suits received support from the US Attorney for Massachusetts and were combined into one. Eleven states and the District of Columbia have also filed notices of intention to intervene as plaintiffs in the action. At the time, these drugs were approved only for use by adults and the application for use of citalopram in children was specifically rejected by the FDA. Although it is not illegal for physicians to prescribe a medicine for an off-label use not approved by the Food and Drug Administration, it is illegal for a manufacturer to promote the drugs for such uses. The government alleged that a research study showing lack of effectiveness when taken by children was concealed from its own medical advisers and sales personnel, as well as from researchers who conducted a study financed by the company. From 2001 to 2004, Forest heavily promoted results from another clinical trial it had financed which showed the drug was effective. Federal prosecutors also allege that the company has paid kickbacks to doctors to induce them to prescribe the medicines to children. The kickbacks allegedly included baseball tickets, a $1000 certificate to one of the most expensive New York restaurants, and paid vacations. Further, the complaint alleges that in September 2004, a Forest executive testified before Congress: “I want to emphasize that, because the FDA has not approved pediatric labeling of our products, Forest has always been scrupulous about not promoting the pediatric use of our antidepressant drugs, Celexa and Lexapro. That is the law and we follow it.” It is also alleged that the company conducted so-called "seeding studies" that were, in reality, marketing efforts to promote the drug's use by doctors. Forest responded to these allegations that it "is committed to adhering to the highest ethical and legal standards, and off-label promotion and improper payments to medical providers have consistently been against Forest policy."
Only one independent study has shown that Escitalopram is more effective than citalopram, but in October 2011 it was reported that the Russian company that sponsored the study, Arbacom, had employee links to Lundbeck, the makers. In Britain, the form Cipralex costs £14.91, while Lundbeck's older Cipramil can be found for £1.31. The Independent
newspaper reported that this costs Britain's National Health Service
(NHS) almost £25m extra per year, with no clear clinical benefits. The Independent also describes the patenting of Escitalopram as an example of evergreening
- slightly changing a drug that is about to go off-patent in order to acquire a patent for the new version, despite it containing similar ingredients to the previous version. Lundbeck has denied that it has 'evergreened' Escitalopram.
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
of the selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
(SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder and generalized anxiety disorder. Escitalopram is the (S)-stereoisomer (enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
) of the earlier Lundbeck
Lundbeck
H. Lundbeck A/S is a Danish international pharmaceutical company engaged in the research and development, production, marketing, and sale of drugs for the treatment of disorders in the central nervous system , including depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease,...
drug citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
, hence the name escitalopram. Escitalopram is noted for its high selectivity with serotonin reuptake inhibition
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
. Its side effects
Side Effects
Side Effects is an anthology of 17 comical short stories written by Woody Allen between 1975 and 1980, all but one of which were previously published in, variously, The New Republic, The New York Times, The New Yorker, and The Kenyon Review. It includes Allen's 1978 O...
are typical for the SSRI class.
Only one independent study has shown that Escitalopram is more effective than citalopram, but in October 2011 it was reported that the company that sponsored the study had links to Lundbeck, the makers. The similarity between Escitalopram and citalopram has led to accusations of 'evergreening
Evergreening
Evergreening refers to a variety of legal and business strategies by which technology producers with patents over products that are about to expire, retain rent from them by either taking out new patents or by buying out or frustrating competitors, for longer periods of time than would normally be...
', an accusation that Lundbeck has rejected.
Medical uses
Escitalopram is primarily used for the treatment of major depressive disorder and general anxiety disorderGeneral anxiety disorder
Generalized anxiety disorder is an anxiety disorder that is characterized by excessive, uncontrollable and often irrational worry about everyday things that is disproportionate to the actual source of worry...
in adults. There is some evidence favouring escitalopram over the antidepressants citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
and fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
in the first two weeks of major depression. Concerns of sponsorship bias with the studies is however noted. In another review escitalopram and sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
had the highest rate of efficacy and acceptability among adults receiving treatment for major depression with second-generation antidepressants.
Adverse effects
The side effectAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
profile of escitalopram is similar to that of other SSRIs. For example, according to the FDA analysis of depression trials common side effects for the highest approved dose of escitalopram are insomnia (14% vs. 4% for placebo), constricted pupils (15% vs. 5% for placebo), dry mouth (9% vs 3% for placebo), somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(9% vs 1% for placebo), dizziness (7% vs 2% for placebo), sweating (8% vs 1% for placebo), constipation (6% vs 1% for placebo), fatigue (6% vs 2% for placebo) and indigestion (6% vs. 1% for placebo). Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
, delayed ejaculation
Delayed ejaculation
Delayed ejaculation is the inability to ejaculate or persistent difficulty in achieving orgasm despite the presence of normal sexual desire and sexual stimulation...
, genital anesthesia, and anorgasmia
Anorgasmia
Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
. Although usually reversible upon discontinuation, these sexual side effects can last for months or years after the drug has been completely withdrawn. This is known as Post SSRI Sexual Dysfunction
Post SSRI Sexual Dysfunction
Post-SSRI sexual dysfunction is a name given to a reported iatrogenic sexual dysfunction caused by the previous use of selective serotonin reuptake inhibitor antidepressants. While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. ...
. SSRI can rarely cause extrapyramidal side effects including akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
through the indirect inhibition of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
.
Escitalopram is not associated with significant weight gain. For example, 0.6 kg mean weight change after 6 months of treatment with escitalopram for depression was insignificant and similar to that with placebo (0.2 kg). 1.4–1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression, and generalized anxiety disorder. A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain. Escitalopram may help reduce weight in those treated for binge eating
Binge eating
Binge eating is a pattern of disordered eating which consists of episodes of uncontrollable eating. It is sometimes as a symptom of binge eating disorder. During such binges, a person rapidly consumes an excessive amount of food...
associated obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications. Similarly, the UK MHRA
MHRA
MHRA is an initialism that can stand for:*Malta Hotels and Restaurants Association*Medicines and Healthcare products Regulatory Agency*Michigan Hot Rod Association*Modern Humanities Research Association** MHRA Style Guide...
data indicate an 80% increase of suicide-related events, not reaching statistical significance
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
, in the escitalopram vs placebo patients. The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients. A single case report
Case report
In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrence....
described a patient developing suicidal ideations after beginning treatment with escitalopram, and suicidal ideation disappearing after stopping the treatment.
Escitalopram should be taken with caution when using St John's wort
St John's wort
St John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
. Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
. The authors of this study, employed by Lundbeck, suggested that this increase is unlikely to be of clinical concern Caution should be used when taking cough medicine containing dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
(DXM) as serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
, liver damage, and other negative side effects have been reported.
Discontinuation symptoms
Escitalopram discontinuation, particularly abruptly may cause certain withdrawal symptomSymptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s such as "electric shock" sensations (also known as "brain shivers" or "brain zaps"), dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, acute depressions and irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
,bladder control issues, as well as heightened senses of akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
.
Overdose
Excessive doses of escitalopram usually cause relatively minor untoward effects such as agitation and tachycardia. However, dyskinesiaDyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
, hypertonia
Hypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
and clonus
Clonus
Clonus is a series of involuntary muscular contractions and relaxations. Clonus is a sign of certain neurological conditions, and is particularly associated with upper motor neuron lesions such as in stroke, multiple sclerosis, spinal cord damage and hepatic encephalopathy...
may occur in some cases. Plasma escitalopram concentrations are usually in a range of 20-80 μg/L in therapeutic situations and may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolizers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.
Pharmacology
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
by blocking the reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market escitalopram has the highest affinity for the human serotonin transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
(SERT). The enantiomer of escitalopram ((R)-citalopram) counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram is a more potent antidepressant than citalopram, which is a mixture of escitalopram and (R)-citalopram.
In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.
Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram, and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that R-citalopram decreases binding of escitalopram to the transporter. Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.
In vitro studies using human liver microsomes indicated that CYP3A4
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...
and CYP2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
are the primary isozymes involved in the N-demethylation of escitalopram. The resulting metabolites, desmethylescitalopram and didesmethylescitalopram, are significantly less active and their contribution to the overall action of escitalopram is negligible.
History
Escitalopram was developed in close cooperation between LundbeckLundbeck
H. Lundbeck A/S is a Danish international pharmaceutical company engaged in the research and development, production, marketing, and sale of drugs for the treatment of disorders in the central nervous system , including depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease,...
and Forest Laboratories
Forest Laboratories
Forest Laboratories is a pharmaceutical company headquartered in New York City, USA. Its revenues for the year ended 31 March 2007 were US$3.4 billion. The company's research and development spending has grown rapidly in recent years, and as of 2007, approached almost a billion US dollars a year,...
. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
, which has similar pharmacology.
The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. Escitalopram can be considered an example of "evergreening
Evergreening
Evergreening refers to a variety of legal and business strategies by which technology producers with patents over products that are about to expire, retain rent from them by either taking out new patents or by buying out or frustrating competitors, for longer periods of time than would normally be...
" (also called "lifecycle management")– the long-term strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an enantiopure compound
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
of the racemic mixture citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
, used for the same indication, and for that reason it required less investment and less time to develop. Two years after escitalopram's launch, when the patent on citalopram expired, the escitalopram sales successfully made up for the loss. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva. On July 14 of that year, however, the U.S. District Court of Delaware
United States District Court for the District of Delaware
The United States District Court for the District of Delaware is the Federal district court having jurisdiction over the entire state of Delaware. The Court sits in Wilmington...
decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.
In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram. This pushed the patent expiry from December 7, 2009 to to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date is March 14, 2012.
Controversy
According to The New York TimesThe New York Times
The New York Times is an American daily newspaper founded and continuously published in New York City since 1851. The New York Times has won 106 Pulitzer Prizes, the most of any news organization...
, aggressive pharmaceutical marketing
Pharmaceutical marketing
Pharmaceutical marketing , sometimes called medico-marketing, is the business of advertising or otherwise promoting the sale of pharmaceuticals or drugs. There is some evidence that marketing practices can negatively affect both patients and the health care profession...
of escitalopram by Forest Laboratories has been controversial: the generic alternatives to the drug are cheaper, but a substantial number of doctors continue to prescribe the more expensive proprietary drug. The United States Senate Special Committee on Aging
United States Senate Special Committee on Aging
The United States Senate Special Committee on Aging was initially established in 1961 as a temporary committee; it became a permanent Senate committee in 1977...
has released portions of the "Lexapro Fiscal 2004 Marketing Plan" which gives some of the details of the plans to promote use of the drug by doctors.
In 2004, two separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers, one by a non-practicing physician named Joseph Piacentile, and the other by a Forest salesman named Christopher Gobble who was disturbed by what he witnessed at Forest.
In February 2009, these two suits received support from the US Attorney for Massachusetts and were combined into one. Eleven states and the District of Columbia have also filed notices of intention to intervene as plaintiffs in the action. At the time, these drugs were approved only for use by adults and the application for use of citalopram in children was specifically rejected by the FDA. Although it is not illegal for physicians to prescribe a medicine for an off-label use not approved by the Food and Drug Administration, it is illegal for a manufacturer to promote the drugs for such uses. The government alleged that a research study showing lack of effectiveness when taken by children was concealed from its own medical advisers and sales personnel, as well as from researchers who conducted a study financed by the company. From 2001 to 2004, Forest heavily promoted results from another clinical trial it had financed which showed the drug was effective. Federal prosecutors also allege that the company has paid kickbacks to doctors to induce them to prescribe the medicines to children. The kickbacks allegedly included baseball tickets, a $1000 certificate to one of the most expensive New York restaurants, and paid vacations. Further, the complaint alleges that in September 2004, a Forest executive testified before Congress: “I want to emphasize that, because the FDA has not approved pediatric labeling of our products, Forest has always been scrupulous about not promoting the pediatric use of our antidepressant drugs, Celexa and Lexapro. That is the law and we follow it.” It is also alleged that the company conducted so-called "seeding studies" that were, in reality, marketing efforts to promote the drug's use by doctors. Forest responded to these allegations that it "is committed to adhering to the highest ethical and legal standards, and off-label promotion and improper payments to medical providers have consistently been against Forest policy."
Only one independent study has shown that Escitalopram is more effective than citalopram, but in October 2011 it was reported that the Russian company that sponsored the study, Arbacom, had employee links to Lundbeck, the makers. In Britain, the form Cipralex costs £14.91, while Lundbeck's older Cipramil can be found for £1.31. The Independent
The Independent
The Independent is a British national morning newspaper published in London by Independent Print Limited, owned by Alexander Lebedev since 2010. It is nicknamed the Indy, while the Sunday edition, The Independent on Sunday, is the Sindy. Launched in 1986, it is one of the youngest UK national daily...
newspaper reported that this costs Britain's National Health Service
National Health Service (England)
The National Health Service or NHS is the publicly funded healthcare system in England. It is both the largest and oldest single-payer healthcare system in the world. It is able to function in the way that it does because it is primarily funded through the general taxation system, similar to how...
(NHS) almost £25m extra per year, with no clear clinical benefits. The Independent also describes the patenting of Escitalopram as an example of evergreening
Evergreening
Evergreening refers to a variety of legal and business strategies by which technology producers with patents over products that are about to expire, retain rent from them by either taking out new patents or by buying out or frustrating competitors, for longer periods of time than would normally be...
- slightly changing a drug that is about to go off-patent in order to acquire a patent for the new version, despite it containing similar ingredients to the previous version. Lundbeck has denied that it has 'evergreened' Escitalopram.
External links
- Lexapro (Forest Laboratories) Official Lexapro Homepage
- Cipralex (Lundbeck) Official Cipralex Homepage
- Pharmacological information Lexapro
- Cipla Medpro Official Cipla Medpro Homepage
- portions of the "Lexapro Fiscal 2004 Marketing Plan" released by the United States Senate Special Committee on Aging
- U.S. National Library of Medicine: Drug Information Portal - Escitalopram