Generic Paxil & Zoloft Birth Defects - Manufacturers Have Duty To Warn

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While hundreds of Paxil and Zoloft birth defect lawsuits have been filed against GlaxoSmithKline and Pfizer, a number of lawsuits have been filed against manufacturers of generic Paxil (sold as Paroxetine) and Zoloft (sold as Sertraline) as well. Legal experts say that manufacturers of generic antidepressant drugs have the same duty to warn consumers of birth defects that brand label manufacturers do.
Generic manufacturers claiming preemption
Bryan Aylstock, a Florida attorney whose practice represents parents and their children who have suffered birth defect injuries due to an SSRI (selective serotonin reuptake inhibitor) drug such as Paxil and Zoloft, says that while a number of lawsuits have been filed against generic manufacturers, they have not yet reached the trial stage. He says that generic manufacturers are claiming a legal defense called preemption. He explained:
Preemption is the legal principle that if Congress intended to regulate an entity or entities to the point of excluding any private lawsuits, then the court will not allow such lawsuits. The Supreme Court of the United States recently commented on that in the context of a name brand pharmaceutical and determined that there was no preemption. What the Court said is that Congress never intended to preempt the field and prohibit lawsuits by creating the U.S. Food & Drug Administration (FDA) and the Food, Drug and Cosmetic Act. In fact, the opposite is true and the legislative history bears that out.
Generic manufacturers have same duty to warn
Aylstock and other Paxil birth defect attorneys say that generic manufacturers of various drugs are still defending on the basis of preemption with very mixed results.
Most courts have reviewed the [U.S. Supreme Court] decision, Wyeth vs. Levine, and they understand that the generic manufacturers also have duties. They can change the label as well and do not have to rely on what the FDA approved as the name brand label. As they get information, they also have legal obligations to put out safe products and properly warn about any risks associated with those products.
The foregoing article has been prepared by an attorney who is a regular contributor to FreeAdvice.com, and is now undergoing review by the site's editorial staff.

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PAXIL Prescribing Patterns in the USA

The table below shows the changes in prescribing year on year. The desease classification id based on the International Statistical Classification of Diseases measuring number of prescriptions written by non hospital based physicians.


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 RX Latest Year RX Prior Year
PAROXETINE 5,745,031 6,144,590
F41 OTHER ANXIETY DISORDERS 1,753,640 1,755,649
F32 DEPRESSIVE EPISODE 1,496,915 1,798,911
F33 RECURR DEPRSV DISORDER 841,031 850,575
F43 REAC-SVRE STRESS/ADJ DIS 219,598 248,078
F42 OBSESS/COMPULS DISORDER 206,882 230,137
F31 BIPOL AFFECT DIS 188,884 207,502
F40 PHOBIC ANXIETY DISORDERS 184,087 198,126
F90 HYPERKINETIC DISORDERS 102,762 73,163
F20 SCHIZOPHRENIA 100,253 33,334
F34 PERSIST MOOD(AFFECT)DIS 95,530 112,773
F25 SCHIZOAFFECTIVE DIS 63,452 93,630
F30 MANIC EPISODE 60,712 79,330
R69 UNK/UNSP CAUSE MORBID 52,087 50,798
M79 OTH SOFT TISS DIS NEC 31,911 13,339
F60 SPEC PERSNLTY DIS 30,133 22,479
F53 MNTL/BHV DIS ASS+PUERPER 21,490 21,475
F06 O/MNTL DIS-BRN DMG ETC 20,681 14,683
F39 UNSP MOOD(AFFECTIVE)DIS 20,067 19,424
G30 ALZHEIMER'S DISEASE 19,804 34,448
F99 MNTL DIS NOT O/WISE SPEC 19,495 15,394


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Original Letter from GSK.

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IMPORTANT PRESCRIBING INFORMATION
Dear Healthcare Professional:
GlaxoSmithKline (GSK) would like to advise you that it is changing the Pregnancy subsection the PRECAUTIONS section in the labels for PAXIL®(paroxetine HCl) and PAXIL CR®(paroxetine HCl) Controlled-Release Tablets.
SUMMARY
  • Paroxetine currently carries a Category C pregnancy precaution, indicating that there are no adequate and well-controlled studies in humans to determine the effect of paroxetine on the fetus. Labeling states that the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The label also currently includes information related to possible nonteratogenic effects, including symptoms and complications observed in neonates exposed to paroxetine in the third trimester of pregnancy.
  • GSK recently conducted a retrospective study of major congenital malformations in infants born to women taking antidepressants during the first trimester of pregnancy. Preliminary results suggest an increase in the risk of congenital malformations associated with the use of paroxetine as compared to other antidepressants. The types of congenital malformations, which were most commonly cardiovascular, were reflective of those seen in the general population. The most common cardiovascular malformations observed in the study were ventricular septal defects.
  • The preliminary results of this study and recent abstracts published by Alwan & Wogelius differ from previous epidemiologic studies, making it difficult to conclude whether a causal relationship exists. For example, data from the Swedish Medical Birth Registry, one of the largest available birth registries, have not provided evidence for an increased risk of major malformations with SSRI medications, including paroxetine.

GSK believes it is important to draw your attention to these recent findings, and is voluntarily adding this information to the paroxetine label. GSK will post the September 2005 results of this study to its Clinical Trial Register where it can be read by anyone with Internet access. The website is http://ctr.gsk.co.uk/welcome.asp.
RECOMMENDATIONS
  • As with all Pregnancy Category C drugs, health care providers are advised to carefully weigh the potential risks and benefits of using paroxetine therapy in women during pregnancy. It is recommended that health care providers discuss these latest findings, described in more detail below, as well as treatment alternatives, with their patients.
  • If you choose to discontinue paroxetine in a patient, please refer to the Discontinuation of Treatment with PAXIL/PAXIL CR subsection of the PRECAUTIONS section in the labeling for further information.
  • Paroxetine should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus.
Please see below for the full text of the amended PRECAUTIONS (new text has been underlined). copies of the revised package inserts for PAXIL and PAXIL CR are enclosed.
PAXIL CR:
PRECAUTIONS
Pregnancy: Teratogenic Effects: Category C.
There are no adequate and well controlled studies in pregnant women. A recent retrospective epidemiological study of 3,581 pregnant women exposed to paroxetine or other antidepressants during the 1st trimester suggested an increased risk of overall major congenital malformations for paroxetine compared to other antidepressants (OR 2.20; 95% confidence interval 1.34-3.63). There was also an increased risk for cardiovascular malformations for paroxetine compared to other antidepressants (OR 2.08; 95% confidence interval 1.03-4.23); 10 out of 14 infants cardiovascular malformations had ventricular septal defects. A separate study based on the Swedish Medical Birth Registry evaluated 4,291 infants exposed to SSRIs in early pregnancy. This study reported no increased risk for overall major in 708 infants born to women with paroxetine exposure in early pregnancy.
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the MRHD on an mg/m2basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing
occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. Paroxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
PAXIL:
PRECAUTIONS
Pregnancy: Teratogenic Effects: Category C.
There are no adequate and well controlled studies in pregnant women. A recent epidemiological study of 3,581 pregnant women exposed to paroxetine or other antidepressants during the st trimester suggested an increased risk of overall major congenital malformations for paroxetine compared to other antidepressants (OR 2.20; 95% confidence interval 1.34-3.63). There was also an increased risk for cardiovascular malformations for paroxetine compared to other antidepressants (OR 2.08; 95% confidence interval 1.03-4.23); 10 out of 14 infants with cardiovascular malformations had ventricular septal defects. A separate study on the Swedish Medical Birth Registry evaluated 4,291 infants exposed to SSRIs in early pregnancy. This study reported no increased risk for overall major malformations in 708 infants born to women with paroxetine exposure in early .
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are equivalent to 9.7 (rat) and 2.2 (rabbit) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, GAD, and PTSD (50 mg) and 8.1 (rat) and 1.9 (rabbit) times the MRHD for OCD, on an mg/m2basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or 0.19 times (mg/m2) the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD; and at 0.16 times (mg/m2) the MRHD for OCD. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. Paroxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
BACKGROUND
GSK conducted a retrospective study of major congenital malformations in infants born to women taking antidepressants during the first trimester of pregnancy. A preliminary analysis has recently been conducted which yielded adjusted odds ratios of 2.20 (95% Confidence interval [CI]: 1.34-3.63) for congenital malformations as a whole, and 2.08 (CI: 1.03-4.23) for cardiovascular malformations alone, for paroxetine as
compared to the other antidepressants in the database. The prevalences of congenital malformations as a whole and cardiovascular malformation alone were approximately 4% and 2%, respectively. Of the cardiovascular malformations reported in infants whose mothers were dispensed paroxetine, the majority were ventricular septal defects.
It is important to note that because the GSK study was designed to evaluate the relative of congenital malformations in infants born to women exposed to antidepressants, the study did not include a comparison to infants who were not exposed to any antidepressant. Therefore, these data should be viewed within the context of the overall prevalence of congenital malformations in the general population, which is estimated in the US to be approximately 3% for any malformation and approximately 1% for cardiovascular malformations alone (Honein 1999).
Previous epidemiological studies of pregnancy outcome following first trimester
exposure to selective serotonin reuptake inhibitors (SSRIs), including paroxetine, have not provided evidence for an increased risk of major malformations for SSRI
medications. In the most recent publication based on the Swedish Medical Birth Registry (Hallberg 2005), which unlike the GSK study above, included a comparison to infants not exposed to antidepressants, data on 4,291 infants born to mothers exposed to SSRIs in early pregnancy demonstrated an overall prevalence of 2.9% for congenital malformations, which the authors concluded did not differ from the expected rate of 3.5% among unexposed infants. 708 exposures to paroxetine in this registry, the prevalence of malformations was 3.4%.
In addition to the data by Hallberg et al, there are three published reports of small, epidemiologic case-control studies based on prospectively gathered data in women exposed to paroxetine during their first trimester (Kulin, 1998; Unfred, 2001; Diav-Citrin, 2002). The number of paroxetine-exposed pregnancies reported in the three studies ranged from 89 to 97, and all studies found no major teratogenic risk. A small study (19 paroxetine-exposed pregnancies) based on medical records review found congenital anomaly rates in accord with the general population (Hendrick, 2003).
More recently, Alwan et al (2005) have reported data obtained from the National Birth Defects Prevention Study of infants delivered from 1997-2001. Adjusted analyses showed that women who took an SSRI were more likely than those who were not exposed to have an infant with omphalocele (n=161) (odds ratio [OR] 3.0, CI 1.4-6.1). The strongest effect was reported to be with paroxetine, which accounted for 36% of all SSRI exposures (OR 6.3, CI 2.0-19.6). The authors also found an association of exposure to any SSRI and having an infant with craniosynostosis (n=372) (OR 1.8, CI 1.0-3.2).
A second abstract, from Wogelius et al, just presented at the 21stInternational Conference on Pharmacoepidemiology and Therapeutic Risk Management (August 21-24, 2005), reported an adjusted OR of 1.4 (CI 1.1-1.9) for congenital malformations overall and 1.6 (CI 1.0-2.6) for congenital cardiac malformations in women who redeemed a prescription for SSRIs (paroxetine-specific data were not presented) from 30 days before conception
to the end of the first trimester compared to women with no SSRI prescriptions during this period.
The differences in the results from the available studies and the diversity in type of abnormalities recently reported makes it difficult to definitively conclude a causal relationship for any particular congenital abnormality with paroxetine, however GSK believes it is important to draw your attention to the most recent findings. GSK is conducting additional epidemiologic studies to more fully understand these preliminary findings.
PAXIL is indicated for the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder; PAXIL CR is indicated for the treatment of major depressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder.
The medical community can further our understanding of PAXIL and PAXIL CR by reporting adverse events to GlaxoSmithKline at 1-888-825-5249 or to the FDA MEDWATCH program by phone at 1-800-FDA-1088, by FAX at 1-800-FDA-0178, by modem at 1-800-FDA-7737 or by mail:
MEDWATCH HF-2 FDA
5600 Fisher’s Lane Rockville, MD 20857
GlaxoSmithKline encourages you to familiarize yourself with these revisions to labeling. If you have any questions about the new information, please contact our Customer Response Center at 1-888-825-5249. You can find other useful information related to this issue as well as to clinical trials involving other GSK products at our Clinical Trial Registry website (http://ctr.gsk.co.uk/welcome.asp).
Sincerely,
Regional Medical Director Worldwide Development GlaxoSmithKline


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The letter from Glaxo SmithKline can be read on the FDA website here - Original GSK Letter

Updated Product Labeling Warns of Birth Defect Risk with Paxil

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Medical Author: Melissa Conrad Stoppler, MD
Medical Editor: Dennis Lee, MD
The U.S. Food and Drug Administration (FDA) recently announced that early research studies with the drug Paxil (paroxetine) suggest that taking the drug during the first three months of pregnancy may increase a woman's risk of having a baby with birth defects, particularly heart defects.
Paxil is an antidepressant drug belonging to the class of medications known as the selective serotonin reuptake inhibitors (SSRIs). Drugs in this group affect levels of the chemicals that nerves in the brain use to communicate with one another, known as neurotransmitters. Many experts believe that an imbalance among the amounts of the different neurotransmitters in the brain leads to depression. The SSRI class also contains fluoxetine (Prozac) andsertraline (Zoloft). Paxil is approved by the FDA for the treatment of depression and several other psychiatric disorders.
Results of two early studies reviewed by the FDA showed that women who took Paxil during the first three months of pregnancy were about one and a half to two times as likely to have a baby with a heart defect compared with women who took other antidepressants or women in the general population. Most of the heart defects reported in these studies were of the type known as atrial and ventricular septal defects (holes in the walls of the chambers of the heart). These types of heart defects can range in severity from relatively minor that resolve without treatment to those that cause serious symptoms and need to be repaired surgically. The risk for this type of heart defect is approximately one per cent of births in the general population. In one of the studies with Paxil, women taking the drug had an approximately two per cent risk of having a baby with heart defects, and in the second study, women taking Paxil in the first trimester had an approximate 1.5% risk of having a baby with heart defects.
According to the FDA announcement:
FDA is advising health care professionals to discuss the potential risk of birth defects with patients taking Paxil who plan to become pregnant or are in their first three months of pregnancy. Health care professionals should consider discontinuing Paxil (and switching to another antidepressant if indicated) in these patients. In some patients, the benefits of continuing Paxil may be greater than the potential risk to thefetus. FDA is advising health care professionals not to prescribe Paxil in women who are in the first three months of pregnancy or are planning pregnancy, unless other treatment options are not appropriate.
The manufacturer of Paxil, Glaxo Smith Kline, has changed the product labeling from pregnancy class C to class D, meaning that that studies in pregnant women (controlled or observational) have demonstrated a risk to the fetus. However, the benefits of therapy with Paxil may outweigh the potential risks to the fetus.
It's important to note that these conclusions are preliminary and are based on early results of two studies. The FDA is collecting additional data and waiting for the final results of these and other studies in order to better characterize and understand the risk for birth defects associated with Paxil. If you're currently taking Paxil, talk to your doctor if you are pregnant or planning to become pregnant. He or she can advise you on the best course of action for your situation and medical condition.

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Paxil Patent 6063927 With Pediatric Extention

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Patent Family
paroxetine (product, mesilate, 1998)
Trade Name(s)
CASBOL
SEROXAT
AROPAX
PAXIL
TAGONIS
FROSINOR
DEROXAT
SEREUPIN
MOTIVAN
Generic Name(s)
paroxetine (INN)
paroxetine hydrochloride (INN)
paroxetine mesylate (USAN)
Lab Code(s)
FR 7051
BRL 29060
BRL 29060A
SI 211103
CAS Number
61869-08-7 paroxetine
110429-35-1 paroxetine hydrochloride hemihydrate (1:1:0.5)
78246-49-8 paroxetine hydrochloride (1:1)
121368-57-8 paroxetine hydrobromide (1:1)
64006-44-6 paroxetine maleate (1:1)
217797-14-3 paroxetine mesylate (1:1)
63952-24-9 replaced by 61869-08-7
172501-13-2 replaced by 78246-49-8
217797-12-1 replaced by 64006-44-6
Chemical Name
(3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine
Class Description
SSRI antidepressants (N6A4)
Tranquillisers (N5C)
Indication
depression
obsessive compulsive disorder
anxiety
panic disorder
Action
5HT reuptake inhibitor
Latest Phase
Marketed
Company
GlaxoSmithKline, UK
Patentee
SmithKline Beecham, UK
Patent Country
USA
Priority Details
02 Jul 1998 : UK, 14316
06 Oct 1998 : UK, 21732
10 Feb 1999 : UK, 2935
22 Jun 1999 : UK, 14601
23 Jun 1999 : UK, 14709
23 Jun 1999 : UK, 14712
28 Jun 1999 : UK, 15096
19 Nov 1999 : UK, 27498
19 Nov 1999 : UK, 27501
03 Dec 1999 : UK, 28693
Patent Number
6063927
Patent Date
16 May 2000
Patent Type
Process
Filing Date
23 Apr 1999
Est. Expiry Date
23 Oct 2019
Expiry Comment
Extended
Country Comment
US 6063927 claims paroxetine mesilate in crystalline form and claims paroxetine hydrochloride formed by reacting this with hydrochloric acid.Pediatric exclusivity of 6 months has been granted in the USA for US 6063927. The new expiry date is 23 October 2019 from 23 April 2019.US 6063927 was quoted by the FDA Orange Book as relating to the PAXIL 10 mg, 20 mg, 30 mg and 40 mg oral tablet formulations, the PAXIL CR 12.5 mg, 25 mg a nd 37.5 mg oral extended release tablet formulations and the PAXIL 10 mg/5 ml oral suspension formulation of paroxetine hydrochloride equivalent to paroxetine base.All of these formulations have since been delisted from the FDA Orange Book.US marketing exclusivity for the PAXIL oral suspension for the treatment of social anxiety disorder expired on 17 May 2002.US marketing exclusivities for the PAXIL extended release tablet formulations expire on 16 February 2002. US marketing exclusivities for the PAXIL oral tablet formulations expired on 17 May 2002 for the treatment of social anxiety disorder and on 13 April 2004 for the treatment of generalised anxiety disorder.
General Comment
The patent family here is quite complex with 10 inter-related priorities and give rise to 4 PCT applications:WO 00/1692 which quotes UK priority 14316 and claims paroxetine acid salts where the acid is from a defined list of several thousand named acids. The salts claimed can be non-crystalline or crystalline. Also claimed is the use of each salt as an alternative to the currently marketed hydrochloride or as an intermediate in the preparation of the hydrochloride.WO 00/1694 which quotes UK priorities 14316, 21732 and 14601 and has specific product claims to paroxetine mesilate, in crystalline or non-crystalline form. The preparation of paroxetine hydrochloride from paroxetine mesilate is also claimed.WO 00/78290 which quotes UK priorities 14601, 14712, 27498 and 28693 claims compositions of paroxetine salts which are more water soluble than paroxetine hydrochloride hemihydrate. Compositions of paroxetine mesilate are specifically claimed.WO 00/78291 which quotes UK priorities 14601, 14709 and 27501 and claims compositions of paroxetine mesilate.The patent family listed here relates to the PAXIL and PAXIL CR formulations of paroxetine.Last reviewed: June 2009




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PAXIL - A development overview

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Trade Name
CASBOL
SEROXAT
AROPAX
PAXIL
TAGONIS
FROSINOR
DEROXAT
SEREUPIN
MOTIVAN
Generic Name
paroxetine (INN)
paroxetine hydrochloride (INN)
paroxetine mesylate (USAN)
Lab Code
FR 7051
BRL 29060
BRL 29060A
SI 211103
Latest News
20 March 2006: On 23 January 2006 GlaxoSmithKline reported that paroxetine hydrochloride has been approved in Japan for the treatment of obsessive compulsive disorder. Filings seeking approval of the product in Japan for the treatment of social anxiety disorders, generalized anxiety disorders and post-traumatic stress disorders are planned. In addition, it was reported that the CDFS's Committee on Safety of Drugs has approved a change in the labeling of paroxetine in Japan, involving removing use of the drug in patients with major depressive disorder under the age of 18 as a contraindication, and including this information as a special precaution. ....Paroxetine hydrochloride, a 5HT reuptake inhibitor, is marketed in most countries worldwide for the treatment of depression, panic disorder and obsessive compulsive disorders, and has been approved in several countries for the treatment of social anxiety disorder and generalized anxiety disorder.
Minor Update
03 Aug 2009 Analyst prediction.
27 Jul 2009 Chemical data added.
27 Jul 2009 Synonyms added.
06 Jul 2009 Patent data added.
29 Jun 2009 Indexing modified.
Licensor
Novo Nordisk
Licensee
FAES
Han Dok Remedia
Janssen-Cilag
Novartis
Ravizza
Solvay
GlaxoSmithKline
Latest Phase
Marketed
Active Program
Yes
Indication
depression
obsessive compulsive disorder
anxiety
panic disorder
Action
5HT reuptake inhibitor
Mode of Administration
oral
Class Description
SSRI antidepressants (N6A4)
Tranquillisers (N5C)
Company
Novo Nordisk (Denmark)
FAES (Spain)
Han Dok Remedia (South Korea)
sanofi-aventis (France)
Janssen-Cilag (Belgium)
Johnson & Johnson (USA)
Novartis (Switzerland)
Ravizza (Italy)
BASF (Germany)
Solvay (Belgium)
GlaxoSmithKline (UK)
Franchise
Company
Nationality
Corporation
Corp Nationality
Relationship
License Region

Novo Nordisk
Denmark
Novo Nordisk
Denmark
licensor


FAES
Spain
FAES
Spain
licensee
Spain

Han Dok Remedia
South Korea
sanofi-aventis
France
licensee
South Korea

Janssen-Cilag
Belgium
Johnson & Johnson
USA
licensee
USA

Novartis
Switzerland
Novartis
Switzerland
licensee
Spain

Ravizza
Italy
BASF
Germany
licensee
Italy

Solvay
Belgium
Solvay
Belgium
licensee
Spain

GlaxoSmithKline
UK
GlaxoSmithKline
UK
licensee : licensor
Worldwide
Country Status
Phase
Country
Indication

Marketed
Worldwide
depression

Registered
UK
anxiety

Registered
USA
anxiety

Registered
USA
panic disorder

Registered
USA
obsessive compulsive disorder

Registered
Canada
anxiety

Registered
Japan
obsessive compulsive disorder




Chemical Name
(3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine
CAS Number
61869-08-7 paroxetine
110429-35-1 paroxetine hydrochloride hemihydrate (1:1:0.5)
78246-49-8 paroxetine hydrochloride (1:1)
121368-57-8 paroxetine hydrobromide (1:1)
64006-44-6 paroxetine maleate (1:1)
217797-14-3 paroxetine mesylate (1:1)
63952-24-9 replaced by 61869-08-7
172501-13-2 replaced by 78246-49-8
217797-12-1 replaced by 64006-44-6
Patentee
Ferrosan
Patent Data
Product (Ferrosan; paroxetine): GB 1422263 1976, priority GB 4496 1973. Equivalents identified. Product (paroxetine HCl, crystalline): EP 223403 B 1993, priority GB 26407 1985. Equivalents identified.
Dev. Summary
Commercial overview
Paroxetine (SEROXAT;PAXIL), a 5HT reuptake inhibitor, was first launched in the UK in February 1991 for the treatment of depression, and has since been marketed in more than 50 countries worldwide. Paroxetine is also approved in several territories for the treatment of panic disorder, obsessive compulsive disorder and social anxiety disorder. Paroxetine hydrochloride is also approved in the USA and Canada for the treatment of generalized anxiety disorder (GAD) and in the USA and Europe for the treatment of post-traumatic stress disorder (PTSD). In 1973, Ferrosan, a subsidiary of Novo Nordisk, filed a priority product patent application for paroxetine in the UK. GlaxoSmithKline and Janssen have signed an agreement to co-promote paroxetine in the USA. Ravizza has rights to co-promote paroxetine in Italy with GlaxoSmithKline and in Spain with Novartis, Fournier (now known as Solvay) and Faes.

Launches
Paroxetine was launched for depression in the UK, its first market, in February 1991. It has since been marketed in over 50 countries, including the USA, Canada, Europe, Latin America, South Africa, New Zealand and Japan. A controlled-release formulation of paroxetine (PAXIL CR) has been approved in the USA for the treatment of panic disorder, premenstrual dysphoric disorder and social anxiety disorder.

Regulatory progress
GlaxoSmithKline has received follow up approval in many markets for paroxetine as a treatment for panic disorder and for obsessive compulsive disorders. Approval has also been obtained in some markets including the UK (SmithKline Beecham, OCT 1998) and USA (SmithKline Beecham, MAY 1999) for social anxiety disorder. GlaxoSmithKline has additionally received US approval for the use of paroxetine in generalized anxiety disorder (GAD) (GlaxoSmithKline, APR 2001). The product has also been approved for this indication in Canada (GlaxoSmithKline, OCT 2001). Paroxetine was approved for the treatment of post-traumatic stress disorder (PTSD) in Europe in September 2000 and in the USA in December 2001. Paroxetine has been approved in Japan for the treatment of obsessive compulsive disorder. Filings seeking approval of the product in Japan for the treatment of social anxiety disorders, generalized anxiety disorders and post-traumatic stress disorders are planned (Pharma Japan, FEB 2006). The European Medicines Evaluation Agency has begun a safety review of paroxetine because of concern that the drug causes suicidal tendencies (EMEA, JUN 2003). The US FDA and the UK MCA ruled in June 2003 that the drug should not be given to children. The CDFS's Committee on Safety of Drugs has approved a change in the labeling of paroxetine in Japan, to remove use of the drug in patients with major depressive disorder under the age of 18 as a contraindication, and to include this information as a special precaution (Pharma Japan, FEB 2006).

Controlled-release formulation

Approval was obtained in the USA in February 2002 for a controlled release formulation of paroxetine for panic disorder (GlaxoSmithKline, APR 2002). The controlled release formulation, PAXIL CR, was approved for continuous treatment of premenstrual dysphoric disorder (PMDD) in August 2003. In October 2003 PAXIL CR was approved for social anxiety disorder.

R&D progress
A trial of paroxetine involving over 1200 patients with generalized anxiety disorder (GAD) in the USA, Europe and Canada has been conducted to determine therapeutic efficacy and safety of the compound for this indication (SmithKline Beecham, MAY 2000).

SmithKline Beecham reviewed, OCT 1997. GlaxoSmithKline, confirmed status, FEB 2003. GlaxoSmithKline confirmed status, DEC 2003.

Licensing/Partnering
Paroxetine was originally developed by Ferrosan, a subsidiary of Novo Nordisk, which retains rights to it in Scandinavia. Novo Nordisk markets the product in Scandinavia.

In the USA, GlaxoSmithKline and Janssen have signed an agreement to co-promote paroxetine with Janssen's risperidone.

Ravizza will co-promote paroxetine with GlaxoSmithKline in Italy, and with Novartis, Fournier (now known as Solvay) and Faes in Spain.

Analyst predictions
Latest prediction

Analyst, Morgan Stanley, reporting on GlaxoSmithKline, estimates sales for SEROXAT/PAXIL (paroxetine hydrochloride) of STG534 million in 2009, STG480 million in 2010, STG432 million in 2011 and STG389 million in 2012 (Morgan Stanley, JUL 2009).

Morgan Stanley

Analyst, Morgan Stanley, reporting on GlaxoSmithKline, estimates sales for SEROXAT/PAXIL (paroxetine hydrochloride) of STG551 million in 2007, STG480 million in 2008, STG436 million in 2009, STG396 million in 2010, STG361 million in 2011, STG330 million in 2012 and STG302 million in 2013 (Morgan Stanley, JUL 2007).

Merrill Lynch

Analyst, Merrill Lynch, reporting on GlaxoSmithKline, estimates sales for PAXIL (paroxetine hydrochloride) of STG590 million in 2007, 2008, STG433 million in 2009, STG365 million in 2010, STG332 million in 2011 and STG304 million in 2012 (Merrill Lynch, JUN 2007).

Morgan Stanley

Analyst, Morgan Stanley, reporting on GlaxoSmithKline, estimates sales for SEROXAT/PAXIL (paroxetine hydrochloride) of STG567 million in FY2007, STG492 million in FY2008, STG447 million in FY2009, STG407 million in FY2010, STG371 million in FY2011, STG339 million in FY2012 and STG311 million in FY2013 (Morgan Stanley, MAR 2007).

Analyst, Morgan Stanley, reporting on GlaxoSmithKline, estimates sales for SEROXAT (paroxetine hydrochloride) of STG632 million in FY2006, STG509 million in FY2007, STG452 million in FY2008, STG411 million in FY2009, STG374 million in FY2010, STG342 million in FY2011 and STG313 million in FY2012 (Morgan Stanley, SEP 2006).
Scientific Summary
Preclinical data
Paroxetine is a phenylpiperidine which acts by specifically inhibiting the reuptake of 5HT into brain neurons.

Clinical data
Paroxetine had comparable efficacy to amitriptyline but a better side effect profile. Trial results showed an elevation of mood in patients usually within 14 days from start of treatment as well as an improvement on the Hamilton depression rating scale and the clinical global impression scale.

Results from a study of paroxetine on seizure length during electroconvulsive therapy showed the mean length of seizures of the paroxetine group to be about twice that of the control group (who were taking tricyclic antidepressants) (Curran, S., EMBASE: 95248259).

In panic disorder, paroxetine was as active as clomipramine, may have been faster acting and better tolerated, and was effective for at least one year. In a ten-week study, paroxetine was significantly better than placebo at reducing the number of panic attacks, and in patients switched to placebo after paroxetine treatment, relapse risk was significantly greater than those patients maintained on paroxetine. Side effects in clinical trials for panic disorder and obsessive compulsive disorder with an incidence of 10% or greater were sleepiness, nausea, dry mouth, constipation, dizziness, tremor, abnormal ejaculation, sweating, and weakness.

Results from a comparative meta-analysis study indicated that paroxetine is an effective alternative first-line therapy for treatment of depression in the elderly (Dunbar, G.C., EMBASE: 95262866).

In patients with social phobia, treatment with paroxetine resulted in greater reductions in the Liebowitz Social Anxiety Scale from baseline than for placebo (SmithKline Beecham, APR 1998; 11th World Congress of Psychiatry, AUG 1999).

Results of two double-blind, placebo-controlled, multicenter trials involving 897 patients with generalized anxiety disorder (GAD) showed that administration of the drug resulted in a 60% reduction of anxiety symptoms as measured by the Hamilton Anxiety Scale (GlaxoSmithKline, APR 2001).
History
JAN 2006 Registered, Japan (obsessive compulsive disorder).
JUL 2005 Fournier acquired by Solvay.
MAR 2002 Phase III, USA, Europe, (PMDD - controlled release formulation).
FEB 2002 Registered, USA (panic disorder - controlled release formulation).
DEC 2001 Registered, USA (PTSD).
APR 2001 Registered, USA (GAD).
SEP 2000 Registered, Europe (PTSD).
2000 Pre-registration, USA, Canada (GAD). Marketed, Japan.
MAY 1999 Registered, USA (social anxiety).
OCT 1998 Registered, UK (social anxiety).
MAR 1997 Registered, Australia (panic, OCD).
1996 Marketed, Norway.
MAY 1996 Registered, USA (panic disorder, OCD). Phase III, Japan.
SEP 1995 Registered, Austria (panic disorder, OCD). Phase III, South Korea.
MAR 1995 Marketed, France.
MAY 1994 Marketed, Peru.
1993 Marketed, Canada, Switzerland, Brazil, Belgium, Hong Kong, Austria, Greece, Mexico, Chile, Venezuela, Denmark.
SEP 1993 Copromotion agreement with Ravizza, Italy.
APR 1993 Care program established, USA.
JAN 1993 Marketed, USA.
DEC 1992 Marketed, Finland, Spain. Registered, USA.
OCT 1992 Recommended for approval, USA. Marketed, Germany. Registered, Spain, Greece, France, New Zealand.
JUL 1992 Marketed, South Africa. Phase II, Japan.
MAR 1992 Marketed, Netherlands. Registered, Italy, South Africa.
SEP 1991 Marketed, Sweden.
JUN 1991 Marketed, Ireland.
MAR 1991 Marketed, UK.
DEC 1990 Registered, UK.
JAN 1990 Pre-registration, Scandinavia, USA.
SEP 1989 Pre-registration, UK.
MAY 1988 Pre-registration, Denmark.
FEB 1988 Phase III, USA.
NOV 1986 Phase III, France, West Germany.
JUL 1986 Phase III, Denmark.
MAR 1986 Phase III, UK.
NOV 1985 Phase III, Europe.
OCT 1985 Priority product (paroxetine HCl, crystalline) patent application filed in the UK, by Ferrosan.
MAY 1984 Phase II, Denmark.
FEB 1983 Phase I, Denmark.
OCT 1980 License agreement with SmithKline Beecham.
JAN 1973 Priority product (paroxetine) patent application filed in the UK, by Ferrosan.




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