GlaxoSmithKline

GlaxoSmithKline plc

Type Public limited company

(LSE: GSK
NYSE: GSK)
Industry Pharmaceutical
Founded 2000, by merger of Glaxo
Wellcome and SmithKline
Beecham
Headquarters London, United Kingdom
Key people Chris Gent, Chairman
Andrew Witty, Chief Executive
Revenue £28.392 billion(2010)[1]
Employees 99,000 (2009)[2]
Website www.gsk.com

GlaxoSmithKline plc (LSE: GSKNYSE: GSK), often abbreviated to GSK, is a

global pharmaceutical, biologics, vaccines and consumer healthcare company
headquartered in London, United Kingdom. It is the world's third largest
pharmaceutical company measured by revenues (after Johnson & Johnson and Pfizer).
It has a portfolio of products for major disease areas includingasthma, cancer, virus
control, infections, mental health, diabetes and digestive conditions. It also has a large
consumer healthcare division which produces and markets oral healthcare products,
nutritional drinks and over-the-counter medicines,
including Sensodyne, Horlicks and Gaviscon.Its primary listing is on the London
Stock Exchange and it is a constituent of the FTSE 100 Index. It has a secondary
listing on the New York Stock Exchange.
History

Former GlaxoSmithKline building inHamburg, Germany

GSK was formed in 2000 by the merger of GlaxoWellcome plc (formed from the
acquisition of Wellcome plc by Glaxo plc), and SmithKlineBeecham plc (from the
merger of Beecham plc, and SmithKline Beckman Corporation).

GlaxoWellcome

In 1880, Burroughs Wellcome & Company was founded in London by American

pharmacists Henry Wellcome and Silas Burroughs. The Wellcome Tropical Research
Laboratories opened in 1902. In 1959 the Wellcome Company bought Cooper,
McDougall & Robertson Inc. to become more active in animal health. The Wellcome
Company production centre was moved from New York to North Carolina in 1970
and the following year another research centre was built.

Glaxo was founded in Bunnythorpe, New Zealand in 1904. Originally Glaxo was a
baby food manufacturer processing local milk into a baby food by the same name: the
product was sold in the 1930s under the slogan "Glaxo builds bonny babies". Still
visible on the main street of Bunnythorpe is a derelict dairy factory (factory for drying
and processing cows' milk into powder) with the original Glaxo logo clearly visible,
but nothing to indicate that this was the start of a major multinational company.
 Glaxo became Glaxo Laboratories, and opened new units in London in 1935. Glaxo
Laboratories bought two companies, Joseph Nathan and Allen & Hanburys, in 1947
and 1958 respectively. After the Company bought Meyer Laboratories in 1978, it
started to play an important role in the US market. In 1983 the American arm Glaxo
Inc. moved to Research Triangle Park (US headquarters/research) and Zebulon (US
manufacturing) in North Carolina. Burroughs Wellcome and Glaxo merged in 1995 to
form GlaxoWellcome. In the same year, GlaxoWellcome opened its Medicine
Research Centre in Stevenage. Three years later GlaxoWellcome bought Polfa Poznan
Company in Poland.

SmithKline Beecham

In 1843, Thomas Beecham launched his Beecham's Pills laxative in England giving
birth to the Beecham Group. Beechams opened its first factory in St Helens,
Lancashire, England for rapid production of medicines in 1859. By the 1960s it was
extensively involved in pharmaceuticals.

The GSK Headquarters in Brentford

In 1830, John K. Smith opened its first pharmacy in Philadelphia. In 1865 Mahlon
Kline joined the business which, 10 years later, became Smith, Kline & Co.
Subsequently, in 1891, it merged with French, Richard and Company. It changed its
name to Smith Kline & French Laboratories as it focused more on research in 1929.
Years later, Smith Kline & French Laboratories opened a new laboratory
in Philadelphia; it then bought Norden Laboratories, a business doing research into
animal health.

Smith Kline & French Laboratories bought Recherche et Industrie

Thérapeutiques (Belgium) in 1963 to order to focus on vaccines. The Company started
to expand globally buying seven laboratories in Canada and the US in 1969. In 1982,
it bought Allergan, a manufacturer of eye and skincare products. The Company
merged with Beckman Inc. later that year and then changed its name to SmithKline
Beckman.

In 1988, SmithKline Beckman bought its biggest competitor, International Clinical

Laboratories, and in 1989 merged with Beecham to form SmithKline Beecham plc.
The headquarters of the Company were then moved to England. To expand research &
development in the US, SmithKline Beecham bought a new research center in 1995.
Another new research centre at New Frontiers Science Park in Harlow was opened in
1997.

In 2000, Glaxo Wellcome and SmithKline Beecham merged to form

GlaxoSmithKline.

Recent developments

In 2001 it completed its purchase of New Jersey-based Block Drug.

On 16 November 2009 the US Food and Drug Administration (FDA) announced that a
vaccine for 2009 H1N1 influenza protection (manufactured by GSK's ID Biomedical
Corp. subsidiary) would join the four vaccines approved on 15 September.

In June 2010, the company acquired Laboratorios Phoenix, an Argentine

pharmaceutical company focused on the development, marketing and sale of branded
generic products, for a cash consideration of approximately $253m.

In December 2010, GSK announced its acquisition of the sports nutrition

company Maxinutrition.

Operations

As the second largest pharmaceutical company in the world, based on net income, the
company had sales of £22.7 billion and made a profit of £7.8 billion in 2007. It
employs over 90,000 people worldwide, according to GSK website, including over
40,000 in sales and marketing. Its global headquarters are GSK House in Brentford,
London, United Kingdom, with its United States headquarters based in Research
Triangle Park (RTP) in North Carolina and its consumer products division based in
the Pittsburgh suburb of Moon Township, Pennsylvania. The research and
development division has major headquarters in South East
England, Philadelphia and Research Triangle Park (RTP) in North Carolina.

The company's stock is listed on the London stock exchange and ADRs are listed on
the NYSE. The single largest market is in the United States (approximately 45% of
revenue), although the company has a presence in almost 70 countries.

In November 2009 GlaxoSmithKline formed a joint venture with Pfizer to create ViiV
Healthcare. Viiv Healthcare received all of Pfizer and GlaxoSmithKline's HIV assets.
ViiV Healthcare is 85% owned by GlaxoSmithKline and 15% owned by Pfizer.

Products

The company's products include:

Advair Ceftin Levitra Sensodyne
 Lovaza Serlipet
Albenza Coreg
Lucozade Setlers
Alli Coreg CR
Macleans SKF 38393
Amerge Dexedrine
Nicoderm SKF 82958
Amoxil Flixonase
Nicorette Tagamet
Aquafresh Geritol
NiQuitin Treximet
Arixtra Gly-Oxide
Pandemrix Tums
Arranon Goody's Powder
Panadol Trizivir
Augmentin GSK-189,254
Panadol night Tykerb
Avandia GSK-873140
Parnate Valtrex
Avodart GW-320,659
Parodontax Ventolin HFA
BC Powder GW 501516
Paxil Veramyst
Beano Horlicks
Promacta Vesicare
Beconase Imitrex
Ralgex Wellbutrin
Biotene Keppra
Relenza Zantac
Boniva Lamictal
Requip Zofran
Boost Lanoxin
Ribena Zovirax

Initiatives to eradicate disease

Glaxo SmithKline has been active in a global alliance to eliminate lymphatic

filariasis. Jean-Pierre (JP) Garnier, former CEO of GlaxoSmithKline has said, “The
Egyptian data shows that we can now eliminate a disease that has plagued the world
for centuries. We remain committed to donating as much albendazole as required to
eliminate this disabling disease, but ultimate success will depend on continued long-
term commitments by all partners across the globe.”

In addition Glaxo has been short-listed for awards such as the Worldaware Business
Award for its work to eliminate malaria in Kenya.

GlaxoSmithKline recently donated money to the British flood appeal, and was ranked
first on the 2006 UK Corporate Citizenship Index for donations.

Global locations

Factory in Ulverston

An entrance to the Ulverston plant

Global Pharmaceutical Operations headquarters in Brentford, United Kingdom with

US operations based in Research Triangle Park, North Carolina.

Consumer Products headquarters in Moon Township, Pennsylvania suburb

of Pittsburgh

Major R&D sites in Stockley Park, Stevenage and Ware in the United
Kingdom; Zagreb, Croatia; Evreux and Les Ulis in France; Research Triangle Park,
North Carolina; Laval, Quebec and Upper Merion and Collegeville, Pennsylvania

Major centre for biopharmaceutical products in Belgium (Wavre and Rixensart),

Germany (Dresden), Canada (Quebec, QC) and USA (Marietta PA & Hamilton MT)

New R&D centres in Thane, India and Nashik, India

R&D centres in Shanghai, China and Boston, USA

 Major manufacturing sites for prescription products
in Irvine, Ware, Montrose, Barnard Castle, Crawley, Worthing and Ulverston in the
United Kingdom; Evreux, France; Bristol, King of Prussia and Zebulon in the United
States; Cidra, Puerto Rico; Jurong, Singapore; Cork, Ireland;Poznań, Poland; Parma,
Italy; Brasov, Romania; Boronia, Australia.

Major manufacturing sites for consumer products in Maidenhead, United

Kingdom; Dungarvan, Ireland; Mississauga, Ontario; Aiken, South Carolina; Clifton,
New Jersey; and St. Louis, Missouri, and Kenya

GSK has a presence in 99 cities across 39 countries

Corporate governance

Current members of the board of directors of GlaxoSmithKline are:

• Sir Christopher Gent (Non-Executive Chairman);

• Andrew Witty (Chief Executive Officer, Executive Director);
• Dr Stephanie Burns (Non-Executive Director);
• Lawrence Culp (Non-Executive Director);
• Sir Crispin Davis (Non-Executive Director);
• Julian Spenser Heslop (Chief Financial Officer, Executive Director);
• Sir Deryck Maughan (Non-Executive Director);
• Sir Ian Prosser (Senior Independent Non-Executive Director);
• Dr Ronaldo Schmitz (Non-Executive Director);
• Moncef Slaoui (Chairman, Executive Director, Research & Development);
• Robert Wilson (Non-Executive Director);
• Dr Daniel Podolsky (Non-Executive Director);

On 8 October 2007 it was announced that Dr Garnier would be succeeded as Chief

Executive by Mr Andrew Witty. Mr Witty, 44, has taken up the position in May 2008
and joined the Board. Although job losses have been widespread in the company, Mr
Witty himself has seen his pay increase by 76% over the last year.

Diversity

GlaxoSmithKline was named one of the 100 Best Companies for Working Mothers in
2007 by Working Mother magazine and was recognised by the International Charter
for its efforts. GSK also received a perfect score of 100 percent from the Human
Rights Campaign Foundation's 2008 Corporate Equality Index, an annual report card
of corporate America's treatment of gay, lesbian, bisexual, and transgender (GLBT)
employees, customers and investors. GSK also supports employee diversity networks
for groups such as ECN, PTPN, GLBT, AAA, etc.

Controversy

Paroxetine (Seroxat, Paxil) is an SSRI antidepressant released in 1992 by

GlaxoSmithKline. In March 2004 the FDA ordered a black box warning placed on
SSRI and other antidepressants, warning of the risk for potential suicidal thinking in
children and adolescents. Since the FDA approved paroxetine in 1992, approximately
5,000 U.S. citizens have sued GSK. On 29 January 2007, the BBC in the UK
broadcast a fourth documentary in its 'Panorama' series about Seroxat. There is as yet
no proven link between SSRI's and actual suicide, and the addition of blackbox
warning labels was said to be controversial But many recent analyses prove the link,
even with older patients.

In November 2007, a United States Congressional committee released a

report describing intimidation of Dr John Buse (University of North Carolina at
Chapel Hill by GlaxoSmithKline over his concerns about the cardiovascular risks
associated with the company's antidiabetes drug Rosiglitazone (Avandia).

In March 2006, California Attorney General Bill Lockyer announced that

"GlaxoSmithKline (GSK) will pay $14 million to resolve allegations that state-
government programs paid inflated prices for the firm’s anti-depressant drug Paxil
because GSK engaged in patent fraud, antitrust violations and frivolous litigation to
maintain a monopoly and block generic versions from entering the market."

At the AGM on 19 May 2003, GSK shareholders rejected a motion regarding a

£22 million pay and benefits package for CEO, JP Garnier. This was the first time
such a rebellion by shareholders against a major British company has occurred, but
was regarded as a possible turning point against other so-called "fat cat" deals within
executive pay structure.

The company and its shareholders have been targeted by animal rights activists
because it is a customer of the controversial animal-testing company, Huntingdon Life
Sciences(HLS). HLS has been the subject since 1999 of an international campaign
by Stop Huntingdon Animal Cruelty (SHAC) and the Animal Liberation Front (ALF),
ever since footage shot covertly by People for the Ethical Treatment of
Animals (PETA), which was shown on British television, showed staff punching,
kicking, screaming and laughing at the animals in their care. On 7 September 2005,
the ALF detonated a bomb containing two litres of fuel and four pounds of explosives
on the doorstop of the Buckinghamshire home of Paul Blackburn, GSK's corporate
controller, causing minor damage.

In November 2005, AIDS Healthcare Foundation accused the company of boosting its
short-term monopoly profit by not increasing production of the anti-AIDS
drug AZT despite a surge in demand, hence creating a shortage that affected many
AIDS patients in Africa. GSK announced that it had halted clinical trials of the CCR5
entry inhibitor, aplaviroc(GW873140), in HIV-infected, treatment-naive patients
because of concerns about severe hepatotoxicity. In June 2006 GSK said it was further
cutting, by about 30%, the not-for-profit prices it charges for some of these medicines
in the world's poorest countries.

In December 2003, Allen Roses, the then worldwide vice-president of genetics at

GlaxoSmithKline, admitted that most prescription medicines do not work on most
people who take them. "The vast majority of drugs – more than 90 per cent – only
work in 30 or 50 per cent of the people," Dr Roses said. "I wouldn't say that most
drugs don't work. I would say that most drugs work in 30 to 50 per cent of people."

The U.S. Department of Justice announced in October 2010 that GlaxoSmithKline

would pay $150 million in criminal fines and $600 million in civil penalties.
GlaxoSmithKline agreed to pay the $750 million settlement in response to criminal
and civil complaints against the company stemming from production of improperly
made and adulterated drugs at their subsidiary SB Pharmco Puerto Rico Inc in Cidra,
Puerto Rico.

Legal

In 2003 GSK signed a corporate integrity agreement and paid $88 million in a civil
fine for overcharging Medicaid for the antidepressant Paxil, and nasal-allergy
spray Flonase. Later that year GSK also ran afoul of the Internal Revenue
Service (IRS) and was facing a demand for $7.8 billion in backdated taxes and
interest, the highest in IRS history.

On 26 August 2004, New York State Attorney General Eliot Spitzer's office
announced it had settled legal action against GlaxoSmithKline. The settlement
required GSK to post a registry which would include much more information about
pretrial and clinical drug study results than what the U.S. Food and Drug
Administration (FDA) and other pharmaceutical companies had thus far been willing
to make public. Attorney General Spitzer hailed the settlement as "transformational in
that it will provide doctors and patients access to the clinical testing data necessary to
make informed judgments." This part of the settlement was the main objective of the
New York AG and Rose Firestein, who worked in the office of the AG and initially
argued the case should be undertaken. As for the monetary compensation, both sides
finally agreed to $2.5 million. On 3 August 2004, shortly before the
settlement, Senator Charles Grassley, a Republican senator from Iowa sent a letter to
GSK, stating that he was concerned that "some drug companies" may not have
provided the FDA with all the information at their disposal. His letter was spurred by
statements earlier in 2008 by Dr. Andrew Mosholder, an FDA official, who had told
senators at a 2 February 2004 hearing that "GlaxoSmithKline, in his opinion, was
attempting to 'sugar-coat' the adverse effects of Paxil on children by 'miscoding'
suicidal ideations and/or suicidal behavior." Glaxo officials never commented on
whether there was any connection between Senator Grassley's letter and their decision
to pursue a settlement with the New York State attorney general's lawsuit.

On 12 September 2006 GSK settled the largest tax dispute in IRS history agreeing to
pay $3.1 billion. At issue in the case were Zantac and the other Glaxo Group heritage
products sold from 1989–2005. The case was about an area of taxation dealing with
intracompany "transfer pricing"—determining the share of profit attributable to the US
subsidiaries of GSK and subject to tax by the IRS. Taxes for large multi-divisional
companies are paid to revenue authorities based on the profits reported in particular
tax jurisdictions, so how profits were allocated among various legacy Glaxo divisions
based on the functions they performed was central to the dispute in this case.

In February 2007, the Serious Fraud Office in the UK launched an investigation into
allegations of GSK being involved in the discredited oil-for-food sanctions regime in
Iraq. They are accused of paying bribes to Saddam Hussein's regime.

Paroxetine

For the first 10 years of paroxetine's availability, GlaxoSmithKline's marketing of the

drug stated falsely that it was "not habit forming". In 2001, the BBC reported the
World Health Organization had found paroxetine to have the hardest withdrawal
problems of any antidepressant. In 2002, the U.S. Food and Drug
Administration published a new product warning about the drug, and the International
Federation of Pharmaceutical Manufacturers Associations (IFPMA) declared GSK
guilty of misleading the public about paroxetine on US television.The British Medical
Journal quoted Charles Medawar, head of Social Audit: "This drug has been promoted
for years as safe and easy to discontinue.... The fact that it can cause intolerable
withdrawal symptoms of the kind that could lead to dependence is enormously
important to patients, doctors, investors, and the company. GlaxoSmithKline has
evaded the issue since it was granted a licence for paroxetine over 10 years ago, and
the drug has become a blockbuster for them, generating about a tenth of their entire
revenue. The company has been promoting paroxetine directly to consumers as 'non-
habit forming' for far too long."

On 22 December 2006, a US court decided in Hoorman, et al. v. SmithKline Beecham

Corp that individuals who purchased Paxil(R) or Paxil CR(TM) (paroxetine) for a
minor child may be eligible for benefits under a $63.8 million Proposed
Settlement. The lawsuit stemmed from a consumer advocate protest against Paroxetine
manufacturer GSK. Since the FDA approved paroxetine in 1992, approximately 5,000
U.S. citizens – and thousands more worldwide – have sued GSK. Most of these people
feel they were not sufficiently warned in advance of the drug's side effects and
addictive properties.

According to the Paxil Protest website, hundreds more lawsuits have been filed against
GSK. The original Paxil Protest website was removed from the internet in 2006. It is
understood that the action to take down the site was undertaken as part of a
confidentiality agreement or 'gagging order' which the owner of the site entered into as
part of a settlement of his action against GlaxoSmithKline. (However, in March 2007,
the website Seroxat Secrets discovered that an archive of Paxil Protest sitewas still
available on the internet via Archive.org)

In January 2007, according to the Seroxat Secrets website, the national group litigation
in the United Kingdom, on behalf of several hundred people who allege withdrawal
reactions through their use of the drug Seroxat, against GlaxoSmithKline plc, moved a
step closer to the High Court in London, with the confirmation that Public Funding
had been reinstated following a decision by the Public Interest Appeal Panel. The
issue at the heart of this particular action claims Seroxat has a propensity to cause a
withdrawal reaction. Hugh James Solicitors have confirmed this news.

In March 2008 the Medicines and Healthcare Products Regulatory Agency concluded
that GSK should have warned of the possible ill effects of taking Seroxat a lot
sooner. GSK could not be prosecuted under the old legislation.

As of 2008, GlaxoSmithKline's prescribing information acknowledges that "serious

discontinuation symptoms" may occur.

Ribena

On 27 March 2007, GSK pleaded guilty in an Auckland District Court to 15 charges

relating to misleading conduct brought against them under the Fair Trading Act by
New Zealand'sCommerce Commission. The charges related to a
popular blackcurrant fruit drink Ribena which the company had led consumers to
believe contained high levels of vitamin C. As part of a school science project, two 14-
year-old school girls (Anna Devathasan and Jenny Suo) from Pakuranga
College in Auckland (New Zealand) discovered that ready-to-drink juice sold in
100ml containers contained very little vitamin C. Approaches by the two teens to the
company didn't resolve the issue but after the matter was publicised on a national
consumer affairs television show (Fair Go) the matter came to the attention of the
Commerce Commission (a government funded 'consumer watch-dog'). The
commission's testing found that ready-to-drink Ribena contained no detectable vitamin
C.

The company was fined $217,000 for the 15 charges. The number of charges was
reduced from 88 and covered a period from March 2002 to March 2006. GSK
maintains that it did not intend to mislead consumers and that the advertising claims
were based on testing procedures that have since been changed. It was ordered to run
an advertising campaign to provide the facts after it admitted misleading the public
about the vitamin C component in its Ribena drink. Through its lawyer, Adam Ross,
the company accepted Commerce Commission allegations that claims that ready-to-
drink Ribena contained 7 mg of vitamin C per 100ml, or 44 per cent of the
recommended daily intake, were incorrect. The company also agreed television
advertising claiming the blackcurrants in Ribena had four times the vitamin C of
 oranges, while literally true, were likely to mislead consumers about the relative levels
of vitamin C in Ribena.

Avandia

On 14 June 2007, an article was published by Steve Nissen, Chair of the Division of
Cardiovascular Medicine at the Cleveland Clinic in the New England Journal of
Medicine. This meta-analysis demonstrated an increased odds ratio of myocardial
infarction in patients taking rosiglitazone marketed as Avandia. More recently, the
New York Times published an article detailing Nissen's conversation with
pharmaceutical executives. These conversations were recorded unbeknownst to the
GSK executives but are legal in the State of Ohio as long as one participating party is
aware. Currently, a Congressional investigation has been initiated to determine what
information was known at the time of the approval of rosiglitazone as well as post
approval and whether or not GSK willfully suppressed such information. On February
2010 GlaxoSmithKline tried to suppress publishing of a critical article concerning
rosiglitazone.In July a US Finance Committee Letter accessed GSK of failing "to
publish studies in a timely manner that found problems with Avandia".

Announced policy change

In February 2009, GSK head Andrew Witty announced that the company will cut drug
prices by 25% in 50 of the poorest nations, release intellectual property rights for
substances and processes relevant to neglected disease into a patent pool to encourage
new drug development, and invest 20% of profits from the least developed countries
in medical infrastructure for those countries.The decision has received mixed reactions
from medical charities.Médecins Sans Frontières welcomed the decision, encouraging
other companies to follow suit, but criticised GSK for failing to include HIV patents in
their patent pool, and for not including middle-income countries in the initiative.

Anticoagulant

An anticoagulant is a substance that prevents coagulation; that is, it stops blood from
clotting. A group of pharmaceuticals called anticoagulants can be used in vivo as a
 medication forthrombotic disorders. Some chemical compounds are used in medical
equipment, such as test tubes, blood transfusion bags, and renal dialysis equipment.

As medications

Anticoagulants reduce blood clotting. This prevents deep vein thrombosis, pulmonary
embolism, myocardial infarction and stroke.

Coumadins (Vitamin K antagonists)

These oral anticoagulants are a class of pharmaceuticals that antagonize the effects
of vitamin K. Examples include warfarin. It takes at least 48 to 72 hours for the
anticoagulant effect to develop. Where an immediate effect is required, heparin must
be given concomitantly. These anticoagulants are used to treat patients with deep-vein
thrombosis (DVT), pulmonary embolism(PE), atrial fibrillation (AF), and
mechanical prosthetic heart valves.

Adverse effects

Patients aged 80 years or more may be especially susceptible to bleeding

complications with a rate of 13 bleeds per 100 person-years.

These oral anticoagulants are used widely as poisons for mammalian pests,
especially rodents. (For details, see rodenticide and warfarin.)

Depletion of vitamin K by coumadin therapy increases risk of arterial calcification and

heart valve calcification, especially if too much vitamin D is present.

Available agents

 Warfarin (Coumadin) This is the main agent used in the U.S. and UK[3]
 Acenocoumarol and phenprocoumon This is used more commonly outside the
U.S. and the UK
 Brodifacoum Rat poison, not used medically
 Phenindione

Heparin and derivative substances

Heparin is a biological substance, usually made from pig intestines. It works by

activating antithrombin III, which blocks thrombin from clotting blood. Heparin can
be used in vivo (by injection), and also in vitro to prevent blood or plasma clotting in
or on medical devices. Vacutainer brand test tubes containing heparin are usually
colored green.

Low molecular weight heparin

 Low molecular weight heparin is a more highly processed product that is useful as it
does not require monitoring of the APTT coagulation parameter (it has more
predictable plasma levels) and has fewer side effects.

Synthetic pentasaccharide inhibitors of factor Xa

 Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharide)

in heparin that bind to antithrombin. It is a smaller molecule than low molecular weight
heparin.
 Idraparinux

Major pharmaceutical Heparin recall due to contamination

In March 2008 major recalls of Heparin were announced by pharmaceuticals due to a

suspected and unknown contamination of the raw Heparin stock imported from China.
[4][5]
The contaminant was later found to be a non-naturally occurring compound called
oversulfated chondroitin sulfate. The U.S. Food and Drug Administration was quoted
as stating that at least 19 deaths were believed linked to a raw Heparin ingredient
imported from the People's Republic of China, and that they had also received 785
reports of serious injuries associated with the drug’s use. According to the New York
Times: 'Problems with heparin reported to the agency include difficulty breathing,
nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some
cases led to life-threatening shock'.

Direct thrombin inhibitors

Another type of anticoagulant is the direct thrombin inhibitor. Current members of this
class include argatroban, lepirudin, bivalirudin, and dabigatran. An oral direct
thrombin inhibitor,ximelagatran (Exanta) was denied approval by the Food and Drug
Administration (FDA) in September 2004 and was pulled from the market entirely in
February 2006 after reports of severe liver damage and heart attacks.

Other types of anticoagulants

Many other anticoagulants exist, for use in Research & Development, and more or less
uses as drug candidates or diagnostics

 Batroxobin, a toxin from a snake venom that clots platelet-rich plasma without
affecting platelets functions (lyses fibrinogen).
 Hementin is an anticoagulant protease from the salivary glands of Haementeria
ghilianii

Food supplements

Food supplements with blood thinning effect include Nattokinase and Lumbrokinase
 General indications

Therapeutic uses of anticoagulants include atrial fibrillation, pulmonary

embolism (PE), deep vein thrombosis (DVT), or venous
thromboembolism (VTE), congestive heart failure, stroke,myocardial infarction,
genetic or acquired hypercoagulability

Anticoagulants outside the body

Laboratory instruments, test tubes, blood transfusion bags, and medical and surgical
equipment will get clogged up and become nonoperational if blood is allowed to clot.
Chemicals can be added to stop blood clotting. Apart from heparin, most of these
chemicals work by binding calcium ions, preventing the coagulation proteins from
using them.

 EDTA is denoted by mauve or purple caps on Vacutainer brand test tubes. This
chemical strongly and irreversibly binds calcium. It is in a powdered form.
 Citrate is usually in blue Vacutainer tube. It is in liquid form in the tube and is
used for coagulation tests, as well as in blood transfusion bags. It gets rid of the
calcium, but not as strongly as EDTA. Correct proportion of this anticoagulant to blood
is crucial because of the dilution. It can be in the form of sodium citrate or ACD.
 Oxalate has a mechanism similar to that of citrate. It is the anticoagulant used
in fluoride (grey top) tubes.

Fondaparinux

Fondaparinux
 Systematic (IUPAC) name

2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-
glucopyranosyl-(1→

4)-O-β-D-glucopyranuronosyl-(1→4)-O-2-deoxy-
3,6-di-O-sulfo-2- (sulfoamino)-α-D-glucopyranosyl-
(1→4)-O-2-O-sulfo-α-L-idopyranouronosyl-(1→ 4)-
O-methyl-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-
glucopyranoside, decasodium salt.
Chemical data
Formula C31H43N3Na10O49S8
Mol. mass 1726.77 g/mol
Pharmacokinetic data
Bioavailability N/A
Protein binding 94%
Metabolism renally excreted unchanged
Half-life 17-21 hours
Therapeutic considerations
Licence data EMA:Link, US FDA:link
Legal status POM (UK) ℞-only (US)
Routes subcutaneous

Fondaparinux (trade name Arixtra) is an anticoagulant medication chemically related

to low molecular weight heparins. It is marketed byGlaxoSmithKline.

Structure and mechanism

Fondaparinux is a synthetic pentasaccharide Factor Xa inhibitor, as evident by its

chemical structure on the right. Apart from the O-methyl group at the reducing end of the
molecule, the identity and sequence of the five monomeric sugar units contained in
fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated
after either chemical or enzymatic cin]] and heparan sulfate (HS). Within heparin and
heparan sulfate this monomeric sequence is thought to form the high affinity binding site
for the anti-coagulant factorantithrombin III (ATIII). Binding of heparin/HS to ATIII has
been shown to increase the anti-coagulant activity of antithrombin III 1000 fold. In
contrast to heparin, fondaparinux does not inhibit thrombin.

Administration

Fondaparinux is given subcutaneously daily. Clinically, it is used for the prevention

of deep vein thrombosis in patients who have had orthopedic surgery as well as for the
treatment of deep vein thrombosis and pulmonary embolism.

Comparison to other agents

One potential advantage of fondaparinux over LMWH or unfractionated heparin is that

the risk for heparin-induced thrombocytopenia is substantially lower. Furthermore, there
have been case reports of fondaparinux being used to anticoagulate patients with
established HIT as it has no affinity to PF-4. However, its renal excretion precludes its
use in patients with renal dysfunction. Unlike direct factor Xa inhibitors, it mediates its
effects indirectly through antithrombin III, but unlike heparin, it is selective for factor Xa.

Uses

Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine

days, but it substantially reduces major bleeding and improves long term mortality and
morbidity. It has been investigated for use in conjunction with streptokinase. Can be used
as treatment against Heparin-induced Thrombocytopenia.

ARIXTRA®
(fondaparinux sodium)
Injection
Indications and Important Safety Information
WARNING: SPINAL/EPIDURAL HEMATOMAS
Epidural or spinal hematomas may occur in patients who are anticoagulated with low
molecular weight heparins (LMWH), heparinoids, or fondaparinux sodium and are
receiving neuraxial anesthesia or undergoing spinal puncture.
These hematomas may result in long-term or permanent paralysis. Consider these risks
when scheduling patients for spinal procedures. Factors that can increase the risk of
developing epidural or spinal hematomas in these patients include:
• use of indwelling epidural catheters
• concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-
inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants
• a history of traumatic or repeated epidural or spinal puncture
• a history of spinal deformity or spinal surgery
Monitor patients frequently for signs and symptoms of neurologic impairment. If
neurologic compromise is noted, urgent treatment is necessary.
Consider the benefit and risks before neuraxial intervention in patients anticoagulated or
to be anticoagulated for thromboprophylaxis.

INDICATIONS AND USAGE

Prophylaxis of Deep Vein Thrombosis
ARIXTRA is indicated for the prophylaxis of deep vein thrombosis (DVT), which may
lead to pulmonary embolism (PE) in patients undergoing:
• hip fracture surgery, including extended prophylaxis;
• hip replacement surgery;
• knee replacement surgery;
• abdominal surgery who are at risk for thromboembolic complications.
Treatment of Acute Deep Vein Thrombosis
ARIXTRA is indicated for the treatment of acute deep vein thrombosis when
administered in conjunction with warfarin sodium.
Treatment of Acute Pulmonary Embolism
ARIXTRA is indicated for the treatment of acute pulmonary embolism when
administered in conjunction with warfarin sodium when initial therapy is administered in
the hospital.
CONTRAINDICATIONS
ARIXTRA is contraindicated in the following conditions:
• Severe renal impairment (creatinine clearance <30 mL/min) in prophylaxis or
treatment of venous thromboembolism.
• Active major bleeding.
• Bacterial endocarditis.
• Thrombocytopenia associated with a positive in vitro test for anti-platelet
antibody in the presence of fondaparinux sodium.
• Body weight <50 kg (venous thromboembolism prophylaxis only).
WARNINGS AND PRECAUTIONS
• Use with caution in patients who have conditions or who are taking concomitant
medications that increase risk of hemorrhage.
• Bleeding risk is increased in renal impairment and in patients with low body
weight <50 kg.
• Thrombocytopenia can occur with administration of ARIXTRA.
• Periodic routine complete blood counts (including platelet counts), serum
creatinine level, and stool occult blood tests are recommended.
• The packaging (needle guard) contains dry natural rubber and may cause allergic
reactions in latex sensitive individuals.