Lipitor is the trade name for atorvastatin, a statin drug produced by Pfizer used to lower cholesterol. It works by inhibiting the enzyme HMG-CoA reductase in the liver to reduce cholesterol production. Lipitor was discovered in 1985 by Bruce Roth while working at Warner-Lambert and became the best-selling drug of all time after its launch, generating $12.4 billion in global sales in 2008. It faces competition from generic versions after losing patent protection in 2012. Lipitor is regulated by the FDA and underwent various stages of development and clinical trials before being approved.

1. Lipitor – The Blockbusting Drug of the Early 21st
Century
Higher Certificate in Science in Good
Manufacturing Practice & Technology 2011/12
Industrial Project
Presented by Leonard Allen

2. Introduction – What is Lipitor?
Lipitor is the trade name for Atorvastatin produced by Pfizer and is a member of the Statin
family of pharmaceuticals with the primary purpose of lowering cholesterol.
It lowers triglyceride and low density lipoproteins (LDL) or “bad cholesterol” levels in the
bloodstream by inhibiting the enzyme HMG-CoA Reductase which produces cholesterol in
the liver and in turn increases high density lipoprotein (HDL) or “good cholesterol” levels.
High cholesterol levels give rise to cardiovascular diseases such as strokes and heart attacks
and Lipitor works as a preventative measure through anti-inflammatory and other
mechanisms and it also stabilizes plaque.
Lipitor is a slow-release drug, because one of its purposes is to maintain steady levels of
drugs in the bloodstream.
Reference: (http//:www.lipitor.com/)
Discovery of Lipitor
The drug discovered by Bruce Roth in 1985 when he was working at Warner-Lambert (now
Pfizer). It was a late entry into the cholesterol management market as its development was
marked by setbacks including an early formula that consisted of 50% waste material and
mediocre results in animal studies, because the drug performed similarly to other products
that were available at the time.
Warner-Lambert had created a process for eliminating waste from the compound, but were
reluctant to proceed with testing the product.
While the animal studies showed disappointing results, Lipitor showed great promise for
humans as an initial study of twenty-four people found that 10 milligrams of Lipitor lowered
counts of “bad cholesterol” by 38% and 80 milligrams lowered LDL levels by 80%.
In both cases the results were higher than other drugs of this class at higher doses.
Warner-Lambert were still unsure about placing this product on the cholesterol management
market and they teamed up with Pfizer for marketing purposes. As a result of the success of
Lipitor, Pfizer acquired Warner-Lambert in the year 2000 (fifteen years after Bruce Roth
discovered the drug!)
Pfizer is renowned for its aggressive marketing practices, particularly its direct campaigns to
doctors. It is still unclear as to whether Lipitor was a success due to a marketing campaign or
actual results.
Reference: http://en.wikipedia.org/wiki/Atorvastatin

3. History of Lipitor
Lipitor is a trade name for Atorvastatin which is a modern drug used to lower serum levels of
cholesterol. It is a synthetic statin, unlike earlier statins that were extracted from natural
sources. It works by preventing the build-up of “bad cholesterol” and conversely increases
the body’s “good cholesterol” requirements.
Early Natural Statins
Natural Statins had been known to herbal and natural medicine for centuries. One such
remedy was red rice yeast which was also used as a staple food in China as it is also a main
ingredient in Chinese red barbecued pork.
Early Statin Extracts
Early statins were produced by extracting naturally occurring statins form different sources,
including red rice yeast, but the problem with extracting statins from natural sources was
supply and control over the molecule.
Synthetic Statins
The desire for better results from statin drugs and for drugs not dependent on limited natural
supplies led to the development of synthetic statins. Atorvastatin was discovered in 1985 by
Bruce Roth and released a few years later after successful clinical trials. This development
prompted other manufacturers (competitors of Warner-Lambert in the 1980’s) to look for
synthetic statins that were cheaper and more effective.
Reference: http://en.wikipedia.org/wiki/Atorvastatin
Manufacturing & Marketing Companies
Lipitor is the trade name of atorvastatin and its patent expires in November of this year when
Ranbaxy intend to produce Lipitor as a generic. Ranbaxy also currently produce Lipitor under
licence from Pfizer under the brand name Atarvadel in India.
Competitor Products
In addition to Lipitor, Pfizer also produce three other cholesterol lowering drugs which are
Livas, Sortis and Torvast.
Lipitor’s closest competitor product is Crestor which is produced by Astra-Zeneca (AZ).
Other main competitors are Atoris which is produced by KRKA in Slovenia and Torvacard
which is produced by Zentiva in the Czech Republic and these are both sold on the East
European markets. Another competitor product is Atorlip which is produced by Cipal in India
and is sold on the South American and Far-Eastern markets.
Reference: http://en.wikipedia.org/wiki/Atorvastatin

4. Product Details
Product Family – Statins
There are two groups of statins- those that are fermentation-derived, such as lovastatin,
simvastatin and pravastatin and those that are synthetic, such as fluvastatin, atorvastatin,
cericastatin and rosuvastatin.
The International Non-proprietary Name (INN) or generic name for Lipitor and similar
products is atorvastatin. These are statins that primarily target cholesterol by stabilizing
plaque and reduce the risk of strokes through anti-inflammatory and other measures. Like all
statins, atorvastatins work by inhibiting HMG-CoA Reductase, which is an enzyme found in
the liver an plays a key role in the production of cholesterol in the body.
With global sales of US $ 12.4 billion in 2008, Lipitor was the best-selling branded
pharmaceutical in the world.
Its US patent protection was due to expire in June 2011, but this was delayed because Pfizer
made an agreement with Ranbaxy Laboratories to launch Lipitor as a generic in November
2011. In India Ranbaxy sell Lipitor under the trade name Atarvadel.
Reference: http://en.wikipedia.org/wiki/Statin
Side Effects
Lipitor is not for everyone. It is not for pregnant women, people with liver problems or
arthritis.
Common side effects of Lipitor relate to the digestive system, such as diarrhoea and upset
stomach as well as muscle and joint pain.
When exercise and diet do not suffice in the objective of lowering one’s cholesterol, Lipitor
or one of the other statins may be recommended by one’s doctor.
There were also concerns that statins were likely to increase the risk of cancer, but this was
proved wrong by various studies which showed that statins actually reduce the risk of cancer
by 50%.
A large study by Dr Jennifer N. Poynter and her colleagues at the Department of
Epidemiology at the University of Michigan in 2005 compared 1,953 patients with colorectal
cancer to 2,015 people not affected by the disease found that taking statins over a five-year
period reduced the risk of developing cancer by 50%.
In May 2005, another observational study of half a million American military veterans
showed that taking statins reduced the risk of developing several types of cancer by 50%.
Statins did not have a casual role in reducing the risk of cancer as other patients taking statins
would have benefited from medical advice.
References: http:www.lipiotor.com/aboutLipitor/sideEffects.aspx and
http://chealth.canoe.ca.ca/channel_section_details.asp?
text.id=3729&channel_id=12&relation_id=14412

5. Chemical Structure of Lipitor and its Ingredients
Atorvastatin calcium is the molecular term for Lipitor and other similar lipid-lowering agents.
An atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
Reductase. Lipitor catalyses (speeds up the reaction) the conversion of HMG-CoA to
mevalonate, which is an early step in lowering the rate of cholesterol biosynthesis.
Atorvastatin’s chemical structure is [R-(R*R*)]-2-(4-fluorophenyls)-dihydroxy-5-(1-
methylethyl)-3-phenyl-4-[(phenyl-amino)carbonyl]-Hpyrrole-1-heptanoicacid, calcium salt
(2:10 trihydrate).
Atorvastatin is a whitish crystalline powder that is insoluble in strongly acidic pH’s, such as
those lower than 4, but is slightly soluble in distilled water, pH 7.4 phosphate buffer,
acetonitrile ethanol and is very soluble in methanol, which all have neutral pH’s.
Lipitor tablets for oral administration contain 10, 20 or 40 mg atorvastatin and the following
excipients or inactive ingredients:
• Calcium Carbonate (USP);
• Candelilla Wax (FCC);
• Crosscarmelose Sodium (NF);
• Hydroxypropyl Cellulose (NF);
• Lactose Monohydrate (NF);
• Magnesium Stearate (NF);
• Microcrystalline Cellulose (NF);
• Opadry White YS-1-7040 (hydroxypropylmethylcellulose, polyethylene glycol, talc
and titanium oxide);
• Polysorbate 80 (NF) and
• Simethicone Emulsion.
Reference: http://www.rxlist.com/lipitor-drug.htm
Production Process
Atorvastatin Calcium is mixed with the above excipients and then goes through the tableting
process known as wet granulation.
The process begins when the API is milled to remove lumps which hinder reactions by
slowing them down or preventing their completion. This is because product specification lays
down a fixed particle size range and this is often the case with API’s before they are
transferred to secondary plants and this also ensures tablet uniformity and requisite
bioavailability.
Delumping is the milling process used for Lipitor, because this provides a more manageable
feed for the normal milling process or the next stage of production.
Once the API has been milled it is blended with the above excipients and a liquid is added in

6. an agitator-based vessel to form a uniform mass. This is followed by wet screening where the
damp mass is forced through a screen similar to a sieve to form a wet coarse pellet. These are
dried by an automated vacuum and they go through a simultaneous milling and sieving
process before further excipients such as lubricants are added and the mixture is blended
before being compressed.
Reference: Toebes, Dr A; 2010; Manufacturing Technology Course Notes; Milling; (Reasons
for Milling) Page 121; (Delumping) Page 123; Manufacture of Tablets (Wet Granulation)
Page 154; Cork Institute of Technology
Lipitor Molecule
Chemical Formula: (C33H34FN2O5)2Ca.3H2O
Molecular Weight: 1209.42 Dalton or AMU (Atomic Mass Units)
Reference: http//www.aurorafinechemicals/images/index55-1_image002.gif
Mode of Action
Statins act by completely inhibiting HMG-CoA Reductase in the body’s metabolic pathway
for the synthesis of cholesterol.
Although statins primarily reduce the build-up of cholesterol within the body, their action
actually goes much further than this. By reducing cholesterol levels of individual cells, statins
aid the liver in the removal of LDL’s or “bad cholesterol” from the bloodstream by up
regulating the expression of the LDL receptor. Dr Michael S Brown and Dr Joseph L
Goldstein were jointly awarded the Nobel Prize for Physiology in 1985 for clarifying this
mechanism.
Statins also have non-cholesterol functions the main one being the prevention of
cardiovascular disease by four proposed mechanisms, namely
• Improving endothelial function (the function of the layer of flat cells lining
closed spaces within the body);
• Modulation of inflammatory responses;
• Maintaining plaque stability and
• Prevention of the formation of thrombus.

7. Lipitor in the Media
In “The Irish Times” edition of Thursday September 1st 2011 appeared an article entitled
“Sanofi plans generic cholesterol drug.”
This article stated that Paris-based Sanofi had been awarded a licence by Pfizer to produce a
generic of Lipitor as the product is to lose its patent protection next year.
In the French newspaper “Les Echos” sources close to the matter stated that Sanofi’s generic
drug maker Zentiva will be allowed to produce Lipitor when its patent expires on May 7th
2012.
This deal is part of France’s Strategic Council of Health Industries (CSIS – Le Conseil
Strategique pour les Industries Santes) programme which is a cooperative agreement between
the French government and the pharmaceutical sector which gives Pfizer a tax break for
allowing Zentiva to produce cheaper copies of Lipitor when its patent expires.
This agreement is aimed at keeping pharmaceutical production sites and employment in
France as Sanofi has targeted generics as a growth sector as their own branded drugs are also
losing their patents.
Reference: “The Irish Times” Thursday September 1st
2011
http://www.irishtimes.com/newspaper/breaking2011/0901/breaking8.html
The “Sunday Independent” edition of June 27th
2010 contained a broad article on Irish
industry in general which mentioned Pfizer and its products in one sentence: “Pfizer’s Irish
plants make its blockbuster medicines such as impotence drug Viagra, cholesterol controller
Lipitor and anti-depressant Effexor.”
Reference: “Sunday Independent” June 27th
2010
http://www.independent.ie/business/irish/what-things-does-ireland-make-2236692.html
Regulatory History
How is Lipitor regulated?
Lipitor is monitored by the Center for Drug Evaluation & Research (CDER), which is a
division of the FDA with responsibility for monitoring most drugs as defined by the US
Federal Food Drug & Cosmetic Act of 1938.
The CDER reviews and manages current Good Manufacturing Practice (cGMP) Regulations
for pharmaceutical manufacturing and determines which medicines require a prescription. It
also monitors the advertising of approved medications and analyses safety data about
pharmaceutical products that are already on the market.
The regulatory process consists of eleven phases which are:
• Drug Discovery
• Drug Design;

8. • Drug Development;
• New Drug Application (NDA);
• Investigational New Drug Application (IND);
• Clinical Trials (Four Phases);
• Randomized Controlled Trials;
• Pharmacovigillance;
• Abbreviated New Drug Application (ANDA);
• Fast track approval and
• Off-label use.
Drug Discovery
This is the process by which drugs are discovered by identifying the active ingredient from
traditional remedies or by finding it form an unexpected source. A new approach has been to
understand how disease and infection are controlled at the molecular and physiological stages
and to target specific entities based on this knowledge. The process of drug discovery
involves the identification of candidates, synthesis, characterization, screening and the
determination of therapeutic efficacy. Despite advances in technology and a better
understanding of biological systems, drug discovery is still a long drawn out process due to a
low rate of new therapeutic discoveries and the high research and development (R&D) costs
associated with each new molecular entity (NME).
Reference: http://en.wikipedia.org/wiki/Drug_discovery
Drug Design
This is also known as rational drug design or structure based drug design and it is the
inventive process of finding new medications based on available knowledge of the biological
target. The drug is typically a small organic molecule which activates or inhibits the function
of a biomolecule, such as a protein, which results in a therapeutic benefit to the patient. The
most basic drug design technique involves the design of small molecules that are equal in size
and charge to the biological target for which they are intended and that they will also bind to
it. This phase frequently, but not always relies on computer modeling techniques, which are
known as Computer-aided drug design. The term drug design can also be slightly misleading,
because strictly speaking this is ligand design, whereby a substance forms a complex with a
biomolecule to serve a biological purpose. Modeling techniques for predicting binding
affinity have been successful in the majority of cases. But other properties, such as bio-
availability, half-life and a lack of side-effects have to be optimized before a drug can be
deemed to be fit for purpose.
Reference: http://en.wikipedia.org/wiki/Drug_design
Drug Development
This is a broad term which is used to describe the process of bringing a new pharmaceutical
product or medical device onto the market. It incorporates drug/product development and

9. design, pre-clinical research on animals or microorganisms and clinical trials on humans. This
term can be divided into clinical and pre-clinical work. In the pre-clinical phase, compounds
called New Chemical Entities (NCE’s), which are also known as New Molecular Entities
(NME’s) emerge from the drug discovery process. They will have promising activity against
a biological target believed to be important in a disease, but little will be known about the
toxicity, pharmacokinetics and metabolism in humans as the purpose of drug development is
to assess all of these parameters before human clinical trials. Another objective is to make a
recommendation of the dose and schedule to be used the first time an NCE is used in a human
clinical trial. In addition, the drug development phase is required to establish the
physiochemical properties of the NME, such as its chemical composition, its stability and
solubility as well as satisfying the requirements of the drug regulatory authorities, such as the
FDA.
Reference: http://en.wikipedia.org/wiki/Drug_development
New Drug Application (NDA)
This is a process used in the US whereby drug sponsors formally propose that the FDA give
formal approval to a new pharmaceutical for sale and marketing. The objectives of the New
Drug Application (NDA) are to provide the FDA with enough information to establish the
following particulars:
• Is the drug safe and effective in its proposed use(s) when used as directed and
does it carry more benefits than risks?
• Is the drug’s proposed packaging appropriate and what information should it contain?
and
• Do the manufacturers adhere to the CGMP regulations and are there adequate
controls in place to maintain the drug’s quality, preserve its identity, strength
and purity?
Before trials on humans, drug manufacturers are obliged by law to obtain an Investigational
New Drug (IND) designation form the FDA, which is based on clinical data, typically form
studies on animals that show that the drug is safe to be tested on humans. Typically such new
drugs submitted for IND designations include NME’s or modified versions of old
medications to determine differential pharmacological effects or elimination of side effects
previously experienced with old medications.
Reference: http://en.wikipedia.org/wiki/New Drug_Application
Investigational New Drug Application (IND)
An Investigational New Drug Application (IND) is a process whereby sponsors acting on
behalf of pharmaceutical manufacturers in the US seek exemption from the FDA’s approved
marketing application before transporting the investigational drug to across state lines to
clinical investigators in different states. During a new drug’s early pre-clinical development,
the sponsor’s primary goal is to find out if the product is not harmful to humans and also to
determine whether it shows pharmacological activities that justify its future commercial
development. When the product is identified as viable for further development, the sponsor
collects the data and all other information necessary to establish that the product will not
expose humans to unreasonable risks, when used in limited early stage clinical trials. The
FDA comes into play when the sponsor (manufacture or potential marketer has screened the

10. new molecule for pharmacological activity and astute toxicity potential in animals and then
proceeds to test its diagnostic and therapeutic potential in humans. The molecule then
changes status from under the US Federal Food, Drug & Cosmetics Act of 1938 whereby it
becomes a new drug subject specific to the requirements of the regulatory authorities.
Reference:
http://ww.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApprove
d/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm
Clinical Trials (Four Phases)
Clinical trials are a set of procedures in medical research and drug development that are
conducted to allow safety and efficacy data to be collected for health interventions. These
trials can only take place after satisfactory information has been collected regarding the non-
clinical safety of a new drug. Health Authority and/or Ethics Committee approval is then
granted in the country in which the trial is taking place. Depending on the drug type and its
stage of development, investigators select healthy volunteers and/or patients in small pilot
studies, followed by larger scale studies with patients often compare the new product with
currently prescribed treatment as positive safety and efficacy data are collected and the
number of patients is typically increased. Clinical trials can vary in size from a single centre
in a small country, such as Ireland, to multicentre trials in a number of bigger countries, such
as the US or Germany. The costs of clinical trials are very substantial and are borne by the
sponsor (a pharmaceutical or biotechnology company). As the diversity of roles may exceed
the resources of the sponsor, clinical trials are managed by an outsourced partner, such as a
contract research organization or a clinical trials unit in the academic sector (a university or
similar such institution).
Reference: http://en.wikipedia.org/wiki/Clinical_trial
The four phases of Clinical Trials are as follows:
• Phase I Initial Safety Trials on a New Medicine;
• Phase II Pilot Clinical Trials;
• Phase III Pre-regulatory Trials and
• Phase IV Post-Marketing Surveillance.
Phase I Initial Safety Trials on a New Medicine
These trials establish the dose range tolerated by volunteers in single and multiple doses.
These can take place on seriously ill patients, such as cancer patients or those with minor
illnesses, when a new drug’s effect on metabolism has been addressed.
Phase II Pilot Clinical Trials
This phase of the clinical trials process evaluates the safety and efficacy of a drug on selected
populations with the disease or condition that is targeted by the product, such as cholesterol
which is the case with Lipitor. Objectives may focus on dose response such as allergic
reactions, the type of patient it is suitable for and other characteristics regarding its safety and
efficacy. Pivotal trials are also part of this phase and these represent the most rigorous
demonstration of a medicine’s efficacy.

11. Phase III Pre-regulatory Trials
These trials take place after the safety and efficacy of a medicine have been determined, but
prior the submission of an NDA or other document to the regulatory authorities (FDA). These
trials are conducted in populations of patients with the condition (high cholesterol) for which
the medicine (Lipitor) is intended. Additional efficacy and safety data is generated from large
numbers of patients in both controlled and uncontrolled trials. Clinical trials are also
conducted on specific groups of patients such as those with renal (kidney) failure or under
special conditions determined by the nature of the medicine and the disease. These particulars
form the basis for what should be contained on the package insert and the label of the
medicine and supplement or completer earlier trials sand may be directed towards new trials
such as quality of life or marketing.
Phase IV Post-marketing Surveillance
This phase consists of trials or studies conducted after a medicine has been marketed to
produce further information about its efficacy and safety profile. Different formulations,
dosages, durations of treatment, medicine interactions and comparisons with other medicines
–such as comparisons between Lipitor and Crestor- may also be evaluated, by studying the
effects of a new medicine on specific age groups, races or other types of patients. The
detection and definition of previously unknown or unidentified adverse reactions are another
important aspect of this phase. This is observational or non-experimental in nature to
distinguish it from well-controlled Phase IV Clinical Trials or Marketing Studies.
Reference: http://www.virginia.edu/vpr/irb/HSR_docs/CLINICAL_TRIALS-Phases.pdf
Randomized Controlled Trials
A randomized controlled Trial (RCT) is a type of clinical trial used specifically to determine
adverse reactions to and other medical treatments and to determine the efficacy or
effectiveness of healthcare services (medicine or nursing) and/or health technologies (surgery,
medical devices or pharmaceuticals. The primary distinguishing feature of these trials is that
subjects to be studied, after the assessment of their eligibility and recruitment are randomly
allocated to receive one or the other of the alternative treatments under study. Random
allocations in real trials is complex, but it is based on the principles of probability in that it is
similar to the tossing of a coin. After having been randomly selected, the two (or more)
groups of subjects are followed up in the same way and the only differences in the care that
they receive should be similar to those being compared. The most important advantage of
proper randomization is that it reduces allocation bias in selecting candidates for the various
treatments under review and balances unknown diagnostic factors in the allocation of
treatments.
Reference: http://en.wikipedia.org/wiki/Randomized_controlled_trial
Pharmacovigillance
This is the process relating to the detection, assessment, understanding and prevention of side
effects associated with medicines. This is a science of collecting, monitoring, researching,
assessing and evaluating information form healthcare providers and patients on the adverse
side effects of medications, biological products, herbal products and traditional medicines
with a view to identifying new information about hazards and preventing harm to the patients.
This process begins in Phase I of the clinical trials, before the drug is approved and it
continues after the drug has been approved, whereby several post-market safety studies are

12. conducted and many of these are being made compulsory by regulatory authorities
worldwide, such as the US FDA and Irish Medicines Board (IMB). This is becoming more
important for doctors and scientists because of a global surge in product recalls being
outlined in the mass media. These trials involve populations consisting of several thousand
patients at most and when a drug enters the market for the first time, its less common side
effects or adverse drug reactions (ADR) are often unknown. Severe ADR’s such as liver
damage are often undetected as such populations are small. Post-marketing surveillance uses
tools such as data mining (gathering of large scale data) from spontaneous reporting systems
and patient registries and the investigations of reports of such cases identify relationships
between drugs and ADR’s.
Reference: http://en.wikipedia.org/wiki/Pharmacovigillance
Abbreviated New Drug Application (ANDA)
An Abbreviated New Drug Application (ANDA) is a US application for generic drug
approval. Such applications are submitted to the FDA’s CDER Office of Generic Drugs,
which provides for review and ultimate approval of generic drug products. Once a generic has
been approved an applicant (pharmaceutical company) may manufacture and market a
generic drug product to provide a safe, effective and low-cost alternative to innovator drugs
(those that are protected by patents), such as Crestor as a cheaper alternative to Lipitor. As a
result of electronic submissions there has been a 70% increase in ANDA’s since November
2008. A generic drug is comparable to an innovator drug in terms of dosage form, strength,
route of administration, quality, performance characteristics and intended use. All approved
products are listed in the FDA’s “Approved Drug Products with Therapeutic Equivalence
Evaluations” also known as the “Orange Book”. Generic drug applications are termed
“abbreviated” because they are generally not required to include pre-clinical (animal) and
clinical (human) trial data to establish safety and effectiveness. The alternative to clinical
trials in the ANDA process is that applicants must scientifically demonstrate that their
proposed generic drug has the same bioequivalence (performs in the same manner) as the
innovator drug. One way of determining the bioequivalence of a proposed generic drug is to
measure the time it takes for the generic drug to reach the bloodstream of 24 to 36healthy
volunteers. This gives an indication of the rate of absorption and bioavailability of the generic
drug and the results of these tests will determine the efficacy of the generic drug when results
are compared with similar tests on its closest innovator drug. Using bioequivalence as the
basis for approving generic versions of innovator drugs was established under the US Drug
Price Competition and Patent Term Restoration Act 1984 (also known as the “Hatch-Waxman
Act”). This Act outlines the availability of cheaper generic drugs by allowing the FDA to
approve applications to market generic versions of brand-name drugs without conducting
costly clinical trials. Brand- name companies also have the option of applying for a five-year
extension to the patent protection of the new medicines that they developed to make up for
lost time as a result of the slow FDA approvals process. Brand-name drugs are also subject to
the same bioequivalence tests as generics upon reformulation.
Reference: http://en.wikipedia.org/wiki/Abbreviated_New_Drug_Application
Fast-track Approval
This is a designation of the FDA that prioritizes particular investigational new drugs for
approval while undergoing clinical trials. This status is given to agents that are believed to be
potentially more effective than others in treating serious life-threatening illnesses, such as
cancer or cardiovascular diseases, for which there is currently no other effective drug

13. available. This process is designed to facilitate the development and review of drugs to treat
serious illnesses and to fill a medical need that had never been previously encountered. The
purpose of this process is to get drugs to the patient quicker and to address a broad range of
serious diseases. Determining the seriousness of a disease is a matter of judgement on behalf
of the medical profession but it is generally based on whether the new drug will have an
impact on factors such as survival, day-to-day functioning or the likelihood that a disease
may spread rapidly (like cancer) if left undetected.
Reference: http://en.wikipedia.org/wiki/FDA_Fast_Track_Development_Program
Off-label Use
This is the practice of prescribing pharmaceutical products for an unapproved indication, an
unapproved age group or in an unapproved does format or route of administration. The FDA’s
CDER reviews each new drug application for data from clinical trials to see if the results of
the clinical trials support the drug for a specific use. If the CDER is satisfied that the drug is
safe and effective, the manufacturer and the FDA agree on specific language used to describe
the dosage and route of administration and other information to be included on the label and
what extra detailed information is required to be included on the packaging insert. The FDA
then approves the drug for prescription use and will continue to regulate the Pharmaceutical
industry through the work of its Division for Drug Marketing, Advertisement and
Communication (DDMAC). The FDA does not have legal authority to regulate the practice
of the medical profession, but a physician may prescribe a medicine off label. Ironically it is
legal in the US and other countries to use controlled substances, such as opiates off label.
Actiq is one such example, even though it is a Section II controlled substance. While it would
be legal for a physician to prescribe Actiq off label, it is illegal for a manufacturer to promote
such a product for off-label uses. The Food Drug and Cosmetic Act (FDAC) 1938 forbids
manufacturers from directly marketing a drug for use other than an approved FDA indication.
THE FDA Modernization act 1997 created and exception to the prohibition of off-label
marketing whereby manufacturers are now able to provide medical practitioners with off-
label information in response to an unsolicited request.
Reference: http://en.wikipedia.org/wiki/Off-label_use
Cost of Lipitor to the Patient
O’Reilly’s Pharmacy Bishopstown Tuesday September 13th
2011
As part of my research I carried out a speculative visit to O’Reilly’s Pharmacy in
Bishopstown, which is not far from the Cork Institute of Technology and interviewed the
pharmacist Mr Edward O’Reilly with regards to the cost of Lipitor the patient, its
effectiveness and popularity and what does Mr O’Reilly think will happen when Lipitor goes
off patent.
The costs of the various dose strengths of Lipitor are as follows (per packet of 28 tablets):
• 10 mg € 27.90;
• 20 mg €49;
• 40 mg €52 and
• 80 mg €59.

14. Each packet of the various dose strengths listed above comes with a month’s supply of Lipitor
tablets and the recommended daily dosage is one tablet per day.
How effective is it?
According to Mr O’Reilly, Lipitor has been very effective in lowering cholesterol, because
oxidized cholesterol has been the main risk factor with patients who require Lipitor.
Complaints about adverse reactions
O’Reilly’s Pharmacy has received complaints about side effects of the drug such as
• weakening of the heart muscle;
• trans-global amnesia;
• aches and pains and
• lowering of Vitamin D levels.
Weakening of the Heart Muscle
This condition is known as cardiomyopathy and is a deterioration of the heart muscle. This
term relates to any heart disease but, specifically severe forms that lead to heart failure and
other cardiovascular diseases. This is different form congestive heart failure (CHF) in that the
heart muscle may be normal even if CHF is present in cases caused by Thyroid problems,
anaemia or other causes. Ironically CHF may also be absent from a patient with a weakened
heart muscle.
There are three types of cardiomyopathies which are:
• Congestive: This type is characterized by weakened heart muscle. The heart is
generally enlarged and its pumping action is slower than normal.
• Hypertrophic: This type of cardiomyopathy is characterized by the heart
muscled being thickened and stiffened and is also known as Idiopathic
Hypertrophic Sub aortic Stenosis (IHSS) or Hypertrophic Obstructive
Cardiomyopathy (HOCM). This is a cardiomyopathy in which there is an
obstruction to the outflow of blood form the ventricle caused by an overgrowth
of tissue below the aortic valve.
• Restrictive: This is an unusual cardiomyopathy where the heart muscle is
usually stiff, but not thickened.
Reference: http://www.heartpoint.com/congheartfailuretellme.html#anchor45600
Transient Global Amnesia (TGA)
This is one of the most striking syndromes of clinical neurology, whereby a patient has a
temporary, both short-lived disruption of short-term memory combined with a complex series
of difficulties in accessing older memories. A person in a state of TGA shows no other signs
of malfunctioning mental processes, but can only recall the last few moments of
consciousness as well as deeply encoded facts from one’s past as well as one’s own name. A
TGA event can last from 2 to 8 hours. One of its most bizarre features is that the victim of an
attack consistently repeats questions with identical intonation and gestures and is a defining

15. characteristic of the condition. An individual in a state of TGA retains their social skills and
old significant memories. The causes of such a condition range from an epileptic event, a
problem with blood circulation around the brain or a migraine headache or related illness.
Reference: http:en//wikipedia.org/wiki/Transient_global_amnesia
Aches and Pains
The most common aches and pains suffered by patients on Lipitor are muscular pains. In
2004 some Lipitor patients reported severe pains which resulted in a loss of muscle control
and coordination. Refraining from taking Lipitor was believed to have been one solution to
this problem. Pfizer then advised Lipitor patients to inform their doctor if they were feeling
unwell due to this side effect of the drug. Some Lipitor users had taken Pfizer to court
because in some instances This side effect resulted in permanent muscle damage. Muscular
pains were mainly experienced by one in ten Lipitor patients and it was recommended that
such patients took lower dosages of the drug or changed to a different statin. In smaller
numbers such as one in 1,000 Lipitor caused muscular inflammation that resulted in
tenderness and fever and in an even smaller sample (one in 10,000) Lipitor caused
rhabdomyolysis, which is a breakdown of muscle fibres which leads to kidney failure and can
be fatal if left undetected.
References: http://heatlh.howstuffworks.com/medicine/medication/10-wierd-precription-
drug-side-effect2.htm
and
http://health.msn.com/health-topics/cholesterol/aches-and-pains%e2%80%94is-your-statin-
to-blame
Lowering of Vitamin D Levels
This is another side effect of Lipitor resulting from the fact that as cholesterol is lowered or
even virtually eradicated, Vitamin D levels are simultaneously reduced, because a Vitamin D
precursor is synthesized form cholesterol in the skin in response to the body absorbing light
from ultra-violet B (UVB) rays. The precursor if Vitamin D is converted in the lever to an
intermediary known as calcidiol, which then reacts with an enzyme in the kidneys to produce
its final product which is responsible for a wide range of anti-inflammatory activities. As
Vitamin D levels are dependent on adequate levels of cholesterol, an urgent review of
Vitamin D content of is needed as a result of Vitamin D levels to counteract Lipitor’s ability
to lower Vitamin D levels.
Reference: http://www.spacedoc.com/statins_vitaminD.html
Is it the most popular statin sold by O’Reilly’s Pharmacy?
Yes, Lipitor is the most popular statin sold by O’Reilly’s with sales volumes of Crestor,
which is very similar to Lipitor in that it is synthetic, coming in at a very close second.
What will happen when Lipitor comes off patent?
According to Mr O’Reilly the price of Lipitor will come down when the product loses its
patent and he also believes that there is a big sea of change to question the validity that
cholesterol is the villain that it is perceived to be, which it actually is not.

16. When Lipitor loses its patent the price will come down by 15% because generic drugs are
cheaper than those that are protected by patent and this will result in increased competition
between all statins on the market.
Comparisons with other Statins – Crestor
Crestor is slightly different form Lipitor in that it is a Rosuvastatin (non-proprietary term for
Crestor) and it also contains sulphur. It is marketed by Astra-Zeneca (AZ) as Crestor and as
R2 in India by Abbott Laboratories.
Crestor is available in doses of 5 mg, 10 mg, 20 mg and 40 mg and comes in packets
containing 28 tablets and one tablet per day is also the recommended daily dosage with
Crestor.
Cost of Crestor to the Patient
The costs of the various dose strengths of Crestor are as follows (per packet):
• 5 mg € 30;
• 10 mg €30;
• 20 mg €51 and
• 80 mg € 54.
Crestor also won approval from the Japanese Ministry of Health and Welfare (equivalent of
FDA) produce doses ranging from 2.5mg to 20 mg outside the US. 97% of Crestor’s global
sales have been at or below the 20mg dose.
Structure of Crestor
Crestor Molecule

17. Chemical Formula: (C22H28FN3O6S)2Ca
Molecular Weight: 481.539 Dalton or A MU (Atomic Mass Units)
Reference: http://www.ganfyd.org/images/8/8b/Rosuvastatin.png
Crestor is rosuvastatin calcium in which calcium replaces the H in the carboxylic acid group.
It is also different from Lipitor because it contains sulphur and it is 727.881 Dalton or AMU
lighter than Lipitor.
Crestor is a competitive inhibitor of the enzyme HMG-CoA reductase and has a similar
mechanism to other statins. Its approximate elimination half-life is 19 hours and its time to
peak plasma concentration is 3-5 hours following oral administration.
It is believed that the beneficial effects of rosuvastatin therapy on chronic heart failure may
be ruled out by increases in the production of collagen as well as a reduction in the plasma of
the coenzyme Q10 (CoQ10) levels in patients with chronic heart diseases.
Regulation
Rosuvastatins are regulated for the treatment of levels of high LDL, total cholesterol and/or
triglycerides. In February 2010 Crestor was approved for the primary prevention of
cardiovascular diseases.
As of 2004 rosuvastatins were approved in 154 countries and launched in 56. It was approved
by the FDA in the US on August 12th
2003.
Results of the JUPITER Trial in 2008 suggested that rosuvastatins may decrease the relative
risk of cardiovascular diseases in patients who do not have total cholesterol, but who have
highly sensitive C-reactive protein. This clinical trial was awarded the FDA seal of approval
in the prevention of cardiovascular diseases.
Crestor’s effect on cholesterol levels
The effects of rosuvastatins are dose related. One trial found that the 10mg of Crestor reduced
LDL levels by 46%, while the 40mg dose was less effective as it reduced LDL levels by a
mere 9%.
The FDA also issued a special advisory for Asian patients of Crestor, because there was an
increased risk of muscle weakness among Asian-Americans.
Rosuvastatins are processed differently in Asia than in the Western world, because half the
standard Western dosage suffices for Asians according to a study by Astra-Zeneca. It has also
been recommended that physicians start Asians on the lowest available dose levels.
Patent Protection
The patent for rosuvastatins RE37314 which is due to expire in 2016 was challenged as being
an improper issue of an earlier patent. This challenge was rejected in 2010 and the patent
extended for a further six years.

18. Marketing
Crestor was billed as a “super-statin” during its clinical development, claiming that it offered
high potency and improved cholesterol lowering mechanisms than other statins, such as
Lipitor and Zocor, which is a simvastatin.
Some people have been known to combine ezetimibe with rosuvastatins or atorvastatins and
other agents on their own for better cholesterol lowering rates.
Some publicized information for comparing rosuvastatin, atorvastatin and
ezetimibe/simvastatin results are available, but some of the relevant studies are still in
progress.
Cost of Crestor to the Patient
The costs of the various dose strengths of Crestor are as follows (per packet of 28):
• 5 mg € 30;
• 10 mg €30;
• 20 mg €51 and
• 80 mg € 54.
Side Effects of Crestor
Crestor has the same side effects as Lipitor but it also carries one other undesired side-effect
known as rhabdomyolysis, which is a condition whereby skeletal muscle ceases to function
and can also lead to kidney failure. The breakdown products of muscle cells, such as the
protein myoglobin which is harmful to kidneys, are released into the bloodstream and this in
turn can lead to kidney failure. The severity of the symptoms, which may include muscle
pains, vomiting and confusion, depend on the extent of the muscle damage and this is a key
factor in determining whether kidney failure will or will not occur. Muscle damage causing
rhabdomyolysis can have physical factors, such as an injury sustained in a crush or as a result
of vigorous exercise. Other factors are Medications, drug abuse or infections. Hereditary
muscular conditions can also increase the risk of rhabdomyolysis. Diagnosis of this condition
is determined by the results of blood and/or urine tests. Patients with this condition may
require the feeding of intravenous fluids through a drip or in more severe cases, dialysis or
haemofiltration, which is a kidney replacement therapy.
Reference: http://en.wiki.org/wiki/Rhabdomyolysis
According to the FDA: “it does not appear that the risk [of rhabdomyolysis] is greater with
Crestor than with other marketed statins”, but mandated that a warning about this side effect
as well as a kidney toxicity warning be added to the product label.
Warning Letters
In July 2001 Pfizer were served with a warning letter from the US Food & Drug
Administration (FDA) concerning an advertisement for Lipitor in an American
Pharmaceutical journal.
Reference: http://www.pharmcast.com/WarningLetters/Yr2001/Pfizer0701.htm

19. The FDA’s complaint stated that this advertisement created an overwhelming impression that
Lipitor reduced the risk of coronary heart disease, which was false, as the effects of Lipitor
on cardiovascular morbidity had not been established.
The advertisement was also described as being misleading because it failed to present
important information relating to the risks associated with the drug and contained an over
emphasis on efficacy claims with statements such as
• “Lipitor provides impressive LDL-C reductions”;
• “72% of patients reached their NCEP-LDL-C goal at 10mg” and
• “Powerful effect on lipid parameters”.
Presentation was also a big issue as the advertisement had an over emphasis on efficacy than
warnings. Efficacy items, such as specific reductions in LDL-C, TG and HDL-C were
indicated in big print and that warning information was printed too small with no headers to
alert the readers to the importance of specific items in this section.
The disclaimer “when diet and exercise fail” was also printed too small and the advertisement
broadened the benefits of Lipitor with minimal information about its correct use.
The FDA also requested that Pfizer ceased distribution of the advertisement and all
promotional material with the above information or similar claims about Lipitor. Pfizer were
also set a deadline by which to state their intention to comply with this request and to submit
a list of materials discontinued and the dates on which they ceased to be used.
Did Lipitor have Recalls?
In October 2010 Pfizer recalled specific bottles of 40 mg Lipitor due to a small number of
complaints regarding an uncharacteristic odour relating to the bottles in which the drug was
packaged. A medical assessment determined that the uncharacteristic odour was not likely to
cause adverse effects for Lipitor users, but patients who were taking Lipitor from 40 mg
bottles were requested to return these bottles to their pharmacist if they experienced the
uncharacteristic odour which gave rise to the recall.
Pfizer, who are committed to ensuring the safety of patients who take their medicines, then
investigated the cause of the uncharacteristic odour with the bottle supplier to address the
matter promptly.
Further information was available through a Pfizer helpline (1-888-LIPITOR) or
http://lipitor.com/recall.aspx as well as through consultation with one’s doctor or pharmacist.
Pfizer took a number of steps to ensure that there was no shortage of 40 mg bottles of Lipitor
and also advised patients to consult with their pharmacist about refund policies as Pfizer did
not provide a direct refund to the patients.
Reference: http://www.fda.gov/Saftety/Recalls?ucm228998.htm

20. Has Lipitor been subject to counterfeiting?
In May 2003 the FDA confirmed that Albers Medical Distributors Inc. had voluntarily
recalled three lots of 90-count bottles of Lipitor and warned healthcare providers that this
quantity of counterfeit Lipitor represented a significant risk to consumers.
This product was repackaged by Med-Pro Inc. of Lexington, Nebraska and the labels on the
product read “Repackaged by MED-PRO Inc., Lexington, Neb.”
The items concerned by this recall were:
• 20272V – 90 tablet bottles – Expiry Date September 2004;
• 04132V – 90 tablet bottles – Expiry Date January 2004 and
• 16942V – 90 tablet bottles – Expiry Date September 2004.
The FDA also urged healthcare providers and patients to check the packaging very carefully
and to also requested the prompt return by patients to their p[pharmacists of bottles produced
in any of the three above lots and carrying the inscription “Repackaged by MED-PRO Inc.,
Lexington, Neb.” on the labels.
The FDA’s Office of Criminal Investigations investigated the existence of counterfeit Lipitor
as part of the FDA’s efforts to investigate and address suspected counterfeiting activities.
This recall was part of the FDA’s public health mission, whereby it regularly conducts
investigations and tests to identify and remove products that are counterfeit or have been
tampered with from the market.
Reference: http://medicinenet.com/script/main/art.asp?articlekey=23487
What measures are in place to prevent counterfeiting?
Counterfeiting of medicinal products has been on the increase in the US and around the
globe, which is dangerous by nature as the products are not produced under cGMP conditions
and evade inspections by the FDA.
The increase in this criminal practice is attributed to the growing involvement in the medicine
supply chain of under-regulated wholesalers and repackagers and the proliferation of internet
pharmacies, combined with advances in technology that have made it easier to produce
counterfeit medicines.
In 2010, 8.4 million tablets, capsules and vials of counterfeit Pfizer medicines were seized
across 53 different countries. These seizures resulted from raids by Pfizer Global Security.
Pfizer has no higher priority than ensuring that consumers have safe and effective medicines
by working with the regulatory authorities to combat counterfeiting and to secure the integrity
of the pharmaceutical supply chain.
Pfizer has a team of experts who constantly assess new and existing technologies to identify
which technologies will make it more difficult to make convincing copies and for patients
and healthcare professionals to distinguish between authentic and counterfeit Pfizer products.
While there is no “catch-all” solution, Pfizer works closely with the FDA and other regulatory

21. bodies to ensure that pharmaceutical companies have the resources needed to implement anti-
counterfeiting technologies that will work most effectively for their products.
Pfizer is also working closely with wholesalers, pharmacies, customs offices and law
enforcement agencies worldwide to address product integrity issues as they arise and to work
proactively to increase inspection coverage, monitor distribution channels and improve
surveillance of distributors and repackagers.
Pfizer has also created a diversified international team with the objective of rapidly
addressing product integrity issues as they arise and to work proactively to prevent them from
occurring. The team is focused on implementing business practices designed to protect
patient health, increase cooperation with law enforcement agencies, prosecute counterfeiters
and promote public policy that will help to eliminate counterfeiting.
Addressing this issue is a sophisticated, coordinated and united response.
Pfizer recognizes that as well as its own initiatives, partnerships must be forged across
government agencies, the healthcare community, patients and third-party stakeholders to
ensure that patients have a safe supply of medicines and that justice will be served on those
engaged in counterfeiting.
Reference:
http://www.pfizer.com/products/counterfeit_and_importation/counterfeit_importation.jsp
How effective is the FDA’s initiative for the prevention of counterfeiting?
The FDA created a task force that developed recommendations in collaboration with other US
government agencies and the private sector to prevent counterfeit medicines form getting into
the supply chain.
The risks of counterfeit drugs present serious health and safety concerns as they contain
inactive ingredients (excipients), the wrong ingredients and are in stronger or lower dose
strengths than those officially recommended.
Drug counterfeiting has been a very rare occurrence and I believe the FDA’s anti-
counterfeiting measures are very effective, because in the 1990’s there was only a 5%
occurrence in the production of counterfeit drugs (as detected by the FDA) but in the early
years of this century there has been a 20% increase in the production of counterfeit
medicines. This is where the volume of counterfeit finished pharmaceuticals is greater than
the corresponding volume of counterfeit API.
As the drug manufacturing and distribution system has become more complex, there is
increased opposition to the introduction of legitimate appearing products into the US drug
supply chain as the challenge of protecting society against unsafe medicines is becoming
more difficult.
The FDA has an aggressive enforcement strategy in the war against counterfeit drugs as it
detected 73 cases of counterfeiting between October 1996 and June 2003. This process
resulted in 44 arrests and 27 convictions, with fines of in excess of US $250,000 also being
imposed. There are also a few related criminal investigations still in progress.
The FDA has public and private partners in the war to assist in identifying and tracking down
counterfeiters. High volume and high cost drugs, such as Lipitor and other statins are targeted

22. by those engaged in counterfeiting, who also see this as a quick get rich scheme!
Collaboration between the FDA and the US Bureau of Customs and Border Controls
identifies suspect packages that enter the US from other countries and enter the US
distribution system. This is a very challenging exercise, because of the large volumes of
packages entering he US on a daily basis containing drugs purchased online and the FDA has
also alerted consumers about the risks associated with medicines obtained from unknown
sources.
Drug manufacturers also play their part in the war on counterfeit drugs, whereby they
voluntarily inform the FDA within five working days of determining if there has been a
reasonable basis to believe that a pharmaceutical product has been counterfeited. This is also
extended worldwide if the FDA and drug manufacturers are of the opinion that such products
were intended for import into the US.
This came into effect in May 2009 when reports of counterfeit Lipitor were detected. Under
this legislation the FDA is seeking to improve its deterrence and detection measures in
enforcing the law against healthcare criminals as part of its efforts in protecting American
society from counterfeit drugs. This is the operation of the FDA’s Office of Criminal
Investigation (OCI) which works in conjunction with Federal (US national) and state
(California, Texas etc) law enforcement agencies.
In one instance the OCI worked closely with Florida’s law enforcement officials in the
investigation, arrest and conviction of healthcare criminals.
Details of FDA’s initiative to combat counterfeit drugs
In order to respond to the increased sophistication and opportunities for the counterfeiting of
prescription drugs before it becomes a widespread problem, the FDA launched a new anti-
counterfeit initiative designed to identify the risks and threats posed by such products and to
coordinate efforts both the public and private sectors in the war against counterfeiters. It also
seeks to identify tools and technologies to identify, deter and combat counterfeiting. A new
internal FDA Counterfeit Drug Task Force is engaged in exploring new and existing measures
in place to prevent patients from being exposed to the dangers of counterfeit drugs.
The areas explored by the FDA task force include
• Technology
• Border study
• Alert system
• Strengthening of distribution system
• Engaging private sector stakeholders
• Engaging other government agencies
• Public education and
• Higher penalties.

23. Technology
The task force is examining technologies currently available and potential future low-cost
technologies that can be used to assure product and package integrity and to track whether or
not products in the supply chain are legitimate. Known technologies already in place that are
adequate to be identified by the naked eye include inks and watermarks. These are used in
existing packaging mechanisms and are beneficial in determining the legitimacy of a product
to pharmacies and/or patients. In some cases covert methods, such as an ultra violet
spectrometer may be used to determine a product’s authenticity. One drawback with these
technologies is that if they are not unique to a particular product (such as using marks on
blister packs) it is possible that counterfeiters could repackage illegitimate drugs in
legitimate packaging. It may also be costly and time consuming to use the tools required to
authenticate such packaging labels. An alternative technology that is currently being
developed is the use of microchip-based detection taggants to determine the legitimacy of
products in the supply chain by emitting radio frequency signals to provide very specific
information about each individual item in the supply chain. This technology is currently in its
infancy and further cost effective analysis is needed for the FDA to decide if this will be the
most effective tool in the war against healthcare criminals.
Border Study
With assistance from US Customs and Border Protection the FDA is initiating a study of
pharmaceutical products entering the US at seaports. The findings of such a study will
determine the type and extent of drugs being imported and whether or not counterfeit
products are contained within such consignments.
Alert System
The task force is currently seeking to improve upon the current counterfeit alert system to
enhance communication about known or suspected counterfeit medicines at all phase of the
supply chain form the manufacturers through intermediaries (wholesalers and retail
pharmacies) to the patient.
Strengthening of Distribution System
This will identify mechanisms to improve the wholesale distribution system such as creating
a model code of conduct for wholesalers on top of strengthening the model practice act for
individual States to implement on wholesalers. This objective is to increase consumer
protection in a low-cost fashion.
Engaging Private Sector Stakeholders
The task force gathers information from the private sector and collaborates with healthcare
professionals, pharmacists, drug manufacturers, consumer organizations and other
stakeholders on the best methods of combating criminal practices.
Engage Other Government Agencies
The task force will improve coordination with other Federal US government agencies,
including the US Customs & Border Protection Service, the treasury department (US
Ministry of Finance), The Federal US Department of Justice and governments of individual
States in which counterfeiting has occurred.

24. Public EducationThis recommends methods of educating consumers about steps that they
can take to minimize the risks associated with counterfeit drugs. It also informs patients about
what to look for and what action to take if they suspect that they have received a counterfeit
medicine.
Higher Penalties
The task force is exploring potential deterrence and stiffer effects of penalties to be imposed
on those found guilty of producing counterfeit prescription drugs. The current such penalties,
which are ironic, are ten years imprisonment for counterfeiting the label of a drug product
compared with three years imprisonment for the production of an actual counterfeit drug
product.
Task Force Reports
In December 2009 the FDA issued an interim report with recommendations for public
comment. Following input form interested parties with regard to the report and its
recommendations, the FDA finalized a report in May 2010 to issue a strategic plan of action
outlining public and private sector actions needed to address their concerns about counterfeit
drugs.
Reference: http://www.fda.gov/Drugs/DrugSafety/ucm180899.htm
What will happen when Lipitor loses its patent
protection?
Lipitor is one of the most notable statins that has helped lower the rates of cardiovascular
diseases worldwide.
At its peak, annual global sales were in excess of US$13 billion, which surpassed those of its
nearest generic competitor Crestor, which lost its patent in 2010 and achieved annual global
sales of US$10.7 billion.
Lipitor's success was down to a number of factors, primarily its large and expensive clinical
trials, which Pfizer carried out over a number of years and showed that patients at risk of
cardiovascular diseases had greatly reduced adverse effects compared with placebo (sham or
simulated medical intervention). Lipitor's efficacy and long-term safety profile have also
made it a household name.
In November 2011 when Lipitor comes off patent, generic drug manufacturers will be able to
start selling atorvastatins at lower prices. It is not unusual for generics to be 10% to 20%
cheaper than branded drugs. Pfizer's sales of Lipitor will fall dramatically as pharmaceutical
industry analysts have believed for the past few years.
Astra-Zeneca (AZ) sells Crestor (generic term Rosuvastatin), which garnered global sales of
US$5.6 billion when the drug lost its patent the same year. AZ had believed that Crestor was
a superior drug when it became to lowering LDL (bad cholesterol) levels and conversely
increasing HDL (good cholesterol) levels.
Lipitor was on the market before Crestor and there was no great difference between either
product according to physicians who were already familiar with Lipitor and this resulted in
doctors not transferring patients to a newer drug, such as Crestor. While Crestor is also an

25. important drug on the cholesterol management market, it has consistently trailed Lipitor in
terms of sales which has always been a drawback for AZ.
With Lipitor losing its patent, AZ will be presented with a bigger problem, which is the fact
that the generic price of atorvastatin will be a tenth of the value of Crestor. Payers-insurance
companies and Medicare (US social insurance program providing over 65's with health
insurance) will have to insist that patients new to cholesterol lowering medicines be
prescribed generic Lipitor as opposed to Crestor. It will cause more concern for healthcare
plans that will try to transfer patients currently on Crestor to generic Lipitor in order to reduce
costs to the patient. The loss of Lipitor's patent will affect sales of Crestor as well as having
an impact on Pfizer.
AZ was aware of this and over the years had taken steps to differentiate Crestor from
atorvastatins. Crestor's two main differences from Lipitor are that chemically it contains
sulphur and biologically it lowers levels of the inflammatory C-Reactive Protein (CRP)
which causes a variety of inflammatory conditions including atherosclerosis ("hardening of
the arteries"). it is scientifically believed that high cholesterol damages walls of the arteries
and that the process of repairing them results in the formation of atherosclerosis, resulting
from high levels of CRP.
For some unknown reason Crestor lowers CRP levels and this also distinguishes it from other
statins.
AZ ran the SATURN trial to compare Crestor directly against Lipitor in measuring the levels
of plaque in the arteries of patients with cardiovascular diseases.
AZ's thinking was that differences in the biochemical profile of Crestor V Lipitor would
produce meaningful clinical differences in slowing down the build-up of atherosclerosis. If
this theory held up AZ would then be able to show clearly that Crestor is superior to Lipitor.
The earliest available results of the SATURN trials showed encouraging trends in Crestor's
ability to reduce fatty deposits in arteries. These results were not statistically significant when
compared with results from similar tests carried out on Lipitor. AZ is carrying out as an in-
depth review of these results and the findings will be up for discussion at the next meeting of
the American Heart Association, (which is also taking place around the same time as when
Lipitor is coming off patent!) where the claim for Crestor's superiority over Lipitor is likely to
be deemed invalid. The drop in price for generic atorvastatins will be difficult for physicians
to justify when prescribing cheaper drugs.
Lipitor's patent expiration will affect sales of both Lipitor and Crestor, resulting in increased
competition in the cholesterol management market.
Reference: http://johnlamattina.wordpress.com/2011/09/23/loss-of-exclusivity-of-pfizer's-
lipitor-will-also-impact-astrazeneca-az/
References
Cover Image of packet of Lipitor tablets
http://www.drugs-expert.com/wp-content/uploads/2010/06/Lipitor.jpg
Introduction – What is Lipitor?

26. http//:www.lipitor.com/
Discovery of Lipitor, History of Lipitor and Marketing & Manufacturing Companies
http://en.wikipedia.org/wiki/Atorvastatin
Product Details –Statin Types
http://en.wikipedia.org/wiki/Statin
Side Effects
http:www.lipiotor.com/aboutLipitor/sideEffects.aspx
http://chealth.canoe.ca.ca/channel_section_details.asp?
text.id=3729&channel_id=12&relation_id=14412
Chemical Structure of Lipitor and its Ingredients and Side Effects
http://www.rxlist.com/lipitor-drug.htm
Production Process
Toebes, Dr A; 2010; Manufacturing Technology Course Notes; Milling; (Reasons for
Milling) Page 121; (Delumping) Page 123; Manufacture of Tablets (Wet Granulation) Page
154; Cork Institute of Technology
Schematic of Lipitor Molecule
http//www.aurorafinechemicals/images/index55-1_image002.gif
Lipitor in the Media
“The Irish Times” Thursday September 1st
2011
http://www.irishtimes.com/newspaper/breaking2011/0901/breaking8.html
“Sunday Independent” June 27th
2010
http://www.independent.ie/business/irish/what-things-does-ireland-make-2236692.html
Regulatory History
http://en.wikipedia.org/wiki/Center_for_Drug_Evaluation_and_Research
Comparisons with Lipitor – Crestor
http://en.wikipedia.org/wiki/Crestor
Schematic of Crestor Molecule
http://www.ganfyd.org/images/8/8b/Rosuvastatin.png
Warning Letters
http://www.pharmcast.com/WarningLetters/Yr2001/Pfizer0701.htm
Recalls

27. http://www.fda.gov/Saftety/Recalls?ucm228998.htm
Counterfeiting
http://medicinenet.com/script/main/art.asp?articlekey=23487
Measures to Prevent Counterfeiting
http://www.pfizer.com/products/counterfeit_and_importation/counterfeit_importation.jsp