Discuss the “Right to Try” legislation, designed for a special population. Do you think it will help them? What about the supply chain for these drugs- can the manufacturers reasonably supply them?. What if the drugs turn out to be dangerous? What if they start being used by people who aren’t terminal.
Off Label Use of Drugs:
1. Discuss the ramifications of off-label use of drugs.
2. Find and discuss two examples of off-label uses of drugs that have been successful. Find one example where a manufacturer has promoted an off-label use of a drug in a manner that was not in compliance with the law. Don’t use the examples from the powerpoint!
3. Discuss the influence of globalization of drug production and clinical trials on the availability and safety of drugs (hint, think of the aftermath of Hurricane Maria and the effects it had, or the effect that the COVID pandemic has had, on availability of drugs). One drug that became difficult to get for a while is tacrolimus, used to prevent organ transplant rejection. You might want to investigate a drug shortage and discuss what you think the reasons were.
Week 5, Lecture 11
Counterfeit Drugs
HCR 555
Pamela Potter, PhD
©PE Potter/ASU 2022
Global Manufacturing
India has 5000 pharmaceutical manufacturers
Some are large companies, others small formulators
There is little regulation
Pharmacists often supply drugs without prescriptions in many
countries
Prescribers in many countries feel there is a lack of
standardization and worry about the quality of medicines
They are often very cheap, which drives global sales
Global Manufacturing
Many drugs are counterfeited, and much of this is occurring
globally
Counterfeiting is most common in countries where there are few or no
rules about making drugs.
In the industrialized world (US, Australia, Japan, Canada, New
Zealand, and EU), less than 1% of medicines sold are counterfeit.
An estimated 10%–30% of medicines sold in developing
countries are counterfeit.
– Even 1% affects millions of people
– Especially common for drugs that are expensive
– Sadly, also common for drugs used for serious illnesses
– Most counterfeit medicines (48%) come from Western Asia, and
most are for infectious diseases (51%), especially malaria and
tuberculosis
Counterfeit drugs
WHO defines a counterfeit drug as:
– One which is deliberately and fraudulently mislabeled with
respect to identity, source, or both.
– Can apply to both branded and generic products.
– Can include
products with correct ingredients
wrong ingredients
insufficient (or too much) active ingredient
fake packaging
Substandard Drugs
WHO defines substandard drugs as
– Genuine drug products that do not meet quality
specifications set for them
– If a drug, upon laboratory testing in accordance with
the specifications it claims to comply with, fails to meet
the specifications, then it is classed as a substandard
drug
A drug could be both counterfeit AND substandard
Counterfeit and Substandard Products
In India, syringes are often re-packaged and re-used
In India, 13-30% of drugs are counterfeit
Ireland has reported fake avian flu vaccine, and veterinary drugs repackaged and sold for human use
In Nigeria, 36% of drugs, and 48% of anti-infectives, are substandard
or fake
In Thailand, that number is 40%
In Burma, about 20% of anti-infectives are fake
In Vietnam, about 8% are substandard, but not fake
In 2017, WHO found that 1/10 medical products in developing countries
is substandard or counterfeit, leading to thousands of deaths
https://www.who.int/news-room/detail/28-11-2017-1-in-10-medical-productsin-developing-countries-is-substandard-or-falsified
https://www.who.int/bulletin/volumes/88/4/10-020410/en
Effects of Counterfeit and Substandard
Products
Serious adverse events may occur as a result of
counterfeit or substandard drugs
500 children died in the 1990s in Bangladesh, after using
cough syrup that contained fake acetaminophen and
diethylene glycol, which is toxic to the kidneys
192,000 people died in China in 2001 due to fake drugs
The Chinese government investigated 480,000
counterfeiting cases for drugs valued at $57 million US and
shut down 1300 companies
Pills containing fentanyl present a risk in US, causing
deaths from unintentional overdose
DEA Considers Fentanyl-Containing Counterfeit Medications a Global Threat
Effects of Counterfeit and Substandard
Products
People may get drugs that contain substances not indicated
on the label
These could be substances they are allergic to or cannot
take for other reasons
Drugs with little or no active ingredient will not be as
effective, and this may lead to drug resistance developing
Drug resistance for malaria, tuberculosis, and HIV is
thought to result in part from use of substandard or
counterfeit drugs
Bacteria in some eye drops have caused serious infections
Adulterants
Fake drugs may contain harmful materials
– Water containing bacteria in solutions
– Dyes
– Powdered cement
These contaminants are
frequently seen in herbal
– Clay
products as well!
– Toxic road paint
– Floor wax
– Boric Acid
– Antifreeze
– Fake inhalers for cystic fibrosis patients
contaminated with bacteria going into the lungs
– Cancer drugs containing only dirty water
Salting
Another technique is to add some real drug to the fake drug
The real drug is often expired and/or purchased from a
foreign country
It is then mixed with the faked ingredients so that if it is
tested, it will actually contain the drug
This is called “salting”
Why Counterfeit?
It is profitable
– About $300 BILLION in sales, fake medicine in developing
countries could be a $30 billion dollar business (not to mention
the rest of the world..)
– Criminal activity may combine both counterfeit pharmaceuticals
with illegal drugs
– Counterfeit drugs safer- fewer penalties
– A lot of criminal organizations switching away from aggressively
pursued illegal drugs
– Pursue multiple markets at different price points
– Counterfeiters may be quite skilled
– Hard to tell the difference without chemical analysis
An Example
A Senior director of global security for Pfizer
– Found counterfeit anti-malarial pills in Tanzania
– They looked identical to the Pfizer product
– Batch numbers were identical to the Pfizer pills
– The expiration dates were identical
– The packaging was indistinguishable from the genuine
– The blister packs looked identical
– The tablets looked identical
– When tested in a laboratory, they contained NO active
ingredients at all
– Women and unborn children would die due to not
receiving treatment for malaria, the criminals don’t care
Counterfeiting
Many countries have little or no regulation
Penalties are severe in some countries, but mild
in others
– In the Philippines, you get 6 months to life, and a
$25,000 fine
– In India, it was 5 years in prison, and $108 fine but
prison time has increased to 10 years to life and
the death penalty is possible
– China imposed strict penalties and decreased
counterfeiting
– Interpol has encouraged more global cooperation
Internet Pharmacies
Make life easy for counterfeiters
Hard to tell where the pharmacy really is sometimes
– There are legitimate US pharmacies that sell onlinethey will require a prescription
– There are legitimate Canadian pharmacies, that also
will require a prescription
– PharmacyChecker.com approves legitimate pharmacies
– If no prescription required, probably NOT legitimate
https://www.theatlantic.com/sponsored/pfizer-2017/need-to-know-fakemedicine-is-a-bigger-problem-than-youthink/1610/?gclid=CjwKCAjw2Jb7BRBHEiwAXTR4jchGhC6ZROyZuZ2Bo_exUCf
3c5orH4p0SJ4eCcWj1k8DCh51VdciYBoC8WEQAvD_BwE
Internet Pharmacies
More than 30% of people have bought drugs online
The US online prescription drug market is about $12 billion
– Used by people without insurance
– Used by people who are embarrassed to go to doctor
– May be used by people for whom going to pharmacy is difficult
– People think drugs MIGHT be substandard, but willing to take
the risk for lower price
Where are the Pharmacies?
Many claim to be in Canada
Drugs are actually shipped or claim to be shipped from
Australia, India, China, Cyprus, Germany, Austria, Switzerland
Many ship products labeled and packaged for foreign markets,
not US or Canada
Drugs patented in the US can be manufactured without paying
the patent fee and sold as generic products in India- these
often make their way into Internet sales…
Internet Pharmacies
Popular drugs purchased from Internet pharmacies in US
include:
– Lipitor (atorvastatin), to lower cholesterol, Pfizer
– Viagra (sildenafil), erectile dysfunction, Pfizer
– Celebrex (celcoxib), arthritis, Pfizer
– Nexium (esomeprazole), GERD, AstraZeneca
– Zoloft (sertraline), depression, Pfizer
FDA information on Online Pharmacies
Online Pharmacies
Fake Pharmacies
Allow you to buy drugs without a
prescription from your doctor
Offer deep discounts or cheap
prices that seem too good to be
true
Send spam or unsolicited email
offering cheap drugs
Are located outside the US
Are not licensed in the United
States
Legitimate Pharmacies
Always require a doctor’s
prescription
Provide a physical address and
telephone number in the
United States
Offer a pharmacist to answer
your questions
Have a license with the state
board of pharmacy
Drugs for Erectile Dysfunction
A good market, online sales very popular
Expensive drugs- all are patented
Need to see a doctor and be examined
Need to go to pharmacy and pay premium
price
Embarrassing for many
Inconvenient
Viagra
In one study, 50 samples of Viagra were obtained from online
pharmacies
The drugs were then tested to see what they contained
Some pills did not look right and couldn’t be assessed- they
may have been knockoffs of Cialis instead
Some pills were very over-priced
Others, which were cheaper, were generally not real
•Surpisingly, most of
the pills really WERE
Viagra!
•The pharmacies that
were not
recommended or not
identifiable provided
the fake pills (8% and
25%)
•The recommended or
legally compliant
pharmacies provided
the real deal- all of
them were real, no
drugs failed in testing
Mostly, you got what you paid for…
But many pharmacies overcharged
Other Viagra Experiences
A counterfeit version of Viagra in Singapore was sold
in 2008- it actually contained an anti-diabetic drug
– 150 patients were hospitalized for hypoglycemia, 7
remained comatose, and 4 died
– This has also recently occurred in Australia
Most counterfeit Viagra and similar drugs are sold
over the internet
The prices may not be lower- in fact they are
often higher
People pay for the convenience
Cialis
A similar product, tadalafil, also for erectile dysfunction,
has been found in a counterfeit version
Counterfeit version label lists “AUSTR81137” on the front of the bottle;
does not include an NDC number on the front of the bottle
does not include the tablet strength in a colored box; has different patterns
and colors; it has yellow and darker green designs on the front label; has
misspellings; lists, “CLALIS is a product of: Eli lilly Australia PTY Limited”
on the side of the bottle;
lists the manufacturer location as “112 Wharf Road, WEST RYDE, NSW
2114” on the side of the bottle; and lists “Lot: AC 066018, Exp: 01SEP17”
on the side of the bottle.
It has been marketed by online pharmacies
It can probably be assumed that any product for erectile
dysfunction from an online pharmacy, especially without a
prescription, is going to be counterfeit
There is no evidence that the legitimate supply chain is
affected
BOTOX
Botox very popular- injected to decrease wrinkles- women go to
“Botox parties” like our mothers went to Tupperware parties
The genuine product is safe, but
A counterfeit version was identified in the US in April 2015
FDA says this product is unsafe- the vial and carton are counterfeit,
and labeled incorrectly
Some of my friends go to Mexico
• The vial is missing the lot number
• The outer carton does not have any
entries next to the LOT: MFG: EXP:
• The outer carton and vial display the
active ingredient as “Botulinum
Toxin Type A” instead of
“OnabotulinumtoxinA”
to get BoTox- what do they get?
……I’m not sure
Counterfeit Products in the US
There have been instances of counterfeit drugs
manufactured in the US as well
– In 2003, it was estimated that sales of counterfeit or
tainted drugs were $200 million
– In 2003, 200,000 bottles of Lipitor were confiscated in the
US- fake drug mixed with actual drug produced in South
America
– 88% of foreign drug imports examined at US international
mail facilities were unapproved, stored incorrectly, and
had safety issues
– Many drugs purchased from Mexico have issues, especially
Lipitor and Viagra
current
https://www.fda.gov/Drugs/ResourcesFor
You/Consumers/BuyingUsingMedicineSafel
y/CounterfeitMedicine/default.htm
Last year
Diclofenac is an NSAID- there are people allergic to
this drug who would NOT know they were getting it!
Micheal Carlow
He noticed that patients with HIV got their (expensive) drugs
free from Medicaid in Florida
– He bought the drugs for a small price from many of the patients,
so they could by cocaine or heroin instead
– He then re-packaged and re-introduced these drugs into the
legitimate drug supply
– Very profitable
– The patients with AIDS didn’t get better, and other patients got
drugs that might, or might not, have been legitimate
Micheal Carlow
He noticed that some drugs used in oncology come in similar
vials but at different doses
– One of these is Epogen, to combat chemotherapy induced
anemia
– He bought vials of a lower dose, then re-labeled them with
labels identical to the real product but stating they contained a
higher dose
– The higher dose is more expensive
– These were then sold for a nice profit
– The patients who received them didn’t get the benefit of the
right dose of drug
Micheal Carlow
By now, there was a family of companies
– They located offshore sources of US drugs
– They re-imported the medications
– They were re-labeled to meet US specifications
– They were then sold to unsuspecting dealers and pharmacies
– Lipitor was a popular counterfeit product
– They had warehouses in the back rooms of strip clubs
– They were earning $3 million per month before they got caught
Micheal Carlow
19 people were arrested in the ring who had been selling
adulterated, counterfeit and stolen drugs for years
Micheal Carlow was sentenced to 9 years in prison
For more information on this case, click here
http://katherineeban.com/dangerous-doses/summary/
For more information on efforts to control counterfeiting, click here:
http://www.phrma.org/issues/counterfeit-drugs
And it goes on…….
Real HARVONI costs $84,000 for a 12 week treatment. That
is a big profit margin for a fake drug.
Patients go to Thailand or India to get it cheaply. Is the
product they get real? If it works, probably. But who knows?
https://philamedsoc.org/fda-warns-pharmaciesof-a-potentially-counterfeit-drug-purchasedfrom-a-suspended-pharmacy-in-philadelphia/
https://www.popsci.com/whatcan-we-do-to-stop-fake-medicines
https://www.npr.org/2021/09/27/1040899776/deapublic-safety-alert-fake-prescription-drugs-fentanyl
Some websites to visit
https://www.pfizer.com/news/articles/fake_drugs_
101_facts_on_illegal_counterfeit_drugs
https://www.bayer.com/en/health/backgroundinformation-on-counterfeit-drugs
https://www.fda.gov/drugs/buying-usingmedicine-safely/counterfeit-medicine
https://wwwnc.cdc.gov/travel/page/counterfeitmedicine
Some interesting News Stories
http://www.newsweek.com/2015/09/25/fake-drug-industry-
exploding-and-we-cant-do-anything-about-it-373088.html
http://www.cbsnews.com/news/the-difficult-fight-againstcounterfeit-drugs/
http://usatoday30.usatoday.com/money/industries/health/drugs/st
ory/2011-10-09/cnbc-drugs/50690880/1
http://www.pbs.org/wgbh/nova/next/body/uncovering-counterfeitmedicines/
Week 5, Lecture 10
Biosimilar Drugs
HCR 555
DR PAMELA POTTER
©PE Potter/ASU 2022
Biopharmaceuticals
These are copies of endogenous human proteins
They mimic compounds such as growth factors, erythropoietin and other blood
forming factors, insulin, and cytokines that are normally manufactured by the body
Many of them are peptides or antibodies to specific cell types
They are large, complex molecules
There are huge numbers of these drugs being developed
They have provided effective treatments for a host of diseases that were previously
untreatable
Uses include treatment of cancer, autoimmune diseases, reversal of neutropenia,
anemia, etc
http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedand
approved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm428732.pdf
Biologicals
The FDA has recently amended this act to provide some clarification
Biological product means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood,
blood component or derivative, allergenic product, protein, or analogous product, or
arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic
compound), applicable to the prevention, treatment, or cure of a disease or condition of
human beings.
A protein is any alpha amino acid polymer with a specific, defined sequence that is
greater than 40 amino acids in size.
Biopharmaceuticals
These compounds are exact copies of normal human proteins
They are produced by recombinant DNA technology or by hybridoma
technology
They are large molecules, and the process for making them is very
difficult, and it is proprietary
The average molecular weight is 4000- 140,000 Daltons
This compares to 160-800 Daltons for the majority of small molecule
drugs
Biological Drugs are
much larger and more
complex than most
drugs, which are small
organic molecules
They generally need to
be administered via
injection
Because of their
complexity, they can be
difficult to produce
Biopharmaceuticals
These are very expensive drugs
They are expensive to make – and expensive to consumers
They are produced in cell culture of genetically modified cell lines
They need to be extracted through complicated, lengthy, purification
procedures
Quality control is essential- even a tiny change can completely change the
drugs properties
The patent life on many of these drugs has or will soon expire
Biopharmaceuticals
Examples of drugs made by biotechnology include:
◦ Filgrastim (Neupogen)- used to treat neutropenia
◦ Erythropoetin (Epogen), darbepoetin (Aranesp)- used for anemia
◦ Interferon beta- used to treat MS (multiple sclerosis)
◦ TNFalpha antibodies or fusion proteins: adalimumab (Humira),
enteracept (Enbrel), infliximab (Remicade) – for rheumatoid arthritis
and other autoimmune diseases)
◦ Omalizumab (Xolair)- asthma
◦ Trastuzumab (Herceptin)- breast cancer
◦ Insulins
Biosimilars
How would you make a generic product for these drugs?
When the patent expires on a small molecule, you can
manufacture the product so long as it conforms to FDA
specifications
◦ It will be an exact copy of the brand name drug
◦ It will contain the same amount of the same active ingredient
◦ It will have similar dissolution and bioavailability properties
But there can’t be an exact match for most biological
drugs… They are too complicated
Biosimilars
The “generic” versions of biologicals cannot be
identical to the original
The preparation process is proprietary, so is not
shared
These drugs will be similar, but not identical, to the
brand name drug
They are called “biosimilars”
Biosimilars
Biosimilars are not going to be identical in their
active substances because the process to make them
is different
It is even difficult to maintain homogeneity in
batches from the same company!
There are no analytical techniques to determine
whether they are identical anyway
They can only be similar
Biosimilars
These compounds have a significant possibility to generate an immune
response
Adding peptides or antibodies to mimic natural compounds may
generate production of antibodies to these compounds
The degree of immunogenicity may differ between products that mimic
the same compound from different manufacturers
Reactions may include allergy, anaphylaxis, or serum sickness
The biological activity may be neutralized
Biosimilars
Biosimilars, or Follow-on products, are now in wide use
Rules for testing and use have been developed and agreed upon
The FDA requires that the biosimilar product must be compared to
the reference product
A biosimilar must have no clinically meaningful differences in safety,
purity and potency from the FDA-approved reference product
Biosimilar manufacturers do not have to conduct the lengthy clinical
trials that the original product went through but the FDA closely
regulates their manufacturing processes
The first bio-similar was approved in the
US in 2015
http://www.webmd.com/cancer/news/20150310/biosimilar-drugs-faq
Biosimilar Drugs: FAQ, By Kathleen Doheny, WebMD Health News
Reviewed by Arefa Cassoobhoy, MD, MPH
March 10, 2015 — Drugs known as biologics have grabbed headlines over the years, both for their
potential in fighting cancer and other diseases, and for their high price tag.
Now, the FDA’s approval of the first so-called “biosimilar” drug clears the way for manufacturers to
make lower-cost versions of those expensive drugs, saving patients money and improving access to
the medications.
The company Sandoz got approval last week to market its drug Zarxio as a biosimilar product to
Amgen’s Neupogen, originally licensed in 1991. Both drugs help people with cancer whose white
blood cell counts have fallen to low levels, which puts them at risk for dangerous infections. But the
biosimilar product is expected to cost up to a third less than the original, experts predict.
A list of currently approved drugs in the US is on the next slide- this is only for your
information, you certainly are not expected to know this
Biosimilars
Here is a good article
about Biosimilars from
Popular Science
/what-is-biosimilar
FDA Guidance on Biosimilars
The FDA provides considerable guidance on
biosimilar products.
In fact, they provide a course on
Biosimilars.
If this is an area that interests you, I would
recommend it you check it out.
Here is a link to the course:
http://fdabiosimilars.e-paga.com/
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/ApprovalApplications
/TherapeuticBiologicApplications/Biosimilars/default.htm
Approval
FDA has an abbreviated approval process for biosimilars
The product application must contain:
Analytical studies demonstrating high similarity to the reference product
Animal studies, including assessment of toxicity
Clinical studies sufficient to demonstrate, safety, purity and potency for
one of the indications that the reference product is approved for
This will also contain information on immunogenicity and
pharmacokinetics for the biosimilar product
The biosimilar must be as clinically effective as the reference, and it
should not be a problem to switch between the two products
FDA must be allowed to inspect the facility where it will be made
Interchangeable Biosimilars
Biosimilars that meet additional FDA requirements are approved as
interchangeable
That means that the pharmacist can substitute it for the prescribed
one without having to contact the doctor
The same rule applies to generic drugs unless the doctor specifies it
must be name brand
FDA has a purple book that lists biological products
https://purplebooksearch.fda.gov/
Some Interchangables
• Byooviz (ranizumab-zuna)/Mvasi (ranizumab-awwb)/ Lucentis
(ranizumab)
• Semglee (insulin glargine-yfgn)/Lantus (insulin glargine)
• Hulio (adalimumab-fkjb)/ Abrilada (adalimumab-afzb)/ Hadima
(adalimumab-bwwd)/ Hyrimoz (adalimumab-adaz)/ Cyltezo
(adalimumab-adbm)/ Amjevita (adalimumab-atto) Humira
(adalimumab)
Some examples of problems: Erythropoetin
Neutralizing natural erythropoetin can result in Ab-mediated pure red
cell aplasia (PRCA)
This had been EXTREMELY rare with Epoetin alfa treatment for anemia
PRCA increased in patients treated with Eprex, a formulation of
epoetin alfa in which the product was changed slightly
◦ Human serum albumin was replaced by glycine and polysorbate 80 was used as
a stabilizer
◦ While rare, it was a problem, so Eprex is no longer available
◦ There is an interchangeable biosimilar available now, Retacrit, which
is epoetin alfa-epbx
Biological Products-different brand names
Many biological products exist in more than one form or come from
more than one supplier
Epoetin is currently available with the brand name Epogen or Procritboth come from the same manufacturer and are not considered
biosimilar. An interchangeable biosimilar, epoetin alfa-epbx (Retacrit)
is now available
Peginterferon alfa-2b has two brand names from the same
manufacturer (PegIntron and Sylatron)- with different usage labelling
Interferon beta-1b also is available under two brand names from two
manufacturers but is not considered biosimilar
There are many distinct forms of insulin available- they are different,
not biosimilar
Pharma is informing consumers about it
https://www.merckclarifiesbiosimilars.com/?&gclid=CjwKCAjwmqHPBR
BQEiwAOvbR82cn3qewbTOeOOoxzLmwgmfLtR0iGInEN7jqP0y3097_Q5
e__-E9sxoCSAEQAvD_BwE
http://www.pfizerbiosimilars.com/characteristics-ofbiosimilars?source=google&HBX_PK=s_biosimilars&o=203
087745|402889600|0&skwid=43700023263730260
Week 5, Lecture 9
Off-Label Use of Drugs
https://www.fda.gov/forpatients/other/offlabel/default.htm
HCR 555
DR PAMELA POTTER
©PE Potter/ASU 2022
Drug Labeling Defined
The FDA considers a drug label to be
◦ The display of written, printed or graphic
matter upon the immediate container of
any article
◦ This also includes the wrapping or any
other article that may accompany the drug
◦ Accompany means anything that
supplements or explains the product
Drug Labeling
The FDA includes:
◦ Brochures, booklets, mailers, letters
◦ Detailing pieces, house publications
◦ Bulletins, calendars, file cards
◦ Catalogs, price lists
◦ Films, film strips, slides, sound recordings, exhibits
◦ Literature and reprints, published references for use
by medical practitioners, nurses, or pharmacists
Drug Labeling
According to the US Supreme Court,
“accompanying” means
◦Any matter that explains or supplements
the product
◦Whether or not that material is attached
◦Includes anything disseminated by the
manufacturer and reaches customers,
doctors or patients before, with, or after,
the product
Drug Labeling
Cannot contain instructions for “off-label”
uses
Manufacturers can be prosecuted for
illegally “misbranding” a drug if the label
contains information regarding “off-label”
use
The Federal Food, Drug and Cosmetic Act of
1938 made misbranding illegal
Drug Labeling
Misbranding occurs if the label contains false
or misleading information
Misbranding may include:
◦Information on the label
◦Information omitted from the label
◦ If every intended use is not included
◦ If adequate instructions for each use are not there
What is Off-Label Use?
Once a drug is approved for a specific
purpose, it can be used for other purposes,
even if not approved for it
An unapproved use is off-label whether:
◦Prescribed by a physician
◦Used by a patient
◦Marketed by the manufacturer
Off-Label Use
The 1997 Modernization Act stated
◦“nothing in this act shall be construed to limit or
interfere with the authority of a health care
practitioner to prescribe or administer any legally
marketed device to a patient for any condition or
disease within a legitimate health-care-practitionerpatient relationship”
This limits the FDA’s ability to control off-label
use of drugs
Off-Label Use
An FDA Drug Bulletin states that
◦ Once a drug has been approved for marketing, a
physician may prescribe it for uses or in treatment
regimens or patient populations that are not
included in the approved labeling
◦ “Unapproved”, or more precisely “unlabeled” uses
may be appropriate and rational in certain
circumstances, and may, in fact, reflect approaches
to drug therapy that have been extensively reviewed
in the literature
FDA Role
The FDA cannot regulate a doctor’s off-label
prescription of a medicine
The FDA can also not regulate the ways in which
a patient uses medication that was prescribed by
a doctor
The FDA CAN regulate a manufacturer’s
marketing of a drug
FDA Role- the 1997 Law
Before, 1997, a manufacturer could promote a
drug ONLY for its FDA approved purpose
It was argued that these rules violated the rights
of free speech for the drug manufacturers
The manufacturers were given more leeway
regarding disseminating information regarding
unapproved uses for their drugs
FDA Role- the 1997 Law
The 1997 Act states a manufacturer
◦Is allowed to distribute written information concerning
the safety, effectiveness, or benefit of a use not
described in the approved labeling of a drug
The 1997 law allowed manufacturers to give less than complete
information to a doctor
Doctors could request information about off-label use from the
manufacturer
FDA Role- the 1997 Law
DIRECT promotion was not allowed
But INDIRECT means could be employed to inform
doctors about off-label uses
◦ Research published in journal articles could be used
◦ Some of this was sponsored by the pharmaceutical
companies
◦ Textbooks could be used
◦ Education programs for doctors also
Off-label information
Manufacturers were allowed to provide financial
support for these “educational programs” where
speakers discussed off-label uses
BUT- the programs had to be organized by an
independent entity
The manufacturers were required to disclose their
financial interests and that these were unapproved
uses
Off-Label Information
Information for off-label use could be disseminated if:
◦ A new drug application had been filed
◦ Information did not pose a significant risk to public health and was
not abridged, false, or misleading
◦ It is not from another manufacturers research unless permission
was obtained
◦ A copy of the information was sent to the FDA 60 days prior to
sending to doctors
◦ A supplemental application or exception had been filed
◦ It must contain a statement that it was NOT an approved use
Off-Label Information
This information can be given to
◦ A health care provider
◦ A pharmacy benefit manager
◦ A health insurance issuer
◦ A group health plan
◦ A Federal or State government agency
There must be a fair balance of information regarding
effectiveness and risks of the drug, as well as any
significant limitations to its use
What about The Information?
Manufacturers may design the studies, control data
analysis, and publication
Researchers supported by industry are likely to find positive
results and publish them
Unfavorable studies may not be published
Physicians may receive financial benefits for finding the
drug “useful”
The 2009 Guidelines
In 2009, new guidelines were posted regarding off-label
promotion of drugs to physicians, health care professionals,
health plans, and pharmacy benefit managers
It allowed manufacturers to disseminate “truthful and nonmisleading medical and scientific information on unapproved
uses of approved drugs” if “Good Reprint Practices” are
followed
Good Reprint Practices
Unacceptable:
Retained from before:
•False, misleading info
•Poses risk to public health
◦Letters to the editor
◦Abstracts
◦Phase I reports in healthy subjects
◦“reference publications” with little or no
discussion of the relevant data
◦Publications funded by manufacturers or
anyone with a financial interest
◦Clinical investigations previously ruled as
not adequate or well-controlled by FDA
Even with Peer-Review..
Selective publication
◦Body of literature is still incomplete and may be
biased, as many studies showing negative results
may not be published
◦This was shown for antidepressants, where only
the positive clinical trials were published
Even with Peer-Review..
Ghost authorship
◦The literature can be manipulated by having authors
put their names on material written by ghost-writers
from the pharmaceutical industry
◦Ghost management of the study may eliminate
critical or unfavorable
◦Inadequate off-label supervision may encourage
NDAs for the easiest use and avoid better clinical
trials showing real risk-benefit relationships
Why Not Get Approval?
Drug is already on the market- physicians are allowed to
prescribe it
Approval will have little effect on sales
Testing process is very expensive
The patent may expire too soon to allow much profit
This is especially true for orphan diseases
The Learned Intermediary
Doctrine
Pharmaceutical companies have an exception to the
law requiring that consumers be warned of dangers
associated with a product
This is the learned intermediary doctrine, which
allows them to disseminate this information to
health care providers, instead.
This discharges the manufacturer from liability, and
puts it on the doctor
What About the Physicians?
Physicians are allowed to prescribe drugs off-label
◦ “It is the physician’s duty to weight the risks
and rewards of a particular course of treatment
when prescribing medication”
This assumes the physician has adequate
knowledge regarding the drug and its use
The court believes that doctors are best able to
evaluate and treat their patients
Physicians Become Liable
If the physician knows the risks of a drug, he or she,
not the manufacturer, becomes liable for problems
The patient then can only sue the doctor, not the
company
This is true whether the drug is prescribed according
to the label or off-label
Off-Label Prescribing
Widespread in the medical community
Estimated that from 40-60% of drugs prescribed for off-label uses
Off-label use accounts for 40-50% of prescription drug spending
Doctors are frequently unaware that the use is off-label
◦ Only half correctly identified whether uses of certain drugs
were approved or off-label
Off-Label Prescribing
Benefits
◦Science often moves faster than regulation
◦May provide state of the art treatment
◦Necessary for “orphan diseases”
◦Many groups would not have any treatments,
as few drugs are approved for them, e.g.
children
◦May save hundreds of thousands of lives per
year
Off-Label Prescribing
90% of people with rare diseases have to use drugs off-label
Most diseases affecting less than 200,000 Americans have no
approved treatment
Many cancer treatments must be off-label, especially if they
are rare
33% of all cancer treatment is off label
Three of the most common cancer drugs are used off-label
85% of the time
Off-Label Prescribing
Drugs are generally approved in adults, not children
Very few drugs are approved for use in children
95% of the drugs used in neonatology are off-label
80% of drugs in children are off-label uses
80-90% of pediatric patients are treated with off-label drugs
Standard of Care
For many conditions, off-label use of drugs is
considered “standard of care”
Physicians would be considered to commit malpractice
if they DIDN’T use these drugs
This is true in many serious and life-threatening
diseases
Example: Dexamethasone for COVID-19
The Down Side
Drugs prescribed off-label did not go through testing for that
condition or in that population
A disease state may change the way that a drug acts in the body
Side effects may not be monitored as closely, although the drug
companies are required to monitor side effects EVEN if used off-label
Over 125,000 patients die every year from adverse drug reactions
Are They Effective?
Many drugs are prescribed for off-label uses because
they work well
Others are not effective, but used anyway
Many are just used in a different patient population
Some are just used for a different period of time, but for
a similar purpose
Examples
Antihistamines are approved for seasonal allergies
What if you have allergies all year?
They are used chronically by many people, with no
harm done
In these cases, the underlying condition is the same, the
mechanism is the same, but the duration is different
Scientific Basis
Sometimes, large randomized clinical trials are conducted for offlabel uses of drugs, to determine if they are effective
Case studies, cohort studies and clinical experience may also
provide useful information
Drugs approved for one indication may be used for more or less
serious forms of that condition, or one caused by a similar
mechanism, or with similar symptoms
Scientific Support
There is good scientific support for many off-label uses
BUT- for many drugs, the level of scientific support of
effectiveness is low
Data is hard to obtain for many of these uses
Often, prescribing is done based on anecdotal information, not
scientific evidence
Side Effects and Other concerns
A recent article in JAMA Internal Medicine (Jan 2016) discussed the concern of
unexpected side effects with off-label use of drugs. This led to commentaries
and discussion regarding off-label prescribing
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2467782
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2467779
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2580726
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2525573
Other Issues
Health insurers, especially Medicare and Medicaid, only cover offlabel prescriptions some of the time
They will cover indications supported by scientific research and in
major drug compendia
The regulations change, which is confusing for physicians and
patients
Not allowing reimbursement for off-label prescriptions may be
quite expensive for patients, and sometimes the rules change
Bevacizumab (Avastin)
Monoclonal antibody, which inhibits VEGF, and decreases
angiogenesis
Was developed as a chemotherapy agent for some cancers
There were several FDA approvals following clinical trials
◦ 2004 – colorectal cancer
◦ 2006 – non-small cell lung cancer
◦ 2008 – HER2 negative breast cancer
◦ 2010 – FDA recommended removal for this purpose after examining further
evidence
◦ 2009 – glioblastoma
Bevacizumab (Avastin)
Accelerated approval was granted for metastatic HER2 negative
breast cancer in 2008
◦ Based on open-label study where progression-free time was increased by
5.5 months, but overall survival was unchanged
FDA Oncology Drug Advisory Committee (ODAC) voted 5/4
AGAINST it- but the drug was still approved
◦ Concerns included open-label design of clinical trial, toxicity of the drug,
missing data, uncertain sample size, shortcomings in safety data, and
whether the measured endpoint in the trial was meaningful
Bevacizumab (Avastin)
In 2010, ODAC voted 12/1 against keeping it on the market for use in HER2negative breast cancer
◦ Based on 3 new clinical trials designed to convert accelerated
approval to regular approval and increase the number of
applications for the drug
There was a slight increase in progression-free survival (~1 month)
The committee felt that this not a viable endpoint- although FDA had
approved it in 2008
There was NO change in overall survival, and there was considerable
toxicity
Bevacizumab (Avastin)
Based on this, FDA recommended withdrawing its approval for breast
cancer
However, it worked in some women; off-label use is possible
Insurance companies and Medicare are less likely to cover it off-label
for HER2-negative breast cancer, and although private payers follow
clinical compendia, not FDA regulations, many will not cover it for this
use
Each treatment costs about $5000
Bevacizumab (Avastin)
Because it decreases angiogenesis, it has some utility in treating
macular degeneration by decreasing vascularity in the retina
It was used off-label for age-related macular degeneration (AMD) for
several years
It was considered effective by most ophthalmologists
Thus, it became the standard of care for AMD
It was made in compounding pharmacies for about $27 per dose
Medicare/Medicaid reimbursed the doctor $50 per dose
It was cost effective for the patient and for the opthalmologist
Bevacizumab (Avastin)
Then, a new drug, ranibizumab (Lucentis), was approved for AMD
It has the same mechanism of action, is also an antibody, but is a
little smaller, and penetrates into the eye a bit better
An NIH clinical trial to compare the two was proposed, but the
manufacturer would not cooperate with the idea
The effectiveness of the two drugs appears similar
Cost of ranibizumab is about $2000/dose
Bevacizumab (Avastin)
Once it was approved, Medicare reimbursement to doctors changed
◦ Ranibizumab- $2039/treatment
◦ Bevacizumab- decreased to $7/treatment (but it costs them >$25)
Doctors now penalized for off-label use of bevacizumab
This change increased Medicare costs about $3 billion to cover
ranibizumab instead of bevacizumab
After protest, the decrease in reimbursement was overturned and
doctors now receive $55 for bevacizumab
◦ Some patients then filed a complaint that Medicare allowed bevacizumab
because they were motivated by cost rather than patient care!
◦ Patients are responsible for a fair proportion of cost on Medicare….
Money, money, money…
Fraud can occur in the prescription drug arena
There is big money to be made
Pharmaceutical spending was $327 billion in 2017
Post-marketing approval for new uses is very expensive
Fraudulent marketing has occurred
Kick-backs were once common
Off-Label Law Suits (some examples)
2017: Bristol Myers Squibb- $19.5 million for promoting Abilify in children and
adults with dementia
2013: Johnson& Johnson- $1.4 billion because they marketed Risperdal for
dementia
2012: Abbott- $800 million because they marketed Depakote to control
aggression in the elderly
2010: Astra Zeneca-$520 million for illegal marketing of Seroquel (they made
$4.9 billion in sales in 2009 from Seroquel)
2009: Eli Lilly- $1.415 billion for illegal marketing of Zyprexa in children and
elderly
https://en.wikipedia.org/wiki/List_of_off-label_promotion_pharmaceutical_settlements#BristolMyers_Squibb_Company:_Off-label_promotion_of_Abilify,_December_2016
Gabapentin (Neurontin)
Gabapentin was approved by the FDA in 1993 as adjunct treatment
for partial seizures
It has subsequently been approved for post-herpetic neuralgia and
for restless legs syndrome
It is widely used for many off-label purposes
It is very effective for neuropathic pain
It is effective for reduction in hot flashes
It is not very effective for its original approved use- seizures
Uses Promoted by Manufacturer
Gabapentin
Gabapentin was agressively marketed for off-label use
Off-label use of this drug for pain increased from 1% in 1995,
to 41% of use of the drug in 2000
Overall, 83% of gabapentin use is off-label
95% of Medicare prescriptions for gabapentin are off-label
In 2000, sales of gabapentin were $1.3 billion- most of it offlabel
Gabapentin
A “whistle-blower” who had been a salesman claimed that the
manufacturer illegally promoted the use of gabapentin for off-label
purposes to doctors
The company was reported to have
◦ Given false and misleading statements to health care providers regarding
efficacy
◦ Given false statements regarding FDA approval
◦ Paying doctors to attend meetings to hear presentations regarding off-label use
◦ Sponsoring and providing input to medical education events that were supposed
to be “independent”
◦ Misleading physicians about these events
Gabapentin
About of ½ of physicians received marketing appeals between 1995 and 1998 from
drug company salesman for off-label uses of gabapentin
Pfizer bought the drug, and said they would comply with the law in future
Parke-Davis/Warner Lambert/Pfizer was fined $430 million in 2004 (sales in 20013
were $2.7 billion)
Theywere fined $142 M in Canada in 2010 for fraudulent marketing
Pfizer was hit with more fines for Neurontin in 2014
https://www.fiercepharma.com/sales-and-marketing/pfizer-adds-another-325m-to-neurontin-settlement-tally-total-945m
There were 46 million prescriptions for gabapentin in 2017 (its generic now though)
Gabapentin- the evidence
Bipolar disorder
◦ 8 trials
◦ Ranged from1 or 2 patients, 8-37
◦ All were short term
◦ Mania improved slightly in some patients
◦ Depression improved slightly in some
Overall, not considered effective over the long term
Gabapentin- the evidence
ADHD
◦ No clinical trials- anecdotes
◦ No evidence of effectiveness
◦ ADHD should be treated with stimulants and other
measures
Migraine
◦ Some effectiveness, but there are better
treatments
◦ Considered if nothing else has worked
Gabapentin- the evidence
Neuropathic Pain
◦Now approved for post-herpetic neuralgia
◦Used for diabetic neuropathy, has shown effectiveness
◦Effective for other types of neuropathic pain
◦Pregabalin (Lyrica) is also approved
◦Tricyclic antidepressants, old and cheap, are also useful for
this type of pain
◦Gabapentin is now also quite cheap now
Gabapentin- the evidence
Restless legs syndrome
◦Inconclusive data, only 2 case studies
◦Limited effectiveness
◦Has received FDA approval for this purpose
Drug/alcohol withdrawal
◦No evidence for effectiveness
Overall, gabapentin fairly safe, now generic, and may
be useful in many situations
Psychiatric
Drugs Off-Label
Antipsychotics were
originally approved for
treatment of schizophrenia
The use of the newer drugs
has increased markedly,
much of it originally offlabel
https://www.medgadget.com/2020/02/antipsychotic-drugs-market-share-growingrapidly-2020-global-analysis-size-trends-revenue-statistics-business-insights-leadingplayers-competitive-landscape-with-regional-forecast-to-2026.html
Psychiatric Drug Off-Label
Uses
Astra Zeneca fined for off-label marketing of quetiapine
(Seroquel)
Quetiapine an effective antipsychotic
Originally approved for schizophrenia
Manufacturer pushed for use in bipolar disorder, now
approved for this purpose
Quetiapine
Now being used as an antidepressant
Approved only for refractory depression, but
doctors are prescribing as initial treatment
Used as anti-anxiety agent
◦One clinical study suggested effectiveness,
improved sleep
Highly sedating, used for sleep disorders
Quetiapine
A Few of the Side Effects
◦ Sleepiness
◦ Increased blood glucose
◦ Weight gain
◦ Increased cholesterol
◦ Cardiac problems
◦ Gastric problems
◦ Postural Hypotension
◦ Increased risk of death in elderly with dementia
Olanzapine (Zyprexa)
Approved for schizophrenia and bipolar disorder
◦ Subsequently approved for adjunct treatment of depression
Eli Lilly fined for promoting its use in agitation, depression, dementia,
sleep disorders
◦ “Viva Zyprexa!” campaign to expand use into primary care
◦ “5 at 5” marketing campaign- 5 mg at 5 pm to promote sleep
Side effects include weight gain, hyperglycemia, Type II
diabetes, increased death
◦ Manufacturer suggested weight gain could be beneficial in some
patients
Aripiprazole
This is an anti-psychotic that was used off-label for treatment
resistant depression- This is a BIG market
The manufacturer has obtained FDA approval for adjunct
treatment of depression to be a labelled use for this drug now
It has also obtained FDA approval for a monthly maintenance
dose to treat bipolar disorder
Ketamine, an anesthetic, is now being used off-label for
treatment-resistant depression
Antipsychotics in Dementia
Patients with Alzheimer’s disease sometimes have
hallucinations or are psychotic/hard to manage
Few therapeutic options for these patients
Newer antipsychotics became popular as off-label
treatments
Risperidone, olanzapine were most frequently used,
but older, conventional drugs have been used as well
All of the antipsychotics increased mortality in these
patients and are not recommended for use in patients
with Alzheimer’s disease
Mortality in older patients with
dementia treated with atypical or
typical antipsychotics
Black Box Warning
17 clinical trials were eventually
conducted, using most of the newer
antipsychotics
Risk of death increased 1.6-1.7
The FDA has issued a Black Box
Warning for ALL Antipsychotics
Antipsychotics in Dementia
Prior to the Black Box warning,
prescriptions for antipsychotics in
elderly with dementia were increasing
by 16% per year
◦ Now, the rate of prescriptions for these
drugs in nursing homes for elderly went
down some (but not entirely)
So- the post-marketing system worked
New guidelines have been released
https://www.psychiatry.org/newsroom/news-releases/apa-releases-newpractice-guidelines-on-the-use-of-antipsychotics-in-patients-with-dementia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549220/figure/
BMJOPEN2012002080F1/
Antipsychotics in Other Populations
A recent study of VA patients showed that 60% of 279,778 patients
taking antipsychotics had no diagnosis for which their use was
approved
◦ PTSD- 40%
◦ Minor Depression- 40%
◦ Major Depression- 23%
◦ Anxiety- 20%
◦ Alcohol dependence- 15%
◦ Drug abuse- 13%
Antipsychotics in Parkinson’s Dementia
Patients with Parkinson’s disease also get dementia
They may hallucinations and delusions
Atypical antipsychotics have been used in this population but are not
recommended
A new drug, pimavanserin, was approved by the FDA although it was
only slightly more effective than placebo
There have been concerns about the safety of this drug
https://www.mdmag.com/medical-news/pimavanserin-underscrutiny-for-reported-deaths-in-parkinsons-patients
Look at the FDA FAERS for reports on pimavanserin…..
Antipsychotics in Other Populations
In a Georgia Medicaid study
◦ Off-label use 64%
Cost of antipsychotic drugs about $13.1 billion/year in
the US
At least $4-5 billion for off-label use
◦ Lower doses used makes it a bit cheaper…
Little evidence for effectiveness in most of these
conditions
So, What Have We Learned?
Off-label use of drugs is very common
Doctors often do not know that the use of the drug is off-label
It is legal to use the drug off-label
◦ Unless manufacturer promotes incorrectly
It allows treatment of many groups who would be untreated (eg children,
since most drugs are not approved for them)
Adverse effects may be tracked and labeling changes made for off-label uses
Independent evidence is important in deciding whether drug is effective
Unexpected side effects can be a concern
Drug Interactions and
Special Populations
Pamela E Potter, PhD
HCR 555, Week 4 Lecture 8
©PE Potter/ASU 2022
Adverse Effects of Drugs
• Adverse effects that are rare, or that only affect
certain populations, are unlikely to show up in
clinical trials
• In trials, the patients are selected for their
similarities and lack of confounding factors
(other diseases, taking other drugs, certain
conditions, etc)
• In the real world, everyone will start taking the
drug
• Adverse effects show up
http://www.centerforhealthjournalism.org/fellowships/projects/
decade-questions-over-paxil-study-and-military-suicides
Adverse Drug Reactions
• They are 2.2 million serious ADRs per year in US hospitals
• Another 350,000 in nursing homes
• Adverse reactions in outpatients are often not well recorded
• There may be close to 50,000 deaths per year as a result of ADRs
• 1 out 5 injuries or deaths to hospitalized patients are a result of
ADRs
• ADRs double length of stay, morbidity and mortality for these
patients
• Children, elderly and those on multiple medications are at the
highest risk
Johnson, JA et al, Arch Int Med 1995, 155, 1949-1955
Leape, LL et al, N Engl J Med 1991, 324, 377-384
Classen, DC, JAMA, 1997, 277,301-306
Adverse Drug Reactions in US- FAERS Dashboard
https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a9609a5f7f1c25ee/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis
Where do the ADRs come from?
• At least 2/3 of patients who see a physician get a
prescription
• In 2009, there were 3.7 billion OUTPATIENT
prescriptions filled in the US
• 12 Rx drugs for each person in US
• 31 per capita over age 65
• 11.3 for age 19-64!
• Potential for drug interactions is very high
http://www.statehealthfacts.org/comparemaptable.jsp?ind=265&cat=5
Drug Interactions
• 3-5% of preventable in-hospital ADRs
• Contribute significantly to ER visits and hospital
admissions
• One study found 27% of hospitalized patients had drug
interactions
• 10% generated automatic alert to physician
• Adverse reactions included:
▫ decreased effectiveness of drug (25%)
▫ increased risk of bleeding (22%)
▫ hypotension (15%)
▫ nephrotoxicity (13%)
Leape, LL, JAMA 1995, 274, 35-43
Zwart-van Rijkom, J, Br J Clin Pharm 2009, 68, 187-193
Drug Interactions
• Electronic medical records and computerized pharmacy records
could decrease number of interactions
• BUT- outpatients especially do not always tell you all the drugs
they take
• Patients may use different pharmacies to fill prescriptions
• Patients go to several doctors, who may not know all the
prescriptions taken
• Over The Counter drugs can produce significant interactions!
▫ For example cimetidine (Tagamet) interacts with many drugs
Leape, LL, JAMA 1995, 274, 35-43
Drug Interactions
• Pharmacodynamic
▫ Similar mechanisms of action- agonists/antagonists
▫ Similar side effects
• Pharmacokinetic
▫ Altered absorption of drugs
▫ Increased metabolism/elimination of drug
▫ Decreased metabolism/elimination of drug
Pharmacodynamic Drug Interactions
• Two drugs act on same target
▫ Will magnify the response to the drug (e.g., tricyclic
antidepressants/ SSRIs)
• Two drugs acting on different receptors/similar effect
▫ Benzodiazepines and alcohol (potentiation of CNS depression)
▫ Beta blockers and calcium channel blockers (both slow the heart)
• Two drugs have same adverse effects
▫ Aminoglycoside antibiotics with calcineurin inhibitors used to
prevent organ transplant rejection (nephrotoxicity)
▫ Protease inhibitors for HIV with corticosteroids (Cushing’s-like)
Pharmacokinetic Drug Interactions
Oral Absorption/ Bioavailability
Drug Given
Affects
• Antacids, Sucralfate
• Iron Products
• Milk products
• Quinolones, digoxin,
phenytoin, tetracycline,
azithromycin, theophylline,
thyroid hormone
• Proton Pump Inhibitors
• H2 antagonists
• Ketoconazole, delaviridine
• Cholestyramine
• Thyroid hormone
• Warfarin
Pharmacokinetic Interactions
Metabolism
• Cytochrome P-450 Isoforms
▫ CYP1A2
▫ CYP3A (4/5)
▫ CYP2C9
▫ CYP2C19
▫ CYP2D6
• Enzymes frequently involved in drug metabolism in
humans
• Anything that increases or decreases activity of these
enzymes may greatly affect drug concentration
Drug Metabolism- CYP3A
• Metabolizes more than 50% of drugs
▫ Most Ca++ channel blockers
▫ Most benzodiazepines
▫ Most protease inhibitors (HIV treatment)
▫ Most statins
▫ Cyclosporine and tacrolimus (transplant antirejection drugs)
▫ MANY others!
• In liver and in GI tract
• Inhibited or induced by MANY drugs
Drug Metabolism- CYP3A
Selected Inhibitors
Selected Inducers
• Ketoconazole
• Itraconazole
• Fluconazole
• Cimetidine (Tagamet; OTC)
• Clarithromycin
• Erythromycin
• Ritonavir
• Grapefruit juice
• Carbamazepine
• Rifampin
• Rifabutin
• Efavirenz
• Phenytoin
• Phenobarbital
• St John’s Wort (OTC, herbal)
Grapefruit Juice Inhibition of Drug Metabolism
Grapefruit juice inhibits metabolism of drugs
in the GI tract
Greatly increases their absorption
This can lead to serious drug interactions
British Journal of Clinical Pharmacology
Volume 46, Issue 2, pages 101-110, 4 JAN 2002 DOI: 10.1046/j.1365-2125.1998.00764.x
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2125.1998.00764.x/full#f1
The interaction was discovered in a clinical trial
of a drug that slowed heart rate
The drug had a bitter taste, so patients could
differentiate it from placebo
They covered up the taste with grapefruit juice,
which produced a much higher level of drug
than expected
Some patients hearts almost stopped
Drug Metabolism- CYP 2D6
Selected Inhibitors
Drugs Affected
• Fluoxetine(Prozac)
• Paroxetine (Paxil)
• Duloxetine (Cymbalta)
• Bupropion (Wellbutrin)
• Chlorpromazine (Thorazine)
• Haloperidol (Haldol)
• Amiodarone (Cordarone)
• Chlorpheniramine (ChlorTrimeton)
• Diphenhydramine (Benadryl)
• Cimetidine (Tagamet)
• Terbinafine (Lamisil)
• Codeine*
• Oxycodone*, Hydrocodone*
• Tramadol*
• Tamoxifen*
• Amitriptyline, Nortriptyline
• Imipramine, Desipramine
• Fluoxetine, Paroxetine
• Duloxetine, Venlafaxine
• Diphenhydramine
• Propranolol, Carvedilol,
Metoprolol, Timolol
• Haloperidol, Chlorpromazine
• Risperidone
* Inhibits metabolism to active drug or active metabolite
Other CYPs
CYP1A2
CYP2E1
• Induced by
▫ Barbiturates, Carbamazepine
Cruciferous vegetables
Grilled meat
Rifampin, Smoking
• Inhibited by
▫ Cimetidine
▫ Ciprofloxacin
• Metabolizes
▫ Clozapine, Olanzapine
▫ Ramelteon, Flutamide
▫ Theophylline, Tizanidine
▫ others
• Induced in people who drink
alcohol chronically
• Metabolizes acetaminophen
(Tylenol)
• When induced, creates too much
of a toxic metabolite which can
cause liver damage
http://www.pharmacytimes.com/issue/pharmacy/2007/2007-11/2007-11-8279
More CYPs
CYP2C9
• Induced by
▫ Rifampin
• Inhibited by
▫ Fluconazole
▫ Valproic acid
• Metabolizes
▫ NSAIDs
▫ Phenytoin
▫ Angiotensin receptor blockers
▫ Fluvastatin
▫ Sulfonylureas
CYP2C19
• Induced by
▫ Carbamazepine, Phenytoin
▫ Barbiturates, Rifampin
• Inhibited by
▫ Fluoxetine
▫ Omeprazole, Esomeprazole
▫ Fluconazole, Voriconazole
▫ Cimetidine, Clopidogrel
• Metabolizes
▫ Citalopram, Escitalopram
▫ Fluoxetine, Sertraline
▫ Diazepam, Clopidogrel
http://www.pharmacytimes.com/issue/pharmacy/2008/2008-05/2008-05-8538
Inhibitors of Drug Metabolism
• These inhibit the metabolism of many drugs
• Ketoconazole- antifungal drug
▫ Drugs in this class have many interactions
• Erythromycin- antibiotic
▫ Drugs in this class widely used
• Cimetidine- OTC H2 blocker for gastric acid
▫ Will increase the concentration of those drugs
▫ Particularly problematic in the elderly
• The consequences can be serious
King, Queen and Crown Prince of drug inhibitors
Terfenadine (Seldane)
• Was approved in 1985 as the first non-sedating
antihistamine
• It rapidly became very popular
• It is a pro-drug, that is rapidly metabolized to the active
compound, fexofenadine
• In June 1990 reports came to the FDA of serious cardiac
arrhythmias in patients who had taken terfenadine
• These patients had also taken the antibiotic erythromycin or
the anti-fungal drug ketoconazole
Terfenadine (Seldane)
• Erythromycin and ketoconazole had decreased the metabolism of
terfenadine to fexofenadine
• Terfenadine, which normally wouldn’t be in the plasma, was causing
arrhythmias such as Torsades de Pointes- can be fatal
• The FDA sent a “Dear Doctor” letter
• In 1992 they added a Black Box warning
• In 1997 they took the drug off the market
• It was replaced by fexofenadine (Allegra)
Astemizole (Hismanal)
• Astemizole was a similar non-sedating antihistamine
• It was approved in 1988
• It is metabolized by CYP3A4
• Inhibition of metabolism led to increased blood concentrations
• Lengthened QT interval and arrhythmias including Torsades de
Pointes occurred in some patients
• A Black Box warning was added
• It was taken off the market in 1999
Mail advertising campaign for Hismanal
Astemizole
Black Box
Warning
Antidepressants
• Number of antidepressant prescriptions continues to
increase
• Increased from 154 million to 170 million between 20002005
• Doubled from 13.3 to 27 million people 1996-2005
• Prescriptions are written by:
▫ Psychiatrists- 29%
▫ Family practice- 23%
▫ General practice- 20%
▫ Internal medicine- 10%
http://www.meps.ahrq.gov/mepsweb/data_files/publications/st206/stat206.shtml
Antidepressants
• SSRIs
▫ Selective inhibition of serotonin reuptake
▫ Fluoxetine, paroxetine, sertraline, citalopram, escitalopram
• SNRIs
▫ Inhibit reuptake of serotonin and norepinephrine
▫ Venlafaxine, desvenlafaxine, duloxetine
• TCAs
▫ Inhibit reuptake of serotonin and norepinephrine
▫ Amitriptyline, nortriptyline, imipramine, desipramine
• MAOIs
▫ Inhibit metabolism by monoamine oxidase
▫ Phenylzine, tranylcypromine
• Bupropion
▫ Inhibits DA reuptake
Antidepressant Main Side Effects
• SSRIs
▫ GI, Sexual
• SNRIs
▫ Hypertension, Possible liver toxicity
• TCAs
▫ Torsades de pointes in overdose
▫ Anticholinergic/alpha receptor blockade
▫ Weight gain
• MAOIs
▫ Many, plus drug interactions
• Bupropion
▫ Seizures, anxiety
Drug Interactions with SSRIs
• Fluoxetine (Prozac) & paroxetine (Paxil)
▫ Increase levels of TCAs 2-4 fold
Producing signs of toxicity
▫ Impair elimination of some antipsychotics
35% increase in haloperidol (Haldol)
70% increase in clozapine (Clozaril)
75% elevation in risperidone (Risperdal) levels
Extrapyramidal symptoms occurred in some patients
▫ Increase levels of warfarin
Increased risk of bleeding, death
Spina, E et al, Clin Ther, 2008, 30, 1206-1227
Drug Interactions with SSRIs
• Fluoxetine (Prozac) & paroxetine (Paxil)
▫ Increase levels of propranolol and metoprolol
Bradycardia and heart block
▫ Anticholinergic (benztropine)
Hallucinations
▫ Clarithromycin
Delirium, psychosis
▫ Statins (citalopram)
Rhabdomyolysis
Spina, E et al, Clin Ther, 2008, 30, 1206-1227
Interactions with TCAs
• Fluoxetine, paroxetine, citalopram, escitalopram,
sertraline all increase levels of TCAs by inhibiting
metabolism
▫ Seizures, death
• Fluconazole with sertraline increased TCA levels
▫ Torsades de pointes and death
• Antipsychotics (chlorpromazine, haloperidol)
▫ Seizures, ventricular tachycardia, psychosis
• Methylphenidate
▫ Aggression, violence, suicidal ideation
Nieuwstraten, C et al, 1006, Can J Psychiat, 51, 300-316
Interactions with TCAs
• Clonidine
▫ Hypertension
• Olanzapine
▫ Seizures
• Prednisone
▫ Psychosis
• L-dopa
▫ Hypertensive crisis
Nieuwstraten, C et al, 1006, Can J Psychiat, 51, 300-316
Then, there are the MAOIs
• Monoamine oxidase inhibitors
• Not used often, but still used for severe depression
refractory to other treatments
• MANY drug and food interactions
• Also, some other drugs inhibit MAO
▫ Linezolid (Zyvox)
▫ St John’s Wort
▫ Methylene blue
Shulman, K et al, J Clin
Psychiat, 2009, 70, 1681-1686
Interactions with MAOIs
• Meperidine (Demerol)
▫ Seizures, coma, hypertension, death
• Stimulants (phenylephrine, amphetamine)
▫ Hypertension, coma, death
• L-Dopa
▫ Hypertension
• Tyramine from food
▫ Hypertensive crisis, death
• Other antidepressants or drugs that inhibit
serotonin uptake
▫ Serotonin syndrome
Nieuwstraten, C et al, 1006, Can J Psychiat, 51, 300-316
Serotonin
Syndrome/Toxicity
• Most serious side effect
associated with
antidepressants
• Too much serotonin in
synapse
• Hyperstimulation of 5HT2A
receptors
• May occur with high doses
of one drug
• More common as drug
interaction
Incidence of Serotonin Syndrome
• Rare, but increasing with use of SSRIs
▫ In 2002, 26,733 cases with SSRIs in ERs
▫ 7369 significant toxicity
▫ 93 deaths
• About 14-16 % of people who overdose on SSRIs
• 30% with venlafaxine (Effexor) alone
• Most likely to occur with drug interactions,
especially with drugs that inhibit MAO and
serotonin uptake- 50% likelihood
Sun-Edelstein, C, Expert Opin Drug Saf, 2008, 7, 587-596
Frank, Can Fam Physic, 2008, 54, 988-992
Boyer, E & Shannon, M, N Engl. J Med, 2005, 352, 1112-1120
St John’s Wort
• Over the counter herbal product used for mild depression
• Active compound Hypericium
• Sales continue to increase- thought to be “Safe”
• Mechanism of action unclear, but probably inhibits MAO to some
degree
• Serotonin syndrome possible with antidepressants
• Also induces CYP3A4, CYP2E1 and CYP2C19, increasing
metabolism and decreasing therapeutic levels of many drugs
Borelli, F & Izzo, A, AAPS Journal, 2009, 11, 710-727
St John’s Wort Interactions
Drug (s) Affected
Result
• Cyclosporine, tacrolimus
• Oral Contraceptives
• Organ transplant rejection
• Pregnancy, intra-cycle
bleeding
• Decreased INR
• Increased LDL
• Decreased efficacy
• Loss of effect, increased
viral load
• Warfarin
• Statins
• Verapamil, nifedipine
• Antiretroviral drugs (protease
inhibitors and NNRIs)
Borelli, F & Izzo, A, AAPS Journal, 2009, 11, 710-727
St John’s Wort Interactions
Drug (s) Affected
Result
• Buspirone (BuSpar)
• SSRIs/SNRIs
• General Anesthetics
• Methadone
• Oral Contraceptives
• Protease Inhibitors for HIV
• Serotonin syndrome
• Serotonin syndrome
• Delayed emergence
• Withdrawal
• Unexpected pregnancy
• Increased viral load
Borelli, F & Izzo, A, AAPS Journal, 2009, 11, 710-727
An Example: Statins
• Statins are widely used for treatment of high cholesterol
• Patients taking statins often take multiple other drugs
• They have numerous drug interactions (and grapefruit juice!)
▫ Some antibiotics
▫ Some antifungal drugs
▫ Drugs for HIV
▫ Drugs for heart disease
▫ Drugs for type II diabetes
▫ Drugs for heartburn
Just to Highlight the Issue….
https://www.bmj.com/content/350/bmj.h949
Drugs in the Elderly
• Geriatric patients are generally considered those over the age of
75, although this varies with the person
• Some recommendations- pneumonia vaccines, hospitalization
for certain conditions, go into effect for those 65 and over
• There is an increased incidence of many chronic diseases in older
people
• They tend to take a lot of medications
• The potential for drug interactions is high
• Nutritional and financial problems are also common
Drugs in the Elderly
• Both absorption and distribution of drugs is different
▫ Different nutrition, less lean body mass
▫ Changes in binding of drugs to plasma proteins
• The elderly often metabolize or excrete drugs less effectively than
younger people
▫ Kidney function declines with age, so drug elimination may be
reduced
▫ Dosing should be compensated for clearance
▫ Decreased hepatic metabolism of some drugs occurs
• Respiratory capacity decreases, and they are more affected by
drugs which cause respiratory depression
Drugs in the Elderly
• The metabolism of many benzodiazepines is reduced in the
elderly
▫ The elderly also are more prone to memory loss
▫ Elderly patients taking benzodiazepines for anxiety or as sleep aids
are sometimes misdiagnosed with Alzheimer’s disease
• The elderly are more susceptible to respiratory depression with
opioid analgesics
▫ They also often have reduced respiratory function
• Other CNS drugs may show decreased effectiveness or increased
side effects
Drugs in the Elderly
• Hypertension is more common over age 50
▫ Guidelines for treatment are controversial, but now not as aggressive
as previously
▫ Higher incidence of type II diabetes, concurrent cardiac diseases and
airway disease make drug choices a bit more difficult
• Heart failure is common and often lethal
▫ Toxicity of cardiac glycosides worse in elderly since they are more
susceptible to arrhythmias and elimination by kidney
• Arrhythmias and electrolyte disturbances are also more common
Drugs in the Elderly
• Antibiotics are prescribed more commonly as infections
become more common
▫ Clearance of some antibiotics a problem
▫ More likely incidence of serious organ toxicities, especially
kidney toxicity with aminoglycosides
• Osteoarthritis very common in the elderly
▫ Treatment with NSAIDs more likely to cause gastric bleeding
▫ Some NSAIDS may cause kidney damage
▫ Corticosteroids increase risk of osteoporosis and have many
other side effects
Drugs in the Elderly
• The elderly take several drugs, on average 14 over age 65,
18 over age 80 (and see next page)
• Incidence of adverse effects when taking 1 drug is about
1%
• It will increase to nearly 100% when 10 drugs are taken
• About half of patients in long-term care have some
adverse reactions to drugs
• Errors in prescribing and drug use contribute to the large
number of adverse effects in elderly
http://kff.org/other/state-indicator/retail-rx-drugs-by-age
Drug Interaction Checkers can be useful
• https://healthtools.aarp.org/drug-interactions
• https://www.rxlist.com/drug-interaction-checker.htm
• https://www.drugs.com/drug_interactions.html
Drugs in Children
• Most drugs are dosed for the theoretical 70 kg man
• Most children are smaller than that
• They may not metabolize drugs as well, as their livers are still
developing many of the inducible CYPs
• They are physiologically different than adults
• Most drugs are not tested in children
• Most drugs are not approved for use in children
• BUT- even drugs approved for children have caused problems
Cough/Cold Products in Children
• CDC report January 2007
▫ 3 infants, all less than 1 year old, died after use of cough and
cold products
▫ 1,519 children younger than 2 were treated for adverse
events during 2004 and 2005
• FDA Review February 2007
▫ children younger than 6 years from 1969 -2006
▫ 54 reported deaths with decongestants
▫ 69 with antihistamines
• Mostly children younger than 2 years of age
FDA Review 2007
• OTC Drugs
• Adverse-event reporting not required
• Usage not reported
• FDA concluded “we have no way of definitely knowing
how many fatalities occurred in relation to the number of
children given cough and cold products during this time,
nor whether the medicine was really the only problem.”
• Several of the serious adverse effects appeared to result
of overdose
FDA Advisory
2008
• Applies to ALL OTC
Cough and Cold
Products
• DO NOT USE in
children under age 4
• Not effective, may
be dangerous
• Many OTC products
were removed from
shelves
Tussionex
• Contains hydrocodone, and opioid that is a cough
suppressant similar to codeine
• Also contains chlorpheniramine, an older
antihistamine that can be somewhat sedating
• FDA received reports of deaths in children under age
6 who received this drug
• Labeling was changed to reflect this concern
Drugs in Children
• FDA Issued Warning 2010
• Benzonatate (Tessonate)
▫ approved for children >10
• 31 cases of overdose reported (median age 10)
▫ many only 1 or 2 pills
▫ Cardiac arrest, coma, convulsions occurred
• 7 accidental poisonings in children under 10
▫ 5 of these (under age 2) died
• FDA warned that these looked like candy
• Must not be used in small children
Drugs in Pregnancy
• 1 in 33 babies are born with a birth defect
• In most cases the cause is not known
• Some drugs are more likely to cause birth defects than others
• About 5% of birth defects are caused by drugs
• No drug is 100% safe!
• DON’T use unless really necessary
▫ Always have to weigh the risk vs. benefit (true in all
patients really)
Drugs in Pregancy
• Some drugs are so likely to cause birth defects that they require two
types of contraception in any female of childbearing age using them
• Sometimes the female has to use contraception if her male partner uses
the drug
• OTCs and herbals can be dangerous in pregancy!
• Alcohol can cause damage at ANY time
• First trimester is often the worst time for drugs, BUT for some drugs first
trimester is NOT the only bad time- some drugs are more toxic later on
• Effect of drug may be different in mother than fetus
• Effects may be seen some years after birth
• Metabolism of drugs may be slower in pregnancy- doses may need to be
adjusted
Drugs in Pregnancy
• Most drugs cross the placenta, but some, like heparin, do not
and are safe
• The endocrine system is altered in pregnancy
• Hypertension, hyperglycemia may occur
▫ Mother may need drug treatment
• Drugs may have beneficial effects in fetus too
▫ Corticosteroids are used to help mature lungs
▫ Antiviral drugs are used to prevent transmission of herpes or HIV to
baby
▫ Drugs may be given for fetal heart problems
▫ Folic acid given to the mother prevent neural tube defects in the baby
▫ Thyroid hormone may be given to hypothyroid mother
Warfarin Syndrome
• Multiple abnormalities
Some
examples of
known
teratogenic
effects
saddle nose
broad, short hands
opthalmic
bone
• Fetal death common
• Use heparin instead!
▫ Doesn’t cross placenta
Thalidomide
• Was marketed worldwide as a sedative and to
combat nausea in pregnant women
• No adverse effects were seen in animal testing
(they didn’t use enough species)
• It may damage DNA through oxidative stress
• Multiple limb deformities occurred in the
children of mothers using thalidomide
• Was not approved for use in the US, and Frances
Kelsey, head of FDA at that time, was given an
award for not approving it
• As soon as defects appeared, use stopped
everywhere
• It is used currently for other purposes with strict
controls to ensure no woman of childbearing age
takes it!
Anticonvulsants
• Phenytoin: fetal hydantoin syndrome
▫ Growth retardation, mental deficiency
▫ Short broad nose, cleft palate
▫ Cardiac abnormality
▫ Abnormal genitalia
▫ No finger- or toe- nails
• Most anticonvulsants are associated with some
increase in birth defects
Diethylstilbestrol
• Used from 1940-1970 to decrease the risk of miscarriage
• Very high doses were used – 25-100 mg of DES daily
• For comparison, current oral contraceptives contain µgs of
estrogens
• The current pharmacology textbook of the day, said it was
“not effective…. but has no untoward effects, harmless”
G&G, 1965
• 20 years later……… women whose mothers used DES
Teratogenic effects are not
developed vaginal adenocarcinoma
always seen immediately!
• FDA withdrew DES for use in pregnancy in 1970
• FDA also passed law that drugs must be EFFECTIVE for the
use they are promoted for
Isotretinoin (Accutane)
• Isotretinoin is used to treat acne, often in young
women
• In pregnancy, it case produce structural
malformations in baby
▫ Craniofacial, cardiac, thymus, CNS and intellectual
impairment
▫ 20-30% exposed fetuses likely to have birth defects
• Increased spontaneous abortion & premature birth
• A single dose can be teratogenic
• This may occur before awareness of pregnancy, or
drug effect may last a month or so after stopping
iPLEDGE Program
• Was created to monitor women to ensure they don’t become
pregnant while taking the drug
• Physician, pharmacist and patient are all involved in
monitoring drug use and pregnancy status
• Two negative pregnancy tests are required before starting
the drug
• Two methods of birth control must be used at all times
• Before each refill of the drug, patient must have a negative
pregnancy test and verify use of birth control
• Must register and log in monthly to web site
• Birth control pills are a good treatment option for acne in
many young women, which may decrease the need for
isotretinoin
Herbal Medicines
• Many herbal products are toxic to the fetus or may
cause uterine contractions
▫ Aloe: increase uterine contractions
▫ Black cohosh, dong quai: uterine contraction,
estrogen-like compounds
▫ Chamomile: uterine stimulant at high doses
▫ Comfrey: causes liver problems
▫ Ephedra: increases blood pressure
▫ St. John’s Wort: may stimulate contraction, baby
may be lethargic
Drugs that are used in Pregnancy
• Acyclovir, some HIV drugs to prevent transmission of disease to baby
• Acetaminophen for pain
• NSAIDS (except aspirin can cause bleeding; should not be used close to
delivery
• Opioids, generally safe until close to delivery (but risk of dependence in
baby if used chronically)
• Cephalosporins, penicillin, erythromycin to treat infections
• Corticosteroids, thyroid hormone, when used for replacement
purposes
• Folic acid to prevent neural tube defects
FDA Labelling
• FDA used to label Category A- safe, B, C, D, X based on level of
teratogenic potential – not too informative
• New labelling includes the letter, but also:
• Pregnancy:
▫ Pregnancy Exposure Registry
▫ Risk Summary
▫ Clinical Considerations
▫ Data- Human, Animal
• Lactation:
▫ Risk Summary, Clinical Considerations, Data
• Females and Males of Reproductive Potential
▫ Pregnancy Testing, Contraception, Infertility
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm
Example of Phenytoin labelling- pregnancy
• Usage in Pregnancy
• Clinical
• Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics.
Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to
appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will
probably be indicated.
• Risks to the Fetus. Phenytoin crosses the placenta. If this drug is used during pregnancy, or if the patient becomes pregnant while
taking the drug, the patient should be apprised of the potential harm to the fetus.
• Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes.
Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial
features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among
children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There
have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during
pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or
others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of
antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been
possible to attribute specific developmental abnormalities to particular antiepileptic drugs.
• Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
• Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors
may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to
the mother before delivery and to the neonate after birth.
• Nonclinical
• Administration of phenytoin to pregnant animals resulted in teratogenicity (increased incidences of fetal malformations) and other
developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple animal species at
clinically relevant doses.
http://labeling.pfizer.com/ShowLabeling.aspx?id=544
Here is an article that just appeared on CNN which seems pertinent to this
topic: https://www.cnn.com/2019/11/14/health/fda-dollar-tree-warningbn/index.html
Links to an external site.
Please review the following websites:
1. http://www.pbs.org/wgbh/nova/next/body/uncovering-counterfeitmedicines
Links to an external site./
Links to an external site.
2. http
Links to an external site.://
Links to an external
site.www.newsweek.com/2015/09/25/fake-drug-industry-exploding-and-wecant-do-anything-about-it-373088.html
Links to an external site. http
Links to an external site.://www.cbsnews.com/news/the-difficult-fight-againstcounterfeit-drugs
Links to an external site./
Links to an external site.
3. http://www.plosmedicine.org/article/fetchObject.action?uri=info:doi/10.1371/
journal.pmed.1001228&representation=PDF
Links to an external site.
4. https://biosimilarsrr.com/2017/08/24/is-there-reason-for-confidence-in-bigpharma-for-biosimilar-manufacturing/
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