‘Amendments the list of drugs that are not

‘Amendments to the Regulation Regarding the List of
Drug Products That Have Been Withdrawn or Removed From the Market for Reasons
of Safety or Effectiveness’

Food and drug administration has its roots since 1906,
constantly working with the determination to bring safe and effective drugs and
medical devices into the market. It is the responsibility of the FDA to monitor
what products go into the market and to the patients.

In this essay, I summarize one of the proposed rules
of the agency. This proposed rule was posted on the Federal Register portal on
October 18, 2016. This register acts as a daily journal for publication of what
the agency has on its mind. It is made available to the public in order to
review and comment. The original list was added on October 9, 1998 to the
federal register which was codified on March 8, 1999 in 21 CFR 216.24.

My topic ‘Amendments to the Regulation Regarding the
List of Drug Products That Have Been Withdrawn or Removed From the Market for
Reasons of Safety or Effectiveness’ describes the view of the agency about
adding three drug names to the list of drugs that are not safe or are in
effective to the patients. (Department of Health and Human services, 2016)21 CFR 216.24 has a
list of drugs that are withdrawn or removed which cannot be used for
compounding the medications.

The three entries to the list are all products
containing Aprotinin, all products that contain Bromocriptine mesylate which
are used for prevention of physiological lactation and all products that
contain Ondansetron hydrochloride and those are used as intravenous drug
products and contain greater than 16 mg single dose of the drug. (Department of Health
and Human services, 2016)

To brief about the background of the provision, I
would like to mention that the section 503A and 503B of the FD&C Act states
conditions that the compounded human drug products must satisfy in order to be
exempt from FD&C Act. Drugs in 21 CFR 216  may not be compounded under the section 503A
and 503B.

Aprotinin containing all drugs are to be included in
the list. TRASYLOL, a product of Bayer was recalled from marketing in November
2007 because of the safety issues. The indication was ‘prophylactic use to
reduce perioperative blood loss and the need for blood transfusion in patients
undergoing cardiopulmonary bypass who are at the risk of blood loss and blood
transfusion’. One of the known adverse events included anaphylactic reactions. Some
deaths during the trials were also reported. (Department of Health and Human
services, 2016)

But in January 2006, Mangano et al. reported that
there were possibilities of renal dysfunction, stroke, myocardial infarction
and CHF in patients that were treated with aprotinin. (Mangano, 2006) A public health advisory was issued on
TRASYLOL by the FDA and a Cardiovascular and Renal Advisory Committee was
setup. And therefore the sponsor funded a study that involved evaluation of
medical database of the patients that were being treated with aprotonin and
other antifibrolytic agents. The study found that there were more deaths of patients
being treated with aprotinin than other drugs. The advisory committee voted to
continue the marketing of the drug. But a subsequent randomized trial was being
conducted in Canada under the name BART study that was testing the drug. However
the results could not be given out for few years. Later the study had to be
terminated because there were increased numbers of deaths of patients being
treated with aprotinin (Dean A.
Fergusson, 2008).
In 2017 a safety alert for human medical products was issued by the FDA on the
basis of initial data from the BART study (Aprotinin
Injection (marketed as Trasylol) Information). The sponsor
subsequently suspended the marketing of the drug and the drug never entered the
USA market after that. But FDA was never successful in getting the data from
the trial. (Department of
Health and Human services, 2016)

The second drug,
Bromocriptine mesylate was added to the list. It was used for preventing
physiological lactation. (Department of
Health and Human services, 2016)The risks associated
with the drug were hypertension, seizures and cardiovascular effects. PARLODEL,
manufactured by Sandoz, was approved in 1980 as an alternative to estrogenic
therapy. But post market reports to the FDA showed that there was life threatening
adverse effects. There were FDA findings stated 28 reports of hypertension, 36
reports of seizures, and 19 reports of cerebrovascular accidents. FDA got 85
cases of serious adverse events among which were 10 cases of deaths ever since
the drug was used for physiological lactation. (Department of Health and
Human services, 2016) Later in 1994 the Fertility and
Maternal Health Drugs Advisory Committee put forth that no drug product with Bromocriptine
mesylate would be used for the labeled use that is suppression of lactation. On
February 16, 1995 it became effective that the drug will be withdrawn from the
market because of unfavorable benefit risk balance specific to suppression of
physiological lactation and no other indication for use.

The third drug to
the list is Ondansetron hydrochloride. Any intravenous product containing more
than 16 mg single dose has to be added to the list. It was found that the
treatment was associated with a condition called QT interval prolongation and
any dose greater than 16mg had high chances of causing the condition. ZOFRAN
and its generic products were at high risk of causing the prolongation (FDA Drug Safety
Communication: Abnormal heart rhythms may be associated with use of Zofran
(ondansetron), 2011). A drug safety communication was sent
out by FDA regarding the issue. GlaxoSmithKline upon getting the noting found
that there was QT prolongation associated with 32 mg single dose and therefore
they submitted supplement to remove the information from labeling.  Later FDA informed 1 NDA and 4 ANDA holders
to withdraw their products that contained 32 mg single IV dose Ondansetron
hydrochloride from the market with regards to the safety issues.  FDA also informed the health professionals
regarding the potential cardiac risks associated with the drug through Drug
Safety Communication. (FDA Drug Safety
Communication: Updated information on 32 mg intravenous ondansetron (Zofran)
dose and pre-mixed ondansetron products, 2012)

As I summarize the
proposed rule, I believe that the decision to remove the three drugs from the
market and to put them under the unsafe or ineffective category is very
accurate. However I would like to add a point regarding the results that were obtained
from the clinical trials. If the phase III results from the clinical trials of
Aprotinin showed significant number of deaths in patients, why was the drug
approved into the market. The benefits overshadowed the risks. Also that the
drug trial reports from the BART study were not accessible to the FDA which is
a serious event. Therefore I suggest there should be vigilant review of NDA or
ANDA and the FDA should not give a thumps up until all data have been in place.
This is important because the drugs stated above, were in the market for over a
decade. They caused a lot of serious adverse events. Those weren’t in the light
until the number of deaths increased.

There should be
some mechanism by which the patients that are being benefited by the drugs be
provided with the drug but a management system should be made available in
place to treat the adverse effects. It is very much necessary that the FDA
considers options other than just recalling the drug from the market and adding
to unsafe or ineffective list of drugs because there are chances that a
particular group of patients could be benefited from the drugs. (Comment, 2016)

Therefore I conclude
by saying that withdrawal of the drugs for safety and effectiveness concerns is
both logical and acceptable.

Works Cited
FDA
Drug Safety Communication: Abnormal heart rhythms may be associated with use
of Zofran (ondansetron). (2011, September 15). Retrieved
from U.S. Food & Drug Administration:
https://www.fda.gov/drugs/drugsafety/ucm271913.htm
FDA Drug Safety Communication: Updated information on
32 mg intravenous ondansetron (Zofran) dose and pre-mixed ondansetron products.
(2012, OCTOBER 12). Retrieved from U.S.FOOD & DRUG ADMINISTRATION:
https://www.fda.gov/drugs/drugsafety/ucm330049.htm
Comment. (2016, December 8).
Retrieved from Regulations.gov – Your Voice in Federal Decision Making:
https://www.regulations.gov/document?D=FDA-2016-N-2462-0017
Aprotinin Injection (marketed as Trasylol) Information.
(n.d.). Retrieved from U.S. Food & Drug Administration:
https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm142720.htm
Dean A. Fergusson, P. C. (2008). A Comparison of
Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery. The New
England Journal of Medicine, 358(22):2319-2331.
Department of Health and Human services, F. a. (2016,
october 16). Amendments to the Regulation Regarding the List of Drug Products
That Have Been Withdrawn or Removed From the Market for Reasons of Safety or
Effectiveness. United States Of America.
Mangano, D. a. (2006). The Risk Associated with
Aprotinin in Caediac Surgery. New England Journal of Medicine,
354(4):353-356.