The Mylan Patch

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I believe that this may give SWIM's information from the fda about the Mylan patch and even aid them in whatever their objective is. I'm sorry it's so difficult to read as far as line stops but it was nearly impossible to copy and paste properly without me spending an hour editing. I enlarged the text because it is already difficult to read, and I removed numbers coresponding to other pages/documents. It is still fully in tact and anyone who emails me for a direct link will receive one immediately. Please take care. Be careful, Knowledge means everything.

January 12,2005
Division of Dockets Management
Food and Drug Administration
Room 1061
5630 Fishers Lane
Rockville, MD 20852
Re: Docket No. 2004P-0506 (fentanyl transdermal products)
These comments are submitted by ALZA Corporation (ALZA) in response to comments
submitted by Mylan Technologies, Inc. (Mylan) on ALZA’s citizen petition cited above and in
response to comments submitted by Noven Pharmaceuticals, Inc. (Noven) to a different docket
that nevertheless dealt with issues raised in our petition.’ In our petition, we pointed out that
fentanyl matrix transdermal products presented a different and potentially larger potential for
diversion and abuse in the United States than the fentanyl reservoir transdermal product
Duragesic@.

ALZA’s petition requested that FDA require manufacturers of fentanyl matrix transdermal
systems to develop and implement risk minimization programs to address the specific issues
presented by their products. In addition, we requested FDA to classify matrix and reservoir
fentanyl transdermal systems, as well as products with and without rate-controlling mechanisms,
as different dosage forms.
We discuss below the various points raised by Mylan and Noven. First, however, ALZA wishes
to refute any allegation that ALZA or any other Johnson & Johnson entity colluded with other
parties who have recently tiled citizen petitions pertaining to fentanyl transdennal patches,
including petitions questioning whether a fentanyl matrix system may introduce safety risks or
increase the potential for a fentanyl matrix patch to be abused or diverted. We did not initiate or
help generate those citizen petitions, and we did not provide input, review, or advice to their
’ Noven submitted its comments to Docket No. 2004P-0472 in a letter dated December 10,2004.
In those comments, Noven stated that it would be separately commenting on the ALZA petition,
but we have not yet seen those comments. We may file an additional response to Noven’s
comments on ALZA’s petition.
ALZA aoow=osbb RCA CORPORATION 1900 CHARLESTON ROAD P.0. Box 7210 PHONE 650.564.5000
MOUNTAIN VIEW CA 94039-7210 http://www.alza.com
authors.

The timing for submission of the other citizen petitions was the decision of their
authors. Having recognized the potential for increased abuse and diversion of a fentanyl matrix
patch in the United States, ALZA and Janssen Pharmaceutics conducted studies of fentanyl
extraction and attractiveness early in 2004 and received further input on the potential for abuse
and diversion from experts in the field of prescription drug abuse. ALZA tiled a citizen petition
with data suggesting that these risks are real, soon after these data were available and analyzed.

I. Mylan and Noven Have Failed To Refute the Evidence That Fentanyl Matrix
Systems Present a Larger Potential for Abuse
In our citizen petition, we presented substantial evidence that fentanyl matrix systems present a
different and possibly larger potential for abuse in the United States than Duragesic@. We
showed that abusers are interested in fentanyl but that, based on databases such as DAWN,
current abuse rates of Duragesic@ are relatively low, presumably because of the difficulty of
extracting fentanyl from a reservoir system combined with an inability to control the dose;
abusers risk a fatal overdose if they abuse Duragesic@. By contrast, a matrix system permits
abusers to accurately control the dose by cutting the system into a desired size, and a study on
relative abuse liability submitted with our petition showed that a fentanyl matrix system would
be significantly more attractive to abusers than Duragesic@ in the United States.

Abusers could
put a fragment of a fentanyl matrix system in their mouths for buccal or sublingual absorption, or
they could extract the contents of a matrix system with common solvents for oral or intravenous
administration or for smoking.
A. Fentanyl Can Be Effectively Absorbed By Placing a Matrix System Fragment
in the Mouth
Mylan and Noven simply dismiss the possibility of buccal or sublingual absorption, arguing that
their systems will not adhere to oral mucosal tissue and that, in any event, the controlled release
mechanisms of their systems would prevent rapid release of fentanyl in the mouth just as they do
when the systems are in contact with the skin. ALZA does not contend that a matrix system
releases fentanyl faster in the mouth than on the skin. Rather, the body’s absorption of the
fentanyl is much faster through buccal tissue than through skin, which allows an abuser, by
placing a piece of a matrix system in the mouth, to rapidly absorb an amount of fentanyl that can
be controlled to avoid overdose and sufficient to create the effect desired by the abuser.
Attempted oral abuse of fentanyl transdermal systems can be expected. Indeed, oral abuse of
Duragesic@, including chewing and sucking the product, is the most common type of abuse
reported in our safety database.

Mylan’s response to the concern about cutting a matrix system into pieces seems to assume,
erroneously, that the issue is whether cutting the product into pieces would accelerate drug
delivery. Cutting a matrix system would permit the abuser to control the fentanyl dose, thus
preventing toxic or fatal amounts, whereas the inability to control the dose from a reservoir patch
is apparently an important factor underlying the relatively low rate of abuse of Duragesic@.

As our petition showed, significant fentanyl can be extracted from a matrix system by water, and
much higher amounts can be extracted by alcohol. Thus, it seems very likely that abusers could
successfully extract fentanyl from a matrix system through its contact with saliva and common
solvents.

Mylan and Noven have provided data supporting this expectation even while they deny the
conclusion. Mylan states that only 15 percent of the fentanyl in its system was released in 30
minutes when soaking in water, and Noven claims that only 28 percent of the fentanyl in its
system was released in an hour under stress conditions. By Mylan’s admission, a matrix system
that contains 10 milligrams of fentanyl could therefore release 1500 micrograms of fentanyl
during a 30-minute exposure to water. Since 50 to 100 micrograms is an abusable dose, the rate
of fentanyl release conceded by Mylan seems ample to allow for “party” use of pieces of a
matrix system and, indeed, a matrix system could release a toxic or lethal dose. Although Mylan
suggests that this release rate, which was measured in 500 ml of water, would not occur in the
smaller liquid volume of saliva, Mylan does not take into account the likelihood that an abuser
would chew the system fragment, potentially hastening drug release, or that an abuser could use
alcohol to sharply increase drug release.
Mylan also minimizes the concern by pointing to the low oral bioavailability of fentanyl.

However, although fentanyl has reduced bioavailability when swallowed, considerable drug will
still enter the bloodstream. Additionally, and more importantly, fentanyl is rapidly absorbed
buccally and is highly bioavailable through that route. These effects are illustrated by the
following statement in the package insert for ActiqB (oral transdermal fentanyl citrate), which
explains that about one-fourth of an oral fentanyl dose will be rapidly absorbed through the
buccal mucosa and another fourth will be systemically absorbed more slowly after swallowing:
“The absorption pharmacokinetics of fentanyl from the oral transmucosal dosage
form is a combination of an initial rapid absorption from the buccal mucosa and a
more prolonged absorption of swallowed fentanyl from the GI tract. . . . Absolute
bioavailability, as determined by area under the concentration-time curve, of 15
mcg/kg in 12 adult males was 50% compared to intravenous fentanyl. Normally,
approximately 25% of the total dose of Actiq is rapidly absorbed from the buccal
mucosa and becomes systemically available. The remaining 75% of the total dose
is swallowed with the saliva and then is slowly absorbed from the GI tract. About
l/3 of this amount (25% of the total dose) escapes hepatic and intestinal first-pass
elimination and becomes systemically available. Thus, the generally observed
50% bioavailability of Actiq is divided equally between rapid transmucosal and
slower GI absorption.”
In short, despite the incomplete oral bioavailability of fentanyl, the combination of buccal and
gastrointestinal absorption would provide an ample and controllable amount of fentanyl to
abusers from a piece of a matrix system held in the mouth. If sponsors of matrix fentanyl
transdermal systems believe otherwise, they should be required to generate clinical data
documenting the buccal absorption of fentanyl from their systems.

B. The Extraction Study Submitted in ALZA’s Petition Was Sound
Apart from the ease with which abusers could extract a controlled dose of fentanyl through
buccal or sublingual absorption from a piece of a matrix system, a study summarized in our
petition showed that abusers who wanted fentanyl for injection or smoking could rapidly extract
much more fentanyl from a matrix system than from a reservoir system by soaking the products
in common solvents. Mylan objects to the validity of this study since it used Janssen’s matrix
system, which Mylan says has a different adhesive system and more fentanyl than the Mylan
product.

Although the unavailability of the Mylan product required us to use the Janssen product in this
study, there is no reason to believe that the different adhesive systems and fentanyl loads could
be responsible for the very large differences in percentage yield between the matrix system and
Duragesic@. For example, the use of rum as a solvent extracted over 90 percent of the fentanyl in
the matrix system but less than 10 percent from Duragesic@.

C. The Existence of Janssen Cilag’s European Matrix System Does Not Refute
the Need To Manage the Abuse Risk in the United States
As stated in our petition, Janssen Cilag markets a matrix fentanyl system in parts of Europe.
This fact, however, does not prove the lack of abuse potential of matrix systems in the United
States, as Mylan argues.
Prior to a decision whether to market a matrix system, independent experts consulted by Janssen
Cilag advised that the environment for prescription drug diversion and abuse in major European
countries differs substantially from that in the United States and that the introduction of a
fentanyl matrix system in those countries would not lead to significant increases in diversion and
abuse. On that basis, Janssen Cilag concluded that a fentanyl matrix system is appropriate for
Europe. Janssen Cilag is monitoring for evidence of abuse in Europe and would take appropriate
action if developments warrant. By contrast to expert opinion in Europe, experts on United
States drug abuse whom we consulted about our matrix product expressed substantial concern
about the introduction of a fentanyl matrix system in the United States.

D. Classifying Matrix and Reservoir Products As Different Dosage Forms Is
Warranted
In our petition, we requested FDA to classify fentanyl transdermal systems into multiple dosage
forms depending on whether they use a reservoir or matrix technology and whether they have a
rate-controlling mechanism. As we showed in our petition, in the case of fentanyl products,
some physicians may want to select a product based on its potential for abuse, and various forms
of the products may have different delivery characteristics when applied to compromised skin or
in the presence of heat, even if they have been determined to be bioequivalent under normal
conditions. Differentiation based on dosage form would permit clinicians to select a product
with certain characteristics. Mylan asserts that FDA has already rejected this proposal by
treating all nitroglycerin and nicotine transdermal products as the same dosage form.

In the case of nitroglycerin and nicotine transdermal products, there may have been no reason to
distinguish among types of systems for purposes of dosage form classification, as these other
types of products do not have the known potential for abuse and diversion characteristic of
scheduled narcotics. As our petition showed, however, there is a different potential for abuse
and diversion between matrix and reservoir fentanyl systems, and clinicians may want to select a
reservoir system for some patients, for that reason.

In addition, products that lack a rate-controlling membrane may perform differently than
products that have one under certain conditions, such as on compromised skin or in the presence
of heat. Mylan argues that skin integrity is difficult to compromise and visible when it exists,
but this argument does not exclude the real possibility that, in actual clinical use, a matrix system
could be applied to compromised skin and deliver more fentanyl than a reservoir system would.
Similarly, we have determined that heat applied to the Duragesic@ reservoir system and the
ALZA matrix system does substantially enhance fentanyl delivery, but this effect is similar for
both systems; however, other products lacking a rate-controlling membrane may release
significantly more fentanyl than those that have one.

Furthermore, we have shown that this is
not just a hypothetical consideration; the safety database contains reports of serious adverse
events related to intentional or accidental heat exposure. These potential differences should be
signaled to clinicians by treating the products as different dosage forms.

II. FDA Can and Should Require the Manufacturers of Generic Fentanyl Matrix
Systems To Have Risk Minimization Programs
Our petition requested that FDA require manufacturers of fentanyl matrix systems to adopt risk
minimization programs to address the new abuse potential raised by their products. Mylan
objects to ALZA’s request on the ground that Duragesic@ does not have such a program.
Moreover, although Mylan does not contest FDA’s authority to impose a risk minimization
program on generic products, Noven does. These arguments do not withstand analysis.
Although there is not a formal risk management in place for Duragesic@, Janssen has consistently
supported all efforts to prevent the misuse of opioid analgesics, with education as the cornerstone
of the risk management programs for health care professionals, patients, and caregivers.
Examples of Janssen’s education and risk management programs in the United States include:

The National Pain Education Council (NPEC), a comprehensive online resource,

educates clinicians about chronic pain management, including state-of-the-art

information on appropriate usage, dosing, instructions, conversion, functionality

measures, and patient types for opioid analgesics.

Pain Chronicles Program, a series of video case studies, teaches physicians about

Duragesic@ patch adhesion, disposal, dosing, and appropriate patient types.




Patient Pak, which physician office staff distribute to new patients at the onset of using

Duragesic@, teaches patients about appropriate patch adhesion, disposal, and potential

side effects.
Janssen also works closely with the American Pain Society, the American Academy of Pain
Medicine, and the National Pain Foundation to help teach clinicians to assess and treat chronic
pain appropriately.

Mylan’s position that a risk minimization program is appropriate only if imposed on all fentanyl
transdermal systems fails to account for the predictable difference in potential abuse liability
between reservoir systems and matrix systems. As we showed in our petition, a fentanyl matrix
system has a different and larger potential for abuse than a fentanyl reservoir system. This
difference warrants treating the systems as different dosage forms and requiring risk
minimization programs appropriate to the risks presented by each type of system.

Noven’s claims about FDA’s alleged lack of authority serve to highlight the value of treating
matrix and reservoir systems as different dosage forms. If the innovator product and its generic
copies share the same risk factors, the generics can be required to adopt risk minimization
programs like the innovator’s because those programs can be described in the innovator’s
labeling, which the generic versions are required by law to copy.
Where the generic product presents risks that are different from the innovator, however, an
approach based on identical labeling is not appropriate. Instead, by declaring the generic product
to be a different dosage form, FDA can, as a condition of approval of the necessary suitability
petition, require that the manufacturer of a generic product adopt an appropriate risk
minimization program and reflect that program in the labeling of its product.

The FDA should adopt
this approach to address the novel abuse potential of fentanyl matrix systems. FDA may well
have other legal authorities that it could also rely on to ensure that generic products presenting
new risks for abuse and diversion are subject to adequate controls.

ALZA’s Petition Is Not a Last Minute Attempt To Block Generic Competition
Contrary to Mylan’s allegation that ALZA timed its petition to block generic competition despite
knowing “for years” that Mylan is developing a matrix system, the fact is that, although ALZA
has been developing data and information on this issue for some time, it has only recently been
in a position to present the information to FDA. As FDA knows, ALZA was developing a
matrix fentanyl system for the U.S. market several years ago but discontinued that plan aRer
receiving a consultant’s report on the risk of diversion and abuse of such a product in this
country. ALZA then began development of a matrix fentanyl system containing naltrexone to
Federal Food, Drug, and Cosmetic Act, 4 505(j)(2)(A)(v), (C) (permitting differences between
the labeling of the innovator product and a generic product based on differences approved in a
suitability petition).
reduce the risk of abuse. As part of this development effort, ALZA continued to work with
consultants on abuse liability and other issues.

Much of this additional work has only recently come to fruition. The consultant who previously
advised us about our own product updated the analysis on the abuse potential of matrix fentanyl
systems and issued a revised report to us in late September 2004. The Butler study to develop
and validate a measurement of abuse attractiveness, which was included in our petition, was
started on February 1,2004, and reported on September 24,2004. The extraction studies
reported in our petition were completed only a few months ago. Mylan’s claim that ALZA could
have submitted its petition years ago but delayed for competitive reasons is baseless.
Mylan’s assertion that ALZA’s petition is anti-competitive under a previously expressed concern
of the Federal Trade Commission because it is similar to three other petitions recently submitted
is a misreading of the FTC’s comments and is otherwise unwarranted. The FTC staff comments
cited by Mylan noted the value of citizen petitions, like ALZA’s, that bring important safety
issues to FDA’s attention:
“Citizen petitions often raise legitimate issues concerning matters within the
agency’s jurisdiction. In fact, issues raised in citizen petitions have played useful
roles in ensuring the safety of various drug products.“4
In the case of “cumulative or duplicative petitions,” the FTC staff suggested only that FDA
might want to require identification of similar petitions so that FDA could “potentially ease its
burdens by allowing it to consolidate the petition with other pending petitions or to respond to
the petition more quickly.“Mylan has identified the petitions for FDA, thus satisfying the FTC
staffs recommendation.
Neither ALZA nor any other unit of Johnson & Johnson caused the submission to FDA of the
other citizen petitions addressing the risks associated with fentanyl matrix systems. These
petitioners acted independently out of concern for the issues they raised. There is no basis for
Mylan’s suggestion to the contrary.

Conclusion:
As stated in our petition, ALZA supports the approval of generic fentanyl transdermal products,
but the approvals should be accompanied by suitable controls and information. Manufacturers of
matrix systems should be required to adopt risk minimization programs that deal with the
specific new abuse risks presented by their products. In addition, FDA should treat matrix and
reservoir systems, and those with and without rate-controlling membranes, as different dosage
forms to allow clinicians to select products with the characteristics they desire.

Mylan and Noven have presented no persuasive arguments against these requests. Their
insistence that matrix products do not pose an increased abuse potential is not supported by any
data and is refuted by the available information, including data submitted by Mylan and Noven
on extracting fentanyl from their own systems. The information indicates that abusers can obtain
controlled, i.e., abusable and nonlethal, doses of fentanyl if they place product pieces in their
mouths, and that fentanyl is more easily extracted from matrix patches than from Duragesic@.
This increased abuse potential is a serious risk that FDA should address by requiring risk
minimization programs and treating the products as distinct dosage forms.

Sincerely,
Susan P. Rinne
Vice President, Regulatory Affairs

Reputation Comments on this post:

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